Article pubs.acs.org/crystal
Development of Continuous Crystallization Processes Using a SingleStage Mixed-Suspension, Mixed-Product Removal Crystallizer with Recycle Shin Yee Wong, Adam P. Tatusko, Bernhardt L. Trout, and Allan S. Myerson* Novartis-MIT Center for Continuous Manufacturing and Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 66-568, Cambridge, Massachusetts 02139, United States ABSTRACT: 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. crusts in the tubing presents the risk of clogging.4 The OBC is a tubular crystallizer containing periodically spaced orifice baffles with oscillatory motion superimposed on the net flow.5 Thus, the improved mass transfer and mixing profile accelerates crystallization and produces uniform crystals. The most popular approach to design continuous crystallization processes, however, is use of the MSMPR crystallizer.6 The MSMPR crystallizers are generally preferred for slow-growing crystals with long residence time.7 It has tolerance for high suspension densities, and by increasing the number of stages, it can operate close to the batch equilibrium condition. Therefore, it is relatively easy to convert existing batch to continuous operation using MSMPR crystallizers, as evidenced by the literature on continuous MSMPR processes.7−10 In addition, the yield of the multistage MSMPR can be boosted by recycling the mother liquor back to the crystallizer. A study of a three-stage MSMPR system for the crystallization of cyclosporine showed a 22% increase in yield with the addition of a recycle stream.8 However, the recycle ratio is limited by impurity buildup. For the cyclosporine study,8 the purity of the crystals was determined as 96% (without recycle) and 94% (with recycle), respectively.
1. INTRODUCTION Crystallization is a separation and purification process used in many industries to manufacture an extensive array of products, such as fine chemicals, food, and pharmaceutical drugs. Specifically, in the pharmaceutical industry, over 90% of active pharmaceutical ingredients (API) are crystals of small organic molecules.1 In the pharmaceutical industry, batch operation is the most common approach for crystallization.2 In recent years, continuous manufacturing has gained significant interest in both academia and industry.3 For a crystallization process, the batch process can achieve a higher yield when the process reaches equilibrium as opposed to a continuous process that operates at steady state.2 However, it is possible to boost the yield (to at least equivalent to batch yield) with the development of an appropriate recycle stream. Coupled with the many other advantages (e.g., uniform/consistent product, low cost, etc.), continuous crystallization has slowly evolved and is beginning to replace conventional batch approaches. For pharmaceutical crystallization, three main types of continuous crystallizers are mixed-suspension, mixed-product removal (MSMPR) crystallizers in single or multiple stage configurations, plug flow reactors, and oscillatory baffled crystallizers (OBC). The plug flow reactor is able to produce crystals of small size and narrow size distribution.1 However, it operates at very high flow rates (a long tube length is required to achieve the desired residence time) and the formation of © 2012 American Chemical Society
Received: August 23, 2012 Revised: October 12, 2012 Published: October 17, 2012 5701
dx.doi.org/10.1021/cg301221q | Cryst. Growth Des. 2012, 12, 5701−5707
Crystal Growth & Design
Article
The multistage MSMPR approach can be further improved and simplified by employing a single-stage MSMPR with recycle (SMR) system. To produce small API crystals, an SMR system with inverted RZ product classification, where the large crystals from the classifier are recycled to a dissolver along with the mother liquor from the filter, was designed.11 However, this system11 must be operated at high levels of supersaturation to promote nucleation and increase the number of small crystals in order to maintain a fixed desired production rate. This paper presents an alternative approach to design a simplified SMR system, having a minimum number of unit operations. With this system, one can focus on the need to control and optimize the crystallization kinetics in a single-stage MSMPR, in order to control the final product crystal particle size distribution and morphology. The crystal yield can then be enhanced by recycling the mother liquor back to the crystallizer. This paper summarizes the approaches to design a continuous SMR cooling crystallization process for cyclosporine and a continuous SMR antisolvent-cooling crystallization process for deferasirox. In addition, the potential benefits and performance of the SMR will be evaluated and discussed.
Figure 2. Schematic diagram of the single-stage MSMPR with recycle (SMR) system.
opening of the separator. An evaporation−condensation unit was used in the cooling crystallization process for the concentration of the mother liquor. A similar strategy cannot be used in the antisolventcooling crystallization of deferasirox, because the antisolvent (water) has a higher boiling point than the solvent (2:1 THF:EtOH). Therefore, a condenser was attached to prevent evaporation of solvent. 2.3. Procedure. 2.3.1. Cooling Crystallization of Cyclosporine. During the experiment, a fresh crude cyclosporine in acetone solution (31.8% w/w, 53 ± 0.5 °C) was continuously pumped into the crystallizer. The working volume of the crystallizer was 155 mL, with a residence time of 3 h. Once crystallized, the slurry of cyclosporine crystals was removed and separated by the filter unit, as shown in Figure 2. Cyclosporine crystals were collected from the filter unit after each residence time, while the filtrate (mother liquor) was concentrated by evaporation in the separator. The separator has four openings, connecting to the filter unit, the evaporation−condensation unit, the recycle stream, and the waste stream. The temperature of the separator was maintained at 40 ± 0.5 °C using a water bath. In order to increase the rate of evaporation, the separator unit was operated in a vacuum condition, with the vacuum level controlled by a vacuum pressure regulator. It was crucial to control the evaporation rate: a high evaporation rate led to the formation of amorphous cyclosporine gel, while a low evaporation rate was detrimental to the process yield and crystal purity. Once concentrated, the solution was distributed either to the waste stream or back to the crystallizer via the recycle stream according to the desired recycle ratio, defined as the ratio of the volumetric flow rates of the recycle stream to that of the feed stream. The process flow diagram of the experiment is shown in Figure 3. The cyclosporine cake collected on the filter unit (Figure 2) was removed from the system after each residence time. The amount of mother liquor trapped in the cake was measured as the weight difference between the semidried (dried under strong vacuum) and wet cake. The semidried cake was then washed with cool acetone (
