Thermal analysis of trace levels of polymorphic impurity in salmeterol xinafoate samples

Henry H.Y. Tong, Boris Yu Shekunov, Peter York, Albert H.L. Chow

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

Purpose. To quantify trace levels of polymorphic impurity in two salmeterol xinafoate (SX) Form I samples: granular SX (GSX) produced by fast-cooling crystallization and micronized SX (MSX) prepared from GSX by micronization. Methods. SX-I and SX-II produced by solution enhanced dispersion by supercritical fluids (SEDS™) were the reference polymorphs (100% pure) used for quantitative comparison. The percentage of polymorphic conversion, α, of each Form I sample to Form II was measured by differential scanning calorimetry (DSC) as a function of time (i.e., at different scanning speeds). The data were analyzed by the Avrami-Erofe'ev (AE) equation using an iterative fitting computer program. SX-I samples containing 1.24, 4.41, and 13.47% (w/w) of SX-II as physical mixtures were subjected to similar analysis and data treatment. A mathematical relationship based on an instantaneous nucleation model was derived to relate the AE rate constants, k, of pure SX-I and physical mixtures to weight percentage of SX-II. This relationship was then used to calculate the percentage polymorphic impurity of GSX and MSX from their k values. For relative comparison of the Form-II nuclei present, the k values of SX-I, GSX, and MSX were used to calculate their differences in free energy of nucleation. Results. The AE equation affords good (r2 ≈ 0.81) to excellent (r2 ≈ 0.99) fits of data for the samples. The levels of polymorphic impurity in GSX and MSX are 0.16 and 0.62% (w/w), respectively. Based on the free energy differences of nucleation between the reference SX-I material and the other samples, the number (and size) of the Form II nuclei present in the samples rank in the order: MSX > GSX > SX-I. Conclusions. DSC is a useful tool for assessing the polymorphic purity of SX materials and possibly other enantiotropic pairs showing similar thermal behavior.

Original languageEnglish
Pages (from-to)1423-1429
Number of pages7
JournalPharmaceutical Research
Volume20
Issue number9
DOIs
Publication statusPublished - 1 Sept 2003
Externally publishedYes

Keywords

  • Nucleation model
  • Polymorphic impurity determination
  • Salmeterol xinafoate
  • Thermal analysis

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