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，这增加了成本和环境影响。相比之下，连续流动微型反应器提供了大的表面积与体积比和反应物之间的密切接触，从而导致非常高的传热和传质速率，从而可以在更严格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使危险反应和不稳定中间体的处理更安全。因此，该研究计划的总体目标是开发连续流微/毫米级反应器技术，该技术可以在跨越临床试验（1至600 ml/min）直至商业化（例如，单一产品小型工厂）。反应器小型化，沿着有更有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工艺，是一个根本性的技术转变，主要依赖于（半）批处理在良好的生产规范。 在过去的几年里，我们开发了一个“工具箱”的概念，其中非常适合的连续微/毫反应器的几何形状和操作模式进行分类的基础上的反应网络，本征动力学和阶段。我们的研究已经系统地为液体和不混溶流体系统创建了高性能的微反应器，而涉及固体的编目反应器仍然需要加强。 因此，本研究提案的具体目标是：A）开发固体形成反应的最佳反应器，以及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。处理颗粒物的小型化连续反应器堵塞或性能损失的风险较小，这将导致过程强化在工业中的更大渗透，因为沉淀反应是精细化学合成的重要类别，而建模将有助于确定有效的混合条件并指导A部分的实验设计）。 精细化学品和药品的连续生产面临的一个重要挑战是，在多个国家建立业务和监管流程的情况下，从已知的（可用的熟练人员）和经常贬值的批量技术过渡的主要成本是否合理。因此，研究生将在多学科工程/科学/政治学环境中的专业，多元化和包容性团队中进行全面培训，因为政策制定会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工和制药行业的有效制造变革，这些行业对加拿大的经济和人类福祉做出了重要贡献。

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.