Ball milling is used, not only to reduce the particle size of pharmaceutical powders, but also to induce changes in the physical properties of drugs. In this work we prepared three crystal forms of furosemide (forms Ⅰ, Ⅱ, and Ⅲ) and studied their solid phase transformations during ball milling. Powder X-ray diffraction and modulated differential scanning calorimetry were used to characterize the samples after each milling time on their path to amorphization. Our results show that forms Ⅰ and III directly converted into an amorphous phase, while form Ⅱ first undergoes a polymorphic transition to form Ⅰ, and then gradually loses its crystallinity, finally reaching full amorphousness. During ball milling of forms Ⅰ and Ⅱ, the glass transition temperature (T_g) of the amorphous fraction of the milled material remains almost unchanged at 75 °C and 74 °C, respectively (whilst the amorphous content increases). In contrast, the T_g values of the amorphous fraction of milled form III increase with increasing milling times, from 63 °C to 71 °C, indicating an unexpected phenomenon of amorphous-to-amorphous transformation. The amorphous fraction of milled forms I and II samples presented a longer structural relaxation (i.e., lower molecular mobility) than the amorphous fraction of milled form III samples. Moreover, the structural relaxation time remained the same for the increasing amorphous fraction during milling of forms I and II. In contrast, the structural relaxation times were always shorter for the amorphous fraction of form III, but increased with increasing amorphous content during milling, confirming amorphous-to-amorphous transformation.

使用球磨不仅可以减小药物粉末的粒径，还可以引起药物物理性质的变化。在这项工作中，我们制备了呋塞米的三种晶型（晶型Ⅰ、晶型Ⅱ和晶型Ⅲ），并研究了它们在球磨过程中的固相转变。粉末 X 射线衍射和调制差示扫描量热法用于在每次研磨时间后对样品进行非晶化过程的表征。结果表明，晶型Ⅰ和晶型Ⅲ直接转变为非晶相，而晶型Ⅱ首先经历多晶型转变为晶型Ⅰ，然后逐渐失去结晶性，最终达到完全非晶态。在形式Ⅰ和Ⅱ_的球磨过程中，研磨材料的无定形部分的玻璃化转变温度（ Tg ）几乎保持不变，分别为75℃和74℃（同时无定形含量增加）。相比之下，研磨形式III的无定形部分的T _g值随着研磨时间的增加而增加，从63℃增加到71℃，这表明非晶态到无定形转变的意外现象。研磨的形式I和II样品的无定形部分呈现出比研磨的形式III样品的无定形部分更长的结构弛豫(即，较低的分子迁移率)。此外，在晶型 I 和 II 的研磨过程中，随着无定形部分的增加，结构弛豫时间保持不变。相比之下，晶型III的无定形部分的结构弛豫时间总是较短，但随着研磨过程中无定形含量的增加而增加，证实了无定形到无定形的转变。