The present study investigates concomitant processes of solid-state disordering and oxidation of simvastatin during milling. The separate dry ball milling of crystalline and amorphous powders of simvastatin were conducted at ambient temperature for 10 and 60 min each. The relative crystallinity was determined using X-ray scattering and oxidative degradation was analyzed using liquid chromatography. The physical and chemical transformations in the milled powder were evaluated using modulated differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy. The disordering during milling of the crystalline powder was found to progressively decrease the crystallinity. For the amorphous starting material, milling for 10 min induced a large extent of recrystallization, while milling for 60 min largely re-amorphized the powder. This solid-state disordering and/or ordering were accompanied by progressive air oxidation during milling. The infrared spectroscopic analysis revealed the molecular manifestations associated with the physicochemical transformations in the disordered solid states. The melting point of simvastatin depressed systematically with the increase in the degree of disorder as well as the degradation. The in situ cooling in DSC of milled samples from their molten state led to the formation of the co-amorphous phase between the drug and degradation products, which showed a consistent increase in glass transition temperature with the increase in the content of degradation products. The study overall demonstrates the solid-state re-ordering and disordering of crystalline and amorphous simvastatin accompanied by chemical degradation as the consequence of the mechano-activation.

中文翻译：

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了解干法球磨过程中辛伐他汀伴随的物理和化学转化。

本研究调查了研磨过程中辛伐他汀的固态无序和氧化的伴随过程。辛伐他汀的结晶和无定形粉末分别在室温下进行干球磨，分别进行10分钟和60分钟。使用X射线散射确定相对结晶度，并使用液相色谱法分析氧化降解。使用调制差示扫描量热法（DSC）和傅里叶变换红外光谱法评估了研磨粉中的物理和化学转变。发现在研磨结晶粉末期间的无序性逐渐降低了结晶度。对于无定形原料，研磨10分钟会引起很大程度的重结晶，而研磨60分钟会极大地重新粉末化。在研磨过程中，这种固态无序和/或有序伴随着进行性的空气氧化。红外光谱分析揭示了与无序固态中的理化转变有关的分子表现。辛伐他汀的熔点随着无序程度和降解的增加而系统地降低。研磨样品的DSC从熔融状态的原位冷却导致药物和降解产物之间形成共非晶相，这表明玻璃化转变温度随降解产物含量的增加而持续增加。