NaproxenâNicotinamide Cocrystals: Racemic and Conglomerate

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Crystal Growth & Design

Naproxen-Nicotinamide Cocrystals: Racemic and Conglomerate

Structures

Generated

by

CO2

Antisolvent Crystallization Clémence Neurohr†, Mathieu Marchivie‡, Sophie Lecomte†, Yohann Cartigny§, Nicolas Couvrat§, Morgane Sanselme§, Pascale Subra-Paternault*† †

Université de Bordeaux, CBMN-UMR5248, Allée Geoffroy St Hilaire, 33600 Pessac, France

‡

Université de Bordeaux, ICMCB-CNRS UPR 9048, 87 av Dr. Schweizer, 33600 Pessac, France

§

Normandie Université, UR, Laboratoire SMS, EA3233, 76821 Mont Saint Aignan, France

ABSTRACT Cocrystallization of naproxen racemic mixture and nicotinamide was investigated in this work, using compressed CO2 as antisolvent. A novel racemic cocrystal structure containing both enantiomers of naproxen linked to nicotinamide has been produced thanks to CO2 antisolvent batch crystallization process. The structure of the molecular complex and the analysis of its intermolecular interactions were investigated by Single Crystal X-ray Diffraction (SCXRD) and Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR). The antisolvent feed rate was found to have a direct influence on the cocrystallization outcome. The racemic cocrystal was obtained at slow and moderate CO2 feed rate, while very fast introduction of CO2 resulted in the formation of a mixture of chiral cocrystals (conglomerate). Cross-seedings, thermal analysis and Temperature Resolved X-Ray Powder Diffraction (TR-XRPD) were used to probe the relationship between the different phases. In addition, all powders produced with CO2 technology were obtained as cocrystal-pure, without significant excess of naproxen or nicotinamide homocrystals. * Pascale Subra-Paternault CBMN UMR-CNRS 5248, F-33600 Pessac, France Phone: +33 05 40 00 68 32, [email protected]

ACS Paragon Plus Environment

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Structures

Generated

by

CO2

Antisolvent Crystallization Clémence Neurohr†, Mathieu Marchivie‡, Sophie Lecomte†, Yohann Cartigny§, Nicolas Couvrat§, Morgane Sanselme§, Pascale Subra-Paternault*† †

Université de Bordeaux, CBMN-UMR5248, Allée Geoffroy St Hilaire, 33600 Pessac, France

‡

Université de Bordeaux, ICMCB-CNRS UPR 9048, 87 av Dr. Schweizer, 33600 Pessac, France

§

Normandie Université, UR, Laboratoire SMS, EA3233,76821 Mont Saint Aignan, France

KEY WORDS

Cocrystal, Racemic Naproxen, Nicotinamide, Enantiomer, Chiral Resolution, Conglomerate, Supercritical, CO2, Crystallization, Antisolvent


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ABSTRACT

Cocrystallization of naproxen racemic mixture and nicotinamide was investigated in this work, using compressed CO2 as antisolvent. A novel racemic cocrystal structure containing both enantiomers of naproxen linked to nicotinamide has been produced thanks to CO2 antisolvent batch crystallization process. The structure of the molecular complex and the analysis of its intermolecular interactions were investigated by Single Crystal X-ray Diffraction (SCXRD) and Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR). The antisolvent feed rate was found to have a direct influence on the cocrystallization outcome. The racemic cocrystal was obtained at slow and moderate CO2 feed rate, while very fast introduction of CO2 resulted in the formation of a mixture of chiral cocrystals (conglomerate). Cross-seedings, thermal analysis and Temperature Resolved X-Ray Powder Diffraction (TR-XRPD) were used to probe the relationship between the different phases. In addition, all powders produced with CO2 technology were obtained as cocrystal-pure, without significant excess of naproxen or nicotinamide homocrystals.

1. INTRODUCTION Cocrystals are molecular complexes at solid state between two entities. When one entity is a drug, formation of cocrystal is a strategy to improve its physicochemical properties1–3. Naproxen (Figure 1) is a non-steroidal drug of the aryl-propionic acids family, widely used for its antiinflammatory, analgesic and antipyretic properties. Categorized as a class II molecule by the Biopharmaceutics Classification System, this molecule is known to have a limited bioavailability caused by its low solubility4. Many strategies were investigated to improve it: formulations with


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various excipients5, nanocrystal formation6, amorphization7, coprecipitation with a polymer8, microparticles

formation9,

liquisolid

tablet

formulation10,

complexation

with

beta-

cyclodextrins11. In case of cocrystal strategy, the potential synthon formation guides the selection of a suitable coformer, and molecules allowing for example acid-acid, acid-amide and acidaromatic nitrogen supramolecular arrangements are known to favor cocrystal formation. For naproxen, Castro et al. screened various coformers of the pyridinecarboxamide family that contained an amide function and at least one aromatic nitrogen12. As a result, cocrystals of naproxen with picolinamide, isonicotinamide and nicotinamide were successfully synthesized and characterized. Nicotinamide being FDA-approved as GRAS (Generally Regarded as Safe), Ando et al. further focused on the naproxen:nicotinamide system and characterized the cocrystal structure by solid-state nuclear magnetic resonance and single-crystal X-ray diffraction13.

(a) * (c) (b) *

Figure 1. Structures of (a) S-Naproxen, (b) R-Naproxen, (c) Nicotinamide

An essential feature of naproxen is its chirality. As for many other chiral drugs, only one enantiomer provides the desired physiological activity, which is the S-enantiomer in case of naproxen14. To obtain enantiopure compounds, chiral chromatography is the most versatile and


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powerful technology but preferential crystallization appears as a cheaper alternative15. Nevertheless, this method is restricted to the possibility for the racemic solution to crystallize as a conglomerate, i.e. for systems in which the enantiomers are immiscible in the solid phase. Unfortunately, naproxen crystallizes as a racemic crystal in which the two enantiomers are present in the lattice16,17. Formation of cocrystal is not a common method in the arsenal of enantioseparation techniques. However, it presents similarities with diastereomeric salt formation with chiral resolving agent for which the molecules recognition depends on the existence and the magnitude of intermolecular interactions18. Cocrystallization of racemic naproxen was investigated by Tilborg et al. using the chiral proline amino acid as coformer19. To broaden the possible combinations, D-proline, L-proline and DL-proline were used and Snaproxen was investigated as well. Seven new solid forms were produced, including four racemic cocrystals that contained one molecule of each naproxen enantiomer. Whatever the combination, no chiral recognition was achieved, i.e. the chiral proline could not form selective interactions with only one enantiomer of naproxen when both enantiomers were available. Manoj et al. also investigated racemic naproxen cocrystallization, but for preferential enrichment purposes20. Bipyridine and piperazine, which are non-chiral molecules, were the coformers. Crystalline structures containing the two enantiomers of naproxen were obtained as well. Those results confirm the ability of naproxen to form racemic crystal or cocrystal, and conversely speaking, the difficulty of obtaining conglomerates from a racemic mixture. Cocrystals are usually prepared by classical crystallization techniques such as solvent evaporation or grinding12,13 but more cutting-edge methods as spray-drying21 or high-pressure homogenization22 are now investigated as well. If CO2-assisted crystallization processes are intensively studied in case of single species, only few studies deal with cocrystallization23–26.


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Padrela et al. screened different CO2-assisted methods and were able to generate theophylline- and indomethacin-based cocrystals24. All produced powders were recovered as cocrystal-pure. Examples of racemic mixtures recrystallized by CO2 are even scarcer. Apart from Charoenchaitrakool et al. who studied the micronization of racemic ibuprofen27, four papers issued between 1999 and 2014 have looked at diastereoisomeric salt formation with supercritical CO228–31. Generation of cocrystals from a racemic mixture has never been addressed with CO2-based techniques. In a previous work, we reported a successful cocrystallization of S-naproxen and nicotinamide using CO2 as antisolvent32. In this method, the species are first dissolved in an organic solvent and the addition of CO2 to the solution induces a decrease of the solute’s solubility and provokes hereafter the species precipitation. In case of S-naproxen / nicotinamide system, the produced cocrystals exhibited the same stoichiometry and the same bonding pattern than cocrystals formed by more conventional methods12,13. When the naproxen:nicotinamide ratio of processed solutions was deviated from the 2:1 stoichiometric ratio, e.g 3:1 and 1:1, the same cocrystal phase was recovered and, thanks to the CO2 procedure, even these solutions yielded powders of 98 ± 2% cocrystal content. This work is in the continuity of our investigations on cocrystallization assisted by CO2. More specifically, the process is hereby applied to the racemic mixture of naproxen instead of the S-enantiomer while nicotinamide was kept as the coformer. The objective was to assess if the technique could first produce a racemic cocrystal (as in naproxene – proline, –bipyridine, or piperazine but never described with nicotinamide), and secondly, could produce a conglomerate of naproxen-containing cocrystals, which to author’s best knowledge has not be obtained so far. Based on the ability of CO2 to influence times of crystallization33 and polymorphism34, we


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focused on the effect of CO2 introduction rate that governs the speed at which the supersaturation is built up. The crystals produced were characterized by powder and single crystal X-ray diffraction, infrared spectroscopy, differential scanning calorimetry and temperature resolved- Xray powder diffraction, in order to identify the molecular arrangement within the crystals.

2. MATERIAL & METHODS S-Naproxen ((+)-(S)-2-(6-methoxynaphtalen-2-yl)propanoic acid, 98%, S-NPX) and nicotinamide (pyridine-3-carboxamide, 99.5%, NCTA) were supplied by Sigma–Aldrich (France). Racemic naproxen (RS-NPX) was prepared from S-Naproxen according to a procedure detailed in the supplementary information. About 20g of RS-NPX were needed and since this amount was not affordable on the market, we had to produce it from less expensive S-NPX. Solvents for racemization were all HPLC grade: methanol was supplied by Scharlau, tetrahydrofuran was purchased from J.T. Baker and DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene) was provided by Chimtec (France). Carbon dioxide (CO2, 99.5%) was supplied from Air Liquide (France). Acetone (99.5%, Scharlau), ethyl acetate (99.8%, Scharlau), dichloromethane (Reagent grade, Scharlau), methanol (grade pur, Xilab), were supplied by Atlantic Labo (France). Acetonitrile (HPLC grade), ethanol (96%), potassium dihydrogenophosphate and phosphoric acid were also purchased from Atlantic Labo (France). Water was obtained from a Milli-Q water purification system.


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2.1. Definitions Figure 1 shows formulae of NPX enantiomers and of NCTA. The concepts of “racemic compound”, “racemic cocrystal”, “chiral cocrystal” and “conglomerate” are illustrated in Figure 2.

Racemic Compound R:S

S-Enantiomer R-Enantiomer Achiral Molecule

Coformer

or

Racemic Chiral Cocrystal Chiral Cocrystal Cocrystal R:Coformer S:Coformer R:Coformer:S Conglomerate

Figure 2. Schematic description of racemic and chiral cocrystals studied in this work.


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2.2. Cocrystallization by CO2 Antisolvent Experiments The CO2 antisolvent process in the so-called GAS version (Gaseous Anti-Solvent) was used. More details of the equipment can be found elsewhere35. Briefly, compressed CO2 is introduced by a pump at a desired flow rate (ISCO Model 260D, Teledyne Isco, USA) into a thermostated vessel of 0.49L filled with 40mL of a naproxen-nicotinamide acetone solution. A Rushton turbine plunging into the solution allows for dispersing the entering CO2 through blades. The stirring rate was settled at 500 rpm. Temperature is regulated to 310K by heating tapes wrapped around the vessel. During the pressurization step, CO2 dissolves progressively in the solution and provokes a decrease of the solutes solubilities. Concomitantly, the pressure rises and the acetoneCO2 mixture evolves from a liquid-vapor system to a monophasic fluid. Crystallization can be watched through sapphire windows located at the bottom half of the vessel. When the pressure inside the vessel reaches 10.0 MPa, the medium is drawn down at the vessel bottom while keeping a CO2 feed to maintain the pressure. A CO2 flow of 25g/min (LEWA EM1 Pump, Lewa, Germany) is maintained for 90 min. A stainless steel filter with a 0.2µm pore size membrane retains the produced crystals during the discharge and drying steps. The vessel is further depressurized and crystals are harvested, weighed and characterized. In this work, the CO2 feed rate during the pressurization step was varied: experiments at 2, 11 and 20g/min were carried out twice for reproducibility. The processed solutions were made of acetone containing RS-NPX and NCTA at a 2:1 molar ratio for an overall concentration of 49.2±0.6mg/mL. Crystallizations of single species, RS-NPX alone and NCTA alone, have also been carried out with the same procedure. In all cases, crystals were visually detected during the pressurization step when a liquid phase still existed, before the mixture went monophasic.


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2.3. Cocrystallization by Conventional Methods In order to better characterize and refine the structure of CO2-produced crystals, more conventional methods of slow evaporation and recrystallization from melt were used. Slow evaporation was carried out on RS-NPX and NCTA mixtures in different solvents. Solutions with RS-NPX:NCTA equimolar ratio (that is 0.5S-NPX:0.5R-NPX:1NCTA) were prepared in methanol, dichloromethane, acetonitrile and in methanol/water and ethanol/water mixtures. An acetone solution was also prepared with 2:1 molar ratio 2RS-NPX:1NCTA molar ratio (that is 1S-NPX:1R-NPX:1NCTA). The clear solutions obtained were left to evaporate overnight at room temperature and the crystalline powders formed were collected and characterized as such by X-ray powder diffraction (XRPD). Single crystals were grown by cooling an equimolar RS-NPX and NCTA mixture melted at 125°C, in order to resolve the new cocrystalline phase structure by single crystal XRD.

2.4. Cocrystals Cross-Seedings Cross seedings were carried out on powders produced with the CO2 method at 2g/min and 20g/min CO2 feed rate. Approximately 100mg of each powder were suspended in 2mL of either acetonitrile, dichloromethane, methanol or ethyl acetate. The suspensions were stirred at 20°C for four days and then filtered on a Büchner funnel. Dry samples of the recovered powders were analyzed by infrared spectroscopy and X-ray diffraction.


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2.5. Cocrystals Characterization Optical microscopy was used to examine crystals morphologies (Olympus BX51TF and camera ColorView U-CMAD3). Phase identification was obtained by powder X-ray diffraction analysis (XRPD) performed on a PANalytical XPERT-PRO diffractometer using a graphite monochromater with CuKα radiation (λ= 1.5418 Å). Powders were placed on stainless steel holders without any preliminary grinding, and measure between 4° to 38° with a step size of 0.0167° and scanning speed of 0.15°/min was carried out. Single Crystal X-ray Diffraction (SCXRD) data were collected at 293 K on a small crystal of 0.05×0.1×0.12 mm3 with a Brucker-Nonius kappa CCD diffractometer with monochromatic Mo-Kα radiation (λ = 0.71073 Å). At 293 K, the full sphere data collection was performed using ϕ scans and ω scans. The unit cell determination and data reduction were performed using the program Dirax36 and EvalCCD37 respectively on the full set of data. Data were corrected from absorption by the multiscan method implemented in the SADABS49 software. The crystal structure was solved by direct methods and successive Fourier difference syntheses with SHELXS-97 program38. The refinement of the crystal structure was performed on F2 by weighted anisotropic full-matrix least squares methods using the SHELXL97 program38. Both pieces of software were used within the OLEX2 package39. All the non-H atoms were refined with anisotropic temperature parameters. The positions of the H atoms were deduced from coordinates of the non-H atoms and confirmed by Fourier synthesis and treated according to the riding model during refinement with isotropic displacement parameters, corresponding to 1.2 to 1.5 times those the atom they are linked to. H atoms were included for structure factor


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calculations but not refined. Crystallographic data have been deposited in the Cambridge Crystallographic Data Centre (CCDC 1045087)*. Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) was performed to explore naproxen-nicotinamide interactions in the different cocrystals. Powders were deposited as such and gently pressed on a diamond crystal (GoldenGate). Spectra were recorded at room temperature with a NEXUS 870 FTIR ESP spectrometer from Nicolet (Madison, USA) equipped with a liquid nitrogen cooled mercury-cadmium-telluride detector. 100 scans were recorded between 800 and 4000cm-1 at a resolution of 4cm-1. Differential scanning calorimetry (DSC) analyses were performed on a DSC 214 Polyma Netzsch equipped with a -70°C intracooler. Dry samples of circa 5mg were weighted in 25 µL aluminum pans with pierced lids. Heating rate of 5°C/min was applied between 25 and 145°C, under nitrogen atmosphere. To elucidate further the DSC data, Temperature Resolved- X-ray Powder Diffraction (TRXRPD) analyses were carried out using a Siemens Bruker D5005 diffractometer, with CuKα radiation (λ= 1.5418 Å) and NiKα filter. Samples were placed on a 0.8mm depth sample holder regulated with a TTK 450 Hot Stage device (Anton Paar) linked to a PT100 probe. For each temperature step, a diffraction analysis was performed between 3° to 30°(2θ) with a step size of 0.04° and a scan duration of 4sec per step. The total duration of one temperature step was thus of

*

Copies of these data can be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: +44 1223 336 033; e-mail: [email protected] or http://www.ccdc.cam.ac.uk/data_request/cif)


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45 minutes. Between two temperature steps, the samples were heated at a rate of 2°C/min. The temperature range so explored went from 23°C up to 128°C. Contents of the produced powders in NPX and NCTA were determined without distinction of the NPX enantiomers by high performance liquid chromatography (HPLC), according to the method previously described32. Presence of S and R-NPX enantiomers was assessed by polarimetry on ethanol solutions of the CO2-produced powders (ATAGO polax-2L).

3. RESULTS & DISCUSSION 3.1. CO2 Antisolvent Experiments Summary of experiments and their characteristics are given in Table 1. It is worthwhile noting that all produced powders were cocrystal pure, i.e. no homocrystals of NPX or NCTA were evidenced by ATR-FTIR or XRPD. All powders obtained from the racemic RS-NPX were found to have no effect on polarized light, whereas a S-NPX2:NCTA cocrystal solution significantly deviated the light. CO2-produced powders were hence interpreted as containing as much S-NPX as R-NPX molecules.


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Table 1. CO2 batch antisolvent experiments CO2 Feed Rate (g/min) 2 11 20

Cocrystal Produced Racemic cocrystal Racemic cocrystal Conglomerate

Yield1 (%wt)

t starting2 (min)

P3 (MPa)

T4 (°C)

x5CO2 (%mol)

t maturation6 (min)

72 ± 2

61 ± 4

5.5 ± 0.4

37 ± 1

72 ± 4

109 ± 12

71 ± 1

19 ± 1

6.3 ± 0.1

38 ± 1

82 ± 1

15 ± 1

64 ± 3

10 ± 2

6.0 ± 0.2

35 ± 1

82 ± 2

11 ± 1

1

Collected amount/initial amount. All powders were characterized as cocrystal-pure, the yield therefore corresponds to the cocrystallization yield. 2 Time point corresponding to the starting of crystallization, t=0 being defined as the beginning of CO2 introduction. 3-4 Pressure and temperature of the liquid phase, at the beginning of crystallization. 5 Calculated CO2 composition of the liquid phase at the beginning of crystallization. PR EOS with quadratic mixing rules was used. 6 Duration between the beginning and the end of crystallization, when the pressure has reached 10MPa in the vessel and the crystallization medium is flushed out.

3.1.1. Slow CO2 Feed Rate of 2g/min From a macroscopic point of view, single NPX, single NCTA and S-NPX2:NCTA crystals usually formed light sparse powders uneasy to manipulate. The recrystallization of racemic RS-NPX and NCTA mixture at a slow CO2 feed rate produced a flowable material of denser aspect, made of small balls of crust. At the microscopic level however, the crystals exhibited the same thin plate-like morphology than that of the S-NPX2:NCTA cocrystals (Figure 3).


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(a)

(b)

(c)

(d)

Figure 3. CO2-precipitated cocrystals. (a), (b) : particles produced at 2 and 11g/min CO2 feed rate respectively, characterized as racemic S-NPX:NCTA:R-NPX cocrystals. (c), (d) : pictures of the powder produced at fast 20g/min CO2 feed rate, identified as a conglomerate of cocrystals.

Crystals harvested after a slow CO2 feed rate recrystallization show a clearly different diffraction pattern (Figure 4-d) than the known S-NPX2:NCTA form and than the single species (Figure 4-a, b, c). A very intense peak at 16.9° and small peaks at 7.2°, 13.1° and 13.2°, 14.3° highlight the formation of a new phase since they do not overlap with any peaks of the single species. A search in the CSD was carried out to look for known polymorphs of the SNPX2:NCTA cocrystal, but no other crystalline structure involving NPX and NCTA was found.


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(a)

(b) (c) (d)

(e) 4

6

8

10

12

14

16 18 2 t hét a °

20

22

24

26

28

30

Figure 4. XRPD patterns of CO2-precipitated material. (a) RS-NPX, (b) NCTA, (c) SNPX2:NCTA cocrystal. (d) corresponds to the racemic S-NPX:NCTA:R-NPX cocrystal produced at 2 and 11g/min CO2 feed rate. (e) corresponds to the conglomerate, produced at fast 20g/min CO2 feed rate.

The complementary conventional crystallization experiments were used to elucidate this new phase. Unfortunately evaporations of {RS-NPX+NCTA} solutions yielded small crystals that, according to XRPD patterns (Figure S1), were a mixture of the known cocrystal and homocrystals of RS-NPX and NCTA. The cocrystal could be the S-NPX2:NCTA or the RNPX2:NCTA since XRPD cannot differentiate the two forms. Since no specific peaks of single S-NPX (or R-NPX) were detected, NPX enantiomers were either present in the RS-NPX homocrystals or cocrystallized with NCTA. The peaks corresponding to the known cocrystal visible in the slow evaporations diffractograms actually corresponded to a conglomerate of SNPX2:NCTA and R-NPX2:NCTA.


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The recrystallization performed by cooling the {RS-NPX+NCTA} melt gave larger crystals than evaporations. One single crystal of 0.05×0.1×0.12 mm3 suitable for X-ray diffraction was collected and analyzed. A new cocrystal built with both R and S-NPX enantiomers and one NCTA molecule was evidenced, whose crystallographic parameters were corresponding to that of the new phase produced in slow CO2 feed rate experiment (Figure 5). Crystallographic data and details of refinement procedure are given in Table 2. This new arrangement has crystallized in the monoclinic space group P21/c (n°14). The asymmetric unit consists of two independent NPX molecules of opposite absolute configuration linked to a NCTA molecule by a similar hydrogen bonding scheme than that observed for the chiral S-NPX2:NCTA cocrystal (Figure 6). Such three-component adducts between the two naproxen enantiomers and the coformer was already observed by Manoj et al. in naproxen-bipyridine or piperazine cocrystals20.

Figure 5. Profile matching for the CO2-produced racemic cocrystal. Open red circles correspond to the experimental XRPD pattern; black continuous line represents the calculated pattern; green vertical lines are predicted Bragg positions; blue continuous line is the difference between experimental and calculated patterns (background corrected Rwp = 0.075).


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Table 2. Crystallographic parameters for racemic and chiral cocrystals

System

S-NPX2:NCTA

S-NPX:NCTA:R-NPX

Source

Ando et al.13

This study

CCDC Number

904098

1045087

Formula

2(C14H14O3).(C6H6N2O)

2(C14H14O3).(C6H6N2O)

Formula weight

582.63

582.63

Crystallographic System

Orthorhombic

Monoclinic

Space Group

P212121

P21/c

a (Å)

5.963 (11)

16.0822(19)

b (Å)

15.128 (3)

5.7965(11)

c (Å)

32.541 (6)

32.892(4)

α (°)

90.0

90.0

β (°)

90.0

99.314(9)

γ (°)

90.0

90.0

V (Å3)

2935.7 (1)

3025.8(8)

Z

4

4

D g/cm3

1.318

1.279

Reflexions collected

33681

47104

Independent reflexions

5368

5408 [Rint=0.1559, Rsigma=0.0951]

R1 [I>2σ(I)], wR2

0.047, 0.149

0.0802, 0.1500

Goodness of Fit

1.147

1.033

Flack parameter

0.0(4)

-


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Figure 6. Top: asymmetric unit of the racemic cocrystal. Bottom: corresponding motif in the chiral S-NPX2:NCTA cocrystal.

Table 3. Hydrogen bonds of the racemic cocrystal (R-NPX:NCTA:S-NPX) D—H · · · A

d(D-H)/Å

d(H-A)/Å

d(D-A)/Å

D-H-A/°

Motif

0.82

1.80

2.614(4)

170.2

0.86

2.03

2.874(4)

166.0

Amide-acid heterosynthon

O5—H5 · · · N11

0.82

1.85

2.664(4)

173.1

Pyridine-acid

N2—H2B · · · O6

0.86

2.15

2.971(4)

159.4

Amide-acid

O2—H2 · · · O12 N2—H2A · · · O3

1

1

Dimers Bridging dimers

X,1+Y,+Z; 2X,-1+Y,+Z


19


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Table 4. Hydrogen bonds of the chiral cocrystal (S-NPX2:NCTA from ref 13)

D—H · · · A

d(DH)/Å

d(HA)/Å

d(D-A)/Å

D-H-A/°

Motif

O3—H11 · · · O72

0.83

1.80

2.620(4)

170.9

3

0.87

2.18

3.019(5)

160.7

Amide-acid heterosynthon

0.83

1.85

2.667(4)

167.6

Pyridine-acid

0.87

2.20 {1.99}

3.07(2) {2.80(3)}

172.4 {154.4}

Amide-acid

N2—H33 · · · O2

O6—H25 · · · N11 4

N2—H34 · · · O5A {O5B4} 1

Dimers

Bridging dimers

-1/2+X,5/2-Y,-Z ; 2-1/2+X,3/2-Y,-Z ; 31/2+X,3/2-Y,-Z ; 4-1/2-X,2-Y,1/2+Z

The different hydrogen bonds generated in this new racemic phase are reported in Table 3 and Figure7a. The same dimer is present in the racemic and in the chiral cocrystals (see Table 3 and 4, Figure 7a and 8a), constituted of an amide-acid heterosynthon. In the new racemic cocrystal, these dimers are built from one molecule of R-NPX and the coformer. The molecule of S-NPX establishes, via its carboxylic function, hydrogen bonds with the nitrogen atom of pyridine ring and the second hydrogen of the amide moiety of two adjacent NCTA molecules along b. As a result, adjacent dimers are linked along b direction and these interactions give rise to periodic bond chains. These periodic bond chains are almost identical in the enantiopure cocrystal (Figure 8a).


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Figure 7a. Racemic cocrystal. Representation of one periodic bond chain constituted of hydrogen bonds interactions between S-NPX, R-NPX and NCTA. (R-NPX is depicted in purple, NCTA in yellow and S-NPX in grey). Hydrogen bonds are displayed in dashed lines, in blue the ones generating the dimer (formed by NCTA and R-NPX molecules), and in pink the ones that ensured the connection between dimers (ensured by S-NPX).

Figure 7b. Crystal packing of the racemic cocrystal. One periodic bond chain is represented in red. The periodic bond chains are spreading along b direction.


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Figure 8a. Chiral S-NPX2:NCTA cocrystal. Representation of one periodic bond chain constituted of hydrogen bonds interactions between S-NPX and NCTA. (NCTA is depicted in yellow and S-NPX in grey). Hydrogen bonds are displayed in dashed lines, in blue the ones generating the dimer (formed by NCTA and one S-NPX molecule), and in pink the ones that ensured the connection between dimers (ensured by a second S-NPX molecules)

Figure 8b. Crystal packing of the chiral S-NPX2:NCTA cocrystal. The periodic bond chains are spreading along b direction.


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A major difference relies in the conformation of the NCTA molecule: torsion angle of the carboxamide is equal to 3.1(8)° in the racemic phase, corresponding to the almost perfect “cisplanar conformation”, meaning that the amide part is on the same side as the aromatic nitrogen (top of Figure 6). The fragment is rotated to 170.1(4)° close to the “trans-planar conformation”, in the chiral structure (bottom of Figure 6). Li and Goldstein studied the difference of potential energy between isolated cis-planar and trans-planar NCTA conformations, and calculated the global energy minimum for the trans-planar one40. NCTA conformation in the new racemic structure is therefore less favorable compared to its conformation in the chiral cocrystal. Moreover, molecules organization is significantly different in the racemic phase: almost completely plane, NCTA entities stack perfectly parallel to one another, but slided far enough so that no π-stacking is possible between pyridine rings. As a consequence, asymmetric units are piled up into a column along the b-axis (Figures 7a and 7b). Two columns are connected only by H-like weak interactions between the methoxy groups of NPX molecules. Columns add-up to form layers within the (a-c) plane and stick together with even weaker Van der Waals interactions between the CH3-end of a NPX methoxy group and the -OH of the carboxylic acid of another NPX, or the aromatic ring of another NPX. In comparison, the assembly of the threecomponent motifs in the chiral cocrystal yields similar column-like chains along the b-axis, but organized differently. In those columns, cavities are formed between two NPX molecules of an asymmetric unit, which are filled with two NPX molecules of another neighboring column, creating a pile of NPX holding up with C-H…π interactions13. Columns of motifs are therefore more deeply interconnected in a three-dimensional network in the chiral structure, whereas the racemic structure is composed of weakly interacting two-dimensional layers. In both cocrystals however, it is noticeable that NPX molecules combine in such a way that NCTA cannot form


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dimers with amide-amide supramolecular synthons, such as in the cocrystal structure with ibuprofen41. Additionally the calculated density of the racemic phase is significantly different than that of the chiral cocrystal: the racemic structure is by 3% less dense than its chiral counterpart (Table 2). This observation would be an exception for the extension of the Wallach’s rule to cocrystals, as discussed for theophylline:DL-tartaric acid cocrystals42. Wallach’s rule states that racemic crystals tend to exhibit greater density compared to crystals of pure enantiomer43. Infrared data performed on the CO2-produced powder (Figure 9) show resemblance with the data of chiral S-NPX2:NCTA cocrystal32. The ν(C=O) stretching signal in the chiral phase is visible at 1700 cm-1 and 1662 cm-1, due to the formation of a hydrogen bond between the C=O of the S-NPX and the NH2 group of NCTA. In the racemic phase, the same double band shows at 1704 cm-1 and 1664 cm-1. The carbonyl part of NCTA is therefore involved in analogous interactions in the two different structures. Two broad bands at 2500 cm-1 and 1981 cm-1 in Figure 9 resemble the ones resulting from the O-Hcarboxylic

acid…Naromatic

hydrogen bond in the

chiral structure. Characteristic bands of the NH2 vibration modes are also expressed around 3300 cm-1 in both phases. From a vibrational point of view, the new phase and the S-NPX2:NCTA cocrystal have the same type of interactions involving the different functional groups of NPX and NCTA. The bands related to the aromatic nitrogen and the amide part of NCTA show however notable shifts in the new racemic phase. One of the O-Hcarboxylic acid…Naromatic bands is red-shifted from 2525 cm-1 in the S-NPX2:NCTA cocrystal to 2500 cm-1. According to the crystal structure, the lengths of the O-Hcarboxylic acid…Naromatic hydrogen bonds are similar in the racemic and in the chiral arrangements (Tables 3 and 4). These vibrational changes are therefore attributed to the modified arrangement of NCTA molecules in the racemic structure: their cis-


24

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planar conformation and their parallel stacking between each other have a direct effect on their vibrational response. The NH2 part of the spectrum exhibits significant changes: in the SNPX2:NCTA cocrystal, the anti-symmetric stretching band of the amide is at 3367cm-1, whereas it shows at 3380cm-1 in the new racemic phase. As for the symmetric stretching band of the amide hydrogens, it is red-shifted towards lower wavenumbers, from 3194 to 3171cm-1 in the racemic cocrystal. These alterations are attributed to conformational and organizational modifications of the NCTA molecules in the racemic structure.

(a)

Relat ive A bsorbance (au)

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


(b) (c) (d)

(e) 3500

3300

3100

2900

2700 2500 2300 W avelengt h (cm - 1)

2100

1900

1700

1500

Figure 9. ATR-FTIR spectra of CO2-precipitated material. (a) RS-NPX, (b) NCTA, (c) SNPX2:NCTA cocrystal. (d) corresponds to the racemic S-NPX:NCTA:R-NPX cocrystal produced at 2 and 11g/min CO2 feed rates, (e) corresponds to the conglomerate produced at fast 20g/min CO2 feed rate.


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3.1.2. Fast CO2 Feed Rate of 20g/min In this experiment, recrystallization was carried out at an antisolvent feed rate 10 times higher than in the previous experiment. The obtained powders were light and expanded, and particles morphologies resembled those of the chiral S-NPX2:NCTA cocrystals (Figure 3). Powders exhibited the same diffraction pattern and the same ATR-FTIR spectrum than SNPX2:NCTA cocrystal (Figure 4 and 9). Polarimetry on the powder showed no deviation of polarized light, i.e. the same quantity of S and of R-NPX is present in the final powder. A conglomerate of S-NPX2:NCTA and R-NPX2:NCTA cocrystals was therefore suspected to be produced from the initial single phased racemic RS-NPX reactant. DSC data later confirmed this hypothesis (see § 3.2). 3.1.3. Moderate CO2 Feed Rate of 11g/min Since the 2 and 20 g/min introduction rates yielded two very different results, a third experiment was carried out at 11g/min. The parameter of CO2 introduction is known to have an influence on supersaturation build-up and crystallization starting point. It was hypothesized here that a slow CO2 feed rate could favor a racemic cocrystal, which is the thermodynamically stable phase, whereas a fast feed rate provokes a catastrophic crystallization that yields to conglomerate cocrystals that should be then kinetically promoted. The moderate condition was used to test which form would take over, and if a mixture of chiral and racemic cocrystals could be possibly produced. X-ray diffraction and ATR-FTIR analysis revealed that particles produced at 11g/min were made of racemic cocrystals only, with no homocrystals of NPX or NCTA or chiral cocrystals


26

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(Figure S2). When looking at some characteristics of the experiments (Table 1), it seems that the times were the most influent parameters since the conglomerate was produced in the experiment that combined a short introduction period of CO2 and a short time given to structures to evolve once they have started to crystallize (hereby called ‘maturation’ time). The amount of CO2 in the liquid phase at the beginning of the crystallization did not seem to be a discriminating factor, although it is probably overestimated in case of the 20g/min case since a poor mixing with CO2 and solution was evidenced at high introduction rate44. This time dependency hypothesis led us to evaluate the relationship between the conglomerate and racemic structures through cross-seedings experiments, DSC and TR-XRPD analysis.

3.2. Relationship between the racemic phase and the conglomerate: Cross-Seedings and Thermal Analyses Cross seedings were carried out on {conglomerate+racemic cocrystal} mixtures in four different solvents. By suspending all the possible cocrystalline phases in a solvent, they are brought to evolve towards the most stable phase45. The methanol suspension yielded RS-NPX only. Acetonitrile, dichloromethane and ethyl acetate suspensions all gave powders containing the racemic R-NPX:NCTA:S-NPX cocrystal, without any chiral cocrystal detected. Hence, it appears that the conglomerate is metastable and the racemic cocrystal is the stable phase. Figure 10 and Table 5 display DSC data of the conglomerate (a) and of the racemic phase (b). The racemic cocrystal signature shows one clear endothermic event at 126.6°C, corresponding to a fusion at a lower temperature than that of single components RS-NPX and


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NCTA, and of S-NPX2:NCTA cocrystals. For the enantiomers forming a conglomerate, it is known that there is one eutectic composition, at 1:1 molar ratio, with a melting temperature below the pure enantiomer melting temperature46,47. DSC plots (a) and (c) on Figure 10 show that a conglomerate of cocrystals follows the same global trend. A multiple endothermic peak starting at 122.3°C would correspond to eutectic melting and/or successive phase transitions. In order to clarify this behavior, TR-XRPD was performed on the racemic phase and on the conglomerate mixture (Figure 11). The diffraction pattern of the conglomerate mixture shows that no structural change occurs until 100°C, but that a racemic cocrystal specific peak appears at 120°C. This peak is still visible until 128°C. A distinctive peak of the chiral cocrystal remains present in all the measurements. Upon heating, the conglomerate phase partly evolves (with low kinetics) towards the more stable racemic compound to finally melt at the racemic cocrystal temperature. The arrow on Figure 10 points out the shoulder corresponding to this final event. In comparison, the racemic cocrystal shows no structural evolution upon heating, including until complete melting and degradation (Figure S3). In terms of enthalpy however, the RNPX:NCTA:S-NPX requires more energy input upon melting than the conglomerate mixture and than the S-NPX2:NCTA chiral phase (Table 5). Nonetheless the melting temperatures of the racemic cocrystal, the conglomerate and the enantiopure cocrystals lay within the same range. As a consequence, energetic stabilization due to conversion of the conglomerate into the racemic cocrystal appears to be relatively small. Thus, the crystallization of the racemic cocrystal would not clearly be energetically favored compared to the conglomerate.


28

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(a) Exo up

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


(b)

(c)

45!

55!

65!

75!

85! 95! 105! Tem perat ure (°C)!

115!

125!

135!

145!

Figure 10. DSC plots of (a) the conglomerate produced at fast 20g/min CO2 feed rate and (b) the racemic S-NPX:NCTA:R-NPX cocrystal produced at 2g/min CO2 feed rate. (c) corresponds to the S-NPX2:NCTA cocrystal.

Table 5. DSC data of CO2-produced powders DSC Sample

Tonset °C

∆Hfus kJ/mol

Reference

Racemic Cocrystal (b)

126.6

75.7

This work, 5°C/min

Conglomerate (a)

122.3

71.7*

S-NPX2:NCTA Cocrystal

128.7

66.9

This work, 5°C/min

Racemic Compound Naproxen

155.8

33.2

Ref 16, 10°C/min

Nicotinamide (form 1)

128.2

23.2

Ref 12, 10°C/min

This work, 5°C/min

*This enthalpy includes more than the fusion event of the conglomerate (see Figures 10 and 11).


29


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128°C 126°C 124°C 122°C 120°C

* * * * *

100°C 23°C 4!

Page 30 of 37

6!

8!

10!

12!

14!

16! 18! 2 t het a °!

20!

22!

24!

26!

28!

30!

Figure 11. TR-XRPD plots of the conglomerate obtained at fast 20g/min CO2 feed rate. Diamond symbol points out the chiral cocrystals peak. Star symbol points out the racemic cocrystal specific peak, appearing at 120°C.

CO2 technology allowed producing either the racemic phase or the conglomerate by changing the antisolvent feed rate. In Figure 12 we suggest a schematic isothermal and isobaric section of the quaternary phase diagram describing a R-NPX/S-NPX/NCTA/Solvent system. In our case, the solvent is a mixture of acetone and CO2 which composition is evolving during the process. The pressure evolves as well, and both parameters influence the equilibrium lines. Strictly speaking, to each acetone-CO2 composition, specific tetrahedral and triangular diagrams should be drawn. Nevertheless, the crystallization behavior can be depicted on the isoplethal section of the quaternary phase diagram (Figure 12, right). For the slow and moderate CO2 feed rate experiments, the system crystallizes by following the stable equilibrium, i.e. the racemic cocrystal precipitates (red lines). Conversely, with fast CO2 feed rate the system is rapidly brought to the metastable crystallization domain and the conglomerate is formed (blue lines).


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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


CO2/ACETONE

CO2/ACETONE

(S-NPX)2 NCTA

NCTA (S-NPX)2 NCTA

S-NPX

(R-NPX)2 NCTA

R-NPX

R-NPX:NCTA:S-NPX

(R-NPX)2 NCTA

Stable equilibrium followed for slow and moderate CO2 feed rates Metastable equilibrium followed for a fast CO2 feed rate Global Composition of the system

Figure 12. Suggested isobaric and isothermal quaternary phase diagram (left) for R-NPX/SNPX/NCTA/Solvent system and isoplethal section (right) for the (R-NPX)2NCTA/(SNPX)2NCTA/{Acetone+CO2} system with a 2:1 molar ratio between NPX and NCTA molecules. Red and blue lines represent equilibria followed during moderate and fast CO2 feed rates respectively.

4. CONCLUSION The CO2-antisolvent crystallization allowed producing a new racemic cocrystal composed of S-NPX, R-NPX and NCTA. By increasing the antisolvent feed rate to induce crystallization with fast kinetics, the same process yielded a conglomerate, i.e. a physical mixture of S-NPX2:NCTA and R-NPX2:NCTA cocrystals. The molecular structure study showed that the same motifs existed in the racemic and in the chiral arrangements, namely the acid-amide heterosynthon and the pyridine-carboxylic acid hydrogen bond, inducing periodic bond chains. The NCTA conformation was however different in the two structures, a change that induced a distinctive packing of the asymmetric units.


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Page 32 of 37

In addition to the structural analysis, the relationship between the two different forms was also established. By cross-seedings in several solvents, the racemic phase was indeed determined to be the stable form. Moreover DSC and TR-XRPD allowed following the transformation of the metastable conglomerate into the stable racemic cocrystal. The formation of a conglomerate of cocrystals, obtained here for the first time with NCTA, could be a first step towards NPX optical resolution. Deracemization from this conglomerate of cocrystals could for example be tested in Viedma ripening assays48. Although the stable racemic cocrystal has not yet an application, the versatility of the CO2 technology is an interesting example of the switch from the production of a racemic cocrystal to the formation of a conglomerate with the sole CO2 feed rate.

ASSOCIATED CONTENT Supporting Information. Crystallographic CIF file for the structure of the racemic cocrystal. SNaproxen racemization protocol to provide initial racemic naproxen as a single phased product. Additional ATR-FTIR, XRPD and TR-XRPD data for COs-precipitated material and evaporations. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author * Phone: +33 05 40 00 68 32. E-mail address: [email protected] (P. Subra-Paternault).


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ACKNOWLEDGMENT Pascal Billot from Sanofi R&D is kindly thanked for the naproxen racemization protocol and for useful advices. The financial support of French ANR Project ANR-11-BS09-41 (2012–2016) is greatly acknowledged.

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FOR TABLE OF CONTENTS USE ONLY


Structures

Generated

by

CO2

Antisolvent Crystallization Clémence Neurohr†, Mathieu Marchivie‡, Sophie Lecomte†, Yohann Cartigny§, Nicolas Couvrat§, Morgane Sanselme§, Pascale Subra-Paternault*†

The batch CO2 antisolvent process produced a new racemic cocrystal where both naproxen enantiomers are linked to nicotinamide in the same crystal structure. By varying the CO2 feed rate, the same process yielded a conglomerate mixture of enantiopur naproxen-nicotinamide cocrystals.


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NaproxenâNicotinamide Cocrystals: Racemic and Conglomerate

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NaproxenâNicotinamide Cocrystals: Racemic and Conglomerate