Department of Biophysics and Molecular Physics, Institute of Physics, University of Silesia, ul. Uniwersytecka 4, 40-007 Katowice, Poland.
Pharm Res. 2011 Dec;28(12):3220-36. doi: 10.1007/s11095-011-0496-4. Epub 2011 Jun 25.
To investigate the effect of cryogrinding on chemical stability of the diuretic agent furosemide and its mixtures with selected excipients.
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.
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.
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.
研究深冷粉碎对利尿剂呋塞米及其与选定辅料混合物的化学稳定性的影响。
将呋塞米在液氮温度下粉碎 30、60、120 和 180 分钟。将呋塞米-PVP 和呋塞米-菊粉（1:1）混合物在低温条件下研磨。通过 XRD、UPLC、MS 和 NMR 对材料进行分析。
随着研磨时间的增加，发现一种未识别的杂质 1 的含量显著增加，可能是主要的降解产物。与 PVP 和菊粉共研磨会降低药物的化学稳定性。随后确定在深冷研磨过程中形成的主要降解产物为 4-氯-5-磺酰胺基邻氨基苯甲酸（CSA）。基于涉及特定研磨条件的一些理论考虑，计算了研磨强度和预期的特定研磨剂量。结果表明，深冷研磨能够引发呋塞米的机械诱导分解。
深冷研磨不仅可以激活和加速结构变化（固态非晶化），还可以加速药物的化学分解。深冷研磨设备应被视为一个化学反应器，在有利的条件下，机械引发化学反应。
