School of Chemical and Process Engineering, University of Leeds, Leeds LS2 9JT, U.K.
Oral Product Development, Pharmaceutical Technology and Development Operations, AstraZeneca, Macclesfield SK10 2NA, U.K.
Mol Pharm. 2021 May 3;18(5):1905-1919. doi: 10.1021/acs.molpharmaceut.0c00918. Epub 2021 Apr 2.
Amorphous solid dispersions (ASDs) are used to increase the solubility of oral medicines by kinetically stabilizing the more soluble amorphous phase of an active pharmaceutical ingredient with a suitable amorphous polymer. Low levels of a crystalline material in an ASD can negatively impact the desired dissolution properties of the drug. Characterization techniques such as powder X-ray diffraction (pXRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR) are often used to detect and measure any crystallinity within ASDs. These techniques are unable to detect or quantify very low levels because they have limits of detection typically in the order of 1-5%. Herein, an ASD of felodipine (FEL) and polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA) prepared via a hot melt extrusion (HME) in a mass ratio of 30:70 was characterized using a range of techniques. No signs of residual crystallinity were found by pXRD, DSC, or FTIR. However, transmission electron microscopy (TEM) did identify two areas containing crystals at the edges of milled particles from a total of 55 examined. Both crystalline areas contained Cl Kα X-ray peaks when measured by energy-dispersive X-ray spectroscopy, confirming the presence of FEL (due to the presence of Cl atoms in FEL and not in PVP/VA). Further analysis was carried out by TEM using conical dark field (DF) imaging of a HME ASD of 50:50 FEL-PVP/VA to provide insights into the recrystallization process that occurs at the edges of particles during accelerated ageing conditions in an atmosphere of 75% relative humidity. Multiple metastable polymorphs of recrystallized FEL could be identified by selected area electron diffraction (SAED), predominately form II and the more stable form I. Conical DF imaging was also successful in spatially resolving and sizing crystals. This work highlights the potential for TEM-based techniques to improve the limit of detection of crystallinity in ASDs, while also providing insights into transformation pathways by identifying the location, size, and form of any crystallization that might occur on storage. This opens up the possibility of providing an enhanced understanding of a drug product's stability and performance.
无定形固体分散体 (ASD) 被用于通过与合适的无定形聚合物动力学稳定活性药物成分的更易溶的无定形相来增加口服药物的溶解度。ASD 中少量的结晶物质会对药物的理想溶解性能产生负面影响。粉末 X 射线衍射 (pXRD)、差示扫描量热法 (DSC) 和傅里叶变换红外光谱 (FTIR) 等表征技术常用于检测和测量 ASD 中的任何结晶度。这些技术无法检测或量化非常低的水平，因为它们的检测限通常在 1-5%左右。本文中，采用熔融挤出 (HME) 法以质量比 30:70 制备了非洛地平 (FEL) 和聚乙烯吡咯烷酮/醋酸乙烯酯共聚物 (PVP/VA) 的 ASD，并使用多种技术对其进行了表征。pXRD、DSC 和 FTIR 均未发现残留结晶度的迹象。然而，透射电子显微镜 (TEM) 确实在总共 55 个被检查的研磨颗粒的边缘处识别出了两个含有晶体的区域。当通过能量色散 X 射线光谱法 (EDX) 进行测量时，这两个晶体区域均包含 Cl Kα X 射线峰，证实了 FEL 的存在（由于 FEL 中存在 Cl 原子，而 PVP/VA 中不存在）。通过 TEM 对 FEL-PVP/VA 的 HME ASD 进行锥形暗场 (DF) 成像的进一步分析，为深入了解在相对湿度为 75%的大气中加速老化条件下颗粒边缘处发生的再结晶过程提供了依据。通过选区电子衍射 (SAED) 可以识别出再结晶 FEL 的多种亚稳多晶型，主要为 II 型和更稳定的 I 型。锥形 DF 成像也成功地在空间上分辨和确定晶体的尺寸。这项工作强调了基于 TEM 的技术提高 ASD 中结晶度检测限的潜力，同时通过识别可能在储存过程中发生的任何结晶的位置、大小和形式，提供了对转化途径的深入了解。这为提供对药物产品稳定性和性能的更深入理解开辟了可能性。
