Application of Continuous Preferential Crystallization to Efficiently

Review pubs.acs.org/OPRD

Application of Continuous Preferential Crystallization to Efficiently Access Enantiopure Chemicals Céline Rougeot†,‡ and Jason E. Hein*,†,‡ †

Chemistry and Chemical Biology, University of California, Merced, California 95343, United States Department of Chemistry, University of British Columbia, Vancouver, BC V6T 1Z1, Canada

‡

ABSTRACT: Preferential crystallization can be a highly efficient method of producing enantiopure chemicals at large scale. While most preferential crystallization processes have been designed around classical batch crystallizers, numerous advantages can be obtained by incorporating continuous crystallization technologies, allowing better process control and reproducibility with higher material throughput. Even with these marked advantages, continuous preferential crystallization is not utilized as often as a conventional batch process. This review aims to introduce the technique and highlight some examples where continuous preferential crystallization has been employed, emphasizing the advantages in process efficiency.

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INTRODUCTION Efficient production and separation of chiral molecules as individual enantiomers remains a fundamental challenge facing synthetic chemistry.1 Access to pure enantiomers has been dominated by leveraging chiral building blocks from easily available sources such as amino acids or sugars.2 These efforts are second only to developments in asymmetric synthesis and catalysis,3 and yet, despite landmark breakthroughs in this field, most highly efficient asymmetric synthetic protocols remain narrow in scope and do not provide general solutions to address growing demands for enantiopure chiral commodity chemicals. In cases where the direct access to a single target enantiomer is not possible resolution of the racemic mixture is necessary.4 Racemic mixture can be separated by preparative chromatography using a chiral stationary phase;5,6 however, this technique suffers from serious limitations in both speed and mass throughput. A potentially more general and more practical method of isolating enantiopure chemicals is separation by crystallization.7 While preferential crystallization (PC) in batch reactors is far more common, modern advances incorporating continuous crystallization techniques have opened the way for dramatic improvements in both the productivity and broad applicability of preferential crystallization to access enantiopure chemicals. The goal of this review is to give an overview of current applications detailing the resolution of enantiomers utilizing continuous preferential crystallization (CPC).

Scheme 1. Chemical Structure of Racemic Tartaric Acid 1, Quinicine 2 and Cinchonicin 3

in the form of a coordination complex or acid−base adduct. Contrary to enantiomeric compounds, diastereomers have different physicochemical properties10 which allows separation to be achieved through exploiting these differences. In order to effect separation using crystallization, the relative solubility difference of the constituent diastereomers is employed. However, for this method to be economical, the chiral agent used in the resolution must be inexpensive and readily available in high enantiomeric purity on an industrial scale. This intrinsic inefficiency can partly be overcome if the chiral agent can be readily recycled.9 A second limitation of this approach stems from the mode of interaction between the chiral agent and the target enantiomer, which is necessarily noncovalent in order to allow easy recovery of the pure enantiomer following crystallization. Most commonly, classical resolution involves the formation of diastereomeric salts, thus requiring that a sufficient difference in the acid/base functionality exists to ensure the generation of a robust compound. The combination of these requirements usually means several candidate diastereomeric salts must be explored in order to find an optimal chiral resolving agent which displays a large difference in solubility between the resulting diastereomeric compounds

1. RESOLUTION BY CRYSTALLIZATION 1.1. Pasteurian Resolution. The most classical and wellknown method of enantiomeric purification using crystallization is known as Pasteurian resolution. This method, also termed diastereomeric resolution or classical resolution, was discovered by Louis Pasteur in 1853 and was applied in his resolution of tartaric acid 1 using chiral quinuclidine bases such as quinicine 2 or cinchonicin 3 (Scheme 1).8 The principle behind classical resolution is to break the symmetry between enantiomers through the addition of a pure chiral agent to a racemic mixture in an achiral solvent.9 The enantiomeric pair is therefore transformed into diastereomeric compounds, usually © XXXX American Chemical Society

Special Issue: Polymorphism & Crystallisation 2015 Received: May 1, 2015

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DOI: 10.1021/acs.oprd.5b00141 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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crystallized by seeding a supersaturated solution at constant temperature. An example of a second generation technique is Auto-Seeded Polythermic Programmed Preferential Crystallization (AS3PC), 17 where crystallization of the pure enantiomer occurs by applying a controlled cooling to a saturated solution. A related variation is known as Auto-Seeded Preferential Crystallization Induced by Solvent Evaporation (ASPreCISE), which utilizes controlled solvent loss to induce supersaturation in order to drive crystallization.18 In each of these techniques, preferential crystallization becomes a cyclic process whereby the mother liquor is recycled, resulting in excellent recovery of both enantiomers. If the target compound can be easily racemized in the solution phase, then a technique known as Second-Order Asymmetric Transformation (SOAT) can be utilized.19 In this approach, fast in situ racemization allows facile interconversion of the two enantiomers. Thus, any depletion in the concentration of a single enantiomer due to preferential crystallization is immediately reset resulting in a constantly racemic solution phase. The SOAT approach is particularly advantageous because undesired crystallization of the opposite enantiomer is more difficult as any supersaturation is alleviated via chemical racemization. In addition, the recoverable quantity of the target enantiomer is greatly enhanced because the undesired enantiomer will be converted to the desired product by way of the chemical racemization. Resolution by preferential crystallization, regardless of the particular variation in operation, is only possible when the racemic mixture forms a conglomerate. That is to say, the two enantiomers crystallize as distinct enantiopure solid phases even when both enantiomers are present in the mother liquor (Figure 1A). Unfortunately, compounds that preferentially

yet permits facile isolation of the target enantiomer following crystallization. Despite these seemingly significant drawbacks, this method provides an excellent and reliable means of resolving enantiomers for industrial production. Specifically, the pure enantiomer of the flavopiridol 4, an anticancer drug, can be obtained by resolution of the intermediate 1-methyl-4-(2,4,5trimethyoxyphenyl)piperidin-3-one 5 using the dibenzoyl-Dtartaric acid 6 (Scheme 2).11 In addition, (S)-naproxen 7, a Scheme 2. Flavopiridol 4 Can Be Obtained from Intermediate 5 by Using Dibenzoyl-D-tartaric Acid 6 as Resolving Agenta

a Similarly, naproxen 7 is resolved by using various N-alkyl-Dglucamine such as N-methyl-D-glucamine 8.

nonsteroidal anti-inflammatory, is produced at thousands of tons per year via separation of the racemic mixture using Nalkyl-D-glucamine 8 as a chiral resolving agent (Scheme 2).12 (For more examples, see refs 4 and 13−15.) 1.2. Preferential Crystallization. Preferential crystallization, also known as crystallization by entrainment, is a stereoselective crystallization process. Unlike classical resolution, a single enantiomer is selectively crystallized from a racemic supersaturated mother liquor using only the addition of an enantiopure seed crystal, obviating the addition of an additional chiral auxiliary.16 Selective growth of one enantiomorphous crystal phase is achieved because the energy barrier for the spontaneous nucleation of the nonseeded enantiomer is higher than the energy required to grow the crystals present from the seed. This difference in energy between crystal nucleation and crystal propagation provides a kinetic advantage, allowing crystallization of the seeded enantiomer to occur while the opposite enantiomer remains fully in the solution phase. One caveat is that the crystallization must be stopped at a time appropriate to the particular system, before the nucleation of the opposite enantiomer becomes likely. The thermodynamically stable state of a PC is indeed a biphasic system made of a racemic liquid and a nearly racemic solid (racemic mixture + seeds). The intrinsic kinetic window invariably limits the maximum recovery of enantiopure crystalline material during a single crystallization event from a racemic solution. However, other more advanced techniques have been developed, allowing both enantiomeric antipodes to be alternatively crystallized using a combination of careful management of crystallization conditions. The oldest variation of the original preferential crystallization method is termed Seeded Isothermal Preferential Crystallization (SIPC). In this approach, the pure enantiomer is

Figure 1. Ternary phase diagrams and representation of the crystals compositions of (A) conglomerates and (B) racemic compounds.

crystallize as conglomerates are relatively rare with 10% or less of organic compounds spontaneously forming stable, discrete conglomerates.2 Instead, most molecules crystallize as racemic compounds in which a stoichiometric mixture of enantiomers is present in the same crystal packing (Figure 1B). Direct resolution of racemic compounds by any existing crystallization technique is not possible with the exception of a few specialized B



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Table 1. Non-exhaustive List of Molecules Resolved by PC and Deracemization

Figure 2. Principle of deracemization.

cases.20,21 These accomplishments have only been possible where crystallization of the pure enantiomer by seeding is highly kinetically favored compared to spontaneous nucleation of the racemic crystal, which is thermodynamically the more stable phase. One such example of the successful deployment of a preferential crystallization approach to a racemic compound was reported by Brandel et al., who described the resolution of diprophylline 9 using SIPC.22 If direct resolution of the target racemic compound is not possible, screening for an appropriate conglomerate form can be performed23,24 with the aim usually to identify a salt, cocrystal, solvate, or some combination thereof that delivers a new crystalline compound displaying the required features to permit preferential crystallization. Some examples of compounds resolved by preferential crystallization are given in Table 1. 1.3. Deracemization. Solid-phase deracemization is a recent method allowing access to a single enantiomer utilizing

recrystallization of a conglomerate coupled to in situ racemization in the solution phase.25,26 Due to these two requirements, deracemization can be considered as an improvement of the SOAT approach as, instead of selectivity forming a single enantiopure crystal phase from a homogeneous starting point, deracemization begins with a saturated biphasic solution and a racemic mixture of conglomerate crystals. Vigorous stirring of the crystalline solid phase in equilibrium with its saturated liquid phase containing a racemizing agent allows the enantiomeric excess (e.e.) of the crystal population to gradually evolve, producing a single crystalline enantiomer (Figure 2).27 The evolution of the crystal-phase enantiomeric excess can be strongly increased by using glass beads,26 sonication,28 or highpressure homogenization29 to break particles and to promote their dissolution. The combination of glass beads and cooling30 is also an alternative, as well as the use of temperature cycling to promote oscillations in solubility.31 C



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Figure 3. Left: representation of a mixed-suspension, mixed-product removal (MSMPR) crystallizer. Middle and right: two different kinds of PFR (a kenics-type mixer PFR and an oscillatory baffled crystallizer, respectively).

differential fluid flow can be utilized, as is seen with oscillatory baffled crystallizers.44

Both SOAT and deracemization are highly appealing because the theoretical yield of the target enantiomer is 100% due to the conversion of the undesired enantiomer by way of the racemization reaction. In practice, deracemization is more productive and easier to perform than SOAT since it is not necessary to carefully manage the supersaturation and crystallization kinetics of the system to ensure the development of a single crystalline solid. Unfortunately, the added requirement for a facile racemization to the already stringent condition of a conglomerate compound further limits the number of molecules that can be addressed by this technique (Table 1). Thus, while deracemization is a highly productive method to obtain a pure enantiomer, its application in the widespread production of chiral chemicals has not yet been realized.

3. COUPLED PREFERENTIAL CRYSTALLIZATION The underlying mechanism that allows preferential crystallization to occur, namely, that a seeded supersaturated system has a kinetic window where a single enantiomer can be separated from its antipode, also provides the source for the primary limitation of the technique. Regardless of the particular method, the preferential growth of one enantiomeric crystal phase from a solution containing both enantiomers does not represent an equilibrium condition, but rather a metastable state. For this reason utilizing preferential crystallization for the isolation of single enantiomers can be labor intensive and require careful monitoring and regulation of process parameters, such as the instantaneous e.e. of the solid and liquid phase, solution concentration, and temperature. Furthermore, multiple cycles of repetitive crystallization are necessary to yield both pure enantiomers in sufficiently high mass recovery from the racemic mother liquor.16 The requirement of having to successfully carry our multiple successive crystallization events only compounds problems associate with management of process conditions and crystallizer control. An alternative method, termed continuous preferential crystallization, incorporates some of the elements common to standard continuous crystallization techniques to address issues related to process control, reproducibility, and ultimate efficiency which are particular challenges in the area of preferential crystallization. The major advantage to adapting continuous crystallization technology to achieve stereoselective crystallization lies in the ability to manage the relative concentration of the two enantiomers in the solution phase. The concentration of both enantiomers remains nearly constant throughout the process when using CPC. Thus, the concentration of the opposite enantiomer never reaches the critical threshold of spontaneous nucleation (the Ostwald’s limit), allowing crystallization of the seeded enantiomer to be carried out with better control and less stringent demands on process parameters. At present there have been a number of successful resolutions of chiral materials using the CPC technique. While each process is related in its concept, the technology and operation varies depending on the particular apparatus that is employed. For this reason we have chosen to discuss each according to the style of crystallizer being utilized: Single container (CPC1): A crystallizer, seeded with pure enantiomer, is fed with supersaturated racemic solution, allowing overflow to regulate the excess of mother liquor. Two containers (CPC2): A crystallizer seeded with pure enantiomer is coupled to a reactor containing the racemic mixture, which it is progressively dissolved.

2. CONTINUOUS CRYSTALLIZATION In general, crystallization stands as the preferred separation and purification method for industrial production of fine chemicals and pharmaceutical compounds. The one major challenge to effectively employ this technique lies with careful control over the process parameters (temperature, nucleation, growth rate, agitation speed, etc.) during the crystallization event in order to reliably control the properties of the final solid (polymorph, crystal size and shape, etc.). In order to meet these stringent needs while balancing constraints of reactor physical footprint within a plant, crystallization in a continuous mode has emerged as a very attractive technology. In general, continuous crystallization methods offer advantages in productivity and material throughput, batch reproducibility and crystal quality.40 A variety of continuous crystallization reactors have been designed, with particular attention given to the mixing and mass transfer properties, which tends to decrease when the size of reactor increases.41 The two main kinds of continuous crystallizers are the mixed-suspension, mixed-product removal (MSMPR) crystallizer and the plug flow removal (PFR) crystallizer (Figure 3). MSMPR reactors are usually used for crystallization operations requiring long residence time. The overall efficiency using a single MSMPR reactor is generally lower than for a similar volume batch crystallization operation, however, performing the technique with several MSMPR reactors in series or using differential setups with multistage crystallizers helps to significantly improve the yield and throughput while keeping the quality of final product very high.42 PFR reactors are tubular reactors used for crystallization requiring shorter residence time. The primary challenge when operating these reactors stems from the issues related to efficient mixing due to a propensity to adopt a laminar flow regime rather than turbulent mixing, particularly for long tubular designs. To combat this drawback mixing elements, such as the Kenics type static mixers43 can be included or D



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develops, the crystal-free liquid phase is continuously pumped between crystallizers in a circular fluidic loop. Thus, the e.e. in the solution phase created by selectively crystallizing one enantiomer is immediately alleviated by delivering the mother liquor to the opposite crystallizer. Due to this circular loop, the local concentration of the opposite enantiomer in whichever crystallizer never reaches the Ostwald limit and therefore minimizes the probability of uncontrolled primary nucleation of the unseeded enantiomer. Of course, this also requires the flow rate of liquid exchange to be balanced against the rate of crystallization following nucleation. In general, the rate of liquid exchange must be adjusted such that the residence time in each reactor is long enough to allow maximal crystallization of the desired enantiomer but short enough to prevent uncontrolled nucleation of the opposite enantiomer. This parameter will be related to both the solubility and the potential degree of entrainment, and thus it will need to be optimized for each individual case. The outcome is greater control over the resolution process, leading to a more facile isolating of enantiopure material. Elsner and co-workers were the first group to study the feasibility of the CPC2 process applied to the resolution of threonine 19 in water, which is an unambiguous conglomerate forming system.46 Experimental parameters, such as solubility and kinetics of crystallization obtained from classical preferential crystallization of threonine, were utilized in a population balance mathematical model to simulate the behavior of a system displaying simultaneous preferential crystallization in a coupled batch operation mode.49 Their simulation examined the impact of several crystallization process parameters, such the mass of crystal seeds, the initial temperature, the initial enantiomeric excess in the liquid phase, and the flow rate of the exchange of mother liquor, on the overall rate and productivity of separation using coupled preferential crystallization. One important point elucidated by their simulation was that the overall efficiency of separation depended heavily on the flow rate of solution between the two crystallizers, as this fundamentally limits the rate at which mass flow can occur. Most interestingly, their model also predicts that the productivity of crystallization (i.e., Pr) as defined by the gain in mass (final mass without the initial mass of seeds) per unit time (eq 1), and the sample purity of the final solid phase were enhanced in the CPC2 protocol when compared with single batch preferential crystallization. mSolid − mseeds − mexcess,0 Pr = k ∈ {p , c} t ·0.5mrac (1)

Three containers (CPC3): Two separate crystallizers (one for each enantiomer) are coupled with a reactor containing the racemic mixture. Alternative methods: Multiple reactors and systems incorporating chemical epimerization (CPC-R).

4. CONTINUOUS PREFERENTIAL CRYSTALLIZATION: SINGLE CRYSTALLIZER (CPC1) Continuous preferential crystallization in one crystallizer is most similar to classical preferential crystallization. A supersaturated solution of the racemic mixture is seeded with a pure enantiomer in a single reactor vessel. To avoid the nucleation of the opposite enantiomer and to increase the yield of the process, the mother liquor is continuously renewed with crystal-free supersaturated racemic mixture, and an overflow regulates the excess of mother liquor. This method was first described by Ito et al. by using either a batch crystallizer or a fluidized bed crystallizer for the resolution of glutamic acid 18 (Figure 4).45

Figure 4. Representation of a single crystallizer in a continuous mode in (A) a fluidized bed and (B) a batch crystallizer.

5. CONTINUOUS PREFERENTIAL CRYSTALLIZATION: TWO CONTAINERS (CPC2) The theoretical study of the preferential crystallization in two separated crystallizers was reported first by Elsner et al.46 and then modeled by Hofmann and Raisch47 and Qamar et al.48 The concept is illustrated in Figure 5. In order to enhance the productivity of the preferential crystallization, two crystallizers, connected by the circulation of a crystal-free liquid, are filled with a racemic supersaturated solution. Then, simultaneously, each crystallizer is seeded separately with one of the two enantiomers. Preferential crystallization is thus initiated in parallel in both crystallizers. As the preferential crystallization

Following this initial theoretical demonstration, Elsner et al. completed the experimental separation of threonine 19 using a CPC2 protocol. This later study represents a practical demonstration and validation of their earlier simulations. Moreover, their results confirm that the productivity of the coupled crystallization approach is superior to that of the batch process.40,50 By using an optimized cooling profile instead of an isothermal crystallization approach, the productivity of the resolution of racemic threonine 19 was increased nearly 300% compared with a similar single batch mode of crystallization while maintaining 100% enantiopurity in both recovered enantiomers. The same group further extended their theoretical investigation to the resolution of asparagine 20 and subsequently developed a CPC2 protocol to allow facile recovery of both enantiomers of this amino acid on decagram scale.51

Figure 5. Two crystallizers connected by the circulation of a crystalfree liquid. E



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ammonium tartrate 2152and threonine 19.53 This method has further been applied to obtain the pure enantiomers of esomeprazole 22 (Nexium), which is a proton pump inhibitor with international yearly sales in the billions of dollars.55 In a recent publication, Levilain et al. have examined this approach more closely and described a theoretical study of the CPCD technique in order to identify the best operating conditions.56 By using a population balance approach they developed a mathematical model in good agreement with their experimental results. Furthermore, process parameters such as the temperature difference, the initial enantiomeric excess of the liquid phase, or the flow rate, which influence the overall productivity and the purity of the resolution, were identified and investigated. This study helped to realize a deeper understanding of the process and serves to provide a model for optimizing the technique for specific systems. In addition to the added operational simplicity, the productivity of the CPCD method is significantly higher than for the simultaneous preferential crystallization in a coupled batch operation mode (CPC2).53 In CPCD the theoretical maximum mass of both pure enantiomers depends only on the initial mass of racemic mixture applied to the dissolver while in CPC2 the maximum mass recovered is limited by the solubility difference between the initial and final temperatures applied in the crystallization process. As a caveat, the rate of the resolution may be higher in CPC2 as it relies on the crystal growth kinetics as well as the mass transfer between coupled crystallizers, which is governed by the flow rate. In contrast, the driving force of crystallization in CPCD is controlled by the temperature difference between the two tanks and the solution phase flow rate. While a larger temperature differential will serve to increase the rate of resolution, this also places the system closer to the Ostwald limit, thereby increasing the possibility for spontaneous nucleation of the opposite enantiomer in the crystallization. Ultimately, a balance between resolution rate and solid phase control can easily be achieved due to the flexibility of the CPCD approach.

An alternative method to the simultaneous preferential crystallization in a coupled batch operation mode was reported by Hein et al.52 and Levilain et al.53 In this variation, preferential crystallization occurs in only one vessel with selective dissolution in the second (Figure 6). Seeding with a

Figure 6. Coupled preferential crystallization and dissolution.

single enantiomer causes the mother liquor to be depleted only in this isomer. The liquid phase therefore becomes undersaturated with respect to the seeded enantiomer when it enters the dissolution tank, leading to its selective dissolution from the solid phase that is present. The process of continuous dissolution and crystallization proceeds, resulting in a net mass transfer of the seeded enantiomer from the dissolver to the crystallizer with no net mass movement of the unseeded compound. This will continue until the solid phase of the seeded compound is depleted in the dissolver, leaving behind two separate enantiopure crystal populations. The supersaturation required to crystallize pure enantiomer can be generated either by a slight temperature difference between the crystallizer and dissolver flasks53,55 or through abrasive grinding under isothermal conditions.52 In this latter case, glass beads are used to break the particles in the flask initially containing a racemic mixture. Therefore, according to the Gibbs−Thomson effect, which describes the difference in solubility of particles based on their size,54 the smaller crystals in the dissolver are more soluble than the seeds present in the crystallizer leading to net dissolution and recrystallization. These approaches, termed Coupled Preferential Crystallization and Dissolution (CPCD) can be regarded as an operationally simpler variant of the CPC2 technique reported by Elsner, as it obviates the need to manage two simultaneous preferential crystallization processes in parallel. The practicality and strength of the CPCD process has been demonstrated by first separating well-understood compounds, including sodium

6. CONTINUOUS PREFERENTIAL CRYSTALLIZATION: THREE CONTAINERS (CPC3) A further variation of the continuous preferential crystallization approach involves a three-container system made up of two crystallizers attached in parallel with a single dissolver. This

Figure 7. CPC3 with continuous renewal of the mother liquor combined with a purge system. F



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passing the mother liquor from the dissolver through the crystallizers and out to collection by way of the purge pumps, the liquid phases from both crystallizers are separately circulated back to the dissolver vessel containing a suspension of the racemic mixture at a temperature higher than either crystallization tank. The racemic mixture was then progressively dissolved until completely consumed, with the option of recharging the dissolver flask with additional racemic material at any time without halting the separation. In this system the supersaturation required to drive crystallization can be created either by a size-dependent solubility difference or a temperature difference between the dissolver and two crystallizer flasks. Resolution of threonine 19 has been achieved by Hein et al.52 using both temperature- and crystal-size-induced solubility driving force. In addition, Galan et al. separated threonine 19 employing a temperature difference in two mixed-suspension mixed-product-removal (MSMPR) crystallizers with an additional exchange of liquid phases between the crystallizers.59 Of all variation, continuous preferential crystallization using three flasks (CPC3) is the most widely applied. Examples of this process have been demonstrated using classical conical bottom cylindrical crystallizers (Figure 9A)45 or by using twopart crystallizers composed by a crystallization vessel (bottom) and a sedimentation zone (top) as described by Baumgard et al. (Figure 9B).60 Using the latter apparatus, it was possible to resolve menthyl benzoate 23 in 60m3 crystallizers with a productivity of 300 kg/h. Ito et al. described the resolution of glutamic acid 18 and threonine 19 employing two parallel columns with a fluidized bed of seed crystals (one enantiomer in each column) coupled with a mixing tank containing the racemic mixture (Figure 10).45 This last apparatus can be operated in a continuous mode, with each column being equipped with a system to regularly withdraw the excess of solid as a slurry. The flexibility and productivity of this approach was demonstrated by Ito et al., who performed the resolution of glutamic acid 18 by using the setup illustrated in Figure 10 over 3 h. This application yielded 2.3 kg of L-glutamic L-18 acid and 2.4 kg of D-glutamic acid D-18 with an optical purity of 95%. In an extension of this procedure, Sato et al. preformed the resolution of the lysine 3,5-dinitrobenzoate 24 (Table 2) at labscale using two columns, 8 cm long and 2 cm diameter, and a flow rate of 250 mL·min−1.61 An improved CPC3-type system was reported by Midler et al.62,63 The two fluidized bed columns, placed in series, are

apparatus relies on simultaneous preferential crystallization of both enantiomers in parallel into the two crystallizers, while the racemic mixture is progressively dissolved from the dissolver tank. As with the other variants, the crystal free liquid phase is circulated to effect mass transfer. Chaaban and co-workers have developed a CPC3 they termed Coupled Continuous Preferential Crystallization (CCPC) based on the process developed by Elsner et al.51 for the crystallization of asparagine 20.57 Their modified apparatus now incorporates liquid circulation of supersaturated racemic mixture coming from the dissolver into both crystallizers, with an additional outflow of solution (Figure 7). This flow-through design incorporates an additional purge system of crystal-free liquid to maintain a constant volume in both crystallizers. The renewal of the supersaturated solution from the dissolver tank allows the separation to be carried out under continuous operation, resulting in very high productivity. Mathematical modeling of this continuous process showed that the mean residence time of the liquid phase within the crystallizers and properties of seeds (mass and size) were critical parameters to improve the performance of the process.58 One of the main issues for the process described by Chaaban et al. is related to the flow-though design and incorporation of the purge system, which results in loss of uncrystallized material. Also, managing the flow system to maintain constant volume in the crystallizer tanks requires additional care and effort. A modified CPC3 process was reported by Hein et al., which utilizes a single liquid circulation circuit between three containers but in a closed system (Figure 8).52 Instead of

Figure 8. CPC3 running in a parallel mode with recycling of the mother liquor and continuous dissolution of the racemic mixture.

Figure 9. CPC3 running in series (A) in cylindrical crystallizers and (B) in two-part crystallizers. G



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Figure 10. CPC3 running with parallel fluidized bed crystallizers. Figure 11. CPC3 using fluidized bed crystallizers equipped with sonicators arranged in series.

equipped with two sonicators (Figure 11). In this setup, the larger crystals settle in the bottom of the column and are broken by ultrasound. The resulting smaller crystals are carried upward due to the fluidized bed setup and are used as new seeds to continue the crystallization. Overall this action serves to improve the efficiency of the resolution process and allow higher throughput of crystalline material. Midler et al. also solved another main issue of PC: the decreasing of the e.e. due to the crystallization of the opposite

enantiomer. They demonstrated that, by increasing the temperature of the contaminated crystallizers above the temperature of the dissolver, that is to say by temporally inverting the role of the dissolver and of the crystallizers, it is possible to purify the solid phases without halting the whole process. In that case, the racemic mixture is “selectively”

Table 2. Summary of Molecules Resolved by CPC

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mother liquor of the first tank is fed to the second tank, then from the second tank to the third tank, and so on. The temperature is gradually decreased as you move through the crystallizers in the series. In order to complete the flow circuit, the mother liquor removed from the last tank is recycled to a dissolver at a high temperature and then returned to the first tank as initial supersaturated solution. This approach represents small modification to the CPCD techniques seen in two container systems. As with other linked-flow designs, such as CPC2 and beyond, the flow rate is determined by a balancing act between the crystallization rate and the potential for uncontrolled primary nucleation. Maximum efficiency is achieved when flow is set such that the residence time in each tank ensures crystallization of the maximum amount of pure enantiomer per batch, but short enough to prevent the nucleation of the opposite enantiomer.

dissolved from the crystallizers and then crystallized in the dissolver. When all the opposite enantiomer has been eliminated from the solid phases, they adjusted the temperatures of the crystallizers back to their original values, and both preferential crystallizations were resumed. Midler et al. applied these cycles of purification either on one (by isolating the other crystallizer from the rest of the system) or on both crystallizers. They performed the resolution of the acetamido-(phydroxyphenyl)-propionitrile 25 by using a setup similar that described in Figure 11.62 Over the course of 1200 h the average productivity of enantiopure material per crystallizer was 30 g per hour with a final purity of 97.0% for the D-enantiomer and of 98.5% for the L-enantiomer. The operating times for a single purification cycle was about 60 h for the D-crystallizer and less than 6 h for the L-crystallizer (5% and 0.5% of the total process time respectively). This same group also performed the resolution of the α-acetamido-α-vanillyl propionitrile 26 (Table 2), a precursor of the α-methyl-3,4-dihydroxyphenylalanine 27 (or α-methyl DOPA, Scheme 3), which is a highly

8. CONTINUOUS PREFERENTIAL CRYSTALLIZATION WITH RACEMIZATION (CPC-R) Continuous preferential crystallization can further incorporate in situ racemization.52 This technique is related to attritionenhanced deracemization normally seen in batch operation mode. The result of such a setup is not the separation of the two enantiomers but instead the total conversion of the entire racemic mixture into only the one enantiomer which was seeded in the crystallizer. This variation was first reported by Hein and co-workers48 and utilized abrasive grinding with glass beads in the dissolver flask promote dissolution of the racemic mixture and drive crystallization (Figure 13). Despite the

Scheme 3. Chemical Structure of α-Methyl-3,4dihydroxyphenylalanine 27 (α-Methyl DOPA)

important medication used to treat hypertension.64 Over 400 h they were able to carry out the resolution of a racemic mixture with a productivity of 2 kg per hour per crystallizer while maintaing a final purity of 97.2% for the D-enantiomer and of 98.9% for the L-enantiomer. The operating times for purification cycle were about 8 h for the D-crystallizer and less than 2 h for the L-crystallizer (2% and 0.5% of the total process time, respectively). Grabowski et al. has also used a similar setup on the lab-scale for the resolution of the 3-fluoroalanine-2-d benzenesulfonate salt 28 (Table 2) to highlight the power of the continuous preferential crystallization for the synthesis of a drug candidate at the kilogram scale.65

Figure 13. CPC combined with in situ racemization.

advantage of being able to isolate a single target enantiomer, operating under racemizing conditions further helps to prevent unwanted primary nucleation. This is because the liquid phase remained racemic despite the consumption of the crystallizing enantiomer. Thus, both enantiomers are equally dissolved from the dissolver flask even if only one is crystallizing. At the end of the process, all the racemic mixture has been converted to pure enantiomer. By using continuous preferential crystallization coupled with racemization, Hein et al. resolved the racemic mixture of the 2-(benzylideneamino)-2-(2-chlorophenyl)-

7. − CONTINUOUS PREFERENTIAL CRYSTALLIZATION BY USING BATCH CRYSTALLIZERS IN SERIES The continuous preferential crystallization technique can be adapted to incorporate several large crystallizers arranged in series with each other. In this setup, the series of batch crystallizers can be compared to a succession of classical preferential crystallization steps in a larger campaign (Figure 12).45 Tanks are filled with supersaturated solution and are then alternately seeded with one of the pure enantiomers. The

Figure 12. Succession of batch crystallizers. I



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original value (lower than the dissolver) and the separation of enantiomers can resume using the normal operating conditions. This reset feature can be applied selectively to one of the two crystallizers if needed. If only one crystallizer has become contaminated with the unseeded enantiomer, the temperature of only this crystallizer would be raised above the temperature of the dissolver, while the other crystallizer would be isolated from the rest of the system. Overall, this aspect of the continuous preferential crystallization method of enantiopurification gives rise to three main advantages over traditional preferential crystallization techniques. First, contamination in the growing solid phase due to uncontrolled primary nucleation of the opposite enantiomer can be easily reversed through the inversion of the role of the dissolver and the crystallizer(s). Second, this simple inversion efficiently addresses the issue of uncontrolled nucleation and contamination without halting the recovery process. Finally, as no disassembly and transfer of the material is needed to recover from contamination by uncontrolled crystallization, no material is lost. While there are a small collection of different applications that utilize this approach, we feel that the benefits offered by this technique will attract significantly more attention in the coming years, leading to an expansion in the utilization and development of the continuous preferential crystallization method.

acetamide 29 (Table 2), a derivative of the 2-chlorophenylglycine 30 which is a precursor of the blockbuster drug clopidogrel 31 (Plavix, Scheme 4). Scheme 4. Chemical Structure of 2-Chlorophenylglycine 30 and Clopidogrel (Plavix) 31

9. - CONCLUSION In summary, continuous preferential crystallization offers numerous advantages in terms of improved process control and crystallization productivity. In addition, continuous crystallization provides several practical improvements when applied to the separation of enantiomers, such as reduced manual manipulation leading to an operationally simplified process. Our discussion has been focused on the various designs of crystallizers as they apply to each resolution. Our aim was to demonstrate the great variety of options as a means to encourage further development and elaboration within the community. When designing a new CPC process for a target compound, we feel that choosing between the various methods or reactor designs to pursue will be greatly governed by the hardware available and the level of technical expertise of the group. In general, the CPC3 design offers the greatest promise for creating a truly continuous crystallization process, allowing constant addition of racemic feedstock with the concomitant recovery of separate individual enantiomers in each respective crystallizer. However, if only a single enantiomer of the desired compound is required and the material is amenable to solution phase racemization, application of the CPC-R design is sufficient. More importantly, the CPC3 technique allows the possibility to recover from a failed resolution where the growing solid phase becomes contaminated by the opposite enantiomer without halting the process and resetting the system. This aspect is perhaps is the most unique and valuable advantage of applying the CPC process. The spontaneous nucleation of the unseeded enantiomer is the main limitation of preferential crystallization: once the first nucleus has appeared, the enantiomeric excess of the growing crystal phase will rapidly decrease. For preferential crystallization in a single batch mode, contamination with the opposite enantiomer means that this cycle of the resolution fails, forcing that batch to be rejected and resubjected to separation by crystallization. However, in the case of continuous preferential crystallization methods in three vessels (CPC3), contamination of the pure enantiomer in the crystallizer is readily reversible without halting the isolation process. To accomplish this, the role of the crystallizers and dissolver can be temporarily inverted by heating the crystallizers to a temperature above the temperature of the dissolver. The small amount of opposite enantiomer (or rather the corresponding quantity of racemic mixture) will be dissolved from the crystallizer and recrystallized in the dissolver. Once the purity of the solid phase has returned to a suitable level, the temperature of the crystallizers can be adjusted back to its

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Dr. Céline Rougeot is a postdoctoral research associate with Prof. Jason Hein at the University of California, Merced. She obtained an Engineer’s degree in organic chemistry at the ENSCM “Ecole Nationale Supérieure de Montpellier” in parallel with a Master degree in engineering of biomolecules at the University of Montpellier II in 2008. She completed her Ph.D. in 2012 in the UMR 5068-SPCMIB “Synthèse et PhysicoChimie des Molécules d’Intérêt Biologique” at the University of Toulouse III in collaboration with the EA 3232-SMS “Sciences des Méthodes Séparatives” at the University of Rouen under the supervision of Dr. Jean-Christophe Plaquevent and Prof. Gérard Coquerel. During her Ph.D., she specialized in resolution of racemic mixtures by deracemization at the solid state, and she is currently working on continuous preferential crystallization. Prof. Jason E. Hein received his B.Sc. in biochemistry at the University of Manitoba in 2000. He completed his Ph.D. in synthetic organic chemistry as an NSERC PGS scholar with Professor Philip G. Hultin at the University of Manitoba. He then moved to The Scripps Research Institute as an NSERC postdoctoral fellow jointly with Prof. K. Barry Sharpless and Prof. Valery V. Fokin. In 2010, he became a senior research associate with Prof. Donna G. Blackmond at The Scripps Research Institute. He then joined began his independent career at the University of California, Merced in 2011. His work focused on employing in situ kinetic reaction analysis as a means to rapidly profile and study complex networks of reactions. In 2015, he moved to the University of British Columbia to continue the development of reaction analytical techniques to serve mechanistic organic chemistry. Current studies are aimed at solving a diverse set of problems, including understanding mechanisms of catalyst induction and deactivation, as well as developing techniques to resolve racemic mixtures using coupled preferential crystallization. J



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Review

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ACKNOWLEDGMENTS The authors acknowledge research support from the National Science Foundation, award number CHE-1300686.

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