Crystallization is a widely used purification technique in the manufacture of active pharmaceutical ingredients (APIs) and precursor molecules. However, when impurities and desired compounds have similar molecular structures, separation by crystallization may become challenging. In such cases, some impurities may form crystalline solid solutions with the desired product during recrystallization. Understanding the molecular structure of these recrystallized solid solutions is crucial to devise methods for effective purification. Unfortunately, there are limited analytical techniques that provide insights into the molecular structure or spatial distribution of impurities that are incorporated within recrystallized products. In this study, we investigated model solid solutions formed by recrystallizing salicylic acid (SA) in the presence of anthranilic acid (AA). These two molecules are known to form crystalline solid solutions due to their similar molecular structures. To overcome challenges associated with the long ¹H longitudinal relaxation times (T₁(¹H)) of SA and AA, we employed dynamic nuclear polarization (DNP) and ¹⁵N isotope enrichment to enable solid-state NMR experiments. Results of solid-state NMR experiments and DFT calculations revealed that SA and AA are homogeneously alloyed as a solid solution. Heteronuclear correlation (HETCOR) experiments and plane-wave DFT structural models provide further evidence of the molecular-level interactions between SA and AA. This research provides valuable insights into the molecular structure of recrystallized solid solutions, contributing to the development of effective purification strategies and an understanding of the physicochemical properties of solid solutions.

中文翻译：

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通过动态核极化 (DNP) 增强 13C 和 15N 固态 NMR 光谱探测固溶体的分子和宏观结构


结晶是活性药物成分 (API) 和前体分子制造中广泛使用的纯化技术。然而，当杂质和所需化合物具有相似的分子结构时，通过结晶分离可能变得具有挑战性。在这种情况下，一些杂质可能在重结晶过程中与所需产物形成结晶固溶体。了解这些重结晶固溶体的分子结构对于设计有效纯化方法至关重要。不幸的是，能够深入了解重结晶产品中杂质的分子结构或空间分布的分析技术有限。在这项研究中，我们研究了在邻氨基苯甲酸（AA）存在下重结晶水杨酸（SA）形成的模型固溶体。已知这两种分子由于其相似的分子结构而形成结晶固溶体。为了克服 SA 和 AA 的长 ¹ H 纵向弛豫时间 (T ₁ ( ¹ H)) 相关的挑战，我们采用了动态核极化 (DNP ) 和 ¹⁵ N 同位素富集以实现固态 NMR 实验。固态NMR实验和DFT计算结果表明SA和AA以固溶体的形式均匀合金化。异核关联 (HETCOR) 实验和平面波 DFT 结构模型提供了 SA 和 AA 之间分子水平相互作用的进一步证据。这项研究为重结晶固溶体的分子结构提供了宝贵的见解，有助于开发有效的纯化策略和了解固溶体的物理化学性质。