Conformation, virtual cocrystal screening, synthesis and determination of dipyridamole

Abstract

Drug development necessitates substantial investments in both human and material resources. In the advanced stages of development, significant solubility challenges frequently emerge, critically influencing a drug's applicability and efficacy. Crystal engineering, particularly through the application of cocrystal technology, presents a novel strategy to address these solubility issues without compromising the drug's effectiveness. However, the success rate of cocrystals formation remains relatively low. This article evaluates the impact of widely used virtual cocrystal screening methods on prediction outcomes, especially in the context of conformational diversity. The study describes the effects of eight dipyridamole (DIP) conformations and 130 cocrystal formers (CCFs) using molecular complementarity and molecular electrostatic potential methods, while the hydrogen bond propensity method did not account for conformations variations. Findings indicate that different DIP conformations lead to variable prediction outcomes in virtual cocrystal screening. Thus, it is crucial consider the conformational states of APIs and CCFs in virtual screenings to enhance prediction accuracy. By comparing virtual screening results with experimental results, this study demonstrated that incorporating conformational considerations can improve cocrystal success rates, minimize experimental workload, and contribute to energy-conservation and emission-reduction. Additionally, this research provides the true positives and true negatives data of DIP's cocrystal, laying the groundwork for further studies.