Pharmaceutical analysis by NMR can accommodate strict impurity thresholds: The case of choline.
Pharmaceutical analysis by NMR can accommodate strict impurity thresholds: The case of choline.
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DOI：
10.1016/j.jpba.2022.114709
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发表时间：
2022-05-30
影响因子：
3.4
通讯作者：
Pauli, Guido F.
中科院分区：
文献类型：
--
作者：
Achanta, Prabhakar S.;Niemitz, Matthias;Friesen, J. Brent;Tadjimukhamedov, Fatkhulla K.;Bzhelyansky, Anton;Giancaspro, Gabriel, I;Chen, Shao-Nong;Pauli, Guido F.
ICH指导原则建议原料药中常规杂质的报告阈值为0.05%或0.03%（w/w），具体取决于每日最大摄入量。因此，任何适用于杂质分析的仪器分析方法都应能够检测和定量这些水平的分析物。本研究旨在验证1H NMR光谱法检测杂质的适用性，作为尝试定量前的第一步。为了尽量减少对设备的需求，本研究采用400 MHz仪器对胆碱（1）和O-（2-羟乙基）胆碱（2）（一种已知杂质）进行结构确认和信号归属。10 mg 1中2的检测限（LOD）分别在400 MHz仪器上确定为0.01%，在60 MHz（台式）NMR光谱仪上确定为2%。因此，在400 MHz或更高频率下可容易地检测到需要定量的杂质。这些结果与普遍认为1H NMR灵敏度不足以用于药物杂质分析的观点相反。此外，我们的实验表明，低至。溶剂的选择被认为是1H NMR LOD分析的关键参数。此外，公开可用的NMR原始数据（HMDB）被证明是有价值的，通过1H NMR迭代全自旋分析揭示隐藏在复杂信号模式中的其他神秘信息。最后，该研究发现了-N+（CH 3）3基团中不太引人注目但具有特征的14 N-1H偶联，为原始NMR数据计划增加了进一步的有力论据。总的来说，数据证明高场NMR的分析能力很容易满足ICH对杂质分析检测的要求。本研究探讨了1H NMR光谱法在实际感兴趣物质存在下检测杂质的潜力，这使其更接近达到监管标准。
The ICH guidelines recommend reporting thresholds for regular impurities in drug substances at the level of 0.05% or 0.03% (w/w) depending on the maximum daily intake. Therefore, any instrumental method of analysis applicable to the impurity analysis should be able to detect and quantify the analytes at those levels. This investigation was designed to verify the suitability of 1H NMR spectroscopy for the detection of impurities, as a first step in the process before attempting quantification. In order to minimize demand on equipment, this study employed a 400 MHz instrument for structural confirmation and signal assignments of choline (1) and O-(2-hydroxyethyl)choline (2), a known impurity. The limit of detection (LOD) of 2 in 10 mg of 1 was established as 0.01% on a 400 MHz instrument and 2% on a 60 MHz (benchtop) NMR spectrometer, respectively. Thus, impurities for which quantification is required are readily detected at 400 MHz or above. These results are in contrast to the widespread belief that 1H NMR sensitivity is insufficient for pharmaceutical impurity analysis. Further, our experiments revealed that as low as. The choice of solvent was recognized as a critical parameter for 1H NMR LOD analysis. Furthermore, publicly available NMR raw data (HMDB) proved to be valuable for unveiling the otherwise cryptic information hidden in complex signal patterns via 1H NMR iterative Full Spin Analysis. Finally, the study uncovered the less noticed, yet characteristic, 14N-1H coupling in the -N+(CH3)3 groups, adding further strong arguments for the Raw NMR Data Initiative. Collectively, the data prove that the analytical capabilities of high-field NMR easily fulfill the ICH requirements for detection of impurity analysis. This study explores the potential of 1H NMR spectroscopy to detect an impurity in the presence of an actual substance of interest which makes it a step closer to achieving regulatory standards.
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影响因子：
6.1
作者：
Belen Ruiz-Muelle, Ana;Garcia Moreno, Paula;Fernandez, Ignacio
通讯作者：
Fernandez, Ignacio
影响因子：
5.1
作者：
Pauli, Guido F.;Chen, Shao-Nong;Lankin, David C.;Bisson, Jonathan;Case, Ryan J.;Chadwick, Lucas R.;Goedecke, Tanja;Inui, Taichi;Krunic, Aleksej;Jaki, Birgit U.;McAlpine, James B.;Mo, Shunyan;Napolitano, Jose G.;Orjala, Jimmy;Lehtivarjo, Juuso;Korhonen, Samuli-Petrus;Niemitz, Matthias
通讯作者：
Niemitz, Matthias
DOI：
10.1016/j.jpba.2020.113601
发表时间：
2021-01-05
影响因子：
3.4
作者：
Achanta PS;Jaki BU;McAlpine JB;Friesen JB;Niemitz M;Chen SN;Pauli GF
通讯作者：
Pauli GF
影响因子：
11.9
作者：
McAlpine JB;Chen SN;Kutateladze A;MacMillan JB;Appendino G;Barison A;Beniddir MA;Biavatti MW;Bluml S;Boufridi A;Butler MS;Capon RJ;Choi YH;Coppage D;Crews P;Crimmins MT;Csete M;Dewapriya P;Egan JM;Garson MJ;Genta-Jouve G;Gerwick WH;Gross H;Harper MK;Hermanto P;Hook JM;Hunter L;Jeannerat D;Ji NY;Johnson TA;Kingston DGI;Koshino H;Lee HW;Lewin G;Li J;Linington RG;Liu M;McPhail KL;Molinski TF;Moore BS;Nam JW;Neupane RP;Niemitz M;Nuzillard JM;Oberlies NH;Ocampos FMM;Pan G;Quinn RJ;Reddy DS;Renault JH;Rivera-Chávez J;Robien W;Saunders CM;Schmidt TJ;Seger C;Shen B;Steinbeck C;Stuppner H;Sturm S;Taglialatela-Scafati O;Tantillo DJ;Verpoorte R;Wang BG;Williams CM;Williams PG;Wist J;Yue JM;Zhang C;Xu Z;Simmler C;Lankin DC;Bisson J;Pauli GF
通讯作者：
Pauli GF
影响因子：
4.2
作者：
Guseva, Maria V.;Hopkins, Deann M.;Pauly, James R.
通讯作者：
Pauly, James R.