Opening Pandora’s Box: Chirality, Polymorphism, and Stoichiometric Diversity in Flurbiprofen/Proline Cocrystals

Abstract

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.

Melting points of one- and two-component molecular crystals as effective characteristics for rational design of pharmaceutical systems

“…The melting temperatures of cocrystals for comparison were obtained by different authors under different conditions (different heating rates and, sometimes, some authors give melting temperatures as onset values, and others as a peak on the DSC curves). In the case of [R-flurbiprofen + dl-proline], where the data was obtained by Tumanova et al (2018a), the melting points are within experimental errors.…”

Chirality in amino acids beyond the Cα configuration

“…In combination with flurbiprofen, proline proved to be a potent coformer, resulting in 18 different modifications (29 entries in Table S1). In Table S1, there are 24 entries of rare earth metal complexes of the types [M 2 (H 2 O) 6 (Pro) 5 ](ClO 4 ) 6 (18 structures) and [M(H 2 O) 4 (Pro) 2 ]Cl 3 (6 structures), containing unidentate and bridging bidentate proline zwitterions as ligands. Although the selectivity in the diastereomer ratio of the pyramidalization angles dr( θ ) = 13:11 is only small, the − ψ /+ ψ separated diastereomer ratios dr( θ ) − ψ = 13:2 and dr( θ ) +ψ = 8:1 demonstrate impressively the control of the pyramidalization of the carboxylic group by the − ψ and + ψ conformation in the second step of the chirality chain.…”

“…In combination with flurbiprofen, proline proved to be a potent coformer, resulting in 18 different modifications (29 entries in Table S1). 8 In Table S1…”

Amino Acids as the Potential Co-Former for Co-Crystal Development: A Review

“…Tumanova et al conducted a study on the ability of co-crystal formation between flurbiprofen and l -proline using the LAG method with five different solvents, i.e., methanol, ethanol, isopropanol, acetonitrile, and water; both compounds are soluble in methanol and ethanol; only flurbiprofen is soluble in isopropanol and acetonitrile, and only l -proline is soluble in water. This study showed that the choice of the solvent used for the LAG method is a factor that can affect the rate of reaction and the reaction pathway, as five co-crystal structures were found with different types of supramolecular synthon [ 86 ]. A similar thing was observed in the formation of co-crystals between naproxen and l -proline using the LAG method with five different solvents by Tilborg et al [ 87 ].…”