Proline has been
widely used for various cocrystallization applications,
including pharmaceutical cocrystals. Combining enantiopure and racemic
flurbiprofen and proline, we discovered 18 new crystal structures.
Liquid-assisted grinding proved highly efficient to explore all the
variety of crystal forms. A unique combination of state-of-the-art
characterization techniques, comprising variable temperature in situ X-ray diffraction and in situ ball-milling,
along with other physicochemical methods and density functional theory
calculations, was indispensable for identifying all the phases. Analyzing
the results of in situ ball-milling, we established
a stepwise mechanism for the formation of several 1:1 cocrystals via
an intermediate 2:1 phase. The nature of the solvent in liquid-assisted
grinding was found to significantly affect the reaction rate and,
in some cases, the reaction pathway.
Although cocrystals have undergone a recent boost in popularity, limited time is spent on exploring the variety of possible cocrystal phases, which is likely due to the popularity and success of grinding methods. The number of studies where cocrystallization is systematically applied in solution remains limited. In this contribution, we present a rapid method for cocrystal synthesis in solution, which not only provides single crystals suitable for X-ray diffraction structural analysis but also allows one to explore the variety of cocrystal systems (polymorphs and solvates). Applying this approach to caffeine/dicarboxylic acid systems, we discovered 7 cocrystals and solved the structures for 6 of them. Astonishingly, the caffeine/mesaconic acid cocrystal system not only seems to be stoichiometrically diverse but furthermore also shows no less than 4 polymorphs of the 2 : 1 cocrystal.
The screening of S-naproxen, S-oxiracetam, S-diprophylline, and levetiracetam with a series of essential and nonessential amino acid co-formers has yielded cocrystals only for S-naproxen, thus showing that amino acids seem to have a preference for forming cocrystals with compounds containing a carboxyl group. Herein, we report the crystal structures of four S-naproxen cocrystals: S-naproxen/L-alanine, S-naproxen/D-alanine, S-naproxen/D-tyrosine, and S-naproxen/D-tryptophan monohydrate. All of the described cocrystals show similar structural motifs, i.e., amino acids form head-to-tail chains with strong charge-assisted hydrogen bonding, which are similar to those found in the individual amino acids, with S-naproxen molecules grafted on them. According to the systematic search of the Cambridge Structural Database for other cocrystals that involve zwitterionic co-formers, charge-assisted hydrogen bonds between amino acid molecules play an essential role, being present in the majority of structures. The results of this work provide an insight into structural aspects of cocrystallization with zwitterionic co-formers, offer new possibilities for S-naproxen pharmaceutical formulations, and can serve as guidelines when developing new cocrystals involving zwitterionic co-formers.
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