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

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, alpha, 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 approximately equal to 0.81) to excellent (r2 approximately equal to 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.