Investigation into the Mechanism of Solution-Mediated Transformation from FI to FIII Carbamazepine: The Role of Dissolution and the Interaction between Polymorph Surfaces

The solution mediated polymorphic transformation (SMPT) of the pharmaceutical compound carbamazepine was investigated in ethanol. Bulk transformation experiments were performed by monitoring the solution concentration and polymorphic composition over time during the transformation from the metastable FI polymorph to the stable FIII polymorph for a variety of initial conditions. Microscopic techniques, single-crystal X-ray diffraction, and computational methods were used to analyze the transformation. The nucleating behavior of the stable FIII polymorph was a significant factor affecting the transformation time across the range of experiments. The surfaces of the metastable FI particles were responsible for the nucleation of FIII during the transformation. However, no specific lattice matching or epitaxy was conclusively identified. A modest amount of dissolution of the FI particles was found to favor the nucleation of FIII but where extensive dissolution or no significant dissolution occurred this had a negative effect on the nucleation of FIII.