5 research outputs found
Effect of Cryogrinding on Chemical Stability of the Sparingly Water-Soluble Drug Furosemide
Purpose 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