(117c) Intensified Continuous Purification Platform for Pharmaceutical Systems - Application to the Continuous Manufacturing of Pure Cannabidiol Crystals

Continuous manufacturing (CM) is attracting a lot of sectors in the pharmaceutical, consumer and fine chemical industries due to its capability to achieve improved product quality and manufacturability while lowering production costs.¹ Capital expenditures were estimated to be 20-76% lower and operating expenditures were estimated to be up to 40% lower for continuous processes.² The main challenges of CM lie in the purification step, which includes crystallization and subsequent steps of filtration, washing, and drying since the quality and purity of the final product crystals are achieved in this purification step.³ Despite numerous successful integrations of continuous filtration systems to continuous crystallization processes, these studies lack of considering factors coming from the interactions between the connected units. Thus, in order to have tight control over crystal product quality and maintain manufacturability, there is a need to examine a new intensified platform on continuous purification step.

In this work, process intensification of an integrated continuous crystallization-filtration-drying system was examined by coupling the oscillatory baffle reactor (OBR) with a continuous filtration carousel (CFC), which includes a drying component. The OBR was chosen for this study because of its improved residence time distribution and better mixing to produce more uniform and less agglomerated crystal product, hence, offering a better filterability of the slurry in the following solid liquid separation steps.⁴ Due to mechanistic restraints of the carousel, a trade-off exists between purity and throughput of the generated final product. In order to balance the bioavailability imposed by the regulatory body and manufacturability of the system, the multiple operation conditions of the carousel are designed in conjunction with the upstream crystallization product on the model API.⁵

The application of the platform is tested with cannabidiol (CBD) as a direct application for the industry where the throughput of the system and purity of the final CBD isolates should be optimized even under the short-term disturbances on process parameters, such as filter fouling and mass flow rate from crystallizer or variations in purity of raw material. The aim of the experiments is to investigate the robust design of process parameters for integrated OBR-CFC system where impurities composition is maintained under the maximum acceptable value throughout the process after reaching steady state. A series of crystallization experiments was conducted by changing the residence time and feed concentration in the OBR. To facilitate mapping the process parameters of a following CFC that satisfies the final product quality after purification, the effect of the slurry properties, e.g. crystal size distribution, has been examined on the cake porosity and resistance.^6,7 The developed design of experiment was demonstrated experimentally on the intensified purification platform. Samples are collected at the outlet of the CFC periodically for the purity analysis and throughout of every cycle. The robustness of the platform has been demonstrated by comparing the product quality and throughput from batch crystallization. The result demonstrated that the coupled CFC product provides more constant product quality than the products generated from typical batch operation.

References

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[2] Schaber, S. D., Gerogiorgis, D. I., Ramachandran, R., Evans, J. M., Barton, P. I., & Trout, B. L. (2011). Economic analysis of integrated continuous and batch pharmaceutical manufacturing: a case study. Industrial & Engineering Chemistry Research, 50(17), 10083-10092.

[3] J. Gursch, R. Hohl, D. Dujmovic, J. Brozio, M. Krumme, N. Rasenack, J. Khinast, Dynamic cross-flow filtration: enhanced continuous small-scale solid-liquid separation. Drug Dev. Ind. Pharm., 42 (2016), 977-984.

[4] Liu, Y. C., Domokos, A., Coleman, S., Firth, P., & Nagy, Z. K. (2019). Development of continuous filtration in a novel continuous filtration carousel integrated with continuous crystallization. Organic Process Research & Development, 23(12), 2655-2665.

[5] Destro, F., Coleman, S., Firth, P., Barton, A., Barolo, M., Nagy, Z.K., 2021. Continuous integrated filtration, washing and drying of aspirin: digital design of a novel intensified unit. Proc. of the 11th IFAC Symposium on Advanced Control of Chemical Processes, Venice (Italy), June 13-16 2021. In press.

[6] Yu, A.B., Zou, R.P., Standish, N., 1996. Modifying the linear packing model for predicting the porosity of nonspherical particle mixtures. Ind. Eng. Chem. Res. 35, 3730–3741.

[7] Bourcier, D., Féraud, J.P., Colson, D., Mandrick, K., Ode, D., Brackx, E., Puel, F., 2016. Influence of particle size and shape properties on cake resistance and compressibility during pressure filtration. Chem. Eng. Sci. 144, 176–187. https://doi.org/10.1016/j.ces.2016.01.023