title: Effect of cryogrinding on chemical stability of the sparingly water-soluble drug furosemide.
abstract: OBJECTIVE
  To investigate the effect of cryogrinding on chemical stability of the diuretic agent furosemide and its mixtures with selected excipients.
  
  
  METHODS
  Furosemide was ground at liquid nitrogen temperature for 30, 60, 120 and 180 min. Mixtures of furosemide-PVP and furosemide-inulin (1:1) were milled under cryogenic conditions. Materials were analyzed by XRD, UPLC, MS and NMR.
  
  
  RESULTS
  Upon increasing the milling time, a significant build-up of an unidentified impurity 1, probably the main degradation product, was noticed. Cogrinding of furosemide with PVP and inulin worsened chemical stabilization of the pharmaceutical. The main degradation product formed upon cryomilling was subsequently identified as 4-chloro-5-sulfamoylanthranilic acid (CSA). Based on some theoretical considerations involving specific milling conditions, the milling intensity and an expected specific milling dose have been calculated. Results indicate that cryogenic grinding is capable to initiate mechanically induced decomposition of furosemide.
  
  
  CONCLUSIONS
  Cryogenic grinding can activate and accelerate not only structural changes (solid state amorphization) but also chemical decomposition of pharmaceuticals. A cryogenic milling device should be considered as a chemical reactor, where under favourable conditions chemical reactions could be mechanically initiated.
authors.affiliation: Department of Biophysics and Molecular Physics, Institute of Physics, University of Silesia, ul. Uniwersytecka 4, 40-007 Katowice, Poland. kadrjano@us.edu.pl
authors.forename: Karolina
authors.initials: K
authors.lastname: Adrjanowicz
authors.forename: Kamil
authors.initials: K
authors.lastname: Kaminski
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Grzybowska
authors.forename: Lukasz
authors.initials: L
authors.lastname: Hawelek
authors.forename: Marian
authors.initials: M
authors.lastname: Paluch
authors.forename: Irena
authors.initials: I
authors.lastname: Gruszka
authors.forename: Daniel
authors.initials: D
authors.lastname: Zakowiecki
authors.forename: Wieslaw
authors.initials: W
authors.lastname: Sawicki
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Lepek
authors.forename: Wojciech
authors.initials: W
authors.lastname: Kamysz
authors.forename: Lukasz
authors.initials: L
authors.lastname: Guzik
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000295:instrumentation; D003080:Cold Temperature; D004232:Diuretics / Q000737:chemistry*; D004355:Drug Stability; D004867:Equipment Design; D005079:Excipients / Q000737:chemistry; D005665:Furosemide / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D010316:Particle Size; D012995:Solubility; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D004232:Diuretics; D005079:Excipients; D014867:Water; D005665:Furosemide