Purpose: The development and validation of a robust dissolution method for a poorly soluble compound (Compound X) formulated with the functional excipient tartaric acid in HPMC capsules that is discriminating.
Methods: Compound X has calculated pKa’s of 0.2 and 4.1 and limited solubility in aqueous solutions above pH 5.0. Compound X is intended for immediate release capsule formulation. Improved solubility and bioavailability of Compound X was shown in the presence of an acidulant which acts as a functional excipient by lowering the pH environment in the capsule. The dissolution method should be able to detect the influence of the acidulant on Compound X solubility. Prior studies with dissolution media below pH 4.5 determined that the in vitro data did not correlate to the in vivo response, therefore buffered dissolution media ranging from pH 5.0-6.8 were evaluated using USP Apparatus II. Various surfactants (Tween 80, SLS, and CTAB) to aid in the solubility of the API were also screened in the method development process.
Results: Low and incomplete release profile and high variability of Compound X was observed for most of the dissolution conditions tested during this study, however dissolution media of 33mM Potassium Phosphate Buffer pH 6.0 with 0.2% Tween 80 was identified as the best candidate for further development. Increases in the concentration of surfactant did improved the solubility of Compound X, while increases to the ionic strength of the dissolution media lowered the pH effect of the tartaric acid reducing solubility. Capsule rupture time and content dispersion variability was reduced by raising the paddle speed from 50 RPM to 75 RPM. Both properties were exploited during the optimization process.
Conclusion: Dissolution of formulated Compound X capsules (200 mg) in 1L of 50mM Potassium Phosphate pH 6.0 with 0.374% Tween 80 using USP Apparatus II at 75 RPM was selected as the optimal conditions from those evaluated. Dissolution testing of Compound X formulated with various levels of tartaric acid was performed and similarity factor calculations confirmed the discriminating power of this method. During method validation 2x sink conditions were achieved.