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

(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 δ_iso, ¹³C δ_iso) with computed shielding parameters calculated by means of the GIPAW method.