Exploring polymorphism and stoichiometric diversity in naproxen/proline cocrystals

This is the authors' abstract. We don't add key points for this paper.

We present naproxen/proline cocrystals discovered when combining enantiopure and racemic naproxen and proline. Using liquid-assisted grinding as the main method to explore the variety of crystal forms in this system, we found 17 cocrystals, of which the structures of only four of them were previously known. The naproxen/proline system exhibited multiple polymorphs of 1 : 1 stoichiometry as well as more rare cocrystals with 1 : 2 and 2 : 3 stoichiometries, two cocrystal hydrates and one cocrystal solvate. In situ ball-milling, used to monitor liquid-assisted grinding reactions, revealed that the solvent dictates the reaction intermediates even if the final reaction product stays the same. Synchrotron X-ray diffraction data collected in situ upon heating allowed us to monitor directly the phase changes upon heating and gave access to pure diffraction patterns of several cocrystals, thus enabling their structure determination from powder X-ray diffraction data; this method also confirmed the formation of a conglomerate in the RS-naproxen/dl-proline system. Proline in cocrystals kept its ability to form charge-assisted head-to-tail N-H...O hydrogen bonds, typical of pure crystalline amino acids, thus increasing the percentage of strong charge-assisted interactions in the structure and consequently providing some of the cocrystals with higher melting points as compared to pure naproxen. The majority of drugs are chiral, and hence, these data are of importance to the pharmaceutical industry as they provide insight into the challenges of chiral cocrystallization. The authors thank the Universite catholique de Louvain and the FNRS (FRIA scholarship allocated to N. Tumanova) for financial support. We thank the ESRF, PSI, BESSY II, and SOLEIL for the beam time allocation. We thank the PC2 platform at the University of Namur for single-crystal and powder X-ray diffraction analysis. Natalia Tumanova is grateful to Dr. F. Emmerling's group for a warm welcome during her STSM funded by COST Crystallize Action (CM1402). The authors highly appreciate advice from Dr. Radovan Cerny concerning the structure solution from PXRD. We thank Lisa Baulard for her help in preparing solutions for single-crystal growth, Pascal Van Velthem for helping us to treat DSC data, and Jean-François Statsyns for measuring the TGA data.