Impact of drug-polymer complexation and media properties on the release performance of amorphous solid dispersions...

Herein, the release performance of amorphous solid dispersions (ASDs) of a weakly basic drug, bedaquiline (BDQ), and a weakly acidic polymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS) was investigated in different media. In conjunction, the complexation tendency between BDQ and HPMCAS was also probed. Amorphous solid dispersions (ASDs) of BDQ were prepared at different drug loadings with LF and MF grades of HPMCAS using solvent evaporation. Drug-polymer complexation was investigated in buffers varying in pH from 5.8 to 10.5 and in biorelevant media. For these experiments, polymer concentration was quantified using colorimetry or high-performance liquid chromatography (HPLC) and evaporative light scattering detection (ELSD). The insoluble drug-polymer complex formed in some media was analyzed using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. Drug release from ASD powders was evaluated as a function of pH (1.6, 3.0, 5.0, 6.5) as well as in fasted and fed state simulated intestinal fluids. HPMCAS showed a high degree of insoluble complex formation (∼90 %) with BDQ at pH 6.0 and the extent of complexation decreased with increasing pH, or when biorelevant media was used. At pH 6.5, ASDs showed a low extent of release in buffer. Release of drug from the ASDs was considerably enhanced in biorelevant media. BDQ remained amorphous in the presence of HPMCAS for extended time periods, hence crystallization was not considered a failure mechanism. Instead, the low release extent observed in pH 6.5 buffer was attributed to the formation of an insoluble BDQ:polymer ionic complex in the ASD particle. Ionic complexation was confirmed using X-ray photoelectron spectroscopy. However, it appears that solubilizing species present in the biorelevant media disrupted the drug-polymer complexation leading to improved release. These studies highlight the convoluted nature of drug release from ASDs with enteric polymers and the need to consider the impact of the release testing conditions. Release as a function of media conditions, is in turn expected to be highly variable from drug to drug depending on the nature of the drug-polymer interactions.