Mesoscale clusters in multicomponent systems: the effect of solution preparation and pre-treatment on primary nucleation of a carbamazepine-saccharin cocrystal

Abstract

In this work, direct investigation of mesoscale clusters in solution using dynamic light scattering is combined with an indirect method based on the study of primary crystal nucleation and its dependence on the conditions of solution preparation and pre-treatment. In a novel approach we have studied how the nucleation induction time of a pharmaceutical cocrystal, a 1 : 1 saccharin–carbamazepine cocrystal, depends on different preparation and pre-treatment conditions, in particular whether solutions are prepared by dissolving the cocrystal solids or the two coformers separately. Nucleation is clearly affected by some pre-treatment conditions, with longer induction times obtained for a high pre-treatment temperature and when solutions are microfiltered after dissolution. The strongest effect was observed when comparing different starting materials, with solutions prepared using cocrystals leading to much shorter induction times than solutions based on the separate coformers. DLS shows that both types of solutions contain mesoscale clusters of the order of 100–300 nm in size, but that there are clear differences in the amount of scattering indicating a higher cluster concentration in the solutions based on cocrystal solids. The results suggest the possibility that mesoscale clusters can have a structural dimension, associated with slow kinetics, which can directly affect nucleation.