Formulation Enhancement of Poorly Water-Soluble Pharmaceuticals by CO2-Based Crystallization Technologies

Abstract

This dissertation demonstrates the applicability of tunable solvent systems to the development of novel particulate formulations which enhance the deliverability and dissolution of poorly water-soluble active pharmaceutical ingredients (APIs). With approximately 40% of APIs discovered through combinatorial chemistry and high throughput screening having an aqueous solubility of less than 10 μM, there is a significant need for formulations which enhance drug dissolution. Furthermore, the processing techniques used must be scalable and environmentally benign while producing formulations which conform to the existing standards of purity and reproducibility. To this end, particulate formulations of two poorly water-soluble APIs were developed using two novel CO2-based crystallization technologies: supercritical antisolvent-drug excipient mixing (SAS-DEM) and gas antisolvent (GAS) cocrystallization. Using a supercritical antisolvent (SAS) crystallization process, rifampicin microparticles were crystallized in the presence of inhalation size appropriate lactose monohydrate particles to create rifampicin/lactose microparticle composites intended to increase the respirable fraction of rifampicin when delivered via a dry powder inhaler. In addition to a decrease in particle size observed by scanning electron microscopy, powder X-ray diffraction (PXRD) revealed conversion of the less soluble (0.59 ± 0.05 mg/mL) crystalline form I of rifampicin to the more soluble rifampicin dihydrate (1.28 ± 0.01 mg/mL) during SAS crystallization from methanol. Through the preparation of rifampicin/lactose microparticle composites, the SAS-DEM process was found effective at preparing inhalation size appropriate rifampicin microparticles (d < 8 μm), preventing particle agglomeration, and providing excellent mixture homogeneity (RSDs < 5.7%), all in a single-step. Guided by the Noyes-Whitney equation, itraconazole microflakes with increased surface area were crystallized from dichloromethane by a SAS process and simultaneously deposited on the surface of excipient lactose particles (d ~ 100 μm) to prevent microflake agglomeration. At low drug loadings (6 wt. %) the presence of lactose prevented microflake agglomeration and facilitated rapid itraconazole dissolution (D60 = 91%), but at high drug loadings (40 wt. %) the surface of the lactose became saturated and the excess microflakes agglomerated, reducing the dissolution rate (D60 = 64%). By adding a tri-block copolymer (Pluronic F-127) in solution with itraconazole during crystallization, particle morphology was altered such that the dissolution of itraconazole was enhanced (D60 = 85%) even at high drug to lactose loadings (50 wt. %). Pluronic F-127 did not affect the crystallinity of itraconazole, as verified by PXRD, but is thought to associate on the surface, thus improving the drug’s wettability. GAS cocrystallization was investigated as a novel means of preparing itraconazole−dicarboxylic acid cocrystals with enhanced dissolution. The crystal lattice of itraconazole, as characterized by PXRD, was unaffected following dissolution in tetrahydrofuran (THF) and subsequent recrystallization by pressurization with CO2. Simultaneous dissolution and recrystallization of itraconazole and L-malic acid from THF gave a primarily amorphous product, attributed to the high solubility of L-malic acid in THF, which demonstrated only marginal improvements in dissolution. Alternatively, GAS cocrystallization of itraconazole with succinic acid from THF gave a stable, crystalline product which featured rapid dissolution (D60 = 76%). Thermal analysis, which revealed the presence of an itraconazole/succinic acid eutectic, confirmed that a greater extent of cocrystallization was achievable using CO2 as the antisolvent compared to a traditional liquid antisolvent, n-heptane. GAS cocrystallization is governed by the pressure-dependent solubilities of drug and former in the CO2-expanded liquid, solubilities which are predictable by thermodynamic modeling. This work lays the foundation for the development of a thermodynamically predictable, highly tunable, and widely applicable technique for producing pharmaceutical cocrystals.