Continuous Crystallization in Multiphase Microfluidic Devices

Crystallization is an important process in a number of industries such as specialty chemicals, food, pigments and most importantly pharmaceuticals. Around 90% of pharmaceutical products are formulated in a crystalline form. The traditional batch crystallizers widely used suffer from non-uniform process conditions often resulting in wider crystal size distributions and reproducibility issues. To achieve the desired physical properties, top-down methods are extensively used, "grow big and mill it small", however, much attention is now drawn to strategies to control the crystal properties and to deliver the final product by well-defined crystallization processes. Control of crystallization processes is achieved by controlling the crystallization kinetics namely crystal nucleation and growth. Nucleation is stochastic and a successful crystallization can only happen by controlling it in a reproducible way. Therefore there is a high demand for crystallization processes which are more efficient and flexible where high quality crystals with desired characteristics can be obtained. On the other hand, microfluidics have gained attention in the last decade and have proven to be a promising technology in many fields due to their superior heat and mass transfer rates which in particle technology provide control over size, composition and morphology. However the greatest challenge in using microfluidics is their susceptibility to channel clogging in the presence of a solid which limits their use in continuous processes. Crystal size distribution is probably the most important factor having an effect on the quality of the final product. It can directly affect the downstream processing such as filtration, granulation and tableting. Crystal size also affects the flowability, bioavalability, dissolution and absorption which are crucial parameters in pharmaceutical industries. This thesis presents a continuous crystallization microfluidic device with an in-line nuclei generator. The developed device consists of separate sections for nucleation and growth. To control the nucleation process nitrogen as an inert gas was used to produce microbubbles in flow acting as heterogeneous nucleation sites. To generate uniform microbubbles a co-flowing system was used. Images were recorded with a high speed camera and analyzed afterwards to investigate the effect of the gas and liquid flow rates on bubble diameter, bubble generation frequency and velocity. Therefore the total bubble surface area per reactor volume could be calculated which shows the available heterogeneous surface for the nucleation to happen. Analyzing the results showed that varying the gas flow rate affects the bubble generation frequency whereas the liquid flow rate affects the microbubble size. The generated microbubbles were then used to design an in-line nuclei generator device. The device was tested in stagnant conditions to identify the location of crystal formation. The results showed that indeed the crystallization starts at the gas-liquid interface and in case it occurs in the bulk due to higher supersaturations, the crystal will eventually move to the gas-liquid interface due to its lower free energy. In the first phase the in-line nuclei generator was connected to a batch growth section providing certain growth times and the CSD was analyzed proving that the presence of the bubbles indeed enhanced the nucleation. Results showed that using the designed nuclei-generator with the presence of the microbubbles doubles the crystal yields compared to the system in the absence of microbubbles. In the second phase, the in-line nuclei generator was connected to a temperature controlled continuous growth section. Various configurations regarding the presence of the gas in the nucleation and/or growth section were investigated. Reproducible results were only obtained when the gas is present in both the nucleation section (as microbubbles) and in the growth section (as gas slugs) and yields up to 70% were achieved. The designed continuous crystallizer can be tuned and manipulated to achieve the desired crystal size distribution with the growth time and the temperature of the growth section as varying parameters.

Publication year:2021

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