A series of memantine based salts with various aromatic and aliphatic carboxylic acids: Crystallographic analysis, Hirshfeld surfaces and dissolution study

Abstract

Memantine.HCl (MEM.HCl), an adamantane based amine is a clinically useful drug for the treatment of various neurological disorders. Surprisingly, applications of MEM salts/cocrystals in crystal engineering, as a supramolecular motif, are rarely reported in literature, in spite of opportunity that MEM salts (primary ammonium monocarboxylate, PAM and primary ammonium dicarboxylate, PAD) provide to study the reliability and stability of various non-bonded interactions such as C–H⋯O, C–H⋯N, van der Waals, etc. in presence of strong ionic hydrogen bonds (N+ –H…O−, O–H⋯ O, etc.). In the present study, a new series of 12 salts with MEM and varied carboxylic acid backbones (aliphatic and aromatic) were synthesized and characterized by various physicochemical techniques such as IR, NMR and single crystal X-ray studies. The focus was also directed to understand the supramolecular synthons present in these salts and establish a structure-property relationship among them. Qualitative (graph set analysis) and quantitative (Hirshfeld surface analyses) approaches were also employed to analyse all the single crystal structures of salts (1A-1K) to gain an insight regarding the supramolecular assemblies formed and some subtle variation in the well-established PAM and PAD supramolecular synthons. Additionally, all the synthesized salts were subjected to solubility studies in water and compared with the standard MEM. HCl salt. All synthesized salts displayed a range of solubility in water from high to medium to low as compared with MEM. HCl salt. Efforts were also directed to understand the possible cause of high and low solubility of newly synthesized MEM salts in water with respect to the carboxylic acid backbone, ratio of acid/amine (present in salts) and the supramolecular synthons present in the single crystal structures. Moreover, supramolecular isomerism of 1D PAM to 0D PAM, with bulky group substituted carboxylic acid (pivalic acid and 4-methylbenzoic acid), suggests bright future prospects of designing new materials from crystal engineering point of view.