Lower melting pharmaceutical cocrystals of metaxalone with carboxamide functionalities

Abstract

Supramolecular reactions between a muscle relaxant drug, Metaxalone, 5-[(3,5-dimethylphenoxy)methyl]-2-oxazolidinone with a few carboxamides like nicotinamide, isonicotinamide, salicylamide and carboxylic acid coformers such as 3-hydroxybenzoic acid, 4-hydroxybenzoic acid resulted binary cocrystals. The cocrystals were initially characterized by PXRD, FT˗IR, ss-NMR, DSC and finally confirmed by single crystal X-ray diffraction. Surprisingly, all the novel cocrystals exhibited melting endotherm lower than the drug and coformer, which is not so common (29%) in the literature. Vibrational spectroscopy suggests the possible stoichiometry of the drug cocrystals based on the number of carbonyl stretching frequencies and hydrate formation in case of 4-hydroxybenzoic acid cocrystal. 13C-ssNMR spectroscopy of metaxalone–salicylamide cocrystal indicates the possibility of more symmetry independent molecule of the drug in the starting material to less in the cocrystal and molecular conformation was also reflected in the spectrum. The corresponding crystal structure consists of one molecule each of metaxalone and salicylamide in the asymmetric unit. Similar to the thermodynamically stable form of the drug and cocrystals with mono/di-carboxylic acids, metaxalone forms centrosymmetric NH⋯O hydrogen bonded imide-imide homodimer in this cocrystal. Salicylamide molecules also form centrosymmetric amide-amide homosynthon. Both the homodimers are perpendicularly (79°) interlinked via bifurcated carbonyl oxygen of the drug, which results 1D chain along the crystallographic b-axis. Auxiliary C˗H⋯O interactions further stabilize the bonding between the drug and salicylamide. Binding energy calculation of metaxalone/salicylamide homodimer and metaxalone‒salicylamide heterodimer using B3LYP/6-311++G** method and in addition, the stacking energy interactions in the API suggest the most preferred API homodimer synthon in the reported polymorphs and cocrystals. The pharmaceutical cocrystals of metaxalone with amide functionalities are reported for the first time in the literature.