Protein crystals have many important applications in many fields, including pharmaceutics. Being more stable than other formulations, and having a high degree of purity and bioavailability, they are especially promising in the area of drug delivery. In this contribution, the development of a continuously operated tubular crystallizer for the production of protein crystals has been described. Using the model enzyme lysozyme, we successfully generated product particles ranging between 15 and 40 μm in size. At the reactor inlet, a protein solution was mixed with a crystallization agent solution to create high supersaturations required for nucleation. Along the tube, supersaturation was controlled using water baths that divided the crystallizer into a nucleation zone and a growth zone. Low flow rates minimized the effect of shear forces that may impede crystal growth. Simultaneously, a slug flow was implemented to ensure crystal transport through the reactor and to reduce the residence time distribution.
Size, shape, and polymorphic form are the critical attributes of crystalline particles and represent the major focus of today’s crystallization process design. This work demonstrates how crystal properties can be tuned efficiently in solution via a tubular crystallizer that facilitates rapid temperature cycling. Controlled crystal growth, dissolution, and secondary nucleation allow a precise control of the crystal size and shape distribution, as well as polymorphic composition. Tubular crystallizers utilizing segmented flow such as the one presented in our work can provide plug flow characteristics, fast heating and cooling, allowing for rapid changes of the supersaturation. This makes them superior for crystal engineering over common crystallizers. Characterization of particle transport, however, revealed that careful selection of process parameters, such as tubing diameter, flow rates, solvents, etc., is crucial to achieve the full benefits of such reactors.
This paper describes a simple model-free (i.e., empirical) control strategy for crystal size tuning in a continuously operated tubular crystallizer. The crystallizer is designed for a seeded cooling crystallization process and acetylsalicylic acid crystallization from an ethanol solution was used as model system. Using a crystal size distribution (CSD) analyzer and minor initial studies, we developed a feedback controller that accurately tuned the mean crystal size within the range of 90–140 μm. In addition, we created a cleaning concept for long-term runs based on a consistency study, which demonstrated that the CSD of the products remained robust when process settings were kept constant. Sufficiently small and uniform seed crystals were generated via ultrasound irradiation.
Besides size and polymorphic form, crystal shape takes a central role in engineering advanced solid materials for the pharmaceutical and chemical industries. This work demonstrates how multiple cycles of growth and dissolution can manipulate the habit of an acetylsalicylic acid crystal population. Considerable changes of the crystal habit could be achieved within minutes due to rapid cycling, i.e., up to 25 cycles within <10 min. The required fast heating and cooling rates were facilitated using a tubular reactor design allowing for superior temperature control. The face-specific interactions between solvent and the crystals’ surface result in face-specific growth and dissolution rates and hence alterations of the final shape of the crystals in solution. Accurate quantification of the crystal shapes was essential for this work, but is everything except simple. A commercial size and shape analyzer had to be adapted to achieve the required accuracy. Online size, and most important shape, analysis was achieved using an automated microscope equipped with a flow-through cell, in combination with a dedicated image analysis routine for particle tracking and shape analysis. Due to the implementation of this analyzer, capable of obtaining statistics on the crystals’ shape while still in solution (no sampling and manipulation required), the dynamic behavior of the size shape distribution could be studied. This enabled a detailed analysis of the solvent’s effect on the change in crystal habit.
Repeated temperature cycling of crystals from a conglomerate forming chiral substance suspended in their saturated solution has shown to be effective in converting a mixture of both enantiomers into an enantiomerically pure state. While by now a large number of different setups has been demonstrated, here we show for the first time how a continuous flow temperature cycler with recycle stream is capable of establishing enantiopurity while converting a racemic starting suspension. By capturing the most significant parameters influencing the process kinetics a competitive productivity could be achieved. We show, that fast crystal dissolution at high undersaturations and fast crystal growth at high supersaturations are speeding up the process as long as nucleation can be kept to a minimum or avoided at all. Temperature cycling has shown to result in a shift towards larger sizes for the particle size distribution of the crystals suspended, which is detrimental to the present process governed by size-dependent solubility. By implementing an ultrasound unit recycled material was comminuted, resulting in nearly stable deracemization rates. Graphical abstract
scite is a Brooklyn-based startup that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
334 Leonard St
Brooklyn, NY 11211
Copyright © 2023 scite Inc. All rights reserved.
Made with 💙 for researchers