SONOCRYSTALLISATION IN CONTINUOUS FLOW MICROCHANNEL CONTACTORS

溶液结晶是化学过程和相关工业主要部门的核心技术。它广泛用于药物生产的中间和最终纯化和分离阶段。该工艺规定了药物的化学纯度和物理性质：晶体形态、大小、大小分布、习性或形状以及完美程度。晶体特性的变化导致了广泛的药物制剂问题，例如与生物利用度、主要的药代动力学性质以及药物在其最终剂型中的化学和物理稳定性有关。在制药行业，高达90%的活性成分以晶体形式生产。晶体产品的技术复杂性不断提高，对研究人员的知识、技能和独创性提出了更高的要求，以开发新材料并设计可行的制造工艺。日益增长的环境限制和可持续发展的需求给这些工艺带来了额外的压力。为了实现这些雄心勃勃的目标，研究人员需要在制造技术中设计创新的工艺解决方案。这一挑战的复杂性无法由单个个体来应对，因为这一层面的创新需要跨学科研究，整合不同学科的方法、技能和优势。根据这一成功的战略，我们打算通过一项新技术，结合并利用连续流处理、微反应技术和超声工程的优势，为制药业带来一个相当大的飞跃。为此，我们将利用团队成员的互补专业知识，将工作建立在坚实的基础之上，以确保对流动声致振动过程中发生的物理化学现象（及其相互作用）有深入的了解。化学工程师已经使用超声波来操纵晶体合成，但通常对超声波技术的有限理解所造成的障碍降低了这些努力的影响。该研究项目的一个独特之处在于，我们将首次设计具有集成超声能力的结晶器，该结晶器基于正确构建的超声物理模型并使用流体动力学工具，使我们能够在反应器内获得所需的超声场。这将确保控制和再现性。这项工作的另一个独特之处是使用连续流动微反应器来重新分配合成阶段，并强化过程，进一步提高控制和效率。这项研究将涉及晶体形成、生长、团聚和破裂的实验和理论研究。超声波可以以不同的方式影响这些过程，例如通过空化或流动。这些可以通过适当操纵合适的变量（例如超声功率）来调节。超声波的效果将通过有针对性的实验进行研究，以便深入了解各种过程。超声波发生器远程操作，因此适用于封闭的无菌环境。因此，可以潜在地在开关的轻弹下控制结晶过程。

Crystallization from solution is a core technology in major sectors of the chemical process and allied industries. It is widely employed in the manufacture of pharmaceuticals during the intermediate and final stages of purification and separation. The process defines drug chemical purity and physical properties: crystal morphology, size, size distribution, habit or shape and degree of perfection. Variations in crystal characteristics are responsible for a wide range of pharmaceutical formulation problems, related for instance to bioavailability, a principal pharmacokinetic property, and the chemical and physical stability of drugs in their final dosage forms. In the pharmaceutical sector up to 90% of active ingredients are produced as crystals. The technical sophistication of crystal products is always rising, placing ever greater demands on the knowledge, skill and ingenuity of researchers to develop novel materials and devise viable processes for their manufacture. The increasing environmental constraints and need for sustainability place additional pressure on these processes.To attain these ambitious goals, researchers need to devise innovative process solutions in manufacturing technology. The complexity of this challenge cannot be met by single individuals, because innovation at this level requires interdisciplinary research that integrates methods, skills and strengths of different disciplines. In line with this winning strategy, we intend to bring about a sizable step change in pharmaceuticals manufacturing through a new technology that combines and exploits the benefits of continuous flow processing, microreaction technology and ultrasound engineering. To do so, we will build on the complementary expertise of the team members, basing the work on strong fundamental foundations that will ensure a deep level of understanding of the physicochemical phenomena (and their interaction) taking place during flow sonocrystallisation. Chemical engineers have used ultrasound to manipulate crystal synthesis, but often barriers posed by limited understanding of ultrasound technology have reduced the impact of these endeavours. One unique feature of this research project is that we will - for the first time - design crystallizers with integrated ultrasound capability based on properly constructed models of ultrasound physics and using fluid dynamic tools that will enable us to obtain within the reactor the desired ultrasonic field. This will ensure control and reproducibility. Another unique aspect of this work is using continuous flow microreactors to repartition the synthesis in stages and intensify the process, enhancing control and efficiency even further. The research will entail experimental and theoretical investigations on crystal formation, growth, agglomeration and disruption. Ultrasound can affect these processes in different ways, for example through cavitation or streaming. These can be adjusted by proper manipulation of suitable variables such as the ultrasound power. The effect of ultrasound will be studied by targeted experiments, so that insight into the various processes is gained. Ultrasound generators operate remotely and therefore are suitable for contained, sterile environments. Thus, the crystallisation processes can potentially be controlled at the flick of a switch.