Microstructure Formation for Improved Dissolution Performance of Lopinavir Amorphous Solid Dispersions

Amorphous solid dispersions (ASDs), where the drug is dispersed in a polymer, have become increasingly prevalent as a formulation strategy for the oral delivery of poorly soluble drugs due to their potential for substantial solubility enhancement. However, ASDs are susceptible to amorphous-amorphous phase separation, which may promote crystallization and/or alter the release performance. Nevertheless, the mechanisms by which phase separation and subtle microstructural changes affect ASD release remain poorly understood. Therefore, understanding the microstructure of ASDs and the subsequent implication for ASD performance are critical to design an optimally performing formulation. In this study, comprehensive investigations of microstructure evolution in lopinavir ASDs, prepared using a solvent-based process, were undertaken. Atomic force microscopy (AFM)-based nanoscale thermal analysis (nanoTA) enabled characterization of local composition at the submicron scale. The formation of heterogeneous domains was found to improve the in vitro release of lopinavir from lopinavir hydroxypropylmethylcellulose (HPMC) ASDs for drug loadings above 33% w/w. The composition and amount of each phase formed, as well as the size and location of drug-rich phases, were found to be critical factors contributing to the altered release kinetics observed. This study highlights the complexity and importance of ASD microstructure and should contribute to a broader understanding of ASD release mechanisms.