Yes / 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), slurry and in situ variable temperature X-ray diffraction (VTXRD). For completeness, we have also re-determined 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 metastable at ambient conditions. Further, the results suggest that the dimorphs are enantiotropically related and the transition temperature is estimated to be 79 Celcius degrees. / This work was supported by Science and Engineering Research Council of A*STAR (Agency for Science, Technology and Research), Singapore.

Yes / Insights into structure–mechanical property correlations in molecular and multicomponent crystals have recently attracted significant attention owing to their practical applications in the pharmaceutical and specialty fine chemicals manufacturing. In this contribution, we systematically examine the mechanical properties of dimorphic forms, Forms I and II of 1:1 caffeine-glutaric acid cocrystal on multiple faces using nanoindentation to fully understand their mechanical anisotropy and mechanical stability under applied load. Higher hardness, H, and elastic modulus, E, of stable Form II has been rationalized based on its corrugated layers, higher interlayer energy, lower interlayer separation, and presence of more intermolecular interactions in the crystal structure compared to metastable Form I. Our results show that mechanical anisotropy in both polymorphs arises due to the difference in orientation of the same 2D structural features, namely the number of possible slip systems, and strength of the intermolecular interactions with respect to the indentation direction. The mechanical properties results suggest that 1:1 caffeine-glutaric acid cocrystal, metastable form (Form I) could be a suitable candidate with desired tablet performance to that of stable Form II. The overall, it demonstrates that the multiple faces of nanoindentation is critical to determine mechanical anisotropy and structure- mechanical property correlation. Further, the structural-mechanical property correlations aids in the selection of the best solid phase for macroscopic pharmaceutical formulation.