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.