Dissolution Enhancement of Poorly Water Soluble Drugs

Abstract

Aqueous solubility is a limiting factor in the oral bioavailability of a certain class of poorly water soluble drugs. A consequence of low aqueous solubility is a slow dissolution rate. For the drugs with low aqueous solubility and high permeability the dissolution rate will be the rate limiting step for absorption. The most successful techniques that are employed for dissolution enhancement are micronization, formulation of amorphous systems and cyclodextrins containing dosage forms. This dissertation focuses on these three approaches to improve the dissolution of some model poorly soluble drugs. Micronization increases the dissolution rate of drugs through increased surface area. The high surface area of drug micro/nano particles renders them thermodynamically unstable, promoting agglomeration and crystal growth. Microparticles of the poorly water soluble drug, Itraconazole (ITZ) were produced by the supercritical antisolvent (SAS) method and simultaneously mixed with pharmaceutical excipients in a single step to prevent the drug agglomeration of drug particles. The drug microflakes were deposited on FFL by the SAS-DEM process and this method was successful in overcoming the agglomeration of drug microflakes. PLX produced crystalline drug microflakes in loose agglomerates with superior dissolution and flow properties even at higher drug loadings. The amorphous form of the drug will have higher solubility than their crystalline form. However, the amorphous form is physically unstable due to a high energy state and may recrystallize during storage. Binary physical mixtures of Efavirenz (EFV) and Eudragit EPO or Plasdone S- 630 were prepared and characterized for thermal and rheological properties to evaluate the miscibility and processibility for hot melt extrusion. Several equations were used to represent the glass transition (Tg) of blends with different drug loadings. The thermal and rheological studies revealed that the drug is miscible with both the polymers and plasticization of the polymers was observed with the drug. The amorphous systems were stable at ambient conditions for nine months and dissolution rate of EFV from these systems was significantly higher than its crystalline form and corresponding physical mixtures. Successful formation of amorphous solid dispersions of various drugs (carvedilol, itraconazole, nevirapine and nimodipine) in Plasdone S-630 was discussed in terms of thermo physical behavior and intermolecular interaction in drug-polymer systems. In the third approach cyclodextrins (CDs) were used as pharmaceutical solubilizers. The inclusion complexes of EFV with β-CD and its derivatives were prepared and characterized both in liquid and solid states. Stability constants (Ks) for EFV-βCD, EFV - hydroxypropyl βCD and EFV - randomly methylated βCD systems were 288, 469 and 1073 M-1, respectively. The dissolution of EFV was substantially higher with hydroxypropyl βCD and randomly methylated βCD inclusion complexes that were prepared by freeze drying method.