Application of Pharmaceutical QbD for Enhancement of the Solubility and Dissolution of a Class II BCS Drug using Polymeric Surfactants and Crystallization Inhibitors: Development of Controlled-Release Tablets

The aim of this study was to apply quality by design (QbD) for pharmaceutical development of felodipine solid mixture (FSM) containing hydrophilic carriers and/or polymeric surfactants, for easier development of controlled-release tablets of felodipine. The material attributes, the process parameters (CPP), and the critical quality attributes of the FSMs were identified. Box-Behnken experimental design was applied to develop space design and determine the control space of FSMs that have maximum solubility, maximum dissolution, and ability to inhibit felodipine crystallization from supersaturated solution. Material attributes and CPP studied were the amount of hydroxypropyl methylcellulose (HPMC; X (1)), amount of polymeric surfactants InutecA (R) SP1 (X (2)), amount of PluronicA (R) F-127 (X (3)) and preparation techniques, physical mixture (PM) or solvent evaporation (SE; X (4)). There is no proposed design space formed if the PluronicA (R) content was below 45.1 mg and if PM is used as the preparation technique. The operating ranges, for robust development of FSM of desired quality, of PluronicA (R), InutecA (R) SP1, HPMC, and preparation technique, are 49-50, 16-23, 83-100 mg, and SE, respectively. The calculated value of f2 was 56.85, indicating that the release profile of the controlled-release (CR) tablet (CR-6) containing the optimized in situ-formed FSM was similar to that of the target release profile. Not only did the ternary mixture of PluronicA (R), HPMC with InutecA (R) SP1 enhance the dissolution rate and inhibit crystallization of felodipine, but also they aided CarbopolA (R) 974 in controlling felodipine release from the tablet matrix. It could be concluded that a promising once-daily CR tablets of felodipine was successfully designed using QbD approach.