Effect of Chloride Ion on Dissolution of Different Salt Forms of Haloperidol, a Model Basic Drug SHOUFENG LI, 1 PAMELA DOYLE, 2 STEPHANIE METZ, 1 ALAN E. ROYCE, 1 ABU T.M. SERAJUDDIN 1 1 Pharmaceutical and Analytical Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936 2 Arnold and Marie Schwartz College of Pharmacy, Long Island University, 75 DeKalb Avenue Brooklyn, New York 11201-5497 Received 17 January 2005; revised 7 June 2005; accepted 12 June 2005 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20440 ABSTRACT: The effect of chloride ion (Cl  ) on dissolution rates of hydrochloride, mesylate (methanesulfonate) and phosphate salt forms of a model drug, haloperidol, was investigated. The dissolution rates of the salts in 0.01M HCl from rotating disks followed the order of mesylate >> phosphate > hydrochloride. With additional chloride ion, a decrease in dissolution rate of the hydrochloride salt was observed due to the common ion effect. Dissolution rates of mesylate and phosphate salts also decreased due to their conversion to the HCl salt form on the surfaces of dissolving disks, however, the dissolution rates of mesylate and phosphate salts under identical chloride ion concentrations were still higher than that of the HCl salt. In powder dissolution studies, it was observed that kinetics of nonhydrochloride-to-hydrochloride salt conversion play a major role in dissolution; the mesylate dissolved completely (<5 min) before its dissolution rate could be impeded by its conversion to the hydrochloride salt form. Therefore, despite the potential for conversion to a hydrochloride salt form, certain nonhydrochloride salt forms may still be preferred for dosage form development due to kinetic advantages during dissolution, such as higher apparent dissolution rate of a nonhydrochloride salt before it could completely convert to the hydrochloride form. ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:2224– 2231, 2005 Keywords: dissolution rate; chloride ion; salt selection; powder dissolution; haloper- idol; basic drug INTRODUCTION Dissolution of pharmaceutical solids such as acids, bases, or salts into reactive media such as buffers, aqueous solutions with differing pH conditions, etc., has been reported and modeled in the litera- ture. 1–6 The published papers are primarily based on the Nernst–Brunner diffusion layer model, where it is assumed that a thin film or diffusion layer of drug solution exists at the surface of a dissolving solid, the drug concentration reaches saturation as the diffusion layer thickness ap- proaches zero, and, as result, a concentration gradient exists across the diffusion layer from the solid surface (diffusion layer thickness appro- aching zero) to the bulk dissolution medium. 1,6 The authors of these papers and others have quantitatively demonstrated how different fac- tors, such as intrinsic solubility of acidic or basic drugs, solubility of salt forms, ionization and pK a of drugs, and concentration of buffering agents, etc., contribute to the dissolution rate of acidic and basic drugs as well as their salt forms. However, one factor that has possibly not been addressed adequately is the effect of chloride ion (Cl  ) on dissolution of different salt forms. There is an abundance of chloride ion in the 2224 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 10, OCTOBER 2005 Correspondence to: Abu T.M. Serajuddin (Telephone: 862- 778-3995; Fax: 973-781-7329; E-mail: abu.serajuddin@novartis.com) Journal of Pharmaceutical Sciences, Vol. 94, 2224–2231 (2005) ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association