Track: Formulation and Delivery - Chemical - Formulation - Oral - Immediate Release
Category: Poster Abstract
Enhanced Solubilization of an Analgesic/Antipyretic Drug with the Use of Polymeric Excipients
Purpose: The purpose of the present study was to increase the solubility of an analgesic/antipyretic drug to achieve a concentrated formula and consequently a smaller capsule compared to the marketed formulations. The API was formulated in a softgel based dosage form using hydrophilic excipients, pH modifiers and Povidone. Povidone helped enhance the solubility of the active and also acted as a precipitation inhibitors. Different grades of Povidone were explored as part of the study to understand the impact on solubilization. High drug loading was achieved with lower grades of Povidone. Upon relative assessment, the rank order in which the Povidone enhanced solubilization was PVP-K90 < PVP-K30 < PVPK17 < PVP-K12. Methods: Preliminary solubility studies for the Compound A were set up in various pharmaceutical vehicles. Several grades of Povidone marketed by BASF were explored as part of the study. A DOE design was set up around drug loading and Povidone concentrations. Formulations were based on a hydrophilic vehicle, pH modifier and Povidone as the precipitation inhibitor/solubilization enhancer. Povidone solubilization was achieved in the base formula by heating at 55 ± 5 °C. API loading was varied from 30-40%.Freeze thaw studies were conducted on the formulations for a minimum of three cycles to evaluate precipitation behavior in the anhydrous state. For bench scale experiments (~ 50-100 g) the formulations were filled in Size “0” 2-piece hard gelatin capsules and evaluated for dissolution performance in simulated gastric fluid (SGF). Once the final formulation was selected based on vial studies, the formulation was encapsulated in two gelatin shell formulas (acid bone and lime bone) and prototype capsules were put on ICH stability at 30 °C/65% RH and 40 °C/75% RH conditions. Results: The DOE study showed that lower grade of Povidone (grades K12 and K17) resulted in achieving a high degree of solubilization for Compound A. A higher concentration of Povidone K12 and K17 was required to enhance the drug loading which resulted in significant increase in the viscosity of the formulation. Although the viscosity was significantly higher compared to the marketed formulation, the dissolution performance was found to be equivalent to the marketed product. The formulations with higher grades of Povidone were encapsulated in a 20 Oblong size softgel and were at a ~30% drug loading. With the use of Povidone K12 and K17 grades, at least 35% drug loading was able to be achieved and subsequent formulations were encapsulated in a 11 Oblong die. The high drug loading coupled with increased concentration of Povidone resulted in significant challenges during encapsulation due to the highly viscous nature of the fill. Shell formulation development explored the use of different blooms and types of gelatin to achieve a robust shell for encapsulation of the highly viscous fill. Process optimization was conducted wherein critical process parameters such as ribbon thickness, gel hold time, gel cooking temperature, encapsulation speed, gel age were explored in order to achieve the critical quality attributes of the product. ICH stability at 30/65% RH and 40 C/75% RH showed no difference in assay performance and impurity profiles for the formulation when compared with the marketed product. Conclusion: Povidones are typically used to stabilize micro-molecular structures in liquid fill formulations. They form hydrogen bonds with active molecules with complementary structures for improved dissolution. Kollidon® 12 PF serves as solubilizing agents and crystallization inhibitors particularly for injectables. The results of this research indicate that the lower grade of Povidone K12 was very effective in solubilizing a significant amount of the active which reduced the overall size of the capsule. A smaller softgel can help with improvement in patient compliance while enhancing overall bioavailability of the molecule.