Estimating Relative Stability of Polymorphs by Generation of Configurational Free Energy Phase Diagram

Relationship between two polymorphs is described to be either enantiotropic or monotropic with transition temperature/transition point (Tt) below the melting point (Tm) of the lower melting form in former case and above the Tm of the higher melting form in latter case. In the present work, a new methodology for assessing thermodynamic Tt of two polymorphs has been developed. Configurational free energy (Gc) of amorphous with respect to each polymorph was calculated to determine the Tt. This method was used to determine the Tt and polymorphic relationship of two model drugs, namely, carbamazepine and nateglinide. This method was also compared with the previous methodologies. Deduced Tt of carbamazepine using this methodology was compared with previously reported values and was found to be in good agreement. A monotropic relationship was established between nateglinide polymorphs based on Tt obtained by present methodology and previous reported methodologies. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:1843-1851, 2012