Thermodynamic Approach for Co-crystal Screening

Co-crystallization is a promising strategy to enhance the water solubility and bioavailability of active pharmaceutical ingredients (APIs). Once possible coformers have been identified, suitable process conditions for an effective generation of pure co-crystals have to be found. In this work, two screening approaches have been developed to find the best-suited solvent and optimum process conditions for co-crystal formation: a shortcut approach based on mass balances and a second one which additionally accounts for thermodynamic nonidealities between the API, the coformer, 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. Phase diagrams were predicted using PC-SAFT and validated by experiments. 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.