Pharm Res (2011) 28:3220–3236 DOI 10.1007/s11095-011-0496-4 RESEARCH PAPER Effect of Cryogrinding on Chemical Stability of the Sparingly Water-Soluble Drug Furosemide Karolina Adrjanowicz & Kamil Kaminski & Katarzyna Grzybowska & Lukasz Hawelek & Marian Paluch & Irena Gruszka & Daniel Zakowiecki & Wieslaw Sawicki & Przemyslaw Lepek & Wojciech Kamysz & Lukasz Guzik Received: 18 November 2010 / Accepted: 27 May 2011 / Published online: 25 June 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com ABSTRACT 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 tempera- ture for 30, 60, 120 and 180 min. Mixtures of furosemide-PVP and furosemide-inulin (1:1) were milled under cryogenic con- ditions. 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. K. Adrjanowicz : K. Kaminski : K. Grzybowska : L. Hawelek : M. Paluch Department of Biophysics and Molecular Physics, Institute of Physics University of Silesia ul. Uniwersytecka 4 40-007 Katowice, Poland I. Gruszka Department of Experimental Physics, Institute of Physics University of Silesia ul. Uniwersytecka 4 40-007 Katowice, Poland D. Zakowiecki Preformulation Department R&D Pharmaceutical Works Polpharma SA Pelplinska 19 83-200 Starogard Gdanski, Poland 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. KEY WORDS amorphous pharmaceuticals . cryogenic grinding . furosemide . mechnochemical reactions . solid state amorphization INTRODUCTION According to Biopharmaceutical Classification System (BCS), pharmaceutically important particles are divided into four categories on the basis of aqueous solubility and permeability via oral route of delivery (1). Because of low solubility and permeability, Active Pharmaceutical Ingre- W. Sawicki : P. Lepek Department of Physical Chemistry Medical University of Gdansk Hallera 107 80-416 Gdansk, Poland W. Kamysz : L. Guzik Department of Inorganic Chemistry Medical University of Gdansk Hallera 107 80-416 Gdansk, Poland K. Adrjanowicz (*) Institute of Physics, University of Silesia ul. Uniwersytecka 4 40-007 Katowice, Poland e-mail: kadrjano@us.edu.pl