Continuous manufacturing of oral solid dosage pharmaceutical products offers attractive benefits spanning from optimized control over critical quality attributes to economical viability
1. Where the batch-wise process development requires scale-up procedures that are cumbersome and uncertain, in particular when considering the magnitude of volume increase from lab-scale to the pilot and production ones, continuous crystallizers instead, given their continuous operability, narrow considerably the scale-up steps magnitude enabling faster process development.
2 However, when a kinetic model is to be implemented, the continuous approach requires the characterization of different steady states, each from a single experiment. Besides, a typical continuous DoE spans from 6 to 9 experimental conditions.
3 Furthermore, in presence of material constrains during early stage process development, the continuous investigations require 5 to 10 crystallizers-volumes of material to be processed until the system can reach steady state and be therefore fully characterized. On the other end, a batch experiment allows the dynamic monitoring of the crystallization process from start to end, providing much richer information per experiment and only one crystallizer-volume of material per experiment. In this work, we present a novel configuration for plug flow crystallization, that conjugates both the batch characteristic data-collection efficiency and the aforementioned benefits of the continuous paradigm. The plug flow crystallizer was operated in a standard configuration for two residence times, after which the outlet was reconnected to the inlet, the feed and antisolvent pumps were bypassed by a valve switch, and the flowrate was provided by a third peristaltic pump, allowing the system to proceed to equilibrium. Once the system is characterized and the optimal operating condition is identified, to transfer the process to continuous fashion, one would only require to multiply the tubular unit for the equivalent number of loops the system spent in the crystallizer. The 104 mL jacketed tubular crystallizer was equipped with Kenics type static mixers to enhance mixing of the feed and antisolvent streams.
4 CFD simulations were carried out to validate the mixing completion before nucleation and within one crystallizer volume. The loop-configuration was assessed with three model systems. Ketoconazole, Azithromycin and Glycine were successfully crystallized from mixtures of methanol-water, acetone-water and water-ethanol respectively. The processes were monitored via a Blaze 900 probe, immersed through a flow-cell. A Tornado-Raman was connected to the Blaze, allowing for simultaneous particle size, microscopy, and Raman spectra in-line monitoring. Worth noting, a satisfactory yield of 93% was attained by processing ketoconazole with 0.5 antisolvent volume fraction. Such condition would require a series of 10 units to attain a continuous output of ~10 Kg/L/day of Ketoconazole.
(1) Rossi, C. V. A Comparative Investment Analysis of Batch Versus Continuous Pharmaceutical Manufacturing Technologies. J. Pharm. Innov. 2022. https://doi.org/10.1007/S12247-021-09612-Y.
(2) Cote, A.; Erdemir, D.; Girard, K. P.; Green, D. A.; Lovette, M. A.; Sirota, E.; Nere, N. K. Perspectives on the Current State, Challenges, and Opportunities in Pharmaceutical Crystallization Process Development. Crystal Growth and Design. American Chemical Society 2020. https://doi.org/10.1021/acs.cgd.0c00847.
(3) Power, G.; Hou, G.; Kamaraju, V. K.; Morris, G.; Zhao, Y.; Glennon, B. Design and Optimization of a Multistage Continuous Cooling Mixed Suspension, Mixed Product Removal Crystallizer. Chem. Eng. Sci. 2015, 133, 125–139. https://doi.org/10.1016/J.CES.2015.02.014.
(4) Alvarez, A. J.; Myerson, A. S. Continuous Plug Flow Crystallization of Pharmaceutical Compounds. Cryst. Growth Des. 2010, 10 (5), 2219–2228. https://doi.org/10.1021/cg901496s.
