Continuous manufacturing has been well developed in food and chemical industries, however, batch operation is still the most common method used in the pharmaceutical industry . For crystallization, continuous processing has the advantages of enhanced reproducibility of results, reduced cost, improved process efficiency and flexibility in production capacity . Due to these reasons, continuous crystallization has obtained great interest in both industry and academia in recent years .
The major challenges associated with the transition from batch to continuous crystallization process are to improve the yield of active pharmaceutical ingredients (APIS) and the purity of products. Batch process can obtain a higher yield by pushing the process to equilibrium while a continuous process is operated at steady state . An appropriate recycle stream can be applied in continuous process to boost the yield. A study of cooling crystallization of cyclosporine showed a 91.8% yield by using a single-stage mixed-suspension, mixed-product removal (MSMPR) crystallizer with concentrated mother liquor recycle system . However, previous research shows that for MSMPR, the mean crystal size and the purity decrease as improving the yield by recycling the mother liquor . This is because mother liquor recycle will make the steady state with low supersaturation and high impurity/API ratio: the slow growth caused by low supersaturation will lead small crystals and the high impurity/API ratio causes more impurity incorporation.
A common approach of improving the yield of continuous crystallization is to lower the operating temperature and thus decrease the solubility of API. However, for some APIs, e.g. cyclosporine, whose growth kinetics are very sensitive to temperature, the growth rate is very low (~0.1 µm/min) at low temperature. Thus, low operation temperature will cause low yield or it is required a much longer process residence time. The goal of this work is to enhance the yield under low temperature and push the steady state close to equilibrium while keep the residence time short and remain the purity of the crystal. To accomplish this goal, a two-stage MSMPR crystallizer with concentrated slurry recycle stream is established for cooling crystallization of cyclosporine. By recycling the crystals back to crystallizer, the total growth surface area increases so that more crystal growth occurs even if the liner growth rate is low. Thus, the yield can be improved. As the residence time of the crystals increases by recycling, crystals can grow more and have larger crystal size. Since the residence time of the mother liquor is shorter than that of the crystals, the impurity in the mother liquor will not accumulate in the crystallizer and the crystal purity can remain.
Moreover, a population balance model in conjunction with experimentally determined crystallization kinetics and distribution coefficients is developed. The model can simulate n-stage MSMPR crystallizer with different number of slurry recycle or mother liquor recycle to any stage(s). Using this model, the optimal stage temperatures, residence time, feed concentration, and recycle ratios can be obtained. Experiments guided by the model is used to obtain higher experimental yield and further valid the model.
This work presents an alternative idea to apply recycle stream to improve the yield and purity and control the crystal size in a continuous process.
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