Structural Study of Prolinium/Fumaric Acid Zwitterionic Cocrystals: Focus on Hydrogen-Bonding Pattern Involving Zwitterionic (Ionic) Heterosynthons

Pharmaceutical compounds are mostly developed as solid dosage forms containing a single crystal form. This implies that the selection of a particular crystal state for a given molecule is an important step for further clinical outlooks. Different methods can be used in the case of polymorphism issues at the time of optimal phase selection. One of the promising techniques developed these last few years is cocrystallization. In this context, proline (pyrrolidine-2-carboxylic acid) is considered in the present work. Cocrystals of proline and fumaric acid ( E -butenedioic acid) are mainly analyzed by powder and single-crystal X-ray diffraction (PXRD and SCXRD, respectively). At first, the cocrystallization conditions are optimized by grinding (dry grinding), a green method for cocrystals screening and synthesis. Under specific conditions, single crystals of a 2:1 l -proline–fumaric acid racemic zwitterionic cocrystal have been obtained, an outcome confirmed by crystallographic analysis. Enantiomeric cocrystal form was obtained starting from d -proline. With the racemic compound ( dl -proline), a three-component cocrystal is formed, the 1:1:1 l -proline– d -proline–fumaric acid cocrystal. Interestingly, this latter seems to be obtained using two distinct synthetic ways. Calorimetric measurements have been performed in order to establish the binary-phase diagram of the l -proline–fumaric acid cocrystal. Structural comparison with related structures from the Cambridge Structural Database revealed similarities in the crystalline network and introduced a systematic and detailed analysis of hydrogen bond interactions in zwitterionic cocrystalline structures involving proline.