Minoxidil Multi-Component Crystals with Aromatic Carboxylic Acids: Theoretical Calculation and Structural Analysis

Screening of co-formers for a specific active pharmaceutical ingredient is challenging during the development of multi-component crystals. Taking minoxidil (MIN) as a model drug, this study aims to examine the predictivity of the Cambridge Structural Database (CSD), Hansen solubility parameter (HSP), and the conductor-like screening model for real solvents (COSMO-RS) methods. First, CSD analysis based on a supramolecular approach was employed. Then, HSP and COSMO-RS methods were used to predict the cocrystallization possibility between MIN and 27 co-formers, where 10 candidate cases were reported. Based on the predicted results, eight aromatic carboxylic acids formed new solid forms with MIN experimentally, which met the criteria of Δδt < 7 MPa0.5 and ΔHex < −2.00 kcal mol–1, respectively, and four single crystals of these were successfully obtained. Single-crystal X-ray diffraction and Hirshfeld surface analysis indicated that the proton transferred from co-formers to MIN, and seven new MIN multi-component crystals showed rapid release in the first 30 min (1.52- to 2.91-fold) with improved solubility. This study confirms the efficiency of the CSD method and demonstrates that the COSMO-RS method performs much better than the HSP method.