Pseudopolymorphism Driven by Stoichiometry and Hydrated/Anhydrous Reagents: The Riveting Case of Methyl Gallate·l‑Proline

Abstract

Among GRAS molecules, α-amino acids have been extensively used to produce molecular salts and cocrystals of APIs thanks to their nontoxicity, ready availability, cheapness, and their zwitterionic nature. Here we report on the use of both anhydrous and hydrated l-proline (Pro and Pro·H2O, respectively) with methyl gallate (MG) to selectively obtain by mechanochemical methods anhydrous and hydrated cocrystals: MG·Pro2 and MG2·Pro2·H2O, respectively. The two new forms were characterized by means of single-crystal and powder X-ray diffraction (SCXRD and PXRD), solid-state nuclear magnetic resonance (SSNMR), DSC, and TGA. Interestingly, the choice of the starting material together with the stoichiometry drives the formation of the cocrystal toward either the anhydrous or the hydrate form: the anhydrous form could be obtained only on starting from anhydrous Pro, whereas the hydrate could be obtained with Pro·H2O or with Pro by matching the correct stoichiometry. An energy framework analysis allowed us to rationalize this peculiar water uptake behavior in terms of both the relative interaction strengths of proline–proline, proline–water, and proline–methyl gallate pairs and packing features