Effect of Cryogrinding on Chemical Stability of the Sparingly Water-Soluble Drug FurosemideReport as inadecuate

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Pharmaceutical Research

, Volume 28, Issue 12, pp 3220–3236

First Online: 25 June 2011Received: 18 November 2010Accepted: 27 May 2011 ABSTRACT

PurposeTo investigate the effect of cryogrinding on chemical stability of the diuretic agent furosemide and its mixtures with selected excipients.

MethodsFurosemide 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.

ResultsUpon 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.

ConclusionsCryogenic 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.

KEY WORDSamorphous pharmaceuticals cryogenic grinding furosemide mechnochemical reactions solid state amorphization  Download fulltext PDF

Author: Karolina Adrjanowicz - Kamil Kaminski - Katarzyna Grzybowska - Lukasz Hawelek - Marian Paluch - Irena Gruszka - Daniel Zako

Source: https://link.springer.com/

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