PROMETHAZINE ORALLY DISINTEGRATING TABLET Except where reference is made to the work of others, the work described in this dissertation is my own or was done in collaboration with my advisory committee. This dissertation does not include proprietary or classified information. ______________________________ Roger Dale Graben Certificate of Approval: ______________________________ ______________________________ Ram B. Gupta Daniel L. Parsons, Chair Professor Professor Chemical Engineering Pharmacal Sciences ______________________________ ______________________________ Jayachandra Ramapuram William R. Ravis Assistant Professor Professor Pharmacal Sciences Pharmacal Sciences ______________________________ Stephen L. McFarland Dean Graduate School PROMETHAZINE ORALLY DISINTEGRATING TABLET Roger Dale Graben A Dissertation Submitted to the Graduate Faculty of Auburn University in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Auburn, Alabama May 11, 2006 iii PROMETHAZINE ORALLY DISINTEGRATING TABLET Roger Dale Graben Permission is granted to Auburn University to make copies of this dissertation at its discretion, upon request of individuals or institutions and at their expense. The author reserves all publication rights. ______________________________ Signature of Author ______________________________ Date of Graduation iv VITA Roger Dale Graben, son of Joseph Olen and Nealene (England) Graben was born in Talladega, Alabama on September 15, 1962. He attended public schools in Clay County, AL and graduated from Lineville High School in 1980. He received the Bachelor of Science (Honors) in Pharmacy and the Masters of Science in Pharmaceutics from Auburn University in 1985 and 1987, respectively. He obtained his pharmacy license in 1985 and has practiced pharmacy in hospital, retail, and clinical settings. Between 1987 and 1995, he worked as a Research Scientist with Solvay Pharmaceuticals and as a Manager of Pharmaceutical Technology and Director of Quality Assurance/ Quality Control with Chelsea Laboratories, a Rugby Generics/Marion Merrill-Dow company. He was self employed from 1996 until 2004, owning Young?s Drug Store in Lineville, AL and Graben Pharma, Inc. in Anniston, AL. In 2004, he returned to Auburn University as a Research Associate. He is married to Pamela Chandler Graben and they have four children.. v DISSERTATION ABSTRACT PROMETHAZINE ORALLY DISINTEGRATING TABLET Roger Dale Graben Doctor of Philosophy, May 11, 2006 (M.S., Auburn University, 1987) (B.S., Auburn University, 1985) 242 Typed Pages Directed by Daniel L. Parsons Orally Disintegrating Tablets (ODTs) which disintegrate rapidly (< one minute) in the mouth and do not require water for administration have become a very popular dosage form. Current methods of manufacturing ODTs are complex and require multiple processes. The specific aim of this study was to develop a simple, inexpensive method of manufacturing ODTs. Promethazine HCL, a highly soluble drug with an extremely bitter taste and an unpleasant anesthetic effect in the oral cavity, was chosen as a model drug. Simple low shear blending followed by direct compression was the preferred manufacturing method and was first examined. Taste-masking studies were conducted by directly mixing Promethazine with a number of substances. Taste-masking was assessed by dissolution studies and informal taste testing. vi A 1:1 Magnesium Stearate: Promethazine mixture V-blended for one hour was effective in masking the bitter taste of this drug. The next step was to formulate an ODT which would rapidly disintegrate with this large amount of Magnesium Stearate. Magnesium Stearate is commonly known to increase both tablet friability and disintegration time, both of which are undesirable in an ODT dosage form. After initial failures with Mannitol, Dextrates, NF was the primary diluent utilized in this system. Tablets were produced with various combinations of disintegrants with various mechanisms of action. Tablets were also manufactured with a variety of materials with potential for producing a less friable tablet with a lower compression force. Flavor and sweetener trials were also conducted. A combination of Promethazine, Magnesium Stearate, Dextrates, and disintegrants was found to yield robust tablets (Friability < 1.0% with 0 broken at 25 rpm, for 4 minutes) with rapid disintegration (in vitro < 21 seconds, in vivo < one minute). Although the bitter taste was masked, the unpleasant anesthetic effect was not completely eliminated. The addition of 3.0% Menthol with sublimation post-tableting resulted in a visibly more porous tablet with shorter in vitro and in vivo disintegration times. These tablets yielded a pleasant taste without numbing. These tablets met compendial Dissolution and Content Uniformity requirements for conventional Promethazine tablets. These trials indicate an acceptable ODT can be produced using conventional excipients and simple blending followed by direct compression. In the case of Promethazine, the addition of Menthol followed by post-tableting sublimation was required to overcome the unpleasant numbing effect. While the sublimation of Menthol is an additional step, it only required a common laboratory oven and 48 hours. vii ACKNOWLEGEMENTS I am grateful to God for life, family, a small amount of talent, and a large amount of determination. All of my life I have enjoyed tremendous family support. My parents worked without end to provide for their children. My brothers and sisters all helped me along the way. I am especially grateful to my late brother Mike who helped his younger brothers and sisters in so many ways. My wife, a great blessing, has faithfully supported me every step of our journey together, even when I?ve been wrong. Helping raise our first two children represents the best thing I?ve done with my life so far. The opportunity to have two more children is both a miracle and a blessing. I am especially grateful to my advisor, Dr. Daniel Parsons, and my department head, Dr. William Ravis. These men have devoted their lives to pharmaceutical education, treating thousands of students with dignity and respect along the way. I am also grateful to my other committee members. Dr. Ram Gupta is a great asset to Auburn, and Dr. Jay Ramapuram is an excellent addition to our faculty. viii Style manual used AAPS PharmSciTech. Computer software used Microsoft Office Word 2003 and Microsoft Office Excel 2003. ix TABLE OF CONTENTS LIST OF TABLES ............................................................................................................ xi LIST OF FIGURES ........................................................................................................ xiii 1. INTRODUCTION .........................................................................................................1 2. REVIEW OF LITERATURE .....................................................................................20 2.1 Promethazine HCl .................................................................................................20 2.2 Orally Disintegrating Tablets ............................................................................... 23 2.2.1 Overview ......................................................................................................23 2.2.2 Current Methods of Manufacture .................................................................26 a) Freeze-Drying b) Molding c) Compaction d) Post-Tableting Treatments 2.2.3 Specific Examples ........................................................................................34 2.3 Specific Aims of Current Study.............................................................................37 References....................................................................................................................39 3. TASTE-MASKING ......................................................................................................42 Abstract .................................................................................................................42 3.1 Introduction ...........................................................................................................43 3.2 Materials ...............................................................................................................45 3.3 Methods .................................................................................................................47 3.3.1 UV Method ..................................................................................................47 3.3.2 Dissolution Method ......................................................................................49 3.3.3 Taste-Masking Trials (Blends) ....................................................................51 3.3.4 Tablet Taste-Masking Trial ..........................................................................55 3.4 Results and Discussion .........................................................................................56 3.4.1 UV Method ..................................................................................................56 3.4.2 Taste-Masking ..............................................................................................66 References ...................................................................................................................82 x 4. ORALLY DISINTEGRATING TABLET FORMULATION .................................. 85 Abstract .................................................................................................................85 4.1 Introduction ...........................................................................................................86 4.2 Materials ...............................................................................................................90 4.3 Methods .................................................................................................................92 4.3.1 General Methods ..........................................................................................92 4.3.2 Initial Active Ingredient Tablet Trials .........................................................94 4.3.3 Placebo Tablet Trials ...................................................................................98 4.3.4 Active Ingredient Tablet Trials ..................................................................101 4.4 Results and Discussion .................................................................................106 4.4.1 Initial Active Ingredient Tablet Trials ................................................106 4.4.2 Placebo Tablet Trials ..........................................................................109 4.4.3 Active Ingredient Tablet Trials ...........................................................118 References ...........................................................................................................143 5. SUBLIMATION Abstract ...............................................................................................................145 5.0 Introduction ...........................................................................................................146 5.1 Materials ...............................................................................................................148 5.2 Methods .................................................................................................................148 5.3 Results and Discussion .........................................................................................153 References ...................................................................................................................164 6. CONCLUSIONS.........................................................................................................166 BIBLIOGRAPHY ...........................................................................................................175 APPENDIX .....................................................................................................................180 xi LIST OF TABLES 2.2 Examples of ODT Products, Applications, and Technologies ...............................25 3.3 Tablet Formulations ................................................................................................55 3.4a Absorbance Data ....................................................................................................57 3.4b Final Trials Absorbance Data ................................................................................63 3.4c Promethazine Dissolution Data ..............................................................................67 3.4d Promethazine + Precirol Dissolution Data .............................................................67 3.4e Promethazine + Gelucire + Compritrol Dissolution Data ......................................68 3.4f Stearate Trials Dissolution Data .............................................................................71 3.4g Tablet Physical Test Data ......................................................................................75 3.4h Tablet Dissolution Data .........................................................................................76 4.3a Initial Tablet Formulations .....................................................................................96 4.3b Batch Quantities .....................................................................................................97 4.3c Glidant Trial Formulations .....................................................................................99 4.3d Additional Placebo Formulations ........................................................................100 4.3e Active Formulations .............................................................................................102 4.4a Initial Trials Summary of Test Results ................................................................107 4.4b Glidant Trials Summary of Test Results ...............................................................110 4.4c Additional Placebo Trial Formulations and Test Results ....................................113 4.4d Disintegrant Trial Formulations and Results ........................................................119 xii 4.4e Additional Formulations and Results I .................................................................122 4.4f Additional Formulations and Results II ................................................................126 4.4g Additional Formulations and Results III ...............................................................178 4.4h Additional Formulations and Results IV ..............................................................132 4.4i Flavored, Sweetened Formulations and Results ....................................................139 4.4j Final In-House Formulation ...................................................................................142 5.2 Menthol Formulations ............................................................................................149 5.3a Menthol Tablet Sublimation Data .........................................................................155 5.3b Physical Test Results ............................................................................................159 5.3c Content Uniformity Data .......................................................................................162 5.3d Dissolution Data ....................................................................................................163 xiii LIST OF FIGURES 2.1 Promethazine HCl: Structure and Properties ..........................................................20 3.4a Effect of End Filter Filtration on Absorbance Values ...........................................58 3.4b Effect of Time and Dilution on Absorbance Values ............................................. 59 3.4c Effect of Filtration with Filter Needle on Absorbance Values ..............................61 3.4d Effect of Filtration on Absorbance Values (Duplicate Trials, Filter Needle) ........64 3.4e Relationship of Absorbance and Concentration .....................................................65 3.4f Initial Taste-Masking Dissolution Plot ...................................................................68 3.4g Stearate Trials Percent Dissolved vs. Time Plot ....................................................72 3.4h 0.67:1 Individual Tablet Dissolution Plot ..............................................................77 3.4i 1:1 Individual Tablet Dissolution Plot ....................................................................77 3.4j 0.67:1 and 1:1 Average Tablet Dissolution Plot .....................................................78 4.1 Photograph of Tablets Post-Friability Testing ......................................................117 5.3a Menthol Sublimation Plots ....................................................................................156 5.3b Photograph of Menthol Formulation Tablets ........................................................159 5.3c Dissolution Plot .....................................................................................................163 1 1. INTRODUCTION Tablet dosage forms which rapidly (< one minute) disintegrate in the mouth and can be taken without water have become extremely popular in recent years 1 . These products offer the convenience of a tablet with the ease of swallowing a liquid 2 . These dosage forms are of particular advantage in certain patient groups such as children, elderly, and psychiatric patients 2-4 . Certain medical conditions such as pain, migraine, nausea, panic attack, allergic conditions, cough/cold, and Alzheimer?s may benefit from these dosage forms 2, 4 . Product life cycle management has led pharmaceutical companies to be very interested in using these dosage forms to extend brand name use after the initial dosage forms become available generically 3 . Although the official name for this dosage form is Orally Disintegrating Tablets (ODTs) 5 , many other names have been utilized. These include, but are not limited to, ?fast-dissolve?, ?fast-melt?, ? rapidly disintegrating?, ?quick-melt?, ?quick-dissolve?, ?crunch-melt?, ?bite-dispersible?, ?mouth-dissolve?, and orodispersible 2, 4, 6-8 . One common misconception with this dosage form regards their time of onset of action 3 . Although assumed to be faster onset than conventional tablets, in some cases this difference may be more perception than reality. This is of special interest for drugs taken to relieve acute symptoms of conditions such as pain, migraine, nausea, panic attack, and so forth. This is best understood by looking at the individual steps which 2 must be completed to achieve onset of action. For systemically acting drugs taken for relief of acute symptoms, these steps include: 1. appearance of symptom(s); 2. drug administration; 3. dissolution and absorption; 4. distribution and onset of action 3 . For Orally Disintegrating Tablets, the step most often affected is the time between symptom appearance and drug administration. The portability and ease of administration of ODTs may significantly reduce this step. In most cases, the rapid disintegration in the mouth does not result in sublingual absorption or substantially faster gastric absorption. In fact, taste coating may actually result in a decreased rate of dissolution 3 . This topic is discussed below after the discussion regarding taste. Market research has shown taste to be an important factor in patient acceptance of an ODT dosage form 9 . Biologically, taste may be defined as a chemical reaction derived from sensory responses from taste perceptions. The four main taste perceptions are salt, sour, bitter, and sweet. Other perceptions include umami (fullness) and trigeminal (burning) 9 . Smell contributes greatly to taste in that the brain interprets combined nasal and taste bud responses into one taste response. Consistency and mouthfeel also greatly contribute to taste 9 . People perceive flavors in different ways and these perceptions are affected by factors such as age and ethnicity 9 . If used in an ODT formulation, most drugs require taste-masking 9 . Methods used typically either prevent dissolution of the drug within the oral cavity or otherwise minimize the presented surface area of the drug 9 . Processes commonly used for ODTs 3 include wet granulation, roller compaction, spray-drying, and coating. Taste-coating may be based upon time or pH dependent dissolution of a coating polymer. Other taste- masking methods include the use of cyclodextrins, encapsulation using coacervation, electrochemical coating, and the use of supercritical fluids 9 . Following oral administration of a solid dosage form, the bioavailability is rate limited by either drug dissolution or absorption 10 . Dissolution rate is directly related to solubility 10 . For an ODT dosage form, the dissolution rate is also affected by the taste- coating. Ideally, any taste-coating method for an ODT should completely prevent dissolution for a short time, such as 2-5 minutes, and then subsequently not delay dissolution. How rapid this subsequent dissolution occurs depends upon the solubility of the drug itself. A rapid rate of dissolution is desired if the drug is to be used for acute symptom relief. Some ODTs are used to deliver enteric-coated or sustained-release products 1, 3 . In this case, delayed or slow dissolution is sought. The effect of any small delay in dissolution upon the rate of absorption will depend upon whether the particular drug in question is bioavailability rate limited by dissolution or absorption. Promethazine HCl was chosen as a model drug for these studies (Why chosen is discussed further below). This drug is very water soluble (500 mg/ml) 11 . The bioavailability of highly soluble drugs is typically not dissolution limited 10 . One pharmacokinetic study showed no significant difference in the area under the plasma concentration time curves (AUC 0-? ) for an oral solution, a generic tablet, and the innovator tablet of Promethazine 12 . Although no precise mathematical relationship was established, this same study concluded the compendial in vitro dissolution test assures satisfactory bioavailability 12 . 4 An ODT dosage form should possess certain ideal properties. These include no water required for administration, disintegration within seconds, pleasant taste and mouthfeel, porous, bioequivalent if a line-extension, sufficient strength to withstand manufacturing/packaging/shipping/environmental factors, adaptable to standard manufacturing and packaging equipment and materials, allow high drug-loading, and be cost effective (directly compressible, royalty-free, etc.) 4, 8 . Fast disintegration and the ability to take without water are required for this dosage form to offer broad advantages over conventional tablets. Pleasant taste and mouthfeel are required for patient acceptance. Porosity is required for water wicking and rapid disintegration. From a regulatory standpoint, bioequivalence to the reference product is required for rapid approval. Even an improvement in bioavailability results in additional regulatory requirements since a larger dose would be delivered in this case. Rapid disintegration must be carefully balanced with sufficient strength to withstand manufacturing, packaging, shipping, dispensing, patient handling, and exposure to moisture and other environmental factors. A friable and/or moisture sensitive product may disintegrate rapidly. However, this product would be of limited value if it could not be packaged, shipped, dispensed, taken by the patient, and have a suitable shelf-life. The ability to adapt to standard manufacturing and packaging equipment and to be produced in a cost effective manner are attributes sought for any new product. Otherwise, the benefit to cost ratio must be exceedingly high. Unless high drug-loading is achievable, the dosage form is limited to low dose drugs. No current ODT product or manufacturing method meets all of the above described ideal properties. Manufacturing methods such as freeze-drying and molding 5 result in rapidly (2-15 seconds) disintegrating yet friable dosage forms 1, 2, 13 . These manufacturing methods are expensive and may be patent protected. Products made using a conventional tablet press are more robust but high porosity and rapid disintegration are more difficult to achieve 1, 2, 13 . Current ODT tableting methods are complex and require pre-tableting treatments such as wet granulation, dry granulation, melt granulation, spray- drying, or flash-heating; or require post-tableting treatments such as sublimation, effervescence, sintering, or humidity treatment 1 . Although direct compression methods using superdisintegrants and/or other excipients exist, a separate taste-coating process is required 1, 2, 9, 13 . Methods to date rely upon complex and/or multiple processes to accomplish both taste-masking and rapid disintegration 1, 2, 9, 13 . The specific aim of this study is to develop a simple method of manufacturing Orally Disintegrating Tablets that better meet the ideal properties listed above. It is hypothesized that a method of manufacturing ODTs which preferably utilizes only simple blending followed by direct compression can be developed (More discussion on the broad hypothesis and secondary hypotheses appears later in this section.). This is the simplest, most economical process of manufacturing any tablet, conventional or rapidly disintegrating 1, 10, 14 . This method should utilize conventional, routinely available manufacturing equipment as well as simple and economical processing methods. This is of special concern for the generic market where manufacturing costs may be more critical. Materials used should be those with a history of safe use in the pharmaceutical industry. Compendial status is preferred for all materials to be utilized. Tablets produced by this method should be rugged enough to be packaged using conventional packaging materials (bottle or blister) and conventional packaging equipment. Tablets should meet 6 friability requirements for conventional tablets and compendial dissolution requirements for the drug. Complicated shipping, dispensing, and patient handling procedures should not be required. Promethazine HCL was chosen as a model drug for these studies. Promethazine is a phenothiazine derivative with antihistamine (H1 receptor blocker) and anti- cholinergic properties 15, 16 . Clinically useful effects include anti-emetic, antihistamine, and sedative effects 15, 16 . Promethazine HCl?s offensive taste and anesthetic effect coupled with its high water solubility (500 mg/ml) 11, 17 enable it to be an excellent model for testing an ODT formulation platform and manufacturing method. Any method which succeeds in taste-masking this highly water soluble and bitter tasting drug should be adaptable to masking the taste of less soluble or less offensive tasting drugs. Not only do taste and solubility characteristics make Promethazine HCl an excellent model, the development of an ODT dosage form of this drug meets an existing clinical need. Alternative dosage forms of Promethazine are needed to overcome the limitations of current dosage forms, especially in the outpatient setting. Conventional tablets generally require fluid intake which may worsen acute nausea and vomiting 15 . In addition, this fluid intake may lead to vomiting and expulsion of the drug delivered via a conventional tablet. This may result in under-dosing whereas repeating the dose may result in over-dosing. Currently available syrups not only share these problems, but also are limited due to their availability only in a single pediatric strength 16, 18 . In addition, syrups lack the portability of an Orally Disintegrating Tablet. Although suppositories overcome some of the above described limitations, they are an undesirable dosage for the majority of the patient population. In addition, Phenergan suppositories require 7 refrigeration 16, 18 which limits portability. An Orally Disintegrating Tablet could overcome many of the above described limitations. The ability to take anytime, anywhere, without fluid, offers numerous advantages in the treatment of nausea and vomiting. Its portability and ease of administration also enable an ODT to be very helpful in the treatment of motion sickness or allergic conditions. A directly compressible formulation for the 25 mg dose could be compressed at lower weights to achieve lower doses for use in children. ODTs are currently used in pain/fever, cold/cough, and other children?s products 1, 2 . The broad hypothesis for this study is that a simple manufacturing method for ODTs can be developed. Preferably, this method should require only simple blending followed by direct compression. In that case, the first component of the broad hypothesis is that a material or combination of materials exists which when simply blended with Promethazine HCL, will result in an acceptable degree of taste-coating. The research was limited to this approach due to the availability of only a V-blender and an open, kitchen-type, planetary mixer. Neither of these pieces of equipment generates a notable amount of heat or shear, both of which can aid in particle coating. No high shear mixer/granulator or fluid bed coater was available. Both of these technologies have been used successfully in producing taste-coatings 1, 9 . The materials to be considered for taste coating primarily consist of tablet lubricants. Lubricants function to prevent sticking of the tablet to the punch faces and to reduce die wall friction during compression and ejection 10 . Boundary lubricants attach to the metal oxide film on the punch and die surfaces 10 . These lubricants include, but are not limited to, Magnesium Stearate, Calcium Stearate, Zinc Stearate, and Stearic Acid. 8 Among these, Magnesium Stearate is the most effective tablet lubricant, probably due to its smaller particle size 10, 14 . These hydrophobic, waxy materials may retard disintegration and dissolution due to the ability of these small particles to physically adhere to and coat the active ingredient and other excipients. Since longer mixing results in greater coating of the drug and excipients, this delay in disintegration and dissolution as well as the compression problems (discussed in next paragraph) caused by these materials increase as mixing time increases. For this reason, these lubricants are added to the final blending stage and blending time is kept at a minimum 10, 14 . These lubricants may also adversely affect compression. To understand how this occurs, we must first understand the physics of tablet compression. Powders (or granules) are subjected to applied mechanical loads to form a tablet via compaction 10 . The behavior of these powders under these applied loads is a major factor in determining the success or failure of the formulation and process. Tableting may be defined as compaction of powders or granules in a die, between two punches, by application of a significant mechanical force 10 . The compaction process itself may be defined as the compression and consolidation of a two-phase (particulate solid/air) system due to applied forces 10 . Compression is the decrease in bulk volume resulting from air displacement. Consolidation is an increase in mechanical strength of the powder mass resulting from particle-particle interactions 10 . During compression, the bulk volume may be decreased by the plastic, elastic, or brittle fracture mechanisms of deformation. In many pharmaceutical systems, the applied force exceeds the elastic limit of the material and subsequent compression is due to visco- elastic or plastic deformation, and/or brittle fracture 10 . Certain materials are ductile or 9 easily deformed whereas some materials are brittle and fracture. Cellulose derivatives are a good example of a ductile material whereas sugars are a good example of a brittle material. A material may exhibit both properties but one property may predominate. Consolidation, an increase in mechanical strength, is due mainly to particle surfaces closely approaching one another and facilitating intermolecular bonding via van der Waals forces 10 . In addition, pressures developed at particle-particle point contacts may lead to localized melting followed by bridging 10 . The boundary lubricants such as Magnesium Stearate may cause a decrease in tablet tensile strength and an increase in friability by adversely affecting particle-particle bonding and bridging 10 . The ability of these lubricants to coat other particles leads to this effect. Brittle materials may be less impacted by this phenomenon since the breaking into multiple particles will expose new surfaces not coated by lubricant and thus available for bonding 10 . Due to these potential problems with boundary lubricants, another type of lubricants will be investigated first for their ability to taste-mask. These lubricants form a finite film on punch and die surfaces and are referred to as fluid lubricants 10 . These have a larger particle size and require a longer blending time. These lubricants include hydrogenated vegetable oil and newer partial glycerides of vegetable origin 10, 19, 20 . The newer glyceride lubricants have been successfully used for taste-masking, but thus far only with the use of heat or high shear 19, 20 . These trials will evaluate whether extended simple blending can accomplish taste coating with these materials. If these larger, spherical particles are ineffective, trials with the boundary lubricants or other hydrophobic or gel forming materials will be undertaken. 10 The V-blender and planetary blender will be used for most trials. Some materials may be preliminarily screened by mixing in a mortar and pestle. The effectiveness of taste coating will be evaluated primarily by dissolution testing. As discussed above, ideally, the dissolution profile would consist of no drug dissolved at the initial time-point followed by subsequent rapid dissolution. Although this type of profile is attainable with true coating processes such as fluid bed coating, a more gradual increase in dissolution rate may be realized with a simple physical mixture. The acceptance criteria will be an initial decrease in dissolution rate as compared to Promethazine HCl powder alone followed by subsequently meeting compendial dissolution requirements for Promethazine HCl tablets. The compendial dissolution method for conventional Promethazine HCl tablets will be utilized. This procedure will be adapted to incorporate modifications recommended for ODT dosage forms. As discussed above, one pharmacokinetic study concluded this compendial method to be acceptable in assessing bioavailability 12 . Although this requirement for subsequent dissolution rate is quantitative, the assessment of dissolution at the initial time point will be a mixture of qualitative and quantitative assessment. Although a numerical value will be obtained, an absolute limit has not been pre-established. So as not to rely solely on dissolution data, taste screening will also be performed by taste testing by two researchers, one of which will be blinded. A small amount of powder will be tasted then expectorated. This qualitative testing is limited due to the limited number (2) of tasters and possible bias. As noted earlier, people perceive taste differently and taste varies with age, ethnicity, and other factors 9 . Therefore, a large sample size of blinded, independent subjects would be required to fully evaluate taste. 11 However, it should be noted that no decisions will be based upon the lack of bitter taste alone without supporting dissolution data. Upon successful development of a simple and inexpensive Promethazine powder taste-coating method, the next step will be to insure the taste-coating will withstand the final blending with other tablet excipients and tablet compression process. At this stage the next hypothesis will be that a taste coated blend prepared by simple blending will withstand further blending and compression. The taste-coating will be evaluated by dissolution and taste as described above. For these purposes, the blend will be mixed with Pharmaburst and compressed. Pharmaburst is an off-the-shelf co-processed mixture of compressible sugars, disintegrants, and other excipients used in producing ODTs 21 . If the hypothesis that the taste-coating process will withstand final blending and compression is accepted, formulation trials will begin. The second hypothesis at this point is that Promethazine HCl taste-coated by the above method can be formulated into a directly compressible, non-offensive tasting, rapidly disintegrating (less than one minute in vivo) tablet which meets compendial Dissolution and Content Uniformity requirements. Content Uniformity assessment is required to demonstrate uniform distribution of active ingredient in individual tablets throughout the entire batch of finished product. Tablets will be primarily assessed by weight, hardness, thickness, friability, and in vitro disintegration testing. Weight variation is accurate, quantitative, and reproducible. However, weight control is not anticipated to be a key factor in this research. Hardness is a term routinely used in the pharmaceutical industry to assess tablet strength 10, 14 . This is not an accurate use of the term hardness. The test is also referred to as crushing strength, 12 which is also a misnomer 10 . The most correct name for this test is breaking force 10 . Tablets are caused to fail by applying a load across the tablet diameter via means of a moving plunger while the tablet rests against a fixed anvil. While newer testers which apply force via an electronic load cell can detect and record the initial break in the tablet, older testers like the one employed in this work may completely demolish the tablet and actually record a demolition force 10 . Older testers like the one employed are also subject to greater user and mechanical variation. Although a numerical result is obtained, there is no strictly defined target value. This value is useful primarily in qualitative comparison to patterns in friability and disintegration time. A very high number typically correlates with a prolonged disintegration time whereas a very low number typically correlates with a friable product. Tablet thickness is quantitative and can be accurately determined. Although at first glance it may appear to be of limited use in evaluating formulations, a more thorough examination reveals otherwise, and especially so in ODT formulations. A formulation capable of forming a stable compact at a lower compression force will be more porous 10 . This tablet will likely be thicker than it would have been if subjected to a higher compression force. As noted previously, porosity is very important in achieving rapid disintegration 4 . Qualitative patterns between hardness, thickness, friability and disintegration will be evaluated. Balancing friability and disintegration is a key driver in developing an ODT formulation. An ODT must be non-friable and rapidly disintegrating. Friability is quantitative in the sense that no broken tablets and less than one percent weight loss (limit recommended by USP for conventional tablets) 22 is acceptable. However, 13 comparisons of values below 1.0% are somewhat qualitative in nature. Disintegration is quantitative and reproducible. However, the overall formulation decisions are based upon qualitative comparisons of these above described physical parameters. No exact value requirements are pre-established and patterns are sought. This approach does not lend itself to statistical analysis and therefore has inherent weaknesses. Taste testing will also be performed by two researchers who will place the tablet in the mouth and leave undisturbed until complete disintegration occurs. All particles will be expectorated followed by rinsing the oral cavity with water. The approximate in vivo disintegration time will be noted. This taste testing is qualitative and subject to the limitations previously noted. However, it should be noted that formulation decisions are not made based upon acceptable taste results alone. The problems encountered from this point onward are dependent upon the material selected as a taste-coating agent. In this case, Magnesium Stearate in a 1:1 ratio with Promethazine HCl was eventually determined to accomplish taste-coating via simple V-blending. This taste-coating was maintained after final blending and compression. As discussed above, Magnesium Stearate both retards disintegration and increases friability, both of which are problematic in an ODT dosage form. At this point the third hypothesis is that certain classes of excipients will overcome the anticipated compression and disintegration problems of Promethazine HCl Orally Disintegrating Tablets. Preliminary trials will be undertaken to evaluate various combinations of diluents, binders, and superdisintegrants (Superdisintegrant is a term used within the pharmaceutical industry to describe newer disintegrants which are typically chemically modified or cross-linked versions of starches or celluloses 14 previously used as disintegrants. These are referred to as superdisintegrants because as compared to older disintegrants, they produce much faster disintegration at much lower use levels 10 .). These trials will be preliminary in nature. The goal of these trials is to determine a basic diluent or diluent/binder system to be studied further. The need for a glidant to aid flow will also be assessed. Preliminary assessment of superdisintegrants will also be undertaken. Excipients to be utilized will be selected based upon properties relevant to requirements for an ODT in general as well as properties important in this system containing a large amount of Magnesium Stearate. For example, spray-dried mannitol will be evaluated as a diluent based upon its fast rate of dissolution as compared to other sugars commonly utilized in ODTs 23 . Dextrates, NF will be evaluated as a diluent because these large crystallized particles 24 are expected to undergo brittle fracture 10 and thus be more likely to overcome lubricant sensitivity problems. Dextrates spherical particle shape 24 is expected to yield good flow properties and this material also dissolves rapidly 23 . A qualitative comparison of physical test results will be utilized to determine what basic diluent or diluent binder system to utilize in subsequent trials. At this point, an acceptable formulation is one which can be compressed and yield a non- friable tablet. The formulation chosen from preliminary trials will then be used in disintegrant trials. Various superdisintegrants with different mechanisms of action (wicking, swelling, wicking and swelling, etc.) will be evaluated. Non-traditional disintegrants will also be investigated. The use of Soy Polysaccharides as a disintegrant in ODT formulations will also be examined. The supplier of this material states this material has not been previously used in this manner. The initial goal prior to beginning this work 15 was to evaluate two disintegrants at a time utilizing the 3 2 randomized full factorial design as utilized by Gohel and coworkers. 25 In our case, the two factors to be investigated are the individual disintegrants at low, medium, and high use levels, based upon use levels routinely used for each specific disintegrant studied. The amount of each individual disintegrant is the independent variable with disintegration time and friability selected as dependent variables. This selection is based upon the balancing of disintegration time and friability being critical to development of an ODT. The statistical model as used allows for the evaluation of the average result from changing one disintegrant at a time from its low to high values and allows for evaluation of the response changes when two factors are simultaneously changed. Terms to investigate non-linearity are also included. This type of design allows for robust results which can be readily generalized. Unfortunately, in our case, the basic formulation was too sensitive to allow for multiple changes at multiple levels. In our trial, only one variable at a time was changed. This resulted in more batches required and data which are less robust. The physical test data were compared with decisions being made primarily based upon a qualitative comparison of disintegration time and friability. Taste was also examined. Beyond this point, this same basic approach was utilized for different types of ingredients. These materials were evaluated stepwise in attempts to further improve factors such as disintegration time, friability, and taste. These materials included: ? Materials which promote binding therefore enabling a lower compression force to be utilized; ? Materials which increase the overall hydrophilic or hydrophobic nature of the tablet; 16 ? Surfactants; ? Flavors/Sweeteners. As before, qualitative comparison of friability and dissolution data were utilized to make formulation decisions. Also as before, taste was a secondary qualitative parameter. In addition to examining different types of materials as described above, the technique of incorporating a volatile substance followed by post-tableting sublimation to increase tablet porosity was examined. A large amount of data will be collected for these studies. Although some limitations in equipment and methods exist, valuable information is expected from these trials. These include: ? Can taste-coating be accomplished via simple blending alone and, if so, what drugs are candidates for this technology; ? Can this taste-coating accomplished by this simple method withstand further blending and compression; ? Can a very high Magnesium Stearate content formulation be combined with other materials to result in a non-friable, rapidly disintegrating tablet; ? Can Soy Polysaccharides be useful as a disintegrant in ODT formulations; ? Can sublimation be combined with this methodology to further improve its usefulness as a method to produce ODT tablets? 17 REFERENCES 1. Fu Y, Yang S, Jeong SH, Kimura S, Park K. Orally fast disintegrating tablets: developments, technologies, taste-masking, and clinical studies. Critical Reviews in Therapeutic Drug Carrier Systems. 2004;21(6):433-475. 2. Bogner RH, Wilkosz MF. Fast-dissolving tablets. U.S. Pharmacist. March 2002;27(03):34-43. 3. Cremer K. Orally disintegrating dosage forms provide drug life cycle management opportunities. Pharmaceutical Technology Supplement. 2003(Formulation & Solid Dosage):22-28. 4. Parakh SR, Gothoskar AV. A review of mouth dissolving technologies. Pharmaceutical Technology. November 2003;27(11):92-100. 5. Klancke J. Dissolution testing of orally disintegrating tablets. Dissolution Technologies. May 2003;10(2):6-8. 6. Viswanathan S. Advances in drug delivery. Pharmaceutical Formulation and Quality. June/July 2004;6(3):20-28. 7. Viswanathan S. The latest in pop technology. Pharmaceutical Formulation and Quality. April/May 2005;7(2):32-34. 8. Joshi AA, Duriez X. Added functionality excipients: an answer to challenging formulations. Pharmaceutical Technology Supplement. 2004(Excipients and Solid Dosage Forms):12-19. 9. Brown D. Orally disintegrating tablets - taste over speed. Drug Delivery Technology. September 2003;13(6):58-61. 10. Gennaro AR, ed. Problem solver and reference manual. Newark, DE: FMC Biopolymer; 1998. 11. Florey K. Analytical profiles of drug substances. Vol 5. New York: Academic Press; 1976:430-464. 12. Zaman R, Honigberg IL, Francisco GE, et al. Bioequivalency and dose proportionality of three tableted promethazine products. Biopharmaceutics & Drug Disposition. May-June 1986;7(3):281-291. 18 13. Sharma N, Ahuja A, Ali J, Baboota S. Manufacturing technology choices for mouth dissolving tablets. Pharmaceutical Technology Supplement. 2003(Formulation and Solid Dosage):11-15. 14. Sheth BB, Bandelin FJ, Shangraw RF. Compressed tablets. In: Lieberman HA, Lachman L, eds. Pharmaceutical Dosage Forms: Tablets. Vol 1. New York: Marcel Dekker; 1980:109-185. 15. Taylor AT. Nausea and vomiting. In: DiPiro JTea, ed. Pharmacotherapy: a pathophysiologic approach. Fifth ed. New York: McGraw-Hill; 2002:641-653. 16. Phenergan prescribing information. Wyeth. Available at: http://www.wyeth.com/products/wpp_products/full_pharma_az.asp. Accessed Nov17, 2005. 17. Connors KA, Amidon GL, Stella VJ. Chemical stability of pharmaceuticals: a handbook for pharmacists. Second ed. New York: Wiley-Interscience; 1986:704- 713. 18. Promethazine Hydrochloride. Available at: http://online.factsandcomparisons.com. Accessed Nov 17, 2005. 19. Precirol ato 5. Available at: http://www.gattefosse.com/pharma/products/precirol.htm. Accessed September 8, 2004. 20. Gattaphen T. Available at: http://www.gattefosse.com/pharma/products/gattapht.htm. Accessed September 14, 2004. 21. 127 Pharmaburst. Available at: http://www.spipharma.com/ProductsFolder/127PharmaBurst/127PharmaBurst.ht ml. Accessed August 18, 2004. 22. The United States Pharmacopeia and The National Formulary (USP/NF). Vol USP 28/NF 23. Rockville,MD: United States Pharmacopeial Convention, Inc.; 2005. 23. Kim H-Sea, inventor; Yuhan Corporation, assignee. Rapidly disintegrable tablet for oral administration. June 13, 2002. 24. Emdex Technical Data Sheet. Vol TDS.QA0.10018.00000.02. Patterson, NY: JRS Pharma LP; 2003:1-4. 19 25. Gohel M, Patel M, Amin A, Agrawal R, Dave R, Bariya N. Formulation design and optimization of mouth dissolve tablets of nimesulide using vacuum drying technique. AAPS PharmSciTech. 2004;5(3):1-6. 2. REVIEW OF LITERATURE 2.1 Promethazine HCl Promethazine is a phenothiazine derivative (Figure 2.1) 1, 2 with antihistamine (H1 receptor blocker) and anti-cholinergic properties 3, 4 . Clinically useful effects include anti-emetic, antihistamine, and sedative effects 3, 4 . Promethazine differs structurally from antipsychotic phenothiazines by the presence of a branched side chain and no ring substitution 3 . This is believed to be responsible for Promethazine?s lack of dopamine antagonist properties 3 . N S CH 2 CH(CH 3 )N(CH 3 ) 2 H Cl Molecular Weight 320.88 Melting Point 220? C pka 9.1 Solvent Solubility (mg/ml @ Room Temperature) Water 500 Chloroform 335 Methanol 320 Ethanol USP 150 Ethanol, absolute 85 Isopropanol 9 Ethyl Acetate 1 Figure 2.1. Promethazine HCl: Structure and Properties 20 21 As shown in Figure 2.1, the hydrochloride salt is very soluble in water and non- polar solvents 1-3 . With a pka of 9.1 1 , Promethazine is essentially completely ionized at all physiological pH ranges. Promethazine is a safe and effective treatment for simple nausea and is among the most prescribed agents for this condition 4 . Essentially every person suffers from nausea and vomiting multiple times within a typical lifespan. Causes are numerous and varied but may include viral or bacterial, environmental (certain foods, alcohol), various disease states, pharmacological agents, and post-operative conditions 4 . Although a common condition, lack of proper treatment can lead to serious conditions, most often associated with fluid and electrolyte imbalances 4 . Promethazine is also among the most effective agents for treating balance disorders 4 . Motion sickness and other balance disorders are common and may be associated with a variety of clinical conditions 4 . Promethazine is also indicated for inducing light sedation, treating various allergic conditions, and as adjunctive therapy for anaphylactic reactions and pain 3 . Promethazine HCl dosage forms commercially available within the United States include tablets (12.5, 25, and 50 mg), a syrup (6.25 mg/5 ml), suppositories (12.5, 25, and 50 mg), and injections (25 mg/ml and 50 mg/ml) 5 . The average effective Promethazine adult dose for nausea and vomiting or motion sickness is 25 mg 3, 5 . The dose for children is typically 0.5 mg/pound of body weight. Promethazine is contraindicated in patients less than two years of age 3 . Dosing may be repeated at four to six hour intervals for nausea and vomiting. Dosing for motion sickness is typically twice a day. 3, 5 The injection dosage forms are limited primarily to inpatient use. The other dosage forms have many disadvantages in the outpatient setting. Oral tablets have a 22 delayed onset of action 3 which is undesirable for acute treatment of emesis, motion sickness, or adjunctive treatment of anaphylaxis or pain. For the treatment of nausea and vomiting, tablets and syrups are inconsistent with the cornerstone of treatment, nothing by mouth in the initial treatment period 4 . In fact, ingestion of these dosage forms and the accompanying required liquids may worsen the condition, resulting in vomiting and expulsion of a portion or the entire dose administered. The amount remaining in the body is now uncertain but further action may result in over dosing. In addition, syrups are currently available only in pediatric concentrations 5 . Although suppositories circumvent some of these specific problems, this is a very undesirable dosage form for the majority of the patient population. Other experimental Promethazine dosage forms have been considered. An experimental nasal spray resulted in mucosal irritability 6 . Although topical Promethazine is of interest in the area of compounding pharmacy 7 , the potential for local irritation and systemic toxicity is a concern with transdermal delivery of any compound 8 . This is especially true in children because of variability in skin thickness and dermal blood flow 8 . In fact, systemic poisoning resulting from topical Promethazine has been reported 9 . An orally disintegrating dosage form overcomes the numerous limitations encountered with the above described dosage forms. An orally disintegrating tablet (ODT) can be taken by children or adults, anytime and anywhere, without the need for water. As previously noted, fluid intake in the initial stages of nausea and vomiting may result in further complications. An ODT gives the benefits of a suppository without the unpleasant experience of administration. In addition, oral administration of Promethazine 23 results in a much shorter (2-3 hours) time to peak plasma concentration (t max ) than rectal administration (7-8 hours) 10, 11 . In addition, any Promethazine absorbed transmucosally would avoid the first-pass effect, which is significant (approximately 75%) for Promethazine 10, 11 . One factor to consider in dosage form development is the chemical stability of the compound to be utilized. Promethazine undergoes both thermal and photolytic oxidation via free radical formation 1, 2 . Commercially available conventional tablets are available in brand and generic versions 3, 5 . This indicates stable solid dosage forms can be formulated and manufactured. The innovator tablets (Phenergan, Wyeth) contain very common tableting excipients; Lactose, Magnesium Stearate, Methylcellulose, Saccharin Sodium, and dyes (in two of three available strengths) 3 . Another important factor in formulation development is the availability of analytical methods. Compendial methods of analysis are available for all commercially available Promethazine dosage forms 5 . Conventional tablet methods are expected to be readily adaptable to an orally disintegrating tablet dosage form. 2.2 Orally Disintegrating Tablets 2.2.1 Overview Orally Disintegrating Tablets (ODTs) may be defined as a tablet which disintegrates and/or dissolves rapidly (< one minute) in the saliva without the need for water or other liquid 12 . The United States Food and Drug Administration Center for Drug Evaluation and Research defines an ODT as a ?dosage form containing medicinal substances, which disintegrates rapidly, usually in a matter of seconds, when placed upon 24 the tongue? 12 . As reflected in Table 2.2 , this dosage form has become extremely popular in recent years 13 . Orally Disintegrating Tablets offer the convenience of a tablet with the ease of swallowing a liquid 14 . These dosage forms are of particular advantage in certain patient groups such as children, elderly, and psychiatric patients 14-16 . Certain medical conditions such as pain, migraine, nausea, panic attack, allergic conditions, cough/cold, and Alzheimer?s may benefit from these dosage forms 14-16 . A review of Table 2.2 reflects these patient groups and disease states. Product life cycle management has led pharmaceutical companies to be very interested in using these dosage forms to extend brand name use after the initial dosage forms become available generically 15 . Although the official name for this dosage form is Orally Disintegrating Tablets (ODTs) 17 , many other names have been utilized. These include 14, 16, 18-20 , but are not limited to, ?fast-dissolve?, ?fast-melt?, ? rapidly disintegrating?, ?quick-melt?, ?quick- dissolve?, ?crunch-melt?, ?bite-dispersible?, ?mouth-dissolve?, and orodispersible. An ODT dosage form should possess certain ideal properties. These include no water required for administration, disintegration within seconds, pleasant taste and mouthfeel, porous, bioequivalent if a line-extension, sufficient strength to withstand manufacturing/packaging/shipping/environmental factors, adaptable to standard manufacturing and packaging equipment and materials, allow high drug-loading, and be cost effective (directly compressible, royalty-free, etc.) 16, 20 . No current ODT product or manufacturing method possesses all of the above qualities 13 . 25 Table 2.2. Examples of ODT Products, Applications, and Technologies 5, 13, 14 Brand Name Active Ingredient Application General Technology Specific Technology Claritin RediTabs? Loratadine Antihistamine Freeze- Drying Zydis? Feldene Melt? Piroxicam NSAID as above as above Maxalt-MLT? Rizatritpan Migraine as above as above Pepcid ODT? Famotidine Heartburn as above as above Zyprexa? Zydis? Olanzapine Anti- psychotic as above as above Zofran? ODT? Ondansetron Anti-emetic as above as above Risperdal? M-Tab Risperidone Schizophrenia as above as above Zubrin? Tepoxalin Dog NSAID as above as above Klonopin? Wafers Clonazepam Anxiety/panic as above as above Childrens Dimetapp? ND Loratadine Antihistamine as above as above Imodium Instant Melts Loperamide Anti-diarrheal as above as above Propulsid? Quicksolv? Cisapride GI prokinetic Freeze- Drying Quicksolv? Tempra Quicklets Acetaminophen Pain/Fever Tableting OraSolv? Remeron? SolTab? Mirtazapine Depression as above as above Triaminic? Softchews? Various Cold/Cough/ Allergy as above as above Zomig-ZMT? Zolmitriptan Migraine Tableting DuraSolv? Alavert? Loratadine Antihistamine as above as above NuLev? Hyoscyamine GI spasms as above as above Kemstro? Baclofen Muscle Relaxer as above as above Niravam? ODT Alprazolam Anxiety/panic as above as above Benadryl? Fastmelt? Diphenhydramine Antihistamine as above WOWTAB? Nasea OD Ramosetron Anti-emetic as above as above Gaster D Famotidine Heartburn as above as above Excedrin? QuickTabs Acetaminophen Pain/Fever Tableting QuickTabs? Prevacid? SolTab Lansoprazole GERD/Ulcer Tableting Flashtab? Ralivia FlashDose? Tramadol Pain Cotton Candy FlashDose? Zolpidem ODT Zolpidem Sleep as above as above Fluoxetine ODT Fluoxetine Depression as above as above Aricept? ODT Donepezil Alzheimer?s - - 26 2.2.2 Current Methods of Manufacture a) Freeze-Drying Methods of manufacturing ODTs can be divided into three broad categories, freeze-drying, molding, or compaction. Freeze-drying or lyophilization was the first technology resulting in a commercialized ODT 5, 13, 14 . Table 2.2 reflects the extensive use of this methodology. In lyophilization, the drug and excipients are dissolved and/or suspended in a liquid which is dosed into a pre-formed blister that forms the tablet shape and serves as the immediate product package. Cryogenic freezing followed by sublimation removes the liquid from the product and the blisters are sealed and further packaged 5, 13 . This results in a very porous, rapidly (as fast as 3 seconds) disintegrating dosage form which has an excellent mouthfeel 5, 14-16, 21 . However, these lightweight units are fragile, moisture sensitive, and require complex packaging and patient handling 5, 14-16, 21 . In addition, the manufacturing process is specialized, expensive, and is often patented and requires outsourcing/partnering 14, 15, 21 . Within the area of freeze-drying, the Zydis? (Cardinal Health, Dublin, Ohio) technology is the most well known 13 . In this method, the drug is physically trapped in a two component (saccharide and polymer) matrix. Mannitol is a common saccharide employed and carrier polymers used include partially hydrolyzed gelatin, hydrolyzed dextran, dextrin, alginates, acacia, polyvinylpyrrolidone (PVP), and poly(vinyl alcohol) ( PVA) 13 . The drug, saccharide, and polymer are combined with other ingredients (flavors, sweeteners, collapse protectants, flocculating agents, etc.); then dissolved and/or dispersed in water. This liquid is then dosed into a pre-formed blister cavity which forms the final tablet shape and immediate product packaging. The package is then passed 27 through a liquid nitrogen freezing tunnel to achieve freezing. The packages are further frozen under vacuum in large scale freeze-dryers to remove the water. The now formed lightweight porous wafer is covered with a peelable foil and further packaged in an outer single-dose foil sachet-like package. 5, 13, 14, 16 . This extremely porous, small-particle size dosage form results in excellent mouthfeel and extremely rapid (as little as 3 seconds) disintegration. Taste-masking can also be achieved as part of the process. However, the dosage form is extremely fragile and moisture sensitive. The patient must deal with multiple packaging layers and must peel away the packaging without pushing the dosage form. Any minor damage to the package, humidity above 65%, or wet or sweaty hands may lead to collapse of the dosage form. In addition, the manufacturing method is patented, expensive, and requires partnering with Cardinal. The method requires a chemically stable drug with a preferred particle size below 50 microns. Doses above 60 milligrams are difficult to achieve with water soluble drugs. 13, 14, 16 The Quicksolv? (Janssen Pharmaceutica, Beese, Belgium)) method utilizes two different solvent systems and is said to yield a product with greater physical strength for handling 13 . The Lyoc? (Pharmalyoc, Lefon, Maisons-Alfort, France) system is based upon freeze-drying of an oil in water emulsion. This system requires a large amount of undissolved filler to maintain content uniformity. The resulting product is less porous, thus slower disintegrating, yet still fragile. 13 The NanoCrystal? (Elan, King of Prussia, PA) system is based upon lyophilization of mixtures of colloidal drug dispersions and water-soluble ingredients. This process can be performed on a small scale which is advantageous for clinical supply 28 manufacturing. This is also beneficial when working with potent or hazardous materials since processes (blending, tableting, etc.) which generate large quantities of aerosolized powder are avoided. The final product is durable enough for blister or bottle packaging and less moisture sensitive than Zydis? products. 13 b) Molding A second broad category of ODT manufacturing methods is molding. The traditional molding process is compression molding. In this process, the major components are water soluble and ethanol, water, or mixtures of the two, are the typical solvents employed. The powder mixture (drug, sugar(s), flavors, sweeteners, etc.) is moistened with solvent then molded into tablets under pressures lower than those used in conventional tablet compression. The tablets are then air-dried. This process is similar to tablet triturates in compounding pharmacy. Heat-molding (melt and pour) and no- vacuum lyophilization (pour and evaporate at standard pressure) are more recent methods of molding tablets. 13, 16, 22 Molded tablets disintegrate rapidly (5-15 seconds), have a good taste, and are less expensive to manufacture than freeze-dried products. However, the product has a low mechanical strength making packaging and handling difficult. The manufacturing process is sometimes proprietary, typically requires partnering, and is more expensive than direct compression 13, 16, 22 . c) Compaction Compaction is a third major category of ODT manufacturing methods. The ability to produce ODTs using a conventional tableting press is very attractive due to the availability of equipment and the low processing costs. Products made using a 29 conventional tablet press are more robust, but high porosity and rapid disintegration are more difficult to achieve 13-15, 21 . Current tableting methods are complex and require pre- tableting treatments such as wet granulation, dry granulation, melt granulation, spray- drying, or flash-heating; or require post-tableting treatments such as sublimation, effervescence, sintering, or humidity treatment 13 . Although direct compression methods using superdisintegrants and/or other excipients exist 13 , a separate taste-coating process is required for unpleasant tasting active ingredients.. Methods to date 12-16, 20-24 rely upon complex and/or multiple processes to accomplish both taste-masking and rapid disintegration. Various methods are reviewed below. Granulation Wet granulation has been utilized to produce ODTs. Wet granulations formed in a fluid bed yield low density, high porosity granules which lead to rapid disintegration of the finished tablet. The use of effervescence, surfactants, and nanoparticles has been combined with wet granulation methods. Taste-masking is typically achieved in the wet granulation process through the use of sugars and polymers. 13 . Wet granulation is more labor intensive, requires more equipment and energy, and is more expensive than direct compression. In addition, moisture and heat-sensitive drugs do not lend themselves to wet granulation 25, 26 .Melt granulation and dry granulation have also been utilized 13 , but suffer many of the same disadvantages as wet granulation 25, 26 . Spray Drying Spray drying can be used to make very porous particles with a large surface area. Active ingredients may be sprayed together with saccharides, flavors, and sweeteners to achieve taste-masking. The use of two polypeptides of the same charge (to promote 30 repulsion) such as non-hydrolyzed and hydrolyzed gelatin combined with an acidifying or alkalinizing agent has been utilized to further increase porosity. Effervescent agents have also been included in spray dried mixtures to further promote rapid disintegration 13, 16 . Although effective, the manufacture of ODTs by spray drying requires several processing steps as well as the use of heat. Some spray drying processes may also utilize organic solvents. Cotton Candy Process Fuisz Technologies (Chantilly, Virginia) has manufactured ODTs utilizing a Cotton Candy type process also known as the Shearform? or Flashdose? technology. Drug, saccharides, and polysaccharides are flash melted while subjected to centrifugal force and a temperature gradient. This process yields a floss-like crystalline structure similar to cotton candy. This floss creates a very high surface area for disintegration and dissolution. The floss is re-crystallized to form freely flowing granules with self-binding properties. These granules are combined with other excipients and compressed into tablets. These tablets disintegrate rapidly, are of acceptable strength, and can accommodate high drug loading. However, this is a specialized, multi-step process. In addition, this process is inappropriate for heat sensitive drugs. 13, 14, 16, 20, 22 Direct Compression Direct compression is the simplest and least expensive tableting process 13 . Direct compression uses conventional blending and tableting equipment as well as commonly available excipients. ODTs made by direct compression are robust and can be easily packaged and handled. However, in vivo disintegration time is longer (30-60 seconds) and good taste and mouthfeel are harder to achieve. For unpleasant tasting drugs, current 31 direct compression methods require a separate taste-coating process for the active ingredient prior to introduction into the direct compression process 13, 16, 20, 22 . Separate processes used for taste-masking include wet granulation, roller compaction, spray-drying, and coating. Taste-coating may be based upon time or pH dependent dissolution of the coating polymer. 12 Other taste-masking methods include the use of cyclodextrins, encapsulation using coacervation, electrochemical coating, and the use of supercritical fluids 12 . For direct compression ODT processes, sugar based excipients (mannitol, sorbitol, xylitol, maltose, etc.) are routinely used for their high water solubility, sweet taste, and pleasant mouthfeel 13, 16, 20, 22 . In addition to taste and mouthfeel, disintegration time is a primary concern. Some ODT technologies use effervescent couples alone or in combination with other disintegrants to achieve rapid disintegration 13, 16, 20, 22 . The use of disintegrants, and especially the more modern superdisintegrants, has made the advent of compression based ODTs possible 16 . Various materials have been utilized as disintegrants. Starches and modified starches have a long history of use as disintegrants 25, 27 . Within this group, the superdisintegrant Sodium Starch Glycolate is of most interest today 25 . This material is commonly used in levels of 2-8% by weight and its primary mechanism of action as a disintegrant is via swelling 25, 27 . Crospovidone, cross-linked polyvinylpyrrolidone, is another superdisintegrant of choice 13, 25, 27 . Although historically used in a range of 2-5% 25, 27 , one manufacturer recommends up to 15% by weight in ODT formulations 28 . In fact, a specific grade featuring a smaller and more narrow particle size distribution has been developed 32 specifically to yield better mouth feel in ODT formulations 28 . Crospovidone is said to promote both wicking and swelling 28 . Crospovidone?s disintegrant action is dependent upon compression force 27 . A certain tablet hardness is required for the swelling and expansion to be effective. Modified celluloses are another common group of disintegrants 13 . Most recommended among this group is Croscarmellose Sodium, an internally cross-linked Sodium Carboxymethycellulose 25, 27 . Typical use levels range from 2-4% although lower and higher amounts have been utilized 25, 27 . This disintegrant works via both wicking and swelling 25, 27 . Calcium Silicate in amounts up to 30% by weight has also been used to promote disintegration 27, 29 . RxCipients? FM 1000? Calcium Silicate from Huber Engineered Materials (Havre de Grace, Maryland) is extremely hydrophobic 29 . When combined with superdisintegrants, the superdisintegrants are said to expand against this hydrophobic material. This expansion against another material is said to promote the tablet rapidly breaking down into primary particles. 29 Other disintegrants employed in ODTs are Alginic Acid, Sodium Alginate, Microcrystalline Cellulose, Methacrylic Acid- Divinylbenzene Copolymer Salts, and Poly(Acrylic Acid) Superporous Hydrogel (SPH) 13 . Inorganic excipients have also been utilized in direct compression ODTs. Disintegration is aided by the combination of disintegrant, insoluble materials, and soluble materials in specific ratios 13 . Di-basic and Tri-basic Calcium Phosphate have been utilized as an insoluble inorganic material. Other insoluble excipients commonly used in tablets may contribute to the total amount of insoluble material used 13 . 33 Lubrication is another important concern when making ODTs. Historically, Magnesium Stearate has been the most effective and most commonly used lubricant used in tableting processes to prevent tablets from sticking to the punch faces and to reduce friction between the die wall and the tablet during compression and ejection 25, 26 . It is commonly used in amounts of less than 2% with 1% or less being the preferred amount 25, 26 . Increases in the amount of Magnesium Stearate or the Magnesium Stearate mixing time tend to retard disintegration and dissolution and increase friability 25, 26 . In fact, some sources recommend against the use of Magnesium Stearate in ODTs because of its hydrophobic nature and tendency to increase disintegration time 30 . Sodium Stearyl Fumarate, a less hydrophobic material not sensitive to blending time, is generally recommended for use in ODTs 30 . One method of producing ODTs is to use a method of lubricating the tablet and press external to the tablet formulation 24, 31 . One patent recommended levels of Magnesium Stearate up to 2.5% be used as a tablet lubricant in ODTs 23 . d) Post-Tableting Treatments Various post-tableting treatments have been used to yield rapidly disintegrating tablets. These methods are described below. Sublimation Sublimation has been used to speed disintegration by increasing tablet porosity 13, 16 A volatile substance is used as part of the tablet composition; the tablets are then compressed followed by sublimation of the volatile substance. Substances used include menthol, camphor, thymol, organic and lower fatty acids, urea, ammonium carbonate, ammonium bicarbonate, and hexa methylene tetramine. Both vacuum and/or 34 heat may be used to sublime the volatile material 13, 16 . Sublimation has been combined with a molding process as well 13 . Humidity Treatment Tablets with low mechanical strength disintegrate rapidly but may be too friable for packaging and handling. Humidity treatment allows a lightly compressed, rapidly disintegrating tablet to gain the ruggedness required for packaging and handling. The weak tablets are placed in a high humidity area then subsequently dried. The humidity results in the formation of liquid bridges which become solid bridges after drying. Humidification and drying may also promote the change of sugars from an amorphous to a crystalline state. This results in an increase in tablet strength 13 . Sintering Sintering is a process of using pressure and heat below the melting point to bond and partly fuse particles. This process has been used to increase tablet strength of rapidly disintegrating tablets which would otherwise be too friable to withstand packaging and handling. 13 In addition to being unsuitable for heat labile drugs, this is a complex, multi-step process. 2.2.3 Specific Examples OraSolv? and DuraSolv? OraSolv? (Cima Labs, Eden Prairie, MN) technology is based upon producing tablets at low compression pressures using an effervescent couple to further speed disintegration 13 . Acid sources include citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, and succinic acids. Carbonate sources include sodium bicarbonate, sodium carbonate, potassium bicarbonate, and potassium carbonate. The effervescent couple 35 comprises 20-25% of the total tablet weight. The liberated carbon dioxide not only speeds the breaking apart of the tablet, but also the mild fizzing sensation results in a positive organoleptic sensation. 13 These tablets are fragile and a special packaging system (PakSolv?) was developed for use with these tablets. A dome-shaped blister package prevents the vertical movement of the tablet within the package as well as provides light, moisture, and child resistance 13 . Cima also developed a second generation technology, DuraSolv?, which results in stronger tablets suitable for packaging in bottles or blisters. This technology is based upon compressing tablets using non-compression grade polysaccharides, such as dextrose, mannitol, sorbitol, lactose, and sucrose, along with up to 2.5% of a hydrophobic lubricant such as Magnesium Stearate 13, 23 . However, taste-coating of unpleasant tasting actives must be achieved in a separate process 23 . DuraSolv tablets are said to disintegrate in vivo in less than 60 seconds 13 . WOWTAB? WOWTAB? (Yamanouchi Pharma Technologies, Inc., Japan), (With Out Water Tablet) technology is based upon granulating a saccharide with low moldability (mannitol, glucose, sucrose, xylitol) using a dissolved saccharide with high moldability (maltose, maltitol, sorbitol) as a binder. Tablets are then compressed with these granules then further subjected to humidity treatment 13, 14 . This is obviously a multiple step process without the advantages of direct compression. Flashtab? Flashtab? (Ethypharm, France) produces ODTs by compression of granular excipients prior granulated by either dry or wet granulation. The drug may be granulated 36 or coated with time or pH dependent polymers such as methylmethacralate copolymers (Eudragit?) 13, 14, 19, 32 . One example of this technology is Prevacid? SolTab which is an ODT containing enteric coated granules used to deliver an acid labile drug 14, 19, 32 . This type of ODT is said to disintegrate in vivo within 30 to 60 seconds 13, 14, 19, 32 . This technology can be applied to high dose drugs and is not limited by drug taste or solubility 32 . However, again it can be seen that this technology is more labor and time intensive than simple direct compression. AdvaTab? AdvaTab? (Eurand, Milan, Italy) is a tableting method of making ODTs based upon the use of an external lubricant 13, 24, 31 . Rather than the tableting blend containing a hydrophobic lubricant, a small amount of lubricant is sprayed onto each tablet during the tableting process. This method results in 10-30 times less hydrophobic lubricant. Since internal lubrication both decreases tablet strength and retards fluid entry, avoiding this process results in a non-friable, rapidly disintegrating tablet 13, 24, 31 . These tablets are rugged enough for blister or bottle packaging. However, this is a patented process using specialized equipment. In addition, unpleasant tasting actives must be taste-coated or otherwise taste-masked in a separate process 13, 24, 31 . Pharmaburst? Pharmaburst? (SPI Pharma, New Castle, Delaware) is an off-the-shelf directly compressible blend of co-processed materials which can be mixed with active and flavors/sweeteners then compressed into an ODT 13, 30 . This method can accommodate high drug loading with in vivo disintegration times of less than 40 seconds. The typical amount of Pharmaburst? ranges from 50-80% of the total tablet weight. A lubricant is 37 also required 13, 30 and Sodium Stearyl Fumarate is recommended 30 . Tablets may be manufactured and packaged under normal conditions 13, 30 . Taste-coating or masking by an independent process is required for unpleasant tasting drugs. Due to high demand, agreements are required with the supplier to prevent a second manufacturer from easily duplicating an original Pharmaburst? product. Frosta? Frosta? (Akina Inc., West Lafayette, IN) technology is based upon wet granulation of a porous and plastic material, a water penetration enhancer, and a binder. These granules are then compressed at low pressures into rugged tablets which disintegrate in 30 seconds or less 13, 24, 33 . This is a patented, multi-step process. OraQuick? OraQuick? (KV Pharmaceuticals, St. Louis, MO) is based upon the sintering process reviewed above 24, 34 . 2.3 Specific Aims of Current Study As can be seen from the reviewed literature, no simple manufacturing method exists which accomplishes both taste-masking and fast (< one minute) in vivo disintegration. The specific aim of this study is to develop a simple method of manufacturing Orally Disintegrating Tablets. Additional information with regard to hypothesis, experimental design, and specific aims is covered in the Introduction section of this dissertation. This method should utilize conventional, routinely available manufacturing equipment as well as simple and economical processing methods. Simple blending followed by direct compression is the preferred method. This is the simplest, most economical process of manufacturing any tablet, conventional or rapidly 38 disintegrating. Materials used should be those with a history of safe use in the pharmaceutical industry. Compendial status is preferred for all materials to be utilized. Tablets produced by this method should be rugged enough to be packaged using conventional packaging materials (bottle or blister) and conventional packaging equipment. Tablets should meet friability requirements for conventional tablets. Complicated shipping, dispensing, and patient handling procedures should not be required. Promethazine was chosen as a model drug for these studies. Its offensive taste and anesthetic effect coupled with its high water solubility enable it to be an excellent model for testing an ODT formulation and manufacturing method. In addition, alternative dosage forms of Promethazine are needed to overcome the limitations of current dosage forms, especially in the outpatient setting. Conventional tablets require fluid intake which may worsen acute nausea and vomiting. In addition, this fluid intake may lead to vomiting and expulsion of the drug delivered via a conventional tablet. This may result in under-dosing whereas repeating the dose may result in over-dosing. Currently available syrups not only share these problems, but also are limited due to their availability only in a single pediatric strength. Suppositories are an undesirable dosage form for the majority of the patient population. An Orally Disintegrating Tablet could overcome many of the above described limitations. The ability to take anytime, anywhere, without fluid, offers numerous advantages in the treatment of nausea and vomiting. Its portability and ease of administration also enable it to be very helpful in the treatment of motion sickness or allergic conditions. 39 References 1. Florey K. Analytical profiles of drug substances. Vol 5. New York: Academic Press; 1976:430-464. 2. Connors KA, Amidon GL, Stella VJ. Chemical stability of pharmaceuticals: a handbook for pharmacists. Second ed. New York: Wiley-Interscience; 1986:704- 713. 3. Phenergan prescribing information. Wyeth. Available at: http://www.wyeth.com/products/wpp_products/full_pharma_az.asp. Accessed Nov17, 2005. 4. Taylor AT. Nausea and vomiting. In: DiPiro JTea, ed. Pharmacotherapy: a pathophysiologic approach. Fifth ed. New York: McGraw-Hill; 2002:641-653. 5. Drug delivery-pts-cardinal health. Available at: http://www.cardinal.com/pts/content/delivery/dd-oral-zydis.asp. Accessed August 19, 2004. 6. Ramanathan R, Geary RS, Bourne DW, Putcha L. Bioavailability of intranasal promethazine dosage forms in dogs. Pharmacological Research. Jul 1998;38(1):35-39. 7. Dugger HA, inventor; Novadel Pharma Inc., assignee. Buccal, polar and non- polar spray or capsule. US patent 6,676,931. March 18, 2002. 8. Berlin CMJ. Alternate routes of drug administration- advantages and disadvantages (subject review). Pediatrics. 1997;100(1):143-152. 9. Shawn DH, McGuigan MA. Poisoning from dermal absorption of promethazine. Canadian Medical Association Journal. June 1 1984;130(11):1460-1461. 10. Schwinghammer TL, Juhl RP, Dittert LW, Melethil SK, Kroboth FJ, Chung VS. Comparison of the bioavailability of oral, rectal and intramuscular promethazine. Biopharmaceutics & Drug Disposition. Apr-Jun 1984;5(2):185-194. 11. Zaman R, Honigberg IL, Francisco GE, et al. Bioequivalency and dose proportionality of three tableted promethazine products. Biopharmaceutics & Drug Disposition. May-June 1986;7(3):281-291. 12. Brown D. Orally disintegrating tablets - taste over speed. Drug Delivery Technology. September 2003;13(6):58-61. 40 13. Fu Y, Yang S, Jeong SH, Kimura S, Park K. Orally fast disintegrating tablets: developments, technologies, taste-masking, and clinical studies. Critical Reviews in Therapeutic Drug Carrier Systems. 2004;21(6):433-475. 14. Bogner RH, Wilkosz MF. Fast-dissolving tablets. U.S. Pharmacist. March 2002;27(03):34-43. 15. Cremer K. Orally disintegrating dosage forms provide drug life cycle management opportunities. Pharmaceutical Technology Supplement. 2003(Formulation & Solid Dosage):22-28. 16. Parakh SR, Gothoskar AV. A review of mouth dissolving technologies. Pharmaceutical Technology. November 2003;27(11):92-100. 17. Klancke J. Dissolution testing of orally disintegrating tablets. Dissolution Technologies. May 2003;10(2):6-8. 18. Viswanathan S. The latest in pop technology. Pharmaceutical Formulation and Quality. April/May 2005;7(2):32-34. 19. Viswanathan S. Advances in drug delivery. Pharmaceutical Formulation and Quality. June/July 2004;6(3):20-28. 20. Joshi AA, Duriez X. Added functionality excipients: an answer to challenging formulations. Pharmaceutical Technology Supplement. 2004(Excipients and Solid Dosage Forms):12-19. 21. Sharma N, Ahuja A, Ali J, Baboota S. Manufacturing technology choices for mouth dissolving tablets. Pharmaceutical Technology Supplement. 2003(Formulation and Solid Dosage):11-15. 22. Dobetti L. Fast-melting tablets: developments and technologies. Pharmaceutical Technology Supplement. 2001(Drug Delivery):44-50. 23. Khankari RK, Hontz J, Chastain SJ, Katzner L, inventors; Cima Labs Inc, assignee. Rapidly dissolving robust dosage form. US patent 6,024,981, 2000. 24. Rocca JG, Park K. Oral drug delivery: prospects & challenges. Drug Delivery Technology. May 2004;4(4):52-57. 25. Gennaro AR, ed. Problem solver and reference manual. Newark, DE: FMC Biopolymer; 1998. 41 26. Sheth BB, Bandelin FJ, Shangraw RF. Compressed tablets. In: Lieberman HA, Lachman L, eds. Pharmaceutical Dosage Forms: Tablets. Vol 1. New York: Marcel Dekker; 1980:109-185. 27. McCarty JA. Eye on excipients. Tablets & Capsules. March 2005;3(2):49-52. 28. Polyplasdone XL-10. International Specialty Products. Available at: www.ispcorp.com. Accessed September 7, 2004. 29. RxCipients overview. Available at: http://208.55.179.223/rxcipients/overview.htm. Accessed August 16, 2004. 30. 127 Pharmaburst. Available at: http://www.spipharma.com/ProductsFolder/127PharmaBurst/127PharmaBurst.ht ml. Accessed August 18, 2004. 31. Eurand : AdvaTab. Available at: http://www.eurand.com/page.php?id=89. Accessed August 19, 2004. 32. Ethypharm. Available at: http://www.ethypharm.com/generate.htm?2. Accessed August 19, 2004. 33. Akina, Inc. Available at: http://www.akinainc.com/. Accessed August 19, 2004. 34. KV Pharmaceutical - quick dissolving tablets. Available at: http://www.kvpharmaceutical.com/tech/3_quick_dissolving_tablets.html. Accessed August 19, 2004. 42 3. TASTE-MASKING Abstract Taste-masking is a critical component of formulation and process development for Orally Disintegrating Tablets (ODTs). The specific aim of this study was to develop a simple process for taste-masking which yields a blend which can be further diluted and directly compressed into an ODT dosage form. Promethazine HCl was chosen as a model drug for these studies. Promethazine HCl is a highly water soluble drug with an offensive, bitter taste and an unpleasant anesthetic effect in the oral cavity. Dissolution testing was utilized to evaluate taste-masking since only dissolved drug is tasted. The USP method for conventional Promethazine HCl tablets was modified to conditions (pH 6.4, paddles, 50 rpm) recommended for this dosage form. Initially, loss of Promethazine HCl to the end-filter of the sampling probe occurred. Use of a filter needle overcame this problem. A linear, reproducible method based upon UV analysis at 249 nm was achieved for dissolution analysis. Excipients did not produce interference. Numerous materials were evaluated for their ability to achieve taste-masking via simple blending. Magnesium Stearate V-blended in a 1:1 ratio with drug proved to be effective based upon dissolution testing and taste screening. Tablets were compressed by diluting this mixture with Pharmaburst, an off-the-shelf ODT platform. The taste-masking was not compromised by final blending and compression. Formulation trials to develop a suitable tablet will proceed using this taste-masking method. 43 3.1 Introduction Orally Disintegrating Tablets (ODTs) have become a popular dosage form. An ODT may be defined as a tablet which disintegrates and/or dissolves rapidly (< one minute) in the saliva without the need for water or other liquid 1 . These readily transportable dosage forms are intended to be taken anytime and anywhere without the need for water or other liquid 1, 2 . Certain patient groups such as children, elderly, and psychiatric patients greatly benefit from this technology 3-5 . This dosage form is especially beneficial in certain medical conditions such as pain, migraine, nausea, panic attack, allergic conditions, cough/cold, and Alzheimer?s 3-5 . Market research has shown a significant amount of consumers prefer an ODT over a conventional tablet. This research has also shown that taste is a very important factor. Longer disintegration times were acceptable if the taste was good. However, the converse was not true; fast disintegration times were not acceptable if taste was bad 1 . Although some drugs have little taste and a simple addition of flavor will result in an acceptable taste, most drugs to be incorporated into an ODT formulation require taste- masking 1 . Although some ODT manufacturing methods allow for taste-masking as part of the manufacturing process, many do not 2-7 . In those methods which do accomplish taste-masking, the steps which do so are often the same or similar processing methods as those used to accomplish taste-masking in independent processes 2-7 . These processes include wet granulation, roller-compaction, spray-drying, and coating 1, 2 . Taste-coating may be achieved using polymers which dissolve based upon time and/or pH 1 . 44 Other taste-masking methods include the use of cyclodextrins, encapsulation using coacervation, electrochemical coating, and the use of supercritical fluids 1 . Direct compression is the fastest, simplest, and least expensive method of manufacturing conventional tablets or ODTs 2, 8, 9 . In its true form, direct compression consists of simple blending followed by compression of the powder blend using a conventional tablet press 8, 9 . Many methods of manufacturing ODTs which are listed as direct compression methods 2 require steps beyond this definition. Otherwise, taste- masking of unpleasant tasting drugs must be accomplished via a separate process. No current method accomplishes both taste-masking and rapid disintegration via simple blending followed by direct compression 2-5, 7, 10-21 . The specific aim of this study was to develop a taste-coating method which could be accomplished by simple blending alone with the resulting blend being suitable for direct compression into a rapidly disintegrating tablet. The hypothesis is that a material or combination of materials exist which when simply blended with Promethazine HCl, will result in an acceptable degree of taste- coating. The taste-coating must withstand the compression process and be effective in the final dosage form. Promethazine HCl was chosen as a model drug for this study. Promethazine HCl is highly water soluble (500mg/ml) 22, 23 and has a very bitter taste as well as an unpleasant anesthetic effect in the oral cavity. These factors combined result in Promethazine HCl being a very challenging model drug for ODT formulation and manufacturing method development. Compendial methods of analysis exist for Promethazine HCl 24 . In addition to taste testing, dissolution is a key method for evaluating taste-masking. Since only dissolved drug is tasted, a reduction in the initial 45 dissolution is an appropriate method for evaluating taste-masking. In addition, it is important to establish that taste-masking does not retard dissolution to the extent that bioequivalence to the conventional dosage form is compromised 1 . Various hydrophobic materials in various concentrations were examined for their ability to mask the bitter taste of Promethazine HCl. The selected material, concentration, and blending method were utilized to produce tablets to insure the taste- masking method withstood the compression process. Dissolution data from powder blend and tablets are compared. One hydrophobic material chosen for extensive study was Magnesium Stearate. Magnesium Stearate is an extremely hydrophobic material used in concentrations below 2% as a tablet lubricant in conventional tablets 8, 9 . In fact, Magnesium Stearate is the most effective and most commonly used tablet lubricant 8, 9 . Magnesium Stearate is more effective than Stearic Acid and other metallic stearates, probably due to its smaller particle size 8 . However, Magnesium Stearate tends to increase tablet friability and retard disintegration, especially as the amount of Magnesium Stearate increases and/or as the Magnesium Stearate blending time increases 8, 9 . For these reasons, some have recommended against the use of Magnesium Stearate in rapidly disintegrating dosage forms 21 . However, one method of producing ODTs utilizes up to 2.5% Magnesium Stearate as a lubricant in combination with non-direct compression grades of diluents 25 . 3.2 Materials The materials listed below were used as received: -Promethazine HCl, USP; Gallipot; Lot 0101139; -Promethazine HCl, USP; Honeywell (Ireland); Lot BPMH119117; 46 -Precirol ATO 5; atomized Glyceryl Dipalmitostearate Type I EP; C16-C18; melting point (drop point, Mettler) 53-57 ?C; HLB 2; Gattefosse lot 28950; fine powder; lubricant, taste-masking, sustained release agent; -Gelucire 33/01; Hard Fat, USP; semi-synthetic glycerides consisting of saturated fatty acids from C8 to C18 triglycerides; melting point 33-37 ?C; HLB 1; Gattefosse lot 27328; semi-solid oily carrier for hard gelatin capsules, protects against light, moisture, and oxidation; -Gelucire 43/01; as per 33/01 with a higher melting point of 42-46 ?C; waxy solid (pellets or blocks); -Compritrol 888 ATO; Glyceryl Behenate USP; Glyceryl Dibehenate EP; >83% C22; melting point 69-74 ?C; HLB 2; Gattefosse lot 31463; fine powder; lubricant, binder, sustained-release agent; -VP AEROPERL 300 Pharma; Colloidal Silicon Dioxide USP/NF, EP; hydrophobic; Degussa lot 315404042191. -Pharmaburst C1; SPI Polyols; Lot 04C139; -Calcium Silicate; RxCipients FM 1000; Huber Lot 294/102; -Stearic Acid, NF, Triple Pressed Powder; Amend, Lot G18042A29; -Magnesium Stearate, NF, Impalpable Powder; Mallinckrodt; Lot SC13325. Other materials used in informal trials included Zinc Stearate, Calcium Stearate, Menthol, Vegetable Shortening, Petrolatum, and Sodium Saccharin. 47 3.3 Methods 3.3.1 UV Method All solutions were prepared using a 0.2 M pH 6.4 Phosphate Buffer. Preliminary trials were conducted by diluting a single 30 mg/100 ml Promethazine HCl stock solution to concentrations of 5.4, 10.8, 32.4, 54.0, 75.6, 97.2, and 118.8 % label claim. In this case, label claim is 25 mg (product strength) per 900 ml (quantity of dissolution media). These concentrations correlate to a range from 0.00150 to 0.03300 mg/ml. Preliminary trials were conducted using a raw material source (Gallipot) other than that planned for use in formulation trials. Initial unfiltered samples were collected by rotating the volumetric then immediately pouring sample into a glass collection tube. Filtered samples were withdrawn into a five ml B-D Luer-Lok plastic syringe via a manual sample probe kit (HR Easi-Probe Kit PN 72-300-305, Hanson Research) with a ten micron sintered polyethylene end filter (HR PN 27-101-074) attached to the sample end of the probe cannula. The sample probe kit consists of a stainless steel cannula with plastic connectors. Each concentration solution utilized a separate, unused filter and probe kit. An initial three ml filtered sample was withdrawn, expressed into a collection tube, followed by the withdrawal and collection of a second three ml sample. Absorbance of all samples was determined at 249 nm using a Beckman Model DU-65 (S/N 4293550) Spectrophotometer. Additional work was conducted the following day using the same diluted solutions. Solutions and samples were stored at ambient lab conditions (21-22 ?C). Standard lighting was employed while measuring, mixing, or analyzing. When not in 48 use, solutions and samples were stored on the lab bench with lighting turned off. An unfiltered sample was collected as done on Day 1. A four ml sample was then withdrawn via the sample probe-syringe system without the end filter. This sample was then expressed via a five micron filter needle (B-D 305200). The first ml expressed was discarded with the remaining three ml collected in a glass collection tube. Samples for the three highest concentrations were diluted with an equal volume of buffer prior to reading. Final UV trials were conducted using the Promethazine HCl (Honeywell) to be used in formulation trials. Two independent trials (labeled as A and B) were conducted by weighing 30 mg quantities of Promethazine HCl and diluting each to 100 ml with filtered (Millipore sintered glass filter apparatus) buffer. These stock solutions were further diluted into two separate sets of dilutions in the same concentrations previously employed (seven dilutions ranging from 5.4 to 118.8 % label claim). Unfiltered samples for each dilution were collected by inverting the volumetric and pouring directly into the glass sample collection tube. Filtered samples were collected by withdrawing five ml into a ten ml plastic B-D Luer-Lok syringe via a Hanson Research manual dissolution sample probe with no end filter. A five micron B-D filter needle (BD Item 305200, 19G, 1.5TW) was attached, two ml was expressed and discarded, and the subsequent three ml was expressed into the sample collection tube. After a spectrophotometer bulb warm-up time of greater than one hour, the absorbance of each sample was read at 249 nm using buffer as a reference solution. Samples for the three highest concentrations were diluted with an equal volume of buffer prior to determining absorbance and the resulting absorbance value was multiplied by two. 49 A solution containing all excipients initially planned for use in formulation trials was prepared and the absorbance determined. Later, a solution was prepared using the final formulation excipients in the concentrations used and the absorbance of a filtered sample was determined. 3.3.2 Dissolution Method For conventional Promethazine HCl tablets, USP dissolution (<711>) is performed in 900 ml of 0.01 N Hydrochloric Acid at 37?C using Apparatus 1 (baskets) at 100 rpm 24 . The USP limit is not less than (NLT) 75% (Q) dissolved in 45 minutes. The amount dissolved is determined by employing UV absorption at a wavelength of about 249 nm on filtered portions of the test solution, suitably diluted, in comparison with a standard solution of known concentration in the same media 24 . Certain modifications were made to the above referenced method based upon current guidelines 26 for dissolution testing of Orally Disintegrating Tablets. A 0.2 Molar pH 6.4 Phosphate Buffer was utilized. Molarity was as per USPP 24 recommendations and pH was chosen based upon the pH of the oral cavity as recommended by current guidelines 26, 27 . Volume was unchanged at 900 milliliters. Apparatus 2 (paddles) at a speed of 50 rpm was utilized as per current recommendations 26, 27 . There is concern that baskets might be clogged by a rapidly disintegrating tablet. Also, 50 rpm with paddles is considered to be equivalent to 100 rpm with baskets 27 . Standard curve and filtration studies were performed as described in UV Methods above to insure this method was accurate and reproducible. The equipment used for dissolution testing included a Beckman Model DU-65 Spectrophotometer (Serial # 4293550) and a Hanson Research SRII 6-Flask Dissolution 50 Test Station (Model 46-100-040, S/N 0196-2364) with HR Validata Control Module (Model 47-200-202, S/N 0196-2366). Test media was 900 ml of 0.2M pH 6.4 (?0.05) Phosphate Buffer. Specific conditions included using Apparatus 2 (paddles) at 50 rpm with a media temperature of 37.0 ? 0.5 ?C. Paddles were centered and the distance from the bottom of each paddle to the bottom of each vessel was 2.5 cm. The sampling point was approximately one-half the distance from the top of the paddle to the surface of the media. The water bath level was maintained above the level of the dissolution media. The buffer was de-aerated by heating in a lab oven to approximately 41?C, followed by vacuum filtration using a Millipore sintered glass apparatus. The buffer was stirred (magnetic stir bar) vigorously under vacuum for 5 minutes. The buffer was then immediately transferred to the dissolution flasks in a pre-heated water bath. Covers were added and stirring started and continued until sample addition. Media temperature was confirmed prior to sample addition. Stirring was stopped for sample addition then immediately restarted. Samples (5 ml) were withdrawn at specified times via a Hanson Research Manual Sample Probe (HR Easi-Probe Kit PN 72-300-305) using a B-D 10 ml plastic syringe. Media was replaced after each sampling. Absorbance was determined for each sample at 249 nm. For each sample, a new 5 micron filter needle (B-D Item 305200, 19G, 1.5TW) was attached to the syringe. The first two ml expressed were discarded and the remaining 3 ml collected in a glass sample tube. For absorbance readings above 1.5, the sample was diluted with an equal volume of buffer, re-read, and the resulting absorbance value was multiplied by two. Percent Dissolved values were determined using a standard curve equation. Media temperature was rechecked and recorded at the 51 end of dissolution. Although not done initially, the media volume remaining was recorded for later trials. 3.3.3 Taste-Masking Trials (Blends) Blending equipment used was as follows: -PK Twin Shell (V) Dry Blender, S/N LB853S, tabletop unit with interchangeable shells, using an approximately two quart acrylic shell (actual volume equals 1820 ml), speed equals 22 rpm; -Planetary Mixer, Kitchen- Aid Artisan 5-quart, single standard attachment; -Planetary Mixer, Sunbeam Mixmaster, dual dough-hook attachments or dual egg-beater attachments as specified, 1580 ml freely rotating bowl. The effectiveness of taste coating was evaluated primarily by dissolution testing. Ideally, the dissolution profile would consist of no drug dissolved at the initial time-point followed by subsequent rapid dissolution. Although this type of profile is attainable with true coating processes such as fluid bed coating, a more gradual increase in dissolution rate may be realized with a simple physical mixture. The acceptance criteria were an initial decrease in dissolution rate as compared to Promethazine HCl powder alone followed by subsequently meeting compendial dissolution requirements for Promethazine HCl tablets. Although this requirement for subsequent dissolution rate was quantitative, the assessment of dissolution at the initial time point was a mixture of qualitative and quantitative assessment. Although a numerical value was obtained, an absolute limit was not pre-established. So as not to rely solely on dissolution data, taste screening was also performed by taste testing by two researchers, one of which was blinded. A small amount of powder 52 was tasted then expectorated. This qualitative testing was limited due to the limited number (2) of tasters and possible bias. Therefore, a large sample size of blinded, independent subjects would be required to fully evaluate taste. However, it should be noted that no decisions were based upon the lack of bitter taste alone without supporting dissolution data. Initial trials were performed with Precirol ATO 5 Glyceryl Dipalmitostearate. Promethazine HCl (100 grams, 80.6% of mixture by weight) and Precirol (24 grams, 19.4% of mixture) were separately passed through a 30 mesh sieve and added to the V- blender in this order. This mixture was blended for 120 minutes with samples removed and internal blend and ambient temperatures recorded at 30 minute intervals. The final blend was subjected to dissolution testing (n=3, 31 mg blend equivalent to 25 mg active ingredient). Unprocessed Promethazine HCl, 25 mg, was also tested. Dissolution samples were taken at 5, 10, 15, and 30 minute time points. The final blend from the V- blender was then blended for 30 minutes in a Kitchen-Aid 5-quart planetary mixer (speed setting two). An attempt was made to screen Gelucire 43/01 Hard Fat pellets through a 20 and 30 mesh sieve. Fifty grams (66.7%) of Promethazine HCl was mixed for approximately thirty minutes with five grams (6.7%) of Gelucire 33/01 Hard Fat in a Sunbeam Planetary Mixer (speed setting seven) with dual dough hook attachments. A total of twenty-five grams (26.7%) of Compritrol 888 ATO Glyceryl Behenate was added incrementally over a total additional mixing time of two hours. An ambient and blend temperature was recorded after the longest uninterrupted blending interval of one hour. One gram samples were taken after various additions and the final blend (n=3, 37.5 mg blend equivalent to 53 25 mg active) was subjected to dissolution testing. Samples were taken at 2, 5, 10, and 15 minute time-points. The dissolution stirring speed was then increased to 100 rpm and samples withdrawn after an additional 10 minutes. The final blend was then mixed for three minutes (speed setting two) with five grams of VP AEROPERL 300 Pharma hydrophobic colloidal silicon dioxide. A number of materials were screened determine what materials to utilize in additional trials. These materials and methods included: ? Menthol + Precirol (mortar and pestle); ? Stearic Acid : Promethazine HCl 0.2:1 (mixed in rotating bottle); ? Pre-heated (69?C) Precirol ATO 5 (Glyceryl Dipalmitostearate) : Promethazine HCl 0.75:1 (pre-heated planetary mixer bowl and dough hooks); ? Precirol : Promethazine HCl 0.75:1 heated (69?C, beaker in water bath); ? Vegetable Shortening : Promethazine HCl 1:1 (mortar and pestle); ? Petrolatum: Promethazine HCl 1:1 (mortar and pestle), also with flavor added; ? Promethazine HCl : Petrolatum Mixture (petrolatum + starch + HPMC) 1:1 (mortar and pestle); ? Stearic Acid : Promethazine HCl 1:1 (mortar and pestle); ? Sodium Saccharin : Promethazine HCl 0.3 : 1 (mortar and pestle); ? Stearic Acid + Promethazine HCl + Sodium Saccharin (mortar and pestle). Additional trials with stearates were then performed. Promethazine HCl (screened 30 mesh) 25 grams and Stearic Acid (screened 40 mesh) 12.5 grams were mixed in a Sunbeam Planetary Mixer (dual egg-beater attachments), Speed 2, for 0.75 hours. An additional 12.5 grams of Stearic Acid was added and 54 mixing was continued for 1.5 hours. This 1:1 Stearic Acid: Promethazine HCl blend (total blend time 2.25 hours) was subjected to dissolution testing (n = 3, 50 mg blend = 25 mg active). One gram of Promethazine HCl was mixed in a mortar and pestle with one gram of Calcium Stearate, Magnesium Stearate, or Zinc Stearate. Each sample was taste screened by two researchers. Promethazine HCl and Magnesium Stearate, 25 grams of each, were added to the planetary mixer. An attempt to blend, even at low speed, resulted in too much dust generation in this open system. This material was transferred to the V- Blender and mixed (22 rpm) for 1.0 hour. This 1:1 blend was subjected to dissolution testing (n = 3, 50 mg blend = 25 mg active). Magnesium Stearate: Promethazine HCl (25 grams) blending was repeated with 12.5 grams and 16.7 grams of Magnesium Stearate. This corresponds to Magnesium Stearate: Promethazine HCL ratios of 0.5:1 and 0.67:1, respectively. An extensive screening process was added in these trials. Each material was screened (40 mesh) prior to weighing. The two materials were then co-screened (40 mesh) ten times prior to being added to the V-Blender. After 0.5 hours of blending, the material was discharged and passed five additional times through a 40 mesh screen. Blending was continued for an additional 0.5 hours (total blend time 1.0 hour). The blend was screened twice more before being subjected to dissolution testing (n = 3 for each blend, 37.5 mg and 41.7 mg respectively for the 0.67:1 and 0.5:1 blends = 25 mg active). 3.3.4 Tablet Taste-Masking Trial Equipment utilized for testing taste-masking in compressed tablets included: -Stokes Single-Station Tablet Press, Model 519.2, Serial Number 662673, Lot 562134, speed = 50 tablets/minute; -Tooling: 9/32 (0.2812) inch diameter round flat-faced beveled edge (FFBE), Natoli Engineering Co., Inc. (Drawing Number 99073); -Hardness Tester, J H DeLamar & Son, Inc., Model PT 102, Serial Number 39; -V-Blender- as previously described (22 rpm). Tablet formulations are shown in Table 3.3 below. Table 3.3 Tablet Formulations 55 Ingredients per Tablet (theoretical tablet weight = 125 mg) Formula/Description Magnesium Stearate Promethazine Pharmaburst Calcium Silicate A. 0.67:1 16.7 mg (13.4%) 25.0 mg (20%) 83.3 mg (66.6%) B. 0.67:1 + CaSiO n 16.7 mg (13.4%) 25.0 mg (20%) 58.3 mg (46.6%) 25 mg (20%) C: 1:1 25.0 mg (20%) 25.0 mg (20%) 75.0 mg (60.0%) Ingredients per Batch (g) Formula/Description Magnesium Stearate Promethazine Pharmaburst Calcium Silicate A. 0.67:1 6.0 9.0 30.0 B. 0.67:1 + CaSiOn 6.0 9.0 21.0 9.0 C: 1:1 15.0 15.0 45.0 Magnesium Stearate: Promethazine HCl blends from previous taste-masking trials were utilized for the initial tablet trials. These pre-blends were V- blended with Pharmaburst for five minutes. Formulation B which included Calcium Silicate was prepared by first V-blending the pre-blend with Calcium Silicate for two minutes followed by the addition of Pharmaburst with three additional minutes of blending. 56 These blends were compressed on the single-station tablet press. Hardness and weight values (n=5) were determined. Three tablets from the Magnesium Stearate: Promethazine HCl-Pharmaburst formulas (A and C) were subjected to dissolution testing. 3.4 Results and Discussion 3.4.1 UV Method Absorbance versus concentration data are shown numerically in Table 3.4a and graphically in Figure 3.4a. These results indicate that a notable loss occurs to the filter and/or sample probe. The second three ml filtered sample results indicate this loss is partially, but not adequately, saturated. In addition, it appears samples with an absorbance value above 1.5 should be diluted prior to measuring. Upon review of these results, additional work was conducted the following day using the same diluted solutions. Hanson Research Technical Support was contacted and suggested that filtering not be employed or filtering be performed with another type filter after the sample is withdrawn into the syringe. The USP method does state to analyze a filtered sample. This also would appear to be the preferred method from a scientific standpoint. The important criterion in filtering after withdrawal is that in actual dissolution trials, this filtering must be performed immediately to reduce the likelihood of dissolution of particles occurring in the sample after the withdrawal time. The results for Day 1 and Day 2 unfiltered data are presented graphically in Figure 3.4b. These results indicate stability of absorbance of drug in solution under ambient conditions for the intended formulation studies and dissolution testing. In addition, dilution of samples with absorbance above 1.5 to fifty percent concentration is sufficient for the range employed in these studies. Table 3.4a. Absorbance Data Absorbance Data at 249 nm 0.5 ? Filter Needle Initial readings Second readings*** % label* Unfiltered 1st 3 ml 2nd 3 ml 2nd 3 ml/ Unfiltered Filtered Unfiltered Filtered Unf. X 100 5.4 0.116 0.050 0.088 75.9 0.063 0.054 0.075 0.062 10.8 0.227 0.156 0.211 93.0 0.180 0.178 0.194 0.187 32.4 0.766 0.514 0.709 92.6 0.718 0.718 0.734 0.734 54.0 1.283 0.997 1.239 96.6 1.247 1.255 1.269 1.263 75.6 1.750 1.436 1.689 96.5 1.700 1.684 1.738 1.722 97.2 2.113 1.823 2.034 96.3 2.200 2.232 2.294 2.294 118.8 2.119 2.119 2.119 100.0 2.730 2.766 2.822 2.880 *After Day 1, samples for the 3 highest concentrations were diluted with an equal amount of buffer, read, and absorbance multiplied by 2 to obtain the reported values. **4 ml sample, 1st ml discarded ***Re-read after additional bulb warm-up time. DAY 1 HR End Filter DAY 2** 57 Figure 3.4a. Effect of End Filter Filtration on Absorbance Values 0.000 0.500 1.000 1.500 2.000 2.500 0 20 40 60 80 100 120 140 Concentration (% label) Absorbance Unfiltered 1st 3 ml Filtrate 2nd 3ml Filtrate 58 Figure 3.4b. Effect of Time and Dilution on Absorbance Values 0.000 0.500 1.000 1.500 2.000 2.500 3.000 0 20 40 60 80 100 120 140 CONCENTRATION (% LABEL) AB S O RBANCE Initial Samples, All Undiluted Aged Samples (>24 hours), Diluted at 80% & above 59 60 Figure 3.4c presents a graphical comparison of Day 2 filtered and unfiltered absorbance data. In this case a four milliliter sample was filtered with a filter needle and the first milliliter discarded, the filtered versus unfiltered curves are nearly identical. This indicates the previous loss on Day 1 was to the end filter. The use of a filter needle did not result in a significant loss at concentrations at or above 10.8 percent label claim. Some loss did occur to the filter needle at the lowest concentration. A single trial where the first two ml rather than one ml expressed were discarded yielded identical readings for unfiltered and filtered and appeared to solve this problem. A closer look at the raw data indicates this concentration may also be below the accurate, reproducible absorbance range for this compound. Lack of precision at the lowest concentration does not invalidate the method. In addition, it was noted that allowing one hour rather than the minimum fifteen minute instrument bulb warm-up time is recommended for more accuracy and reproducibility. Final trials conducted in duplicate were undertaken. These trials incorporated all recommendations from the initial trials. These recommendations included a minimum one hour UV bulb warm-up time, use of a filter needle, withdrawal of five ml with the first two milliliters discarded, and sample dilution when absorbance was above 1.5. Final trials absorbance data are presented in Table 3.4b. Figure 3.4d is a graphical representation comparing absorbance data before and after filtering of samples. This data indicate a slight loss to the filter occurs. The loss is much less dramatic than that seen with the use of a Hanson Research end filter. For example, for this method (filter needle) the maximum loss is about five percent whereas with the end filter the loss at the lowest Figure 3.4c Effect of Filtration with Filter Needle on Absorbance Values 0.000 0.500 1.000 1.500 2.000 2.500 3.000 3.500 0 20 40 60 80 100 120 140 Concentration (% label) Absorbance Unfiltered Filtered (Filter Needle) 61 62 concentration was over sixty percent for the first three milliliters of filtrate and still approximately twenty-five percent for the second filtrate. Figure 3.4e graphically presents average absorbance versus concentration plots for filtered samples. One graph reflects the lines for individual trials A and B whereas the second plot presents average data. The results for A and B unfiltered are very similar as reflected by the indistinguishable lines on the graph comparing these values. This indicates the method is very reproducible, especially when considering that some samples are diluted prior to measurement. This introduces an additional step for potential error. This similarity between the data sets also indicates good technique by the lab personnel. The average values for filtered samples are used to prepare the absorbance versus concentration plot which will be utilized to determine percent dissolved based upon absorbance values of filtered dissolution samples. The trend line indicates the actual concentration values (y) are very similar to predicted concentration values. The coefficient of determination (R 2 ) of 0.9995 indicates a high degree of linearity for this method. This absorbance versus concentration line is described by the equation: y = 0.0231x ? 0.0493 where y = absorbance and x = concentration (% label claim). Absorbance readings at 249 nm were zero for solutions prepared with excipients planned for use and with excipients at concentrations in the final tablet formulation. This indicates Table 3.4b. Final Trials Absorbance Data A A B B Average Average F/U % Label Unfiltered Filtered Unfiltered Filtered Unfiltered Filtered x 100 (%) 5.4 0.069 0.067 0.076 0.071 0.073 0.069 94.5 10.8 0.210 0.199 0.209 0.204 0.210 0.202 96.2 32.4 0.727 0.714 0.753 0.717 0.740 0.712 96.2 54.0 1.232 1.215 1.273 1.233 1.253 1.224 97.7 75.6 1.736 1.654 1.738 1.662 1.737 1.658 95.5 97.2 2.206 2.200 2.220 2.180 2.213 2.190 99.0 118.8 2.774 2.712 2.654 2.726 2.714 2.719 100.2 63 Figure 3.4d. Effect of Filtration on Absorbance (Duplicate Trials, Filter Needle) 0.000 0.500 1.000 1.500 2.000 2.500 3.000 0.0 20.0 40.0 60.0 80.0 100.0 120.0 140.0 CONCENTRATION (% LABEL) ABS ORBANCE A Unfiltered A Filtered 0.000 0.500 1.000 1.500 2.000 2.500 3.000 0.0 20.0 40.0 60.0 80.0 100.0 120.0 140.0 CONCENTRATION (% LABEL) ABS ORB ANCE B Unfiltered B Filtered 64 Figure 3.4e. Relationship of Absorbance and Concentration 0.000 0.500 1.000 1.500 2.000 2.500 3.000 0.0 20.0 40.0 60.0 80.0 100.0 120.0 140.0 CONCENTRATION (% LABEL) ABS ORBANCE A Filtered B Filtered y = 0.0231x - 0.0493 R 2 = 0.9995 0.000 0.500 1.000 1.500 2.000 2.500 3.000 0.0 20.0 40.0 60.0 80.0 100.0 120.0 140.0 CONCENTRATION (% LABEL) ABS ORBANCE Average of A & B Filtered Linear Trend Line 65 66 inactive ingredients should not interfere with UV analysis of Promethazine HCl at 249 nm. The method as used in the final trials is suitable for use in formulation development trials. The method is linear, reproducible, corrected for minor drug loss, and lacks interference by inactive ingredients. 3.4.2 Taste Masking Dissolution data from initial taste masking trials are presented in Tables 3.4c, 3.4d, and 3.4e. These same data are presented graphically in Figure 3.4f. Dissolution of Promethazine HCl powder and Promethazine HCl blended (two hours, V-Blender) with approximately twenty percent Precirol ATO 5 Glyceryl Dipalmitostearate was rapid and complete. This blending did not retard dissolution. Further blending of this blend in a Kitchen-Aid planetary blender did not visually appear to result in any intimate mixing of these materials. As expected, no notable heat build-up occurred during this blending as indicated by the lack of an internal blend temperature difference from ambient temperature of more than one degree Celsius. At this point, Gelucire Hard Fat materials were considered. These materials are labeled by the manufacturer as more semi-solid in nature and used to protect against light, moisture, and oxidation. Gelucire 43/01 has a melting point of approximately 43 ?C and would be preferred for taste-masking since this temperature is above the temperature of the oral cavity. However, this material supplied as pellets was too hard to hand screen and could not be simply mixed with Promethazine HCl. Gelucire 33/01 (melting point around 33 ?C) is a semi-solid with a texture similar to softened margarine. This material would appear to mix and potentially coat better. However, the lower melting point is a concern Table 3.4c Promethazine HCl Dissolution Data Abs @ Conc @ Abs @ Conc @ Abs @ Conc @ Abs @ Conc @ Flask # 5 min 5 Min 10 min 10 min 15 min 15 min 30 min 30 min F1 2.114 93.6 2.510 110.8 2.488 109.8 2.366 104.6 F2 2.268 100.3 2.426 107.2 2.416 106.7 2.380 105.2 F3 2.298 101.6 2.602 114.8 2.646 116.7 2.606 114.9 Mean 98.5 110.9 111.1 108.2 SD 4.3 3.8 5.1 5.8 %RSD 4.4 3.5 4.6 5.4 Table 3.4d. Promethazine HCl + Precirol Dissolution Data* Abs @ Conc @ Abs @ Conc @ Abs @ Conc @ Abs @ Conc @ Flask # 5 min 5 min 10 min 10 min 15 min 15 min 30 min 30 min F1 2.402 106.1 2.392 105.7 2.392 105.7 2.422 107.0 F2 2.320 102.6 2.242 99.2 2.348 103.8 2.376 105.0 F3 2.384 105.3 2.316 102.4 2.334 103.2 2.380 105.2 Mean 104.7 102.4 104.2 105.7 SD 1.9 3.2 1.3 1.1 %RSD 1.8 3.2 1.3 1.0 * Promethazine HCl (80.6%) + Precirol ATO 5 Glyceryl Dipalmitostearate (19.4%) 67 Table 3.4e. Promethazine HCl + Gelucire + Compritrol Dissolution Data* 68 c @ Abs @Con Abs @ Conc @ Abs @ Conc @ Abs @ Conc @ Abs @ Conc @ + 10 min + 10 min Flask # 2 min 2 min 5 min 5 min 10 min 10 min 15 min 15 min 100rpm 100 rpm F1 2.172 96.2 2.384 105.3 2.310 102.1 2.312 102.2 2.334 103.2 F2 2.240 99.1 2.406 106.3 2.352 104.0 2.462 108.7 2.452 108.3 F3 2.238 99.0 2.452 108.3 2.344 103.6 2.428 107.2 2.372 104.8 Mean 98.1 106.7 103.2 106.1 105.4 SD 1.7 1.5 1.0 3.4 2.6 %RSD 1.7 1.4 0.9 3.2 2.5 * Promethazine HCl (66.7%) + Gelucire 33/01 Hard Fat (6.7%) + Compritrol 888 ATO Glyceryl Behenate (26.7%) Figure 3.4f. Initial Taste-Masking Dissolution Plot PERCENT DISSOLVED VS. TIME 0 20 40 60 80 100 120 0 5 10 15 20 25 30 35 TIME (min) PERC EN T D I SSO LVED Promethazine Promethazine + Precirol Prometh + Gelucire 33/01 + Compritrol 69 with regard to taste-masking. A small amount (6.7%) of this material was blended with Promethazine HCl in an attempt to create a ?sticky? surface. This was followed by the addition of Compritrol 888 ATO Glyceryl Behenate (26.7%), a very fine powder lipid with a higher melting point (around 70 ?C). As before, no notable build-up of heat occurred. The graphed profile differs because an earlier (two minute) time point was tested to see if any delay occurred. This blend was then mixed at a slower speed for three minutes with VP AEROPERL 300 Pharma hydrophobic Colloidal Silicon Dioxide. This rapidly converted the waxy appearing blend into a fine, free-flowing powder. This information may be helpful in future trials. For all dissolution trials, percent dissolved values of greater than one hundred percent were obtained. For the first trial with unprocessed Promethazine HCl powder, a long (two-hour) equilibration time was employed between adding media to the flasks and starting the dissolution test. Since excessive evaporation can lead to higher concentrations, subsequent trials were conducted with minimal yet adequate equilibration times of less than thirty minutes and final media volumes were measured and recorded. The trend of these latter trials was lower yet still above ideal. The measurable media loss ranged from one to two percent. This alone would not explain the high percent dissolved results. It was considered, especially with a powder that does not sink before dissolving as a typical tablet would, that slow diffusion at 50 rpm could result in higher concentrations near the sampling point (midway between surface of media and top of paddle). At the completion of the third dissolution test, the stirring rpm was increased to 100 rpm for ten additional minutes. Although the higher speed is visually more effective 70 in mixing, the percents dissolved for these samples were not lower. The high numbers do not appear to be the result of inadequate mixing. It should be noted that the numbers in the latter two trials are not beyond the range sometimes observed in dissolution testing. The shorter dissolution equilibration times employed in the latter trials were employed in all subsequent trials. These materials or and process did not retard dissolution by simple blending without heat, high-shear, or solvents. Subsequent screening trials were conducted. Menthol did not influence the physical form of Precirol. The pre-heated Precirol cooled rapidly and resulted in an uneven mixture of granules, large agglomerates, and uncoated powder. The melted Precirol mixture did not readily appear to mask the drug taste upon cooling (Taste was informally evaluated by the investigator touching a minute portion to the side of the tongue.). A review of solubility data for Promethazine HCl reflects the challenge in masking this bitter tasting drug. Although highly water soluble, Promethazine HCl exhibits lipid soluble properties as well 22, 23 . Vegetable shortening did appear to slightly delay the bitter taste of Promethazine HCl. Petrolatum and petrolatum mixtures helped slightly but less so than shortening. Stearic Acid, Sodium Saccharin, and the combination of these ingredients showed promise in masking this bitter taste. It was decided to pursue formal blending trials with Stearic Acid and metallic stearates. Saccharin or another sweetening agent would be added in later formulations. Dissolution results for Stearic Acid and metallic stearate trials are shown in Table 3.4f. A graphical representation of these same data is presented in Figure 3.4g. Stearic Acid did slow Promethazine HCl dissolution to approximately eighty-five percent at two Table 3.4f. Stearate Trials Dissolution Data 71 PROMETHAZINE DISSOLUTION DATA (PERCENT DISSOLVED) Time (min) 0 2 5 10 15 30 Sample Description Stearic Acid: Drug 1:1 SAF1 0.0 87.2 86.1 92.4 88.2 SAF2 0.0 84.3 83.7 83.0 79.7 SAF3 0 86.0 87.7 89.6 90.4 AVG SA 0.0 85.8 85.8 88.3 86.1 SD 0.0 1.5 2.0 4.8 5.7 %RSD 0 1.7 2.3 5.5 6.6 Magnesium Stearate: Drug 1:1 1:1 F1 0.0 30.4 34.4 38.5 42.6 54.9 1:1 F2 0.0 18.9 21.7 25.3 27.8 35.2 1:1 F3 0.0 37.8 55.3 60.2 63.3 72.4 AVG 1:1 0.0 29.0 37.1 41.3 44.6 54.2 SD 0.0 9.5 17.0 17.6 17.8 18.6 %RSD 0.0 38.0 45.6 42.7 40.1 34.4 Magnesium Stearate: Drug 0.67:1 0.67:1 F1 0.0 58.1 65.4 67.2 73.2 82.2 0.67:1 F2 0.0 78.0 84.3 90.9 92.1 98.4 0.67:1 F3 0.0 81.4 92.0 94.7 95.8 102.6 AVG 0.67:1 0.0 72.5 80.6 84.3 87.0 94.4 SD 0.0 12.6 13.7 14.9 12.1 10.8 %RSD 0 17.4 17.0 17.7 13.9 11.4 Magnesium Stearate: Drug 0.5:1 0.5:1 F1 0.0 86.9 90.7 93.1 96.3 98.3 0.5:1 F2 0.0 70.5 75.4 82.5 84.0 91.0 0.5:1 F3 0.0 96.2 100.1 102.1 101.9 102.6 AVG 0.5:1 0.0 84.5 88.7 92.6 94.1 97.3 SD 0.0 13.0 12.5 9.8 9.2 5.9 %RSD 0 15.4 14.0 10. 9.8 6.0 Figure 3.4g. Stearate Trials Percent Dissolved vs. Time Plot 0.0 20.0 40.0 60.0 80.0 100.0 120.0 0 5 10 15 20 25 30 35 TIME (Min) P E RCE NT DI S S OL V E D Stearic Acid:Drug 1:1;Planetary Mag Stearate:Drug 1:1;V-blender Mag Stearate:Drug 0.67:1;Screen + V-Blender Mag Stearate:Drug 0.5:1; Screen + V-Blender 72 73 minutes. However, dissolution did not notably increase with time. Since this profile did not show the desired effect of initially slowing dissolution followed by subsequent complete dissolution, the use of metallic stearates was examined. For later trials, an additional thirty minute dissolution sample was taken. Informal mortar and pestle trials indicated Magnesium Stearate and Calcium Stearate were more effective in masking taste than Zinc Stearate. Magnesium Stearate appeared to be slightly more effective than Calcium Stearate. Magnesium Stearate and Calcium Stearate have a smaller particle size and better coating properties than Stearic Acid. Magnesium Stearate is considered to be a more efficient lubricant than Calcium Stearate 8 . Based upon observed results and theoretical considerations, blending trials with Magnesium Stearate were undertaken. In a 1:1 ratio, Magnesium Stearate reduced the average Promethazine HCl percent dissolved to below thirty percent at two minutes and below fifty-five percent at thirty minutes. This was by far the greatest reduction in dissolution observed to date. The variation between samples (i.e., between dissolution flasks) was large and did not decrease with time. The blending process incorporated a very small portion of the blender capacity and the Magnesium Stearate appeared to adhere to the acrylic blender shell walls and form small agglomerates at times. This observation coupled with the large variation in percent dissolved between blend samples led to a concern that the blend was potentially not uniform. Therefore, the extensive screening steps were added in subsequent trials. The lower ratio (0.67:1 and 0.5:1) Magnesium Stearate: Promethazine HCl blends both slowed initial dissolution, but dissolution increased with time. As expected, the 74 greater the amount of Magnesium Stearate, the lower the dissolution profile. Variation between samples decreased as the amount of Magnesium Stearate decreased. For the lower ratio blends, variation decreased as time (and subsequently dissolution) increased. It should be noted that the increase in dissolution with time occurred for each flask. The variation in samples correlated with the variation between flasks in initial dissolution. Based upon these observations, the agglomeration of powder on the surface of the dissolution medium may affect initial dissolution. Therefore, this variation may be a phenomenon associated only with powder testing and should decrease when testing a finished dosage form (tablet) which sinks. In addition, the variation in the initial trial was likely not related to blend uniformity. Magnesium Stearate slowed the initial dissolution of Promethazine HCl. Taste screening supported this observation. How this will translate to final blends and compressed tablets is unknown. In order to evaluate the effects of final blending and compression, blending with additional excipients and compression was undertaken with Magnesium Stearate: Promethazine HCl blends. Although some screening is prudent, the extensive amount of screening was reduced. Pharmaburst, a commercially available ODT platform, was chosen as a system which would allow the quick evaluation of the effects of final blending and compression on dissolution of Magnesium Stearate: Promethazine HCl blends. Physical test data for compressed tablets are shown in Table 3.4g. Dissolution test data are shown in Table 3.4h. Graphical representations of dissolution data are shown in Figures 3.4h, 3.4i, and 3.4j. Formula A (0.67:1 Magnesium Stearate: Promethazine HCl- Pharmaburst) tablets 75 Table 3.4g. Tablet Physical Test Data 0.67:1 Magnesium Stearate: Promethazine HCl-Pharmaburst Tablets (Formula A) Parameter Hardness Weight (mg) 4.0 126 4.0 125 5.0 126 5.5 125 4.5 125 Average 4.6 125.4 SD 0.7 0.6 %RSD 14 0.4 1:1 Magnesium Stearate: Promethazine HCl- Pharmaburst Tablets (Formula C) Parameter Hardness Weight (mg) 4.0 121 4.0 119 4.0 117 4.0 119 4.0 121 Average 4.0 119.4 SD 0 1.5 %RSD 0 1.3 Table 3.4h. Tablet Dissolution Data Promethazine 25 mg Tablet Dissolution Data Magnesium Stearate: Promethazine 0.67:1 + Pharmaburst Sample Description Percent Dissolved Time (min) 0 2 5 10 15 30 F1 0.0 85.9 88.4 95.0 96.9 95.3 F2 0.0 31.4 64.3 79.5 83.3 88.2 F3 0.0 77.3 86.5 89.2 90.4 93.3 Average 0.0 64.9 79.7 87.9 90.2 92.3 SD 0.0 29.3 13.4 7.9 6.8 3.7 %RSD 0.0 45.2 16.8 9.0 7.6 4.0 0.67:1 Blend Data(AVG) 0.0 72.5 80.6 84.3 87.0 94.4 SD 0.0 12.6 13.7 14.9 12.1 10.8 %RSD 0.0 17.4 17.0 17.7 13.9 11.4 Magnesium Stearate: Promethazine 1:1 + Pharmaburst Sample Description Percent Dissolved Time (min) 0 2 5 10 15 30 F1 0.0 65.1 75.5 79.2 81.4 85.8 F2 0.0 85.9 81.4 80.7 81.6 86.3 F3 0.0 70.4 80.4 83.2 85.9 89.4 Average 0.0 73.8 79.1 81.0 83.0 87.2 SD 0. 10.8 3.2 2.0 2.5 2.0 %RSD 0.0 14.7 4.0 2.5 3.0 2.3 1:1 Blend Data (AVG) 0.0 29.0 37.1 41.3 44.6 54.2 SD 0.0 9.5 17.0 17.6 17.8 18.6 %RSD 0.0 38.0 45.6 42.7 40.1 34.4 76 Figure 3.4h. 0.67:1 Individual Tablet Dissolution Plot 0.0 20.0 40.0 60.0 80.0 100.0 120.0 0 5 10 15 20 25 30 35 TIME (min) PERC EN T D I SSO L VED F1 F2 F3 Average 0.67:1 Blend Data(AVG) Figure 3.4i. 1:1 Individual Tablet Dissolution Plot 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 0 5 10 15 20 25 30 35 TIME (min) PERC EN T D I SSO L VED F1 F2 F3 Average 1:1 Blend Data (AVG) 77 Figure 3.4j. 0.67:1 and 1:1 Average Tablet Dissolution Plot 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 0 5 10 15 20 25 30 35 TIME (min) PE R C EN T D I SSO LVED Average 1:1 Tablets Average 0.67:1 Tablets 78 79 compressed with no apparent problems. Formula B, which included Calcium Silicate, was very light and fluffy (high bulk volume) and did not flow well. Weight control was difficult and this formula was abandoned. Formula C (1:1 Magnesium Stearate: Promethazine HCl- Pharmaburst) tablets containing a higher ratio of Magnesium Stearate also did not flow well. Enough tablets were compressed for the testing performed with only a small quantity to spare. The weight of these tablets was low (range 117-121 mg, average = 119.4 mg, theoretical = 125 mg). Tablets at the upper end of this range (121mg, 96.8% of theoretical) were selected for dissolution. It should be noted that the addition of an agent such as Colloidal Silicon Dioxide to improve flow at later stages is expected to solve this problem. However, for these trials, the goal was to observe the effect of final blending and compression on dissolution. Therefore, changes from the pre-blends previously tested were kept at a minimum. The 0.67:1 ratio tablets did exhibit some delay (average 65% at two minutes) in dissolution. Flask two was notably slower than flasks one and three. All tablets sunk and the tablets in vessels one and three quickly and completely disintegrated in less than one minute. The tablet in flask two appeared to stick to the bottom of the vessel and disintegrated much slower. After the testing was complete, when cleaning flask two, a residue in the shape of the tablet was evident on the bottom of the vessel. There appeared to be a permanent ring etched in the glass. This flask was removed from service at this point. Also, due to a faulty syringe, the two minute flask one sample was actually drawn at three minutes after replacing the defective syringe. This value was higher than the flask three value. Overall, the average tablet dissolution profile appeared to match the 80 corresponding average pre-blend dissolution profile. This to indicate final blending and compression did not affect dissolution. The 1:1 ratio tablets briefly floated then rapidly disintegrated while sinking. The tablets were completely disintegrated in less than one minute and before the sinking process was completed. A re-examination of these tablets indicated they were soft as compared to the 0.67:1 A tablets. Although the difference in average hardness was not great (4.0 vs. 4.6), further investigation indicates 4.0 may be the minimum reading obtained with the hardness tester utilized (Note: Testing of subsequent batches indicated this was not the case. Re-testing of these tablets at a later date yielded a similar average of 3.6 with variability (2.0-5.5) from tablet to tablet.). Dissolution was very fast as compared to the corresponding pre-blend and dissolution at two minutes was actually faster (74% vs. 65%) than that observed for the 0.67:1 ratio tablets as would be expected, dissolution at the latter time points and the overall profile was lower than for the 0.67:1 tablets. The variation between flasks, especially at five minutes and beyond, was very low (< 4%) as compared to the variation observed with blends and the 0.67:1 tablets, all of which varied more in powder dispersion or tablet disintegration. Based upon observations with blend and tablet dissolution testing, the initial percent dissolved is greatly related to the sample dispersion or disintegration and dispersion, respectively. Overall dissolution trends do correlate with the level of coating agent, Magnesium Stearate. Although both 0.67:1 and 1:1 ratio tablets were better tasting than uncoated drug, informal taste tests indicated the 1:1 ratio tablets were notably better tasting than the 0.67:1 ratio tablets. 81 Although not completely correlated with initial time point dissolution data, Magnesium Stearate does notably improve the taste of both Promethazine HCl blends and tablets. The 1:1 ratio does afford taste improvement while meeting USP dissolution requirements (NLT 75% in 45 minutes) for conventional Promethazine HCl tablets 24 . Higher levels of Magnesium Stearate may adversely affect compressibility and disintegration. Formulation trials proceeded utilizing a 1:1 Magnesium Stearate: Promethazine HCl ratio. 82 References 1. Brown D. Orally disintegrating tablets - taste over speed. Drug Delivery Technology. September 2003;13(6):58-61. 2. Fu Y, Yang S, Jeong SH, Kimura S, Park K. Orally fast disintegrating tablets: developments, technologies, taste-masking, and clinical studies. Critical Reviews in Therapeutic Drug Carrier Systems. 2004;21(6):433-475. 3. Bogner RH, Wilkosz MF. Fast-dissolving tablets. U.S. Pharmacist. March 2002;27(03):34-43. 4. Cremer K. Orally disintegrating dosage forms provide drug life cycle management opportunities. Pharmaceutical Technology Supplement. 2003(Formulation & Solid Dosage):22-28. 5. Parakh SR, Gothoskar AV. A review of mouth dissolving technologies. Pharmaceutical Technology. November 2003;27(11):92-100. 6. Dobetti L. Fast-melting tablets: developments and technologies. Pharmaceutical Technology Supplement. 2001(Drug Delivery):44-50. 7. Joshi AA, Duriez X. Added functionality excipients: an answer to challenging formulations. Pharmaceutical Technology Supplement. 2004(Excipients and Solid Dosage Forms):12-19. 8. Sheth BB, Bandelin FJ, Shangraw RF. Compressed tablets. In: Lieberman HA, Lachman L, eds. Pharmaceutical Dosage Forms: Tablets. Vol 1. New York: Marcel Dekker; 1980:109-185. 9. Gennaro AR, ed. Problem solver and reference manual. Newark, DE: FMC Biopolymer; 1998. 10. Drug delivery-pts-cardinal health. Available at: http://www.cardinal.com/pts/content/delivery/dd-oral-zydis.asp. Accessed August 19, 2004. 11. Quicksolv : all information on www.Janssen-Cilag.be. Available at: http://www.quicksolv.be/. Accessed August 19, 2004. 12. About biovail. Available at: http://www.biovail.com/english/about%20biovail/default.asp?s=1. Accessed August 19, 2004. 83 13. CIMA -- technologies. Available at: http://www.cimalabs.com/tech.htm. Accessed August 19, 2004. 14. WOWTAB. Available at: http://www.ypharma.com/wowtab.shtml. Accessed August 20, 2004. 15. Ethypharm. Available at: http://www.ethypharm.com/generate.htm?2. Accessed August 19, 2004. 16. Excedrin - product information. Available at: http://www.excedrin.com/8_product_info/8-4_quick_spear.html. Accessed August 17, 2004. 17. Akina, Inc. Available at: http://www.akinainc.com/. Accessed August 19, 2004. 18. Eurand : AdvaTab. Available at: http://www.eurand.com/page.php?id=89. Accessed August 19, 2004. 19. KV Pharmaceutical - quick dissolving tablets. Available at: http://www.kvpharmaceutical.com/tech/3_quick_dissolving_tablets.html. Accessed August 19, 2004. 20. RapiTab technology. Available at: http://www.rapitabtech.com/. Accessed August 16, 2004. 21. 127 Pharmaburst. Available at: http://www.spipharma.com/ProductsFolder/127PharmaBurst/127PharmaBurst.ht ml. Accessed August 18, 2004. 22. Connors KA, Amidon GL, Stella VJ. Chemical stability of pharmaceuticals: a handbook for pharmacists. Second ed. New York: Wiley-Interscience; 1986:704- 713. 23. Florey K. Analytical profiles of drug substances. Vol 5. New York: Academic Press; 1976:430-464. 24. The United States Pharmacopeia and The National Formulary (USP/NF). Vol USP 28/NF 23. Rockville,MD: United States Pharmacopeial Convention, Inc.; 2005. 25. Khankari RK, Hontz J, Chastain SJ, Katzner L, inventors; Cima Labs Inc, assignee. Rapidly dissolving robust dosage form. US patent 6,024,981, 2000. 84 26. Siewart M, Dressman J, Brown CK, Shah VP. FIP/AAPS Guidelines to dissolution/in vitro release testing of novel/special dosage forms. Dissolution Technologies. February 2003;10(1):6-15. 27. Klancke J. Dissolution testing of orally disintegrating tablets. Dissolution Technologies. May 2003;10(2):6-8. 85 4. ORALLY DISINTEGRATING TABLET FORMULATION Abstract Orally Disintegrating Tablets (ODTs) which rapidly dissolve in the saliva without the need for water have become a very popular dosage form. This is especially true in certain disease states and/or patient populations. For offensive tasting drugs, no method of simple blending followed by direct compression has resulted in achieving both taste- masking and a robust, rapidly disintegrating tablet. Previous trials indicated Magnesium Stearate V-blended in a 1:1 ratio with Promethazine HCl resulted in taste-masking of this highly soluble, offensive tasting drug. However, a large amount of hydrophobic Magnesium Stearate has a tendency to increase both tablet friability and disintegration time. This is of special concern with ODTs where it is a difficult balance to produce a tablet which both disintegrates rapidly and is robust enough for packaging, shipping, and handling. Formulation trials were undertaken to produce such a tablet via simple blending and direct compression in the presence of this large amount of Magnesium Stearate. The combination of Dextrates, NF as the diluent with multiple disintegrants with different mechanisms of action did yield a robust, pleasant tasting, rapidly disintegrating tablet. This method yielded a tablet with a friability of 0.17%, an in vitro disintegration time of 21 seconds, and an in vivo disintegration time of less than one minute. Although this method overcame the bitter taste of Promethazine, the unpleasant anesthetic effect of this drug in the oral cavity was only greatly reduced, not eradicated. 86 4.1 Introduction Orally Disintegrating Tablets (ODTs) have become a popular dosage form. An ODT may be defined as a tablet which disintegrates and/or dissolves rapidly (< one minute) in the saliva without the need for water or other liquid 1 . These readily transportable dosage forms are intended to be taken anytime or anywhere 1, 2 . Certain patient groups such as children, elderly, and psychiatric patients greatly benefit from this technology 3-5 . This dosage form is especially beneficial in certain medical conditions such as pain, migraine, nausea, panic attack, allergic conditions, cough/cold, and Alzheimer?s 3-5 . Market research has shown a significant number of consumers prefer an ODT over a conventional tablet. This research has also shown that taste is a very important factor. Longer disintegration times were acceptable if the taste was good. However, the converse was not true; fast disintegration times were not acceptable if taste was bad 1 . Although some drugs have little taste and a simple addition of flavor will result in an acceptable taste, most drugs to be incorporated into an ODT formulation require taste- masking 1 . Although some ODT manufacturing methods allow for taste-masking as part of the manufacturing process, many do not 2-7 . In those methods which do accomplish taste-masking, the steps involved are often the same or similar processing methods as those used to accomplish taste-masking in independent processes 2-7 . These processes include wet granulation, roller-compaction, spray-drying, and coating 1, 2 . Taste-coating may be achieved using polymers which dissolve based upon time and/or pH 1 . 87 Other taste-masking methods include the use of cyclodextrins, encapsulation using coacervation, electrochemical coating, and the use of supercritical fluids 1 . Direct compression is the fastest, simplest, and least expensive method of manufacturing conventional tablets or ODTs 2, 8, 9 . In its true form, direct compression consists of simple blending followed by compression of the powder blend using a conventional tablet press 8, 9 . Many methods of manufacturing ODTs which are listed as direct compression methods 2 require steps beyond this definition. For example, taste- masking of unpleasant tasting drugs must often be accomplished via a separate process. No current method accomplishes both taste-masking and rapid disintegration via simple blending followed by direct compression 2-5, 7, 10-16 . Previous studies in our labs indicated Magnesium Stearate V-blended in a 1:1 ratio with Promethazine HCl was effective in masking the bitter, offensive taste of this drug. Preliminary tableting trials with Pharmaburst, an off-the-shelf ODT platform 2, 16 , indicated this taste-masking method was not compromised by additional blending followed by direct compression. The large quantity of Magnesium Stearate resulted in poor tableting and soft tablets. The specific aim of this study was to develop a direct compression formulation with this Magnesium Stearate: Promethazine blend which would yield rugged yet rapidly disintegrating tablets. If successful, this would yield a simple method of producing ODTs which accomplishes both taste-masking and rapid disintegration via simple blending followed by direct compression. This process would be much simpler and less expensive than currently available multi-step ODT manufacturing methods. Magnesium Stearate is an extremely hydrophobic material used in concentrations below 2% as a tablet lubricant in conventional tablets 8, 9 . In fact, Magnesium Stearate is 88 the most effective and most commonly used tablet lubricant 8, 9 . Magnesium Stearate is more effective than Stearic Acid and other metallic stearates, probably due to its smaller particle size 8 . However, Magnesium Stearate tends to increase tablet friability and retard disintegration, especially as the amount of Magnesium Stearate increases and/or as the Magnesium Stearate blending time increases 8, 9 . For these reasons, some authors have recommended avoiding the use of Magnesium Stearate in rapidly disintegrating dosage forms 16 . However, one method of producing ODTs utilizes up to 2.5% Magnesium Stearate as a lubricant in combination with non-direct compression grades of diluents. For direct compression ODT processes, sugar based excipients (mannitol, sorbitol, xylitol, maltose, etc.) are routinely used for their high water solubility, sweet taste, and pleasant mouthfeel 2, 5-7 . In addition to taste and mouthfeel, disintegration time is a primary concern. Some ODT technologies use effervescent couples alone or in combination with other disintegrants to achieve rapid disintegration 2, 5-7 . The use of disintegrants, and especially the newer superdisintegrants, has made the advent of compression based ODTs possible 5 . Various materials have been utilized as disintegrants. Starches and modified starches have a long history of use as disintegrants 9, 17 . Within this group, the superdisintegrant Sodium Starch Glycolate is of most interest today 9 . This material is commonly used in levels of 2-8% by weight and its primary mechanism of action as a disintegrant is via swelling 9, 17 . Crospovidone (cross-linked polyvinylpyrrolidone) is another superdisintegrant of choice 2, 9, 17 . Although historically used in a range of 2-5% 9, 17 , one manufacturer recommends up to 15% by weight in ODT formulations 18 . In fact, a specific grade 89 featuring a smaller and more narrow particle size distribution has been developed specifically to yield better mouth feel in ODT formulations 18 . Crospovidone is said to promote both wicking and swelling 18 . Crospovidone?s disintegrant action is dependent upon compression force 17 . A certain tablet hardness is required for the swelling and expansion to be effective. Modified celluloses are another common group of disintegrants 2 . Most recommended among this group is Croscarmellose Sodium, an internally cross-linked Sodium Carboxymethycellulose 9, 17 . Typical use levels range from 2-4% although lower and higher amounts have been utilized 9, 17 . This disintegrant works via both wicking and swelling 9, 17 . Calcium Silicate in amounts up to 30% by weight has also been used to promote disintegration 17, 19 . RxCipients? FM 1000? Calcium Silicate from Huber Engineered Materials (Havre de Grace, Maryland) is extremely hydrophobic 19 . When combined with superdisintegrants, the superdisintegrants are said to expand against this hydrophobic material. This expansion against another material is said to promote rapid tablet break down into primary particles. 19 Other disintegrants employed in ODTs are Alginic Acid, Sodium Alginate, Microcrystalline Cellulose, Methacrylic Acid-Divinylbenzene Copolymer Salts, and Poly(Acrylic Acid) Superporous Hydrogel (SPH) 2 . Various methods will be utilized to evaluate the ODT formulations. Traditional tablet tests such as hardness, thickness, friability, and disintegration 8, 9 will be performed. Key among these is disintegration and friability testing. A critical balance in formulating ODTs is achieving a rapid disintegration time with a tablet rugged enough to withstand packaging, shipping, and handling. A harder, stronger tablet typically has a longer 90 disintegration time 2, 8, 9 . USP methods for conventional tablets will be utilized 20 . It is assumed that a tablet rugged enough to meet friability requirements for conventional tablets can be packaged, shipped, and handled using conventional materials, equipment, and methods. Although in-vitro disintegration times may differ from in vivo disintegration times 2 , when comparing similar formulations, a reduction in in vitro disintegration time would likely correspond to a reduction in in vivo disintegration time. Informal in vivo disintegration and taste testing will also be performed. 4.2 Materials -Promethazine HCl, USP; Honeywell (Ireland); Lot BPMH119117; -Magnesium Stearate, NF, Impalpable Powder; Fisher Scientific, Lot 974493; -Dextrates, NF; EMDEX, JRS Pharma, LP, Lot 04H502X; -Colloidal Silicon Dioxide, NF; AEROSIL VV 200 Pharma, Degussa, Lot 4020513; -Colloidal Silicon Dioxide, NF; VP AEROPERL 300 Pharma, Degussa, Lot 3154042191; -Croscarmellose Sodium, NF; Ac-Di-Sol, FMC Biopolymer, Type SD-711, Lot T442N; -Crospovidone, NF; Polyplasdone XL-10, ISP Technologies, Inc., Lot 03400117085; -Crospovidone, NF; Polyplasdone XL, ISP Technologies, Inc., Lot 03300106081; -Sodium Chloride, USP; Morton Salt, Hutchinson Plant; -Silicified Microcrystalline Cellulose (Microcrystalline Cellulose, NF + Colloidal Silicon Dioxide, NF); ProSolv HD-90, JRS Pharma, LP, Lot D9B4033X; -Compressible Sucrose; Sugartab, JRS Pharma, LP, Lot 47X; -Copovidone, USP; Plasdone S-630, ISP Technologies, Inc., Lot 05400118999; -Maltodextrin, NF; Maltrin QD M500, Grain Processing Corporation, Lot M031329001; -Sodium Starch Glycolate, NF; Explotab, JRS Pharma LP, Lot 4111034021X; 91 -Microcrystalline Cellulose, NF (PH 102 and PH 105); FMC Biopolymer, Lot 7303C (PH 102) and Lot 5416C (PH 105); -Polyethylene Glycol 8000, NF, Granular, Carbowax Sentry Grade; Dow, Lot SG075557D1(167020); -Mannitol, USP, Spray-dried; Pearlitol 200SD, Roquette, Lot 755074; -STARLAC (spray-dried mixture of 85% Lactose Monohydrate, NF and Corn Starch, NF); Roquette, Lot Y9165; -Microcrystalline Cellulose/Guar Gum, Co-processed; Avicel CE-15, FMC Biopolymer, Lot RH322; -Calcium Silicate; RxCipients FM 1000, Huber, Lot 294/102; -Saccharin Sodium, USP, Powder; Syncal-S, PMC Specialties Group, Inc Lot 3891 (manufacturer); Mutchler (supplier); -Natural Wild Cherry Flavor; WONF FAFW075, WILD Flavors, Inc, Lot F050103382; -Alginic Acid, NF; Satialgine H8, JRS Pharma LP, Lot 2700393X; -Soy Polysaccharides; Emcosoy STS IP, JRS Pharma LP, Lot P660002580X; -Calcium Carbonate DC; Type CS 90L, SPI Pharma, Lot 0408001; -Citric Acid, USP, Monohydrate, Granular; Mallinckrodt, Lot A20613; -Saccharin Sodium, USP, Granular; City Chemical LLC, Lot 01L185; -Artificial French Vanilla Flavor; FAFW079, WILD Flavors, Inc, Lot S05020416H; -Sodium Lauryl Sulfate, NF/FCC; Fisher, Lot 735986-60; -Citric Acid, USP/FCC, Anhydrous; Humco, Lot 519072E; -Masking Flavor, Natural; Flavors of North America, Inc., #936-780/PM, Lot SR-05- 00038744; -Sucralose, NF, Micronized; Tate & Lyle Sucralose, Inc, Lot H3004B36MA; -Bentonite, Powder, Purified Grade; Fisher B-235, Lot 730257B; -Key Lime Flavor, Natural & Artificial (N&A), FAGJ869; WILD, Lot F080901Z; 92 -Lemon Flavor, N&A, 862.001/EN; FONA, SR# SR-05-0041750; -Citrus Flavor, Natural, 828.112/EN; FONA, SR# SR-05-0041750; -Cherry Pineapple Flavor, N&A, FAGJ872; WILD, Lot S05050302B; -Orange Cream Flavor, N&A, FAGJ866; WILD, Lot F0508322. 4.3 Methods 4.3.1 General Methods Blending Blending was performed using a Patterson-Kelley Twin Shell (V) Dry Blender, Serial Number LB853S, tabletop unit with interchangeable shells. An approximately two quart (actual volume equals 1820 ml) acrylic shell with a speed of 22 rpm was used. Specific blend times and procedures are described in the appropriate specific method. Tableting Tableting was performed using a Stokes Single-Station Tablet Press, Model 519.2, Serial Number 662673, Lot 562134, speed equals 50 tablets/minute. Tooling for 125 mg target weight tablets was 9/32 (0.2812) inch (7.1 mm) diameter round, plain, flat- faced beveled edge (FFBE). Tooling for 250mg, 300 mg and 350 mg target weight tablets was 7/16 (0.4375) inch (11.1 mm) diameter, round, plain, standard concave. The one exception was lot GGG which employed 11/32 (0.3438) inch (8.7 mm) diameter, round, plain, standard concave tooling. Hardness, Thickness, and Weight Testing All tablets for testing were randomly selected from each finished lot or sub-lot. Tablet Hardness was determined for ten tablets using a J. H. DeLamar & Son, Inc. Model PT 102, Serial Number 39, Hardness Tester. Although not listed on this instrument, one 93 literature souce 21 lists kg/cm 2 as the units for this tester. Thickness was determined by manually measuring the thickest point of ten individual tablets using a Fisher Scientific battery-operated, digital dial caliper. Ten tablets were weighed individually using an analytical balance. Average and Standard Deviation values were determined and reported for each parameter. Friability Friability was determined as per USP <1216> Tablet Friability method 20 using a Roche-type friabilator rotated at 25 rpm for four minutes for a total of 100 revolutions. Drop-height was 156.0 ? 2.0 mm (6.1 inches). Ten randomly selected tablets were de- dusted, weighed, and placed in the friabilator. After 100 rotations, the tablets were removed, de-dusted, and re-weighed. Percent Friability was determined as: ((Initial Weight ? Final Weight)/ (Initial Weight)) * 100. A maximum weight loss of not more than 1.0 % was considered acceptable. Broken tablets were noted and considered a test failure. Initially, friability was performed on select batches only since early trials produced tablets which were obviously not rugged enough to be friability tested. Beyond this point, friability testing was performed on each lot or sub-lot. Disintegration Disintegration testing was performed as per USP <701> Disintegration 20 for uncoated tablets. Purified water at 37 ? 2 ?C was used as the test media. Six randomly selected tablets were placed into each of the six tubes of the apparatus. The apparatus was operated and the time for the last tablet to disintegrate was recorded as the disintegration time. Notable observations were also recorded. 94 Flavor Testing Individual solutions of flavors were prepared. Concentrations were such that 0.5 ml solution included the amount of the ingredient projected in a 350 milligram tablet. These projections were based upon 25 milligrams Promethazine, 0.4% Flavor, 1.5% Citric Acid, 0.5% Saccharin Sodium, and 0.25% Sucralose. Initially, 1.0 ml of each flavor solution was combined with 1.0 ml drug solution and purified water was added to bring the final volume to 4.0 ml. The mixtures were randomly sorted and 250 microliters of each were independently and blindly tasted by two researchers. A lemon juice in water mixture was used to rinse between each tasting. A single flavor was selected for further testing. Solutions of Saccharin Sodium, Citric Acid, Promethazine + Citric Acid, Promethazine + Saccharin Sodium, and Promethazine + Saccharin Sodium + Citric Acid + Key Lime Flavor were prepared and tasted. The combination of Drug + Flavor + Citric Acid was tasted with the addition of Saccharin Sodium, Sucralose, ? Strength Saccharin Sodium, Saccharin Sodium + Sucralose, and ? Strength Saccharin Sodium + Sucralose. 4.3.2 Initial Active Ingredient Tablet Trials Initial formulations included a Pharmaburst control and four in-house formulations which differed in choice or level of disintegrant. These trials employed materials commonly used in direct compression ODT products to assess the challenges to be encountered with this method. In addition to drug and Magnesium Stearate, in-house formulas contained the following: -Flavors/Sweeteners- Saccharin Sodium, Masking Flavor, Wild Cherry Flavor; -Disintegrants- Sodium Starch Glycolate (2 or 4%), or Crospovidone XL-10 (5 or 10%); 95 -Taste/Mouthfeel Excipients- Maltodextrin and Microcrystalline Cellulose/Guar Gum; -Glidant- Colloidal Silicon Dioxide 200 VV Pharma; -Diluent- Mannitol, Spray-Dried. Specific formulations are shown in Table 4.3a. Individual batch sizes were 1000 tablets (125 grams). Pre-blends for all batches were made together to decrease variables and to save labor. Batch quantities are shown in Table 4.3b. The blending procedure and description of pre-blends follow. 1. Weigh all raw materials and pass individually (except Maltodextrin) through a 20 mesh sieve. ? Flavor/Flow Pre-Blend 2. Add ITEMS, (8) MCC/Guar Gum (skip item 8 for Pharmaburst Control), (2B) Saccharin Sodium, (4B) Nat Wild Cherry Flavor, and ITEM (9) Colloidal Silicon Dioxide to V-Blender; 3. Blend for TEN minutes; 4. Add ITEM (7) Maltodextrin (For Pharmaburst Control, Skip Steps 4 & 5); 5. Blend FIVE minutes; 6. Discharge Flavor/Flow Pre-Blend into a suitable container and retain. ? Drug/Sweetener/Flavor/Magnesium Stearate Blend 7. Add ITEM (1) Promethazine to V-Blender; 8. Add ITEM (2A) Saccharin Sodium; 9. Blend FIVE minutes; 10. Add ITEM (3) Masking Flavor and ITEM (4A) Nat Wild Cherry Flavor; 11. Blend FIFTHTEEN minutes; 12. Add ITEM (5) Magnesium Stearate and Blend SIXTY minutes. Table 4.3a. Initial Tablet Formulations Promethazine 25mg ODT Formulations Item Ingredient Weight Quantity (mg/tablet) No. Percent D.Pharmaburst E.SSG* F. SSG* G.Crospovidone H. Crospovidone Control Low High Low High 1 Promethazine HCl, USP 20.0 25.000 25.000 25.000 25.000 25.000 2A Sodium Saccharin, USP 2.4 3.000 3.000 3.000 3.000 3.000 3 Masking Flavor, FONA 0.2 0.250 0.250 0.250 0.250 0.250 4A Nat Wild Cherry Flavor 0.3 0.375 0.375 0.375 0.375 0.375 5 Magnesium Stearate,NF 20.0 25.000 25.000 25.000 25.000 25.000 6E Sod Starch Glycolate,NF 2.0 2.500 6F Sod Starch Glycolate,NF 4.0 5.000 6G Crospovidone, NF 5.0 6.250 6H Crospovidone, NF 10.0 12.500 7 Maltodextrin, NF 10.0 12.500 12.500 12.500 12.500 8 MCC/Guar Gum 5.0 6.250 6.250 6.250 6.250 2B Saccharin Sodium, USP 0.8 1.000 1.000 1.000 1.000 1.000 4B Nat Wild Cherry Flavor 0.3 0.375 0.375 0.375 0.375 0.375 9 Colloidal Silicon Dioxide,NF 1.0 1.250 1.250 1.250 1.250 1.250 Subtotal 56.250 77.500 80.000 81.250 87.500 10A Mannitol 30.0-38.0 47.500 45.000 43.750 37.500 10B Pharmaburst 55.0 68.750 Total 125.000 125.000 125.000 125.000 125.000 * SSG = Sodium Starch Glycolate, NF 96 Table 4.3b. Batch Quantities Batch Quantities Item Ingredient Weight mg/tablet or g/6000 tablets No. Percent g/1000 tabs Drug/Sweetener/Flavor/Magnesium Stearate Blend 1 Promethazine HCl, USP 20.0 25.000 150.00 2A Sodium Saccharin, USP 2.4 3.000 18.00 3 Masking Flavor, FONA 0.2 0.250 1.50 4A Nat Wild Cherry Flavor 0.3 0.375 2.25 5 Magnesium Stearate, NF 20.0 25.000 150.00 Total 42.9 53.625 321.75 Disintegrant (varies by formula) 6E Sod Starch Glycolate, NF 2.0 2.500 6F Sod Starch Glycolate, NF 4.0 5.000 6G Crospovidone, NF 5.0 6.250 6H Crospovidone, NF 10.0 12.500 Flavor/Flow Pre-Blend (for all batches except Pharmaburst Control) 7 Maltodextrin, NF 10.0 12.500 75.00 8 MCC/Guar Gum 5.0 6.250 37.50 2B Saccharin Sodium, USP 0.8 1.000 6.00 4B Nat Wild Cherry Flavor 0.3 0.375 2.25 9 Colloidal Silicon Dioxide, NF 1.0 1.250 7.50 Pre-Blend Total 17.1 21.375 128.25 10B Pharmaburst 55.0 68.750 10A Mannitol E. SSG Low 38.0 47.500 Mannitol F. SSG High 36.0 45.000 Mannitol G. Crospovidone. Low 35.0 43.750 Mannitol H. Crospovidone. High 30.0 37.500 Individual Batch Size = 1000 tablets (125 grams) Pre-blends made together for all batches 97 98 ? Final Blending 14. Add ITEM 6 Sodium Starch Glycolate or Crospovidone to blend in V-Blender (Drug/Sweetener/Flavor/Magnesium Stearate Blend from Step 13); 15. Blend FIVE minutes; 16. Add Flavor/Flow Pre-Blend (from Step 6); 17. Blend THREE minutes; 18. Add ITEM 10 Pharmaburst or Mannitol; 19. Blend FIVE minutes; 20. Discharge, weigh, calculate yield, and retain in a suitable container. Tablets were compressed using the Stokes Single-Station Tablet Press and the previously described tooling and speed setting. After some initial adjustment trials, a single setting for weight and compression force was used to compress each blend. Tablets were immediately subjected to weight, thickness, and hardness testing. Ten tablets were randomly selected for testing and each tablet was individually tested for weight, thickness, and hardness. Tablets from each blend were randomly selected for disintegration testing per USP methodology (1 trial, 6 tablets, distilled water, 37 ?C). 4.3.3 Placebo Tablet Trials The placebo blends shown in Table 4.3c below were compressed to evaluate the effects of no or different glidants. Magnesium Stearate (20%) and Dextrates (78-80%) alone or with two percent hydrophobic (VP AEROPERL 300 Pharma) or hydrophilic (AEROSIL VV 200 Pharma) Colloidal Silicon Dioxide were prepared and compressed. 99 Table 4.3c. Glidant Trial Formulations Ingredient I. No Glidant J. AEROPERL K. AEROSIL Magnesium Stearate, NF 12.5 g (20%) 12.5 g (20%) 12.5 g (20%) Dextrates, NF (EMDEX) 50.0 g (80%) 48.75 g (78%) 48.75 g (78%) Colloidal Silicon Dioxide, NF; AEROPERL or AEROSIL N/A 1.25 g (2%) 1.25 g (2%) Total (62.5 g = 500 tabs) 62.5 g 62.5 g 62.5 g Blending instructions were as follows: 1. Weigh raw materials; 2. Screen 20 mesh; 3. Blend all materials except Magnesium Stearate in V-Blender (22 rpm) for 4 minutes; 4. Add Magnesium Stearate and blend 6 additional minutes; 5. Discharge, compress (125 mg), and test (weight, thickness, hardness, disintegration). Compression was performed using the Stokes Single-Station Tablet Press and the previously described speed setting and tooling. One set of weight and hardness settings established for the first blend (No Glidant) was utilized for all three blends. Additional trials were undertaken. Individual formulations and target or theoretical tablet weights are shown in Table 4.3d. Formula I from the previous glidant trials is included for comparative purposes. Blend batch sizes were 62.5 grams (500 tablets) and 60.0 grams (200 tablets) for the 125 milligram and 300 milligram tablets respectively. Table 4.3d. Additional Placebo Formulations Formula Ingredient (% w/w) & Target Magnesium Dextrates Coll. Silicon Croscar- Cros- NaCl Co- Other Weight Stearate Dioxide mellose Na povidone povidone I 125 mg 20 80 L " 20 70 2 8 M " 20 60 2 8 XL-10 10 N " 20 58 2 20 O " 20 60 2 8 10 P " 20 55 2 8 XL 5 10 Q " 20 50 2 8 SMCC 20 R " 18 77 1 4 S " 18 72 1 4 5 T 300 mg 8.3 82.7 1 8 U " 8.3 62.7 1 8 Sucrose 20 V " 8.3 77.7 1 8 5 W " 8.3 67.7 1 8 15 X " 8.3 62.7 1 8 10 10 Y " 8.3 62.7 1 8 Maltrin 10 Z1 Hi " 8.3 81.3 Drug 8.3 Z2 Me d " SSG 2 Z3 Lo " Notes: Z: Hi, Med, and Lo refers to high, medium, and low compression force, respectively. I-Q: Final Blending Time = 6 minutes; R-Y: Final Blending Time = 3 minutes; Z: Final Blending Time = 2 minutes. SSG = Sodium Starch Glycolate SMCC = Silicified Microcrystalline Cellulose 100 101 All materials were weighed and passed through a 20 mesh sieve except for Dextrates and Maltodextrin which were passed through a 14 mesh sieve. All materials other than Magnesium Stearate were placed in the V-blender and blended for four minutes. Magnesium Stearate was then added and blending was performed as per the final blending times noted in Table 4.3d. Formulation Z is different in that it contains active ingredient. In this case, Magnesium Stearate: Promethazine 1:1 blend from previous taste making trials was utilized in place of Magnesium Stearate alone. Final blends were discharged, weighed, and compressed into tablets. Tablets were compressed at a single compression force with the exception of Formulation Z which was compressed and tested at low, medium, and high compression force adjustments. Weight, thickness, hardness, and disintegration testing was performed on each lot or sub-lot. Selected batches were subjected to friability testing. 4.3.4 Active Ingredient Tablet Trials Various trials employing active ingredient were undertaken. Formulations are shown in Table 4.3e. Each formulation with a theoretical tablet weight of 300 milligrams consisted of 8.3% w/w each Magnesium Stearate and Promethazine HCl. The exceptions were formulations with a 250 or 350 milligram tablet weight where these percentages were 10.0% and 7.1% respectively. The primary diluent used was Dextrates with its weight percentage varying from 55.8% to 88.3%. Remaining ingredients and their percentages are included in tables and Formula Z2 from previous trials and corresponding results are included for comparison purposes. Table 4.3e. Active Formulations Formula % SSG % Croscar- % Calcium % Other mellose Na Silicate Z2 2 AA 4 BB 8 CC 2 2 CC Low 2 2 DD 2 3 DD Low 2 3 EE 3 2 EE Low 3 2 FF 3 3 FF Low 3 3 GG 3 3 3 Copovi- GG Low 3 3 3 done HH 4 4 HH Low 4 4 II 3 3 1.5 II Low 3 3 1.5 JJ 3 3 2.0 JJ Low 3 3 2.0 KK 3 3 2 MCC PH102 KK Low 3 3 2 MCC PH102 LL 3 3 1.5 2 MCC PH102 LL Low 3 3 1.5 2 MCC PH102 MM 3 3 1.5 2 PEG MM Low 3 3 1.5 2 PEG NN 3 3 1.5 30:00 Dextrates (80%) SD 5.7 0.088 0.6 %RSD 4.7 3.42 21.2 Range 116-132 2.48-2.76 2.0-4.0 J.Magnesium Stearate (20%) Average 116.1 2.59 2.3 >30:00 Dextrates (78%) SD 2.9 0.022 0.6 VP AEROPERL 300 %RSD 2.5 0.85 27.5 Pharma CSD (2%) Range 112-120 2.56-2.62 2.0-4.0 K.Magnesium Stearate (20%) Average 111.4 2.53 2.2 >30:00 Dextrates (78%) SD 2.0 0.029 0.6 AEROSIL VV 200 %RSD 1.8 1.14 28.7 Pharma CSD (2%) Range 109-114 2.46-2.56 2.0-4.0 VP AEROPERL 300 Pharma CSD = Hydrophobic Colloidal Silicon Dioxide AEROSIL VV 200 Pharma CSD = Hydrophilic Colloidal Silicon Dioxide 110 111 The tablet weight setting used for the previous mannitol formulations resulted in a very high tablet weight (188 mg) for the Magnesium Stearate: Dextrates (formulation I, No Glidant) blend. The machine was readjusted using this blend. The effects of glidants were evident even in the blending stage. The blend without glidant had a tendency to adhere to the acrylic blender shell wall. The addition of AEROPERL (blend J) resulted in a better flowing blend which did not adhere to the blender walls at all. The visual difference was dramatic. AEROSIL (blend k) resulted in some minimal blend adherence to the blender wall. The percent yield values calculated from the amount of blend discharged for the various formulas supported these observations (95.5 %, 99.2%, and 98.7% for No Glidant (I),AEROPERL (J), and AEROSIL (K), respectively). Compression of the blend with No Glidant proceeded well with no lamination of tablets. A small percentage of the AEROPERL tablets capped upon ejection whereas a small percentage of the AEROSIL tablets capped while handling after compression. In all cases, lamination was much less prominent than in the earlier trials with mannitol and other excipients. Weight control was much better with glidants. For the No Glidant, AEROPERL, and AEROSIL tablets, respectively, percent relative standard deviation values decreased from 4.7 to 2.5 to 1.8 and the range values decreased from 16 to 8 to 5 milligrams. These results indicate a glidant is required and AEROSIL is the better form of Colloidal Silicon Dioxide to use in this formulation. No notable comparisons are drawn from the hardness or thickness data. Greater thickness variation was observed with AEROSIL, but this is due to one tablet with a value of 1.46 mm. The other nine tablets tested yielded an average of 2.53 mm with a 112 standard deviation of 0.019 mm (%RSD = 0.73%). In all cases, disintegration was greater than thirty minutes. This is perhaps not surprising given the high amount of Magnesium Stearate and the lack of a disintegrant. In all cases the tablets slowly eroded and did not break into pieces. Examination of the remaining cores revealed the No Glidant and AEROSIL tablets left behind only a small, collapsible core whereas the remaining AEROPERL core was larger. The hydrophobic nature of AEROPERL likely explains this difference. This further indicated that proceeding with AEROSIL was the appropriate choice. At this point it was concluded that a glidant was required for this system and AEROSIL at a level of two percent was acceptable. Compression was better than previous trials but still less than optimal due to lamination. As expected, the addition of disintegrant(s) was required. Compression trials were next undertaken with Croscarmellose Sodium, NF (Ac-Di-Sol, FMC Biopolymer). This superdisintegrant also has excellent compression properties 9 . If compression is acceptable and disintegration is still slow, Crospovidone could be added. Crospovidone was shown in earlier trials to be an effective disintegrant. If compression is still unacceptable, other diluent combinations must be evaluated. Compositions and test results for additional placebo trials are shown in Table 4.4c. The last batch, Z, contains active ingredient as well. Physical examination of the tablets from the glidant trials revealed the tablets containing only Magnesium Stearate and Dextrates (Formulation I) to be very robust in nature. The formulations containing a glidant capped during compression. However, the weight variation (%RSD = 4.7) for the formulation without a glidant was notably higher than for the formulation containing the Table 4.4c. Additional Placebo Trial Formulations and Test Results Formula Ingredient (% w/w) Target Magnesium Dextrates Coll. Silicon Croscar- Cros- NaCl Co- Other Weight Stearate Dioxide mellose Na povidone povidone I 125 mg 20 80 L " 20 70 2 8 M " 20 60 2 8 XL-10 10 N " 20 58 2 20 O " 20 60 2 8 10 P " 20 55 2 8 XL 5 10 Q " 20 50 2 8 SMCC 20 R " 18 77 1 4 S " 18 72 1 4 5 T 300 mg 8.3 82.7 1 8 U " 8.3 62.7 1 8 Sucrose 20 V " 8.3 77.7 1 8 5 W " 8.3 67.7 1 8 15 X " 8.3 62.7 1 8 10 10 Y " 8.3 62.7 1 8 Maltrin 10 Z1 Hi " 8.3 81.3 Drug 8.3 Z2 Med " SSG 2 Z3 Lo " Notes: Z: Hi, Med, and Lo refers to high, medium, and low compression force, respectively. I-Q: Final Blending Time = 6 minutes; T-Y: Final Blending Time = 3 minutes; Z: Final Blending Time = 2 minutes. SMCC = Silicified Microcrystalline Cellulose SSG = Sodium Starch Glycolate Formula Average (SD)(%RSD), n=10 & Target Weight (mg) Thickness (mm) Hardness Disintegration Friability (%) Observations Weight Time (min:sec) (25 rpm, 4 min) I 125 mg 122.4 (5.7)(4.7) 2.58 (0.088)(3.42) 2.9 (0.6)(21.2) > 30:00 none broken From glidant trials, robust tablet L " 121.9 (2.1)(1.7) 2.57 (0.035)(1.35) 2.1 (0.2)(7.7) 10:00:00 Capping when handled M " 124.9 (2.0)(1.6) 2.64 (0.042)(1.58) 3.0 (0.9)(30.4) 4:38:00 Capping during compression N " Intact tablet not attained, did not compress O " 124.5 (1.6)(1.3) 2.54 (0.018)(0.71) 3.8 (0.5)(14.4) 6:00 Better tablet, capping when dropped P " 127.0 (4.3)(3.4) 2.61 (0.083)(3.18) 3.2 (0.7)(22.3) 3:10 Capping when handled Q " 123.2 (1.9)(1.6) 2.56 (0.030)(1.15) 3.8 (0.6)(16.9) 4:44 Harder tablet but still caps R " 123.1 (1.7)(1.4) 2.53 (0.040)(1.60) 4.1 (0.2)(3.9) 10:00 all broken Compressed well w/o capping but fails friability S " 126.5 (1.1)(0.9) 2.57 (0.013)(0.53) 4.1 (0.2)(3.9) 9:32 Compressed well T 300 mg 297.2 (1.5)(0.5) 3.34 (0.035)(1.06) 4.1 (1.0)(23.6) 5:19 all broken Compressed well w/o capping but fails friability U " 301.3 (1.6)(0.5) 3.27 (0.025)(0.78) 4.1 (0.5)(12.3) 6:45 Compressed well V " 297.3 (1.8)(0.6) 3.42 (0.019)(0.56) 4.5 (1.0)(22.2) 4:36 all broken Compressed well w/o capping but fails friability W " 297.4 (3.3)(1.1) 3.41 (0.032)(0.94) 4.8 (1.3)(26.1) 8:44 all broken Compressed well w/o capping but fails friability X " Weak tablets, compression abandoned Y " 291.7 (2.3)(0.8) 3.39 (0.021)(0.61) 6.0 (1.4)(22.6) 8:00 9/10 broken Compressed well w/o capping but fails friability Z1 Hi " 300.6 (1.6)(0.5) 3.29 (0.013)(0.39) 7.1 (1.4)(20.1) 9:43 1.2 Excellent compression, better friability Z2 Med " 299.7 (2.1)(0.7) 3.40 (0.008)(0.25) 8.4 (1.7)(20.4) 7:32 0.6 Excellent compression, passes friability Z3 Lo " 297.6 (2.2)(0.7) 3.38 (0.010)(0.31) 9.1 (2.4)(26.9) 7:47 0.6 Excellent compression, passes friability 113 114 AEROSIL VV 200 Pharma Colloidal Silicon Dioxide (%RSD = 1.8%). It was decided to proceed using Colloidal Silicon Dioxide (CSD). A base formulation (L) was produced containing Magnesium Stearate (20%), Dextrates (70%), CSD (2%), and Croscarmellose Sodium (8%). Croscarmellose Sodium (Ac-Di-Sol, FMC Biopolymer) is a wicking and swelling disintegrant known to have favorable compression properties 9, 17 . This addition did result in better compression. The tablets did not cap during compression. However, the tablets did cap when handling (de-dusting, etc.). These tablets yielded a disintegration time of approximately ten minutes. Formulation M was produced by replacing ten percent of the Dextrates with Crospovidone XL-10, a wicking and swelling 9, 17 disintegrant. This did reduce the disintegration time to below five minutes. However, this blend did not compress as well with capping occurring during compression. Another formulation (N) containing a higher amount (20%) of Croscarmellose Sodium did not compress. All additions to formulations were offset by a corresponding reduction in Dextrates, the primary diluent. Sodium Chloride has excellent compression properties 8 and is very water soluble. The addition of ten percent NaCl (formulation O) to the base formulation did yield a harder tablet with a faster disintegration time (six minutes). These tablets compressed well yet still capped when dropped. Five percent Crospovidone XL was added to this formulation to further reduce disintegration time. It was hoped that this larger particle size grade of Crospovidone would not adversely affect compression as previously seen with the smaller particle size XL-10 grade. Although disintegration time was shortened to three minutes, the tablets appeared to be less hard and capped when handled. Neither particle size grade had good compression properties in these formulations. 115 Silicified Microcrystalline Cellulose (SMCC) is a material reported by its manufacturer to have excellent flow and compressibility. The addition of 20% SMCC (formulation Q) to the base formulation yielded a harder tablet yet capping occurred during compression. At this point, no formulation produced a strong tablet which would rapidly disintegrate. None of the tablets produced were as rugged as Formulation I containing only Magnesium Stearate and Dextrates. At this point, a trial was conducted using less Magnesium Stearate (18% vs. 20%), a shorter blending time (3 minutes vs. 6 minutes), and one-half as much CSD and Croscarmellose Sodium (Formulation R). The same formula was tried with the addition of five percent NaCl (Formulation S) since NaCl had previously aided compression and disintegration. Both formulations compressed well without notable differences. However, when subjected to friability testing, all tablets broke. This indicated the tablet was still not robust enough to withstand packaging and shipping. The problems encountered are not completely surprising considering the large amount (20%) of Magnesium Stearate. It was decided to undertake trials with a larger (300 mg. vs. 125 mg.) theoretical tablet weight in an attempt to dilute the effects of Magnesium Stearate. This corresponds with a drop from 20% Magnesium Stearate to 8.3%. This dilution does not affect the Magnesium Stearate: Promethazine 1:1 ratio. A new base formulation (T) was produced comprising 8.3% Magnesium Stearate, 82.7% Dextrates, 1% CSD, and 8% Croscarmellose Sodium. This was compared to formulations with additions of either Compressible Sucrose 20%, Copovidone 5%, Copovidone 15%, or Copovidone 10% + Maltodextrin 10% (Formulations U, V, W, and 116 X, respectively). All formulations compressed well. The addition of Sucrose offered no apparent advantage. The addition of the binder Copovidone and the combination of binders Copovidone and Maltodextrin did produce a harder tablet. A photograph of tablets post-friability testing is shown in Figure 4.1. This photo re-emphasizes the ruggedness of Formulation I containing only Magnesium Stearate and Dextrates. All additions result in a less rugged tablet. Although glidant was required in the smaller, 125 milligram tablet, it was unknown if the large amount of Dextrates in the larger 300 milligram tablet would result in adequate flow without the addition of Colloidal Silicon Dioxide. It was decided to conduct a trial with an active formulation containing minimal additions. Formulation Z containing 8.3% Magnesium Stearate, 8.3% Promethazine HCl, 81.3% Dextrates, and 2% Sodium Starch Glycolate (SSG) was examined. Sodium Starch Glycolate is a swelling type disintegrant 9, 17 which exhibited good flow properties in initial tableting trials. Although SSG was less effective as a disintegrant in earlier trials, this may have been due to the inability to achieve a hard tablet. A certain hardness to expand against is required for optimal performance of a swelling type disintegrant 17 . The final blending time was also reduced in this formulation containing over 80% Dextrates. These large spherical particles have excellent flow and blending properties 22 . Compression was excellent for this minimal formulation with a wide range of compression forces producing acceptable tablets. No capping occurred during or after compression and no tablets broke when subjected to friability testing. The low and medium compression force levels produced tablets with a friability of 0.6%. This is well Figure 4.1 Photograph of Tablets Post-Friability Testing (25 rpm, 4 min) 117 118 within our criteria of NMT 1.0% which is acceptable for conventional tablets 20 and excellent for an ODT. The high compression force tablets were more friable with a result of 1.2%. This is typical for most formulations in that beyond a certain point, further increases in compression force produce a less well bonded, brittle tablet 8, 9 . The coinciding decrease in average hardness for this higher compression force further supports this scenario. Disintegration time was around eight minutes for these tablets. It should be noted that these tablets completely broke apart during disintegration whereas earlier tablets had small remaining cores which floated out prior to completely breaking apart. Weight variation was acceptable with %RSD values of 0.5, 0.7, and 0.7 for high, medium, and low compression force tablets, respectively. This larger tablet with a high percentage of Dextrates had adequate flow without the addition of Colloidal Silicon Dioxide. 4.4.3 Active Ingredient Tablet Trials Initially, additional active ingredient tablet trials were undertaken primarily to evaluate the addition of additional disintegrants and various disintegrant levels. Formulations and a summary of test results are shown in Table 4.4d. Highlighted formulations represent notable improvements and serve as subsequent controls. Summary weight data is not included. Balancing hardness, thickness, disintegration, and friability was the main goal. No problems with weight variation were encountered. All individual data, including weight data, are included in the Appendix. Table 4.4d. Disintegrant Trial Formulations and Results Disintegration Friability (%) Formula % SSG % Croscar- % Calcium % Other Thickness (mm) Hardness Time (25 rpm, 4 min) mellose Na Silicate (min:sec) Z2 2 3.40(0.008)(0.25) 8.4(1.7)(20.4) 7:32 0.60 AA 4 3.37(0.005)(0.14) 14.6(4.6)(31.8) 8:25 0.66 BB 8 3.40(0.029)(0.84) 5.9(2.1)(36.0) 5:31 3 broke CC 2 2 3.40(0.007)(0.20) 15.2(2.8)(18.3) 2:44 0.58 CC Low 2 2 3.49(0.019)(0.54) 12.7(2.1)(16.8) 0:54 0.87 DD 2 3 3.41(0.011)(0.32) 16.1(3.1)(19.0) 3:16 0.60 DD Low 2 3 3.50(0.005)(0.14) 13.8(2.6)(18.6) 1:15 0.59 EE 3 2 3.43(0.008)(0.24) 13.3(2.7)(20.5) 2:53 0.66 EE Low 3 2 3.47(0.007)(0.21) 13.3(2.4)(18.1) 1:59 0.70 FF 3 3 3.45(0.009)(0.27) 14.2(1.5)10.3) 2:36 0.66 FF Low 3 3 3.57(0.007)(0.20) 8.5(2.1)(24.6) 0:35 0.85 GG 3 3 3 Copovi- 3.49(0.014)(0.12) 8.2(1.6)(19.4) 1:34 0.70 GG Low 3 3 3 done 3.57(0.007)(0.20) 7.5(1.3)(17.5) 0:33 1.24 HH 4 4 3.40(0.007)(0.21) 9.4(2.4)(25.5) 3:08 0.63 HH Low 4 4 3.50(0.007)(0.21) 8.6(1.9)(22.1) 1:12 0.94 II 3 3 1.5 3.42(0.008)(0.25) 8.6(0.7)(8.0) 2:55 0.40 II Low 3 3 1.5 3.62(0.004)(0.12) 6.7(1.2)(17.7) 0:22 0.63 (1 broke) JJ 3 3 2.0 3.53(0.011)(0.32) 10.4(1.4)(13.7) 0:41 0.70 JJ Low 3 3 2.0 3.59(0.007)(0.19) 8.8(1.9)(21.3) 0:29 0.82 Average (SD) (%RSD) SSG = Sodium Starch Glycolate 119 120 Increasing the amount of Sodium Starch Glycolate (SSG), a swelling type superdisintegrant 17 , from two (lot Z2) to four (AA) percent did not improve disintegration time. A further increase to 8% (BB) resulted in a friable tablet. The addition of two percent of a second superdisintegrant, the wicking and swelling 9, 17 agent croscarmellose sodium, to 2% SSG reduced the disintegration time from over seven minutes (Z2) to less than one minute (CC Low). An increase in compression force increased disintegration time. This is not surprising since a harder tablet is generally more compacted and less porous. This may be even more pronounced in this system employing a large percentage of hydrophobic magnesium stearate. A corresponding decrease in thickness and increase in hardness was observed. This trend was evident throughout these trials and the compression force window yielding a non-friable yet quick disintegrating tablet was quite narrow. Thickness values proved to be the better indicator of disintegration time between these measures due to this parameter being much less variable than hardness. Variations in the amounts of SSG and Croscarmellose were examined. Overall, equivalent amounts yielded the best combination of friability and disintegration time with 3% of each (FF Low) yielding a disintegration time of 35 seconds in a tablet which passed friability (< 1%, none broken). This combination (FF Low) was chosen as the control for subsequent trials. It should be noted that a further increase to 4% each (HH) resulted in a slower disintegration time. This is not unusual in that a point is commonly reached where additional swelling agent results in gelling and retardation of disintegration 9, 17 . A trial (GG) was conducted with 3% Copovidone added to this new control. This binder may allow a non-friable tablet to be produced with less compression force. In 121 addition, this Vinyl Acetate/Polyvinyl Acetate copolymer has some surfactant properties 23 In our case, the resulting tablet formulation that passed friability had a longer (94 seconds) disintegration time. It appears the binding property outweighed any beneficial properties. RxCIPIENTS FM 1000 Calcium Silicate is produced in a manner that results in the particles being very hydrophobic and water repelling in nature. When mixed with superdisintegrants, this material acts as a background for other disintegrants to wick and swell against, resulting in the tablet more rapidly breaking up into prime particles 19 . The addition of 1.5% Calcium Silicate (II Low) resulted in a decrease in disintegration time to 22 seconds versus 35 seconds for the corresponding control (FF Low). In addition, visual observation of the in-vitro disintegration revealed that these tablets no longer had a core which was slower to disintegrate than the outer portion of the tablet. Informal taste testing reflected the same observation. This lack of a core is consistent with the disintegrant mechanism for Calcium Silicate. One tablet from this sub-lot did break in the final seconds of friability testing. Otherwise the tablets had a good appearance and acceptable friability of 0.63%. It was decided that the friability problem was minor and the improvement in disintegration was notable, thus this formula (II Low) was selected as the new control after the completion of a series of trials. A higher level (2.0%) of this material did not appear to result in any further improvement. Various approaches were tried to further improve disintegration. Formulations and results are shown in Table 4.4e. Microcrystalline cellulose is a multifunctional Table 4.4e. Additional Formulations and Results I Disintegration Friability (%) Formula % SSG % Croscar- % Calcium % Other Thickness (mm) Hardness Time (25 rpm, 4 min) mellose Na Silicate (min:sec) KK 3 3 2 MCC PH102 3.51(0.007)(0.19) 9.3(1.6)(17.3) 0:29 0.84 (1 broke) KK Low 3 3 2 MCC PH102 3.59(0.005)(0.14) 7.2(0.9)(13.2) 0:16 all broke LL 3 3 1.5 2 MCC PH102 3.51(0.009)(0.26) 9.0(1.9)(21.1) 1:02 0.43 LL Low 3 3 1.5 2 MCC PH102 3.58(0.005)(0.14) 6.7(2.1)(31.3) 0:30 4 broke MM 3 3 1.5 2 PEG 3.61(0.006)(0.16) 5.1(0.9)(17.8) 0:26 0.13 MM Low 3 3 1.5 2 PEG 3.65(0.013)(0.37) 5.3(0.8)(14.4) 0:23 2 broke NN 3 3 1.5 one minute) tablet. Thinner tablets typically result when higher compression forces are required to yield tablets which pass friability. More compressible materials could also yield a thinner tablet. Whatever the cause, a thinner tablet in our trials typically resulted in a longer disintegration time. This may be due to a more compact, less porous tablet. Because two variables were changed, the exact cause was unknown. Microcrystalline cellulose (MCC) is typically expected to improve disintegration and friability. Earlier trials had shown large particle size, very compressible microcrystalline cellulose did not improve this product. Trial TT was undertaken using 4% PH105 grade MCC. This grade has a small particle size and high bulk volume. It was believed that this might yield a thicker, more porous tablet. However, friability failed at both compression force levels. Additional non-traditional disintegrants were examined next. Alginic Acid resulted in a thin tablet with very poor disintegration (range of three minutes or greater). Soy Polysaccharides is an all natural, high-fiber, low caloric, and kosher disintegrant popular in the nutritional product industry. Use of this material at a 2.5% level did not improve disintegration. However, observation of the disintegration test indicated a rapid Table 4.4f. Additional Formulations and Results II Formula % SSG % Croscar- % Calcium % Other Thickness (mm) Hardness Time (25 rpm, 4 min) mellose Na Silicate (min:sec) All formulas below based on Formula NN changes/additions noted SS 1% Saccharin Na Powder,0.6% Cherry 3.51(0.007)(0.20) 7.0(1.7)(23.8) 1:30 0.33 SS Low 3.54(0.009)(0.25) 6.4(0.9)(14.6) 1:17 0.26 TT 3.55(0.005)(0.15) 7.3(1.5)(20.9) 0:32 2 broke TT Low 3.59(0.005)(0.14) 6.8(0.9)(14.0) 0:23 4 broke UU 3.37(0.007)(0.22) 7.9(1.2)(15.4) 3:59 0.27 UU Low 3.42(0.008)(0.25) 7.9(1.9)(24.6) 2:55 0.23 VV 3.44(0.013)(0.39) 7.7(1.5)(19.7) 2:07 0.23 VV Low 3.52(0.007)(0.20) 7.8(1.3)(17.3) 0:32 0.23 WW 3.61(0.011)(0.31) 6.3(0.9)(14.1) 0:19 0.33 WW Low 3.68(0.014)(0.37) 5.8(0.5)(9.4) 0:17 7 broke All formulas below based on WW, changes/additions noted XX 3.62(0.011)(0.30) 4.7(0.9)(18.2) 0:18 0.36 XX Low 3.66(0.023)(0.62) 4.5(1.1)(24.5) 0:22 5 broke YY 3.61(0.007)(0.19) 5.7(1.1)(19.1) 0:22 0.42 YY Low 3.65(0.010)(0.28) 5.0(0.8)(15.4) 0:18 8 broke 1.25% Soy Polysaccharides 4% Calcium Carbonate, DC 1.25% Soy Polysaccharides 2% Calcium Carbonate, DC 2% Calcium Carbonate, DC 4% Calcium Carbonate, DC 2.5% Alginic Acid 2.5% Alginic Acid Flavor & Change Blend Procedure 4% MCC PH 105 4% MCC PH 105 2.5% Soy Polysaccharides 2.5% Soy Polysaccharides SSG = Sodium Starch Glycolate 126 127 initial wicking and breaking-up of the outer layer of the tablet. However, as might be expected, the core of the thinner tablet was slower to disintegrate. Based upon this observation, a trial (WW) was conducted with 1.25% Soy Polysaccharides. This yielded a notable improvement in disintegration time (19 seconds versus 24 seconds for control) with good friability (0.33%). This was selected as the new control. Calcium Carbonate has been used in orally disintegrating tablets. Trials were conducted with 2% and 4% direct compression grade of Calcium Carbonate. The 2% formula (XX) yielded a good tablet (friability 0.36%) with an 18 second disintegration time. Although this was not a big improvement over 19 seconds in terms of disintegration time, these tablets had a notable (> 1.5 units) lower average hardness. It was believed a softer yet still robust tablet would be better for an ODT product. Tablets with 4% Calcium Carbonate (YY) which passed friability had a longer disintegration time (22 seconds). Therefore, the 2% Calcium Carbonate formula (XX) was chosen as the control for further study. Additional formulations and results are shown in Table 4.4g. Trial ZZ was conducted by adding 0.5% Colloidal Silicon Dioxide (CSD). Earlier trials had shown larger amounts resulted in friable tablets. A small amount was employed to determine if this hydrophilic silica which typically improves disintegration by wicking would further improve disintegration in this product. In this case, disintegration time was higher (1:13 min) for tablets which passed friability testing. The addition of this hydrophilic agent may have offset the improvement yielded by the hydrophobic Calcium Silicate. With a disintegration time of 18 seconds, attempts were made to flavor and sweeten the current control formulation, XX. The addition of 1% Sodium Saccharin Table 4.4g. Additional Formulations and Results III 128 Disintegration Friability (%) Formula % SSG % Croscar- % Calcium % Other Thickness (mm) Hardness Time (25 rpm, 4 min) mellose Na Silicate (min:sec) All formulas below also contain 2% Calcium Carbonate, changes/additions noted ZZ 3.57(0.009)(0.26) 5.2(0.7)(13.0) 1:13 0.39 ZZ Low 3.64(0.007)(0.19) 5.7(1.0)(17.6) 0:31 9 broke AAA 1% Saccharin Na,Powder,0.6% Cherry Flavor 3.43(0.008)(0.24) 6.3(0.7)(11.5) 2:29 0.39 AAA Low 3.48(0.011)(0.30) 5.5(0.9)(17.1) 1:29 0.26 BBB 3.42(0.006)(0.17) 6.0(0.4)(6.8) 2:07 0.37 BBB Low 3.48(0.007)(0.8) 5.2(0.8)15.9) 0:56 1 broke CCC 3.60(0.016)(0.46) 5.3(1.1)(21.0) 0:21 0.50 CCC Low 3.60(0.020)(0.56) 4.9(1.2)(24.9) 0:19 9 broke DDD 0.5% Saccharin Na,Granular, 0.2% Vanilla 3.50(0.006)(0.18) 7.5(1.3)(18.0) 0:37 0.37 DDD Low 3.53(0.014)(0.39) 5.5(1.5)(28.1) 0:23 2 broke EEE 3.51(0.011)(0.30) 6.2(0.6)(10.2) 0:26 0.44 EEE Low 3.53(0.007)(0.21) 4.5(0.6)(12.8) 0:19 6 broke FFF 3.52(0.016)(0.44) 6.4(0.9)(13.4) 0:35 0.73 FFF Low 3.57(0.013)(0.35) 5.9(1.3)(21.4) 0:19 1 broke GGG 5.33(0.019)(0.35) 4.1(0.3)(7.7) 0:22 1 broke GGG Low 5.34(0.018)(0.34) 4.2(0.5)(11.5) 0:21 all broke HHH 3.49(0.020)(0.58) 7.1(0.8)(1.3) 0:31 1 broke HHH Low 3.55(0.009)(0.26) 7.8(0.9)(11.9) 0:34 0.42 III 3.59(0.009)(0.24) 5.7(1.2)(21.3) 0:18 6 broke III Low 3.62(0.005)(0.13) 5.7(1.2)(21.3) 0:18 2 broke Calcium Carbonate Removed, WW as control JJJ 3.55(0.012)(0.35) 8.0(0.6)(7.2) 0:21 1 broke JJJ Low 3.55(0.008)(0.24) 7.8(1.2)(15.9) 0:21 1 broke after KKK 3.52(0.010)(029) 4.3(0.6)(14.7) 0:17 five broke KKK Low 3.59(0.018)(0.51) 6.4(1.7)(26.5) 0:20 three broke LLL 3.59(0.013)(0.37) 5.4(1.1)(20.4) 0:20 one broke LLL Low 3.60(0.007)(0.19) 5.3(0.9)(17.5) 0:17 seven broke WW + 2% Citric Acid Anhydrous, USP-FCC WW + 2% Citric Acid Anhydrous, USP-FCC WW + 0.3% each Sucralose,Vanilla,and Masking Flavors XX + 0.1% Sodium Lauryl Sulfate XX + 0.1% Sodium Lauryl Sulfate WW, Change Blend Procedure WW, Change Blend Procedure XX With Smaller Diameter (11/32") Tooling XX With Smaller Diameter (11/32") Tooling XX + 25% Mannitol SD 200 XX + 25% Mannitol SD 200 DDD + 1% Citric Acid,Monohydrate, Granular DDD + 1% Citric Acid,Monohydrate, Granular Flavor CCC - Calcium Silicate CCC - Calcium Silicate AAA + 2% Citric Acid,Monohydrate,Granular AAA + 2% Citric Acid,Monohydrate,Granular 2% Citric Acid,Monohydrate,Granular 2% Citric Acid,Monohydrate,Granular Average (SD) (%RSD) 0.5% Colloidal Silicon Dioxide (AEROSIL) 0.5% Colloidal Silicon Dioxide (AEROSIL) 1% Saccharin Na,Powder,0.6% Cherry Flavor SSG = Sodium Starch Glycolate 129 powder and 0.6% Cherry Flavor (AAA) had a surprisingly negative effect on disintegration time. The thinner tablets (higher compression force levels) required to yield a tablet that passed friability had poor disintegration (? 1.5 minutes). The earlier trial with flavor, saccharin, and a blend procedure change yielded similar results. In the same period, formula BBB was made employing the AAA plus 2% granular Citric Acid, Monohydrate. Citric acid is used in flavoring and in this case it also yielded a slight effervescence (visible in-vitro) when combined with Calcium Carbonate. These tablets also had a greatly increased (> 2 min) disintegration time. Surprisingly, the slight effervescence did not improve disintegration. This is one mechanism which has been successfully employed with some ODT products 2 . With regard to flavoring, the Cherry Flavor was too mild. Although the bitter taste was hidden by the Magnesium Stearate, some unpleasant delayed numbness did occur. The Citric Acid formulation seemed to prevent this numbness. It was unknown if this was due to the Citric Acid itself or due to Carbon Dioxide produced via effervescence. Formulation CCC was made by adding only 2% Citric Acid to the control formulation. These tablets were much better (disintegration 21 seconds, friability 0.5%) in terms of disintegration than the previous batch containing Saccharin, Cherry Flavor, and Citric Acid. This indicated the sweetener/flavor effect was more deleterious than the effect of Citric Acid. Although on paper this Citric Acid only formulation appears acceptable, the tablets were crumbly when subjected to hardness testing. Again, the effervescence was observable but did not improve disintegration. The addition of Citric Acid again improved the problem with numbness. 130 A different form (granular rather than powder) and lower amount (0.5% vs. 1.0% in AAA) of Saccharin Sodium and a more potent flavor (0.2% Vanilla vs. 0.6% Cherry in AAA) was added to the control formulation. Although this formula (DDD) was better than AAA, disintegration time (37 seconds) was still greater than control (18 seconds).The Vanilla flavor was good, but mild, and the numbness was present in the absence of Citric Acid. Formulation EEE consisted of the control plus Citric Acid to prevent numbness minus Calcium Silicate. This was undertaken to determine if the effervescence effect would perform the same function as Calcium Silicate in speeding disintegration by aiding in breaking apart the tablet into prime particles. If so, the absence of Calcium Silicate would result in a more hydrophilic tablet which could potentially disintegrate faster. This was not the case and disintegration time (26 sec) was slightly higher than control (18 sec). Formula DDD with Vanilla and Saccharin had a pleasant taste but did exhibit numbness. The DDD Low compression force sub-lot failed friability and DDD had an increased disintegration time of 37seconds. Formulation FFF was made by adding 1% Citric Acid to this formula. This resulted in a reasonably pleasant taste but disintegration time was also higher (35 seconds) than desired. Since attempts to sweeten and flavor the control resulted in increased disintegration times, trials were undertaken to see if fundamental changes could further improve the disintegration time of the control formulation. If successful, subsequent decreases upon sweetening and flavoring would potentially be acceptable. Trials GGG, HHH, and III looked at the effects of changing tablet geometry (smaller diameter, thicker 131 tablet), the addition of a large amount of spray dried Mannitol which had shown potential earlier in a smaller amount, and the addition of a wetting agent, Sodium Lauryl Sulfate. None of these changes resulted in a robust tablet with faster disintegration time. At this point, all trials indicated a fragile formulation which could not be flavored and sweetened without losing ground in terms of disintegration and/or friability. Previous trials had shown this basic formulation to have poor dilution potential. Since the addition of Calcium Carbonate only yielded a softer tablet with no notable improvement in disintegration time, this was removed in subsequent trials. This once again made WW the control. This formulation is the 3-3-1.5- Tablet Friability 11 using a Roche- type friabilator rotated at 25 rpm for four minutes for a total of 100 revolutions. Drop- height was 156.0 ? 2.0 mm (6.1 inches). Ten randomly selected tablets were de-dusted, 152 weighed, and placed in the friabilator. After 100 rotations, the tablets were removed, de- dusted, and re-weighed. Percent Friability was determined as: ((Initial Weight ? Final Weight)/ (Initial Weight)) * 100. A maximum weight loss of not more than 1.0 % was considered acceptable. Broken tablets were noted and considered a test failure. Friability testing was performed on each lot or sub-lot. Disintegration Disintegration testing was performed as per USP <701> Disintegration 11 for uncoated tablets. Purified water at 37 ? 2 ?C was used as the test media. Six randomly selected tablets were placed into each of the six tubes of the apparatus. The apparatus was operated and the time for the last tablet to disintegrate was recorded as the disintegration time. Notable observations were also recorded. Dissolution Three randomly selected final sublimed tablets from the larger batch XXX were subjected to dissolution testing. Dissolution testing was based upon the compendial method 11 for conventional Promethazine HCL tablets with modifications recommended for ODTs 12, 13 . Dissolution test parameters included using a de-aerated 0.2M pH 6.4 Phosphate Buffer, 900 ml, 37 ? 0.5? C, and Apparatus 2 (paddles) at 50 rpm. Samples were taken at 2, 5, 10, 15, and 30 minutes. Five milliliter samples were withdrawn manually with a ten ml plastic syringe. Media was replaced after each sampling. A new 5 micron filter needle was attached to the syringe. The first two ml expressed was discarded and the remaining three ml collected in a glass sample tube. Absorbance was 153 determined at 249 nm for suitably diluted samples. Percent Dissolved values were determined using a standard curve equation. Content Uniformity Ten randomly selected final sublimed tablets from the larger batch XXX were subjected to Content Uniformity testing utilizing the compendial method 11 . This method is performed by dissolving and serially diluting individual tablets or reference sample in 1% W/V Citric Acid Solution and comparing the reference and sample absorbance values at 298 nm using a spectrophotometer. The Promethazine raw material utilized in the tablets was used as a reference. 5.3 Results and Discussion Overall, no major problems were encountered during blending and compression of the Menthol containing formulations. In the initial trials, the 6% Menthol formulation tablets exhibited a visible surface depression slightly off center on the upper punch side of the tablet. Since this was not observed with the three percent tablets, it was initially believed this was related to the amount of Menthol present and rapid sublimation during the compression process. However, when the same defect was observed with the larger batch size 3% Menthol tablets, further investigation was initiated. At this point, removal and examination of the upper punch revealed a barely visible area of punch erosion or damage corresponding to the area of tablet depression. This resulted in powder adhering to this damaged area which subsequently resulted in a corresponding depressed area in the tablet. 154 Sublimation of Menthol was performed in a vented standard laboratory oven at 35 ?C. This mild temperature is above the temperature (21 ?C) at which sublimation begins and below the menthol melting point of 41-42 ?C 6 . It should be noted that a forced air oven would likely be more efficient and yield faster sublimation times. Oven sublimation was chosen over vacuum extraction because this method would be more universally available in solid dosage form pharmaceutical manufacturing facilities. Sublimation data are shown in Table 5.3a. The data are presented graphically in Figure 5.3a. The initial sublimation weight loss determination methods and sampling times were only preliminary in nature and the data were insufficient to describe the sublimation process. The larger batch size yielded more data in this respect as well as provided additional tablets for expanded finished product testing. The larger batch (lot XXX) data were used to more thoroughly evaluate the sublimation process. Batch sublimation was stopped at 48 hours when the Theoretical Percent Remaining was consistently below zero. This was in agreement with the observations from the smaller batch of 6.0% Menthol tablets. The smaller batch of 3.0% Menthol tablets yielded different results but likely utilized too few tablets for accurate weight sampling. The weight sample tablets were sublimed for an additional 48 hours. Further loss had occurred between 48 and 72 hours but detectable loss was not observed between 72 and 96 hours. A plot of Percent Menthol Remaining versus Time readily indicates the sublimation process is not zero order. The curvature observed readily compares to that typically observed with a first or pseudo-first order process. The negative Percent Remaining values (as low as -0.24) also indicate that not all loss is Menthol. Lot/ Drying Time % Loss Theoretical Description (hours) % Remaining VVV 1.0 0.53 2.47 3% 2.0 0.65 2.35 Menthol 4.0 1.05 1.95 6.0 1.15 1.85 22.0 3.03 -0.03 28.0 2.91 0.09 WWW 1.0 0.68 5.32 6% 17.0 3.76 2.24 Menthol 22.0 4.31 1.69 41.0 5.64 0.36 46.0 5.89 0.11 48.0 5.96 0.04 XXX 1.0 0.46 2.54 3% 2.0 0.66 2.34 Menthol 3.0 0.81 2.19 4.0 0.96 2.04 5.0 1.09 1.91 6.0 1.20 1.80 7.0 1.32 1.68 8.0 1.41 1.59 9.0 1.49 1.51 10.0 1.58 1.42 11.0 1.67 1.33 12.0 1.75 1.25 23.0 2.33 0.67 24.0 2.38 0.62 26.0 2.44 0.56 28.0 2.52 0.48 30.0 2.59 0.41 32.0 2.67 0.33 47.0 3.05 -0.05 48.0 3.06 -0.06 72.0 3.24 -0.24 96.0 3.24 -0.24 Table 5.3a. Menthol Tablet Sublimation Data (35?C) 155 Figure 5.3a. Menthol Sublimation Plots (35? C) -0.50 0.00 0.50 1.00 1.50 2.00 2.50 3.00 0 4 8 121620242832364044485256606468727680848 9296 Time (hours) Theore t ical % M e nt hol R e m a ining Lot XXX, 3% Menthol y = -0.0598x + 0.9552 R 2 = 0.9991 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 0.0 4.0 8.0 12.0 16.0 20.0 24.0 28.0 32.0 36.0 Time (hours) LN Theoret ical % Ment hol R e m a ining Lot XXX, 3% Menthol,1-28 hr Lot XXX, 3% Menthol,1-32 hrs Regression Line (1-28 hr) 156 157 When one considers that some sublimation likely occurs during blending and compression (i.e., the intercept is not 3.0) the true Percent Remaining values are likely even more negative than observed. This loss other than Menthol is likely adsorbed water which is commonly present in pharmaceutical excipients. The sublimation temperature of 35?C is too low to remove water of hydration or crystallization. The weight sample tablets quickly gained weight to a level of 0.19 and 0.31 Percent Remaining after exposure to the atmosphere at ambient conditions for one and two hours, respectively. These values rose to approximately 0.5% at both five and seven hours, but had returned to 0.31% after three days. Although this was informal in nature, it readily supports the theory that some of the loss was adsorbed water and varied with humidity. A plot of LN Percent Remaining versus Time indicates the sublimation process to be first or pseudo-first order. The data from 1 to 28 hours yield a straight line with a R 2 value of 0.9991. This same line yields a y-intercept corresponding to 2.6 Percent Remaining. The equation (LN % Remaining = -0.0598*Time + 0.9552) yields a theoretical amount remaining at 48 hours of 0.15%. This represents removal of 95% of the initial 3.0% Menthol. This would indicate 48 hours to be an appropriate sublimation time for these conditions. It is evident that this linearity drops after 28 hours. Although most of the curve may represent Menthol and adsorbed water loss, it is reasonable to expect the latter points represent more water loss than Menthol loss. Whatever the reason, loss of linearity at the extremes is not uncommon. Removal of the one hour data point would increase the R 2 value from 0.9991 to 0.9995. 158 A photograph of tablets with and without Menthol is shown in Figure 5.3b. Physical test results are shown in Table 5.3b. Menthol formulation tablets revealed visible pores not observed with the control tablets. Although this was even more evident after sublimation, pores were visible even before oven sublimation. In the initial Menthol batches, the tablets produced were notably thicker (4.08 mm and 4.07 mm for the 3.0% and 6.0% tablets, respectively) than the control formulation (MMM Low, 4.00 mm). The Menthol appears to have some binding effect. This is not completely surprising considering the adhesive or sticky nature of this substance. After sublimation, the tablets had expanded, yielding an average thickness value of 4.11 mm for both formulations. This is an especially notable increase (2.8%) from the control value of 4.00 mm. This expansion was not anticipated. This could be due to the creation of pores resulting in less bonding within the tablet structure. Another possibility is the tablet expansion being similar to dough rising in the baking process as gases are produced and escape. The larger batch was produced using less compression force and yielded even thicker tablets with a before sublimation average thickness value of 4.15 mm which is 4.8% thicker than the small batch control (MMM Low, 4.00 mm). As observed with the initial batches, thickness was further increased (average = 4.19 mm) when measured after sublimation. Although tablet hardness is variable, both initial lots of Menthol formulation tablets appear less hard (maximum average hardness of 5.4) than the control tablets (average value of 7.2). There was no absolute trend with regard to hardness decreasing after sublimation. It might be expected that sublimation would lead to decreased hardness Figure 5.3b. Photograph of Menthol Formulation Tablets From right to left: 0, 3, and 6 Percent Menthol Formulation Tablets Magnification: 3.7X Table 5.3b. Physical Test Results Formula Weight (mg) Thickness (mm) Hardness DT* ** % Friability MMM Low (No Menthol) 356.3(1.3)(0.4) 4.00(0.006)(0.14) 7.2(1.1)(15.1) 0:21 0.17 3% Menthol-Before Sublim. 348.2(1.6)(0.4) 4.08(0.007)(0.17) 5.1(0.8)(15.2) 0:20 0.29 3% Menthol-After Sublim. 341.2(1.5)(0.4) 4.11(0.007)(0.17) 5.4(0.7)(14.0) 0:20 0.38 6% Menthol-Before Sublim. 347.3(1.2)(0.3) 4.07(0.008)(0.21) 4.7(0.7)(14.4) 0:20 0.40 6% Menthol-After Sublim. 329.0(1.6)(0.5) 4.11(0.006)(0.15) 4.4(0.8)(18.4) 0:21 0.92 3%, Larger Batch, Before 343.3(3.0)(0.9) 4.15(0.015)(0.36) 5.5(0.7)(12.1) 0:16 0.25 3%, Larger Batch, After 333.8(1.9)(0.6) 4.19(0.012)(0.29) 4.5(0.6)(12.4) 0:17 0.59 *Disintegration Time (min:sec) ** % Friability (25 rpm, 4 min) Average (SD) (%RSD) 159 160 and increased friability. The overall trend did reflect a tendency for sublimation to lead to an increase in friability. The 3.0% Menthol tablets had satisfactory friability results before and after sublimation (0.29% and 0.38%, respectively). After sublimation, the 6.0% Menthol formulation tablets yielded a friability result (0.92%) near the upper limit. The larger batch size 3.0% Menthol tablets followed the same trend with regard to friability increasing after sublimation. Acceptable results of 0.25% and 0.59% were obtained before and after sublimation of tablets, respectively. In-vitro disintegration times of 20 to 21 seconds were obtained for the initial Menthol formulation tablets. However, the Menthol formulation tablets were faster disintegrating in-vivo than the control formulation. The 3.0% Menthol formulation yielded an acceptable taste without numbing. It was believed the lack of numbing was a direct result of an improvement in in-vivo disintegration time. However, a small amount of residual Menthol, a phenolic compound, could have some effect. The 6.0% Menthol formulation tablets retained a slightly less pleasant Menthol taste. The 3.0% Menthol formulation tablets were the best produced to date. The decision to make a larger batch was made based upon these positive results. As noted above, this allowed better characterization of the sublimation curve as well as yielded tablets for expanded finished product testing. As previously discussed, these larger batch tablets were produced with a lower compression force. As might be expected, the in vitro and in vivo disintegration times were further improved with the lower compression force. In vitro disintegration times of 16 seconds and 17 seconds were observed for the before and after sublimation tablets, respectively. These values are lower than any observed to date. 161 In vivo disintegration was again much improved over non-Menthol containing formulations. These tablets yielded a pleasant taste without numbing. These tablets, which met all physical and taste requirements, were now subjected to chemical testing. Final mixing times were kept at a minimum for mixing the Promethazine: Magnesium Stearate pre-blend with the inactive ingredient blend. Therefore, assessment of Content Uniformity was critical. Results are shown in Table 5.3c. The results (n=10) yielded a range of 94.4 ? 102.7% Label Claim, an average of 97.4% Label Claim, and a Relative Standard Deviation of 2.8%. These results meet the standard USP requirements (range 85.0 ? 115.0%, RSD ? 6.0%). Thus, the reduced mixing time employed was sufficient. Another critical parameter to be assessed was dissolution. The large amount of Magnesium Stearate employed for taste-masking could potentially adversely affect dissolution. Dissolution data are presented numerically in Table 5.3d and graphically in Figure 5.3c. The tablets (n=3) yield an average percent dissolved of 73.0% at five minutes and 85.7% dissolved at thirty minutes. These results meet the USP limits of NLT 75% (Q) in 45 minutes for conventional Promethazine tablets. In summary, these trials indicate this formulation to meet all requirements of a Promethazine Orally Disintegrating Tablet. More importantly, they were manufactured using only conventional excipients and blending followed by direct compression. While the sublimation of Menthol is an additional step, it only required a common laboratory oven and a time of 48 hours. Table 5.3c. Content Uniformity Data Promethazine 25 mg ODT Lot XXX, 3% Menthol, Larger Batch Size Content Uniformity Data Sample Abs at 298nm mg/tablet % label claim Standard 0.569 25.2 100.8 Tablet 1 0.540 23.9 95.7 Tablet 2 0.569 25.2 100.8 Tablet 3 0.555 24.6 98.3 Tablet 4 0.553 24.5 98.0 Tablet 5 0.549 24.3 97.3 Tablet 6 0.539 23.9 95.5 Tablet 7 0.546 24.2 96.7 Tablet 8 0.533 23.6 94.4 Tablet 9 0.534 23.6 94.6 Tablet 10 0.580 25.7 102.7 Tablet Avg 0.550 24.3 97.4 SD 0.015 0.7 2.7 %RSD 2.8 2.8 2.8 Min 23.6 94.4 Max 25.7 102.7 USP Limits Range: 85.0 - 115.0 % RSD: ? 6.0 % 162 Table 5.3d. Dissolution Data 163 0 Dissolution Data (n=3),900 ml 0.2M pH 6.4 Phosphate Buffer, Paddles, 50 rpm Promethazine 25 mg ODT Tablets, Lot XXX, 3% Menthol Sample Description Percent Dissolved @ Time (min) Time 0 2 510153 Flask 1 0.0 63.0 75.8 80.1 80.3 84.3 Flask 2 0.0 51.7 73.3 77.4 80.7 86.8 Flask 3 0.0 59.0 70.0 74.1 79.5 85.9 Average 0.0 57.9 73.0 77.2 80.2 85.7 SD 0.0 5.7 2.9 3.0 0.6 1.3 %RSD 0.0 9.9 4.0 3.9 0.8 1.5 USP Limits (Conventional Tablet): NLT 75% (Q) in 45 minutes Figure 5.3c. Dissolution Plot 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 0 5 10 15 20 25 30 35 Time (min) % D i ss o l ve d Lot XXX, 3% Menthol 164 References 1. Brown D. Orally disintegrating tablets - taste over speed. Drug Delivery Technology. September 2003;13(6):58-61. 2. Fu Y, Yang S, Jeong SH, Kimura S, Park K. Orally fast disintegrating tablets: developments, technologies, taste-masking, and clinical studies. Critical Reviews in Therapeutic Drug Carrier Systems. 2004;21(6):433-475. 3. Bogner RH, Wilkosz MF. Fast-dissolving tablets. U.S. Pharmacist. March 2002;27(03):34-43. 4. Cremer K. Orally disintegrating dosage forms provide drug life cycle management opportunities. Pharmaceutical Technology Supplement. 2003(Formulation & Solid Dosage):22-28. 5. Parakh SR, Gothoskar AV. A review of mouth dissolving technologies. Pharmaceutical Technology. November 2003;27(11):92-100. 6. Correct use of menthol. Connecticut Agriculture Experimental Station. Available at: www.caes.state.ct.us/BeeInformation/BeeFormsandInformation/Menthol.htm. Accessed Sept 8, 2005. 7. Title 21--Food and drugs. Code of Federal Regulations. Vol 3; 2005:469-471. 8. Wouters MFA, van Apeldoom ME, Speijers GJA. Safety evaluation of certain food additives, substances structurally related to menthol. Geneva: World Health Organization; 1999. 9. Phenergan prescribing information. Wyeth. Available at: http://www.wyeth.com/products/wpp_products/full_pharma_az.asp. Accessed Nov17, 2005. 10. Betageri GV, Deshmukh DV, Gupta RB. Oral sustained-release bioadhesive tablet formulation of didanosine. Drug Development and Industrial Pharmacy. 2001;27(2):129-136. 11. The United States Pharmacopeia and The National Formulary (USP/NF). Vol USP 28/NF 23. Rockville,MD: United States Pharmacopeial Convention, Inc.; 2005. 12. Klancke J. Dissolution testing of orally disintegrating tablets. Dissolution Technologies. May 2003;10(2):6-8. 165 13. Siewart M, Dressman J, Brown CK, Shah VP. FIP/AAPS Guidelines to dissolution/in vitro release testing of novel/special dosage forms. Dissolution Technologies. February 2003;10(1):6-15. 166 6. CONCLUSIONS The broad hypothesis for this work was that a pleasant tasting, rapidly disintegrating (less than one minute in vivo) Orally Disintegrating Tablet could be manufactured through the development of a simple manufacturing method, preferably simple blending followed by direct compression. Promethazine HCl was chosen as a model drug based upon its high degree of water solubility, its bitter taste, and the limitations of current dosage forms of this drug. The immediate secondary hypothesis was that a material or blend of materials could be used to taste-coat Promethazine HCl via simple blending. Dissolution was primarily used to test this hypothesis and limited taste-testing was also employed. The compendial dissolution test 1 for conventional Promethazine HCL tablets was utilized with modifications recommended for ODT dosage forms 2, 3 . One pharmacokinetic study concluded the compendial dissolution test assures satisfactory bioavailability 4 . The preferred dissolution profile is no Promethazine HCL dissolved at the initial time point followed by a rapid increase in dissolution. The taste testing was limited in that only two people, the researchers involved in the project, performed this screening. However, no decision to accept the hypothesis was made based upon acceptable taste alone. Initially, newer lubricants (partial glycerides of vegetable origin) and chemically similar materials were evaluated 5, 6 . These materials have been utilized in taste-coating, 167 but not in the absence of heat or shear 5, 6 . Glyceryl Dipalmitostearate, Hard Fat, and a mixture of Hard Fat and Glyceryl Behenate failed the hypothesis in that they did not retard dissolution or produce taste-masking. The particle size of these materials may be too large to accomplish coating via simple blending since a larger particle size results in less surface area for coating of the drug. Various other materials were screened for taste-coating and failed. The ability of Promethazine HCL to dissolve in aqueous and non-aqueous environments also makes this material very difficult to taste-coat, especially by simple blending alone. Magnesium Stearate, a hydrophobic tablet lubricant with a very small particle size, and therefore a very large surface area, was found to provide some degree of taste-coating. A 1:1 ratio of Magnesium Stearate with Promethazine HCl was found to be superior to lower amounts of this lubricant. Higher amounts were not evaluated due to the known ability of Magnesium Stearate to retard tablet disintegration and increase tablet friability, both of which are inconsistent with the properties of an ideal ODT. Magnesium Stearate resulted in a lower amount of drug dissolved at the initial time-point (two minutes). Taste-testing appeared to support this observation. It was accepted that a 1:1 ratio of Magnesium Stearate and Promethazine HCl V-blended for one hour results in taste-coating Promethazine HCl via a simple blending process. The next hypothesis was that this new taste-coating method would withstand further blending with additional excipients and tablet compression. This 1:1 mixture of Magnesium Stearate and Promethazine HCl was blended with Pharmaburst, an off-the-shelf ODT platform, and compressed. These soft, friable tablets had reduced dissolution at the initial time-point followed by an increase in percent dissolved to above the compendial limits at 168 later time-points. These tablets met the compendial standards for dissolution. Since taste was also graded as acceptable, the hypothesis was accepted. Although the hypothesis was accepted, limitations were noted. A much lower amount of drug dissolved at the initial time-point would be desired. Use of more modern dissolution test equipment would allow collection of moment by moment dissolution data and would allow a better assessment of this method. Even a brief period of no dissolution may allow improved taste in that the interaction of other ingredients such as flavors and sweeteners with taste and smell receptors will affect the subsequent interpretation of drug taste 7 . This new method of taste-coating should be better for drugs which are less water soluble than Promethazine HCl, which is extremely water soluble (500mg/ml) 8, 9 . Not only would a slower initial dissolution rate be possible but lower levels of Magnesium Stearate could likely be utilized possibly resulting in faster disintegration and lower friability. Also, the anesthetic effect was a big problem with Promethazine HCl. An equally soluble drug which is bitter but does not produce an anesthetic effect might be a better candidate for this method. This method may be of limited value for high dose drugs, especially those which are very water soluble. In this case the amount of Magnesium Stearate required would be prohibitive in terms of tablet size, disintegration time, and friability. Having accepted the hypothesis that this simple method results in Promethazine HCl being taste-coated and that this coating withstands further blending and tablet compression, the next hypothesis was that this high Magnesium Stearate content formulation could be combined with other materials to produce a tablet which is both non-friable and rapidly disintegrating. Magnesium Stearate is well known to cause 169 tableting problems, especially in amounts above one or two percent and/or with the use of extended blending times. Magnesium Stearate physically coats the active ingredient and excipients. This hydrophobic coating retards disintegration and dissolution and also decreases bonding between particles during the compression process which leads to increased friability 10 . Initial trials with excipients routinely used in ODTs indicated that, as expected, significant problems with capping and friability occur. Additional early trials were conducted to evaluate various diluents, diluent/binder combinations, and glidants. Some initial evaluations of disintegrants were also performed. A small particle-size grade of spray-dried Mannitol was initially evaluated as a primary diluent. A suitable tablet could not be obtained due to problems with capping. Although sugars in general undergo brittle fracture to overcome lubricant sensitivity 10 , this is less likely with these very small, uniform, spray-dried particles. Dextrates, NF was evaluated next and solved problems with capping. This material consists of large crystalline particles 11 which likely overcome this lubricant sensitivity by undergoing brittle fracture during compression. This brittle fracture results in the creation of new, uncoated surfaces for tablet bonding 10 . In addition, a glidant was not required when using Dextrates. Dextrates particles are large and spherical, both of which promote good flow 11 . This Promethazine HCl/ Magnesium Stearate/ Dextrates system was selected for further evaluation. It was determined that any notable amount of dilution of this Promethazine HCl/ Magnesium Stearate/ Dextrates combination resulted in friable tablets. In this case, the tablet size was increased initially to 300 milligrams total tablet weight and later to 350 milligrams to incorporate more Dextrates. As discussed earlier, this limits this 170 technology from being useful for high dose drugs, especially those which are also highly water soluble. As noted throughout this work, the balancing of friability and disintegration time is critical in the development of an ODT. Now that a formulation resulting in non-friable tablets was developed, trials with various disintegrants were undertaken since the hypothesis was that the tablet could be both non-friable and rapidly disintegrating. Prior to beginning this work, it had been planned to evaluate two disintegrants at a time using a 3 2 randomized full factorial design as utilized by Gohel and coworkers 12 . This approach and its accompanying statistical analysis would have yielded robust results. However, the fragile nature of this high Magnesium Stearate content formulation allowed only small changes in one variable at a time. In this case, a qualitative comparison of friability and disintegration data was used to evaluate formulations. This compromises our ability to generalize these results beyond our current study. Various concentrations of disintegrants with various mechanisms of action were evaluated. A final combination of Sodium Starch Glycolate, Croscarmellose Sodium, Calcium Silicate, and Soy Polysaccharides was selected. Prior use of Soy Polysaccharides as a disintegrant in ODTs has not been reported. At this stage, the product was a non-friable (0.33%) tablet with an in vitro disintegration time of 19 seconds and an in vivo disintegration time of less than one minute. The hypothesis was accepted that a non-friable and rapidly disintegrating tablet could be formulated. However, the taste was judged to be unacceptable at this point and the initial broad hypothesis required the product to also be pleasant tasting. 171 Numerous other trials were undertaken in an attempt to further decrease disintegration time and/or improve taste. Materials evaluated included: ? Materials which promote binding therefore enabling a lower compression force to be utilized; ? Materials which increase the overall hydrophilic or hydrophobic nature of the tablet; ? Surfactants; ? Flavors/Sweeteners. Formulations were evaluated as before. None of the extensive number of formulations evaluated resulted in any notable improvement. Most of these materials likely undergo plastic or visco-elastic deformation and are more subject to lubricant sensitivity. Only a reduction in final blending time and further dilution with Dextrates to a total tablet weight of 350 milligrams resulted in notable improvement. At this point, the tablets obtained were non-friable (0.17%), had an in vitro disintegration time of 21 seconds, and an in vivo disintegration time of less than one minute. Although the bitter taste of Promethazine HCl was masked, the unpleasant anesthetic effect in the oral cavity was not completely eliminated. With regard to the initial broad hypothesis, this formulation and process of simple blending followed by direct compression did yield a robust, rapidly disintegrating, pleasant tasting Orally Disintegrating Tablet. However, in the case of Promethazine HCl, the unpleasant numbing effect was greatly diminished, but not eradicated. As noted earlier, limitations exist with regard to tablet size, scale-up, and overall robustness of the 172 process and methods. As also noted, the method may be more suited to less soluble drugs and less suited to drugs which are both high dose and/or highly water soluble. The next hypothesis was that incorporation of Menthol (3.0% or 6.0%) into the tablet blend followed by post-tableting sublimation could be combined with the above described technology to further improve its usefulness as a method to produce ODTs. Obviously the sublimation would have to be complete in a reasonable period of time using mild conditions to be suitable for the large scale manufacturing of ODTs. Sublimation appeared to follow first order or pseudo-first order kinetics and was complete after 48 hours in a standard laboratory oven at 35?C. This sublimation time could be further reduced in industry through the use of a forced air oven. The 6.0% menthol formulation offered no advantage over the lower 3.0% formulation. The addition of 3.0% Menthol with sublimation post tableting resulted in a visibly more porous tablet with a shorter in vitro disintegration time (17 seconds) and a shorter in vivo disintegration time (45 seconds or less). These tablets yielded a pleasant taste without numbing and met compendial Dissolution and Content Uniformity requirements for conventional Promethazine HCl tablets. The hypothesis was accepted that incorporation of a volatile substance followed by post-tableting sublimation can improve the original method. In summary, this study has shown that an ODT can be produced through simple blending followed by direct compression. The use of Magnesium Stearate as a taste- coating agent combined with Dextrates and disintegrants in certain proportions resulted in a non-friable (0.17%), rapidly disintegrating (21 seconds in vitro, < one minute in vivo) Promethazine HCl Orally Disintegrating Tablet. The tablet was pleasant tasting but the 173 anesthetic effect in the oral cavity was greatly reduced but not eliminated. The addition of Menthol to the formulation followed by post-tableting sublimation resulted in an even better ODT with acceptable friability (0.59%) and faster disintegration (17 seconds in vitro, < 45 seconds in vivo). These tablets had a pleasant taste without the anesthetic effect. These findings have many potential uses. The material will be divided into three serial publications (taste-masking, disintegrant trials, and sublimation). These will be submitted to AAPS PharmSciTech or to Drug Development & Industrial Pharmacy. It should be noted that the concept of a tablet containing these high levels (7-8%) of Magnesium Stearate yet being non-friable and rapidly disintegrating defies all conventional wisdom in the area of pharmaceutical product formulation. In addition, a Technology Disclosure has been filed with the Auburn University Office of Technology Transfer. This office believes this new, simple method of manufacturing an ODT can be patented and a provisional patent has been filed.. As with any study, one must assess how this work could be improved. As noted, improvements in equipment and methods would make any results more robust and more capable of being applied in a general fashion beyond the current work. As to other methods to consider, the combination of Dextrates and multiple disintegrants with a more robust taste-coating method such as fluid bed coating has unlimited potential in the development of Orally Disintegrating Tablets. 174 REFERENCES 1. 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Accessed August 20, 2004. 180 APPENDIX Active Ingredient Tablet Trials Individual Physical Test Results 181 Description Weight (mg) Thickness (mm) Hardness AA. 303 3.38 9.5 Magnesium 304 3.38 19.5 Stearate (8.3%) 301 3.38 19.5 Promethazine 301 3.37 20.0 HCl (8.3%) 303 3.37 13.5 Dextrates 303 3.37 19.5 (79.3%) 302 3.37 9.5 SSG (4%) 302 3.37 12.5 (Sodium Starch 302 3.37 13.0 Glycolate) 300 3.37 9.0 Average 302.1 3.37 14.6 SD 1.1 0.005 4.6 %RSD 0.4 0.14 31.8 Min 300 3.37 9.0 Max 304 3.38 20.0 Description Weight (mg) Thickness (mm) Hardness BB. 301 3.42 7.5 Magnesium 299 3.38 9.5 Stearate (8.3%) 298 3.38 4.0 Promethazine 297 3.40 4.0 HCl (8.3%) 299 3.41 5.5 Dextrates 298 3.37 7.5 (75.3%) 301 3.44 5.0 SSG (8%) 298 3.38 4.0 296 3.36 3.5 301 3.44 8.0 Average 298.7 3.40 5.9 SD 1.7 0.029 2.1 %RSD 0.6 0.84 36.0 Min 296 3.36 3.5 Max 301 3.44 9.5 182 Description Weight (mg) Thickness (mm) Hardness CC. 296 3.40 16.0 Magnesium 294 3.39 12.5 Stearate (8.3%) 298 3.39 18.5 Promethazine 302 3.41 10.0 HCl (8.3%) 294 3.39 16.0 Dextrates 298 3.40 19.0 (79.3%) 297 3.39 12.5 SSG (2%) 298 3.40 16.0 Croscarmellose 299 3.40 15.0 Na (2%) 297 3.40 16.0 Average 297.0 3.40 15.2 SD 2.3 0.007 2.8 %RSD 0.8 0.20 18.3 Min 294 3.39 10.0 Max 302 3.41 19.0 Description Weight (mg) Thickness (mm) Hardness CC.Low 297 3.48 13.5 Magnesium 296 3.48 13.0 Stearate (8.3%) 295 3.48 15.0 Promethazine 297 3.48 9.0 HCl (8.3%) 298 3.54 13.0 Dextrates 297 3.48 12.0 (79.3%) 297 3.48 9.0 SSG (2%) 298 3.49 15.0 Croscarmellose 297 3.48 13.5 Na (2%) 296 3.48 13.5 Average 296.8 3.49 12.7 SD 0.9 0.019 2.1 %RSD 0.3 0.54 16.8 Min 295 3.48 9.0 Max 298 3.54 15.0 183 Description Weight (mg) Thickness (mm) Hardness DD. 301 3.41 9.5 Magnesium 303 3.41 15.0 Stearate (8.3%) 303 3.42 17.0 Promethazine 300 3.40 18.5 HCl (8.3%) 305 3.41 17.5 Dextrates 299 3.39 17.0 (78.3%) 301 3.40 16.0 SSG (2%) 301 3.39 14.0 Croscarmellose 301 3.42 21.0 Na (3%) 301 3.40 15.0 Average 301.5 3.41 16.1 SD 1.6 0.011 3.1 %RSD 0.5 0.32 19.0 Min 299 3.39 9.5 Max 305 3.42 21.0 Description Weight (mg) Thickness (mm) Hardness DD. Low 301 3.50 14.0 Magnesium 302 3.51 15.0 Stearate (8.3%) 304 3.51 12.5 Promethazine 300 3.50 7.5 HCl (8.3%) 303 3.50 16.0 Dextrates 303 3.51 16.0 (78.3%) 301 3.50 12.0 SSG (2%) 300 3.50 15.0 Croscarmellose 300 3.50 14.5 Na (3%) 304 3.50 15.0 Average 301.8 3.50 13.8 SD 1.5 0.005 2.6 %RSD 0.5 0.14 18.6 Min 300 3.50 7.5 Max 304 3.51 16.0 184 Description Weight (mg) Thickness (mm) Hardness EE. 297 3.42 11.0 Magnesium 300 3.43 13.0 Stearate (8.3%) 300 3.44 8.5 Promethazine 301 3.44 14.5 HCl (8.3%) 303 3.44 16.0 Dextrates 300 3.44 17.0 (78.3%) 303 3.44 15.0 SSG (3%) 302 3.43 10.5 Croscarmellose 299 3.42 12.0 Na (2%) 301 3.43 15.0 Average 300.7 3.43 13.3 SD 1.7 0.008 2.7 %RSD 0.6 0.24 20.5 Min 297 3.42 8.5 Max 303 3.44 17.0 Description Weight (mg) Thickness (mm) Hardness EE. Low 301 3.46 15.0 Magnesium 299 3.47 14.5 Stearate (8.3%) 302 3.47 9.0 Promethazine 304 3.47 15.0 HCl (8.3%) 306 3.48 16.0 Dextrates 302 3.47 14.5 (78.3%) 302 3.48 12.0 SSG (3%) 300 3.47 9.5 Croscarmellose 301 3.48 13.0 Na (2%) 302 3.46 14.5 Average 301.8 3.47 13.3 SD 1.9 0.007 2.4 %RSD 0.6 0.21 18.1 Min 299 3.46 9.0 Max 306 3.48 16.0 185 Description Weight (mg) Thickness (mm) Hardness FF. 302 3.44 14.5 Magnesium 304 3.45 17.0 Stearate (8.3%) 303 3.45 12.0 Promethazine 306 3.45 12.5 HCl (8.3%) 303 3.44 15.0 Dextrates 298 3.44 13.5 (77.3%) 303 3.44 13.5 SSG (3%) 303 3.45 15.0 Croscarmellose 307 3.47 15.0 Na (3%) 303 3.45 13.5 Average 303.4 3.45 14.2 SD 2.4 0.009 1.5 %RSD 0.8 0.27 10.3 Min 298 3.44 12.0 Max 307 3.47 17.0 Description Weight (mg) Thickness (mm) Hardness FF. Low 303 3.56 9.0 Magnesium 306 3.56 9.0 Stearate (8.3%) 306 3.57 7.5 Promethazine 304 3.57 6.0 HCl (8.3%) 303 3.57 12.0 Dextrates 305 3.58 5.5 (77.3%) 305 3.57 10.5 SSG (3%) 304 3.56 10.5 Croscarmellose 303 3.56 8.0 Na (3%) 302 3.56 7.0 Average 303.9 3.57 8.5 SD 1.3 0.007 2.1 %RSD 0.4 0.20 24.6 Min 302 3.56 5.5 Max 306 3.58 12.0 186 Description Weight (mg) Thickness (mm) Hardness GG. 299 3.49 7.5 Magnesium 300 3.49 5.5 Stearate (8.3%) 300 3.49 7.5 Promethazine 298 3.49 9.0 HCl (8.3%) 300 3.50 9.0 Dextrates 300 3.49 10.5 (74.3%),SSG(3%) 297 3.49 10.5 Croscarmellose 298 3.49 7.0 Na (3%),Copovi- 298 3.49 7.5 done (3%) 297 3.50 7.5 Average 298.7 3.49 8.2 SD 1.2 0.004 1.6 %RSD 0.4 0.12 19.4 Min 297 3.49 5.5 Max 300 3.50 10.5 Description Weight (mg) Thickness (mm) Hardness GG. Low 303 3.57 7.5 Magnesium 302 3.57 9.0 Stearate (8.3%) 300 3.58 9.0 Promethazine 297 3.56 7.5 HCl (8.3%) 296 3.56 7.5 Dextrates 298 3.56 6.0 (74.3%),SSG(3%) 295 3.56 6.0 Croscarmellose 300 3.57 7.5 Na (3%),Copovi- 294 3.56 9.0 done (3%) 298 3.56 5.5 Average 298.2 3.57 7.5 SD 3.0 0.007 1.3 %RSD 1.0 0.20 17.5 Min 294 3.56 5.5 Max 303 3.58 9.0 187 Description Weight (mg) Thickness (mm) Hardness HH. 301 3.39 7.0 Magnesium 303 3.39 10.5 Stearate (8.3%) 303 3.40 10.5 Promethazine 301 3.39 7.5 HCl (8.3%) 303 3.40 10.5 Dextrates 304 3.40 10.5 (75.3%) 304 3.40 7.5 SSG (4%) 304 3.40 14.5 Croscarmellose 300 3.38 7.5 Na (4%) 303 3.40 7.5 Average 302.6 3.40 9.4 SD 1.4 0.007 2.4 %RSD 0.5 0.21 25.5 Min 300 3.38 7.0 Max 304 3.40 14.5 Description Weight (mg) Thickness (mm) Hardness HH. Low 301 3.50 9.0 Magnesium 301 3.49 10.5 Stearate (8.3%) 302 3.50 6.0 Promethazine 305 3.50 10.5 HCl (8.3%) 303 3.51 5.0 Dextrates 299 3.50 7.5 (75.3%) 297 3.51 9.0 SSG (4%) 297 3.49 9.0 Croscarmellose 299 3.50 10.5 Na (4%) 298 3.49 9.0 Average 300.2 3.50 8.6 SD 2.4 0.007 1.9 %RSD 0.8 0.21 22.1 Min 297 3.49 5.0 Max 305 3.51 10.5 188 Description Weight (mg) Thickness (mm) Hardness II. 302 3.43 8.5 301 3.41 9.0 302 3.41 9.5 302 3.42 8.0 301 3.42 7.5 297 3.40 8.5 301 3.42 9.0 301 3.41 301 3.42 7.5 303 3.42 9.0 Average 301.0 3.42 8.6 SD 1.5 0.008 0.7 %RSD 0.5 0.25 8.0 Min 297 3.40 7.5 Max 303 3.43 9.5 Description Weight (mg) Thickness (mm) Hardness II. Low 302 3.61 6.0 302 3.62 7.5 300 3.62 5.5 301 3.61 6.0 300 3.62 5.5 301 3.62 5.0 303 3.62 7.5 301 3.62 304 3.62 7.5 300 3.62 8.5 Average 301.3 3.62 6.7 SD 1.3 0.004 1.2 %RSD 0.4 0.12 17.7 Min 300 3.61 5.0 Max 304 3.62 8.5 189 Description Weight (mg) Thickness (mm) Hardness JJ. 303 3.54 12.0 301 3.52 12.0 305 3.55 10.0 304 3.53 10.5 302 3.52 8.0 302 3.52 9.5 303 3.53 10.5 303 3.53 12.0 304 3.53 8.5 301 3.51 11.0 Average 302.8 3.53 10.4 SD 1.3 0.011 1.4 %RSD 0.4 0.32 13.7 Min 301 3.51 8.0 Max 305 3.55 12.0 Description Weight (mg) Thickness (mm) Hardness JJ. Low 304 3.58 11.0 304 3.58 9.0 308 3.59 6.0 301 3.59 5.5 306 3.59 10.0 303 3.59 10.5 309 3.60 10.0 305 3.58 9.0 303 3.58 7.5 300 3.58 9.0 Average 304.3 3.59 8.8 SD 2.7 0.007 1.9 %RSD 0.9 0.19 21.3 Min 300 3.58 5.5 Max 309 3.60 11.0 190 Description Weight (mg) Thickness (mm) Hardness KK 295 3.50 11.0 301 3.51 12.0 298 3.51 7.5 298 3.51 9.0 299 3.52 300 3.52 9.0 299 3.52 298 3.51 11.0 297 3.51 7.5 297 3.52 Average 298.1 3.51 9.3 SD 1.5 0.007 1.6 %RSD 0.5 0.19 17.3 Min 295 3.50 7.5 Max 301 3.52 12.0 Description Weight (mg) Thickness (mm) Hardness KK. Low 299 3.59 7.5 295 3.59 6.0 300 3.59 7.5 299 3.60 299 3.59 7.5 299 3.60 6.0 299 3.59 7.0 299 3.60 7.5 297 3.59 6.0 303 3.60 9.0 Average 298.9 3.59 7.2 SD 1.9 0.005 0.9 %RSD 0.6 0.14 13.2 Min 295 3.59 6.0 Max 303 3.60 9.0 191 Description Weight (mg) Thickness (mm) Hardness LL. 307 3.51 10.0 305 3.51 13.5 305 3.52 9.0 307 3.52 7.5 306 3.52 9.5 306 3.51 8.0 306 3.52 10.0 305 3.51 7.5 301 3.49 303 3.51 7.5 Average 305.0 3.51 9.0 SD 2.0 0.009 1.9 %RSD 0.7 0.26 21.1 Min 301 3.49 7.5 Max 307 3.52 13.5 Description Weight (mg) Thickness (mm) Hardness LL. Low 304 3.57 10.5 300 3.56 4.5 299 3.56 7.5 306 3.57 9.0 305 3.57 7.5 301 3.56 304 3.57 4.0 304 3.57 4.5 302 3.56 6.0 307 3.57 Average 303.2 3.58 6.7 SD 2.6 0.005 2.1 %RSD 0.8 0.14 31.3 Min 299 3.56 4.0 Max 307 3.57 10.5 192 Description Weight (mg) Thickness (mm) Hardness MM. 305 3.61 4.5 304 3.61 5.5 307 3.61 6.0 302 3.61 302 3.60 4.0 304 3.61 6.0 303 3.62 4.0 303 3.62 306 3.61 5.0 305 3.61 6.0 Average 304.1 3.61 5.1 SD 1.7 0.006 0.9 %RSD 0.5 0.16 17.8 Min 302 3.60 4.0 Max 307 3.62 6.0 Description Weight (mg) Thickness (mm) Hardness MM. Low 305 3.65 5.0 301 3.65 5.5 302 3.64 304 3.64 6.0 304 3.66 4.0 304 3.63 6.0 304 3.62 5.5 302 3.66 4.0 301 3.65 5.0 301 3.66 6.0 Average 302.8 3.65 5.3 SD 1.5 0.013 0.8 %RSD 0.5 0.37 14.4 Min 301 3.62 4.0 Max 305 3.66 6.0 193 Description Weight (mg) Thickness (mm) Hardness NN. 297 3.60 6.0 299 3.60 7.5 297 3.60 5.0 300 3.62 6.5 299 3.61 7.0 297 3.60 300 3.60 6.0 302 3.60 7.5 300 3.60 298 3.60 7.5 Average 298.9 3.60 6.8 SD 1.7 0.007 0.9 %RSD 0.6 0.19 12.7 Min 297 3.60 5.0 Max 302 3.62 7.5 Description Weight (mg) Thickness (mm) Hardness NN. Low 290 3.66 5.5 299 3.70 6.0 301 3.69 5.0 298 3.68 5.5 297 3.68 4.0 299 3.68 299 3.69 4.0 297 3.67 302 3.68 5.5 290 3.65 4.0 Average 297.2 3.68 4.8 SD 4.0 0.015 0.8 %RSD 1.4 0.40 17.4 Min 290 3.65 4.0 Max 302 3.70 6.0 194 Description Weight (mg) Thickness (mm) Hardness OO. 303 3.56 5.5 305 3.57 6.0 303 3.57 5.5 303 3.57 5.0 303 3.56 7.5 305 3.58 5.5 304 3.59 5.0 303 3.57 7.5 306 3.57 6.0 307 3.58 7.5 Average 304.2 3.57 6.1 SD 1.5 0.009 1.0 %RSD 0.5 0.26 16.8 Min 303 3.56 5.0 Max 307 3.59 7.5 Description Weight (mg) Thickness (mm) Hardness OO. Low 304 3.61 4.0 307 3.64 7.5 304 3.64 9.0 310 3.63 303 3.64 5.5 313 3.66 4.5 307 3.64 4.0 304 3.63 6.0 307 3.62 307 3.64 6.0 Average 306.6 3.64 6.2 SD 3.1 0.014 1.8 %RSD 1.0 0.37 29.9 Min 303 3.61 4.0 Max 313 3.66 9.0 195 Description Weight (mg) Thickness (mm) Hardness PP. 295 3.42 5.5 296 3.44 7.5 296 3.44 7.0 299 3.44 6.0 298 3.45 298 3.44 9.0 296 3.45 6.0 298 3.45 7.5 297 3.44 6.0 298 3.44 Average 297.1 3.44 6.7 SD 1.3 0.009 1.1 %RSD 0.4 0.25 16.3 Min 295 3.42 5.5 Max 299 3.45 9.0 Description Weight (mg) Thickness (mm) Hardness PP. Low 294 3.51 4.0 296 3.52 6.0 295 3.52 297 3.52 5.5 299 3.52 4.5 293 3.52 4.0 299 3.50 6.0 300 3.53 296 3.53 5.0 298 3.53 6.0 Average 296.7 3.52 5.3 SD 2.3 0.009 0.9 %RSD 0.8 0.27 16.2 Min 293 3.50 4.0 Max 300 3.53 6.0 196 Description Weight (mg) Thickness (mm) Hardness QQ. 301 3.53 7.5 301 3.51 8.5 300 3.52 6.0 304 3.54 5.0 303 3.53 6.5 304 3.53 7.5 304 3.53 8.0 302 3.53 9.0 304 3.54 5.0 302 3.53 5.5 Average 302.5 3.53 6.9 SD 1.5 0.009 1.5 %RSD 0.5 0.25 21.2 Min 300 3.51 5.0 Max 304 3.54 9.0 Description Weight (mg) Thickness (mm) Hardness QQ. Low 308 3.60 6.0 303 3.58 306 3.59 7.5 300 3.55 6.0 299 3.57 300 3.58 6.0 304 3.58 4.5 300 3.57 4.0 307 3.59 6.0 303 3.58 Average 303.0 3.58 5.8 SD 3.2 0.014 0.9 %RSD 1.1 0.38 16.4 Min 299 3.55 4.0 Max 308 3.60 7.5 197 Description Weight (mg) Thickness (mm) Hardness RR 306 3.49 9.0 302 3.49 6.5 307 3.49 8.5 304 3.49 6.0 303 3.49 7.5 304 3.48 11.0 301 3.47 9.0 301 3.47 7.5 303 3.48 303 3.49 11.0 Average 303.4 3.48 8.4 SD 1.9 0.008 1.7 %RSD 0.6 0.24 20.4 Min 301 3.47 6.0 Max 307 3.49 11.0 Description Weight (mg) Thickness (mm) Hardness RR Low 307 3.58 5.5 312 3.58 7.0 304 3.56 7.5 304 3.59 308 3.57 7.5 305 3.58 9.0 304 3.57 6.0 304 3.60 7.0 305 3.57 6.0 308 3.59 Average 306.1 3.58 6.9 SD 2.6 0.012 1.0 %RSD 0.9 0.33 15.2 Min 304 3.56 5.5 Max 312 3.60 9.0 198 Description Weight (mg) Thickness (mm) Hardness SS 302 3.49 7.5 303 3.51 11.0 303 3.51 6.0 301 3.51 7.0 302 3.50 302 3.50 7.5 304 3.51 301 3.51 5.0 303 3.51 5.5 303 3.51 6.0 Average 302.4 3.51 7.0 SD 1.0 0.007 1.7 %RSD 0.3 0.20 23.8 Min 301 3.49 5.0 Max 304 3.51 11.0 Description Weight (mg) Thickness (mm) Hardness SS Low 303 3.54 7.5 304 3.54 5.5 301 3.54 306 3.53 7.5 309 3.55 303 3.54 7.0 306 3.54 5.0 302 3.54 6.0 304 3.56 6.5 302 3.53 6.0 Average 304.0 3.54 6.4 SD 2.4 0.009 0.9 %RSD 0.8 0.25 14.6 Min 301 3.53 5.0 Max 309 3.56 7.5 199 Description Weight (mg) Thickness (mm) Hardness TT 298 3.54 7.5 298 3.55 6.0 300 3.55 302 3.54 7.5 301 3.55 6.0 301 3.55 7.5 300 3.55 10.5 299 3.54 6.0 299 3.54 9.0 299 3.54 6.5 Average 299.7 3.55 7.3 SD 1.3 0.005 1.5 %RSD 0.4 0.15 20.9 Min 298 3.54 6.0 Max 302 3.55 10.5 Description Weight (mg) Thickness (mm) Hardness TT Low 299 3.60 5.5 304 3.60 7.5 300 3.59 306 3.59 6.0 303 3.59 7.5 303 3.59 303 3.59 7.0 303 3.59 6.0 303 3.60 8.0 303 3.60 5.5 Average 302.7 3.59 6.8 SD 1.9 0.005 0.9 %RSD 0.6 0.14 14.0 Min 299 3.59 5.5 Max 306 3.60 8.0 200 Description Weight (mg) Thickness (mm) Hardness UU 295 3.36 9.0 295 3.37 10.5 298 3.37 7.0 297 3.37 294 3.36 8.0 297 3.38 9.0 296 3.38 7.5 295 3.37 7.0 296 3.37 298 3.38 7.0 Average 296.1 3.37 7.9 SD 1.4 0.007 1.2 %RSD 0.5 0.22 15.4 Min 294 3.36 7.0 Max 298 3.38 10.5 Description Weight (mg) Thickness (mm) Hardness UU Low 295 3.41 9.0 299 3.42 10.0 296 3.42 6.5 297 3.40 5.0 293 3.41 11.0 296 3.42 9.0 304 3.43 7.0 297 3.41 8.0 300 3.42 5.5 296 3.41 7.5 Average 297.3 3.42 7.9 SD 3.1 0.008 1.9 %RSD 1.0 0.25 24.6 Min 293 3.40 5.0 Max 304 3.43 11.0 201 Description Weight (mg) Thickness (mm) Hardness VV 300 3.41 9.0 303 3.42 8.0 300 3.45 6.5 302 3.44 10.0 302 3.45 7.0 301 3.44 8.0 298 3.44 5.5 301 3.43 8.0 294 3.43 5.5 301 3.45 9.0 Average 300.2 3.44 7.7 SD 2.6 0.013 1.5 %RSD 0.9 0.39 19.7 Min 294 3.41 5.5 Max 303 3.45 10.0 Description Weight (mg) Thickness (mm) Hardness VV Low 298 3.51 6.0 298 3.51 8.0 304 3.52 6.0 301 3.52 10.5 301 3.52 8.0 302 3.51 7.5 300 3.51 7.0 298 3.51 8.0 298 3.53 9.0 299 3.52 7.5 Average 299.9 3.52 7.8 SD 2.1 0.007 1.3 %RSD 0.7 0.20 17.3 Min 298 3.51 6.0 Max 304 3.53 10.5 202 Description Weight (mg) Thickness (mm) Hardness WW 301 3.61 6.0 301 3.60 304 3.60 5.0 301 3.60 6.0 300 3.60 300 3.60 7.5 306 3.62 6.0 302 3.63 5.5 302 3.60 7.5 304 3.62 Average 302.0 3.61 6.3 SD 1.7 0.011 0.9 %RSD 0.6 0.31 14.1 Min 300 3.60 5.0 Max 306 3.63 7.5 Description Weight (mg) Thickness (mm) Hardness WW Low 302 3.65 6.0 304 3.68 303 3.67 6.0 306 3.69 308 3.69 6.0 306 3.69 303 3.67 6.0 306 3.68 4.5 304 3.67 6.0 303 3.66 5.0 Average 304.5 3.68 5.8 SD 1.9 0.014 0.5 %RSD 0.6 0.37 9.4 Min 302 3.65 4.5 Max 308 3.69 6.0 203 Description Weight (mg) Thickness (mm) Hardness XX 303 3.61 4.0 302 3.62 302 3.61 5.5 302 3.62 4.0 303 3.61 302 3.63 6.0 305 3.64 4.5 306 3.63 5.0 304 3.63 6.0 302 3.61 4.0 Average 303.1 3.62 4.7 SD 1.4 0.011 0.9 %RSD 0.5 0.30 18.2 Min 302 3.61 4.0 Max 306 3.64 6.0 Description Weight (mg) Thickness (mm) Hardness XX Low 299 3.60 2.5 305 3.67 4.0 304 3.66 6.0 305 3.68 4.0 305 3.67 6.0 302 3.66 5.5 300 3.66 4.0 303 3.67 4.5 300 3.68 4.0 302 3.66 Average 302.5 3.66 4.5 SD 2.3 0.023 1.1 %RSD 0.8 0.62 24.5 Min 299 3.60 2.5 Max 305 3.68 6.0 204 Description Weight (mg) Thickness (mm) Hardness YY 302 3.60 6.5 304 3.60 4.0 302 3.60 6.0 307 3.61 5.0 302 3.61 6.0 303 3.60 7.5 305 3.62 6.0 304 3.61 302 3.61 4.0 303 3.60 5.5 Average 303.4 3.61 5.7 SD 1.6 0.007 1.1 %RSD 0.5 0.19 19.1 Min 302 3.60 4.0 Max 307 3.62 7.5 Description Weight (mg) Thickness (mm) Hardness YY Low 304 3.64 6.0 309 3.66 300 3.65 4.0 302 3.64 302 3.64 5.0 301 3.65 303 3.64 4.0 302 3.67 5.0 302 3.65 5.5 299 3.64 5.0 Average 302.4 3.65 5.0 SD 2.7 0.010 0.8 %RSD 0.9 0.28 15.4 Min 299 3.64 4.0 Max 309 3.67 6.0 205 Description Weight (mg) Thickness (mm) Hardness ZZ 304 3.55 5.0 304 3.58 5.5 306 3.57 5.0 304 3.57 303 3.56 4.0 306 3.57 5.0 305 3.58 6.0 305 3.57 4.5 306 3.58 6.0 307 3.57 Average 305.0 3.57 5.2 SD 1.2 0.009 0.7 %RSD 0.4 0.26 13.0 Min 303 3.55 4.0 Max 307 3.58 6.0 Description Weight (mg) Thickness (mm) Hardness ZZ Low 308 3.63 6.0 308 3.63 7.5 305 3.63 5.5 307 3.64 6.0 310 3.63 6.5 308 3.64 6.0 308 3.64 4.5 307 3.64 4.0 309 3.65 6.0 306 3.64 5.0 Average 307.6 3.64 5.7 SD 1.4 0.007 1.0 %RSD 0.5 0.19 17.6 Min 305 3.63 4.0 Max 310 3.65 7.5 206 Description Weight (mg) Thickness (mm) Hardness AAA 299 3.42 6.5 302 3.43 7.0 302 3.44 301 3.43 5.5 301 3.44 300 3.43 5.5 299 3.44 301 3.43 7.0 298 3.42 299 3.42 6.0 Average 300.2 3.43 6.3 SD 1.4 0.008 0.7 %RSD 0.5 0.24 11.5 Min 298 3.42 5.5 Max 302 3.44 7.0 Description Weight (mg) Thickness (mm) Hardness AAA Low 300 3.49 5.0 301 3.47 6.0 302 3.47 4.0 303 3.47 5.5 301 3.49 6.0 303 3.49 301 3.48 5.0 300 3.48 302 3.49 5.0 301 3.50 7.5 Average 301.4 3.48 5.5 SD 1.1 0.011 0.9 %RSD 0.4 0.30 17.1 Min 300 3.47 4.0 Max 303 3.50 7.5 207 Description Weight (mg) Thickness (mm) Hardness BBB Low 302 3.49 4.0 298 3.48 5.5 296 3.47 4.0 295 3.48 301 3.49 5.5 298 3.48 300 3.49 6.0 296 3.49 5.5 297 3.48 299 3.48 6.0 Average 298.2 3.48 5.2 SD 2.3 0.007 0.8 %RSD 0.8 0.19 15.9 Min 295 3.47 4.0 Max 302 3.49 6.0 Description Weight (mg) Thickness (mm) Hardness BBB 303 3.42 5.5 299 3.41 6.0 298 3.41 302 3.42 6.0 297 3.42 302 3.42 7.0 301 3.42 6.0 300 3.42 300 3.43 6.0 299 3.42 5.5 Average 300.1 3.42 6.0 SD 1.9 0.006 0.4 %RSD 0.6 0.17 6.8 Min 297 3.41 5.5 Max 303 3.43 7.0 208 Description Weight (mg) Thickness (mm) Hardness CCC Low 298 3.59 4.0 299 3.60 6.0 300 3.63 4.0 299 3.62 297 3.57 4.0 301 3.60 298 3.58 4.5 298 3.59 6.0 304 3.60 5.0 306 3.63 7.5 Average 300.0 3.60 4.9 SD 2.9 0.020 1.2 %RSD 1.0 0.56 24.9 Min 297 3.57 4.0 Max 306 3.63 7.5 Description Weight (mg) Thickness (mm) Hardness CCC 297 3.58 5.5 301 3.59 6.0 302 3.60 7.5 304 3.62 6.0 303 3.60 4.5 301 3.61 300 3.58 6.0 302 3.62 4.0 301 3.62 5.0 301 3.62 4.0 Average 301.2 3.60 5.3 SD 1.9 0.016 1.1 %RSD 0.6 0.46 21.0 Min 297 3.58 4.0 Max 304 3.62 7.5 209 Description Weight (mg) Thickness (mm) Hardness DDD Low 299 3.53 4.5 293 3.52 6.0 299 3.53 7.5 304 3.53 8.5 299 3.53 6.0 294 3.50 4.0 299 3.54 299 3.54 5.5 296 3.54 4.0 301 3.55 5.0 Average 298.3 3.53 5.5 SD 3.2 0.014 1.5 %RSD 1.1 0.39 28.1 Min 293 3.50 4.0 Max 304 3.55 8.5 Description Weight (mg) Thickness (mm) Hardness DDD 297 3.48 6.5 300 3.50 6.0 302 3.50 302 3.50 6.0 301 3.50 9.0 302 3.50 7.5 298 3.50 9.5 301 3.50 7.5 300 3.50 9.0 300 3.50 7.5 Average 300.3 3.50 7.5 SD 1.7 0.006 1.3 %RSD 0.6 0.18 18.0 Min 297 3.48 6.0 Max 302 3.50 9.5 210 Description Weight (mg) Thickness (mm) Hardness EEE Low 295 3.52 5.0 302 3.54 5.5 297 3.53 5.0 297 3.53 4.0 295 3.53 4.5 297 3.53 5.0 296 3.52 4.0 295 3.53 294 3.54 4.0 296 3.54 Average 296.4 3.53 4.5 SD 2.2 0.007 0.6 %RSD 0.7 0.21 12.8 Min 294 3.52 4.0 Max 302 3.54 5.5 Description Weight (mg) Thickness (mm) Hardness EEE 296 3.52 6.0 298 3.51 300 3.50 5.5 299 3.52 6.0 297 3.50 7.5 296 3.49 6.0 298 3.51 5.5 296 3.50 7.0 299 3.52 6.0 296 3.50 Average 297.5 3.51 6.2 SD 1.5 0.011 0.6 %RSD 0.5 0.30 10.2 Min 296 3.49 5.5 Max 300 3.52 7.5 211 Description Weight (mg) Thickness (mm) Hardness FFF Low 306 3.56 4.0 305 3.55 6.0 305 3.55 302 3.56 7.5 300 3.56 5.5 304 3.57 7.5 303 3.58 4.5 307 3.58 7.5 304 3.58 5.5 303 3.58 5.0 Average 303.9 3.57 5.9 SD 2.0 0.013 1.3 %RSD 0.7 0.35 21.4 Min 300 3.55 4.0 Max 307 3.58 7.5 Description Weight (mg) Thickness (mm) Hardness FFF 303 3.53 7.5 303 3.53 6.0 302 3.55 302 3.52 5.5 301 3.51 6.5 301 3.53 5.5 303 3.50 7.5 301 3.52 301 3.51 5.5 302 3.50 6.0 Average 301.9 3.52 6.4 SD 0.9 0.016 0.9 %RSD 0.3 0.44 13.4 Min 301 3.50 5.5 Max 303 3.55 7.5 212 Description Weight (mg) Thickness (mm) Hardness GGG Low 292 5.33 4.0 297 5.34 297 5.34 5.5 291 5.36 4.0 287 5.34 291 5.38 4.0 287 5.35 288 5.34 4.0 288 5.32 290 5.32 4.5 Average 290.8 5.34 4.2 SD 3.7 0.018 0.5 %RSD 1.3 0.34 11.5 Min 287 5.32 4.0 Max 297 5.38 5.5 Description Weight (mg) Thickness (mm) Hardness GGG 296 5.32 4.0 291 5.36 294 5.34 4.0 294 5.31 5.0 294 5.35 4.0 296 5.36 292 5.33 4.0 293 5.33 294 5.31 4.0 292 5.32 Average 293.6 5.33 4.1 SD 1.6 0.019 0.3 %RSD 0.6 0.35 7.7 Min 291 5.31 4.0 Max 296 5.36 5.0 213 Description Weight (mg) Thickness (mm) Hardness HHH Low 304 3.54 8.5 305 3.55 8.0 307 3.56 9.0 308 3.55 308 3.56 7.5 305 3.54 308 3.56 7.5 308 3.56 305 3.56 7.0 303 3.54 6.0 Average 306.1 3.55 7.8 SD 1.9 0.009 0.9 %RSD 0.6 0.26 11.9 Min 303 3.54 6.0 Max 308 3.56 9.0 Description Weight (mg) Thickness (mm) Hardness HHH 305 3.53 7.5 291 3.47 291 3.47 6.0 291 3.47 299 3.51 7.5 300 3.50 8.5 299 3.49 6.5 293 3.47 7.5 293 3.49 7.0 294 3.49 6.5 Average 295.6 3.49 7.1 SD 4.8 0.020 0.8 %RSD 1.6 0.58 11.3 Min 291 3.47 6.0 Max 305 3.53 8.5 214 Description Weight (mg) Thickness (mm) Hardness III Low 304 3.62 4.0 304 3.62 6.0 305 3.62 304 3.62 6.5 305 3.62 4.0 304 3.62 7.0 303 3.61 6.0 305 3.62 7.0 308 3.62 6.0 306 3.63 4.0 Average 304.8 3.62 5.7 SD 1.4 0.005 1.2 %RSD 0.5 0.13 21.3 Min 303 3.61 4.0 Max 308 3.63 7.0 Description Weight (mg) Thickness (mm) Hardness III 303 3.58 4.0 303 3.58 6.0 303 3.59 304 3.59 6.5 305 3.59 4.0 307 3.59 7.0 304 3.59 6.0 305 3.60 7.0 303 3.59 6.0 305 3.61 4.0 Average 304.2 3.59 5.7 SD 1.3 0.009 1.2 %RSD 0.4 0.24 21.3 Min 303 3.58 4.0 Max 307 3.61 7.0 215 Description Weight (mg) Thickness (mm) Hardness JJJ Low 303 3.54 9.0 301 3.56 7.5 303 3.55 302 3.55 7.5 306 3.55 8.5 301 3.55 6.0 301 3.56 9.0 303 3.56 302 3.55 5.5 302 3.57 8.0 Average 302.4 3.55 7.8 SD 1.5 0.008 1.2 %RSD 0.5 0.24 15.9 Min 301 3.54 5.5 Max 306 3.57 9.0 Description Weight (mg) Thickness (mm) Hardness JJJ 302 3.53 7.5 302 3.55 301 3.55 8.0 302 3.56 7.5 301 3.54 8.5 301 3.56 302 3.56 8.5 304 3.54 7.5 301 3.54 9.0 305 3.57 7.5 Average 302.1 3.55 8.0 SD 1.4 0.012 0.6 %RSD 0.5 0.35 7.2 Min 301 3.53 7.5 Max 305 3.57 9.0 216 Description Weight (mg) Thickness (mm) Hardness KKK Low 300 3.57 5.0 307 3.60 8.5 295 3.56 4.0 306 3.61 7.5 301 3.59 6.0 309 3.60 8.5 308 3.61 7.5 295 3.57 4.5 297 3.57 5.0 306 3.59 7.5 Average 302.4 3.59 6.4 SD 5.5 0.018 1.7 %RSD 1.8 0.51 26.5 Min 295 3.56 4.0 Max 309 3.61 8.5 Description Weight (mg) Thickness (mm) Hardness KKK 298 3.54 4.0 288 3.52 289 3.53 5.0 287 3.51 4.0 289 3.52 5.5 286 3.51 4.0 288 3.52 5.0 288 3.53 4.0 289 3.53 287 3.51 3.5 Average 288.9 3.52 4.3 SD 3.3 0.010 0.6 %RSD 1.2 0.29 14.7 Min 286 3.51 3.5 Max 298 3.54 5.5 217 Description Weight (mg) Thickness (mm) Hardness LLL Low 303 3.60 4.0 306 3.60 6.0 304 3.60 302 3.60 4.0 307 3.60 6.0 308 3.61 5.5 301 3.60 4.0 304 3.60 5.0 301 3.60 6.0 310 3.62 Average 304.6 3.60 5.3 SD 3.1 0.007 0.9 %RSD 1.0 0.19 17.5 Min 301 3.60 4.0 Max 310 3.62 6.0 Description Weight (mg) Thickness (mm) Hardness LLL 304 3.59 5.5 305 3.59 7.5 303 3.56 6.5 301 3.58 4.5 300 3.58 4.0 305 3.60 6.0 305 3.59 305 3.59 4.5 304 3.61 301 3.58 5.0 Average 303.3 3.59 5.4 SD 1.9 0.013 1.1 %RSD 0.6 0.37 20.4 Min 300 3.56 4.0 Max 305 3.61 7.5 218 Description Weight (mg) Thickness (mm) Hardness MMM Low 356 4.00 7.5 357 4.00 6.0 359 4.00 7.5 357 4.00 7.0 355 4.00 5.0 357 4.00 9.0 357 4.00 8.0 355 3.99 7.5 357 4.01 355 3.99 7.0 Average 356.3 4.00 7.2 SD 1.3 0.006 1.1 %RSD 0.4 0.14 15.1 Min 355 3.99 5.0 Max 359 4.01 9.0 Description Weight (mg) Thickness (mm) Hardness MMM 355 3.96 8.0 354 3.97 7.5 355 3.96 7.0 356 3.97 7.5 354 3.97 5.5 354 3.96 6.0 355 3.96 5.5 354 3.97 7.5 355 3.98 354 3.98 7.5 Average 354.6 3.97 7.0 SD 0.6 0.008 0.9 %RSD 0.2 0.20 13.3 Min 354 3.96 5.5 Max 356 3.98 8.0 219 Description Weight (mg) Thickness (mm) Hardness NNN Low 254 3.15 6.0 262 3.16 5.5 254 3.16 6.0 256 3.15 4.5 252 3.15 5.5 254 3.15 6.0 255 3.16 5.5 251 3.15 6.0 257 3.16 6.5 252 3.15 6.0 Average 254.6 3.15 6.5 SD 3.1 0.005 0.5 %RSD 1.2 0.16 8.3 Min 251 3.15 4.5 Max 262 3.16 6.5 Description Weight (mg) Thickness (mm) Hardness NNN 253 3.13 7.5 253 3.12 256 3.14 6.0 252 3.14 7.5 252 3.13 6.0 251 3.13 7.5 254 3.13 252 3.12 7.5 251 3.12 253 3.12 7.0 Average 252.8 3.13 7.2 SD 1.3 0.008 0.6 %RSD 0.5 0.25 8.8 Min 251 3.12 6.0 Max 256 3.14 7.5 220 Description Weight (mg) Thickness (mm) Hardness OOO Low 352 4.03 5.5 353 4.03 8.0 352 4.03 6.5 352 4.03 6.0 352 4.03 7.5 352 4.03 5.5 352 4.03 7.5 352 4.04 353 4.04 7.5 353 4.04 Average 352.2 4.03 6.9 SD 0.5 0.005 0.9 %RSD 0.1 0.12 13.6 Min 352 4.03 5.5 Max 353 4.04 8.0 Description Weight (mg) Thickness (mm) Hardness OOO 349 4.00 7.0 351 4.00 355 4.01 6.0 352 4.01 8.0 352 4.01 6.0 350 4.01 350 4.01 6.0 353 4.01 352 4.01 5.5 351 4.02 7.0 Average 351.5 4.01 6.5 SD 1.7 0.006 0.8 %RSD 0.5 0.14 11.8 Min 349 4.00 5.5 Max 355 4.02 8.0 221 Description Weight (mg) Thickness (mm) Hardness PPP Low 347 4.98 5.0 346 4.97 4.0 354 4.98 5.0 345 4.97 5.5 347 4.96 4.5 346 4.96 5.0 348 4.97 4.0 349 4.97 5.0 346 4.96 4.0 347 4.96 5.5 Average 347.4 4.97 4.8 SD 2.4 0.008 0.6 %RSD 0.7 0.16 12.4 Min 345 4.96 4.0 Max 354 4.98 5.5 Description Weight (mg) Thickness (mm) Hardness PPP 346 4.85 4.0 344 4.85 5.5 344 4.87 6.0 346 4.86 5.5 347 4.87 347 4.87 5.0 346 4.86 5.5 345 4.86 5.0 347 4.87 6.0 348 4.87 Average 346.0 4.86 5.4 SD 1.2 0.008 0.6 %RSD 0.4 0.17 11.4 Min 344 4.85 4.0 Max 348 4.87 6.0 222 Description Weight (mg) Thickness (mm) Hardness QQQ Low 355 3.93 5.0 353 3.93 6.0 354 3.93 351 3.93 8.5 352 3.93 6.0 352 3.91 5.5 353 3.92 6.0 355 3.93 7.5 354 3.92 357 3.94 5.5 Average 353.7 3.93 6.4 SD 1.7 0.008 1.1 %RSD 0.5 0.21 17.4 Min 351 3.91 5.0 Max 357 3.94 8.5 Description Weight (mg) Thickness (mm) Hardness QQQ 354 3.88 7.0 353 3.87 351 3.88 6.0 350 3.88 5.5 353 3.87 351 3.87 7.0 352 3.87 352 3.86 8.0 352 3.88 7.5 353 3.88 7.0 Average 352.0 3.87 6.8 SD 1.1 0.007 0.8 %RSD 0.3 0.18 12.2 Min 350 3.86 5.5 Max 354 3.88 8.0 223 Description Weight (mg) Thickness (mm) Hardness RRR Low 354 3.92 6.0 355 3.91 5.5 360 3.93 354 3.93 6.0 355 3.92 5.5 356 3.92 6.0 350 3.92 354 3.92 7.0 354 3.92 5.5 352 3.92 5.0 Average 354.3 3.92 5.8 SD 2.5 0.006 0.5 %RSD 0.7 0.14 9.3 Min 350 3.91 5.0 Max 360 3.93 7.0 Description Weight (mg) Thickness (mm) Hardness RRR 357 3.88 8.0 354 3.88 7.0 353 3.88 355 3.89 7.0 356 3.89 353 3.89 7.0 356 3.88 7.5 355 3.88 7.0 354 3.88 6.0 356 3.88 8.0 Average 355.0 3.88 7.2 SD 1.5 0.005 0.6 %RSD 0.4 0.12 8.1 Min 353 3.88 6.0 Max 357 3.89 8.0 224 Description Weight (mg) Thickness (mm) Hardness SSS Low 355 4.09 5.0 358 4.10 5.5 356 4.09 4.0 355 4.09 358 4.10 4.5 355 4.08 5.5 355 4.09 6.0 354 4.10 4.0 356 4.10 5.0 357 4.09 Average 355.7 4.09 4.9 SD 1.5 0.007 0.7 %RSD 0.4 0.16 14.6 Min 354 4.08 4.0 Max 358 4.10 6.0 Description Weight (mg) Thickness (mm) Hardness SSS 352 4.06 4.0 349 4.06 5.5 349 4.07 6.5 347 4.06 5.5 348 4.07 4.5 352 4.07 4.0 350 4.06 5.0 345 4.05 6.0 349 4.06 351 4.06 4.5 Average 348.9 4.06 5.2 SD 2.2 0.006 0.9 %RSD 0.6 0.16 17.2 Min 345 4.05 4.0 Max 352 4.07 6.5 225 Description Weight (mg) Thickness (mm) Hardness TTT Low 351 4.00 5.0 351 4.01 6.0 351 4.01 352 4.01 5.5 351 4.01 348 4.02 4.0 352 4.01 4.5 351 4.01 4.0 350 4.00 5.0 354 4.01 4.5 Average 351.0 4.01 5.0 SD 1.5 0.006 0.7 %RSD 0.4 0.14 14.9 Min 348 4.00 4.0 Max 354 4.02 6.0 Description Weight (mg) Thickness (mm) Hardness TTT 349 3.98 4.0 349 3.98 5.5 348 3.98 346 3.97 5.5 348 3.98 4.0 348 3.98 5.0 352 3.99 348 3.98 5.0 346 3.98 347 3.98 5.0 Average 348.1 3.98 5.0 SD 1.6 0.005 0.6 %RSD 0.5 0.12 11.1 Min 346 3.97 4.0 Max 352 3.99 5.5 226 Description Weight (mg) Thickness (mm) Hardness UUU Low 350 4.82 6.0 349 4.81 4.0 343 4.83 351 4.81 5.5 345 4.82 4.0 351 4.82 347 4.81 4.0 347 4.81 353 4.82 4.0 347 4.82 Average 348.2 4.82 4.4 SD 3.1 0.007 0.7 %RSD 0.9 0.14 17.2 Min 343 4.81 4.0 Max 353 4.83 6.0 Description Weight (mg) Thickness (mm) Hardness UUU 340 4.70 5.5 345 4.71 4.0 341 4.68 342 4.71 4.0 346 4.71 344 4.66 4.0 348 4.66 341 4.68 4.0 346 4.68 348 4.70 3.5 Average 344.3 4.69 4.1 SD 3.0 0.020 0.5 %RSD 0.9 0.42 12.6 Min 340 4.66 3.5 Max 348 4.71 5.5 227 Description Weight (mg) Thickness (mm) Hardness VVV (Before Drying) 347 4.08 6.0 347 4.08 351 4.08 4.0 349 4.08 6.0 349 4.07 5.0 349 4.07 346 4.09 5.5 346 4.07 4.0 348 4.08 5.0 349 4.07 4.5 Average 348.2 4.08 5.1 SD 1.6 0.007 0.8 %RSD 0.4 0.17 15.2 Min 346 4.07 4.0 Max 351 4.09 6.0 Description Weight (mg) Thickness (mm) Hardness VVV (After Drying) 341 4.10 5.5 342 4.10 340 4.11 6.0 341 4.11 4.0 343 4.11 5.5 343 4.11 340 4.09 5.5 344 4.11 6.0 341 4.11 339 4.11 4.0 Average 341.4 4.11 5.4 SD 1.5 0.007 0.7 %RSD 0.4 0.17 14.0 Min 339 4.09 4.0 Max 344 4.11 6.0 228 Description Weight (mg) Thickness (mm) Hardness WWW 347 4.07 4.5 (Before Drying) 349 4.06 4.5 345 4.09 5.5 348 4.07 346 4.07 5.5 347 4.07 4.0 347 4.08 5.0 349 4.08 4.0 348 4.07 347 4.08 4.0 Average 347.3 4.07 4.7 SD 1.2 0.008 0.7 %RSD 0.3 0.21 14.4 Min 345 4.06 4.0 Max 349 4.09 5.5 Description Weight (mg) Thickness (mm) Hardness WWW (After Drying) 331 4.12 6.0 332 4.10 4.5 327 4.11 4.0 329 4.11 5.0 329 4.11 4.5 328 4.12 3.0 330 4.12 4.0 326 4.11 330 4.11 4.0 329 4.11 5.0 Average 329.0 4.11 4.4 SD 1.6 0.006 0.8 %RSD 0.5 0.15 18.4 Min 326 4.10 3.0 Max 332 4.12 6.0 229 Description Weight (mg) Thickness (mm) Hardness XXX 343 4.16 6.0 Before Drying 341 4.14 6.0 346 4.15 345 4.13 5.5 346 4.18 6.0 340 4.15 4.0 346 4.16 6.0 341 4.17 5.0 347 4.14 340 4.15 5.5 Average 343.5 4.15 5.5 SD 3.0 0.015 0.7 %RSD 0.9 0.36 12.1 Min 340 4.13 4.0 Max 347 4.18 6.0 Description Weight (mg) Thickness (mm) Hardness XXX 334 4.19 4.0 After Drying 335 4.19 5.5 332 4.21 5.0 335 4.20 4.0 334 4.20 335 4.20 5.0 332 4.17 4.0 330 4.20 336 4.18 4.5 334 4.18 Average 333.8 4.19 4.5 SD 1.9 0.012 0.6 %RSD 0.6 0.29 12.4 Min 330 4.17 4.0 Max 336 4.21 5.5