Bioavailability-Enhancing Cocrystals: Screening, in Vivo Predictive Dissolution, and Supersaturation Maintenance

Cocrystal engineering for bioavailability enhancement is still a serendipitous process, which requires systematic solution crystallization, in vivo predictive dissolution, and biopharmaceutical simulation. The purpose of this study is to improve bioavailability through cocrystal engineering, with a focus on understanding the mechanism of supersaturation maintenance during dissolution. BI 639667 is a poorly soluble and fast precipitating compound. The ability of its cocrystal with salicylic acid (SA) to maintain supersaturation was assessed using a modified two-step dissolution method, and its bioavailability was determined in rats. Biopharmaceutical simulation and dissolution modeling were performed to predict the in vivo performance in humans. Conductor-like screening model for realistic solvents and molecular dynamics (MD) simulation were used to study the interactions between the active pharmaceutical ingredient (API) and coformers in vacuum and aqueous media, respectively. A high melting cocrystal with SA, crystallized in dichloromethane, showed moderate solubility enhancement with prolonged supersaturation during dissolution, which was able to enhance bioavailability with reduced C_max, compared to amorphous dispersion. The radial distribution function (RDF) between the API and selected coformers was calculated using MD simulation to determine the mean distance between the API and coformer molecules in aqueous media. The result suggests that SA could better compete against water for interactions with the API and could penetrate the API molecular clusters to inhibit nucleation. Thus, the RDF by MD simulation may be used to determine the disruptive effect of water on the interaction between the API and coformer and improve cocrystal engineering for bioavailability enhancement.