(700f) Fast Sreening and Production of Pure Co-Crystals Via Thermodynamic Modeling

Co-crystallization is a promising strategy to enhance the water solubility and bioavailability of active pharmaceutical ingredients (APIs). Once possible co-formers have been identified in silico, suitable screening compositions for experimental co-crystal (CC) formation have to be found. In this work, two screening approaches have been developed to find suitable screening compositions for co-crystal formation: a shortcut approach based on mass balances and a second one which additionally accounts for thermodynamic non-idealities between the API, the co-former, and the solvent via the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). The enhanced efficiency of the two approaches compared to conventional ones is demonstrated for the two co-crystal-forming systems carbamazepine/ acetylsalicylic acid and carbamazepine/ salicylic acid. Appropriate conditions for co-crystal formation were identified in the solvents ethanol, ethyl acetate, acetonitrile, and methanol using the novel screening approaches. The latter approach is furthermore extended to predict phase diagrams using PC-SAFT. These phase diagrams are validated by experiments and it will be shown, that the co-crystal screening approach based on thermodynamic predictions yields an appropriate preselection of suitable solvents and thus can be used to determine best-performing solvents for co-crystal production with minimal experimental effort.