An investigation into the solubility and stability of amorphous solid dispersions of BCS class II drugs

The poor water solubility of many drugs has emerged as one of the major challenges in the pharmaceutical world. Amorphous solid dispersions (ASDs) are one of the most widely used formulation strategies for the enhancement of in-vitro and in-vivo performance of poorly water-soluble drugs. However, because of their meta-stable nature the physical stability of amorphous solid dispersions has been considered to be the main obstacle for their formulation development and commercialization by the pharmaceutical industry. Significant upfront development is therefore required to generate stable amorphous formulations. The aim of this project was to understand, predict and enhance the solubility and physical stability of ASDs. Two model drugs (dipyridamole and cinnarizine) and three polymeric matrices (polyvinyl pyrrolidone, polyacrylic acid and hydroxypropyl methyl cellulose) were formulated by spray drying into binary and ternary solid dispersions. A series of physicochemical characterization techniques including mDSC, PXRD, FTIR, DVS, in-vitro dissolution and NMR were used to evaluate the systems. Physicochemical characterization of the various systems including amorphous drug crystallization kinetic studies, prediction of drug-polymer miscibility, in-vitro dissolution studies, physical stability studies and investigation into polymer-surfactant combinations of ternary solid dispersions were carried out. Across the project, several key achievements were obtained. It was revealed that the crystallization tendency of the amorphous drugs, drug-polymer miscibility, drug-polymer interaction, robustness of drug-polymer interaction under stress conditions, processing conditions, drug loading and antiplasticization effect are some of the dominant factors controlling the physical stability and solubility of the amorphous systems. The results of the project are expected to contribute to the formulation development of amorphous solid dispersions in terms of screening suitable drug and polymer candidates, selecting “safe” (physically stable) drug loadings and the identification of methodologies to improve the physical stability and solubility of formulations