In Situ Characterization of Pharmaceutical Formulations by Dynamic Nuclear Polarization Enhanced MAS NMR.
In Situ Characterization of Pharmaceutical Formulations by Dynamic Nuclear Polarization Enhanced MAS NMR.
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DOI：
10.1021/acs.jpcb.7b07213
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发表时间：
2017-08-31
期刊：
影响因子：
--
通讯作者：
Su Y
中科院分区：
文献类型：
--
作者：
Ni QZ;Yang F;Can TV;Sergeyev IV;D'Addio SM;Jawla SK;Li Y;Lipert MP;Xu W;Williamson RT;Leone A;Griffin RG;Su Y
魔角旋转(MAS)核磁共振波谱的主要优势在于它能够以非侵入性和定量的方式确定分子结构。因此，MAS应广泛应用于活性药物成分(API)和制剂的结构研究。然而，在低浓度下天然丰度原料药的光谱分析遇到的低灵敏度限制了MAS实验的成功。动态核极化(DNP)可以提高核磁共振的灵敏度，只要在不改变固体剂量完整性的情况下，在系统中加入合适的顺磁极化剂，就可以避免这一问题。在这里，我们证明了在通过喷雾干燥和热熔融挤压制备无定形固体分散体(ASD)的过程中可以原位添加DNP偏光剂，从而可以在药物开发过程中检测ASD。具体地，深入研究了样品组成、自由基浓度、API和赋形剂的松弛性质、极化剂类型和质子密度对DNP增强的依赖关系。对于含有1%w/w自由基浓度的ASD，可获得最佳的增强值。偏光剂TOTAPOL和AMUPol都提供了合理的增强。赋形剂的部分氢化产生了高3倍的增强值。在这些参数下，含有泊沙康唑和乙酸乙烯酯的ASD产生32倍的增强，这可能导致核磁共振测量时间减少∼1000。这种信号强度的增强使得能够通过多维相关实验来充分分配天然丰度药物配方。
A principal advantage of magic angle spinning (MAS) NMR spectroscopy lies in its ability to determine molecular structure in a noninvasive and quantitative manner. Accordingly, MAS should be widely applicable to studies of the structure of active pharmaceutical ingredients (API) and formulations. However, the low sensitivity encountered in spectroscopy of natural abundance APIs present at low concentration has limited the success of MAS experiments. Dynamic nuclear polarization (DNP) enhances NMR sensitivity and can be used to circumvent this problem provided that suitable paramagnetic polarizing agent can be incorporated into the system without altering the integrity of solid dosages. Here, we demonstrate that DNP polarizing agents can be added in situ during the preparation of amorphous solid dispersions (ASDs) via spray drying and hot-melt extrusion so that ASDs can be examined during drug development. Specifically, the dependence of DNP enhancement on sample composition, radical concentration, relaxation properties of the API and excipients, types of polarizing agents and proton density, has been thoroughly investigated. Optimal enhancement values are obtained from ASDs containing 1% w/w radical concentration. Both polarizing agents TOTAPOL and AMUPol provided reasonable enhancements. Partial deuteration of the excipient produced 3× higher enhancement values. With these parameters, an ASD containing posaconazole and vinyl acetate yields a 32-fold enhancement which presumably results in a reduction of NMR measurement time by ∼1000. This boost in signal intensity enables the full assignment of the natural abundance pharmaceutical formulation through multidimensional correlation experiments.
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DOI：
10.1016/j.jmr.2009.03.003
发表时间：
2009-06
期刊：
Journal of magnetic resonance (San Diego, Calif. : 1997)
影响因子：
--
作者：
Barnes AB;Mak-Jurkauskas ML;Matsuki Y;Bajaj VS;van der Wel PC;Derocher R;Bryant J;Sirigiri JR;Temkin RJ;Lugtenburg J;Herzfeld J;Griffin RG
通讯作者：
Griffin RG
固体和溶液生物NMR的高场动态核极化。
影响因子：
1
作者：
Barnes, A. B.;De Paepe, G.;van der Wel, P. C. A.;Hu, K. -N.;Joo, C. -G.;Bajaj, V. S.;Mak-Jurkauskas, M. L.;Sirigiri, J. R.;Herzfeld, J.;Temkin, R. J.;Griffin, R. G.
通讯作者：
Griffin, R. G.
影响因子：
5.5
作者：
AFEWORKI, M;SCHAEFER, J
通讯作者：
SCHAEFER, J
DOI：
10.1016/j.jmr.2011.09.010
发表时间：
2011-12-01
期刊：
Journal of magnetic resonance (San Diego, Calif. : 1997)
影响因子：
--
作者：
Bajaj, V S;Farrar, C T;Griffin, R G
通讯作者：
Griffin, R G
影响因子：
2.2
作者：
Can, T. V.;Ni, Q. Z.;Griffin, R. G.
通讯作者：
Griffin, R. G.