Novel salts of the antiemetic drug domperidone: synthesis, characterization and physicochemical property investigation

Abstract

Domperidone (DOM) (6-chloro-3-[1-[3-(2-oxo-3H-benzimidazol-1-yl)propyl]piperidin-4-yl]-1H-benzimidazol-2-one) is an antiemetic, galactagogue and gastrokinetic that works by blocking the dopamine receptor D2. Due to its low solubility, it has difficulty in crossing the blood–brain barrier. In this work, mechanochemistry and solution crystallization methods were used to effectively synthesize nine new domperidone salts, utilizing various generally recognized as safe (GRAS) salt formers, namely oxalic acid (OA), malonic acid (MA), succinic acid (SA), fumaric acid (FA), adipic acid (AA), citric acid (CA), 4-hydroxybenzoic acid (4-HBA), 2,4-dihydroxybenzoic acid (2,4-DHBA), and pyrazine-2-carboxylic acid (PCA). All the synthesized molecular salts were characterized using powder X-ray diffraction (PXRD), single crystal X-ray diffraction (SCXRD), and thermal analysis (thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)). Structural analysis revealed that out of the nine salts, DOM·SA, DOM·FA, DOM·AA and DOM·CA were crystallized as hydrates. In all the salts, proton transfer from the carboxylic acid group of the salt formers to the piperidine nitrogen atom of DOM was observed, with the predominant interactions involved being N–H⋯O, O–H⋯O and C–H⋯O hydrogen bonds. At ambient temperature, the solubility of the anhydrous form of DOM and its molecular salts at pH 1.2/pH 6.4 was determined. In comparison to the parent drug, in most of the cases, an increase in molecular salt solubility is observed. At pH 6.4, the order of solubility is DOM·AA > DOM·SA > DOM·FA > DOM·MA > DOM·OA > DOM·PCA > DOM·CA > DOM > DOM·4-HBA > DOM·2,4-DHBA whereas there is a change in the equilibrium solubility order at pH 1.2 i.e., DOM·FA > DOM·2,4-DHBA > DOM·SA > DOM·AA > DOM·PCA > DOM·MA > DOM·OA > DOM·4-HBA > DOM·CA > DOM. The PXRD analysis of the resulting residue following solubility demonstrated that the bulk of the molecular salts were stableand did not undergo any phase change or dissociation. This research implies that a better solubility of DOM molecular salts might aid in the creation of novel DOM formulations.