Measuring the Solubility of a Quickly Transforming Metastable Polymorph of Carbamazepine

摘要

The solubility of the stable Fill polymorph of the pharmaceutical compound carbamazepine was measured by determining its solubility gravimetrically in ethanol and methanol. Where the metastable FI polymorph was suspended in a solution of ethanol, the stable Fill polymorph nucleated immediately, initiating a solution-mediated transformation from FI to Fill. This meant that the FI polymorph was not in thermodynamic equilibrium with the solution as FI was continually dissolving while Fill was growing. We show that the solubility of FI can be accurately measured by in situ microscopy using an adaption of the bracketing method, and the results show that the solubility is close to but higher than the maximum solution concentration reached during the solution-mediated transformation from FI to Fill carbamazepine in both solvents. The technique demonstrates a relatively simple and robust method for determining the solubility of a metastable crystalline phase which transforms quickly in solution.