American Chemical Society
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π‑Philic Molecular Recognition in the Solid State as a Driving Force for Mechanochemical Formation of Apremilast Solvates and Cocrystals

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journal contribution
posted on 2018-05-29, 00:00 authored by Marta K. Dudek, Maciej Kostrzewa, Piotr Paluch, Marek J. Potrzebowski
(S)-N-{2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}­acetamide (Apremilast, APR), a novel anti-inflammatory drug used in psoriasis (Ps) and psoriatic arthritis (PsA) treatment, forms in the solid state well organized structures with a π-philic pocket susceptible to aromatic–aromatic interactions. It has been proven that such specific arrangement is preserved even after melting the APR sample. The empty π-philic APR pocket can be filled with different small molecules (dichloromethane, ethyl acetate, acetonitrile, toluene, benzene, pyridine) by means of mechanochemical grinding forming appropriate solvatomorphs; however, the strong preference for favorable interactions with aromatic species is unquestionable. During grinding of APR with a mixture of solvents (dichloromethane, acetonitrile, toluene), only toluene is embedded into the crystal lattice. Hence, it has been concluded that APR in the solid state behaves as a selective π-philic mechanoreceptor. The strong tendency for π-philic molecular recognition was employed in a mechanochemical process as a driving force for the formation of pharmaceutical cocrystals with coformers, which belong to the group of aromatic natural products (catechol, pyrogallol, resorcinol). The obtained cocrystals were characterized by advanced one-dimensional and two-dimensional solid state NMR techniques, differential scanning calorimetry, and powder X-ray diffraction. The molecular structure of APR/catechol cocrystal was refined employing an NMR crystallography approach, comparing the set of experimental NMR data (1H δiso, 13C δiso) with computed shielding parameters calculated by means of the GIPAW method.