Discovery of cilnidipine cocrystals with enhanced dissolution by the use of computational tools and semiautomatic high-throughput screening

Abstract

Cocrystals are an attractive option for overcoming drug limitations, such as a low dissolution rate and absorption of poorly water-soluble compounds. Nevertheless, the discovery of new cocrystals remains a trial-and-error approach in which hundreds of coformers and several experimental methods are often tested. To streamline the cocrystal screening, computational methods can be used to select the coformers most likely to form a cocrystal, while high-throughput screening (HTS) approaches can rapidly screen them experimentally. In this manuscript, a new cocrystal of the extremely poorly soluble drug cilnidipine (solubility ≈30 ng/mL, 0.06 μM) was successfully discovered by applying HTS approaches. Only one cocrystal resulted from the screening with a total of 52 coformers, whereby the computational approach molecular complementarity successfully ranked this coformer (p-toluenesulfonamide) at the third position of the screening list. Dissolution studies conducted on the cocrystal in blank FaSSIF (fasted-state simulated intestinal fluid) and FaSSIF pH 6.5 revealed enhanced drug dissolution with a maximum achieved supersaturation equal to seven times the solubility of the crystalline drug. Dissolution rates of drug and coformer were compared for better mechanistic understanding of the cocrystal dissolution–supersaturation–precipitation behavior. The case of cilnidipine with a rare occurrence of cocrystals emphasized the importance of using joint computational and HTS approaches to enable successful cocrystal identification for pharmaceutical development.