Continuous Preferential Crystallization of Chiral Molecules in Single

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Continuous Preferential Crystallization of chiral molecules in single and coupled Mixed-Suspension Mixed-Product-Removal crystallizers Kamila Galan, Matthias J. Eicke, Martin P. Elsner, Heike Lorenz, and Andreas Seidel-Morgenstern Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/cg501854g • Publication Date (Web): 18 Feb 2015 Downloaded from http://pubs.acs.org on February 24, 2015

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Crystal Growth & Design

1

Continuous Preferential Crystallization of chiral molecules in single and coupled Mixed-Suspension Mixed-Product-Removal crystallizers

Kamila Galan†, Matthias J. Eicke†, Martin P. Elsner§, Heike Lorenz†, Andreas Seidel-Morgenstern†,‡ †

Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany Georg Simon Ohm University of Applied Sciences, Nuremberg, Germany ‡ Otto von Guericke University, Magdeburg, Germany§ §

Abstract In several industrial fields, the existence of chiral molecules causes challenges, when only one enantiomer is the desired active ingredient in the final product. The separation of pairs of enantiomers can be achieved with different techniques. Once these enantiomers crystallize as conglomerates, preferential crystallization (PC) is a very attractive alternative. So far, various batchwise operating strategies have been developed and applied successfully. Very likely, however, it can be more beneficial to use PC in a continuous manner, since continuous processes can often outrun their batch counterpart in terms of productivity, product quality and process complexity. In this contribution chiral separation is investigated and performed in a continuous manner adapting the concept of Mixed-Suspension Mixed-Product-Removal (MSMPR) to the requirements of preferential crystallization. Continuous PC could be realized successfully in two different experimental setups involving only one MSMPR crystallizer and two MSMPR crystallizers coupled via an exchange of their liquid phases. For the model system D/LThreonine/water this first experimental demonstration of the concept proves that the process can continuously separate enantiomers with purities >99%. The agreement of the experimental results with results of process simulation indicates the strength and usefulness of a previously published mathematical model.

Introduction The three-dimensional structure of organic molecules can lead to challenging aspects regarding their synthesis, production or purification, especially when a compound contains a chiral center and exists in the form of two non-superimposable mirror images of each other referred to as enantiomers. Very often the synthesis of chiral pharmaceuticals leads to racemates (equimolar mixtures of both chiral molecules). When such drugs are administered, our body can easily distinguish between both enantiomers due to the different three-dimensional arrangement of their constituent atoms. As a result, pharmacokinetic and/or pharmacodynamic properties exhibited by ACS Paragon Plus Environment


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2 chiral drugs in human bodies can vary [1-3] and it is necessary to administer enantiopure substances. This currently causes the so-called ‘chiral switch’ because regulations move towards approving only the single enantiomer with the desired properties instead of racemic mixtures [4]. There are several strategies to obtain pure enantiomers. One path deals with the asymmetric synthesis, such as fermentation or asymmetric catalysis. These techniques directly result in enantiopure products. On the other hand, one can simply synthesize a racemate and perform a subsequent separation step [5]. A very powerful and established method is chromatography, which, however, leads to a dilute product stream requiring further processing. Since many products are sold as solids, it is reasonable to combine separation and solid formation of enantiopure crystals in one unit operation. Preferential crystallization (PC) is an alternative process, which can be applied once the enantiomers crystallize as a conglomerate, i.e. a physical mixture of both species in the solid phase [5]. Up to now research has mainly focused on batchwise operation of PC, which was shown to be a feasible approach to resolve enantiomers [6]. It is, however, commonly acknowledged that continuous processes can outperform batch operation in many ways. Among the major arguments are an improved and constant product quality and productivity, while reducing process costs and complexity. There are a couple of concepts regarding the implementation of continuous operation in the area of crystallization [7, 8]. One of them is to employ a plug flow crystallizer by using either a series of continuous stirred tank reactors or a tubular reactor design. Turbulent flow, which is necessary to achieve near plugflow conditions, requires relatively high flow rates in case of a tubular reactor. Recently, the technical implementation could be improved by using a continuous oscillatory baffled crystallizer, which provides much better mixing, even at low flow rates, allowing a reduction in the dimensions of the crystallizer [9, 10]. Another typical approach is the use of a mixedsuspension mixed-product-removal (MSMPR) crystallizer [11]. To further enhance yield and product characteristics, MSMPR crystallizers can be equipped with a recycle system [12, 13] or can be used as a cascade of several connected vessels [14, 15]. In the specific case of enantioseparation by preferential crystallization, continuous operation is more challenging due to an impurity with identical physicochemical properties that amounts to 50% of the chiral raw material. Although discontinuous operation has already been enhanced significantly in terms of robustness [16] and productivity [17], continuous operation of PC should lead to a further improvement and intensification of this process. Currently, two different approaches are investigated systematically. One is based on a fluidized bed reactor, which was described in the patent of Midler in 1970 [18] and was shown to be an effective process for the separation of stereoisomers by Tung [19]. In addition, a configuration exploiting fluidized bed reactors was investigated by Binev [20, 21], in which a mixture of enantiomers can be resolved in a continuous manner. The conical shape of the crystallizer allows removing a specific fraction of the product crystals with a target crystal size distribution. Larger crystals are destroyed by ultrasound and returned to the vessels as seeds. An alternative to this approach is the use of ACS Paragon Plus Environment

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3 continuous stirred tank reactors. In this contribution, the focus is to investigate the applicability of a continuous MSMPR crystallization process for the separation of chiral molecules. In the following sections we will first explain the general working principle of PC and some of its variants followed by a description of possibilities to perform the enantioselective resolution process in a continuous manner. Preliminary simulation studies using a previously published process model [22] together with the parameters of the D/L-Threonine/water system [23] will be applied to evaluate process dynamics and basic trends under different process conditions. The major part of this article is devoted to the experimental proof of the concept. This involves investigating scenarios performed either in a single or in two coupled MSMPR crystallizers. Finally, the performance of the continuous processes will be evaluated and compared with an optimized coupled batch experiment performed with the same chiral system.

Principle of preferential crystallization Classical batch operation The process of preferential crystallization operates under conditions at which the solution is metastable. Within the metastable zone, unwanted spontaneous nucleation is kinetically inhibited for some period of time. Therefore, this time window can be exploited for enantioseparation. The basic principle of PC is illustrated in Figure 1. Usually, a racemic undersaturated solution is the starting point of PC. Next, the system is cooled down in a careful manner, so it can pass the saturation temperature and enter the metastable zone without leaving it. When in this region a crystal-free supersaturated solution exists, resolution is initiated by adding enantiopure seed crystals. These seeds grow and undergo secondary nucleation, leading to a homochiral product. However, the process must be terminated before the onset of unwanted nucleation of the antipode. By doing so, high purity can be ensured. If not, the final product is composed of both enantiomers and no homochiral crystals can be obtained. E1 seeds

racemic, metastable solution

growth secondary nucleation of E1

solid phase (E1 + E2), racemic liquid phase

STOP

otherwise

depletion of supersaturation

nucleation of E2

until solid liquid equilibrium is reached

Figure 1: The basic idea of preferential crystallization in the standard batch mode using a single crystallizer (left: process range, right: not part of the process).

The main drawback of this process is a relatively low yield, because the concentration of the impurity is 50%. Moreover, for some systems, the induction time for nucleation of the opposite enantiomer can be so small that 100% purity is very unlikely to be achieved and hence the ACS Paragon Plus Environment


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4 process has to be modified [25]. For further reading about the resolution of enantiomers, the authors refer to the book of Jacques [26].

Advanced batch operating modes To overcome these limitations, an advanced configuration consisting of two crystallizers was proposed, where the mother liquors are exchanged between both vessels. Each tank is seeded with its own homochiral crystals and kept at the same temperature. The concentration of both liquid phases is racemic throughout the process due to the liquid exchange and thus, the likelihood of impurity nucleation is reduced [16]. Another possible enhancement is a combination of preferential crystallization and dissolution. In this case, two crystallizers, set at two different temperatures, are again connected via their liquid phases, but only in one tank classical PC takes place, while in the other a selective dissolution of a racemic solid phase takes place [17].

Continuous operation In order to transfer the theoretical concept of MSMPR crystallization to enantioselective crystallization, a couple of requirements have to be met. The crystallizer has to be fed continuously with a racemic liquid phase, preferably at a temperature identical to the crystallization temperature. Furthermore, the tank should be well mixed to guarantee uniform conditions [7]. In that case, the withdrawn product suspension is characterized by the same crystal size distribution (CSD) as the suspension inside the vessel. Since enantioselective PC involves seed crystals they have to be introduced to the system. Usually, MSMPR crystallization processes are maintained by secondary nucleation, which generates the required crystal surface. In case of the investigations presented in this work, a constant supply of homochiral seed material was ensured by periodic seeding rather than through secondary nucleation. This deviates from the classical MSMPR principle. Preferential crystallization, however, requires the presence of pure target enantiomer in solid form. A generation of seed material via secondary nucleation requires conditions, which might also work in favor of nucleation of the counter enantiomer, e.g. a higher degree of supersaturation or installations that enhance attrition but may also act as a larger heterogeneous surface resulting in a higher risk of unspecific nucleation. Seeding was therefore implemented to obtain a higher degree of robustness and control during this challenging initial investigation of continuous enantioselective crystallization, devoted to show its general applicability. Seed crystals can be provided either continuously or periodically. In case of periodic seed crystal addition, one should make sure that intervals between the additions are relatively small and do not result in a wide or bimodal product size distribution. To avoid nucleation of the counter enantiomer the mother solution has to stay in the metastable zone throughout the process. Considering the above described situation, the continuous process is performed in one single MSMPR vessel A. However, the resolution process can be further improved by the addition of a second crystallizer B, which is operated under the same conditions as the first one but is seeded ACS Paragon Plus Environment

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5 with the opposite enantiomer. In addition to the feed and product suspension streams, both tanks A and B continuously receive solution from each other (see Figure 2). This liquid phase exchange results in a reduced danger of impurity nucleation [16] and expands the range of feasible process conditions for continuous PC.

Experimental section The equipment used for the continuous processes was a modification of the setup described in [16, 17]. Thus, a meaningful comparison between continuous and previous batch results can be made. The conglomerate forming system D/L-Threonine in water was selected as a model substance because detailed solubility and kinetic data are available [23] as well as the data concerning the metastable zone width [24].

Materials L-Threonine and D-Threonine were purchased from Sigma-Aldrich (Germany, purity>98%) as well as from Iris Biotech (Germany, purity>99%). L-Threonine and D-Threonine seed crystals were generated from Sigma-Aldrich and Iris Biotech material, respectively by milling and subsequent sieving. Seeds were then taken from the sieve fraction 20-38 µm for all experimental studies. As solvents, water, which was purified by Milli-Q gradient system from Milipore Corporation (France) and HPLC gradient ethanol (Merck, Germany) were used.

Setup The experimental setup consisted of three glass double jacketed stirred tanks. Each of the two crystallization vessels had a maximum working volume of 450 mL. The third vessel served as the feed tank and had a capacity of 5 L. A constant stirring rate of 250 rpm for the MSMPR crystallizers and 150 rpm for the feed tank were set to ensure sufficient mixing of the suspensions. To control the temperature of the solutions, each vessel was equipped with a Pt-100 sensor, which was connected with the process control system PCS7 (Siemens). Figure 2a illustrates the core parts of the experimental rig. Shown are the two MSMPR vessels with their major in- and outlet streams. In order to maintain constant feed and suspension outlet flows, gear pumps (Tuthill, D-Series) together with mass flow controllers (mini Cori-Flow, Bronkhorst Maettig GmbH, Germany) were used. Fresh solution from the feed tank (not shown) was continuously supplied to both crystallizers through ports in their lids.

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6

Figure 2: Schematic illustration of (a) the setup applied for single and coupled continuous PC, (b) an improved product collection unit (PCU) with thermostatization and (c) an early design of the product collection unit.

Suspension was removed via riser pipes and collected temporarily in a product collection unit (PCU) (Figure 2b, c). An early design of the PCU, which was used in experiments 1 and 2a is depicted in Figure 2c. It consisted of a parallel connection of silicon tubes that allowed the suspension stream to split up by letting the crystals settle in the lower part. Nearly solid free solution was fed back into the feed tank (solution recycle) in order not to lose the target enantiomer still dissolved in the liquid phase. The improved design shown in Figure 2b enabled for more reproducible conditions since it was thermostated and solid transport to the feed tank was prevented by a solvent filter. For further processing of the collected product, the 50 mL glass bottle was removed and immediately replaced by a new one. In case of the early design, solid was removed via a valve at the bottom of the settling zone. The feed tank contained a saturated racemic suspension, which acted as a buffer to ensure a constant composition and concentration of the feed stream. Depleted solution entering via the recycle stream (in the coupled case two streams from each crystallizer) was mixed with the feed solution, resulting in a transient small undersaturation. Subsequently, the corresponding enantiomer dissolves from the suspended racemate, which immediately counterbalances the respective drop in concentration. This is analogous to the process recently reported by Levilain et al. [17] and ensures that the feed stream remains unchanged throughout the process. Additionally, the volume of the feed tank was 10 times larger than that of the MSMPR crystallizers, making it even less sensitive towards fluctuations of the concentration/composition of the incoming recycle solution. The depicted plant was used for both single and coupled crystallizer operation. Coupling was realized by two gear pumps (Tuthill, D-Series) equipped with solvent filters to ensure crystal-free exchange of mother liquors between both tanks. Constant and equal flow rates were provided by mass flow controllers (mini Cori-Flow, Bronkhorst Maettig GmbH, Germany). Single vessel operation was done simply by leaving the exchange inactive. To prevent crystallization in the ACS Paragon Plus Environment

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7 feed, exchange and suspension-removal lines, all pipes were heated above saturation temperature by a tube-in-tube configuration.

Process analytics The experiments were monitored by online measurement of the optical rotation angle (POLARmonitor, IBZ Messtechnik, Germany) and the density (DE40 Density Meter, Mettler Toledo, Germany) of the liquid phases in each MSMPR vessel. The analytical devices were connected in series to create an external loop through which crystal-free mother liquor was pumped and returned to the corresponding crystallizer. The constant solution stream was generated by a peristaltic pump (Heidolph PD 5201, Heidolph Electro GmbH & Co., Germany) operated at a flow rate of 3.5 mL/min. The analytical paths were kept at 50 °C to avoid nucleation and by that any signal disturbance. In case of the feed liquid phase, only the density was measured using a similar setup. In order to determine the product purity, a conventional system of high pressure liquid chromatography was used. A chiral chromatographic column “Astec Chirobiotic T” (25 cm x 4.6 mm, 5 µm) manufactured by Supelco Analytical (USA) was attached to the HPLC equipment (Agilent HP 1260 or Agilent HP 1200, Germany), where a mobile phase containing 70% ethanol and 30% water was pumped with a flow rate of 0.5 mL/min. The column was thermostated at 25 °C. Representative samples were prepared by dissolving product crystals in water at a concentration of 1%. For measurements 5 µL were injected and the corresponding chromatograms were obtained at a wavelength of 210 nm.

Evaluation The signals of the above described detectors were subsequently used to evaluate the process in terms of productivity, purity and the state of the liquid phase, using a couple of basic equations, which are detailed below. The liquid phase compositions were determined as mass fractions. The definition is given as

w IL =

m IL , I = E1, E2 ∑ mIL + mH 2O

(1)

I

where the symbols E1 and E2 denote L- and D-Threonine, respectively. Based on the measured liquid phase density ρL and the optical rotation angle α, it is possible to calculate the mass fractions of each enantiomer with

1  ρ (t) − ρ0 α(t)  w E1L (t) =  L −  2  kd k pol 

(2)

and



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8

1  ρ (t) − ρ0 α(t)  + w E2L (t) =  L . 2  kd k pol 

(3)

The three parameters kd, ρ0 and kpol were determined before every experiment by calibration of the analytics. On the basis of eqs. 2 and 3, one can calculate the driving force, either in terms of absolute supersaturation

w IL (t) w (eq) IL (T)

SI (t) =

or as the relative supersaturation

w IL (t) − w (eq) IL (T) ⋅100% . σI = (eq) w IL (T)

(4)

The product purity PuI can be expressed as the ratio of the mass of enantiomer I, mIS, and the total solid mass,

Pu I =

m IS ⋅100% . ∑ mIS

(5)

I

& Pr and m & Seeds The productivity PrI is the difference between the product and seed mass flow, m respectively per crystallizer volume Vcryst. For the simulation study it is calculated as

PrI,sim =

& Pr − m & Seeds m . Vcryst

(6)

However, for the experiments it is defined as

 m  1 m PrI,exp =  Pr − Seeds  ,  ∆t coll ∆t add  Vcryst

(7)

taking into account that product slurry removal from the PCU and seeding were done periodically. Here ∆tcoll and ∆tadd, denote the time intervals of product collection and seed addition, respectively.

Procedures Before the start of each experiment, the feed tank was filled with 3991 g of water and heated up to 55 °C, T> Tsat. Then, 504.5 g of each enantiomer were added and dissolved. The final solution concentration corresponds to a saturation temperature of Tsat = 42 °C. Subsequently, the solution was cooled to 42 °C (Tsat) and 300 g of solid racemate was added to create a suspension. This was done to maintain a constant feed concentration of racemic composition throughout every experiment (see section 3.2). At the same time the solution in the MSMPR vessel was prepared at 50 °C using 359.19 g of water and 45.405 g of each enantiomer. These masses produce a


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9 solution, which is saturated at the chosen temperature Tsat = 42 °C. In the coupled experiments, two separate solutions of identical concentration and composition were prepared in both MSMPR tanks. All flows were then activated and cooling of the MSMPR vessel(s) was performed until the final crystallization temperature within the metastable zone was reached. The process was subsequently initiated by the addition of the first seed crystals marking the beginning of the

& Seeds of 1g/h was approximated by periodic, resolution. Subsequently, a continuous seed flow m manual addition of 0.5 g optically pure seeds every 30 min (sieve fraction 20-38 µm). The mass flow of the seed crystals was selected on the basis of previous investigations of batch PC and preliminary test runs of the continuous operation. During the process the product suspension was temporarily accumulated in the product collection unit (PCU), which was scheduled to be emptied periodically every 1 h (∆tcoll). At times, it was, however, necessary to empty the PCU more frequently, when the unit reached its maximum capacity earlier. This was considered precisely in the calculation of the experimental productivity values. The dense suspensions were then filtered and washed with ice-cold water and ethanol. Finally, the product crystals were placed in a desiccator for a minimum of five days until a constant dry mass was obtained.

Process conditions In total, four different scenarios were investigated experimentally and by simulation. Table 1 summarizes the considered cases, which differ in the chosen crystallization temperature Tcryst, residence time τ, as well as the process type. The first three scenarios were performed in a single MSMPR crystallizer and include one repetition (case 2). In the final scenario 4, the coupled configuration was studied using the same process conditions as in scenario 3. Table 1:

*

Variable process conditions of the experimental and simulated scenarios ( VSolution = 420 mL).

Scenarios experiment simulation 1 1

single

Tcryst [°C] 35

τ∗ [min] 70

Process type

2a, 2b (rep.)

2

single

35

46.5

3

3

single

38

46.5

4

4

coupled

38

46.5

Table 2 summarizes the initial process conditions used in all experiments and simulations. Here, the solution concentrations in the crystallizers and feed tank are given in terms of mass fractions wrac,cryst and wrac,feed, respectively. Tsat denotes the saturation temperature of the initial solution, Tcryst is the crystallization temperature and τ the mean residence time of the liquid and solid & . /V phase, which is defined as V solution

feed



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10 Table 2: Operating parameters for all continuous experiments and simulations (* periodic addition of 0.5 g every 30 min (experiments) and continuous seeding (simulations)).

Parameter

Symbol

Value

Unit

solution conc. (crystallizer)

wrac,cryst

0.2018

grac /gsolution

solution conc. (feed)

wrac,feed

0.2018

grac /gsolution

Tsat

42

°C

mass flow of seeds

& Seeds * m

1

g/h

seeds sieve fraction

zSF & V

20-38

µm

30

mL/min

solution saturation temperature

exchange rate (scenario 4 only)

ex

Preliminary simulation study of the continuous PC process Model and parameters In order to get a better understanding of the processes to be studied experimentally, we first repeated some of the simulations done by Qamar et al. [22]. To estimate the dynamic and steady state behavior, we again use the D/L-Threonine/water system for the case studies, however, under process conditions specific to the experiments discussed in this article. We considered the two above mentioned process options: continuous PC in a single MSMPR crystallizer and the improved configuration using two coupled MSMPR crystallizers. The model has already been used to simulate single and coupled batch PC [16] and a more recent experimental implementation involving coupled PC and selective dissolution in two crystallizers [27]. With respect to continuous PC, Qamar et al. [22] published comprehensive parametric studies, which investigated single and coupled crystallizers as well as different means of suitable seeding strategies. Furthermore, the effects of fines dissolution were studied theoretically, which, when used in continuous crystallization, can lead to instabilities. This was, however, not subject to investigation in this publication. The mathematical description of the continuous PC process was based on one-dimensional population balances that describe the evolution of the crystal size distributions in connection with mass balances of the liquid phase. Furthermore, the model contains standard kinetic expressions for growth, primary and secondary nucleation of each enantiomer. Growth and secondary nucleation are described in terms of standard power-laws and depend on supersaturation as well as temperature. Primary nucleation kinetics are based on classical nucleation theory described by Mersmann [8]. The influence of one enantiomer on the other is captured via the solubility correlation and the primary nucleation kinetics. The model equations and parameters were the same as in the previous publication of Qamar et al., [22, table 1 therein]. All kinetic and thermodynamic parameter values are specific for the ACS Paragon Plus Environment

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11 chiral compound D/L-Threonine in water as the solvent and have been determined and validated by the group of the authors in various batch experiments [23, 24]. Tables 1 and 2 summarize the specific process parameters that differ from those used previously by Qamar et al. [22]. In the simulations we assume continuous seed addition at a mass flow rate

& Seeds as opposed to periodic seeding applied in the experiments. The seed distribution is m described by a log-normal distribution with a mean length zmean = 38 µm of the needle like particles, which is in good agreement with the experimentally determined seed crystal size distributions.

Results of the simulation study The following simulation results show the experimentally observable liquid phase composition wIL (gsolute / gsolution; I=E1,E2) (cf. section 3.4), relative supersaturation degree σI and the solid

& Pr leaving the crystallizer. The latter is more challenging to measure exactly, product mass flow m due to the relatively small scale of the equipment, which sometimes resulted in fluctuations of the collected product masses (experimental “noise”).

product mass flow mPr [g/h]

0.102 w(1,2,3) Lfeed

0.100

10

10

8

8

.

w(3) E1L

0.098 0.096

(2) E1L

w 0.094

.

m(2) Pr

6

.

6

(1) Pr

m 4

4 .

2

σ(3) E1

σ(1) E1

(1) E1L

m(3) Pr

σ(2) E1

2

w

0

0.092 0

2

4

6

8

10

12

14

16

18

0

2

4

6

8

10

12

14

16

relative supersaturation σE1 [%]

The first three scenarios (see Table 1) deal with continuous PC in a single vessel and are analogous to the first four experiments (1, 2a, 2b, 3). Except for the varied crystallization temperature Tcryst and residence time τ, all process parameters were identical. As we consider MSMPR crystallization, the residence time τ is the same for both, liquid and solid phase. The left plot in Figure 3 shows the predicted trends of the mass fraction wE1L of the seeded enantiomer E1 in solution. The effect of lowering the residence time is demonstrated with simulations 1 and 2, whereas the effect of an increase in crystallization temperature can be seen by comparing simulations 2 and 3. In all cases, the steady states are reached between 3 to 5 hours after seeding. mass fraction in liquid phase wE1L [-]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0 18

time t [h]

time t [h]

Figure 3: Simulation of continuous PC in a single vessel under three different process conditions (superscripts 1-3 represent scenarios 1-3, Table 1). Left: Mass fractions of the seeded enantiomer E1. Right: Corresponding supersaturation levels and the product mass flows.

Simulations for scenarios 1 and 2 start with a higher initial degree of supersaturation compared to simulation 3, which results in a lower steady state concentration and therefore a higher output of ACS Paragon Plus Environment


12 product mass (right plot, solid lines). Interestingly, although the steady state concentration of simulation 2 is slightly higher than in case 1, scenario 2 leads to the highest product output. Due to the lower residence time (and therefore a higher feed flow rate) the concentration shifts towards the feed concentration. At the given temperature this results in a higher steady state supersaturation and thus leads to faster crystal growth and secondary nucleation (Figure 3, right). In scenario 3, the crystallization temperature Tcryst is increased by 3 K compared to scenario 1 and 2. Thus, the initial supersaturation is lower than in the other two cases, however almost the same steady state value as in the first simulations is reached. Naturally, less product is obtained compared to case 2. With respect to the first case, although the feed flow rate is higher, this does not compensate for the slight reduction in driving force at steady state. In all three cases, the supersaturation of the unseeded enantiomer E2 (not shown) remains at its initial value and the model predicts a steady state purity of above 99.9% with respect to the seeded enantiomer. It should be noted, that the purity values have to be considered with care, since the mathematical description of primary nucleation is known to be challenging. The model used here, does not account for its stochastic nature. Thus, in order to account for unwanted product contamination, the process can be operated in a safer manner by using the above mentioned coupled two-vessel configuration (cf. section 2). Figure 4 shows the simulation results of scenario 4 (compare Table 1), which, in terms of residence time and temperature is identical to the previous scenario 3. Tank A (Figure 4, left) is continuously seeded with enantiomer E1, while Tank B (Figure 4, right) continuously receives E2 seed crystals. In addition, the liquid phases are constantly exchanged & of 30 mL/min. between both tanks at a volumetric flow rate V

0.100

wLfeed

w(c) E2L

8

0.098

6 w(p) E1L

0.096

4 .

.

mPr σ(c) E2

0.094

σ(p) E1

0.092

2 0

0

2

4

6

8

10

0.102

10

0.100

wLfeed

w(c) E1L

8

0.098

6 w(p) E2L

0.096

4 .

.

mPr σ(p) E2

0.094

σ(c) E1

2

0.092

0 0

2

time t [h]

4

6

prod. mass flow mPr [g/h], rel. supersat. σI [%]

10

mass fraction in liquid phase wIL [-]

0.102

prod. mass flow mPr [g/h], rel. supersat. σI [%]

ex


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Page 12 of 25

8

10

time t [h]

Figure 4: Simulation of continuous PC in two coupled vessels (scenario 4). Shown are the trends for mass fraction, supersaturation and product mass flow for each crystallizer. Tank A (left) is seeded with E1, tank B (right) is seeded with E2.

As in the single crystallizer scenarios, steady state is again reached within approximately 5 h. Since the two enantiomers have identical physicochemical properties, both tanks work in absolute symmetry concerning the evolution of the liquid phase compositions and the rates of solid product output. It can further be noticed that the relative supersaturations σ(c) of the respective I counter enantiomers are at a much lower level than in the single vessel process, particularly in ACS Paragon Plus Environment

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13 comparison to scenario 3, where it remained at its initial value of approximately 4% (data not shown in Figure 3). This is the key advantage of the coupled process for batch and also for continuous operation and the reason for the higher process robustness. When simulating the continuous preferential crystallization process, it has to be kept in mind that all model parameters are specific to the considered compound Threonine. They were either measured experimentally or estimated mathematically using data from various preliminary batch experiments. It is thus doubtful that simulation studies of the continuous process can exactly reproduce experimental data. However, the reported theoretical investigations on continuous PC clearly indicate the strength and feasibility of this type of process. These simulations allow evaluating the effect of crucial operating parameters. On the basis of these theoretical results, decisions concerning the range of crystallization temperature Tcryst and the residence time τ can be made. This facilitates the experimental design and realization. Below, we report a first time experimental demonstration of continuous PC.

Experimental results Related to the preliminary theoretical study, continuous enantioselective separation of D- and LThreonine using PC was performed in five different runs. Four experiments were conducted in a single MSMPR vessel (exp. 1-3, with one repetition) and one using the coupled configuration (exp. 4). All processes lasted for at least more than 10 residence times to ensure that steady state operation could be reached. This is sufficient for processes of orders not too different from unity, which applies to the crystal growth kinetics of Threonine. The following experiments in the single vessel setup (scenarios 1-3) had the main purpose to find process conditions close to steady state at which the impurity remains in the liquid phase as long as possible. These conditions then served as a starting point for the subsequent first investigation of the coupled configuration (scenario 4). In addition technical aspects of continuous enantioselective crystallization regarding long-term operation were assessed during the single MSMPR experiments.

Single MSMPR experiments (scenarios 1, 2a, 2b, 3) & Pr and product purity Liquid phase mass fractions wIL, supersaturation SI, product mass flows m PuI (eq. 5) are used for the evaluation of the process performance. Due to the periodic addition of homochiral seed crystals, small oscillations of these parameters can be seen in all experimental curves. Each time, when seeds are introduced to the system, supersaturation is depleted at a relatively high initial rate. Due to the constant supply of racemic feed, the resulting drop in concentration of the preferred enantiomer is partly counterbalanced, leading to its increase until the next seed addition. In case of experiment 1, stable operation is reached after approximately 2 hours. The mass fraction in the liquid phase and supersaturation of the preferred enantiomer can be considered ACS Paragon Plus Environment


14 constant from this point onwards (Figure 5 and Figure 6, left). However, the decrease of the liquid phase mass fraction (Figure 5, right) as well as supersaturation (Figure 6, right) of the counter enantiomer after 14 h, indicates the occurrence of nucleation of the unseeded species. According to the purity analysis, product purity started to decline even earlier, namely after 11.5 h (Figure 7, right). Thus, for the process conditions chosen for scenario 1, it was apparently not possible to avoid nucleation of the opposite enantiomer. A steady state with a constant degree of contamination could be expected, had the system been allowed to operate longer. In an attempt to further improve the product purity, the residence time τ was reduced by one third in the following experiment 2a. By doing that, the solid phase present in the vessel had less time to crystallize leading to higher mass fractions of the seeded enantiomer in the liquid phase (Figure 5, left) and higher supersaturation (Figure 6, left). At the same time, this supported a washout of eventually formed nuclei of the impurity. Although the residence time was shorter, the product mass flow did not deteriorate (Figure 7, left). The increased feed flow rate produced a higher driving force for crystallization resulting in a higher product output. Unfortunately, also in this experiment the antipode nucleated after three hours leading to a considerably lower purity of the product compared to scenario 1 (Figure 7, right). 0.102 mass fraction in liquid phase wE2L [-]

0.102 mass fraction in liquid phase wE1L [-]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 25

0.100 0.098 Exp. 3

Exp. 2b

0.096

Exp. 2a

0.094 Exp. 1 0.092

Exp. 1

0.100

Exp. 3

Exp. 2b

Exp. 2a

0.098 0.096 0.094

0.092 0

2

4

6

8

10

12

14

16

0

2

time t [h]

4

6

8

10

12

14

16

time t [h]

Figure 5: Experimentally obtained mass fractions of both enantiomers (left plot: preferred enantiomer E1, right plot: counter enantiomer E2) in the liquid phase. The values were calculated from density and optical rotation signals registered during the experiments (Scenarios 1 – 3).

Even though nucleation of the counter enantiomer occurred, one would have again expected a steady state concentration of the impurity after a certain time, since it was continuously removed along with the product. This was, however, not observed for the given length of the experiment. The strong decrease in purity could have additionally been due to the lack of temperature control in the early design of the product collection unit (PCU, see Figure 2c). The run of scenario 2 was therefore repeated with the improved PCU (compare Figure 2b), which was thermostated at 40 °C (T> Tcryst). This particular temperature was selected, since the average concentration of the solution with respect to the seeded enantiomer E1 corresponded to a saturation temperature Tsat of 40 °C in experiment 2a (Figure 5, left, process time 5 h to 16 h). A slight degree of supersaturation regarding the counter enantiomer was accepted to keep product ACS Paragon Plus Environment

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15 losses by dissolution in the PCU as low as possible. Compared to experiment 2a, the transient of the liquid phase mass fraction of the preferred enantiomer during the repetition experiment (2b) showed an almost identical behavior. The same was true for the values at the later stages of the process as depicted in the left half of Figure 5 and the product mass flow shown in Figure 7. This demonstrates the degree of reproducibility achievable when performing such experiments. Nevertheless, the noticeable differences regarding the counter enantiomer clearly reveal also limits of reproductions. 1.15

1.15

1.12

1.12

supersaturation SE2 [-]

supersaturation SE1 [-]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1.09 Exp. 2b

1.06

Exp. 2a

1.03 Exp. 3

Exp. 1

1.09 Exp. 2b

Exp. 2a

1.06 Exp. 3 1.03

Exp. 1

1.00

1.00 0

2

4

6

8

10

12

14

16

0

2

time t [h]

4

6

8

10

12

14

16

time t [h]

Figure 6: Supersaturation of the preferred (left plot) and counter (right plot) enantiomers during the experimental investigations. (Scenarios 1 – 3)

Contrary to the previous experiment 2a, the mass fraction of the unseeded enantiomer (Figure 5, right) and its supersaturation (Figure 6, right) did not exhibit a strong drift during run 2b. This was also reflected by the purity of the product crystals, which was above 99% throughout the process (Figure 7, right) except for the last three measurements, which showed the beginning of a downward trend. Unfortunately it was not possible to further observe the development due to an unexpected malfunction of the product withdrawal pump causing a stop of the process. A further purity drop could be expected if the process had been continued when taking into account the evolution from the previous run. The product mass flow was comparable with experiment 2a (Figure 7, left), but exhibited far less fluctuations, indicating a beneficial effect of the improved PCU.



16 8

100 Exp. 2a Exp. 2b

6

.

product purity Pu [%]

product mass flow mPr [g/h]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 25

4

2

Exp. 1

Exp. 3

Exp. 2b Exp. 3

95 Exp. 1

Exp. 2a 90

85

.

mSeeds

0 0

2

4

6

8

10

80 12

14

16

0

2

time t [h] Figure 7:

4

6

8

10

12

14

16

time t [h]

Product mass flow (left) and product purity acquired from the HPLC analysis (right) for scenarios 1-3.

On the basis of experiments 2a and 2b, it was concluded that the chosen conditions were still not in an operating region, where nucleation of the opposite enantiomer could be reliably suppressed for an extended period of time, which is necessary for a continuous process. To investigate a third combination of temperature and residence time, the driving force of crystallization was reduced by increasing the crystallization temperature from 35 °C to 38 °C (scenario 3). Thereby, a likely drop in productivity was accepted but a more robust process with respect to impurity nucleation was anticipated. The process conditions of scenario 3 corresponded to a significantly lower degree of supersaturation of the counter enantiomer (Figure 6, right). Simultaneously, the mass fraction remained at almost the same level as in experiment 2b (Figure 5, right). In case of the seeded enantiomer, the mass fraction settled down at a higher stable value (Figure 5, left), owing to the reduced driving force. As a result, the product output was lower in comparison to the previous scenarios, which is evident from the trends depicted in Figure 7 (left). Interestingly, the supersaturation of the product settled at a slightly higher level than in experiment 1, despite of the increased crystallization temperature (Figure 6, left). The reason for this was the faster throughput of feed solution. Compared to experiment 2b, no significant change in purity can be seen (Figure 7, right). Given the lower subcooling, it still can be concluded that the process conditions of scenario 3 are more favorable as it was possible to maintain stable operation up to 36 h. As a result, a prolonged production of homochiral crystals as opposed to the preceding runs was achieved. Therefore, experiment 3 was chosen as a reference case for further investigation of the coupled crystallizer configuration. The purpose of the experiments discussed in this section was to study a process for the continuous separation of enantiomers by means of crystallization in its simplest implementation, i.e. in a single MSMPR crystallizer. This process was found to be feasible, when supersaturation is kept at a level well within the metastable zone of the considered chiral molecule, preferably close to saturation. In the following section, we explore the second process option consisting of ACS Paragon Plus Environment

Page 17 of 25

17 two MSMPR crystallizers that are coupled via the liquid phase, which were expected to result in an even more robust operation.

Coupled MSMPR experiment (scenario 4) Despite changes of the process conditions, nucleation of the impurity remained difficult to predict and control in the single vessel crystallization process. As a consequence, the configuration of two MSMPR crystallizers connected via their liquid phases was considered in a final experiment. For this experiment (scenario 4), the process conditions of experiment 3 were chosen for reasons of comparison and because they were found to provide a safe process in terms of the reduced possibility of impurity nucleation. Figure 8 depicts mass fractions of both enantiomers in the liquid phase. The left plot represents Tank A, which was seeded with L-Threonine (E1), whereas Tank B, seeded with D-Threonine (E2), is represented by the right plot. The mass fractions of the preferred enantiomers were slightly higher compared to experiment 3 (see Figure 5). In contrast, liquid phase mass fractions of the unseeded enantiomers were lower than in experiment 3, because they crystallized in the respective opposite vessel. By realizing the liquid phase exchange, a racemization in the liquid phase in both tanks was mimicked. Mass fractions in both MSMPR crystallizers were identical, indicating a symmetric crystallization. 0.102

0.102 mass fraction in liquid phase wIL [-]


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(c)

0.100

wE2L

0.098

(p)

wE1L

0.096 (eq)

wIL (38 °C)

0.094 0.092

(p)

0.100

wE2L

0.098

(c)

wE1L

0.096 (eq)

wIL (38 °C)

0.094 0.092

0

2

4

6

8

10

0

time t [h]

2

4

6

8

10

time t [h]

Figure 8: Liquid mass fractions of both enantiomers in Tank A (left), which is seeded with E1 and in Tank B (right) seeded with E2 (Scenario 4).

Supersaturation during the coupled experiment was higher for the seeded enantiomer leading to a higher product mass flow, while it is lower for the counter enantiomer reducing the possibility of product contamination by the respective antipode (compare Figure 9 with 6). Supplementary, Figure 9 presents the crystallization temperature in both vessels during the process, which were stable taking into account the additional disturbance due to the exchange of mother liquors next to the feed flows.



18 1.10

40

1.10

38

1.08

40

Tcryst

1.04

34

(p)

SE1 1.02

32

1.00 2

4

6

8

1.06

36

(p)

SE2 1.04

34 (c)

SE1 1.02

30 0

38

32

1.00

10

temperature Tcryst [°C]

36

(c)

SE2

supersaturation SI [-]

supersaturation SI [-]

1.06

temperature Tcryst [°C]

Tcryst

1.08

30 0

2

4

time t [h]

6

8

10

time t [h]

Figure 9: Supersaturation of both enantiomers and crystallization temperature in Tank A (left), which is seeded with E1 and in Tank B (right) seeded with E2 (Scenario 4).

As expected, the product mass flow of each preferred enantiomer increased in comparison to experiment 3 (Figure 10 and Figure 7). The purity of the product crystals was ≥ 99% over the entire process time (> 10 h) for both enantiomers. This rise in the product mass flow as well as the product purity demonstrates the beneficial effect of the continuous exchange of mother liquors. At the same time, both enantiomers can be recovered in a pure form. Furthermore, the coupled process is more stable and robust, since the impurity level is decreased by crystallization in the opposite vessel. Thus, this configuration is a strong improvement, with which steady state operation was achieved. 10

98

•

6

96 •

mPr 4

94 .

2

92

mE1,Seeds

0

90 0

2

4

6

8

10

removed product mass mPr [g/h]

PuE1

8


100

100 PuE2

8

98

•

6

96 •

mPr

4

94 .

2

92

mE2,Seeds

0


10 product mass flow mPr [g/h]

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Page 18 of 25

90 0

2

time t [h]

4

6

8

10

time t [h]

Figure 10: Product mass flow and product purity in Tank A (left), which is seeded with E1 and in Tank B (right) seeded with E2 (Scenario 4).

Summary of experimental results and evaluation In order to evaluate the performance of each experimental scenario, process stages excluding the & Pr , startup phases are considered. Table 3 summarizes mean values of the product mass flow m purity Pu and productivity Pr from these time periods. In case of the single vessel scenarios (1 – 3), the average value of each variable was calculated for a period ranging from process time t =


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19 5 h up to t = 16 h. Scenario 4 was evaluated in the same manner for a period between t = 3 h and t = 11 h. Scenarios 1 and 2 were carried out at the same crystallization temperature. Clearly, the reduction of the residence time τ led to a strong increase in productivity Pr but also resulted in a higher risk of nucleation of the counter enantiomer. Experiment 2a is considered as being an outlier, since its purity was significantly different from all other runs. The rather high purity of experiment 2b should still be judged carefully. It cannot be entirely excluded that nucleation might have occurred later, had the experiment continued. It has to be kept in mind that during the first two runs (1 and 2a) still the early design of the PCU was used. This might have led to less representative results since the product suspension collected with this device was subjected to ambient uncontrolled conditions. The increase of the crystallization temperature in scenario 3 naturally lowered the productivity. At the same time purity stayed at a similar level compared to experiment 2b. Since it was possible to maintain stable operation in case of scenario 3 for up to 36 h, it can be assumed that the process was either at or very close to steady state. A strong improvement can be observed by comparing scenarios 3 and 4 (see also Figure 11). The coupled configuration led to an almost twofold increase in productivity and a very high stable level of purity in both product streams with no indication of an overall downward trend (Figure 10) indicating that steady state was reached. Table 3: Summary of performance criteria of the continuous preferential crystallization runs 1 - 4 and comparison with an additional optimized coupled batch run.

product mass flow & Pr [g/h] m

scenario (experiments)

Pu [%]

productivity (eq. 7) Pr [g/(h L)]

purity (eq. 5)

1 (single)

3.1

98.0

4.6

2a (single)

4.3

90.8

7.2

2b (single)

4.6

99.1

8.0

3 (single)

2.4

98.8

3.2

4 (coupled) Tank A

3.8

99.6

6.3

Tank B

3.8

99.1

6.3

Tank A

2.7

99.6

5.9

coupled batch Tank B

2.7

99.4

5.9

optimized

Although the conditions of the coupled continuous process were not optimized, it already outperformed a coupled batch experiment, which was recently carried out in a parallel project. This batch run was operated with a mathematically optimized temperature trajectory for ACS Paragon Plus Environment


20 maximized product mass after 10 h, subject to a purity constraint of 99.9% (Table 3). The batch run was conducted in the same equipment and under the same conditions as scenario 4 with respect to the initial liquid phase concentration. The same chiral model substance D/L-Threonine was used. Finally, we briefly compare the experimental results with the simulations based on the model introduced in [22], in particular for scenarios 3 and 4. When operation in the single MSMPR is considered, the simulation is in good agreement with the experimental results. The general trends of the simulated liquid phase mass fractions are confirmed by the experiments, though the values do not precisely reflect those obtained experimentally (Figures 3 and 5). Concerning the product mass flows, the trends of the theoretical and practical investigations are comparable (Figures 3 and 7). However, the simulated values are higher because a classified product removal, which is unavoidable in the experiments, is not included in the mathematical description. In case of the coupled process (scenario 4), experimental and simulated trends are in good agreement as well with respect to the liquid phase composition (Figures 4 and 8) and the product mass flows (Figures 4 and 10). Furthermore, the improvement gained by using the coupled MSMPR crystallizers is correctly predicted by the model as shown in Figure 11. Here, the mean & Pr and productivity Pr achieved in scenarios 3 and 4 steady state values of product mass flow m are presented. 10

mPr [g/h], Pr [g/(L h)]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 25

experiment simulation

8 6 4

.

2 0

& Pr and Figure 11: Comparison of experimental and simulated mean steady state values of product mass flow m productivity Pr for scenarios 3 and 4.

Again the model slightly overestimates the amount of product, which also leads to higher calculated productivities. With the now available experimental data, it should be possible to further improve the mathematical description of the described continuous operation of preferential crystallization.


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21

Conclusions An experimental proof of principle regarding continuous enantioselective preferential crystallization is reported. Two process configurations based on the mixed-suspension mixedproduct-removal (MSMPR) concept were proposed. The first setup consisted of a single MSMPR crystallizer, where one enantiomer was recovered in pure form. The second one involved two MSMPR crystallizers connected to each other by continuous exchange of mother liquors, which allows harvesting both enantiomers simultaneously at high purity. In order to identify suitable operating conditions, a model based design exploiting available solubility as well as kinetic data was found to be very helpful. The effect of two important process parameters, i.e. the crystallization temperature Tcryst and the residence time τ was studied in four different scenarios. Initial investigations using the single MSMPR setup were done to become familiar with the technical aspects of continuous preferential crystallization at lab scale. The biggest challenge was the reliable removal of the product suspension. Therefore, two different designs of a product collection unit were employed. It was found that already the simple configuration could be successfully employed to continuously produce pure enantiomers, provided that the process conditions are chosen carefully. A major improvement was achieved by using the configuration of two coupled MSMPR vessels. This setup was shown to be clearly superior over the single crystallizer option under identical conditions and led to an almost twofold increase in productivity. It could be shown that a steady state operation is possible with this configuration. Furthermore, it was already more productive than an optimized batch process yielding the same high level of purity. The goal of successful continuous preferential crystallization is certainly the complete avoidance of nucleation of the unwanted enantiomer over the entire production period. The experimental data obtained during this first study will be helpful for a further fine-tuning and optimization of all available process conditions. Future work should also consider secondary nucleation as an attractive option to eventually avoid the need of continuous seed addition.

Symbols α

optical rotation angle of the liquid phase [°]

∆tadd

time interval of seed addition [min]

∆tcoll

time interval of product collection [min]

kd

calibration parameter of the density measurement [kg/m3]

kpol

calibration parameter of the polarimetry measurement [°]

mH2O

mass of solvent (water) [g]

mIL

mass of component I (I = E1,E2) in the liquid phase L [g]

mIS

mass of component I in the solid phase S [g] ACS Paragon Plus Environment


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Page 22 of 25

22 mPr

product mass [g]

& Pr m

product mass flow [g/h]

mSeeds

mass of seeds [g]

& Seeds m

mass flow of seeds [g/h]

PrI,exp

experimentally determined productivity of component I [g/(L h)]

PrI,sim

simulated productivity of component I [g/(L h)]

PuI

purity of solid component I [%]

ρ0

calibration parameter of the density measurement [kg/m3]

ρL

measured solution density [kg/m3]

SI

absolute supersaturation of component I [-]

σI

relative supersaturation of component I [%]

t

time [h]

τ

residence time [min]

T

temperature [°C]

Tcryst

crystallization temperature [°C]

Tsat

saturation temperature [°C]

Vcryst

crystallizer working volume [L]

& V ex

exchange flow rate [mL/min]

& V feed

feed flow rate [mL/min]

Vsolution

solution volume [mL]

wIL

mass fraction of component I in the liquid phase [gI / gsolution]

w (eq) IL

equilibrium mass fraction of component I in the liquid phase [gI / gsolution]

wLfeed

simulated feed concentration of E1 or E2 in the liquid phase [g / gsolution]

wrac,cryst

solution concentration of the racemate in the crystallizer [grac / gsolution]

wrac,feed

solution concentration of the racemate in the feed [grac / gsolution]

zmean

mean seed size of the log-normal distribution [µm]

zSF

seeds sieve fraction [µm]

Acknowledgments The authors would like to express their gratitude and thanks to Jacqueline Kaufmann, who helped with the HPLC analysis.


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23

References [1] Hutt, A. J. Chirality and pharmacokinetics: An area of neglected dimensionality? Drug Metab. Drug Interact. 2007, 22, 79-112. [2] Lu, H. Stereoselectivity in drug metabolism. Expert Opin. Drug Metab. Toxicol. 2007, 3, 149158. [3] Howland, R. H. Understanding chirality and stereochemistry: Three-dimensional psychopharmacology. J Psychosoc Nurs Ment Health Serv 2009, 47, 15-18. [4] Agranat, I., Caner, H., Caldwell, J. Putting chirality to work: The strategy of chiral switches. Nat. Rev. Drug Discovery 2002, 1, 753-768. [5] Lorenz, H.; Seidel-Morgenstern, A. Processes to separate enantiomers. Angew. Chem. Int. Ed. 2014, 53, 1218-1250. [6] Coquerel, G. Preferential crystallization. Top. Curr. Chem. 2006, 269, 1-51. [7] Randolph, A. D; Larson, M. A. Theory of particulate processes: Analysis and techniques of continuous crystallization, 2nd ed.; Academic Press, Inc.: San Diego, 1988. [8] Mersmann, A. Crystallization technology handbook, 2nd ed.; Marcel Dekker, Inc: New York, 2001. [9] Lawton, S.; Steele, G.; Shering, P.; Zhao, L.; Laird, I.; Ni, X.-W. Continuous crystallization of pharmaceuticals using a continuous oscillatory baffled crystallizer. Org. Process Res. Dev. 2009, 13, 1357-1363. [10] Callahan, C. J.; Ni, X.-W. An investigation into the effect of mixing on the secondary nucleation of sodium chlorate in a stirred tank and an oscillatory baffled crystallizer. CrystEngComm 2014, 16, 690-697. [11] Ferguson, S.; Morris, G.; Hao, H.; Barrett, M.; Glennon, B. Characterization of the antisolvent batch, plug flow and MSMPR crystallization of benzoic acid. Chem. Eng. Sci. 2013, 104, 44-54. [12] Wong, S. Y.; Tatusko, A. P.; Trout, B. L.; Myerson, A.S. Development of continuous crystallization processes using a single-stage mixed-suspension, mixed-product removal crystallizer with recycle. Cryst. Growth Des. 2012, 12, 5701-5707. [13] Ferguson, S.; Ortner, F.; Quon, J.; Peeva, L.; Livingston, A.; Trout, B. L.; Myerson, A. S. Use of continuous MSMPR crystallization with integrated nanofiltration membrane recycle for enhanced yield and purity in API crystallization. Cryst. Growth Des. 2014, 14, 617-627. [14] Alvarez, A. J.; Singh, A.; Myerson, A. S. Crystallization of cyclosporine in a multistage continuous MSMPR crystallizer. Cryst. Growth Des. 2011, 11, 4392-4400. ACS Paragon Plus Environment


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25 For table of contents use only Continuous Preferential Crystallization of chiral molecules in single and coupled Mixed-Suspension Mixed-Product-Removal crystallizers Kamila Galan, Matthias J. Eicke, Martin P. Elsner, Heike Lorenz, Andreas Seidel-Morgenstern

A new continuous process to separate a racemic (equimolar) mixture of two enantiomers by preferential crystallization is investigated experimentally demonstrating its feasibility. A racemic solution is continuously fed to an MSMPR crystallizer, where it is resolved yielding a stream of suspension containing pure solid target enantiomer. Coupling two crystallizers via the liquid phase strongly enhances the process stability.


Continuous Preferential Crystallization of Chiral Molecules in Single

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