One-solvent polymorph screen of carbamazepine

To emphasize the fact that solvents can be either critical or immaterial in crystallizing specific polymorphs, a method for obtaining multiple polymorphs of a compound using only one solvent is demonstrated. By varying the crystallization temperature and level of supersaturation, three of the four polymorphs of carbamazepine (CBZ; 5H-dibenz [b,f]azepine-5-carboxamide) were crystallized from cumene (isopropyl benzene). Form III, also referred to as the primitive monoclinic form, was produced at temperatures below 60 °C from supersaturated solutions concentrated at less than twice the solubility of that form. When the supersaturation was increased to twice the solubility of form III at temperatures below 60 °C, form II, also referred to as the trigonal form, was produced. Form I, also referred to as the triclinic form, was produced regardless of the level of supersaturation at temperatures above 80 °C. Between 60 °C and 80 °C, mixtures of forms were produced. Competition slurries were employed to establish the transition temperature to be between 79 °C and 82 °C for the enantiotropically related forms III and I. These results indicate that crystallization of CBZ from cumene can either be under thermodynamic control or affected by the kinetics of crystallization of metastable forms. This raises the question about the importance of solvent diversity when looking for polymorphs, suggesting that a rational experimental design can be used to greatly reduce the number of solvents and crystallization conditions. The results of this one-solvent polymorph screen correlate somewhat with a phase–solubility diagram for CBZ.