Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.

An ideal pharmaceutical crystallization process produces a pure product at a high yield while minimizing energy input, the process equipment footprint, and its complexity. A good candidate for such a process is a single-stage mixed-suspension, mixed-product removal (MSMPR) crystallizer with recycle (SMR) system, where the characteristics of the refined crystal are controlled by the crystallization conditions of the MSMPR and the yield is manipulated by the recycle ratio. In this study, two continuous SMR systems, for the cooling crystallization of cyclosporine and the antisolvent-cooling crystallization of deferasirox, were developed. Both systems were designed to maintain the desired operating conditions inside the MSMPR crystallizer. For cooling crystallization, the recycle stream was concentrated via vacuum evaporation. For antisolvent-cooling crystallization, the desired solvent to antisolvent ratio was maintained by controlling the flow rates of feed, antisolvent, and recycle streams. The maximum experimental yield and purity of the crystals were determined as 91.8% and 94.3%, respectively (for cyclosporine) and 89.1% with 0.2 ppm impurity A, respectively (for deferasirox). For cyclosporine, this yield is 5.5% higher than that of a multistage MSMPR with a recycle system. Additionally, the SMR system is relatively simple, having a lower operational demand, in terms of space and number of unit operations required.

Abstract:In the dairy industry, crystallization is an important separation process used in the refining of lactose from whey solutions. In the refining operation, lactose crystals are separated from the whey solution through nucleation, growth, and/or aggregation. The rate of crystallization is determined by the combined effect of crystallizer design, processing parameters, and impurities on the kinetics of the process. This review summarizes studies on lactose crystallization, including the mechanism, theory of crystallization, and the impact of various factors affecting the crystallization kinetics. In addition, an overview of the industrial crystallization operation highlights the problems faced by the lactose manufacturer. The approaches that are beneficial to the lactose manufacturer for process optimization or improvement are summarized in this review. Over the years, much knowledge has been acquired through extensive research. However, the industrial crystallization process is still far from optimized. Therefore, future effort should focus on transferring the new knowledge and technology to the dairy industry.

The control of crystal size of any crystallization process is especially important in the pharmaceutical industry where small sizes are often desired. Seeding is often used as a method of controlling crystal size and suppressing primary nucleation in batch processes. The continuous mixed suspension mixed product removal crystallizers are self-seeded; however, crystal attrition and contact secondary nucleation due to crystal interaction with the impeller influence the crystal size. In this study, a nuclei generation device (nucleator) employing contact secondary nucleation is described. The nucleator consists of a "crossed" flow tube with four openings. Two of the openings are the inlet of supersaturated solution and the outlet of crystal slurry, respectively. The other two openings are for contact nucleation, where the parent crystal comes into contact with a platform under an applied stress. The rate of nucleation and the size of the crystals generated can be controlled by supersaturation (S = c/c s ) and residence time (RT) (e.g., with S = 1.2, glycine crystals of a 14 μm mean size was generated with a 10 s RT). Once nuclei were generated, the slurry was directed to a tubular crystallizer for further growth of crystals. The integrated nucleator− crystallizer experiments showed that nucleation and growth were decoupled, thus allowing better control of the final crystal characteristics.