Novel approach to control pharmaceutical crystallisation using heterogeneous nucleation

结晶被广泛用于提纯商品和特种化学品和药品，并用于制造催化、分离和传感应用的先进材料。开发强健和高效的结晶工艺的主要挑战之一是控制成核速率。此外，许多体系倾向于以相同组成的多种结构形式结晶，称为多晶型，由于多晶型具有不同的性质，如溶解度、溶解速度和由此产生的剂量形式的生物利用度，因此控制多晶性在药物产品的开发中非常重要。成核主要通过多相机制发生，核心形成在表面或界面上，而不是在整体溶液中。在大规模的工业过程中，非均相成核在工业上往往是不可取的，因为它会导致容器结垢和较低的产品产率，然而，经常添加成核剂来诱导成核和/或通过非均相成核产生特定的晶型。在三个大的领域：外延和表面拓扑，以及表面化学，已经提出了许多设计成核剂表面的策略。然而，晶体/晶核界面上的色散和偶极-偶极相互作用的作用通常被忽视。本项目将采用实验和模拟相结合的方法来了解如何操纵表面偶极子层和色散相互作用来控制成核速率和特定多晶型的直接形成。在实验部分，我们将系统地研究可调单分子膜对医药行业相关代表性有机化合物非均相成核的影响，以探索新型非均相成核剂的设计空间。对功能化表面和生长在其上的晶体的表征将使用位于TIC的CMAC国家设施提供的一套先进的表征技术，包括AFM、SEM、拉曼显微镜和GI-SAXS。在模拟部分，我们将结合量子力学计算和经典分子动力学模拟来获得分子水平的洞察力，这将使我们能够计算与实验研究的系统相对应的各种界面上竞争多态的相对能量。

Crystallisation is widely used for purification of commodity and speciality chemicals and pharmaceuticals and for making advanced materials for catalysis, separations and sensing applications. One of the main challenges in developing robust and efficient crystallisation processes is to control the nucleation rate. In addition, many systems tend to crystallise in multiple structural forms of the same composition called polymorphs, and controlling polymorphism is extremely important in the development of pharmaceutical products as polymorphs have different properties, such as solubility, dissolution rate and thus bioavailability in resulting dosage forms.Nucleation mainly occurs via heterogeneous mechanisms, with the nucleus forming on a surface or interface, rather than in bulk solution. In large-scale industrial processes, heterogeneous nucleation is often undesirable in industry as it leads to fouling of vessels and a lower product yield, however, nucleants are often added to induce nucleation and/or produce a particular polymorph via heterogeneous nucleation. Numerous strategies have been proposed for the design of nucleant surfaces under three broad areas: epitaxy and surface topology, and surface chemistry. However, the role of dispersion and dipole-dipole interactions at crystal/nucleant interfaces is generally overlooked. This project will take a combined experimental and simulation approach to understand how to manipulate surface dipole layers and dispersion interactions to control nucleation rate and the direct formation of a particular polymorph. In the experimental part, we will systematically investigate the effect of tunable monolayers on heterogeneous nucleation of representative organic compounds relevant to the pharmaceutical industry in order to explore the design space of novel heterogeneous nucleants. Characterisation of functionalised surfaces and crystals grown on them will be performed with a suite of advanced characterisation techniques available in the CMAC National Facility housed in TIC, including AFM, SEM, Raman microscopy and GI-SAXS. In the simulation part, we will gain a molecular level insight using a combination of quantum mechanical calculations and classical molecular dynamics simulations, which will enable calculation of relative energetics of competing polymorphs on various interfaces corresponding to systems investigated experimentally.