Characterization of two polymorphs of salmeterol xinafoate crystallized from supercritical fluids

Purpose. To characterize two polymorphs of salmeterol xinafoate (SX-I and S X-II) produced by supercritical fluid crystallization. Methods. SX-I and SX-II were crystallized as fine powders using Solution En hanced 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), diff erential scanning calorimetry (DSC), thermogravimetric analysis (TGA), aque ous solubility (and dissolution) determination at 5-40 degreesC, BET adsorp tion analysis, and inverse gas chromatography (IGC). Results. Compared with SX-T, 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 differe nt FTIR spectrum (reflecting differences in intermolecular hydrogen bonding ). Solubility ratio plot yielded a transition temperature (similar to 99 de greesC) below the melting points of both polymorphs. MSX showed essentially the same crystal form as SX-T (confirmed by PXRD and FTIR), but a distinct ly 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 endoth erm at similar to 109 degreesC, corresponding to solid-solid transition of SX-I to SX-II Surface analysis of MSX, SX-I, and SX-LI by IGC revealed sign ificant differences in surface free energy in terms of both dispersive (non polar) interactions and specific (polar) acid-base properties. Conclusions. The SEDS-processed SX-I and SX-II display high polymorphic pur ity and distinctly different physical and surface properties. The: polymorp hs are related enantiotropically with SX-T being the thermodynamically stab le form at room temperature.