Influence of Operating Temperature and Pressure on the Polymorphic Transition of Salmeterol Xinafoate in Supercritical Fluids HENRY H.Y. TONG, 1 BORIS Y. SHEKUNOV, 2 PETER YORK, 3 ALBERT H.L. CHOW 4 1 School of Health Sciences, Macao Polytechnic Institute, Macao, China 2 Ferro Pfanstiehl Laboratories, Independence, Ohio 4413 3 Drug Delivery Group, School of Pharmacy, University of Bradford, Bradford BD7 1DP, United Kingdom 4 School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China Received 28 January 2007; revised 3 March 2007; accepted 13 March 2007 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21011 ABSTRACT: Precipitation of pure polymorphic forms (I and II) of salmeterol xinafoate (SX) in supercritical fluids was investigated as a function of operating pressure and temperature. It has been shown that the formation of each polymorph is governed by both thermodynamic shift and kinetic effects, which are closely associated with the extent of miscibility between the supercritical CO 2 and methanol cosolvent. In addition, the surface energetics of SX exhibit a sharp discontinuity at the transition point in concordance with the particular polymorphic form generated, being essentially independent of the temperature or pressure below and above this point. The conditions of complete miscibility of the two solvent phases involved are critical for the formation of SX Form II. ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1025–1029, 2008 Keywords: supercritical fluid crystallization; pressure and temperature; poly- morphic transition; surface energetics; salmeterol xinafoate INTRODUCTION The ability of supercritical fluid crystallization (SFC) to control the production of specific crystal forms has been exemplified by a number of pharmaceutical materials, for example, fluti- casone propionate, 1 carbamazepine, 2 and salme- terol xinafoate. 3–7 However, as SFC is still largely operated as an empirical process in industry, it is imperative to elucidate the underlying thermo- dynamic and kinetic factors governing the process so as to improve the prediction of the crystal forms produced. In our previous studies, two pure polymorphic forms (I and II) of the long acting anti-asthmatic agent, salmeterol xinafoate (SX), have been crystallized at 40 and 908C, respec- tively, from supercritical carbon dioxide (SC CO 2 ) under a constant pressure of 250 bar. 3 The two forms have been found to be related enantiotro- pically with a transition temperature of 998C at atmospheric pressure 3 and to display distinctly different solid-state and surface properties. 3–9 In order to define more precisely the SFC conditions for the production of the two polymorphs, the present study has examined the effects of operat- ing temperature and pressure on the physical forms and surface energetics of the SX materials produced in SC CO 2 . Correspondence to: Albert H.L. Chow (Telephone: (852) 26096829; Fax: (852) 26035295; E-mail: albert-chow@cuhk.edu.hk) Journal of Pharmaceutical Sciences, Vol. 97, 1025–1029 (2008) ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 2, FEBRUARY 2008 1025