Thermal and in Situ X-ray Diffraction Analysis of a Dimorphic Co-Crystal, 1:1 Caffeine–Glutaric Acid

Abstract

Spurred by the enormous interest in co-crystals from the pharmaceutical industry, many novel co-crystals of active pharmaceutical ingredients have been discovered in recent years, and this has in turn led to an increasing number of reports on polymorphs of co-crystals. Hence, a thorough characterization and understanding of co-crystal polymorphs is a valuable step during drug development. The purpose of this study is to perform in situ structural analysis and to determine thermodynamic stability of a dimorphic co-crystal system, 1:1 caffeine–glutaric acid (CA–GA, Forms I and II). We performed thermal and structural characterizations by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM), and slurry and in situ variable temperature X-ray diffraction (VTXRD). For completeness, we have also redetermined crystal structures of CA–GA Forms I and II at 180 K using single crystal X-ray diffraction. Our results revealed that Form II is stable and Form I is metastab...