Multiplicity of Equilibrium States in Separating Stereoisomeric Mixtures

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Multiplicity of equilibrium states in separating stereoisomeric mixtures of nafronyl oxalate by crystallization Maksymilian Olbrycht, Dawid Kiwala, Maciej Balawejder, Andreas Seidel-Morgenstern, Wojciech Piatkowski, and Dorota Antos Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b00624 • Publication Date (Web): 11 Jul 2016 Downloaded from http://pubs.acs.org on July 13, 2016

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Crystal Growth & Design

Multiplicity of equilibrium states in separating stereoisomeric mixtures of nafronyl oxalate by crystallization Maksymilian Olbrychta, Dawid Kiwalab, Maciej Balawejderc, Andreas Seidel-Morgensternb,d, Wojciech Piątkowskia, Dorota Antosa,* a

Department of Chemical and Process Engineering, Faculty of Chemistry, Rzeszow University of Technology,

35-959 Rzeszow/PL b

Max Planck Institute for Dynamics of Complex Technical Systems, 39106 Magdeburg/DE

c

Chair of Chemistry and Food Toxicology, University of Rzeszow, 35-959 Rzeszow/PL

d

Institute of Process Engineering, Faculty of Process and Systems Engineering, Otto von Guericke University Magdeburg, 39106 Magdeburg/DE

Abstract Nafronyl

oxalate,

i.e.,

2-(diethylamino)ethyl

3-(naphthalen-1-yl)-2-((tetrahydrofuran-2

yl)methyl)propanoate oxalate, is a pharmacologically active compound, which is used as a drug ingredient. The nafronyl molecule possesses two stereogenic centers. It is manufactured as a stereoisomeric mixture of two pairs of racemates being diastereoisomers to each other. The mixture components are characterized by different biological activity. Only one of the racemates contains the stereoisomer with the highest pharmacological efficacy. To separate the racemates an efficient crystallization process was designed and performed. This was based on SLE data, which were acquired in a wide composition range at temperatures between 10 and 40°C. A specific SLE region was detected with an unusual phase behavior, where different equilibrium states could be established. The crystalline products of each state differed with respect to the excess of the target racemate. This phenomenon was found to be temperature dependent; it diminished with decreasing temperature. The occurrence of a desired equilibrium state could be induced either by altering the process temperature or by seeding the supersaturated solutions. The separation was implemented by applying a multistage crystallization process, which provided the pure target racemate. The process performance was further improved by adjusting the temperature in each crystallization stage.

*

Corresponding authors:

[email protected], phone.: +48 178651853; fax: +48 178543655

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1. INTRODUCTION Chirality plays an important role for the development of new drugs. More than half of the drugs currently manufactured consist of chiral ingredients.1-6 However, the individual enantiomers of a drug may differ with respect to biological activity, pharmacology, toxicology, pharmacokinetics, and metabolism. Usually, only one enantiomer interacts specifically with a cell receptor and provides a desired pharmacological outcome, whereas the other may have no effect, cause entirely different effects, or may even be harmful.3,5,6 Therefore, most of the new drugs marketed today are single enantiomers.4,6 The manufacturing of a chiral compound in an enantiopure form can be realized by stereoselective synthesis from a prochiral compound or derived from a chiral pool.5,7-10 Both these methods can provide products with high enantiomeric enrichment in a cost-effective way, however, they require an efficient catalyst, chiral auxiliary or precursor, applicable to bring about enantioselective reactions. Therefore, manufacturing of enantiomers under achiral conditions is usually more economical than stereoselective synthesis and is widely applicable.2 The products are formed as a racemic mixture of two enantiomers, which is subsequently subjected to downstream processing in chiral environment to isolate a target enantiomer. The most frequently used resolution methods are diastereomeric crystallization and enantioselective chromatography. Manufacturing of enantiopure drugs is particularly complicated when the active pharmaceutical ingredients have several stereogenic centers in their molecular structure. Nonselective synthesis of such a compound generates a stereoisomeric mixture that consists of racemates being diastereoisomers to each other. The isolation of a target stereoisomer out of such a complex mixture may involve several purification stages. An efficient way for the realization of that process is to remove the most abundant impurities at first, i.e., to separate two pairs of racemates in achiral environment in a first, typically simpler, purification stage.11 The racemate containing the target enantiomer can be then resolved in the presence of a chiral agent. Since the two pairs of racemates (diastereoisomers) differ in solubility, conventional crystallization can be efficiently exploited for their resolution. However, the success of the operation requires knowledge of the SLE of the components of the stereoisomeric mixture. Different types of solid phase behavior of chiral systems can be distinguished, i.e., mixture components can form: a) simple eutectics, when they are completely immiscible in the solid 2 ACS Paragon Plus Environment

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phase, which provides mixtures of the individual crystals; b) intermediate compounds, in which both components form a well-defined arrangements in the solid phase; c) solid solutions (designated also as mixed crystals or isomorphic mixtures), which occur in cases of complete miscibility in the solid phase.12-15 The formation of solid solution usually results from the substitution of isomorphous species, which have very similar unit-cell dimensions.16 Continuous solid solutions in chiral organic systems are rare, however, partial solid solutions with limited miscibility in the solid phase occur quite often.17-28 Typical phase diagrams, illustrating SLE of various diastereomeric systems, are presented in Figure 1. In the upper part of Figure 1, ternary phase diagrams are presented, in which the SLE of two compounds (D1, D2) in a solvent is demonstrated. In the lower part, the corresponding melting point diagrams are illustrated, where SLE for binary phase systems (crystalline phase – melt) is shown.

Figure 1. Illustration of different types of ternary and binary phase diagrams for a mixture of compounds D1 and D2. Upper – ternary phase diagrams; bottom – melting point diagram. a) Simple eutectic; b) intermediate compound; c) solid solution. Dashed lines illustrate tie-lines; L – denotes composition of liquid phase in equilibrium with pure crystal D2 (Figure 1a, b, upper), or with binary crystalline phase, S (Figure 1c, upper); dash-dotted horizontal lines illustrate ideal solid solution (Figure 1 c, upper and bottom).

It can be observed that single-stage crystallization can provide a pure component in the solid phase only for systems that form a simple eutectic or intermediate compound (Figures 1a and 1b). This is illustrated on the ternary phase diagrams by the tie-lines connecting the equilibrium concentrations of species in the liquid phase (L) with the triangle vertex representing a pure crystalline phase of target compound (e.g., the compound D2 was the target in Figure 1). In cases of solid solution formation, multistage crystallization needs to be employed to gradually enrich a solution with respect to a target component.11,29-34 An 3 ACS Paragon Plus Environment


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exception is an ideal solid solution, represented by horizontal lines in Figure 1c, which indicate either composition-independent solubility in a ternary phase system or compositionindependent temperature of melting point in binary phase systems. The design of the multistage crystallization process requires an accurate preliminary quantification of SLE. Nevertheless, the description of solid phase behavior of systems exhibiting solid solution is difficult, particularly for compounds having more than one stereogenic center. In such a case, both solid and liquid phases at equilibrium contain a few stereoisomers. In this study, SLE of stereoisomeric mixtures of nafronyl oxalate, i.e., 2-(diethylamino)ethyl 3-(naphthalen-1-yl)-2-((tetrahydrofuran-2-yl)methyl)propanoate oxalate, has been studied using acetone as a solvent. Nafronyl molecule possesses two stereogenic centers in the position 2 of the propionic acid backbone and in the position 2' of the tetrahydrofuryl carbon atom. Therefore, it has four stereoisomers, which form two racemates:35,36 (2R,2'R):(2S,2'S) and (2R,2'S):(2S,2'R), being diastereoisomers to each other. The compound is marketed in the form of addition salt with oxalic acid (Figure 2) as a mixture of four stereoisomers. It is used for the treatment of vascular diseases, including intermittent claudication, stroke and dementia.37,38 The isomer having (2S,2'R) configuration contributes most to the therapeutic efficacy.36

2

2'

CH3

O

N O

O

CH3

2

2'

CH3

O

N O

O

1. 2R, 2'R

CH3

2. 2R, 2'S

.

2

2'

CH3

O

N O

O

3. 2S, 2'S

CH3

2

2'

COOH

CH3

O

N O

COOH

O

CH3

4. 2S, 2'R

Figure 2. Chemical structure of nafronyl oxalate. Solid lines indicate the pairs of enantiomers, dashed lines – the pairs of diastereoisomers.

In our recent study, we have developed a procedure for isolating the most active stereoisomer, (2S,2'R), from a raw material, which was a quaternary stereoisomeric mixture enriched with the racemate (2R,2'S):(2S,2'R).11 The procedure consisted of batchwise four-stage crosscurrent crystallization, followed by racemization of exhausted mother liquors, and 4 ACS Paragon Plus Environment

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enantioselective chromatography. The crystallization process was performed under isothermal conditions at temperature 20°C, and it provided pure target racemate, (2R,2'S):(2S,2'R), containing the most active enantiomer. The process was designed based on SLE data that were measured for stereoisomeric mixtures enriched with the target racemate. The analysis of SLE data revealed that nafronyl stereoisomers formed solid solution in the crystalline phase. In this study, the analysis of solid phase behavior of nafronyl stereoisomers was performed in a much wider concentration range compared to our previous work.11 The lowest content of the racemate (2R,2'S):(2S,2'R) in the analysis was limited by the composition of alyotropic point, which corresponded to a mixture depleted with the target racemate in the crystalline phase. The measurements were performed at various temperatures, in the range between 10 and 40°C. The examination of SLE data in the vicinity of alyotropic point revealed the existence of the concentration window characterized by an unusual phase behavior, which we have not detected previously. In that window frame, different equilibrium states corresponded to the same supersaturated initial feed solution. The uncertainty of the equilibrium phase composition was an obstacle for processing of stereoisomers by crystallization. Therefore, we have made attempts to develop a method for effective separation of stereoisomers in the critical region and extend the operating widow up to the alyotropic point. The concept was based on altering the process temperature or seeding supersaturated solutions with seeds of the target racemate. Both polythermal and seeded crystallization was found to be efficient method for inducing the desired equilibrium state, in which a preferred composition of the crystalline phase could be achieved. Finally, temperature mediated multistage counter-current crystallization was realized experimentally to accomplish the resolution of the two racemates. The method developed allowed marked improvement in the separation performance compared to that achieved previously in isothermal cross-current crystallization system.11

2. EXPERIMENTAL SECTION 2.1.

Substances

Nafronyl oxalate (molecular formula C26H35NO7, mass weight 473.559 Da) was purchased from Santa-Cruz Biotechnology (Santa Cruz, USA) in the form of stereoisomeric mixture with the HPLC purity of 98%. The material contained 72% of the racemate (2R,2'S):(2S,2'R). To perform crystallization experiments the following chemicals were used: acetone with purity Pu ≥ 99.8% purchased from POCH (Poland); water, which was filtered using a SolPure-78Z unit equipped with 0.2 µm membrane (Elkar, Poland). For the HPLC analysis 5 ACS Paragon Plus Environment


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n-hexane, Pu ≥ 99% and propan-2-ol, Pu ≥ 99.9%, with HPLC-grade (POCH) and diethylamine, Pu ≥ 99.5% (Sigma-Aldrich), were used.

2.2.

Procedures

2.2.1. HPLC analysis The HPLC analysis was performed with LaChrom System (Merck, Germany). The HPLC device consisted of a high pressure quaternary pump, autosampler, thermostatted column compartment, UV detector. The system was equipped with an analytical column with CHIRALPAK IC (Chiral Technologies Europe, Illkirch Cedex, France) with the particle size 5 µm, the column length was 250 mm, ID 4.6 mm. The chiral stationary phase consisted of cellulose tris(3,5-dichlorophenylcarbamate) as a chiral selector, which was immobilized onto a silica matrix. The mobile phase was n-hexane/propan-2-ol/diethylamine mixed in the proportion 90/10/0.1 (v/v). The mobile phase flowrate was 1 mL/min, temperature 25°C. The chromatograms were detected at 226 nm. The polarimeter signal was recorded during chromatographic elution and compared to the optical rotation data for nafronyl stereoisomers reported in literature.39 The following elution order was identified: (2R,2'R), (2R,2'S), (2S,2'S), (2S,2'R).11 To simplify the nomenclature, the numbers are assigned to each of stereoisomers, accordingly to the elution order: (2R,2'R) ≡ 1, (2R,2'S) ≡ 2, (2S,2'S) ≡ 3, (2S,2'R) ≡ 4 (target). The pairs of racemates are named 1,3 and 2,4, respectively. All samples destined for the HPLC measurements were dissolved in propan-2-ol. The concentration of samples acquired from the crystalline phases was 0.25 g/L. The samples of mother liquors were acquired with the amount of 200 µL and diluted 50 times. The HPLC analysis was conducted in triplicate. The maximum standard deviation for the value of diastereomeric excess, d2,4, did not exceed 0.3. The d2,4 ratio was defined as follows: de2,4 =

(x (x

2 ,4

− x1,3 )

2 ,4

+ x1,3 )

100% , where x denotes corresponding mole fraction.

2.2.2. Pre-separation of the raw material Since nafronyl oxalate is commercially available only in the form of a quaternary mixture, to determine SLE in a wide range of diastereomeric excess, the raw crystalline mixture with

de2S,4 = 44% (72% of the target racemate, section 2.1) was subjected to preliminary resolution by multistage crystallization. To enrich the mixtures with racemate 2,4, the crystalline phase was recrystallized several times, whereas diastereomeric excess of racemate 1,3 was achieved 6 ACS Paragon Plus Environment

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by repetitive processing of the mother liquors. The procedure for the crystalline phase enrichment has been developed in our previous work.11 The reaction route for the enrichment of mother liquors has been proposed in this study. 2.2.2.1.

Purification of racemate 2,4

To achieve a high enrichment of stereoisomeric mixtures with racemate 2,4, four-stage crystallization was performed. In the first stage 20 g nafronyl oxalate salt from the raw material and 500 mL acetone were mixed in a double-walled vessel connected to a thermostat (Thermostat Lauda Ecoline RE-104, Germany). The batch was heated up to 50°C until entire dissolution, then it was electromagnetically stirred for 72 h at temperature 25°C with frequency of rotation 800 rpm, in order to establish SLE. Samples of the mother liquor were acquired using a syringe with a filter having anhydrous pores of 0.2 µm and subjected to the HPLC analysis (section 2.2.1). The solid phase was separated out of the mother liquor and dried in a vacuum dryer at temperature 50°C and pressure 0.4 bar, for 24 h. Samples of dried crystalline phase were also analyzed by HPLC. Next, the enriched crystalline phase was mixed with pure acetone and subjected again to crystallization for further enrichment. The amount of acetone was adjusted according to the solubility of the mixture. The procedure was repeated four times. The final product obtained in the fourth stage was the crystalline phase with de2,4 of 98%. 2.2.2.2.

Purification of racemate 1,3

The mother liquor obtained in crystallization of the raw material was partially evaporated in order to induce crystallization. Subsequently, the solution was stirred for 72 h in the thermostatted vessel at temperature 25°C, with frequency of rotation 800 rpm, until SLE was established. Samples of the mother liquor and crystalline phase were acquired and subjected to the HPLC analysis. The mother liquor obtained after the separation of phases was processed again, according to the same procedure. The de2,4 ratio of the crystalline phase obtained in the subsequent stage was –50%. The lower bound for the de2,4 value was determined by the composition of alyotropic point.

2.2.3. Determination of SLE To quantify SLE, several samples of the crystalline phase were prepared by mixing the raw material (de2,4 = 44%) with the purified racemate 2,4 (de2,4 = 98%) or with the material enriched with racemate 1,3 (de2,4 = –50%), to obtain various de2,4 ratios, ranging from –50% to 98%. The solid mixtures obtained were suspended in acetone in closed glass vials. The volume of solvent was adjusted by trial and error method to obtain supersaturated solutions. 7 ACS Paragon Plus Environment


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All samples were heated up to 50°C in water bath for complete dissolution. Next, the vials were placed into the thermostatted vessel and stirred at a defined temperature (10, 25, 33, 40°C), until SLE was established. Then, the solutions were centrifuged at the same temperature, with 4000 rpm for 4 min. Samples of the mother liquors and crystalline phases were acquired in the same manner, as described above and subjected to the HPLC analysis. The composition of the phases was also determined for samples subjected to a long term equilibration in the thermostatted vessel (150 h). Moreover, the composition of dry crystalline phases was analyzed after a long-time storage (one month).

2.2.4. Controlling SLE by seeding or nucleation at a reduced temperature The experiments of polythermal and seeded crystallization were performed within the range of de2,4, in which multiple equilibrium stages were observed. The crystalline phase was prepared by mixing the raw material (de2,4 = 44%) with that enriched with 1,3 racemate (de2,4 = –50%), to obtain de2,4 ratio equal to –19%. Subsequently, samples of 0.28 g of the solid mixture were placed in several thermostatted glass vials and each of them was suspended in 7.3 g of acetone. The mass of the solvent was adjusted based on the sample solubility, to obtain the supersaturated solution. The concentration of the racemates in the solution was: , = 0.0150, , = 0.0220, at the supersaturation , = 1.70, , = 1.13,

, , respectively. The supersaturation was defined as follows: , = ∗ ; , = ∗ , where ,

∗ ,

and

∗ ,

,

are the equilibrium concentrations in the mother liquor.

The solutions in vials were heated up to 50°C in water bath for complete dissolution. Then, the vials were divided into a few batches that were subjected to crystallization realized in three different modes: isothermal, polythermal, or seeded crystallization with different types of seeds. 2.2.4.1.

Isothermal crystallization

The solutions in a few parallel vials of the first batch were electromagnetically stirred for 72 h at constant temperature, t = 25°C, with frequency of rotation 800 rpm, to establish SLE. Samples of the mother liquors and crystalline phases were acquired in the same manner as described in section 2.2.2, and subjected to the HPLC analysis. 2.2.4.2.

Polythermal crystallization

The solutions in the second batch were initially thermostatted at t = 7°C for about 1 h in order to induce nucleation. After first crystals appeared, the solution was heated up to 25°C, and then treated in the same manner as the first batch in the isothermal crystallization. 8 ACS Paragon Plus Environment

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2.2.4.3.

Seeded crystallization

The solutions in the remaining batch of vials were seeded with 0.0005 g crystalline seeds with various enrichments: de2,4 = 98%; 73%; –38%, and treated in the same manner as in the isothermal crystallization.

2.2.5. Counter-current crystallization to isolate racemate 2,4 from quaternary mixtures The crystallization process was realized batchwise according to the scheme presented in Figure 3. The feed mixture was prepared by mixing the raw material (de2,4 = 44%) with that enriched with racemate 1,3 (de2,4 = –50%), to obtain the de2,4 ratio equal to –19%. The separation was initiated in a zeroth stage, where polythermal crystallization was performed, according to the procedure described in section 2.2.4.2. The crystallization product of that stage, with de2,4 = 44%, was the feed for the first stage of counter-current crystallization (S0, Figure 3), which was performed as follows.

Sol S0

S

S0

0 W

1 L1

S2

S1

2 L2

S3

3 L3

Sol

Figure 3. Flowsheet scheme of counter-current crystallization. S - solid phase, L - liquid phase, Sol - fresh solvent, W - waste solution.

To mimic the counter-current process, the crystalline phase for the second and third stage (S2, S3) was artificially generated by mixing proper amount of the raw material (de2,4 = 44%) with the purified racemate 2,4 (de2,4 = 98%). In the third stage, the prepared crystalline phase was mixed with fresh acetone, whereas in the first and second stage - with the mother liquors withdrawn from the previous stages (L2, L3 Figure 3). The solutions in each stage were heated up to 50°C in water bath until complete dissolution. Afterwards, the solutions were subjected to crystallization according to the same procedure, as described in section 2.2.2.1. The process was realized in two modes: isothermally, at 25°C for each stage, or different temperatures were used for each stage: the first stage was performed at 10°C, the second - at 33°C and the third one - at 25°C. The crystalline phase obtained from the third stage was the final product of the crystallization process. 9 ACS Paragon Plus Environment


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2.2.6. XRPD Analysis The samples of crystal powder acquired from crystalline phases with different de2,4 ratios were subjected to the XRPD analysis using PANalytical X’Pert Pro diffractometer (PANalytical GmbH, Germany) with an X'Celerator detector. The radiation source was Cu Kα. Samples were measured on Si holders and scanned in a 2-Theta range of 3 to 40° with a step size of 0.017° and counting time of 50 s for each step.

2.2.7. DSC Analysis Thermal analysis was performed by DSC using Setaram DSC131 instrument (Setaram, France). Samples with 5-13 mg acquired from the crystalline phases were closed in 30 µL Alcrucibles under a helium atmosphere. The temperature program was set to heat up the samples from 40 to 120°C at a constant rate of 1 K/min.

3.

RESULTS AND DISCUSSION

3.1. SLE of nafronyl oxalate SLE for stereoisomeric mixtures of nafronyl oxalate was determined for the de2,4 ratio ranging from –50% to 98%, at various temperatures, i.e., 10, 25, 33, 40°C, as described in section 2.2.3. The lower limit of the de2,4 ratio was determined by the alyotropic point. Both liquid and crystalline phase contained at equilibrium four stereoisomers. Since the properties of enantiomers in liquid are identical, the mother liquor can be considered as a pseudo-ternary mixture of two diastereoisomers and a solvent. However, enantiomers may differ in their activity in the crystalline phase, which forms a real quaternary mixture. To simplify the presentation of crystallization equilibrium in such a complex system, the SLE data can be plotted on the ternary phase diagram, as shown in Figs 4a-d. The bottom vertexes of the triangle correspond to pure racemates. The dashed lines on diagrams represent tie-lines connecting the equilibrium composition of racemates in both phases. It can be observed that for all temperatures the stereoisomeric mixtures exhibit solid solution phase behavior with minimum of solubility for pure racemate 2,4, and the enrichment of the target racemate occurs in the crystalline phase. In all diagrams unusual SLE regions can be distinguished, where tie-lines connecting the equilibrium compositions obviously cross each other. The initial composition points, at which two lines cross, are connected with different liquid and solid phase equilibrium compositions. This indicates the existence of more than one equilibrium state.


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In systematic experiments starting from the same initial non-equilibrium composition, the equilibrium states were found to establish in a random way, i.e., crystallization of the same solution, under identical conditions, and without an external stimulus, provided crystalline phases and mother liquors with different compositions; no preferred state was identified regardless of the process duration. However, the equilibrium composition of both phases remained unchanged, even in a long time duration. Furthermore, the composition of dry crystalline phase, which was subjected to a long term storage (section 2.2.3), did also not changed. The phenomenon of multiplicity of equilibrium states diminished at lower temperatures (compare Figs 4a-d); the region of tie-line crossing, which was large at 40°C, shrunk at 10°C. The phenomenon is also illustrated on the corresponding distribution phase diagrams in Figure 5, where the equilibrium dependencies between the mass fraction of racemate 2,4 in the solvent-free mother liquor, x2L,4 , defined as: x2L,4 = x2L,4

(x

L 2 ,4

+ x1L,3 ) , and its mass fraction in

the solid phase, x2S,4 , are shown. The course of the equilibrium dependencies exhibits inflections points in the regions corresponding to the crossing of tie-lines on the ternary phase diagrams. In the upper part of each curve, the equilibrium liquid phase concentration, x2L,4 , is correlated with only one value of the solid phase concentration, x2S,4 ; therefore, only one equilibrium state is possible. In the lower part of the curves, a single x2L,4 value is correlated with two or three values of x2S,4 , which indicates that two or three equilibrium states can be established (Figure 5b). As racemate 2,4 is the target for the separation, the state with its highest content in the crystalline phase is preferable. The existence of multiple equilibrium states makes the separation process unpredictable, which hinders its realization in the critical operation region. Nevertheless, with decreasing temperature the region shifts towards lower values of x2L,4 , at simultaneous marked reduction in size. The position of alyotropic point, where the curves approach the diagonal, shifts along the critical region, which results in widening operating widow with the temperature reduction. Hence, a low temperature is preferred for the process realization, which however may create additional energy costs.



0 0 . 0

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3 0 . 0 4 0 . 0 5 0 . 0 6 0 . 0 7 0 . 0 9 0 . 0 0 1 . 0

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0.10

0.90

0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10

xS2,4

Figure 4. Ternary phase diagram for nafronyl oxalate in acetone at: a) 10; b) 25; c) 33; d) 40°C.

xS2,4

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Figure 5. Distribution diagram of nafronyl oxalate in acetone. a) Overall diagram for temperatures 10, 25, 33, 40°C; b) ilustration of region of multiple equilibrium stages for 25°C; s1, s2, s3 – three possible equilibrium stages, shaded area – region of multiple equilibrium states. Symbols – experimental data, lines – to guide eye.


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3.2.

Controlling crystallization by altering temperature or seeding

To reach the desired equilibrium state under ambient conditions, i.e., at the lowest energy consumption, two different approaches were used, i.e., polythermal and seeded crystallization. In both approaches the initial process conditions were altered; in the former - by the manipulation of temperature, in the latter - by seed composition. In both cases the same supersaturated solution was processed, for which multiple equilibrium states could be established. The composition of the solution (de2,4 = –19) is illustrated by the mixing point M marked on the ternary phase diagram in Figure 6.

Sol 0.00

1.00

0.01

0.99

0.02

0.98

0.03

0.97

M

0.04

0.96

0.05

0.95

0.06

0.94

0.07 0.08

0.93

4 1

2

3

0.09

0.92 0.91

0.10

0.90

0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10

1,3

2,4

Figure 6. Controlling of SLE by polythermal crystallization and seeded crystallization with seeds of different de2,4. M - mixing point (initial supersaturated solution), tie-lines: 1 - seeding with seeds of de2,4 = –38%; 2 - with seeds of de2,4 = 73%; 3 - with seeds of de2,4 = 98%; 4 - polythermal crystallization. Temperature for the SLE establishment was 25°C.

In case of polythermal crystallization, the process was initiated at temperature slightly below 10°C, at which the region of multiple equilibrium stages was diminished, and the equilibrium curve was shifted towards lower values of x2L,4 (Figure 5a). Therefore, the nucleation started outside the critical region, at the x2S,4 values located in the upper part of the equilibrium curve, which corresponded to a higher enrichment of the crystalline phase with racemate 2,4. After first crystals appeared, the process was continued at ambient temperature (25°C) until equilibrium was reached. The equilibrium composition of both phases was determined by the HPLC analysis (Table 1). The direction of establishing the SLE is illustrated by the tie-line “4” in Figure 6.



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The seeded crystallization experiments were performed at 25°C using seeds with different diastereomeric enrichment, de2,4: 98, 73 and –38%. The negative de2,4 value refers to seeds enriched with racemate 1,3. For each type of seeds different SLE was established. The nucleation with seeds of the lowest de2,4 ratio, de2,4 = –38%, provided the product with the lowest enrichment of racemate 2,4 in the crystalline phase (tie-line 1, Figure 6), seeding with seeds of de2,4 = 73% - the product with an intermediate enrichment (tie-line 2), whereas seeding with seeds of 98% - the product with the highest enrichment (tie-line 3 and Table 1). The polythermal and seeded crystallization experiments were repeated, as described in section 2.2.4, and in all cases similar results were obtained. The products were found to be stable, their composition and structure sustained over time (section 2.2.3). The process was also performed isothermally at temperature 25°C, without external stimulus. In this case, multiplication of the experiments under identical conditions provided different results, represented randomly by either the tie-line 1 or 3. This indicates that conditions of nucleation are critical for the course of crystallization process. The equilibrium can be moved into the desired direction by either reduction of the initial process temperature to below the critical region, or by seeding the supersaturated solution using seeds with the de2,4 ratio from above that region. The former method involves higher energy costs, whereas the latter one requires an investment of seeds enriched with the target racemate. In both cases, when nucleation is initialized and first crystals are formed, the course of the process cannot be changed, and the transition from one equilibrium state to another is not possible. To investigate possible structure difference, the crystalline phases obtained in different equilibrium states were further analyzed by XRPD and DSC. Table 1. Results of polythermal crystallization or seeded crystallization with seeds of de2,4 = 98%. INLET OUTLET SOLID LIQUID SOLID LIQUID , , , , , S0 de2,4 Sol S de2,4 L [g] [%] [g] [g] [g] [g/g] [g/g] [%] [g/g] [%] [g/g] 0.2801 0.4052 –19 7.29 0.0657 0.7171 43 7.5181 0.0086 0.0214 –42.7 Exp. 0.2795 0.4052 –19 7.30 0.0683 0.6902 38 7.5117 0.0088 0.0194 –37.6 Theory* Relative error [%] 3.81 3.90 0.08 2.27 1.31 Overall Y [%] Pu [%] 41.5 71.7 Exp. 41.6 69.0 Theory 0.24 3.90 Relative error [%] 34 *Predictions with a mathematical tool developed in a previous study.


Page 15 of 31

3.3. XRPD analysis The XRPD analysis was performed for crystalline phases with different de2,4, according to the procedure described in section 2.2.6. The obtained spectra are depicted in Figure 7.

25000

de2,4 = 98%

20000

Intensity [counts]

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


73%

3; 4

44%

15000

2

12%

1

-11%

10000

5000

-38% 0 5

10

15

20

25

30

35

2 - Theta [°] Figure 7. XRPD patterns of crystalline phases with different de2,4. The spectra indicted by the numbers: 1, 2, 3, 4, denote the crystalline phase obtained in polythermal and seeded crystallization, represented by the corresponding tie-lines marked in Figure 6.

The XRPD spectra measured for crystals with various de2,4 have a similar pattern. Similar set of reflexes can be observed, but with different intensity according to the composition change. Pure racemates 2,4 and 1,3, which are diastereoisomers of each other, can form similar but not identical crystalline lattices, therefore, a difference in the pattern can be observed only for the extreme excess of racemate 2,4 in the mixture. The patterns indicate formation of continuous solid solution within the composition range investigated, which occurs as a result of mutual substitution of molecules of diastereoisomers in the crystalline structure. The crystalline phase obtained by polythermal and seeded crystallization illustrated in Figure 6 by the tie-lines 1, 2, 3, 4, was also subjected to XRPD analysis. The recorded spectra were overlaid in Figure 7. It can be seen that those patters also contain similar, but not identical reflexes.

3.4. DSC measurements The DSC thermograms were recorded for the crystalline phase with different de2,4 ratio. No existence of new phase formation (i.e., solvates) was detected within the concentration range investigated. Typical courses of the measurements are presented in Figure 8. 15 ACS Paragon Plus Environment


The melting point for all samples with various de2,4 ratios was very similar and varied between 108 and 112°C, while the heat of fusion - from 94 to 103 J/g. This proves that the crystalline solutions have very similar thermal properties. The invariability of temperature versus the solution composition is characteristic for ideal solid solutions (section 2, Figure 1c bottom). This means that the stereoisomers could not be separated in the melt phase. As the separation was yet possible in the solvent environment, it can be concluded that the difference in the phase behavior of diastereoisomers can be attributed to their selective interactions with the solvent. 5 0

Heat Flow [mW]

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Page 16 of 31

-5 -10

de2,4 = 98 73 29 -14 -47

-15 -20 -25 -30 20

40

60

80

100

120

140

t [°C] Figure 8. Typical DSC thermograms obtained for crystalline phase with different de2,4.

3.5. Multistage crystallization At a final step of the research reported in this study, we performed multistage counter-current crystallization in a sequential batchwise mode. A hypothetical situation was considered, in which a stereoisomeric feed mixture was processed with a composition located in the region of multiple equilibrium stages. The artificial feed contained an excess of racemate 1,3, similar to that used for polythermal and seed crystallization. The solution was subjected to polythermal crystallization, to obtain crystalline phase enriched with the desired racemate (zeroth stage of the crystallization). The separation was continued by multistage countercurrent crystallization (see flowsheet scheme in Figure 3 in section 2.2.5). The realization of the first run of counter-current process requires an investment of either mother liquors or crystalline phases, with the composition and amount adequate for each of stages. The solutions produced in the first run can be subsequently processed in a next one.


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In this study, to initialize the process the crystalline phase was invested, whereas the mother liquor was exchanged between stages. This allowed us to analyse whether the presence of raw material impurities (2%, section 2.2.1), which were transported from stage to stage along the mother liquors, had an influence on the process performance. The multistage process was performed in two modes: at constant temperature in each stage, i.e., at 25°C, or temperature for each stage was adjusted to improve yield of the whole operation. The choice of the temperature profile was based on the mathematical model reported in detail in another study.34 The model predictions were based on solving a set of material balance equations for each stage, which accounted for the interconnections of streams between subsequent stages, and the SLE relationship for each stage. The results of the experiments are summarized in Table 2 and Table 3. Table 2. Experimental results and predictions of three-stage counter-current crystallization with constant temperature for each stage I stage (t = 25°C) INLET SOLID S0 [g] 3.9951 4.0000

,

[g/g] 0.7200 0.7200

OUTLET LIQUID

,

L2 [g]

,

SOLID ,

[%] [g/g] 44 81.57 0.0068 44 82.79 0.0071 Relative error [%]

[g/g] 0.0050 0.0051

S1 [g]

,

[g/g] 3.4505 0.8345 3.3134 0.8464 4.14 II stage (t = 25°C)

INLET SOLID S1 [g] 3.3137 3.3134

,

[g/g] 0.8464 0.8464

L3 [g]

,

[g/g] 0.0015 0.0017

S2 [g]

,

[g/g] 3.0711 0.9237 2.9494 0.9317 4.13 III stage (t = 25°C)

INLET S2 [g] 2.9498 2.9494

,

[g/g] 0.9317 0.9317

,

[%] 86 86 Relative error [%] Overall Y [%]

82.1100 83.4800 1.64

SOLID

,


SOLID

[%] 67 69 1.41

L1 [g]

,

,

[g/g] 0.0077 0.0080 3.75

[g/g] 0.0134 0.0124 8.06

Exp. Theory

OUTLET LIQUID

,

LIQUID ,

LIQUID

,

[%] 85 86 0.86

L2 [g] 88.6600 89.4600 0.89

,

,

[g/g] 0.0068 0.0071 4.23

[g/g] 0.0050 0.0051 1.96

Exp. Theory

OUTLET LIQUID

SOLID

Sol [g]

,

S3 [g] 94.97 94.98

2.2800 2.1665 5.46

LIQUID ,

[g/g] 0.9723 0.9800

[%] 95 96 0.79 Pu [%]

73.7 77.2 4.77

L3 [g] 95.6400 95.7600 1.54 98.0 97.2 0.79

,

,

[g/g] 0.0066 0.0065 5.88

[g/g] 0.0016 0.0017 5.46

Theory Exp. Relative error [%]


Exp. Theory


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Page 18 of 31

The overall yield of the three-stage operation reported in the tables was calculated as follows:

Ytotal =

S3 x2S,34 100% F x2F,4

where F is the mass of feed; x2F,4 is the mass fraction of racemate 2,4 in feed; S3 is the mass of the crystalline phase withdrawn from the last stage, 3; x2S,34 is the mass fraction of racemate 2,4 in the corresponding solid phase. Table 3. Experimental results and predictions of temperature mediated three-stage counter-current crystallization with optimized temperature for each stage I stage (t = 10°C) INLET SOLID ,

S0 [g] 4.0014 4.0000

[g/g] 0.7200 0.7200

OUTLET LIQUID

,

L2 [g]

,


SOLID ,

[g/g] 0.0105 0.0105

S1 [g]

,

LIQUID ,

[g/g] 5.5483 0.7458 5.4682 0.7546 1.46 II stage (t = 33°C)

[%] 49 51 1.16

INLET SOLID

S1 [g] 5.4685 5.4682

, [g/g] 0.7546 0.7546

L3 , , [g] [%] [g/g] 51 119.14 0.0068 51 119.12 0.0065 Relative error [%]

SOLID

, [g/g] 0.0016 0.0017

S2 [g]

, [g/g] 0.9180 0.9243

S2 [g] 3.4487 3.4487

, [g/g] 0.9243 0.9243

, [g/g] 0.0087 0.0087 0.50

Exp. Theory*

3.6518 3.4487 5.89 III stage (t = 25°C)

LIQUID

, [%] 84 85 0.68

INLET SOLID

109.58 109.67 0.08

, [g/g] 0.0029 0.0030 3.48

OUTLET LIQUID

L1 [g]

L2 [g] 120.96 121.14 0.15

, [g/g] 0.0134 0.0142 5.65

, [g/g] 0.0105 0.0105 0.89

Exp. Theory*

OUTLET LIQUID

SOLID

Sol , [g] [%] 85 128.06 85 128.06 Relative error [%] Overall Y [%]

S3 [g] 2.5474 2.3925 6.47

,

LIQUID

,

[g/g] 0.9730 0.9800

[%] 95 96 0.71

L3 [g] 128.96 129.12 0.12

, [g/g] 0.0068 0.0065 4.62

, [g/g] 0.0016 0.0017 5.88

Exp. Theory

Pu [%] 86.1 81.5 5.64

97.3 98.0 0.71

Exp. Theory

Relative error [%]

*Calculated according to the mathematical model analogical to that reported by Olbrycht et al. 34

The course of the process was predictable, as confirmed by the agreement between the expectations and the experimental data. This also proved that a small amount of contaminants in the raw material did not influence on the process performance. In case of the isothermal operation, overall yield of 77% was reached, whereas for the temperature mediated mode, in which the temperature profile was optimized - 86%. 18 ACS Paragon Plus Environment

Page 19 of 31

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This indicated a potential of the latter to improve the separation efficiency. The overall yield might be further improved by racemization and recycling of the exhausted mother liquor of the first stage. Nevertheless, regardless of the mode used, counter-current crystallization outperformed cross-current one, for which maximum overall yield of the process realized without racemization was about 60%.11

4.

CONCLUSIONS

In this study stereoisomeric mixtures of nafronyl oxalate were pre-separated by crystallization in an achiral environment using acetone as a solvent. Nafronyl possesses two stereogenic centers and is synthetized in the form of quaternary mixtures containing two pair of racemates that are diastereoisomers to each other. The racemate that contains the enantiomer with the highest biological activity was the target for the separation. The stereoisomeric mixtures exhibited an unusual phase behavior within the temperature range between 10 and 40°C, where from the same supersaturated initial solution two or three equilibrium states were achieved. This phenomenon manifested itself by crossing of different tie-lines on the ternary phase diagram through the initial composition point. The region of multiple equilibrium states vanished with decreasing temperature. To force the establishment of a desired equilibrium state, polythermal and seeded crystallization were used. In the former, nucleation was initiated at lower temperature and continued at ambient one, in the latter - the supersaturated solution was seeded by seeds of the desired racemate. In both cases the operation was successful, i.e., the desired equilibrium states were established and sustained. The results indicate that the specification of the initial conditions for nucleation from outside of the critical region allows an efficient realization of the process. The separation was subsequently continued by batchwise counter-current crystallization, which was performed either at constant temperature for each stage or in a temperature mediated mode. In the latter case, the temperature of each stage was adjusted to optimize the overall yield. The temperature mediated process markedly outperformed the isothermal one.

5.

AUTHOR INFORMATION

Corresponding Author Phone/fax: +48 178651853/ +48 178543655 e-mail: [email protected] Notes The authors declare no competing financial interest. 19 ACS Paragon Plus Environment


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6.

Page 20 of 31

ACKNOWLEDGEMENTS

Financial

support

of

this

work

by

National

Science

Center

(project

UMO2013/08/M/ST8/00982) is gratefully acknowledged.

7.

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For Table of Contents Use Only

Multiplicity of equilibrium states in separating stereoisomeric mixtures of nafronyl oxalate by crystallization Maksymilian Olbrycht, Dawid Kiwala, Maciej Balawejder, Andreas Seidel-Morgenstern, Wojciech Piątkowski, Dorota Antos

Synopsis An efficient crystallization process for the separation of stereoisomeric mixtures of nafronyl oxalate was designed and performed based on SLE data. A specific SLE region was detected, which was characterized by an unusual phase behavior. For the same supersaturated solution of the stereoisomers, different equilibrium phase compositions could be obtained.



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Multiplicity of Equilibrium States in Separating Stereoisomeric Mixtures

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