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Investigation of Discoloration of Furosemide Tablets in a Light-Shielded Environment.

Authors
  • Katsura, Shinji1
  • Yamada, Nobuo
  • Nakashima, Atsushi
  • Shiraishi, Sumihiro
  • Gunji, Mihoko
  • Furuishi, Takayuki
  • Endo, Tomohiro
  • Ueda, Haruhisa
  • Yonemochi, Etsuo
  • 1 Research & Development Division, Teva Pharma Japan Inc. , (Japan)
Type
Published Article
Journal
Chemical and Pharmaceutical Bulletin
Publisher
Pharmaceutical Society of Japan
Publication Date
Jan 01, 2017
Volume
65
Issue
4
Pages
373–380
Identifiers
DOI: 10.1248/cpb.c16-00835
PMID: 28381678
Source
Medline
License
Unknown

Abstract

We observed that uncoated furosemide tablets turned yellow in a light-shielded automatic packaging machine and discoloration of the furosemide tablets was heterogeneity and occurred on the surface of the tablets only. The machine was equipped with an internal blower to maintain a constant temperature. Therefore, we investigated the effect of air flow on the discoloration of the furosemide tablets using a blower in a dark environment. The color difference (ΔE) of the furosemide tablets increased linearly as the blowing time increased. We performed structural analysis of the yellow compound in the furosemide tablets by LC-MS and identified the compound as a hydrolysate of furosemide. This suggested that furosemide hydrolysis was accelerated by the air flow. The furosemide tablets were prepared with the most stable furosemide polymorph, form I. X-Ray powder diffractometry and IR spectroscopy showed that during tablet preparation, no crystal transition occurred to an unstable furosemide polymorph. Furthermore, IR spectroscopy showed that the crystal form of furosemide in the yellow portion of the tablets was form I. To elucidate the factors producing the discoloration, we investigated the effect of humidity and atmosphere (air, oxygen, and nitrogen) on the discoloration of the furosemide tablets. The results suggested that the discoloration of the furosemide tablets was accelerated by oxidation, although humidity did not affect the hydrolysis. Therefore, we concluded that the discoloration of the furosemide tablets in the automatic packing machine was caused by acceleration of oxidative degradation by air flow.

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