Predicting the Influence of Drug Solubilizing Agents on Cocrystal Solubility, Stability, and Transition Points.

Abstract

Pharmaceutical cocrystals have emerged as a useful strategy to improve the aqueous solubility of inherently poorly soluble drugs to improve their oral absorption and bioavailability. Aqueous cocrystal solubility can be orders of magnitude higher than that of the constituent drug. Chemical interactions between cocrystal constituents and dissolution media additives are critically important for cocrystals to achieve a wide range of solubility and stability (Scocrystal/Sdrug) behaviors. In the presence of drug solubilizing agents, a cocrystal with high aqueous Scocrystal/Sdrug can display higher, equal, or lower solubility than the drug, depending on the nature and concentration of the additive. This dissertation explores the mechanisms of cocrystal solubilization by solubilizing agents and the impact on cocrystal solubility, Scocrystal/Sdrug, and transition points. The objectives of this work are to (1) understand the effect of solubilization by physiologically relevant solubilizing agents on cocrystal solubility, solubilzation ratio (SRcocrystal), and Scocrystal/Sdrug (2) develop models to describe cocrystal solubility, SRcocrystal, and Scocrystal/Sdrug based on cocrystal dissociation and constituent ionization and micellar solubilization solution equilibria, (3) expand these models to consider the effect of multiple solubilizing agents, and (4) develop simplified models for the facile estimation of cocrystal transition points from commonly reported drug solubility descriptors. Cocrystal solubility, SRcocrystal, and Scocrystal/Sdrug, were investigated in fed state simulated intestinal fluid (FeSSIF) for seven cocrystals comprised of constituents with a range of ionization and micellar solubilization properties. Mathematical models that predicted cocrystal solubility and Scocrystal/Sdrug based on cocrystal dissociation and constituent ionization and micellar solubilization were derived and expanded to consider two ideally mixing solubilizing agents (FeSSIF and Tween 80). The models were found to be in excellent agreement with the experimentally measured values. SRcocrystal was found to be correlated with the log octanol-water distribution coefficient (log D) and models derived to predict SRcocrystal from log D. Cocrystal solubility at the transition point (S*) was found to be independent of solubilizing agent and solely depend on drug and cocrystal aqueous solubility and models derived to predict this behavior. The influence of solubilizing agents on the position of cocrystal solubility relative to the transition point was predicted by comparing SRdrug with S*.