Rational Coformer Selection and the Development of New Crystalline

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Rational Coformer Selection and the Development of New Crystalline Multicomponent Forms of Resveratrol with Enhanced Water Solubility. Basant Kumar Mehta, Shiv Shankar Singh, Swati Chaturvedi, Muhammad Wahajuddin, and Tejender S. Thakur Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01537 • Publication Date (Web): 24 Jan 2018 Downloaded from http://pubs.acs.org on January 25, 2018

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Crystal Growth & Design

Rational Coformer Selection and the Development of New Crystalline Multicomponent Forms of Resveratrol with Enhanced Water Solubility. Basant Kumar Mehta,1 Shiv Shankar Singh,1 Swati Chaturvedi,2 Muhammad Wahajuddin2 and Tejender S. Thakur1,* 1

Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow

226 031 INDIA 2

Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute,

Lucknow 226 031 INDIA Email: [email protected]

Abstract We report the development of ten new cocrystal forms of the nutraceutical compound resveratrol obtained through a rational coformer screening by utilizing the site interaction pairing energy differences computed based on the MESP calculations. A new monohydrate form of resveratrol and ten novel cocrystals with nine different coformers were characterized in the study. Among the newly developed solid forms of resveratrol, two of its cocrystals with (1) a GRAS compound piperazine and (2) the bioactive compound methenamine were subject to aqueous solubility determination. The newly developed piperazine cocrystal exhibits highest aqueous solubility among the previously known cocrystals of resveratrol. Keywords: Conformational Analysis, Crystal Engineering, Molecular Electrostatic Potential Surfaces, Nutraceuticals.

Introduction Multicomponent crystals offer an alternative approach for tuning the physicochemical properties of drugs without changing its therapeutic properties. 1

ACS Paragon Plus Environment

1-3

However, a reliable

Crystal Growth & Design 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

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strategy to identify most probable cocrystal formers (or coformer), is always desired to reduce time and efforts required in the new cocrystal form development. Intermolecular interaction complementarity and supramolecular synthon hierarchy are commonly used as an empirical guideline for the coformer selection for the cocrystal development. Recently, Hunter and coworkers have suggested the use of molecular electrostatic potential (MESP) surfaces to identify most probable interaction sites and to calculate the interaction site pairing energy differences for the ranking of coformers. 4 This approach has been found very helpful in many recent cocrystal-screening studies.

5-9

Alternative computational approaches for

coformer screening have also been proposed in the literature. Valega and coworkers have proposed the use of Hansen solubility parameters (HSP) to predict the miscibility of drug and coformer for cocrystal screening studies.

10

Abramov et al. proposed the use of conductor-

like screening model for real solvents (COSMO-RS) calculations for obtaining the excess enthalpy to prediction miscibility in the melt phase as a tool for coformer screening.

11

Besides these methods, use of crystal structure prediction (CSP) and lattice energy comparison has also been employed for computational cocrystal screening.

12

However, the

use of CSP is less preferred for screening studies due to computer intensive nature of these calculations. H2 O1

O2

C2 C1

H2A

H1A

C3

1

C6

C4 H4

H6

C5 C7

H7 H8 C8 C9

H10

C14 C10

H14

2

Torsion angles τ1 = C2-C3-O2-H2A τ2 = C2-C1-O1-H1A τ3 = C6-C5-C7-C8 τ4 = C7-C8-C9-C10 τ5 = C11-C12-O3-H3A

C13 C11 H11

C12

H13

O3 H3A

trans-resveratrol

piperazine

N,N-dimethyl-4-aminopyridine

4,4’-bipyridine

phenazine

1,10-Phenanthroline

Acridine

2


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DABCO

methenamine

Succinimide

Scheme 1

Herein, we report the characterization of ten new co-crystals of nutraceutical compound trans-resveratrol obtained by employing an MESP based coformer screening method. A monohydrate form and ten new co-crystals of trans-resveratrol with nine different coformers

4,4’-bipyridine,

piperazine,

phenazine,

1,10-phenanthroline,

1,4-

diazabicyclo[2.2.2]octane (DABCO), methenamine (or hexamethylenetetramine), acridine, succinimide and N, N-dimethyl-4-aminopyridine are reported in the present study (Scheme 1). The aqueous solubility determination of two of the newly isolated cocrystals with piperazine, a GRAS (Generally Recognized As Safe) compound and methenamine, a urinary tract infection drug were performed in this study to assess their suitability for the development of alternative crystalline formulations. Resveratrol

(5-[(E)-2-(4‒Hydroxyphenyl)ethenyl]benzene-1,3-diol

or

3,5,4’-

trihydroxy-trans-stilbene) is a naturally occurring stilbenoid widely present in plants species and also in some fruits and vegetables such as knotweed, pine trees, grapes, berries, and peanuts.

13

Resveratrol is being used widely in various over-the-counter dietary supplements

in the pure form or in combination with other nutraceuticals such as flavonoids, polyphenols, and procyanidins. In the literature, several studies indicate a wide range of physiological activities for resveratrol. These include anti-inflammatory, antioxidant, anti-obesity, anticancer, cardioprotective and antiaging properties. 13-15 However, the role of resveratrol as anticancer, anti-aging agent and in the metabolic disease management has been contested in some of the recent clinical studies. 16-18 Resveratrol belongs to BCS class II as it exhibits high permeability but very poor water solubility. Resveratrol shows high absorption but low bioavailability due to its poor solubility, rapid metabolism, and clearance via glucuronidation and sulfation pathways.

19-21

A survey of the recent literature shows reports on structural

3



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modification and reformulation approaches that have been tried to address the bioavailability issue in resveratrol. 22-29 The crystalline forms of resveratrol have also been extensively studied in the literature. Rossi and coworkers 23 was the first to report the crystal structure of the anhydrous form of resveratrol. The structure was refined as a Z’=1 form with all three hydroxyl H-atoms exhibiting disorder over two positions and was referred to as a result of dynamic hydrogen bonding network present in the crystal. Pinkerton and co-workers have recently redetermined the crystal structure at 120 K and proposed a revised structure for resveratrol based on superstructure reflections with a-axis double and two well-ordered resveratrol molecules in the asymmetric unit (Z’=2) having a static hydrogen bonding network.

30

Recently, Chadha et al., have reported the identification of four new crystalline forms of resveratrol (one corresponds to a cis-resveratrol) from a combined powder X-ray crystallography (PXRD) and CSP study. resveratrol with betaine.

26

25

Kavuru et al., have reported the first cocrystal of

Additionally, three cyclodextrin inclusion complexes of

resveratrol with permethylated α- and β-cyclodextrins had also been reported by Caira and co-workers.

27

Zhou et al., have reported two cocrystals of resveratrol with 4-

aminobenzamide and isoniazid that exhibits improved aqueous solubility, intrinsic dissolution rate, and tabletability properties.

28

Aboarayes have discussed solubility enhancement of

resveratrol by cocrystallization with coformers ɛ-caprolactam, flavone and 4,4̍-bipyridine her thesis.

31

Mei and co-workers have recently reported cocrystal of resveratrol with

nicotinamide, isonicotinamide and L-proline with improved mechanical and solubility properties. 32 Further, they recently reported four new cocrystals of resveratrol with a natural product, piperine.

29

However, they reported a poor dissolution and lower aqueous solubility

for these cocrystals.

Experimental Details Materials: High purity, trans-resveratrol (>99% GC), pyrimethamine and 3-aminopyrazine2-carboxylic acid were procured from TCI Chemicals (India) Pvt. Ltd. Phenazine, 4,4̍bipyridine, piperazine, 1,10-phenanthroline monohydrate, 2-aminopyimidine, isonicotinic acid, 4-aminosalicylic acid, nicotinic acid, methenamine (or hexamethylenetetramine), 1,44


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diazabicylo[2,2,2]octane,

succinimide,

nicotinamide,

4-cyanopyridine,

pyrazinamide,

pyrazine, sulfadiazine and N,N-dimethyl-4-aminopyridine were purchased from Sigma– Aldrich. Whereas, 8‒Hydroxyquinoline, propyl-4‒Hydroxybenzoate, orcinol, resorcinol, 2,2bipyridyl, and 2-aminopyridine used in the cocrystallization studies were obtained from Loba Chemie. Methyl-4‒Hydroxybenzoate was obtained from Acros Organics. Solvents (HPLC grade) used in this study were purchased from Sigma–Aldrich. Crystallization Experiments: Plate-shaped yellow color crystals of resveratrol monohydrate were obtained by dissolving ~5 mg of compound in a 1:1 dioxane and water mixture kept for crystallization at room temperature by slow evaporation method after three days. No, other polymorphs or solvated form was isolated in the primary screening of resveratrol from different solvent systems. All cocrystal screening experiments were performed by a slow evaporation method by dissolving resveratrol and the coformer taken in the varying molar ratios in different solvent systems (see Table S1). A liquid assisted grinding (LAG) of the powder mixture with 1-2 drops of solvent was performed in each case with the help of a mortar and pestle for ~15 minutes before dissolving them in the crystallizing solvent. X-ray Diffraction Studies: Single crystal X-ray diffraction studies for 1a, 1b, 1d-1i, and 1k were performed on the Rigaku Saturn 724+ CCD diffractometer using Mo-Kα radiation. Whereas, for 1c and 1j datasets were collected on a Bruker D8 Venture diffractometer using the Cu-Kα radiation. Structure solution in each case was performed with the direct methods using SHELXS-97.

33

Model refinement was performed on F2 by Full-matrix least-squares

method using SHELXL-2016

34

with the help of WinGX.

35

The hydrogen atoms attached to

O/N-atoms were located from the difference Fourier maps, and remaining hydrogens were refined isotropically using a riding model. Crystallographic data, structure refinement details for reported crystal structures are given in Table S10. Coformer in the cocrystals 1c, 1g, and 1h exhibits a positional disorder in the crystal structure. The atomic positions were resolved and refined through disorder modeling by using the PART command in SHELX. The resveratrol—acridine cocrystal hydrate 1i, crystal data was poorly refined with Rint ~20% and R1 ~11% as the crystal exhibit degradation due to the rapid solvent loss during data collection. Cocrystal 1k exhibited difficulty in modelling the disordered solvent molecules trapped in solvent channels. The structure, in this case, was refined using the SQUEEZE method (see Supporting Information). Reported crystal structures can be accessed free of 5



charge from www.ccdc.cam.ac.uk/data_request/cif (CCDC nos. 1583804-1583813 and 1816538). Powder X-ray diffraction (PXRD) dataset for bulk powder samples of resveratrol anhydrous form, 1c, and 1f was recorded on PANanalytical Xpert-Pro diffractometer using CuKα radiation over the 2θ range 5-60º at a scan rate of 2º min-1 and step size of 0.02º. Differential Scanning Calorimetry (DSC) For DSC analysis of resveratrol anhydrous form and cocrystal 1c and 1k was performed on DSC 25, TA Instruments. Approximately 2±0.1mg of ground sample was taken and crimped in an aluminum Tzero pans for the study. Samples were first equilibrated at 25°C and then heated at 10 °C/min from 25 to 300 °C. DSC data for 1f was collected on Perkin Elmer DSC 8000 by taking ~1.5 mg solid in aluminium pan and heated from 30 to 300 °C at the rate of 20 °C/min. Solubility Determination Studies: Solubility of resveratrol and its cocrystals were determined using the shake flask method. An excess quantity of solid sample was placed in a 25 mL conical ﬂask containing 1 mL of Milli-Q® water (pH ~7) and shaken for 24 h at 37±0.1°C. The supernatant solution was then passed through a 0.22 µm membrane filter, and the amount of the drug dissolved was analyzed using Shimadzu Prominence HPLC equipped with Photodiode array (PDA) detector. Resveratrol and its cocrystals were separated on a Supelco, C18 column (15cm X 4.6 mm, 5µm) with a mobile phase consisting of acetonitrile and 0.1% formic acid in the ratio of 40:60 (v/v). The mobile phase was duly filtered (using 0.22 µm Millipore filter), degassed (ultrasonically for 15min), and delivered at a flow rate of 0.7 ml/min for chromatographic separation. Detection of the dissolved amount of resveratrol in each case was performed at λmax = 305 nm. All solubility measurements were performed in triplicate. Computational Details: Conformers of resveratrol were identified from lowModeMD, a molecular dynamics based conformation search method using MMFF94x force-field using the MOE, version 2016.08 software suite. These conformers were subjected to full geometry optimization using DFT method at M062X/6-311G++(d,p) level of theory using Gaussian 09 36

. The molecular geometry of all the coformers compounds used in the study was optimized

at M062X/6-311G++(d, p) level of theory. The local maxima (MESPmax) and minima (MESPmin) sites on the molecular electrostatic potential surfaces (mapped on the electron 6


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density isosurface with isovalue 0.002 Bohr Å–3) were calculated with the help of Multiwfn software (version 3.3.9).

37

Local maxima and minima values are transformed into

corresponding hydrogen bond donor and acceptor interaction site parameters (α and β). These parameters were used in the computations of interacting site pairing energy using the method described by Hunter et al. The difference between the total interaction site pairing energies (∆E) of the heteromeric and homomeric pairs of pure components was used for coformer selection.

Results and Discussion Conformation Analysis Resveratrol is a conformationally flexible molecule with five rotatable bonds (three hydroxyl groups and two phenyl rings) represented by torsional angles τ1-τ5 (Scheme 1). A molecular dynamic based LowMD conformation search was performed to identify possible conformers of resveratrol and are classified into eight different sets of conformers (A-F, Table 2 and Figure S1). These conformers were subjected to full optimization by DFT method. These conformers do not show significant variation in their relative conformation energies, ∆Econf < 0.9 kcal/mol and are considered equiprobable (Table 2). Some of these conformers are also observed in the multicomponent crystalline forms reported in the present study (Table S2). Resveratrol conformers show differences in the MESP values computed at interaction site and hence explain variation in the homomeric/heteromeric interaction site pairing energies obtained for these conformers. The interaction site pairing energies obtained for resveratrol conformers (A-F) was ranges from 102-118 kJ/mol. The conformer A1 showed the highest homomeric pair stability of –118 kJ/mol and was used as a reference for resveratrol in the MESP based coformer screening. Table 2 Relative energies (∆Econf in kcal/mol) and torsional angle values (τ in °) obtained for geometry optimized resveratrol conformers and that in reported crystal structures. Conformer A1 A2 B1

τ1 179.21 -179.70 179.90

τ2 0.70 -0.20 0.30

τ3 159.54 -163.04 161.22

τ4 161.01 -164.44 162.72

7


τ5 179.20 -179.88 -0.58

∆Econf 0.03 0.05 0.04


B2 C1 C2 D1 D2 E1 E2 F1 F2 G1 G2 H1 H2

-179.55 -0.56 0.25 -0.84 0.46 1.21 0.08 -0.77 1.45 -179.70 -179.34 -179.44 179.85

-0.11 179.57 -179.64 179.83 -179.50 -0.10 -0.48 -0.72 -0.16 179.58 -179.76 179.27 -179.49

-162.37 -164.38 161.79 -160.15 161.94 159.84 -162.64 -164.18 159.90 -159.08 -161.93 -159.63 160.32

165.23 -165.92 163.28 -165.34 165.51 160.74 -160.92 -171.27 162.40 -163.02 163.24 -165.16 165.79

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0.19 -179.95 179.67 0.60 0.77 179.31 179.62 0.83 0.75 -179.40 179.82 0.33 0.08

0.03 0.18 0.11 0.00 0.03 0.76 0.87 0.77 0.72 0.25 0.29 0.17 0.21

Identification of Possible Coformers from Cambridge Structural Database A survey of the Cambridge Structural Database (CSD 2017 version) was performed to identify probable coformers for resveratrol cocrystal development. A CSD search of multicomponent crystals of 1,3-dihydroxybenzene derivatives which resulted in the identification of N-heterocycles (pyridines, pyrimidines, pyrazines, piperazines, pyrrolidines, quinolones and triazoles), amides, imides, phenols, benzoquinones, aminobenzene and cyanobenzenes class of compounds as potential coformers (Supporting Information, Table S3). The role of O–H···N hydrogen bonds has been found well explored in the earlier studies and have led to the development of several new cocrystals with distinct types of supramolecular assemblies for this class of compounds. 38-40 Study of the structural landscape of orcinol—N-heterocyclic bases cocrystals performed by Mukherjee et al., provides detailed information on the possible structural variations originating from O–H···N hydrogen bonds.

41

Besides these,

Nicotinamide, isonicotinamide, and L-proline were also found being used very frequently as coformers in the cocrystal development studies for flavonoids and other polyphenols.

32, 42-46

A list of forty-one potential coformers were identified from the CSD analysis and were further subjected to MESP based coformer screening studies. Coformer Selection Based on Molecular Electrostatic Potential (MESP) Surface Calculations The intermolecular interaction site pairing energies for resveratrol and coformers were estimated from the gas phase molecular electrostatic potential surfaces using the method proposed by Hunter and coworkers was used for primary coformer screening. 4 The maxima and minima on the molecular electrostatic potential surfaces of resveratrol and coformer compounds were identified, and the corresponding donor-acceptor interaction parameters (αi 8


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and βj) values were estimated. These parameters were used further in the computation of site pair interactions energies for homomeric and heteromeric molecular pairs. Since a priori information on the cocrystal stoichiometry is not available, all computational were performed for a 1:1 molecular pair. A benchmarking of the coformer screening method was performed first with orcinol and resorcinol to assess the prediction rate of this approach (Supporting Information, Table S4-S8). A better correlation with the probability of cocrystal formation was obtained when the total number site interaction pairs used in the heteromeric drug and coformer complex stability estimations were restricted to top four interaction pairs only. The known coformers of resveratrol (betaine, 4-aminobenzoic acid, isoniazid, L-proline, nicotinamide, and isonicotinamide) were included in the MESP calculations as a test set for testing the predictability of method for new cocrystal development this class of compounds. The relative stabilities of complexation between coformers and resveratrol are given in Table 3. Betaine showed highest relative stability for the heteromeric pair among the selected coformers due to the significant contributions from electrostatic interactions due to its zwitterionic nature. The N-heterocyclic coformers, 1,10-phenanthroline, DABCO, and piperazine showed a high probability of cocrystal formation of resveratrol from the selected set of coformers. The formation of cocrystals in each case was tested by performing extensive cocrystal screening studies (see Supporting Information, Table S1). Table 3 Site pairing energy differences (∆E in kJ/mol) obtained for resveratrol complexes with various coformers. # Sr. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Coformer Betaine 1,10-phenanthroline DABCO Piperazine 4,4-bipyridyl Caffeine N,N’-dimethyl-4-aminopyridine Sulfadiazine Carbamazepine Methenamine (HMTA) Pyrazine L-proline 4-aminobenzamide Isoniazid Pyrazinamide 4-cyanopyridine Phenazine 3-aminopyrazine-2-carboxylic acid Succinimide

∆E -36.93 -19.41 -17.59 -12.77 -9.36 -9.32 -7.92 -7.67 -7.60 -7.32 -6.27 -4.79 -4.69 -4.58 -4.55 -4.31 -4.01 -4.00 -3.90

Stoichiometry (RSV: COF: SOL) 1:1:0.5 (H2O) 2:7:2(H2O) 1:1.5:1(H2O) & 3:3.5:4(H2O) 1:1 1:1.5 1:2:Solvent(disordered) 1:1 1:1; 1:2 NA NA 1:3.5 1:2

9



20 Nicotinamide -3.54 1:1 21 Pyrimethamine -3.15 22 Isonicotinamide -3.02 1:2 23 2-aminopyridine -2.85 24 Theophylline -2.70 25 Urea -1.94 26 Benzoquinone -1.15 27 Sulfasalazine -0.76 28 Nicotinic acid -0.66 29 Isoquinoline -0.64 30 4-aminosalicylic acid -0.46 31 Glutaric acid -0.26 32 Orcinol -0.08 33 Resorcinol -0.04 34 2,2-bipyridyl 0.30 35 Isonicotinic acid 0.31 36 Trimesic acid 0.50 37 Pyrazine-2-carboxylic acid 0.63 38 1.51 Acridine 1:4:1(H2O) 39 Propyl-4-hydroxybenzoate 2.73 40 Methyl-4-hydroxybenzoate 2.82 41 8-hydroxyquinoline 3.39 42 2-aminopyridine 23.90 # Cocrystals that are observed in the cocrystal screening are highlighted in grey and bold (present study). NA = stoichiometry data not available was as cocrystals were identified from PXRD data.

Crystal Structure Analysis A new monohydrate form (1a) and ten new cocrystals for resveratrol were obtained from the experimental cocrystal screening studies with 4,4̍-bipyridine (1b), piperazine (1c), phenazine (1d), 1,10-phenanthroline (1e), methenamine (1f), DABCO (1g and 1h), acridine (1i), succinimide (1j) and N,N-dimethyl-4-aminopyridine (1k) were identified from melting point determination and further characterized with the help X-ray diffraction studies. Resveratrol monohydrate (1a) Resveratrol monohydrate 1a crystallizes in the orthorhombic space group, P212121 with one molecule each of resveratrol and water in the asymmetric unit. Resveratrol molecule adopts a B-type conformation in the crystal (Figure S1 and Table S2). The 1,3 hydroxyl groups of resveratrol are found oriented in an syn-anti arrangement in the crystal and are found involved in the formation of an O‒H···O helical hydrogen-bonded chain formed between molecules related by a 21 screw axis (Figure 1 and Table S9). Water serves as a bridge between the resveratrol molecules and creates a 3D network of hydrogen bonds by accepting a hydrogen bond from a para hydroxyl group of ring-2.

10


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Figure 1 Resveratrol molecules held by O‒H···O hydrogen-bonded helical chain propagating along 21 screw axis parallel to a-axis and interlinking water molecules. Resveratrol–4,4̍-bipyridine cocrystal (1b) Cocrystal 1b, crystallizes in the triclinic space group, P1 with two molecules of resveratrol and three molecules of 4,4̍-bipyridine in the asymmetric unit. One of the bipyridine molecule in the crystal exhibits positional disorder. Resveratrol adopts an F-type conformation in the crystal (Table S2). The resveratrol and 4,4̍-bipyridine molecules forms two sets of tetrameric units (one consists of a ordered and one with disordered bipyridine) held by O‒H···N hydrogen bonds formed between the hydroxyl groups of ring-1 and pyridine N-atoms. Third symmetry independent bipyridine molecule act as linker between these two tetrameric units held by O‒H···N hydrogen bonds formed with the para hydroxyl group of the ring-2 of resveratrol (Figure 2). Geometrical parameters for various intermolecular interactions found in the crystal are provided in the Supporting Information, Table S9. A polymorphic form of the resveratrol–4,4’-bipyridine cocrystal (with the same 2:3 stoichiometry and F-type conformation) had been reported previously by Aboarayes.

31

However, a comparison of unit cell parameters clearly shows significant differences in the cell parameters for 1b (P1; 9.51, 10.08, 26.11 Å; 86.8, 79.5, 73.1°; vol. 2355.3 Å3) and the cocrystal (P1; 9.50, 10.32, 26.49 Å; 91.3, 95.7, 108.6°; vol. 2444.8 Å3) reported ealier.

11



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Figure 2 The arrangement of tetrameric units (fully order set) held by O‒H···N hydrogen bonds found in resveratrol–bipyridine cocrystal. Resveratrol–piperazine cocrystal (1c) Resveratrol forms a 1:1 cocrystal (1c) with piperazine and crystallizes in the triclinic space group, P1. The asymmetric unit of 1c contains two resveratrol molecules, one full molecule of piperazine and two half molecules of piperazine, which sits on a crystallographic inversion center. Resveratrol molecules adopt an anti-anti conformation of H-type in the cocrystal. The hydroxyl groups of ring-1 of two symmetry-independent resveratrol molecules form two sets of a homo-molecular 1D infinite chain involving O2–H2A···O1, and O5–H5A···O4 hydrogen bonds. The hydroxyl group of the ring-2 of these resveratrol molecules interacts with the piperazine molecule from either side by forming a 8 motif consisting of O– H···N and N–H···O hydrogen bonds (Figure 3 and Table S9). Other two-piperazine molecules are forms a 26 hydrogen-bonded motif involving piperazine N–H and hydroxyl groups of ring-1 of resveratrol.

(a)

(b)

12


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Figure 3 (a) Molecular packing in the resveratrol–piperazine cocrystal showing (a) the tetrameric 8 motif, view down b-axis and (b) the tetrameric 26 motif, view down aaxis Resveratrol–phenazine cocrystal (1d) Resveratrol forms a 2:7 cocrystal (1d) with phenazine and crystallizes in monoclinic space group P21/c. The asymmetric unit of 1d contains one molecule of resveratrol, three full and a half-molecule of phenazine sitting on a crystallographic inversion center. Resveratrol adopts a G-type conformation in the crystal. The two hydroxyl groups are found oriented in an antianti arrangement that holds the two phenazine molecules on either side via O‒H···N hydrogen bonds. The four symmetry independent Phenazine molecules arrange in the πstacked columns along the b-axis (Figure 4). The two interleaving phenazine molecules do not involve in the strong hydrogen bonding and were found interacting by weak C‒H···N and C‒H···π interactions formed with the ethenyl and phenyl H-atoms of resveratrol molecules, (Figure 4, shown in yellow and red color and Table S9).

Figure 4 The molecular packing in the crystal structure of resveratrol phenazine cocrystal. Symmetry independent phenazine molecules are color coded. Resveratrol–1,10-Phenanthroline cocrystal hydrate (1e) Resveratrol‒1,10-phenanthroline dihydrate (1e) crystallizes in monoclinic space group, Pn. The asymmetric unit of 1e consists of seven 1,10-phenanthroline molecules and two 13



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molecules each of resveratrol and water. Both resveratrol molecules adopt an E-type conformation geometry in the crystal. The two-hydroxyl groups on ring-1 are found oriented in an syn-syn arrangement. Interaction environment around the two symmetry-independent resveratrol molecules shows very distinct feature. In the first case set-A, resveratrol is surrounded by three phenanthroline molecules each anchored to hydroxyl groups by O‒H···N hydrogen bonds (Figure 5). In the second case set-B, four phenanthroline molecules surround resveratrol. In which two phenanthroline molecules interact directly with the hydroxyl groups of resveratrol, and the others interaction is mediated through water molecules. Molecular packing in crystal show presence of several weak C‒H···O and C‒H···π interaction formed between the phenanthroline and resveratrol (see Table S9).

Set-A

Set-B (a)

(b) Figure 5 (a) Interaction environment of two symmetry in depended resveratrol molecules (Set-A, and Set-B) (b) Molecular packing in 1e viewed down b-axis. Resveratrol–Methenamine cocrystal (1f) Resveratrol and methenamine forms a 1:1 cocrystal (1f) and crystallizes in monoclinic space group, I2/a. The asymmetric unit of 1f consists of one molecule each of resveratrol and 14


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methenamine. Resveratrol adopts an F-type conformation in the crystal. The two hydroxyl groups on ring-1 are found oriented in an syn-syn arrangement and forms a tetrameric 20 motif with methenamine held by O‒H···N hydrogen bonds (Figure 6a). The para hydroxyl group of ring-2 of resveratrol form O‒H···N hydrogen bond with the third N-atom of methenamine and form an interpenetrated 2D-network of molecules parallel to the abplane. Fourth N-atom of methenamine remains do not participate in hydrogen bonding in the crystal (Figure 6b).

(a)

(b)

Figure 6 (a) Illustration of hydrogen bonding interaction between resveratrol and methenamine and the tetrameric 20 motif. (b) Interpenetrated 2D-network of resveratrol and methenamine molecules in 1f viewed down c-axis. Resveratrol–DABCO cocrystal hydrate, Form-I (1g) Cocrystal 1g crystallized in the triclinic space group, P1. The asymmetric unit of 1g contains two molecules of resveratrol adopting a B-type conformation and one full and a halfmolecule of DABCO (disordered over two positions) sitting on an inversion center and a disordered water molecule. One of the hydroxyl group of ring-1 of resveratrol interacts with the DABCO by forming an O‒H···N hydrogen bond whereas, the other hydroxyl group was found involved in the formation of an O‒H···O cyclic tetramer synthon (Figure 7). The para hydroxyl groups of ring-2 hold the disordered DABCO molecule form either side through O‒ H···N hydrogen bonds in the crystal. Water molecule serves as a bridge between the 1,3hydroxyl groups of other symmetry independent resveratrol.

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Figure 7 Molecular packing in the resveratrol-DABCO (2:1.5:1) monohydrate cocrystal, 1g. Resveratrol–DABCO cocrystal hydrate, Form-II (1h) The asymmetric unit of 1h is composed of three resveratrol molecules, three and a halfmolecule (sitting on the inversion center) of DABCO and four water molecules in the asymmetric unit. The resveratrol adopts A and B-type conformations in the crystal. Three out of four DABCO molecules were found disordered in the crystal. Overall packing in 1h was found very different from 1g, for example, no tetrameric O‒H···O cyclic tetramer synthon was observed instead of a water-mediated O‒H···O chain was seen in the crystal (Figure 8). Resveratrol molecules show both direct and water-mediated interaction with DABCO molecules in the crystal. Crystals show gradual degradation due to solvent loss during data collection.

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Figure 8 Molecular packing in cocrystal 1h view down b-axis (disordered atoms have been removed for clarity). Resveratrol–Acridine cocrystal hydrate (1i) Resveratrol forms a 1:4 cocrystal hydrate with acridine and crystallizes in the monoclinic space group; P21/n. Resveratrol molecule adopts an A-type conformation in the crystal structure. Among the four symmetry independent acridine molecule three were found directly involved in the O‒H···N hydrogen bond formation with the three hydroxyl groups of resveratrol. The fourth symmetry independent acridine molecule shows no direct interaction with resveratrol and however, forms a weak C‒H···π and π···π stacking interactions with neighboring acridine molecules. Water molecule serves as a bridge between the two adjacent resveratrol molecules forming a molecular tape in the direction parallel to c-axis (see Figure 9).

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Figure 9 Molecular packing in cocrystal 1i, view down a-axis. Resveratrol–Succinimide cocrystal (1j) Resveratrol forms a 1:2 cocrystal with succinimide and crystallizes in the triclinic space group, P1. The asymmetric unit of 1j contains one molecule of resveratrol that adopts an Htype conformation in the crystal structure and two molecules of succinimide. The two antianti hydroxyl groups of the phenyl ring-1 of resveratrol interact with the carboxyl groups of the succinimide molecules and form an O‒H···O hydrogen-bonded chain along the a-axis. The second symmetry independent succinimide interacts with the para-hydroxyl group of ring-2 of resveratrol by accepting O‒H···O from one side and by donating N‒H···O and C‒ H···O hydrogen bonds from another (Figure 10).

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Figure 10 The molecular packing in the resveratrol succinimide cocrystal, viewed down baxis. Resveratrol–N,N-dimethyl-4-aminopyridine cocrystal (1k) Resveratrol forms a 1:2 cocrystal (1k) with N,N-dimethyl-4-aminopyridine and crystallizes in the orthorhombic space group, Pnma. The asymmetric unit of 1k contains a one-half molecule of resveratrol having a plane of symmetry passing through the molecular plane and two half molecules of aminopyridine with a plane of symmetry bisecting it into two halves. Resveratrol molecule adopts a C-type in the cocrystal and forms a homo-molecular 1D infinite chain involving O1–H1A···O2 hydrogen bonds along a-axis. The remaining two hydroxyl groups holds the two pendant aminopyridine molecules through O–H···N hydrogen bonds (Figure 11 and Table S9). Solvent channels (with void volume = 1236 Å3 per unit cell and electron count of 353 electrons per unit cell) were observed in the direction parallel to baxis in the crystal. Solvent molecules in these channels remain unresolved, and the structure was finally refined using the SQUEEZE method (see Supporting Information).

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Figures 11 Crystal packing in cocrystal 1k, exhibits solvent channels parallel to b-axis (view down b-axis). PXRD analysis of bulk powder samples Bulk powder samples of pure resveratrol anhydrous form and its cocrystals 1c and 1f were subjected to PXRD analysis to establish the bulk phase purity before performing the solubility studies. Experimental PXRD patterns of bulk powder samples were compared with simulated powder patterns obtained from single crystal X-ray diffraction data and are shown in Figure 12. The PXRD pattern of resveratrol anhydrous form show characteristic peaks at 6.6°, 10.1°, 11.6°, 13.2°, 16.3°, 19.2°, 20.4°, 22.4°, 23.0°, 23.6°, 24.1°, 25.2°, 28.3° and 29.0°. These peaks are matched with the simulated pattern of resveratrol determined previously by Pinkerton and co-workers.30 The phase purity of the bulk powder samples of cocrystal 1c and 1f was established by the presence of distinct peaks in the PXRD patterns when compared to the known crystalline forms of resveratrol and coformer. Cocrystal 1c show characteristic peaks at 13.3°, 15.4°, 16.8°, 18.7°, 19.1°, 19.6°, 19.9°, 21.5°, 22.8°, 23.5°, 23.9°, 25.4°, 26.7°, 28.7° and 30.4°. Whereas, cocrystal 1f show characteristic peaks at 7.6°, 15.3°, 15.7°, 17.0°, 17.7°, 19.3°, 21.1°, 23.0°, 23.3°, 25.5°, 26.2°, 26.9° and 31.2°. These peaks were found in congruence with simulated PXRD pattern generated from single crystal data. The DSC profiles of pure resveratrol show a single sharp endothermic peak at 268.2 °C. The cocrystals 1c and 1f also show distinct endothermic peak at 204.5 and 221.6 °C respectively in comparisons to starting materials (see Supporting Information) 20


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(a)

(b)

(c) Figure 12 PXRD comparison bulk powder samples for (a) resveratrol anhydrous form, (b) cocrystal, 1c, (c) cocrystal 1f.

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Solubility determination Different aqueous solubility values have been reported in the literature for resveratrol (transform).47 Previous studies indicate that prolonged exposure to sunlight may result in the gradual conversion of trans-resveratrol to a cis-form in solution48 hence may affect the solubility determinations. The trans and cis-forms resveratrol are characterized by distinct UV absorption peaks (λmax) observed at ~305 and ~280 nm respectively. We determined the aqueous solubility of resveratrol (anhydrous form) as 58.21±1.11 µg/mL by shake flask method at 37 ºC. Amongst the newly developed forms of resveratrol, two of its cocrystals, with piperazine (GRAS compound) and methenamine (a urinary tract infection drug) were subjected to aqueous solubility determination. Both cocrystals exhibit enhanced aqueous solubility in comparison to the anhydrous form of resveratrol. Piperazine cocrystal (1c) show a ~150% increase whereas, the methenamine cocrystal (1f) exhibits a ~40% increase in aqueous solubility for resveratrol (Table 4). The previously reported cocrystals of resveratrol with nicotinamide and isonicotinamide show slightly better apparent solubility (measured at pH 2.0) of 82.6 and 147.1 µg/mL respectively. These cocrystals show an overall enhancement of ~44% and ~156% in comparison to resvertrol.32 However, these values were obtained in the presence of a surfactant (0.1% PVP K30) and reduced to < 20% in the absence of surfactant. The cocrystals of resveratrol with 4-aminobenzamide and isoniazid reported by Zhau et al., show maximum apparent solubility (at pH 3.6) of 65.6 and 113.2 µg/mL respectively with an enhancement of 19%, and 105%.28 Hence, the solubility enhancement achieved in the case of piperazine cocrystal (1c) can be considered best among the all known cocrystals of resveratrol. Table 4 Solubility (mean ± SD) of trans-resveratrol with its cocrystals 1c and 1f in water determined as per USP definition. Solid form Resveratrol (anhydrous) Piperazine cocrystal (1c) Methenamine cocrystal (1f)

Solubility (µg/mL) 58.21±1.11 144.38±1.53 81.88±2.93

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Challenges involved in the development of an efficient, rational cocrystal design strategy Crystallization is a complex phenomenon and involves steps namely, molecular recognition, aggregation, nucleation and growth of the crystal. Molecular recognition is the first step in the crystallization and happens primarily through intermolecular interactions. Therefore, it is crucial to get information on the stability of molecular complexes (held by these intermolecular interactions) and about the likelihood of their formation. Synthon propensity data retrieved from CSD help in obtaining this information in crystals, which can be extrapolated to heteromeric complexes present in the solution phase during cocrystallization, however, with a caution. 49 The probability of formation of a multi-component crystal may be thus be correlated to the relative stability of heteromeric interactions over homomeric interactions as they contribute towards the stability of initial cluster or nuclei’s formation during crystallization. Recently, Gavezzotti et al. had performed a comprehensive analysis of a large dataset of cocrystals retrieved from CSD to understand the cocrystal formation.

50

They found that the most stable heteromeric pairs (top five) are observed with a very high frequency in the cocrystals. Therefore, the higher stability of heteromeric pairs can be considered conducive to the growth of cocrystal from solution, and they will have a higher probability of involvement in the pre-nucleation stage during cocrystallization. The role of solvent is also considered significant as they can help in stabilizing the heteromeric complexes and nuclei in solution. Labile nuclei may dissolve back into the solution and favor the growth of more stable crystals. 51 During cocrystal screening, we came across four solvated cocrystal forms (1e, 1g-1i). The role of solvent in crystal growth of all these cases is noteworthy. In the case of cocrystal 1e, resveratrol forms a 2:7 cocrystal dihydrate with 1,10-phenanthroline comprising two sets of heteromeric hydrogen-bonded clusters with very similar interaction environment (Figure 5a). One set involves direct interaction between the resveratrol and three phenanthroline molecules through O‒H···N hydrogen bonds. The other set contains one of the three O‒ H···N hydrogen bond replaced by a water-mediated interaction. Additionally, it has a second water molecule that helps in attaching the fourth phenanthroline molecule to the resveratrol molecule and in the extension of the hydrogen-bonded network. A priori prediction of such cases of solvent inclusion and unusual stoichiometry extremely difficult as they are governed by crystallization kinetics. Similar is the case of resveratrol‒DABCO cocrystals; two23



hydrated cocrystals of different stoichiometry (1g: 2:1.5:1 and 1h: 3:3.5:4) were obtained in this case. In cocrystal, 1g water mediates a homomeric interaction between two resveratrol molecules whereas; in 1h water mediates the heteromeric complex formation between resveratrol and DABCO. Both forms originate forms a complex interplay of solute-solvent interactions observed during crystallization when taken in different stoichiometry. The resveratrol‒acridine cocrystal hydrate (1i) represent an unusual example wherein, the MESP derived molecular site pair energy calculations predict poor stability for the heteromeric resveratrol‒acridine complex. Despite this, a resveratrol‒acridine cocrystal hydrate was isolated during crystallization although, the crystal show reduced stability due to rapid desolvation. These examples indicate that the formation of a stable heteromeric complex (with strong intermolecular interactions) between the components can only be considered as a prerequisite for cocrystal formation that governs the primary molecular recognition process during cocrystallization. The MESP based coformer selection helps in identifying the most probable molecular pairs from a given set. However, it is important to note that the crystal growth depends on the stability of growing nuclei, which in turn is affected the presence of a solvent and the stoichiometric ratio of components. These factors are difficult to predict a priori and pose new challenges towards the development of an efficient coformer selection method.

Conclusions We have developed ten new cocrystals for resveratrol with nine different coformers selected based on the MESP based site interaction pairing energy differences. Two distinct hydrate cocrystal forms with different stoichiometry were obtained in the case of resveratrol‒1,4diazabicylo[2,2,2]octane (DABCO). A monohydrate form of resveratrol was also identified for the first time during experimental screening studies. Aqueous solubility determination of piperazine cocrystal (1c) and methenamine cocrystal (1f), show an increase in the solubility of resveratrol by ~150% and ~40% respectively. The solubility enhancement achieved in the case of 1c was found largest among the known cocrystals of resveratrol. These newly developed cocrystal forms help in the expansion of the available crystalline phase space for 24


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resveratrol and can be very helpful in the design of alternative formulations with better bioavailability in future.

Acknowledgements BKM thanks the University Grants Commission (UGC) of India for the award of a Senior Research Fellowship. TST thanks, Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Government of India for financial assistance under Extra Mural Research (EMR) Funding (project no. EMR/2016/005154). We also thank Mr. S. Nagaarjun, TA instruments, Bangalore and Dr. Naba Kamal Nath, NIT Shilong for providing help with DSC data collections.

Supporting Information is available: Crystallization, crystallographic data collection and refinement details (Table S1, S10 and S11); Conformation analysis of known and reported forms (Table S2); CSD search details (Table S3); Site interaction pairing energy differences calculation data (Table S4-S8);

Analysis of intermolecular interactions (Table S9); Resveratrol conformers (Figure S1); DSC Thermograms (Figure S2); Solubility comparison graph (Figure S3). This material is available free of charge via the Internet at http://pubs.acs.org.

Notes CSIR-CDRI manuscript communication number 0000. The authors declare no competing financial interest.

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For Table of Contents Use Only Rational Coformer Selection and the Development of New Crystalline Multicomponent Forms of Resveratrol with Enhanced Water Solubility.

Basant Kumar Mehta, Shiv Shankar Singh, Swati Chaturvedi, Muhammad Wahajuddin and Tejender S. Thakur*

Synopsis: Ten new co-crystals of a poorly soluble neutraceutical compound resveratrol were developed through a rational coformer screening approach by using MESP calculations.

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Rational Coformer Selection and the Development of New Crystalline

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