Reactor intensification for continuous multiphase fine chemical synthesis

许多精细化学品和药品是通过溶剂密集型（半）批量工艺生产的，这增加了成本和对环境的影响。相比之下，连续流微型反应器提供了大的表面体积比和反应物之间的密切接触，这导致了非常高的传热传质速率，允许在更恶劣的操作条件下改善反应控制和选择性。这一点和它们的小体积可以更安全地处理危险反应和不稳定的中间体。因此，该研究项目的总体目标是开发连续流动微/毫米级反应器技术，该技术可以在各种单相和多相精细化学反应中强劲地超越当前（半）批反应器，其生产速度跨越临床试验（1至600 ml/min）直至商业化（例如，单一产品微型工厂）。反应器小型化，以及更高效的反应途径和自动化程序（即工业4.0），将加强精细化工和制药行业的加工，并且是一个基本的技术转变，该行业主要依赖于良好生产规范（gmp）中的半批处理。在过去的几年里，我们开发了一个“工具箱”概念，其中非常适合的连续微/毫微米反应器几何形状和操作模式是根据反应网络、固有动力学和存在的相进行分类的。我们的研究已经系统地为液体和非混相流体系统创造了高性能的微反应器，而涉及固体的分类反应器仍然需要在强化方面取得进展。因此，本研究计划的具体目标是：A)开发最适合固体形成反应的反应器；B)通过计算流体动力学对所提出的液（固）相反应器进行建模。由于沉淀反应是精细化学合成的重要类别，因此处理颗粒的小型连续反应器堵塞或丧失性能的风险较小，将导致过程强化在工业中的更大渗透，而建模将有助于确定有效的混合条件并指导A部分的实验设计)。精细化学品和药品持续生产面临的一个重要挑战是，从经济上证明从一种已知的（现有的熟练人员）和经常贬值的批量技术向多个国家的既定业务和监管程序过渡的主要成本是合理的。因此，研究生将在一个多学科的工程/科学/政治学环境中，在一个专业、多样化和包容性的团队中接受全面的培训，因为决策影响工程师和化学家的技术开发，反之亦然。这将有助于加速精细化学和制药工业有效制造的变化，这是加拿大经济和人类福祉的重要贡献者。

Many fine chemicals and pharmaceuticals are produced by solvent-intensive (semi)-batch processes increasing costs and environmental impact. In comparison, continuous-flow miniature reactors offer a large surface-to-volume ratio and intimate contact between reactants, which leads to very high heat and mass transfer rates, permitting improved reaction control and selectivity at more severe operating conditions. This and their small volume enable safer handling of hazardous reactions and unstable intermediates. The overall goal of this research program is thus to develop continuous-flow micro/milli-scale reactor technology that can robustly outperform current (semi)-batch reactors for a variety of single and multiphase fine chemical reactions over production rates spanning the clinical trials (1 to 600 ml/min) up to commercialization (e.g., single product mini-plant). Reactor miniaturization, along with more efficient reaction pathways and automated procedures (i.e., industry 4.0), will process intensify the fine chemical and pharmaceutical industries and is a fundamental technical shift for an industry reliant on primarily (semi)-batch processing within Good Manufacturing Practices. Over the last few years, we developed a "toolbox" concept where well-suited continuous micro/milli-reactor geometries and modes of operation are categorized based on the reaction network, intrinsic kinetics and phases present. Our research has systematically created high performing micro-reactors for liquid and immiscible fluid systems, whereas catalogued reactors involving solids still require advances for intensification. Therefore, the specific objectives of this research proposal are to A) develop reactors optimal for solids-forming reactions and B) model the proposed liquid-(solid) phase reactors via computational fluid dynamics. Miniaturized continuous reactors that handle particulates with less risk of clogging or losing performance will lead to much greater penetration of process intensification into the industry since precipitation reactions are an important class of fine chemical syntheses, while modelling will help identify effective mixing conditions and guide the experimental design in part A). An important challenge to the continuous manufacturing of fine chemicals and pharmaceuticals is to financially justify the major cost of transitioning from a known (available skilled personnel) and often depreciated batch technology with established business and regulatory processes in multiple countries. Graduate students will thus be comprehensively trained in a professional, diverse and inclusive team within a multi-disciplinary engineering/science/political science environment since policy-making affects technology development by engineers and chemists and vice versa. This will help accelerate changes for effective manufacturing in the fine chemical and pharmaceutical industries, which are important contributor to Canada's economy and human well-being.