Physicochemical Characterization of L-691, 121, a Potent and Selective Class III Antiarrhythmic Agent

Abstract

The physicochemical properties of the novel antiarrhythmic agent L-691, 121 [methanesulfonamide, N- (1′- (2- (5-benzofirazanyl)ethyl)-3, 4-dihydro-4-oxospiro(2H-1-benzopyran-2, 4′-piperdin)6-yl), hydrochloride] have been studied, with particular emphasis on the stability, solubility, and dissolution properties of the drug. Solubility data in the pH range 0.5 to 11 show several distinct regions which are consistent with the existence of dicationic, cationic, neutral, and anionic forms of the drug. Dissolution studies were carried out using a continuous flow system which employed a conductance flow cell to monitor dissolved drug concentration. It is shown that the surface area of the drug is an important property in determining the dissolution rate. Solution stability studies indicate that the drug is prone to undergo a base-catalyzed elimination reaction which produces an N-dealkylated product. The preformulation data are used to develop intravenous and oral dosage forms suitable for clinical use.