期刊
PHARMACEUTICAL RESEARCH
卷 18, 期 6, 页码 852-858出版社
KLUWER ACADEMIC/PLENUM PUBL
DOI: 10.1023/A:1011000915769
关键词
supercritical fluid crystallization; salmeterol xinafoate polymorphs; physical properties; solubilities; surface energetics; polymorphic purity
Purpose. 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 degreesC, BET adsorption 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 different FTIR spectrum (reflecting differences in intermolecular hydrogen bonding). Solubility ratio plot yielded a transition temperature (similar to 99 degreesC) below the melting points of both polymorphs. MSX showed essentially the same crystal form as SX-T (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 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 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-T being the thermodynamically stable form at room temperature.
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