Phase Purity and Phase Stability of Trimorphic Etoricoxib−2,6-Dihydroxybenzoic Acid Salt Forms

Abstract

The study of polymorphism in drug crystals is of great importance due to its implications on patentability and the biopharmaceutical attributes of an active pharmaceutical ingredient (API). The study of polymorphism, particularly in multicomponent systems, is more challenging due to greater complexity and a larger number of variables involved. We report here three polymorphs (I, II, and III) and a monohydrate (form IV) of the COX-2 inhibitor etoricoxib, with the 2,6-dihydroxybenzoic acid 1:1 salt. We noted that a choice of crystallization solvent (polar vs non-polar) and method (mechanochemical vs solution) can yield specific polymorphs (I or II). Additionally, we found that a skewed crystallization stoichiometry also influences crystallization outcomes, leading to the isolation of another metastable polymorph, III. The reported crystal forms were thoroughly studied using thermal, diffraction, spectroscopic, and microscopic methods. Additionally, the relative stabilities, phase transformations, and physicochemical properties of reported crystalline salts were studied.