Hughes Colan E, Williams P Andrew, Keast Victoria L, Charalampopoulos Vasileios G, Edwards-Gau Gregory R, Harris Kenneth D M
School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, Wales, UK.
Faraday Discuss. 2015;179:115-40. doi: 10.1039/c4fd00215f. Epub 2015 Apr 10.
The application of in situ techniques for investigating crystallization processes promises to yield significant new insights into fundamental aspects of crystallization science. With this motivation, we recently developed a new in situ solid-state NMR technique that exploits the ability of NMR to selectively detect the solid phase in heterogeneous solid-liquid systems (of the type that exist during crystallization from solution), with the liquid phase "invisible" to the measurement. As a consequence, the technique allows the first solid particles produced during crystallization to be observed and identified, and allows the evolution of different solid phases (e.g., polymorphs) present during the crystallization process to be monitored as a function of time. This in situ solid-state NMR strategy has been demonstrated to be a powerful approach for establishing the sequence of solid phases produced during crystallization and for the discovery of new polymorphs. The most recent advance of the in situ NMR methodology has been the development of a strategy (named "CLASSIC NMR") that allows both solid-state NMR and liquid-state NMR spectra to be measured (essentially simultaneously) during the crystallization process, yielding information on the complementary changes that occur in both the solid and liquid phases as a function of time. In this article, we present new results that highlight the application of our in situ NMR techniques to successfully unravel different aspects of crystallization processes, focusing on: (i) the application of a CLASSIC NMR approach to monitor competitive inclusion processes in solid urea inclusion compounds, (ii) exploiting liquid-state NMR to gain insights into co-crystal formation between benzoic acid and pentafluorobenzoic acid, and (iii) applications of in situ solid-state NMR for the discovery of new solid forms of trimethylphosphine oxide and L-phenylalanine. Finally, the article discusses a number of important fundamental issues relating to practical aspects, the interpretation of results and the future scope of these techniques, including: (i) an assessment of the smallest size of solid particle that can be detected in in situ solid-state NMR studies of crystallization, (ii) an appraisal of whether the rapid sample spinning required by the NMR measurement technique may actually influence or perturb the crystallization behaviour, and (iii) a discussion of factors that influence the sensitivity and time-resolution of in situ solid-state NMR experiments.
应用原位技术研究结晶过程有望为结晶科学的基础方面带来重大的新见解。出于这一动机，我们最近开发了一种新的原位固态核磁共振技术，该技术利用核磁共振能够在非均相固液体系（即从溶液中结晶时存在的那种类型）中选择性检测固相的能力，而液相在测量中“不可见”。因此，该技术能够观察和识别结晶过程中产生的第一批固体颗粒，并能够监测结晶过程中存在的不同固相（例如多晶型物）随时间的演变。这种原位固态核磁共振策略已被证明是确定结晶过程中产生的固相序列以及发现新多晶型物的有力方法。原位核磁共振方法的最新进展是开发了一种策略（名为“经典核磁共振”），该策略允许在结晶过程中（基本上同时）测量固态核磁共振和液态核磁共振光谱，从而获得关于固相和液相中随时间发生的互补变化的信息。在本文中，我们展示了新的结果，突出了我们的原位核磁共振技术在成功揭示结晶过程不同方面的应用，重点关注：（i）应用经典核磁共振方法监测固体尿素包合物中的竞争性包合过程，（ii）利用液态核磁共振深入了解苯甲酸和五氟苯甲酸之间的共晶形成，以及（iii）原位固态核磁共振在发现氧化三甲基膦和L - 苯丙氨酸新固体形式方面的应用。最后，本文讨论了与这些技术的实际方面、结果解释和未来范围相关的一些重要基本问题，包括：（i）评估在结晶的原位固态核磁共振研究中可检测到的最小固体颗粒尺寸，（ii）评估核磁共振测量技术所需的快速样品旋转是否实际上会影响或干扰结晶行为，以及（iii）讨论影响原位固态核磁共振实验灵敏度和时间分辨率的因素。
