The unexpected discovery of the ninth polymorph of tolfenamic acid

Abstract

Tolfenamic acid (TFA) is a very well-studied polymorphic compound with eight polymorphs discovered to date. Here, we report on a new polymorph of TFA, form IX, which was unexpectedly crystallised from isopropanol at low temperatures. Crystals of form IX appeared concomitantly with the more common forms I and II, raising the question as to why this polymorph had never been reported before. With the aid of dispersion corrected DFT, paired with calculations of vibrational frequencies, we analysed the stability of this new polymorphic form of TFA. Thermal measurements, solubility measurements and solvent-mediated phase transformation experiments confirm that TFA form IX is a metastable polymorph, with a stability that is close to the well-known forms I and II.