Effect of Cryogrinding on Chemical Stability size decreases and the transformation of crystalline drug to amorphous one is attained, mechanically activated degra- dation of furosemide would speed up due to increased surface area of the cryoground material and its enhanced chemical reactivity. Finally, it should be also noted that the UPLC analysis of furosemide ball-milled at room temperature for 1440 min revealed total impurity level less than 0.6% (data not shown in this paper). Accordingly, we think that there must be a relationship between full amorph- ization of furosemide and acceleration of its degradation. Since we are not able to completely amorphize furose- mide in the ball-mill, just small amounts of impurities were found in that sample. Only by performing the cryogenic experiment we are able to monitor the degradation of furosemide, because only this high- impact device is able to provide enough mechanical energy for full amorphization of the material. We also conjecture that in a region very close to complete amorphization and just above that point, this process proceeds at a maximum rate. In our opinion, the fact that the decomposition proceeds faster between time intervals of 30–60 min and 60–120 min and slower between 120 and 180 min (see Fig. 5 or Table I) indicates that this reaction has slowly reached a saturation point, and longer mechanical treatment won’t change anything. CONCLUSIONS Cryomilling of a crystalline powder is becoming a very popular way of micronization as well as amorphization. Since the milling takes place at a liquid nitrogen temperature, it is possible to effectively reduce particle size within a relatively shorter time and, as believed, to prevent local heating. Mechanical milling of pharmaceuticals offers a lot of advantages, especially in the context of solubility and bioavailability improvement. The high-impact cryomilling enables production of completely amorphous materials that otherwise could not be obtained during the room temperature ball-milling. However, current studies revealed that in some circumstances it can activate and accelerate not only structural changes (solid state amorphization) but also chemical decom- position of drug. For this reason, more attention should be paid to controlling the purity of the starting cryoground materials. The examined herein drug substance, furosemide, was found to be physically and chemically unstable after extensive cryomilling. The chemical decomposition of the mother material was found to be directly correlated with the duration of the cryomilling process. Degradation of furosemide that proceeds upon cryogenic grinding is most probably initiated in the vicinity of the amorphization region, since amorphous 3235 materials are known for their greater chemical reactivity, and in opposition to crystalline counterparts, they are more susceptible to any unwanted chemical changes. Acid- catalyzed hydrolysis of the cryoground amorphous sample proceeds at an almost twice greater pace than that of the crystalline drug. It is a clear sign of intensified chemical reactivity of the amorphous material in solution. During long- term storage of the cryomilled material in the solid state at ambient conditions, the degradation proceeds, albeit much slower. However, most surprising is its acceleration provoked by the high-impact mechanical treatment. Only after 180 min of cryomilling, the increment of Imp.1 (CSA) reached the same value as that found in the acid solution after dozen of hours. It is worthwhile to note that in a low pH medium the rate of hydrolysis is reported to be the highest. This attracts our attention to an enormous potential of the high-impact device, creating a favourable environment for various reactions activated mechanically to arise, with no need of any solvents. The degradation pathway of furosemide in the solid state and solution involves formation of the same product, CSA. The lower activation barrier required for such transformation is probably the direct consequence of weakening of the C-N bond and can be overcome by providing enough mechanical energy during the crashing process. Mechanical milling, due to randomness of each collision provides repeatedly new reaction interface and facilitates decomposition of the compound. Since chemical reaction activated by mechanical treatment does not need a thermal factor to begin, decomposition of furosemide is likely to proceed even at a liquid nitrogen temperature. The scenario which assumes local heating in the milling device, causing melting and thermal decomposition of furosemide, is less likely to happen, especially because of the temperature at which the milling is performed. ACKNOWLEDGMENTS & DISCLOSURES The authors are deeply thankful for the financial support of their research within the framework of the project entitled “From Study of Molecular Dynamics in Amorphous Medicines at Ambient and Elevated Pressure to Novel Applications in Pharmacy” (Contract No. TEAM/2008–1/6), which is oper- ated within the Foundation for Polish Science Team Programme co-financed by the EU European Regional Development Fund. The authors are deeply grateful to Professor Ryszard Piękoś from Department of Inorganic Chemistry, Medical University of Gdansk, Poland, for helpful discussions and valuable advice. 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