TY - JOUR

T1 - Amorphization of different furosemide polymorphic forms during ball milling

T2 - Tracking solid-to-solid phase transformations

AU - Wang, Mengwei

AU - Gong, Junbo

AU - Rades, Thomas

AU - Martins, Inês C.B.

N1 - Publisher Copyright: © 2023 The Author(s)

PY - 2023

Y1 - 2023

N2 - 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 (Tg) 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 Tg 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.

AB - 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 (Tg) 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 Tg 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.

KW - Amorphous form

KW - Amorphous relaxation

KW - Ball milling

KW - Furosemide

KW - Glass transition temperature

KW - Polymorphs

U2 - 10.1016/j.ijpharm.2023.123573

DO - 10.1016/j.ijpharm.2023.123573

M3 - Journal article

C2 - 37931725

AN - SCOPUS:85176097015

VL - 648

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

SN - 0378-5173

M1 - 123573

ER -