Magnetic Levitation as a Tool for Separation: Separating Cocrystals

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Magnetic Levitation as a Tool for separation: Separating Cocrystals from Crystalline phases of individual compounds Chloé Matheys, Natalia Tumanova, Tom Leyssens, and Allan S. Myerson Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01018 • Publication Date (Web): 10 Aug 2016 Downloaded from http://pubs.acs.org on August 12, 2016

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Crystal Growth & Design

Magnetic Levitation as a Tool for separation: Separating Cocrystals from Crystalline phases of individual compounds Chloé Matheys,† Natalia Tumanova,† Tom Leyssens,*† and Allan S. Myerson‡ † IMCN, MOST, Université Catholique de Louvain, 1, Place Louis Pasteur, B-1348, Louvain-laNeuve, Belgium. ‡ Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachussets Avenus, Cambridge, MA 02139.

ABSTRACT In this contribution, we extend the phase separation abilities of Magnetic Levitation, applying it to co-crystal systems. Most of these systems show incongruent solubility in solution. Crystallisation from an equimolar mixture often leads to the crystallization of both cocrystal and coformer (one of the individual cocrystal formers). Using carbamazepine/salicylic acid and carbamazepine/camphoric acid systems, we demonstrated that magnetic levitation (MagLev) is an efficient and straightforward tool for phase separation in these systems.

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Introduction. An active pharmaceutical ingredient (API) can show different physical properties such as solubility, bioavailability or biocompatibility, depending on the nature of its solid state1-4. Given this behavior, the pharmaceutical industry is continuously on the lookout for alternative solid forms of a given compound to improve the efficiency of their drugs. This is why cocrystals have been the focus of many investigations5-7 over the last decade. Cocrystals are in general obtained through mechanochemical grinding or via crystallization from solution8,9. It is not uncommon to find inhomogeneous samples at the outset of both production methods containing cocrystal as well as coformer. At this stage, one can either optimize the production process, or introduce a physical phase separation step. Of the physical properties that could be used for phase separation, density is attractive in the case of cocrystals for the following reasons: 1) cocrystals are a molecular adduct of at least two coformers; they have a different packing compared to the parent compounds, and hence different density; 2) separations by density do not destroy the crystals. Magnetic levitation, has been shown to be a phase separation method that discriminates compounds in regard of their density and was successfully used amongst others for the separation of different polymorphs10, as well as the enantiopurification of crystalline material11. The theory of the MagLev has been described in detail by G. M. Whitesides et al. in 200912. The device, the main principles, influencing factors, and limitations are described in detail in the supporting information. In short, a magnetic levitation device represents a paramagnetic solution placed between two magnets with like poles facing one another (Fig.1). Three forces act on diamagnetic particles introduced in the paramagnetic media : (i) the gravity force, depending on the mass of the particle; (ii) the buoyant force, depending on the volume of the particle; and (iii)


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a magnetic force, whose magnitude varies as a function of position between the magnets (result of the magnetic field). The equilibrium between these forces results in the levitation of the particle at a specific position, a specific height, between the magnets. This implies that compounds with different densities levitate at different heights in the device.

Figure 1. Diamagnetic particle in a paramagnetic media between magnets with like poles facing one another undergoing three forces, (i) the gravity force, (ii) the buoyant force, and (iii) the magnetic force. Pattern in background represents the magnetic field.

Previous studies12,13 showed some care needs to be taken when dealing with the device. (i) As particles are introduced in an aqueous paramagnetic solution, solubility of compounds in water should be limited or the dissolution rate slow enough for the phases to get separated before significant solubilization occurs. A clear separation of compounds can take up to 48h. (ii) Crystals ideally have sufficient size (a diameter larger than 5 µm) so that Brownian motion remains negligible in regard of the gravitational and magnetic forces. (iii) The density and composition of the paramagnetic media have to be adjusted. When working with e.g. MnCl2 and


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water, the density range of compounds to be separated should stand between 1.2 and 1.5 g/cm3 in order for the particles to levitate into the medium and not sink or float. Taking these precautions into account, Maglev can find broad applications, either for precise density

measurements12,

for

purifications;

polymorph

separations10

or

enantiomeric

enrichement11. In this contribution, we apply the phase separation abilities of the MagLev to cocrystal systems, showing how the device allows to separate cocrystal from coformer crystals (Fig.2).

Figure 2. Schematic illustration of the separation of a mixture of CBZ:SA cocrystal and SA crystals showing a density of respectively 1.356 and 1.443 g/cm3. Particles with the lower density levitate the highest.


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Results and Discussion To demonstrate that MagLev is an efficient tool in this context, we selected two model systems. We started by crystallizing pure cocrystal and coformer phases. We then adjusted the MagLev parameters (magnetic susceptibility and density of the paramagnetic solution) to fit these systems before separating cocrystal/coformer mixtures.

Scheme 1. a) CBZ:SA cocrystal b) CBZ:CA cocrystal

We opted to work with carbamazepine/salicylic acid and carbamazepine/camphoric acid (Chart 1) as these compounds have a relatively low solubility in water (17.7 mg/l for CBZ, 2.2 g/l for SA and 8 g/l for CA). Pure compounds and co-crystals have well-defined structures14 and thus accurately known densities (Table 1). Carbamazepine can crystallize in several forms (II and III) under experimental conditions used in this work15,16. As the goal was to show the efficiency of the Maglev as a separation tool, we decided to limit the possible number of phases present, therefore rather focusing on the separation of co-crystals from the other coformer involved. The carbamazepine:salicylic acid cocrystal (CBZ:SA) was thus separated from salicylic acid (SA), with a the density difference of 0.087 g/cm3 between both solid forms, and the


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carbamazepine:camphoric acid cocrystal (CBZ:CA) from camphoric acid (CA), with a density difference of 0.038 g/cm3 between phases.

Table 1. CCDC REF, temperature at which structures were determined, and densities obtained from these Density Density CCDC REF / T(K)

Salicylic acid

SALIAC19 (150K)

Cocrystal CBZ:SA

MOXWAY (173K)

Camphoric acid

HUSVOG (150K)

Cocrystal CBZ:CA

MOXXAZ (173K)

(g/cm3)

difference (g/cm3)

1.443 0.087 1.356 1.219 0.038 1.257

Pure cocrystal, and coformer phases as well as mixtures of both were obtained by crystallization from solution under specific conditions identified by construction of appropriate ternary phase diagrams17-19 (Fig.3). See supporting information for a detailed procedure on the construction of these. Pure coformer phases were obtained from crystallization of pure phases, whereas for pure cocrystal and mixtures crystallization conditions were chosen appropriately (eg. an equimolar evaporation crystallization of carbamazepine and salicylic acid in acetonitrile at 9°C will lead to pure cocrystal phase).


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Figure 3. a) Carbamazepine/salicylic acid ternary phase diagram (%w) at 9°C in acetonitrile and b) Carbamazepine/camphoric acid ternary phase diagram (%w) at -10°C in acetonitrile.


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Next, the MagLev device requires adjustment for each system, by working on the density and magnetic susceptibility of the paramagnetic solution. This is achieved by modifying NaCl, sucrose and MnCl2 concentrations. The different solutions tested (see Supporting information) were evaluated by measuring their ability to separate two glass beads of precise density (standing for the cocrystal and coformer crystal). The solutions selected for the separation of each system are presented in Table 2 and separation ability is illustrated in Figs.4a and b. Table 2. Composition of the paramagnetic solution selected for the separation of both systems. [MnCl2] (mol/L)

[NaCl] (mol/L)

[Sucrose] (mol/L)

Separation (cm)

CBZ/SA

2.0

1.5

0.3

1.4

CBZ/CA

1.1

1.2

0.2

0.7

MagLev’s ability to separate cocrystal from coformer material was evaluated on the separation of 16 physical mixtures of pure cocrystal and pure coformer crystals in different ratios. A total of 20 to 22mg of the desired mixture was introduced in a beaker with five drops of diluted Tween 20 (surfactant to prevent hydrophobic aggregation and the sticking of gases on crystal surfaces). The beaker was then filled with 50 ml of paramagnetic solution before being placed in an ultrasound bath for a couple of minutes (to prevent hydrophobic aggregation and gases sticking) after which the beaker was placed between the magnets of the MagLev. After 24h, the crystals separated into two distinct clouds standing at different heights (Fig.4 c and d). At that stage, crystals from the top and bottom clouds can be collected, by slightly lifting the upper magnet and extracting the solid phases using a pipette. If the solution is taken completely from the magnetic field before taking out the solid phases, the latter will be remixed again. The beaker can be improved by embedding an outlet directly in the beaker’s wall, so there will not be any need to


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disturb magnetic field; however, we wanted to show that a simple unmodified beaker works as good. Solid phases are analyzed using XRPD and HPLC measurements in order to determine their exact compositions. If required, solid phases can be washed with cold water to remove traces of the paramagnetic medium.

Figure 4. a) Glass beads of precise density levitating in the MagLev; 1.35 (red) and 1.45 (green) g/cm3 glass beads standing for CBZ:SA and SA crystals in a 2M MnCl2, 1.5M NaCl and 0.3 sucrose solution. b) 1.25 (dark green) and 1.30 (light green) g/cm3 glass beads standing for CBZ:CA and CA crystals in a 1.2M MnCL2, 1.5M NaCl and 0.3M sucrose solution. c) Picture of a mixture of 13 mg cocrystal and 8 mg of coformer crystals after 24h in the MagLev; CBZ:SA and SA d) CBZ:CA and CA.

X-ray powder diffraction (XRPD) measurements showed conservation of the different solid phases: both cocrystal and coformer crystals were observed unchanged (Fig.5). Quantitative HPLC measurements were carried out on a reverse HPLC to measure the amount of both components in each cloud (see supporting information for details). Ratios between the coformer and CBZ were determined within an approximate 11% error (95% confidence interval; see supporting information). Results are shown in Tables 3 and 4. These tables show the initial


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amount of each phase used to create a mixture. From these mixtures four separation experiments were performed, and the composition (Eq.) of respectively top and bottom clouds are shown in these tables.

Table 3. Separation of physical mixtures of CBZ:SA cocrystals and SA crystals , evaluated by HPLC measurements.

Initial w added to the mixture (mg) CBZ:SA

5

8

13

15

Eq. SA

Cloud

SA 1.01

1.00

0.99

1.00

Top

1100

Pure SA

500

Pure SA

Bottom

0.98

1.00

2.19

0.96

Top

83

4700

Pure SA

Pure SA

Bottom

0.93

0.98

1.78

1.03

Top

83

4700

2.97

12.6

Bottom

0.97

0.96

0.93

0.97

Top

No Data

No Data

5.44

Pure SA

Bottom

15

13

8

5


10

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Table 4. Separation of physical mixtures of CBZ:CA cocrystals and CA crystals , evaluated by HPLC measurements. Initial w added to the mixture (mg) Eq. CA

Cloud

CBZ:CA CA 5

8

Pure CA

Pure CA

Pure CA

Top

No Data

0.79

0.97

1.00

Bottom

Pure CA

Pure CA

165.00

58.30

Top

1.03

0.90

1.11

1.01

Bottom

Pure CA

Pure CA

Pure CA

Pure CA

Top

13

13

15

Pure CA 15

8 1.01

1.02

1.01

0.99

Bottom

1649

426

187

Pure CA

Top

1.03

1.03

1.02

0.87

Bottom

5

Figure 5. Measured XRPD patterns of the CBZ/SA top cloud (in blue) and CBZ/SA bottom cloud (in red) with respect to the simulated CBZ:CA and CA profile (in black).


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Ratios are given in coformer equivalent : the number of equivalents of coformer per equivalent of CBZ. For the cocrystals, which have a 1:1 stoichiometric ratio, Eq SA (Eq CA) should ideally equal 1. The effectiveness of the separation is therefore evaluated by aiming for this number (upper cloud for CBZ and SA and bottom cloud for CBZ and CA). For the other cloud, we expect to obtain pure coformer, the Equivalent coformer number should therefore be as high as possible. When the equivalent value exceeded 10 000, the material was considered pure. For CBZ and SA, the separation led to pure cocrystal phase in the top cloud with the exception of two samples highlighted in red in Table 3. These latter two values are either due to a less good separation suggesting a composition of 2/3 of CBZ:SA cocrystals and 1/3 of SA crystals or due to the relatively important error from the HPLC analysis (see CBZ:CA system). Statistical analysis on the remaining 14 samples did not show a dependence of the initial composition or total amount of mixture on the separation ability (see Supporting information). The overall 95% confidence interval [0.96-1.00] indicates pure cocrystal phase within this cloud. Numbers for the bottom cloud are more disperse: but nevertheless indicate very little to no cocrystal phase present in most cases. For the less pure bottom clouds entrainement of some cocrystal by SA crystals during the separation is possible explaining a less good separation. On the whole, MagLev is very efficient to separate a physical mixture of CBZ:SA cocrystals and SA crystals. For the CBZ/CA system, the separation led to pure cocrystal in the bottom cloud. Two outlier values are observed (0.79 and 0.87) highlighted in red in Table 4. These latter can only be due an analytical error and not due to the separation, as it would imply an excess of CBZ crystals. All samples were verified with XRPD analysis, and disproportionation of the cocrystals never occurred. As for the first system, statistical analysis did not show an effect of the amount of


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material or proportion of phases on the separation efficiency. The overall 95% confidence interval [0.94-1.03] clearly evidences the bottom cloud to contain pure cocrystal. Furthermore, pure CA appeared in the top cloud in 11 cases, with the remaining cases showing only a limited amount of CBZ. Maglev is thus extremely efficient to separate a physical mixture of CBZ:CA cocrystals and CA crystals. The last part of this work, was to test the ability of the MagLev “in a true crystallization application”: meaning separating different phases that crystallized together (the conditions to crystallize such a mixture were deduced from the eutectic conditions defined by the phase diagram in Fig.3 and are given in the supporting information). For the CBZ/SA system, a visual observation of the crystallized eutectic showed two types of crystals: thin needle shaped crystals and much larger needle shaped crystals; indicating the crystallization of two different phases (Fig. 6). An XRPD measurement confirmed the concomitant crystallization of both phases (see supporting information). For the CBZ/CA system, both phases are not visually distinguishable, but during separation both phases became apparent. For each system, trials were performed separating 22 mg of the crystallized mixture.

Figure 6. Mixture of CBZ:SA cocrystals (thin needles) and SA crystals (larger needles) obtained by spontaneous concomitant crystallization starting from the eutectic composition.


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After 24 hours in the MagLev, visual observation showed separation into two clouds similar to the separations that occurred for the physical mixture. The composition of each cloud was determined and results are presented below in Tables 5 and 6.

Table 5. Separation of CBZ:SA cocrystals from SA crystals in a crystallized mixture

Initial w mix. Eq SA

Cloud

(mg) 1.26

0.98

1.01

Top

Pure SA

Pure SA

Pure SA

Bottom

22

Table 6. Separation of CBZ:CA cocrystals from CA crystals in a crystallized mixture. Initial w mix. Eq CA

Cloud

(mg) Pure CA

50

Top

1.11

1.45

Bottom

22

As shown by Tables 5 and 6, the maglev remains efficient in separating cocrystals from pure coformer crystals, even for a concomitantly crystallized mixture. Results for the CBZ/CA system are less evident due to agglomeration of different crystal forms.


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Conclusions After testing the MagLev for the separation of two cocrystal/coformer crystal systems, we established that MagLev is an efficient method to separate and isolate cocrystals from coformer crystals at laboratory scale. The repeated evaluation showed that the method is reliable and leads to the relatively good separation of pure cocrystal phase from both a physical as well as a crystallized mixture. Maglev offers multiple future advantages such as an easy one-step separation, phase identification, the possibility to purify small samples and the production of pure cocrystal phases which can be used to seed saturated solution and produce a bigger amount of cocrystals.

ASSOCIATED CONTENT Supporting Information. The supporting information contains: Materials and methods; construction of ternary phase diagrams; MagLev device description; selection of paramagnetic medium; detailed analysis of separations ; This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *[email protected] ACKNOWLEDGMENT The authors would like to thank the FNRS for financial support (N. Tumanova is a FRIA PhD student, PDR-T.0099.13.), as well as the UCL for the MIT-SEED FUND and FAI-fund. The authors thank Dr. Nikolay Tumanov for making a MagLev device at UCL.


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For Table of Contents Use Only Magnetic Levitation as a tool for separation: Separating cocrystals from crystalline phases of individual compounds Chloé Matheys, Natalia Tumanova, Tom Leyssens, and Allan S. Myerson

Magnetic Levitation, an interesting tool for phase separation of cocrystals from excess coformer material at laboratory scale. Carbamazepine:Salicylic acid and Carbamazepine:Camphoric acid are separated from their respective acidic coformers using a Maglev device.


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Magnetic Levitation as a Tool for Separation: Separating Cocrystals

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