Department of Chemistry and Francis Bitter Magnet Laboratory, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
Merck Research Laboratories, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
J Phys Chem B. 2017 Aug 31;121(34):8132-8141. doi: 10.1021/acs.jpcb.7b07213. Epub 2017 Aug 17.
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.
魔角旋转（MAS）NMR 光谱的一个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 应该广泛适用于活性药物成分（API）和制剂结构的研究。然而，在低浓度下天然丰度 API 的光谱学中遇到的低灵敏度限制了 MAS 实验的成功。动态核极化（DNP）增强了 NMR 灵敏度，并可以用于解决这个问题，只要可以在不改变固体剂量完整性的情况下将合适的顺磁极化剂掺入系统中即可。在这里，我们证明可以通过喷雾干燥和热熔挤出在制备无定形固体分散体（ASD）的过程中现场添加 DNP 极化剂，以便在药物开发过程中检查 ASD。具体而言，彻底研究了 DNP 增强与样品组成、自由基浓度、API 和赋形剂的弛豫特性、极化剂和质子密度的类型的依赖性。从含有 1%w/w 自由基浓度的 ASD 中获得最佳增强值。TOTAPOL 和 AMUPol 这两种极化剂都提供了合理的增强效果。赋形剂的部分氘化产生了 3 倍的增强效果。使用这些参数，含有泊沙康唑和醋酸乙烯酯的 ASD 产生了 32 倍的增强，这可能导致 NMR 测量时间减少约 1000 倍。这种信号强度的提高使通过多维相关实验对天然丰度药物制剂进行全分配成为可能。
