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)间歇工艺生产的，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积与体积比和反应物之间的紧密接触，这导致了非常高的传热和传质速率，从而在更恶劣的操作条件下改善了反应控制和选择性。它及其体积小，能够更安全地处理危险反应和不稳定的中间体。因此，这项研究计划的总体目标是开发连续流动微/毫级反应器技术，在从临床试验(1至600毫升/分钟)到商业化(例如，单一产品迷你工厂)的生产速度上，对于各种单相和多相精细化学反应，该技术可以显著超过当前的(半)批式反应器。反应器小型化，以及更高效的反应路径和自动化程序(即工业4.0)，将强化精细化工和制药行业的工艺，对于一个主要依赖于良好制造规范中的(半)批处理的行业来说，这是一个根本性的技术转变。在过去的几年里，我们开发了一个“工具箱”概念，根据反应网络、本征动力学和存在的相对适合的连续微/毫级反应器的几何形状和操作模式进行分类。我们的研究已经系统地创建了用于液体和不混相流体系统的高性能微反应器，而涉及固体的已编目的反应器仍需要在强化方面取得进展。因此，本研究方案的具体目标是：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一类重要类别，而建模将有助于确定有效的混合条件并指导A部分中的实验设计，因此，处理堵塞或丧失性能风险较小的颗粒的小型连续反应器将大大提高过程强化在工业中的渗透率。精细化学品和药品的持续生产面临的一个重要挑战是，从已知(可用的技术人员)和经常折旧的间歇技术过渡的主要成本在财务上是合理的，这些间歇技术在多个国家建立了业务和监管流程。因此，研究生将在多学科工程/科学/政治学环境中的专业、多样化和包容性团队中接受全面培训，因为决策影响工程师和化学家的技术开发，反之亦然。这将有助于加快精细化工和制药行业有效制造的变革，这些行业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.