Abstract
A framework for conceptualization of scalable solution-crystallization processes for cocrystals is developed and demonstrated using carbamazepine-nicotinamide as the model system. Calculation of intermolecular interactions and crystal lattice energy were carried out to understand the structure and strength of the binding synthons as well as to predict the likely growth morphology and overall crystal growth rate at scale. Experimental measurements of the solubility behavior of the pure components, the solid form stability domain, speciation in solution and effects on nucleation kinetics were employed to establish solvent system and optimize solution crystallization conditions including specifying the initial concentration of the coformer—nicotinamide. A seeding strategy was established, various factors affecting de-saturation kinetics, including nicotinamide concentration, were evaluated and optimized and washing strategy post filtration was developed to deliver and demonstrate a robust process at a 1 L scale with yield in excess of 90% and throughput of 14 L kg−1.
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