Rapid Characterization of Formulated Pharmaceuticals Using Fast MAS 1H Solid-State NMR Spectroscopy
Rapid Characterization of Formulated Pharmaceuticals Using Fast MAS 1H Solid-State NMR Spectroscopy
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DOI：
10.1021/acs.molpharmaceut.9b00343
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发表时间：
2019-07-01
影响因子：
4.9
通讯作者：
Rossini, Aaron J.
中科院分区：
文献类型：
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作者：
Hirsh, David A.;Wijesekara, Anuradha V.;Rossini, Aaron J.
活性药物成分（api）可以以许多不同的固体形式和相制备，这会影响其物理化学性质和口服剂型的适用性。剂型的开发和商业化需要能够确定和量化最终药品中原料药阶段的分析技术。C-13固态核磁共振（SSNMR）光谱被广泛用于表征纯和配方固体原料药；然而，由于低灵敏度和辅料的干扰，低API负载剂型的C-13 ssmr实验往往具有挑战性。本研究表明，快速魔角旋转H-1 SSNMR实验适用于低药量配方的快速表征。采用频率选择性饱和和激发脉冲、二维实验、H-1自旋扩散周期相结合的方法，获得片剂内原料药的诊断H-1 SSNMR谱。选择性饱和脉冲有效地抑制了来自乳糖和纤维素等最常见辅料的宽1H SSNMR信号，从而可以观察到高频API H-1 NMR信号。与标准C-13 SSNMR实验相比，H-1 SSNMR实验时间减少了1-3个数量级，能够在几分钟内获得片剂内稀释原料药的诊断SSNMR光谱。H-1 SSNMR光谱可用于定量，前提是在已知API负载的标准样品上进行校准。
Active pharmaceutical ingredients (APIs) can be prepared in many different solid forms and phases that affect their physicochemical properties and suitability for oral dosage forms. The development and commercialization of dosage forms require analytical techniques that can determine and quantify the API phase in the final drug product. C-13 solid-state NMR (SSNMR) spectroscopy is widely employed to characterize pure and formulated solid APIs; however, C-13 SSNMR experiments on dosage forms with low API loading are often challenging due to low sensitivity and interference from excipients. Here, fast magic angle spinning H-1 SSNMR experiments are shown to be applicable for the rapid characterization of low drug load formulations. Diagnostic H-1 SSNMR spectra of APIs within tablets are obtained by using combinations of frequency-selective saturation and excitation pulses, two-dimensional experiments, and H-1 spin diffusion periods. Selective saturation pulses efficiently suppress the broad 1H SSNMR signals from the most commonly encountered excipients such as lactose and cellulose, allowing observation of high-frequency API H-1 NMR signals. H-1 SSNMR provides a 1-3 orders of magnitude reduction in experiment time compared to standard C-13 SSNMR experiments, enabling diagnostic SSNMR spectra of dilute APIs within tablets to be obtained within minutes. The H-1 SSNMR spectra can be used for quantification, provided calibrations are performed on a standard sample with known API loading.