Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process.

The present work deals with improving the solubility of vemurafenib, a practically insoluble drug, by converting it into an amorphous-solid dispersion using a solvent-controlled precipitation process. The dispersion containing vemurafenib and hypromellose acetate succinate (HPMCAS), an enteric polymer, is termed microprecipitated bulk powder (MBP), in which the drug is uniformly dispersed within the polymeric substrate. HPMCAS was found to be the most suitable polymer for vemurafenib MBP, among a series of enteric polymers based on superior physical stability and drug-release characteristics of the MBP. The MBP provided a greater rate and extent of dissolution than crystalline drug, reaching an apparent drug concentration of 28-35 µg/mL, almost 30-fold higher than solubility of crystalline drug at 1 µg/mL. The supersaturation was also maintained for more than 4 h. Upon exposure to high temperature and humidity, the MBP was destabilized, resulting in crystallization and lower dissolution rate. The control of moisture and temperature is essential to maintain the stability of the MBP. In a relative human bioavailability study, vemurafenib MBP provided a four- to fivefold increase in exposure compared with crystalline drug. Improving solubility with an amorphous-solid dispersion is a viable strategy for the development of practically insoluble compounds.

Characterization of physico-mechanical properties of indomethacin and polymers to assess their suitability for hot-melt extrusion processs as a means to manufacture solid dispersion/solution.

The objective of the study was to characterize the physical and viscoelastic properties of binary mixtures of drug and selected polymers to assess their suitability for use in the hot-melt extrusion (HME) process as a means to improve solubility by manufacturing either solid dispersion or solid solution. Indomethacin (INM) was selected as a model drug. Based on comparable solubility parameters, the selected polymers were Eudragit EPO (EPO), polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA), polyvinylpyrrolidone K30 (PVPK30), and poloxamer 188 (P188). The various drug and polymer systems were characterized for thermal and rheological properties as a function of drug concentration to provide an insight into miscibility and processibility of these systems. From the thermal analysis studies, a single T(g) was observed for the binary mixtures of INM/EPO, INM/PVP-VA, and INM/PVPK30, indicating miscibility of drug and polymer in the given ratios. In the case of mixtures of INM/P188, two melting endotherms were observed with decreasing drug melting point as a function of polymer concentration indicating partial miscibility of drug in polymer. As part of the rheological evaluation, zero rate viscosity (eta(o)) and activation energy (E(a)) was determined for the various systems using torque rheometer at varying shear rates and temperatures. The eta(o) for binary mixtures of drug and EPO, PVP-VA and PVPK30 were found to be significantly lower as compared to pure polymer, indicating disruption of the polymer structure due to miscibility of the drug. On the other hand, INM/P188 mixtures showed a higher eta(o) compared to pure polymer indicating partial miscibility of drug and polymer. With respect to E(a), the mixtures of INM/EPO showed an increase in E(a) with increasing drug concentration, suggesting antiplasticization effect of the drug. These findings corroborate the thermal analysis results showing increase T(g) for the various binary mixtures. The mixtures of INM/PVP-VA showed a decrease in the E(a) with the increasing drug concentration suggesting a plasticization effect of the drug. The understanding of thermal and rheological properties of the various drug/polymer mixtures help established the processing conditions for hotmelt extrusion (such as extrusion temperatures and motor load) as well as provided insight into the properties of the final extrudates. Using the actual hot-melt processing, a model was developed correlating the zero rate viscosity to the motor load determined by rheological evaluation.