Structural insights into ketanserin salts with aliphatic acids and their physiochemical properties†

Abstract

Ketanserin (KTS), a BCS class II drug, is used as an alpha-blocking serotonin antagonist. The drug decreases blood pressure by lowering peripheral vascular resistance. In order to improve its poor aqueous solubility, multicomponent solid forms of KTS with aliphatic acidic coformers such as maleic acid (MA), fumaric acid (FA), adipic acid (AA), and sulfamic acid (SA) were synthesized via wet granulation. The salts were characterized by XRD, DSC, TGA and single crystal XRD. Proton transfer from acidic coformers to the most basic piperidine nitrogen atom of KTS confirmed salt formation. KTS·FA and KTS·MA are anhydrous salts, while KTS·SA and KTS·AA are hydrates. KTS·SA crystallized as both monohydrate (MH) and dihydrate (DH), with the dihydrate being the more thermodynamically stable phase. The KTS hydrogen-bonded amide dimer is replaced by piperidinium⋯carboxylate/sulfonate ionic heterosynthons in the salts. Hirshfeld surface analysis quantified the non-covalent interactions governing the salt assembly. Solubility studies in 0.1 N HCl (pH 1.2) and phosphate buffer (pH 6.8) revealed improved solubility for all salts compared to KTS, with the order being KTS·SA (DH) > KTS·FA > KTS·MA > KTS·AA > KTS in phosphate buffer. Slight solubility improvement was observed in acidic medium (pH 1.2). KTS salts maintained their integrity in phosphate buffer but transformed into their HCl salts under acidic conditions. The enhanced solubility of KTS·SA (DH) is attributed to higher ΔpK_a, polar contacts, extended conformation, and ionic heterosynthons. These new solid forms of KTS present an opportunity to overcome solubility-related bioavailability challenges.