Probing Pharmaceutical Mixtures during Milling: The Potency of Low-Frequency Raman Spectroscopy in Identifying Disorder
Probing Pharmaceutical Mixtures during Milling: The Potency of Low-Frequency Raman Spectroscopy in Identifying Disorder
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DOI：
10.1021/acs.molpharmaceut.7b00803
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发表时间：
2017-12-01
影响因子：
4.9
通讯作者：
Fraser-Miller, Sara J.
中科院分区：
文献类型：
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作者：
Walker, Greg;Romann, Philipp;Fraser-Miller, Sara J.
这项研究使用多模式分析方法来评估研磨药物和赋形剂的(共)非晶化率，以及不同分析方法在检测这些变化方面的有效性。以吲哚美辛和色氨酸为模型物质，分析方法包括低频拉曼光谱(785 nm激发，可测量低频(10~250 cm(-1))和中频(450~1800 cm(-1)、830 nm系统(5~250 cm(-1))、常规(200~3000 cm(-1))拉曼光谱、傅里叶变换红外光谱(FTIR)和X射线粉末衍射(XRPD)。研究发现，混合物的非晶化动力学较快，而对于消炎痛，只有部分非晶化发生(球磨360分钟后)。每种技术都能够识别转换，但有些技术，如低频拉曼光谱和XRPD，提供的特征比中频技术(传统的拉曼和FTIR)提供的模糊特征更少。低频拉曼光谱显示结晶态和共晶态样品具有较强的声子模带，可以作为灵敏的有序探针。多变量分析被用来进一步解释光谱变化。总体而言，这项研究展示了低频拉曼光谱在药物加工过程中探测(破坏)顺序的潜力，展示了其未来发展的潜力，并作为一种在线过程监测方法实施，与XRPD相比具有几个实际优势。
This study uses a multimodal analytical approach to evaluate the rates of (co)amorphization of milled drug and excipient and the effectiveness of different analytical methods in detecting these changes. Indomethacin and tryptophan were the model substances, and the analytical methods included low-frequency Raman spectroscopy (785 nm excitation and capable of measuring both low- (10 to 250 cm(-1)) and midfrequency (450 to 1800 cm(-1)) regimes, and a 830 nm system (5 to 250 cm(-1))), conventional (200-3000 cm(-1)) Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR), and X-ray powder diffraction (XRPD). The kinetics of amorphization were found to be faster for the mixture, and indeed, for indomethacin, only partial amorphization occurred (after 360 min of milling). Each technique was capable of identifying the transformations, but some, such as low-frequency Raman spectroscopy and XRPD, provided less ambiguous signatures than the midvibrational frequency techniques (conventional Raman and FTIR). The low-frequency Raman spectra showed intense phonon mode bands for the crystalline and cocrystalline samples that could be used as a sensitive probe of order. Multivariate analysis has been used to further interpret the spectral changes. Overall, this study demonstrates the potential of low-frequency Raman spectroscopy, which has several practical advantages over XRPD, for probing (dis-)order during pharmaceutical processing, showcasing its potential for future development, and implementation as an in-line process monitoring method.