Screening and Formation Thermodynamics of Co-Crystal: Salicyclic Acid-Benzamide Co-Crystal System Case Study

Selecting a suitable co-former is the most important aspect of co-crystal design. Several knowledge-based, computational, and experimental techniques are available to guide the search for novel co-crystals. However, most are based on complex methodologies, are not readily accessible, and demand high computational costs. Moreover, when used solely, they do not guarantee that co-crystals with the predicted structures will form. In this work, a step-by-step approach towards co-crystal screening involving well-established knowledge-based methods and commonly available analytical techniques is illustrated using salicylic acid-benzamide co-crystal as a model system. The approach quickly and reliably predicted the formation of stoichiometrically diverse co-crystals between salicylic acid and benzamide. The thermodynamic formation functions necessary to understand the nature of co-crystallization were estimated for salicylic acid-benzamide (1:1) co-crystal using a predictive model based on the melting point and sublimation thermodynamic data. The formation of the co-crystal was found to be endothermic and entropy-driven.