title: Characterization of two polymorphs of salmeterol xinafoate crystallized from supercritical fluids.
abstract: OBJECTIVE
  To characterize two polymorphs of salmeterol xinafoate (SX-I and SX-II) produced by supercritical fluid crystallization.
  
  
  METHODS
  SX-I and SX-II were crystallized as fine powders using Solution Enhanced Dispersion by Supercritical Fluids (SEDS). The two polymorphs and a reference micronized SX sample (MSX) were characterized using powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), aqueous solubility (and dissolution) determination at 5-40 degrees C, BET adsorption analysis, and inverse gas chromatography (IGC).
  
  
  RESULTS
  Compared with SX-I, SX-II exhibited a lower enthalpy of fusion, a higher equilibrium solubility, a higher intrinsic dissolution rate, a lower enthalpy of solution (based on van't Hoff solubility plots), and a different FTIR spectrum (reflecting differences in intermolecular hydrogen bonding). Solubility ratio plot yielded a transition temperature (-99 degrees C) below the melting points of both polymorphs. MSX showed essentially the same crystal form as SX-I (confirmed by PXRD and FTIR), but a distinctly different thermal behaviour. Mild trituration of SX-I afforded a similar DSC profile to MSX while prolonged grinding of SX-I gave rise to an endotherm at -109 degrees C, corresponding to solid-solid transition of SX-I to SX-II. Surface analysis of MSX, SX-I, and SX-II by IGC revealed significant differences in surface free energy in terms of both dispersive (nonpolar) interactions and specific (polar) acid-base properties.
  
  
  CONCLUSIONS
  The SEDS-processed SX-I and SX-II display high polymorphic purity and distinctly different physical and surface properties. The polymorphs are related enantiotropically with SX-I being the thermodynamically stable form at room temperature.
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin NT, SAR, China.
authors.forename: H H
authors.initials: HH
authors.lastname: Tong
authors.forename: B Y
authors.initials: BY
authors.lastname: Shekunov
authors.forename: P
authors.initials: P
authors.lastname: York
authors.forename: A H
authors.initials: AH
authors.lastname: Chow
mesh_terms: D000420:Albuterol / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000302:isolation & purification; D001993:Bronchodilator Agents / Q000737:chemistry* / Q000302:isolation & purification; D002152:Calorimetry, Differential Scanning; D002849:Chromatography, Gas; D025924:Chromatography, Supercritical Fluid / Q000379:methods; D003460:Crystallization; D018360:Crystallography, X-Ray / Q000379:methods; D011208:Powders; D000068299:Salmeterol Xinafoate; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013499:Surface Properties; D013816:Thermodynamics
chemical_list: D001993:Bronchodilator Agents; D011208:Powders; D000068299:Salmeterol Xinafoate; D000420:Albuterol