A comparative assessment of the influence of different crystallization screening methodologies on the solid forms of carbamazepine co-crystals

Abstract

A comparative examination of different co-crystal screening approaches that employ different crystallization techniques and conditions is presented through the study of a set of sixteen co-crystal forms of carbamazepine (CBZ). The selection of co-crystals used herein captures representation from all the three common packing motifs for CBZ co-crystals. The screening was conducted using non-stoichiometric (addition of CBZ to saturated solutions of co-crystal former (CCF)) and stoichiometric crystallisation (equivalent mol amount of CBZ and CCF) methods. For non-stoichiometric experiments, various mixing regimes were studied, whereas for stoichiometric experiments, evaporation, solvent drop grinding and dry grinding techniques were assessed. An overall success rate of 85% was achieved with the various experiments using the non-stoichiometric approach with respect to co-crystallization, whereas only 61% of the experiments using the stoichiometric approach via grinding (dry and wet) and evaporation produced co-crystals. The findings of this work suggest that, contrary to the common practice wherein grinding and solvent evaporation based methods are most commonly used, the non-stoichiometric crystallization screening method should be first pass screen of choice. This reflects its higher success rate and higher utility towards the overall solid form development process. The fact that in our study, CBZ-GA co-crystals could only be obtained from grinding based methods, nonetheless, clearly illustrates the utility of other screening methods when hits are not obtained from the non-stoichiometric crystallization screening method.