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Keywords:

  • milling;
  • stability;
  • hygroscopicity;
  • synthesis;
  • oxidation;
  • X-ray powder diffractometry;
  • HPLC (high-performance/pressure liquid chromatography);
  • mass spectrometry;
  • NMR spectroscopy

Abstract

The novel steroid sulfatase inhibitor KW-2581 is poorly soluble in water, and jet milling was used in an attempt to increase its oral bioavailability. Unfortunately, however, the milled powder exhibited poorer qualities than the intact sample, including a lower level of crystallinity, higher water content, and increased decomposition rate. A comprehensive study of the jet milled sample was performed to identify the impurities and degradation mechanisms. The degradants were identified as the hydrolyzed and air-oxidized byproducts of KW-2581. The radical propagation mechanism of the oxidation reactions associated with the degradation of KW-2581 was assumed to be mediated by water or metal catalysis. The inclusion of a drying process following the micronization step allowed for the decomposition mechanism to be successfully controlled in the subsequent storage of the jet mill-micronized KW-2581 drug substance. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1760–1772, 2013