Process-induced phase transformations (PIPTs) of active pharmaceutical ingredients (APIs) can alter APIs’ physicochemical properties and impact performance of pharmaceutical drug products. In this study, we investigated compression-induced amorphization of crystalline posaconazole (POSA), where the impact of mechanical stresses and excipients on amorphization were explored. ¹⁹F solid-state NMR (ssNMR) was utilized to detect and quantify amorphous content in the compressed tablets, and finite element analysis (FEA) was conducted to understand stress distributions in the compression process. Both applied macroscopic axial stress and shear stress were found to be important to amorphization of crystalline POSA. Punch velocity, an important compression process parameter, had negligible effect on amorphization up to 100 mm/s. Two diluents, microcrystalline cellulose (MCC) and dibasic calcium phosphate anhydrous (DCPA), and one lubricant, magnesium stearate (MgSt), were evaluated for their impact on amorphization in this study. It was found that both MCC and DCPA significantly enhanced amorphization of POSA at a low drug loading (5% w/w). The 1% (w/w) blended lubricant effectively reduced the amorphous content in MCC-POSA tablets; however, it had minimal effect on either neat POSA or DCPA-POSA tablets. Drug loading, or excipient concentration, was demonstrated to have a significant impact on the extent of amorphization. These observed excipient effects support the important role of interparticulate stresses in amorphization of crystalline POSA.

中文翻译：

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了解结晶泊沙康唑的压缩诱导非晶化

活性药物成分（API）的过程诱导相变（PIPT）可以改变API的理化性质和药物产品的性能。在这项研究中，我们调查了结晶泊沙康唑（POSA）的压缩诱导非晶化，其中探讨了机械应力和赋形剂对非晶化的影响。¹⁹利用F固态NMR（ssNMR）来检测和量化压制片剂中的无定形含量，并进行了有限元分析（FEA）以了解压制过程中的应力分布。发现施加的宏观轴向应力和剪切应力都对结晶POSA的非晶化很重要。冲压速度是重要的压缩过程参数，对高达100 mm / s的非晶化影响可忽略不计。在本研究中，评估了两种稀释剂微晶纤维素（MCC）和无水磷酸氢钙（DCPA），以及一种润滑剂硬脂酸镁（MgSt）。发现MCC和DCPA均以低载药量（5％w / w）显着增强了POSA的非晶化。1％（w / w）的混合润滑剂有效地降低了MCC-POSA片剂中的无定形含量；但是，它对纯POSA或DCPA-POSA片剂的影响最小。载药量或赋形剂浓度对无定形程度有重大影响。这些观察到的赋形剂效应支持了颗粒间应力在结晶POSA非晶化中的重要作用。