(702f) Solvent-Dependent Stability of Crystal Forms

Polymorphism, the ability of a molecule to exist in different crystalline forms with distinct physical properties, is a phenomenon of critical importance in chemical industry, particularly in the production of active pharmaceutical ingredients. Mefenamic acid, MFA, 2-[(2,3-dimethylphenyl) amino] benzoic acid, is an anthranilic acid derivative and is widely used as a non-steroidal anti-inflammatory drug. MFA exhibits at least three polymorphs (I, II, III) with significantly different bioavailability. Under ambient conditions, the order of stability of these polymorphs follows I > II > III, whereas at elevated temperatures the order shifts to II>I>III. MFA polymorphs, due to their dissimilar structures, display distinct thermodynamic characteristics, including the parameters of their solution-crystal equilibria. In recent years, numerous studies have claimed that the effect of solvent is not thermodynamic in nature and solvents only affect the kinetics of polymorphic transformations. Our results challenge this conventional understanding. We demonstrate that the relative stability of MFA polymorphs is solvent dependent. To identify and characterize the polymorphs, we employ Raman spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. We use four solvents of pharmaceutical relevance: formamide, dimethylformamide, toluene and water. We develop a new method to measure the solubilities of metastable crystal forms and quantify their temperature dependences to evaluate the thermodynamic characteristics of MFA crystal forms. Independently, we measure the transformation rates between polymorphs. We find that that relative differences in free energy, enthalpy and entropy of crystallization for both MFA polymorphs are influenced by the chosen solvent. At lower temperatures, in formamide, form II becomes more stable than form I. The found solvent-dependent polymorph stability enables an additional pathway for polymorph control.