Optimization of manufacturing processes based on scientific evidence is important in the quality control of active pharmaceutical ingredients (APIs) and drug products, particularly when crystal forms change during production, which could affect subsequent drug performance. In this study, we verified crystalline states using various crystal faces and excipients during high-shear wet granulation based on non-contact low-frequency (LF) Raman probe monitoring. Four model drugs [indomethacin (IND), acetaminophen (APAP), theophylline (TP), and caffeine (CAF) polymorphs and cocrystals] were mixed with microcrystalline cellulose and hydroxypropyl cellulose with the addition of water over time. The LF Raman probe showed comparatively high sensitivity in monitoring 5-20% APAP and IND in a wet mass. Notably, as observed from the characteristic LF Raman peak shifts, form I TP and CAF and their cocrystals were more susceptible to transformation to the monohydrate form than form II. This method was also shown to be applicable in monitoring a commercial formulation of eight excipients and revealed crystalline transformations after 15 min of mixing. Therefore, probe-type LF Raman spectroscopy can be successfully employed to distinguish and monitor the crystalline state of APIs in real time during high-shear wet granulation, in which there is a risk of crystal transformation.

中文翻译：

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使用低频拉曼探针在高剪切湿法制粒过程中原位监测活性药物成分的结晶状态。

基于科学证据的制造工艺优化对于活性药物成分（API）和药物产品的质量控制非常重要，尤其是在生产过程中晶形发生变化时，这可能会影响后续的药物性能。在这项研究中，我们基于非接触式低频（LF）拉曼探针监测，在高剪切湿法制粒过程中使用各种晶体面和赋形剂验证了晶体状态。将四种模型药物[吲哚美辛（IND），对乙酰氨基酚（APAP），茶碱（TP）和咖啡因（CAF）多晶型物和共晶体]与微晶纤维素和羟丙基纤维素混合，并随时间添加水。LF拉曼探针在监测湿物料中5-20％APAP和IND时显示出较高的灵敏度。尤其，如从特征LF拉曼峰移动所观察到的，晶型I TP和CAF及其共晶体比晶型II更易转变为一水合物形式。还显示了该方法可用于监测八种赋形剂的商业配方，并在混合15分钟后显示出结晶转变。因此，在高剪切湿法制粒过程中，探针型LF拉曼光谱法可成功地用于实时区分和监测API的结晶状态，其中存在晶体转化的风险。还显示了该方法可用于监测八种赋形剂的商业配方，并在混合15分钟后显示出结晶转变。因此，在高剪切湿法制粒过程中，探针型LF拉曼光谱法可成功地用于实时区分和监测API的结晶状态，其中存在晶体转化的风险。还显示了该方法可用于监测八种赋形剂的商业配方，并在混合15分钟后显示出结晶转变。因此，在高剪切湿法制粒过程中，探针型LF拉曼光谱法可成功地用于实时区分和监测API的结晶状态，其中存在晶体转化的风险。