Solvent-Dependent Relative Stability of Crystal Forms

Mefenamic acid (MFA), a nonsteroidal anti-inflammatory drug, exhibits at least three neat polymorphs (I, II, and III) with distinct MFA conformations. Under ambient conditions, the order of stability of the first two polymorphs is I > II. Numerous recent studies have claimed that solvents only affect the kinetics of polymorphic transformations and do not modify the relative thermodynamic stability of polymorphs. Here, we challenge this notion. We demonstrate that the relative stability of MFA forms I and II is dependent on the solvent in which the crystals grow. To identify and characterize the polymorphs, we deploy Raman spectroscopy, solid-state nuclear magnetic resonance (SS-NMR), powder X-ray diffraction (PXRD), microcrystal electron diffraction (microED), and differential scanning calorimetry. We find that the relative differences in Gibbs-free energy, enthalpy, and entropy of crystallization of MFA forms I and II strongly depend on the solvent and that at low temperature in formamide, there is a reversal in stability (II > I). This finding is supported by a competition slurry along with Raman, SS-NMR, PXRD, and microED characterizations of the competing forms. All-atom molecular dynamics simulations reveal that the transformations between MFA solution conformations and those in Form I and II crystals take longer times than MFA ingress into crystal growth sites, creating a population of growth-incompetent molecules that are incapable of joining a crystal. These times are solvent- and temperature-dependent, and their balance favors crystallization of form II at lower temperatures in formamide, whereas form I is preferred at higher temperature in formamide and at both tested temperatures in toluene. The identified solvent-dependent polymorph stability via the balance of growth-competent and incompetent solute conformations enables additional pathways for polymorph control.