Crystal Engineering of Pharmaceutical Co-crystals: Application of Methyl Paraben as Molecular Hook

Abstract

Applicability of the O-H...N heterosynthon for synthesis of a pharmaceutical co-crystal comprised of a commonly used tablet excipient methyl paraben and quinidine, an anti-malarial constituent of Cinchona tree bark, has been successfully demonstrated. Insights into local conformation and hydrogen-bonding were derived from advanced multinuclear solid-state NMR techniques, where interpretation of the obtained NMR data was supported by DFT quantum-chemical computations. Furthermore, an approach for selective separation of quinidine from its stereoisomer quinine based on the molecular specificity of methyl paraben is presented. It was found that methyl paraben picked its target via hydrogen-bond-mediated molecular recognition, thereby acting as "molecular hook".

Probing Intermolecular Crystal Packing in γ-Indomethacin by High-Resolution 1H Solid-State NMR Spectroscopy

“…1-3 While 13 C crosspolarisation (CP) MAS is an established workhouse technique, the power of high-resolution 1 H solidstate NMR experiments is starting to be recognised: 1 H chemical shifts have been determined from onedimensional fast-MAS spectra and two-dimensional 1 H- 13 C correlation spectra, [4][5][6][7][8][9][10][11][12][13] with H-H proximities being identified in two-dimensional 1 H-1 H DQ (double-quantum) MAS and DQ CRAMPS (combined rotation and multiple-pulse spectroscopy) spectra. [10][11][12]14,15 The emerging field of NMR crystallography of organic solids employs experimental solid-state NMR usually in combination with calculation to probe solid-state structures.…”

“…[10][11][12]14,15 The emerging field of NMR crystallography of organic solids employs experimental solid-state NMR usually in combination with calculation to probe solid-state structures. [16][17][18][19][20] In the context of organic molecules, a particular focus is upon the interactions that govern the adopted intermolecular packing, notably hydrogen bonding and aromatic - effects.…”

Crystal engineering rescues a solution organic synthesis in a cocrystallization that confirms the configuration of a molecular ladder

“…For a CCF, we selected a carboxylic acid, which was expected to interact with the ladderane via the robust pyridyl⋯ carboxylic acid supramolecular synthon (Scheme 4) (25). Cocrystallization of the ladderane with a monoacid (1∶4 ratio) was expected to generate a two-component solid wherein the ladderane and acid self-assemble via O-HðacidÞ⋯NðpyridylÞ hydrogen bonds.…”

“…The interaction between a CCF and ladderane would enable the components to pack more efficiently relative to the pure ladderane. Whereas cocrystallizations are often successfully used to aide the elucidation of the structures biological molecules (22), the application of a cocrystal strategy to determine the relative configuration of a diastereomer had not been reported (23)(24)(25)(26)(27).…”

“…To circumvent difficulties to obtain single crystals, we revisited principles of crystal engineering by employing a cocrystallization (Scheme 3). Cocrystallizations are often used to determine structures of biomolecules (e.g., proteins) (22), yet applications to parallel problems involving small molecules have been less explored, with absolute structure determinations of steroids (23,24) and, more recently, separations and structure determinations of natural products (25,26) and a bicyclobutyl being the only examples (27). Here, a cocrystallization of the second isomer with 3,5-dinitrobenzoic acid (3,5-DNBA) readily afforded single crystals that enabled the relative configuration of chiral 1b to be confirmed.…”