Influence of polymorphism on the surface energetics of salmeterol xinafoate crystallized from supercritical fluids

H. H.Y. Tong, B. Y. Shekunov, P. York, A. H.L. Chow

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45 Citations (Scopus)


Purpose. To characterize the surface thermodynamic properties of two polymorphic forms (I and II) of salmeterol xinafoate (SX) prepared from supercritical fluids and a commercial micronized SX (form I) sample (MSX). Methods. Inverse gas chromatographic analysis was conducted on the SX samples at 30, 40, 50, and 60°C using the following probes at infinite dilution: nonpolar probes (NPs; alkane C5-C9 series); and polar probes (PPs; i.e., dichloromethane, chloroform, acetone, ethyl acetate, diethyl ether, and tetrahydrofuran). Surface thermodynamic parameters of adsorption and Hansen solubility parameters were calculated from the retention times of the probes. Results. The free energies of adsorption (-ΔGA) of the three samples obtained at various temperatures follow this order: SX-II > MSX ≅ SX-I for the NPs; and SX-II > MSX > SX-I for the PPs. For both NPs and PPs, SX-II exhibits a less negative enthalpy of adsorption (ΔHA) and a much less negative entropy of adsorption (ΔSA) than MSX and SX-I, suggesting that the high -ΔGA of SX-II is contributed by a considerably reduced entropy loss. The dispersive component of surface free energy (γsD) is the highest for MSX but the lowest for SX-II at all temperatures studied, whereas the specific component of surface free energy of adsorption (-ΔGASP) is higher for SX-II than for SX-I. That SX-II displays the highest -ΔGA for the NP but the lowest γsD of all the SX samples may be explained by the additional -ΔGA change associated with an increased mobility of the probe molecules on the less stable and more disordered SX-II surface. The acid and base parameters, KA and KD, that were derived from ΔHASP reveal significant differences in the relative acid and base properties among the samples. The calculated Hansen solubility parameters (δD, δP, and δH) indicate that the surface of SX-II is the most polar and most energetic of all the three samples in terms of specific interactions (mostly hydrogen bonding). Conclusions. The metastable SX-II polymorph possesses a higher surface free energy, higher surface entropy, and a more polar surface than the stable SX-I polymorph.

Original languageEnglish
Pages (from-to)640-648
Number of pages9
JournalPharmaceutical Research
Issue number5
Publication statusPublished - 2002
Externally publishedYes


  • Hansen solubility parameters
  • Inverse gas chromatography
  • Salmeterol xinafoate polymorphs
  • Supercritical fluid crystallization
  • Surface energetics


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