Characterization of Pharmaceutical Cocrystals and Salts by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy
Characterization of Pharmaceutical Cocrystals and Salts by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy
复制标题
通过动态核偏振增强固态核磁共振波谱表征药物共晶和盐
DOI：
10.1021/acs.cgd.8b00203
复制
发表时间：
2018
影响因子：
3.8
通讯作者：
Rossini, Aaron J.
中科院分区：
文献类型：
--
作者：
Zhao, Li;Hanrahan, Michael P.;Chakravarty, Paroma;DiPasquale, Antonio G.;Sirois, Lauren E.;Nagapudi, Karthik;Lubach, Joseph W.;Rossini, Aaron J.
多组分固体，如共晶体，已经成为控制和控制固体活性药物成分(API)的稳定性、溶解性和可制造性的一种方法。晶体通常是由原料药与适当的共晶构型(通常是弱酸)进行溶液或固相反应而形成的。关于给定的多组分固体的一个关键结构问题是，它是应该被归类为盐，其中碱性API被酸质子化，还是应该被归类为共晶体，其中API和辅助剂保持中性并进行氢键作用。以往的研究表明，固体核磁共振波谱是研究原料药共晶和盐中结构的一种强有力的探针，然而，固体核磁共振波谱的低灵敏度通常限制了可以进行的实验类型。在这里，继电动态核极化(DNP)被用来减少复杂原料药的盐和共晶体的固体核磁共振实验时间1-2个数量级。从DNP获得的高灵敏度有助于快速获取天然同位素丰度13C和15N固态核磁共振谱。关键的是，DNP实现了双共振1H-15N固态核磁共振实验，例如2D1H-15N HETCOR、1H-15N CP-BUD、15N{1H}J分辨/附加质子测试、1H-15N DIPSHIFT和1H-15N PRESTO。后两个实验能够准确地测量1H-15N偶极耦合常数和H-N键长，明确地指定了氮质子化状态，并明确地将多组分固体分类为共晶体或盐。这些类型的测量在多晶型识别、核磁共振晶体结构测定以及探测各种有机材料中的氢键方面也应该非常有用。
Multicomponent solids such as cocrystals have emerged as a way to control and engineer the stability, solubility, and manufacturability of solid active pharmaceutical ingredients (APIs). Cocrystals are typically formed by solution- or solid-phase reactions of APIs with suitable cocrystal coformers, which are often weak acids. One key structural question about a given multicomponent solid is whether it should be classified as a salt, where the basic API is protonated by the acid, or as a cocrystal, where the API and coformer remain neutral and engage in hydrogen bonding interactions. It has previously been demonstrated that solid-state NMR spectroscopy is a powerful probe of structure in cocrystals and salts of APIs; however, the poor sensitivity of solid-state NMR spectroscopy usually restricts the types of experiments that can be performed. Here, relayed dynamic nuclear polarization (DNP) was applied to reduce solid-state NMR experiment times by 1–2 orders of magnitude for salts and cocrystals of a complex API. The large sensitivity gains from DNP facilitates rapid acquisition of natural isotopic abundance13C and15N solid-state NMR spectra. Critically, DNP enables double resonance1H–15N solid-state NMR experiments such as 2D1H–15N HETCOR,1H–15N CP-build up,15N{1H}J-resolved/attached proton tests,1H–15N DIPSHIFT, and1H–15N PRESTO. The latter two experiments allow1H–15N dipolar coupling constants and H–N bond lengths to be accurately measured, providing an unambiguous assignment of nitrogen protonation state and definitive classification of the multicomponent solids as cocrystals or salts. These types of measurements should also be extremely useful in the context of polymorph discrimination, NMR crystallography structure determination, and for probing hydrogen bonding in a variety of organic materials.