Laser-induced nucleation for crystallisation of high-value materials in continuous manufacturing processes

罐中间歇加工是工业上生产高价值固体化学品的最受欢迎的方法，如农用化学品、染料和药品。批处理有许多缺点：每个阶段都要投入大量材料；失败可能会导致整个批的损失；批处理的重复性可能有很大差异；由于热流的限制，很难扩大到更大的容量。与批处理相比，管道中的连续流程制造提供了显著的改进：小批量的连续处理降低了工艺故障的风险；它是更环保的技术，因为它产生的废物更少；产能可以增加；资本和运行成本更低；更大的表面积使工艺更容易加热和冷却。实现连续流动制造的一个重大挑战是固体的处理，特别是细晶的形核。固体的性质，如晶体的大小、形状和内部结构，对它们的适用性有很大的影响，例如作为药物、农药、化肥。这些属性可能很难控制。混合和剪切改变了流体生长晶体的准备。我们的研究计划旨在通过使用短而强烈的激光脉冲在连续流动反应器的管子中在特定点和特定时间诱导成核来改进当前的连续流动结晶方法。到目前为止，我们的激光诱导结晶方法只使用静态样品瓶和液滴在实验室进行了研究。因此，我们需要在混合和流动条件下研究我们的技术。我们的目标是证明我们的方法可以在流体条件有利于某些晶体形状、大小和结构的不同位置生长晶体。这种技术目前还不适用于工业界。通过这种方法即使是细微的改进也可以在固体质量上产生实质性的改善，并可能鼓励工业转向连续流以进行更多的工艺。当然，我们并不是说这将是解决持续生产高价值固体的所有挑战的灵丹妙药。然而，我们相信这项技术可以在一些工艺上做出显著的节省和改进，例如在制药行业。为了使我们的计划与工业的需求相关，我们的项目将开始与最近成立的一个联盟合作进行连续制造和结晶(CMAC)。该集团通过政府(EPSRC)、七所大学、三家顶级全球制造商(葛兰素史克、阿斯利康、诺华)以及另外28个行业合作伙伴获得了大量投资。CMAC的目标是加速采用连续制造工艺、系统和设备来生产药品和精细化学品，以更低的成本、更快的速度和更可持续的方式提高质量水平。我们的合作将确保行业领先者能够快速、直接地获得我们研究计划的结果。

Batch processing in tanks is the favoured method in industry for manufacture of high-value solid chemicals, such as agrochemicals, dyes and pharmaceuticals. There are a number of disadvantages to batch processing: large amounts of material are committed to each stage; failure can cause loss of the entire batch; there can be large variations in batch repeatability; and it is difficult to scale-up to larger volumes due to limitations on heat flow. Continuous flow manufacture in pipelines offers significant improvements over batch processing: continual processing of small volumes reduces risks in process failures; it is greener technology because it produces less waste; throughput can be increased; capital and running costs are lower; higher surface areas make it easier to heat and cool processes. A grand challenge in implementing continuous flow manufacture is handling of solids, in particular nucleation of fine crystals. Properties of the solid, such as size, shape and internal structure of crystals have enormous effects on their suitability, e.g., as drugs, pesticides, fertilizers. These properties can be difficult to control. Mixing and shear changes the fluid's readiness to grow crystals.Our research programme aims to improve on current methods for crystallisation in continuous flow by using short, intense pulses of laser light to induce nucleation at specific points and times in the tubes of a continuous flow reactor. So far our laser-induced crystallisation method has been studied in the laboratory using only static sample vials and droplets. We therefore need to study our technique under mixing and flow conditions. Our objective is to demonstrate that our method can grow crystals at different locations where the fluid conditions favour certain crystal shapes, sizes and structures. Such techniques are not already available to industry. Even fractional improvements through this method could yield substantial improvements in the quality of solids, and could encourage industry to switch to continuous flow for more processes. Of course we do not claim that this will be a magic bullet to solve all challenges for continuous manufacture of high-value solids. However, we believe that the technique could stand to make significant savings and improvements in some processes, e.g., in the pharmaceutical industry.To make our programme relevant to the needs of industry, our project will embark on collaboration with a recently formed consortium for Continuous Manufacture and Crystallisation (CMAC). This group have secured significant investment through government (EPSRC), seven universities, three top-tier global-scale manufacturers (GlaxoSmithKline, AstraZeneca, Novartis), and another 28 industrial partners. CMAC aims to accelerate the adoption of continuous manufacturing processes, systems and plants for the production of pharmaceuticals and fine-chemicals to higher levels of quality, with lower costs, more quickly, and in a more sustainable manner. Our collaboration will ensure that industry leaders have fast and direct access to the outcomes of our research programme.