Structural Study of Prolinium/Fumaric Acid Zwitterionic Cocrystals: Focus on Hydrogen-Bonding Pattern Involving Zwitterionic (Ionic) Heterosynthons Anaë lle Tilborg, † Tom Leyssens, ‡ Bernadette Norberg, † and Johan Wouters* ,† † Unite ́ de Chimie Physique Thé orique et Structurale, Department of Chemistry, University of Namur, 61, rue de Bruxelles, B-5000 Namur, Belgium ‡ IMCN, MOST, UCL, 1, Place Louis Pasteur, B-1348 Louvain-la-Neuve, Belgium * S Supporting Information ABSTRACT: Pharmaceutical compounds are mostly devel- oped 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. ■ INTRODUCTION Different methods can be used to deal with problems when a compound of therapeutic interest (active pharmaceutical ingredient or API) presents unsuitable physicochemical proper- ties (e.g., melting point too low for the further development; inappropriate dissolution rate or solubility itself) or exhibits different polymorphic forms that interconvert at ambient temperature with only one being therapeutically appropriate. 1-3 To improve physicochemical properties (e.g., solubility, dissolution rate), formulation scientists turn to various basic approaches, such as salt formation, or solid-state approaches, such as amorphization or metastable phase formation. 1,4 Although the formation of salts is an excellent means of altering the physicochemical properties of an API, 5 it requires at least one ionizable center. Furthermore, the number of pharmaceutically acceptable salt formers is relatively small. 6,7 When the pharmaceutical compound of interest does not present ionizable functions and when the formation of amorphous or metastable phase is not a viable option, formation of pharmaceutical cocrystal is a well-adapted method for improving physicochemical properties of APIs. 8,9 Indeed, cocrystallization is regarded as one of the promising approaches in the field of pharmaceutical solid-state chemistry, 4,10-12 and recent studies highlight the advantages of using cocrystallization as a mean to optimize physicochemical properties or avoid the appearance of unwanted polymorphic forms. 8,13-15 Our interest in proline (Pro) lies in the fact that, besides being one of the natural α-amino acids composing proteins, this molecule has already been implicated in cocrystals and hence could be a valuable cocrystal former (considering the ease of forming cocrystal with the selected partner of interest). 16-19 Its precise role to stabilize the cocrystals and a detailed understanding at the molecular level of the interactions involved in these multicomponent molecular complexes deserve attention. Recent studies on the mediator role of proline in aldol organic catalysis and amplification of enantiomeric excess 20-22 further justify solid-state studies of this molecule, in the framework of preparation of solid-solid Received: January 15, 2013 Revised: May 10, 2013 Published: May 14, 2013 Article © 2013 American Chemical Society 2373 dx.doi.org/10.1021/cg400081v | Cryst. Growth Des. 2013, 13, 2373-2389