Enhancing Adamantylamine Solubility through Salt Formation: Novel Products Studied by X-ray Diffraction and Solid-State NMR

Abstract

The reactivity of the neuroleptic drug adamantylamine toward aliphatic carboxylic acids, sulfone derivatives, and aromatic amino acids was screened for the first time using simple mechanochemical methods. Seven new molecular salt structures were reported exhibiting improved physicochemical properties. To carefully characterize these compounds, multiple complementary techniques were combined: single crystal and powder X-ray diffraction, 13 C/ 15 N solid-state NMR, and Fourier transform infrared-attenuated total reflectance spectroscopies, employed to solve cocrystal/salt ambiguities. In all molecular salts, the crystal packing is supported on a common synthon, a N−H + (ADA) •••O − (coformer) charge assisted hydrogen bond. Different supramolecular arrangements were obtained induced by the size of the counterions as well as their complementary functional groups. Two salts, with glutaric and methanesulfonic acids, presented higher solubility than the commercially available pharmaceutical product.

The Lisbon Supramolecular Green Story: Mechanochemistry towards New Forms of Pharmaceuticals

“…Figure 12. General experimental conditions and products obtained in the reactions between adamantylamine and aliphatic acids, sulfone derivatives, and aromatic acids [76].…”

“…The presence of the N-H ... (4-AMINO) ... O -(4-AMINO) HB interaction allows the R 6 8(40) synthon, where ADA aliphatic domains face each other. Some aliphatic hydrogen atoms were omitted for clarity [76].…”

“…8 (40) synthon, where ADA aliphatic domains face each other. Some aliphatic hydrogen atoms were omitted for clarity [76].…”

“…15 N CPMAS NMR spectra for all salts. Red, blue, and green rectangles highlight the15 N CS associated with ADA protonated amine, saccarin and sulfanilic acid, respectively[76].Molecules 2020, 25, x FOR PEER REVIEW 15 of 20…”

“…13 C CPMAS NMR spectra for all salts, showing the CS range for C1 (right side) and carboxylic/carboxylate resonances (left side). Filled circles in the ADA structure indicate the position of the C1 quaternary carbon[76].…”