A Novel Design Approach To Scale Up the Temperature Cycle

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A Novel Design Approach to Scale-Up of the Temperature Cycle Enhanced-Deracemization Process: Coupled Mixed-Suspension Vessels Kittisak Suwannasang, Adrian E. Flood, and Gérard Coquerel Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01139 • Publication Date (Web): 21 Sep 2016 Downloaded from http://pubs.acs.org on September 27, 2016

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Crystal Growth & Design

A Novel Design Approach to Scale-Up of the Temperature Cycle Enhanced-Deracemization Process: Coupled Mixed-Suspension Vessels. Kittisak Suwannasang†, Adrian E. Flood†, and Gérard Coquerel*‡ †

Department of Chemical and Biomolecular Engineering, School of Energy Science and Engineering, Vidyasirimedhi Institute of Science and Technology, Rayong 21210, Thailand. ‡ Normandie Univ, France, SMS Unité de Crystallogénèse EA3233, Université de Rouen, 76821, Mont-SaintAignan Cedex, France. KEYWORDS: deracemization, enantioseparation, conglomerate forming compounds. ABSTRACT: An improved process for the deracemization of a racemic conglomerate suspension of enantiomorphs has been created based on principles developed in an earlier method using temperature fluctuations. The method consists of circulating the suspension between two vessels, each controlled at a specific temperature in order to make the process more effective and faster to achieve a homochiral solid state. Crystals in the suspension were partially dissolved in the hot vessel and the remaining crystals were re-grown in the cold vessel. The crystals in the cold vessel have a longer residence time than those in the hot vessel to allow more time for the crystal growth process. The results show that complete deracemization can be achieved via this process far more rapidly than by using the previous temperature cycling (one-vessel) process. Moreover, the new process could easily be scaled up to an industrial scale. The current process can be an effective alternative to currently used enantiopurification methods, with simple processing implementation and low cost.

1. INTRODUCTION times. Unfortunately, the production yield of preferential crystallization is limited to 50% since the unwantMany active pharmaceutical ingredients (APIs) are ed form is not converted into the desired enantiomer. one of a pair of enantiomers, either the R- form or the S- form. There are several pathways for directly obIn 2005, Viedma demonstrated a new process, now taining pure enantiomers such as a stereoselective called Viedma ripening, for the symmetry breaking of synthesis and biocatalytic synthesis. Otherwise, a a racemic mixture of D- and L- crystals of sodium 4 simple chemical synthesis usually produces a racemic chlorate (NaClO3). Three years after Viedma’s mixture (an equimolar mixture of the two demonstration, the groups of Vlieg and Blackmond enantiomers). Consequently, an additional process first demonstrated deracemization of an intrinsically will be performed to separate the target enantiomer chiral organic molecule, N-(2-methylbenzylidene)(eutomer) from the unwanted enantiomer (distomer). phenylglycine amide, based upon the technique of 5,6 About 46% of chiral APIs were obtained from a resoViedma ripening. Since this time many organic chilution of a racemic mixture produced from chemical ral molecules have been deracemized using the attri7-10 synthesis, in comparison to synthesis using molecules tion enhanced-deracemization technique. Recentfrom the chiral pool (45%), and synthesis based upon ly, the group of Vlieg has experimentally shown that 1 the e.e. in the solution phase is persistently opposite an asymmetric procedure (9%). to the e.e. in solid phase even when the deracemizaThere are several methods of chiral resolution to tion is complete, as long as the grinding of the partiaccess to target enantiomers. In addition to the Pascles is continued. They have also presented an imteurian method and its variants, preferential crystalliproved model based upon the simple cluster incorpozation (PC) is the favored method for separating the 11-12 ration model, which predicts the persistent oppositwo enantiomers when a racemic mixture crystallizes tion between the e.e. of the solution phase and that of as a stable conglomerate. The two enantiomers can 13 the solid phase as observed during the experiments. be quantitatively obtained in high purity using this 2,3 The mechanisms of Viedma ripening were investigatmethod when the mother liquor is recycled several ACS Paragon Plus Environment


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ed by the use of isotopic labeling in experiments with 14 and without attrition by Hein et al. An interesting conclusion to this study is that there is “a distinct correlation between the stochastic, transient growth of crystals and the emergence of a single solid enantio14 morph under attrition conditions”. This emphasizes the importance of growth and dissolution processes even for the attrition controlled deracemization experiments. However, attrition using glass beads, as used in the Viedma ripening processes, can be a source of impurities that ensures that a further separation step is required. The process is also not easily amenable to scale-up to industrial scales. A complete deracemization process can be achieved via the use of temperature gradients and/or fluctuations in temperature (combined with racemization in the solution phase if the enantiomorphs are chiral molecules). The group of Viedma demonstrated complete deracemization by boiling a suspension of 15 sodium chlorate crystals without grinding. In 2013 the groups of Coquerel and Flood demonstrated that complete deracemization of a racemic mixture of a chiral molecule could be achieved via a temperature 16 cycling technique. However, the mechanism behind 17-20 this form of deracemization is still debated. Further studies on the application of the temperature cy21-23 cling technique has been performed as well as the combination of temperature and pressure gradients 24 using high-pressure homogenization . The use of 25,26 ultrasound for deracemization and several other methods to reach homochirality have been demon27-29 strated. The deracemization process using temperature cycles requires a time-dependent temperature control system that has both heating and cooling capacity and the ability to switch between the two. The need for both heating and cooling of a large amount of suspension in an industrial scale system may require a substantial heat transfer area. Moreover, the operating time of the ordinary temperature cycling system is long since it requires significant time to heat and cool a large quantity of suspension. In the current work we present a new process which provides a better means of large scale resolution based on the temperature cycling operation. This process has a production yield higher than that of the PC process since all crystals in the suspension are converted to the desired pure enantiomer. It also prevents the problem of impurities caused in the attrition deracemization process. Moreover, the implementation of the novel process is uncomplicated, since only isothermal control is required, resulting in enantiopure crystals being obtained in a single step operation. 2. EXPERIMENTAL PROCEDURE 2.1 Materials Racemic 4,4-dimethyl-1-(p-toluyl)-2-(1H-1,2,4triazol-1-yl)pentan-3-one (Me-Tak) was synthesized

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using an efficient four step method described else30 where. Distilled water/methanol mixtures were used for deracemization experiments. Materials needed for the HPLC analysis of the e.e. are described in the supplementary material describing the HPLC method (S1). The definition of e.e. in this study is given in the supplementary material (S2). 2.2 Setup The experimental setup consisted of two roundbottom thermostated glass flasks (Figure 1). A small volume double jacket flask, with a working volume of 25 mL, served as the dissolution part of the system. A larger flask, having a working volume of 50 mL, was used as a crystallization vessel. Temperature was controlled by connecting the jackets of the flasks to temperature controlled baths. Stirring at 500 rpm using oval magnetic stirrer bars was used to make the particle distribution uniform and ensure that the temperature in each of the vessels was uniform. The suspension was continuously transferred between the two vessels with a constant flow rate using a peristaltic pump. In general, crystals in suspension can be damaged by pumping, however the peristaltic pump has a gentle pumping action that has a minimal damage to the crystals in the suspension in comparison to other pumps such as the centrifugal pump. The temperature of the suspensions in the vessels and in the connecting tubes between the vessels was measured by thermocouples.

Figure 1. The experimental setup used for temperature cycle enhanced-deracemization via coupled mixed-suspension vessels. T1: temperature indicator in the cool vessel; T2>T1: temperature indicator in the hot vessel; T3: temperature indicator in the tube. 2.3 General procedure 2.5 g of a racemic mixture of Me-Tak (0.6 g of which remains as a solid in the suspension at 20°C), 50 g of methanol/water mixture (65/35 %wt), and 0.4 g of NaOH were chosen as a standard solution. Fifty milliliters of the standard mixture was used for each experiment. Solubility of the Me-Tak under the experimental conditions is give in the supplementary material S3. The first experiment on this setup (Exp I) was performed to ensure that the deracemization seen in the system was due to thermal fluctuations rather than due to grinding caused by agitation or pumping. Further experiments were performed on a system with

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temperature variations within the process (Exp II-IV) and with a single vessel using temperature cycles (Exp V). Previous work has shown that in both the Viedma ripening process and the thermal fluctuation process, the process of deracemization appears self-catalytic; the rate of deracemization is very low near 0% e.e. however the rate increases as the e.e. increases. Since it was desired to clearly determine whether significant evolution in the e.e. occurred in a system without temperature fluctuation, an experiment was performed with all parts of the system at the same temperature but with agitation and pumping at the same rates as in other experiments; this system was started with a significant e.e. to more easily see any changes in the e.e.. The initial e.e. in Exp I was achieved by biasing the nucleation event that created the initial suspension by seeding a small amount of one of the enantiomorphs. Initially, the standard mixture was totally dissolved at 40°C. The solution was then cooled down to 20°C with a cooling rate of 1°C/min. Ten milligram of pure enantiomer was introduced into the solution at 23°C, before the mixture has nucleated, to create an initial e.e.. Since the pure enantiomer seed crystals have a strong effect on the nucleation of the mixture, this relatively small amount of seeds can create a significant initial e.e. (note the initial e.e. values in Exp. I-III and V). The same technique was performed for two experiments with temperature variations within the experimental setup (Exp II and III) and for the sake of comparison one experiment using one vessel with temperature cycles (Exp V). Exp. IV was started with a racemic suspension in order to determine the potential of the process for driving a racemic suspension to become a homochiral suspension. After the solution reached 20°C, the suspension was continuously circulated between the two vessels with a flow rate of 15 mL/min until the e.e. reached the homochiral state in the crystal phase. The suspension volumes in the cold vessel and the hot vessel were 30 mL and 10 mL, respectively. The remaining volume (10ml) was in the tubes connecting the two vessels. In Exp. V, the standard solution of 50 mL was stirred at 500 rpm in the large vessel. Temperature cycles were applied to the system throughout the experimental period. The programmed temperature cycles consisted of 4 steps per cycle; 1. Holding at 20°C for 5 min, 2. Ramping the temperature up to 22.4°C over a period of 3 min, 3. Holding the temperature at 22.4°C for 5 min, 4. Ramping the temperature down to 20°C over a period of 10 min. One cycle lasts 23 min. An example of a single temperature cycle is shown in Figure 2.

Figure 2. Temperature versus time for a single temperature cycle. 3. RESULTS AND DISCUSSION An initial experiment was performed at a constant temperature in order to investigate the effect of potential attrition appearing in this system on the evolution of the e.e. by setting the temperature in all parts of the system to 24°C (the ambient temperature) and allowing the system to operate with flow of suspension between the vessels as before. The magnetic stirrers were used at a speed of 500 rpm to ensure a uniform temperature and crystal distribution within the vessels. The suspension was circulated between the two vessels at 15 mL/min using the peristaltic pump. The result shows that the e.e. in solid phase did not change over 35 hours even though the initial e.e. was high (ca. 30 % e.e.). This indicates that the evolution of the e.e. was not due to attrition caused by magnetic stirrer bars or the peristaltic pump, at least during the operating times used in later experiments. Exp. II, with an initial e.e. of ca. 30% in the solid phase, was carried out with the same operating conditions as Exp. I, with the exception that the temperature in the hot vessel was changed from 24°C to 26°C. The second experiment was conducted in order to test the feasibility of the deracemization process. It can be seen that when the two vessels were maintained at different temperatures the e.e. started evolving as soon as the circulation of the suspension was commenced. The e.e. in the solid phase progressed towards complete deracemization, and reached a homochiral state at ca. 15 hours. It is not surprising that there is no induction time required for initiation of the symmetry breaking, since the system is not racemic at the beginning of the deracemization process. This result also indicates that even a small temperature difference (ca. 2°C) is enough to drive the system to the homochiral solid state.



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newly designed circulating system (ca. 3.3 min) which includes periods in both the hot and cold vessels, is approximately equivalent to 1 cycle of the programmed temperature cycle system (where the time required for a cycle is 23 min). That makes the circulating system more effective since there is a larger number of temperature cycles occurring in the system, resulting in a faster access to complete deracemization. One cycle of the circulating process takes a very short time compared with the previous temperature cycling process and this ensures that the new process requires a shorter operating time.

Figure 3. Evolution of e.e. versus time. Exp. I – Isothermal circulation of the suspension between two vessels, Exp. II – Operation by circulation of the suspension between two thermostatted vessels at different temperatures, 24 and 26°C, Exp. III – Operation by circulation of the suspension between two vessels at the same temperature, 20°C, however the temperature in the tube is 22.4°C. Exp. III was conducted to verify the reproducibility of the new process for deracemization. Two vessels were isothermally controlled at 20°C by double jackets connected to temperature controlled baths. The ambient temperature was at 24°C. The temperature of the suspension in the tube was not controlled by a thermostat, and therefore the temperature of the tube depended on the ambient temperature during the experiment which resulted in T3 (the temperature of the fluid in the tube) in Exp. II and III being 24.5°C and 22.4°C, respectively. The experimental result of Exp. III shows that the e.e. in the solid phase also changed along the period of the experiment after starting the circulating of the suspension between the small vessel and the large vessel through the tubes. The suspension volume in the tubes, which is the hot part of the system in Exp. III, is 10 mL. This 2.4°C change in temperature is enough to partially dissolve the crystals in the suspension in the tube. The result clearly shows that this modified operating process can be used to obtain pure enantiomeric crystals as a result of temperature gradients in the system rather than attrition. The temperature difference in the system is an essential feature of this process for deracemization. This ∆T does not need to be large (ca. 2°C is enough) for a fast deracemization. All crystals in the suspension grow in the cold vessel and then partially or totally dissolve in the hot vessel. Any secondary nuclei occurring in the system were simultaneously destroyed in the hot part of the system. It could be considered that one residence time of the

Figure 4. Evolution of e.e. versus time. Exp. I – Isothermal circulating suspension between two vessels, Exp. IV – Initial e.e. = 0% by circulating suspension between two different temperature vessels between 20 and 22.5°C, ▼ Exp. V – Ordinary deracemization in one vessel by programmed temperature cycles between 20 and 22.4°C. To investigate the behavior of the evolution of the e.e. in the modified temperature cycle process, Exp. IV was performed with an initial e.e. of 0%. Once the symmetry was spontaneously broken after a few hours (ca. 12 h), the e.e. of the solid phase increased quickly, leading to complete deracemization at ca. 32 hours after the initiation of the circulation of the suspension between the two vessels. It can be seen that the evolution of the e.e. in the process described here is a sigmoidal function, similar to the evolution of the e.e. in the solid phase appearing in the ordinary temperature cycling process (programmed temperature cycles in one vessel). It also indicates that small temperature fluctuations in the system (between 20 and 22.5°C) are enough to break the symmetry in solid phase, and can drive the system to complete deracemization. As fluctuations in temperature are difficult to avoid they could be a universal contribution to deracemization.


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Crystal Growth & Design between the two vessels is too large compared to the size of the vessels, then it is likely that the system will eventually become less efficient since the residence time of the suspension in the vessels is not sufficient for the system to approach the equilibrium state at the low or at the high temperature.

Figure 5. Evolution of ln(e.e.) versus time. Exp. IV – Initial e.e. = 0% by circulating suspension between two different temperature vessels between 20 and 22.5°C, ▼ Exp. V – Ordinary deracemization in one vessel by programmed temperature cycles between 20 and 22.4°C. Exp. V, an experiment using temperature cycles within a single vessel, was carried out using the same total suspension volume (50 mL) as Exp. IV and was conducted by setting the magnitude of temperature fluctuations at 2.4°C. The fluctuations occurred between 20 and 22.4°C. The initial e.e. of the one vessel operation is 13%. It can be seen that even though the one vessel operation (Exp. V) has a significant initial e.e (i.e. 13% e.e.), it took a longer time to achieve complete deracemization in the solid phase compared with the two vessel operation (Exp. IV) which has 0% e.e. at the beginning of the process. It can be emphasized that the two vessels operation, taking 3.3 min/cycle, has a larger number of temperature cycles than the one vessel operation, taking 23.0 min/cycle. The rate of deracemization in the two vessel operating system (Exp. IV) is significantly higher than those being in the single vessel operating system (Exp. V) as seen in Fig. 5. However, the choice of a 23.0 min cycle in the one vessel operation is rather arbitrary. The 23.0 min temperature cycle was used in previous 16 work where the temperature change during the cycle was significantly larger, 5°C. The cycle length was chosen so that the ramps in the temperature were not too fast, particularly in the cooling part of the cycle since a very fast ramp may lead to primary nucleation of the two enantiomorphs rather than crystal growth of the existing crystals in the suspension. With the smaller temperature differences in the current experiment it would be possible to use faster cycles (ca. 10 min) however even in this case the two vessel system is likely to give a faster deracemization. It is also important to note that similar arguments about the period of the cycle can be made for the residence time of the two vessel process. If the residence times are made too small, i.e. the flow rate of the suspension

Figure 6. SEM micrographs of samples taken during the experimental period of Exp. I – Isothermal circulation of the suspension between two vessels, Exp. IV – Initial e.e. = 0% and circulation of the suspension between two vessels at 20 and 22.5°C, and Exp. V – Ordinary deracemization in one vessel by programmed temperature cycles between 20 and 22.4°C. Labels 1A and 1D, labels 4A and 4D, and labels 5A and 5D correspond to labels indicated on Figure 4. SEM micrographs of samples (1A – 1E, 4A – 4F, and 5A – 5E indicated on Fig. 4) can be seen in the Supplementary Material (S4). The scale bar on the SEM micrographs is equivalent to 200 µm.



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Figure 7. High magnification SEM micrographs of samples taken during the experimental period of Exp. I – Isothermal circulation of the suspension between two vessels, Exp. IV – Initial e.e. = 0% and circulation of the suspension between two vessels at 20 and 22.5°C, and Exp. V – Ordinary deracemization in one vessel by programmed temperature cycles between 20 and 22.4°C. Labels 1A and 1D, labels 4A and 4D, and labels 5A and 5D correspond to labels indicated on Figure 4. SEM micrographs of samples (1A – 1E, 4A – 4F, and 5A – 5E indicated on Fig. 4) can be seen in the Supplementary Material (S4). The scale bar on the SEM micrographs is equivalent to 20 µm. Although the attrition effects in the two vessel process is likely to be greater than in the one vessel process, they remain below the threshold of efficiency for deracemization as shown in Exp I; they just help in controlling the crystal size at relatively small size which in turn assists the dissolution in the hot part of the set-up. In the two vessel system it can be seen (1A and 1D and 4A and 4D of the SEM pictures in Fig.6) that the crystals obtained from the modified temperature cycling system (Exp. IV) were visibly larger than the crystals obtained from the stirred isothermal system (Exp. I). The attrition by the stirrers and the peristaltic pump in the two vessel system is not responsible for the evolution of e.e.. The SEM micrographs of the samples taken during Exp. IV indicate that during and after the symmetry breaking the sizes of crystals became larger as shown in the SEM pictures of Exp. IV, 4C – 4F in Fig. S1. It is clear that the evolution of e.e. in Exp. IV is due to dissolution

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and recrystallization phenomena induced by temperature fluctuations in the system. Temperature fluctuations are responsible for enhancing the exchange of mass between the solution phase and the faster growing crystals in the crystal phase, which promotes the evolution of the e.e.. Among other components involved in the driving force of deracemization, the evolution of the e.e. is due to growth rate dispersion where the slower growing (low growth activity) crystals eventually disappear due to the competition with the faster growing (high growth activity) crystals, and this leads to a gradual increase in the mean particle size in the system and a corresponding decrease in the number of crystals. In this process the enantiomorph population which contains the subset of crystals with the highest growth activities will win the competition during the dissolution recrystallization cycles, rather than the enantiomorph having the higher average growth activity. The surfaces of the crystals are shown in Fig. 7, where it can be seen that the final population of crystals after the dissolution/recrystallization phenomena are good quality highly faceted crystals. It is very likely that the crystals of the slow growing population were outcompeted by the crystals of the fast population via dissolution/recrystallization phenomena and racemization in the liquid phase. The competition of the two enantiomorphs may be caused by the difference in crystals growth rate activities between the two 17 populations as described elsewhere. In the case of Me-TAK (and the other TAK compounds we have studied) the rate of racemization is very fast and therefore the rate of the deracemization process is unlikely to be limited by the rate of the racemization in the liquid phase. However, in cases where the rate of the racemization reaction is lower it is possible that the rate of racemization might limit the minimum residence time possible in the two-vessel system, and also give a lower limit for the cycle time required in a system using temperature cycling. In the current work it has become clear that very small thermal fluctuations (ca. 2°C) can cause a racemic mixture to completely deracemize into a homochiral state. At this point it is not yet clear whether there is a lower threshold for the thermal fluctuations below which deracemization will not occur, and if so what this lower threshold is! Future research will explore this significant question. 4. CONCLUSIONS The results presented in this work are very promising in terms of process scale-up since it is a one-step operation with an easy implementation and the use of simple setup. This modified temperature cycling process requires a short processing time compared with the previous temperature cycling process (which takes a couple of days) and the abrasive grinding 16 process (which takes a week). Neither a complicat16 24 ed temperature control system nor a special setup


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is required for this novel process. In comparison to 4,6 the conventional operation of Viedma ripening, the new process does not require further separation after deracemization to remove impurities caused from attrition of the beads, which is a drawback of the Viedma ripening process. An industrial scale of Viedma ripening was designed using a special wear re31 sistance material however recovery of the product from a system with other solids is still required. The difficulties in Viedma ripening on an industrial scale can be removed in the modified temperature cycling process due to the absence of beads or any other mechanism causing mechanical stress in the system, and the use of small temperature fluctuations is not likely to lead to side products. The use of ultrasound for deracemizing a racemic mixture of a conglomerate forming system is also interesting, but the mechanism involved is still unclear, leading to difficulty in control25 ling the process. However there are still a lot of parameters to be investigated for optimizing the novel temperature cycling process, including: the mean residence times in the cold and hot vessels in connection with hot and cold vessel temperatures, suspension density, among others. Optimum values for these variables will also relate to the physical and chemical properties of the system including solubility, the racemization rate achievable, and dissolution/crystallization parameters. The operating parameters can be optimized to increase the performance of the process in terms of improving productivity, reducing processing time, and minimizing energy consumption. This novel scale-up approach for temperature cycling enhanced-deracemization process can be an effective alternative to obtain a pure enantiomer. Beside practical applications of the 2-vessel temperature cycling method, this work prompts the following open fundamental question: is there any minimum fluctuation in temperature below which deracemization does not take place? AUTHOR INFORMATION Corresponding Author * Tel.: +33 02 3552 2927. Fax: +33 06 8933 3281. Email: [email protected]. Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ACKNOWLEDGMENT This work was financially supported by a Post-Doc fellowship from Vidyasirimedhi Institute of Science and Technology (VISTEC) and the University of Rouen. Dr. N. Couvrat is thanked for SEM photos. ABBREVIATIONS e.e., enantiomeric excess; Me-Tak, 4,4-dimethyl-1-(ptoluyl)-2-(1H-1,2,4-triazol-1-yl)pentan-3-one.

Supporting Information Available: Supporting information for experimental techniques (HPLC analysis (S1), calculation of enantiomeric excess in the solid phase (S2), and solubility data of ClTAK (S3)) and SEM photographs of the crystals during deracemization experiments (S4) are given. This material is available free of charge via the Internet at http://pubs.acs.org. REFERENCES (1) Murakami, H. Top. Curr. Chem. 2007, 269, 273299. (2) Coquerel, G.; Petit, M.-N.; Bouaziz, R. Patent WO1995/008522, 1995. (3) Rougeot, C.; Hein, J. E. Org. Process Res. Dev. 2015, 19, 1809-1819. (4) Viedma, C. Phys. Rev. Lett. 2005, 94, 065504. (5) Noorduin, W. L.; Meekes, H.; van Enckevort, W. J. P.; Millemaggi, A.; Leeman, M.; Kaptein, B.; Kellogg, R. M.; Vlieg, E. Angew. Chem. Int. Ed. 2008, 47, 6445-6447. (6) Noorduin, W. L.; Izumi, T.; Millemaggi, A.; Leeman, M.; Meekes, H.; van Enckevort, W. J. P.; Kellogg, R. M.; Kaptein, B.; Vlieg, E.; Blackmond, D. G. J. Am. Chem. Soc. 2008, 130, 1158-1159. (7) Wilmink, P.; Rougeot, C.; Wurst, K.; Sanselme, M.; van der Meijden, M.; Saletra, W.; Coquerel, G.; Kellogg, R. M. Org. Process Res. Dev. 2015, 19, 302308. (8) Levilain, G.; Rougeot, C.; Guillen, F.; Plaquevent, J.-C.; Coquerel, G. Tetrahedron Asymmetry 2009, 20, 2769-2771. (9) Noorduin, W. L.; Kaptein, B.; Meekes, H.; van Enckevort, W. J. P.; Kellogg, R. M.; Vlieg, E. Angew. Chem. Int. Ed. 2009, 48, 4581-4583. (10) Kaptein, B.; Noorduin, W. L.; Meekes, H.; van Enckevort, W. J. P.; Kellogg, R. M.; Vlieg, E. Angew. Chem. Int. Ed. 2008, 47, 7226-7229. (11) Uwaha, M. J. Phys. Soc. Jpn. 2008, 77, 083802. (12) Noorduin, W. L.; van Enckevort, W. J. P.; Meekes, H.; Kaptein, B.; Kellogg, R. M.; Tully, J. C.; McBride, J. M.; Vlieg, E. Angew. Chem., Int. Ed. 2010, 49, 8435– 8438, DOI: 10.1002/anie.201002036. (13) Spix, L.; Engwerda A. H. J. ; Meekes, H.; van Enckevort, W. J. P.; Vlieg, E. Cryst. Growth Des. 2016, 16 (8), 4752-4758. (14) Hein, J. E.; Cao, B. H.; Viedma, C.; Kellogg, R. M.; Blackmond, D. G. J. Am. Chem. Soc. 2012, 134, 12629-12636. (15) Viedma, C.; Cintas, P. Chem. Commun. 2011, 47, 12786-12788. (16) Suwannasang, K.; Flood, A. E.; Rougeot, C.; Coquerel, G. Cryst. Growth Des. 2013, 13, 34983504.



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(17) Suwannasang, K.; Coquerel, G.; Rougeot, C.; Flood, A. E. Chem. Eng. Technol. 2014, 37, 13291339. (18) Steendam, R. R. E.; Dickhout, J.; van Enckevort, W. J. P.; Meekes, H.; Raap, J.; Rutjes, F. P. J. T.; Vlieg, E. Cryst. Growth Des. 2015, 15, 1975-1982. (19) Katsuno, H.; Uwaha, M. J. Cryst. Growth 2014, 401, 59-62. (20) Katsuno, H.; Uwaha, M. Phys. Rev. E 2016, 93, 013002. (21) Steendam, R. R. E.; van Benthem, T. J. B.; Huijs, E. M. E.; Meekes, H.; van Enckevort, W. J. P.; Raap, J.; Rutjes, F. P. J. T.; Vlieg, E. Cryst. Growth Des. 2015, 15, 3917-3921. (22) Wu, Z.; Yang, S.; Wu, W. CrystEngComm 2016, 18(13), 2222-2238. (23) Li, W. W.; Spix, L.; de Reus, S. C. A.; Meekes, H.; J. M. Kramer, H.; Vlieg, E.; ter Horst, J. H. Cryst. Growth Des. 2016 16 (9), 5563-5570. (24) Iggland, M.; Fernández-Ronco, M. P.; Senn, R.; Kluge, J.; Mazzotti, M. Chem. Eng. Sci. 2014, 111, 106-111.

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(25) Rougeot, C.; Guillen, F.; Plaquevent, J.-C.; Coquerel, G. Cryst. Growth Des. 2015, 15(5), 21512155. (26) Xiouras, C.; van Aeken, J.; Panis, J.; ter Horst, J. H.; van Gerven, T.; Stefanidis, G. D. Cryst. Growth Des. 2015, 15, 5476-5484. (27) Sogutoglu, L.-C.; Steendam, R. R. E.; Meekes, H.; Vlieg, E.; Rutjes, F. P. J. T. Chem. Soc. Rev. 2015, 44, 6723-6732. (28) Viedma, C.; Coquerel, G.; Cintas, P. Handbook of Crystal Growth (Second Edition), Elsevier, Boston, 2015, 951-1002. (29) Ribó, J. M.; Blanco, C.; Crusats, J.; ElHachemi, Z.; Hochberg, D.; Moyano, A. Chem. Eur. J. 2014, 20, 17250-17271. (30) Rougeot, C. Ph.D. Thesis, University Paul Sabatier of Toulouse III, Toulouse, France, 2012. (31) Noorduin, W. L.; van der Asdonk, P.; Bode, A. A. C.; Meekes, H.; van Enckevort, W. J. P.; Vlieg, E.; Kaptein, B.; van der Meijden, M. W.; Kellogg, R. M.; Deroover, G. Org. Process Res. Dev. 2010, 14(4), 908-911.


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For Table of Contents Use Only A Novel Design Approach to Scale-Up of the Temperature Cycle Enhanced-Deracemization Process: Coupled Mixed-Suspension Vessels. Kittisak Suwannasang, Adrian E. Flood, and Gérard Coquerel*

An improved process for the deracemization of a racemic conglomerate suspension using temperature fluctuations is presented. The method consists of circulating the suspension between two vessels, each controlled at a specific temperature. The crystals in the cold vessel have a longer residence time than those in the hot vessel. The new process is easy to scale up.


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Graphic for abstract and TOC 77x62mm (300 x 300 DPI)


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Figure 1. The experimental setup used for temper-ature cycle enhanced-deracemization via coupled mixedsuspension vessels. T1: temperature indicator in the cool vessel; T2>T1: temperature indicator in the hot vessel; T3: temperature indicator in the tube. 177x65mm (300 x 300 DPI)



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Figure 2. Temperature versus time for a single temperature cycle. 85x60mm (300 x 300 DPI)


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Figure 3. Evolution of e.e. versus time. ν Exp. I – Isothermal circulation of the suspension between two vessels,  Exp. II – Operation by circulation of the suspension between two thermostatted vessels at different temperatures, 24 and 26°C,  Exp. III – Operation by circulation of the suspension between two vessels at the same temperature, 20°C, however the temperature in the tube is 22.4°C. 85x80mm (300 x 300 DPI)



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Figure 4. Evolution of e.e. versus time. ν Exp. I – Isothermal circulating suspension between two ves-sels, λ Exp. IV – Initial e.e. = 0% by circulating sus-pension between two different temperature vessels between 20 and 22.5°C, ▼ Exp. V – Ordinary derac-emization in one vessel by programmed temperature cycles between 20 and 22.4°C. 85x80mm (300 x 300 DPI)


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Figure 5. Evolution of ln(e.e.) versus time. λ Exp. IV – Initial e.e. = 0% by circulating suspension be-tween two different temperature vessels between 20 and 22.5°C, ▼ Exp. V – Ordinary deracemization in one vessel by programmed temperature cycles between 20 and 22.4°C. 85x65mm (300 x 300 DPI)



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Figure 6. SEM micrographs of samples taken dur-ing the experimental period of Exp. I – Isothermal circulation of the suspension between two vessels, Exp. IV – Initial e.e. = 0% and circulation of the suspension between two vessels at 20 and 22.5°C, and Exp. V – Ordinary deracemization in one vessel by programmed temperature cycles between 20 and 22.4°C. Labels 1A and 1D, labels 4A and 4D, and labels 5A and 5D correspond to labels indicated on Figure 4. SEM micrographs of samples (1A – 1E, 4A – 4F, and 5A – 5E indicated on Fig. 4) can be seen in the Supplementary Material (S4). The scale bar on the SEM micrographs is equivalent to 200 µm. 108x140mm (300 x 300 DPI)


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Figure 7. High magnification SEM micrographs of samples taken during the experimental period of Exp. I – Isothermal circulation of the suspension between two vessels, Exp. IV – Initial e.e. = 0% and circula-tion of the suspension between two vessels at 20 and 22.5°C, and Exp. V – Ordinary deracemization in one vessel by programmed temperature cycles between 20 and 22.4°C. Labels 1A and 1D, labels 4A and 4D, and labels 5A and 5D correspond to labels indicated on Figure 4. SEM micrographs of samples (1A – 1E, 4A – 4F, and 5A – 5E indicated on Fig. 4) can be seen in the Supplementary Material (S4). The scale bar on the SEM micrographs is equivalent to 20 µm. 108x140mm (300 x 300 DPI)


A Novel Design Approach To Scale Up the Temperature Cycle

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