SOLID-STATE TRANSFORMATION OF A LEUKOTRIENE ANTAGONIST

SK&F 104353, a potent leukotriene antagonist, exists in two physically distinct species as a disodium salt. Type I melts with decomposition, showing a single endotherm in the region of 250-270 degrees C in diff erential scanning calorimetry (DSC) thermograms, as well as exhibiting a weak powder X-ray diffraction (XRD) pattern. Type II contains a sin gle DSC melting endotherm in the same region, but in contrast has addi tional, smaller endotherms in the region of 70-85 degrees C; the new t ransitions remain upon cooling and reheating. The powder XRD pattern o f II is very similar to that of I with respect to peak positions, but II's bands are sharper, suggestive of increased crystallinity. Types I and II can also be distinguished using solution calorimetry, manifest ing different heats of solution in an ethanol/water mixture. Apparent irreversible conversion of I to II can readily occur, and has a signif icant impact with respect to physical stability of potential suspensio n aerosol formulations. The results are explained in terms of a solid- state transformation, i.e., from a metastable, partially amorphous for m of low crystallinity (I) to a similar but more physically stable for m of higher crystallinity (II); the conversion is facilitated by the p resence of water, although true 'hydration' is not involved. Temperatu re-dependent Raman spectroscopy has been applied to characterize the t ransformation in more detail. The unusual solid-state behavior of this compound may reflect more general structural characteristics of leuko triene antagonists.