(232c) Development of the Growth Stage for Continuous Crystallization in Microfluidic Devices

Crystallization is a key process in the pharmaceutical industry. Pharmaceuticals in crystalline form are typically manufactured batch-wise; however, owing to the high sensitivity of the end product to the process parameters, standard production methods are poorly reproducible and present large batch-to-batch variability in terms of crystal size distribution (CSD). There is a need to develop new and better controllable technologies. We propose to combine continuous flow and microreactor technology. The former allows to decouple in space the various stages of the process and optimize each of them, while the latter allows to intensify heat and mass transfer, thus improving controllability. Finally, continuous systems can be operated at steady state, rendering the synthesis more reproducible.

Growth is undoubtedly an essential part of the crystallization process that strongly determines the quality of the final product in terms of CSD. Considerable hydrodynamic dispersion, which characterizes microfluidic devices, induces uneven growth and in turn broad CSDs. In our work we aim to understand the relationship between hydrodynamics and end-product size distribution and to use this knowledge to design growth stages with improved controllability and reproducibility. Our methodology involves both experimental and numerical approaches and involves three main areas: residence time distribution (RTD), crystal growth and particle dynamic studies.

We are currently considering a design solution, based on coiled flow inverters (CFIs), which relies on secondary flow as a means of enhancing radial mixing and reducing hydrodynamic dispersion. These systems were firstly proposed by Saxena and Nigam (1984); they consist of sections of helically coiled tubes with 90-degree bends placed at regular intervals along a cylindrical support. They have showed that flow inversions occurring at the bends narrow down the RTDs. Despite these promising results and the potential applications, coiled flow inverters have not been extensively adopted in flow processes. This is mostly due to the lack of data and correlations relating the design parameters and operating conditions to the reduction of hydrodynamic dispersion (quantified through an axial dispersion coefficient). Our aim is first of all to characterize in detail these systems and derive such correlations and then to use CFIs to carry out crystal growth studies.

References

Saxena, A. K., & Nigam, K. D. P. (1984). Coiled configuration for flow inversion and its effect on residence time distribution. AIChE Journal, 30(3), 363–368.