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.
Highlights
Crystal engineering[1] is defined as the understanding of intermolecular interactions in the context of crystal packing and the use of such a comprehension in designing new crystalline materials with the desired physicochemical properties, such as hygroscopicity,[2] optical properties,[3] tabletability,[4] dissolution rate,[5−7] and melting point.[8]
We focused on methyl gallate (MG, Scheme 1, right)
In this paper we present the selective synthesis of anhydrous (MG·Pro2) and hydrated (MG2·Pro2·H2O) cocrystals of MG successfully achieved by employing Pro as a coformer in its anhydrous and hydrated (Pro·H2O) forms, respectively
Summary
Crystal engineering[1] is defined as the understanding of intermolecular interactions in the context of crystal packing and the use of such a comprehension in designing new crystalline materials with the desired physicochemical properties, such as hygroscopicity,[2] optical properties,[3] tabletability,[4] dissolution rate,[5−7] and melting point.[8]. Bilbao Crystallographic Database for pseudosymmetry confirmed the exactness of the P1 space group for MG2·Pro2·H2O with the absence of hidden symmetry elements and defects in the resulting structure, often present for this specific space group.[39] Both MG·Pro[2] and MG2· Pro2·H2O present a high number of molecular entities in the asymmetric unit (three and five, respectively), Z′ equals 1 for both crystal structures. By looking at this peculiarity of our cocrystals, we decided to analyze the Z′ distribution of the reported Pro cocrystals in the CSD. 10 mg) were placed into the furnace inside alumina crucibles and heated with a ramp rate of 10 °C min−1
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