Novel Salt Cocrystal of Chrysin with Berberine - ACS Publications

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Novel Salt Cocrystal of Chrysin with Berberine: Preparation, Characterization, and Oral Bioavailability Rongjian Sa,†,‡,# Yanjie Zhang,†,# Yanping Deng,§ Yali Huang,† Mei Zhang,† and Benyong Lou*,†,‡ †

Institute of Oceanography, Ocean College, Minjiang University, Fuzhou, Fujian 350108, China State Key Laboratory of Structural Chemistry, Fuzhou, Fujian 350002, China § The School of Pharmacy, Fujian Medical University, Fuzhou, Fujian 350122, China ‡

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S Supporting Information *

ABSTRACT: A novel salt cocrystal of chrysin (ChrH) with berberine (BerbOH), [Berb+−Chr−]-2ChrH (1), was prepared. Crystal structure analysis shows one chrysin lost its proton in 7-hydroxyl group and turned into a chrysin anion. Two neutral chrysin molecules interact simultaneously with chrysin anion through charge-assisted strong hydrogen-bonding interactions between phenolic anion and hydroxyl groups of chrysin to give rise to a 1:3 salt cocrystal based on berberine and chrysin. Density functional theoretical calculations indicate that the 1:3 stoichiometry of berberine and chrysin is more stable due to its largest interaction energies. The bioavailability of chrysin in the form of cocrystal 1 in rats is about 1.7 times than that of pure chrysin.

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INTRODUCTION In the past two decades, cocrystallization based on organic small molecules has given rise to various organic cocrystals with applications ranging from functional materials to drug delivery.1−4 Versatile supramolecular synthons have been successfully exploited for cocrystal formation.5−12 Especially, many salt cocrystals could be obtained through cocystallization between an organic molecule and its own salt.13−15 Recently, systematic efforts have been made by Sun’s group to cocrystallize conjugate acid−base pairs of organic molecules based on charge-assisted strong hydrogen-bonding interactions.16−21 Ternary salt cocrystals could be even obtained by cocrystallizing an organic salt with structurally related but chemically distinct neutral molecules.22,23 Flavonoids are a class of natural polyphenolic compounds with antioxidant, anti-inflammatory, antitumor, antibacterial, and cardioprotective effects.24−27 However, therapeutic applications of flavonoids have been greatly limited because of poor oral bioavailability. Recently, significant improvement in oral bioavailability of flavonoids has been achieved by cocrystal formation.28−30 Flavonoids contain more than one hydroxyl group in molecular structures, which could act as both hydrogen-bonded acceptor and donor. The O−H···Narom © XXXX American Chemical Society

heterosynthon has been usually utilized for cocrystal design of flavonoids with N-containing aromatic compounds.31,32 Another effective supramolecular heterosynthon is O−H··· COO− synthon between flavonoids and zwitterionic carboxylic acids.33 In fact, the coformers for cocrystal screening of flavonoids have been limited to just a few organic molecules. Chrysin (Scheme 1) is a kind of simple flavonoid compound with substantial antitumor activity.34 Only four cocrystals have been found by a survey of CSD database (Feb 2018 version). The O−H···COO− interactions between 7-hydroxyl of chrysin Scheme 1. Molecular Structures of Chrysin and Berberine

Received: May 7, 2018 Revised: June 23, 2018

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DOI: 10.1021/acs.cgd.8b00696 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

= 1.54178 Å). The empirical absorption correction was applied by using the CrysAlisPro program.38 The structure was solved by direct methods and refined on F2 by full-matrix least-squares methods using the SHELX program package.39,40 Non-hydrogen atoms were refined anisotropically, and organic hydrogen atoms were generated geometrically. H atoms bonded to O were located by difference maps and refined freely. Computational Studies. The interactions between chrysin moieties and berberine moieties were explored by density functional theoretical calculations. Five models (shown in Figure S1) with different berberine cation, chrysin anion, and neutral chrysin were selected from crystal structure to obtain the origin of chrysin− berberine interactions in cocrystal 1. The M06-2X functional41 was employed in this article to perform all the calculations. The 631G(d,p) basis sets were used for all the geometry optimizations. Vibrational frequency analyses at the same basis sets were used on all optimized structures in order to characterize stationary points as local minima. Larger def2-TZVP basis sets were applied to calculate the interaction energies between chrysin and berberine groups. The basis set superposition error42 (BSSE) corrections were included in our calculations. The Gaussian 09 package43 was used for all of our calculations. DVS. DVS was measured on an Intrinsic DVS instrument from Surface Measurement Systems Limited at 25 °C. The nitrogen flow rate was 200 mL/min. The sample equilibrated at each step with the equilibration criteria of dm/dt ≤ 0.002%. Once one of the criteria was met, the relative humidity (RH) was changed to the next target value, following the 0−95−0% sorption and desorption cycle with a step size of 5% RH. In Vivo Pharmacokinetic Study. To evaluate the effects of cocrystallization for pharmacokinetics of chrysin, the bulk samples of chrysin and cocrystal 1 were utilized to conduct the pharmacokinetics experiments. Healthy male Sprague−Dawley (SD) rats (200 ± 10 g) were obtained from the Laboratory Animal Center of Fujian Medical University. Prior to the experiments, the rats were housed in a temperature and humidity controlled room (20−25 °C, 55 ± 5% air humidity) with 12 h light/dark cycles and free access to water and standard rat chow. All animal experiments were carried out in accordance with the local institutional guidelines for animal care of Fujian Medical University. The rats were fasted overnight with free access to water prior to the start of the experiment. Twelve rats were randomly divided into two groups (six rats in each group) and given either chrysin or cocrystal 1 at a dose of 24 mg/kg chrysin, respectively. The samples were dispersed in the appropriate amount of deionized water and then administered by gavage. The blood samples were collected from the oculi chorioideae vein into a heparinized tube at predetermined time points (0, 0.10, 0.25, 0.75, 1, 2, 3, 6, 8, 10, 12, and 14 h). The plasma samples were separated by centrifugation (4000 rpm, 10 min) and stored at −80 °C until analysis. One hundred microliters of rat plasma was mixed with 10 μL of daidzein (internal standard, 400 ng/mL in methanol). After vortexing for 2 min, the plasma samples were extracted with 500 μL of ethyl acetate by vortex-mixing for 10 min and then centrifuged at 10 000 rpm for 10 min. The supernatant was evaporated to dryness, and the residue was dissolved in a methanol−water (50:50, v/v) solvent mixture. The solution was introduced into the LC−MS system. The separation and determination of chrysin were achieved using a Agilent 1260 LC-6410 MS system and Ultimate XB-C18 (2.1 × 50 mm,3.5 μm). The mobile phase containing methanol and water was run at 0.2 mL/min. The isocratic elution was performed for 6.5 min. The injection volume was 5 μL, and the column temperature was set at 30 °C. The mass spectrometric analysis was operated in negative ion detection mode. Detection and quantification were carried out in the multiple reaction monitoring (MRM) mode, with m/z 253.1 to 222.9 for chrysin. Pharmacokinetic parameters, such as maximum plasma concentration (Cmax), time to reach the maximum concentration (Tmax) and area under the concentration−time curve (AUC0−24h), were estimated by noncompartmental modeling using DAS 3.0 (Mathematical

and zwitterionic carboxylate resulted in two cocrystals with Dproline and L-proline, respectively.33 The O−H···N synthon gave rise to two cocrystals with cytosine and thiamine hydrochloride, respectively.35 Like the other flavonoids, chrysin is a weak acid, and 7-hydroxyl group can transfer its proton to basic molecules.36 It is supposed that chrysin anion could further cocrystallize with neutral chrysin molecule based on charge-assisted strong hydrogen-bonding interactions.16−23 As far as the literature is concerned, no salt cocrystals based on flavonoids were reported. In this article, we choose a natural product, berberine (Berb−OH), as basic source (Scheme 1). Berberine is commonly marketed as berberine chloride, and its organic salts with saccharin and acesulfame have been recently exploited.37 In this work, a 1:1 organic salt of chrysin (ChrH) and berberine, Berb+−Chr−, was expected. The salt was used for cocrystallizing with another chrysin molecule to obtain a 1:2 salt cocrystal [Berb+−Chr−]−ChrH. Interestingly, a novel 1:3 salt cocrystal, [Berb+−Chr−]−2ChrH (1), has been finally identified. The cocrystal was characterized by single crystal Xray diffraction, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and dynamic vapor sorption analysis (DVS). The interactions between chrysin moieties and berberine moieties were explored by density functional theoretical calculations. The oral bioavailability of pure chrysin and chrysin in the form of cocrystal 1 were also evaluated. Cocrystal 1 represents a class of novel drug−drug cocrystals based on alkaloid and flavonoid.

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EXPERIMENTAL SECTION

Chrysin and berberine chloride were purchased as biological reagent (HPLC > 98%) and used without further purification. Differential scanning calorimetry (DSC) was performed on a NETZSCH STA 449C instrument. Powder X-ray powder diffractions (PXRD) were performed on Rigaku MiniFlex 600 diffractometer. Dynamic vapor sorption analysis (DVS) was measured via a SMS (Surface Measurement Systems) DVS Intrinsic. Synthesis of the Precursor Salt Berb+−Chr−. A mixture of berberine chloride (370 mg, 1 mmol), NaOH (40 mg, 1 mmol), and chrysin (254 mg, 1 mmol) with 0.1 mL of ethanol added was ground with a LAB WIZZ 320 ball mill in a 25 mL steel vessel for 15 min with a 15 mm steel ball at 30 Hz. The resulting powder was washed by ethanol to remove the byproduct NaCl and further recrystallized in ethanol. Synthesis of [Berb+−Chr−]−2ChrH (1). Initially, cocrystal 1 was identified through attempting to prepare the expected 1:2 salt cocrysal [Berb+−Chr−]−ChrH. A mixture of Berb+−Chr− (294 mg, 0.5 mmol) and chrysin (127 mg, 0.5 mmol) with 0.1 mL of ethanol added was ground with a LAB WIZZ 320 ball mill in a 25 mL steel vessel for 30 min with a 15 mm steel ball at 30 Hz. The resulting powder was collected for PXRD and DSC. Yellow single crystals of cocrystal 1 could be obtained by recrystallizing the powder product in EtOH. Bulk cocrystal 1 could be repeatedly obtained through one-step grinding methods as follows: A mixture of berberine chloride (185 mg, 0.5 mmol), NaOH (20 mg, 0.5 mmol), and chrysin (381 mg, 1.5 mmol) with 0.1 mL of ethanol added was ground with a LAB WIZZ 320 ball mill in a 25 mL steel vessel for 30 min with a 15 mm steel ball at 30 Hz. The resulting powder was washed by ethanol to remove the byproduct NaCl and dried in air conditions. PXRD and DSC. PXRD data were collected on a Rigaku MiniFlex 600 diffractometer, equipped with Scintillation Counter detector, with Cu Kα radiation (40 kV and 15 mA). Each pattern was collected with a step size of 0.02° in the 2θ range of 5−50°. DSC was determined on a NETZSCH STA 449C analyzer with a heating rate of 10 °C/min under N2 gas atmosphere. X-ray Structure Determination. The data were collected on a SuperNova CCD diffractometer at 100 K, using Cu−Kα radiation (λ B



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could be obtained by grinding the salt Berb+−Chr− and chrysin in a 1:2 molar ratio. PXRD and DSC confirmed that the 1:1 grinding products of Berb+−Chr− and chrysin is a mixture of the salt and cocrystal 1. This is in accordance with the fact that cocrystal 1 was initially isolated by recrystallizing the grinding products. This indicates that cocrystal 1 is a more stable form compared with the expected form of [Berb+−Chr−]−ChrH. Crystal Structure of Cocrystal 1. Crystal structure analysis shows cocrystal 1 contains one berberine cation and three chrysin moieties in the asymmetric unit (Figure. 3 and

Pharmacology Professional Committee of China, Shanghai, China). The results were expressed as the mean ± standard deviation (SD).

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RESULTS AND DISCUSSION Preparation of Cocrystal 1. In presence of NaOH, it is easy that berberine chloride reacts with chrysin to give a 1:1 organic salt through anion exchange reaction. PXRD patterns of the organic salt are different with that of pure berberine chloride and chrysin (Figure 1). The DSC curve of the salt

Figure 3. ORTEP plot of cocrystal 1 with 35% probability level. H atoms on C are omitted for clarity. Dashed lines represent hydrogenbonding interactions. Figure 1. PXRD patterns of berberine chloride (a), chrysin (b), the 1:1 salt (c), 1:2 grinding products (d), cocrystal 1 experimental, (e) and cocrystal 1 simulated (f).

Table 1). Difference Fourier maps showed that chrysin A lost its proton in the 7-hydroxyl group and turned to be chrysin anion ([C4/C9−O4]−). The bond length of C6−O4 (1.322 Å) of chrysin A is obviously shorter than that of neutral chrysins B and C (1.340 and 1.343 Å, respectively). The

shows a melting peak at 120 °C (Figure 2). The melting point is much lower than that of berberine chloride (190 °C) and chrysin (290 °C). A 1:2 salt cocrystal is attempted to obtain through liquid-assisted grinding of the salt Berb+-Chr− and chrysin in a 1:1 molar ratio. However, cocrystal 1, [Berb+− Chr−]−2ChrH, was finally isolated by recrystallizing the grinding products. The pure bulk powder of cocrystal 1

Table 1. Crystal Data and Structural Refinement for 1 formula formula weight crystal size, mm crystal system space group a, Å b, Å c, Å α, deg β, deg γ, deg V, Å3 Z Dc, g/cm3 F000 2θmax, deg reflections collected unique reflections Rint Parameters Final GooF R1 (I > 2σ(I)) wR (all data)

Figure 2. DSC curves of the 1:1 salt (a), 1:2 grinding products (b), and cocrystal 1 (c). C

C65H47NO16 1098.04 0.20 × 0.15 × 0.10 monoclinic P2(1)/c 21.6054(6) 11.4755(2) 21.9743(6) 90 113.248(3) 90 5005.8(2) 4 1.457 2288 73.68 18925 9845 0.0258 761 1.030 0.0437 0.1156 DOI: 10.1021/acs.cgd.8b00696 Cryst. Growth Des. XXXX, XXX, XXX−XXX


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interactions result in a 2D supramolecular layer of the hydrogen-bonded trimers (Figure. 4). Computational Studies. Density functional theoretical calculations were performed to explain if 1:3 stoichiometry of berberine and chrysin in cocrystal 1 is more stable. Table 3 shows the interaction energies between chrysin moieties and berberine moieties in cocrystal 1 (Figure S1). The interaction energy between berberine cation and neutral chrysin molecule is the cation−π interactions with energy −15.17 kcal mol−1 in cocrystal 1. The central ring distance decreasing from 3.579 to 3.408 Å enhances the interaction energy by 4.86 kcal mol−1. In cocrystal 1, the interactions between chrysin anion and neutral chrysin are slightly larger than the interactions of Berb+− ChrH. However, the optimization leads to a reduction by 0.47 kcal mol−1 compared to the crystal structure because the central distance of aromatic rings decreases after a structure optimization. Model 3 contains one berberine cation and one chrysin anion. After optimization, the distance of the central aromatic ring in berberine cation and chrysin anion decreases from 3.842 to 3.188 Å, while the interaction energy changes from −80.86 to −81.42 kcal mol−1. Berb+−Chr− shows larger interaction energy than Berb+−ChrH and ChrH−Chr−. This strong interaction may come from π−π, cation−π, and anion−π interactions between chrysin anion and berberine cation moieties. Energy could increase by 1.0 kcal mol−1 when one neutral chrysin molecule is added to the Berb+−Chr− group. By contrast, 8.73 kcal mol−1 of energy could be increasing when two neutral chrysin molecules are included. Therefore, the 1:3 stoichiometry of berberine and chrysin in cocrystal 1 is more stable than other ratios due to its largest interaction energies. Hygroscopicity. Cocrystal 1 presents a low moisture adsorption curve in the range of 0−75% relative humidity values at 25 °C (Figure. 5). It uptakes 0.7% of water at 80% RH, and the water sorption is up to 1.6% at 95% RH. The

dihedral angles between ring B and ring C are also obviously different for the three chrysins. For chrysins B and C, the dihedral angles between rings B and C are 11.50(7)° and 16.19(7)°, respectively. For chrysin A, the dihedral angle between rings B and C is 25.81(6)°. Chrysins B and C interact simultaneously with chrysin A through hydrogen-bonding interactions between phenolic anion of chrysin A and 7hydroxyl groups of chrysins B and C [O8···O4 = 2.4992(16) Å, O12···O4 = 2.5898(18) Å]. The charge-assisted strong hydrogen-bonding interactions are stronger than common O−H···O interactions.44 There exist similar intramolecular hydrogen-bonding interactions between 4-keto and 5-hydroxyl groups of each chrysin [O3···O2 = 2.5659(17) Å, O7···O6 = 2.6290(19) Å, O11···O10 = 2.6435(18) Å; Table 2]. Table 2. Hydrogen-Bonding Parameters in 1 D−H···A

D−H (Å)

H···A (Å)

D···A (Å)

D-H···A (deg)

O8−H8···O4 O12−H12A···O4 O3−H3···O2 O7−H7A···O6 O11−H11A···O10

0.98(3) 0.98(3) 0.97(3) 0.94(3) 0.94(3)

1.52(3) 1.61(4) 1.66(3) 1.78(3) 1.76(3)

2.4992(16) 2.5898(18) 2.5659(17) 2.6290(19) 2.6435(18)

179.3 179.3 154.3 150.2 156.3

The main structural characteristic of cocrystal 1 is the hydrogen-bonded trimer of chrysins A, B, and C. There also exist the other intermolecular interactions between adjacent trimers. There exist obvious C−H···O interactions [C26− H26···O4 = 3.358 Å] between chrysins A and B (x, y − 1, z). Chrysin A is simultaneously involved in pi−pi interactions with chrysin C (x, −y − 1/2, 1/2 + z) and berberine cation with a distance of 3.573 and 3.842 Å (centroid···centroid), respectively. Berberine cation is also involved in pi−pi interactions with chrysin C (x, 1/2 − y, 1/2 + z) with a distance of 3.579 Å (centroid···centroid). These weak

Figure 4. Supramolecular structure resulting from C−H···O and pi−pi interactions. D



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Table 3. Interaction Energies ΔE with BSSE Correction and Central Aromatic Ring Distances R of Chrysin−Berberine Complex in Optimized Structure and Crystal Structure crystal structure

optimized structure

model

ΔE (kcal mol−1)

Ra (Å)

ΔE (kcal mol−1)

Ra (Å)

Berb −ChrH Chr−−ChrH Berb+−Chr− Berb+−Chr−−ChrH Berb+−Chr−−2ChrH

−15.17 −18.14 −80.86 −81.86 −89.59

3.579 3.573 3.842 3,842,b 3.573c 3.842,b 3.573c

−20.03 −19.56 −81.42 −97.47 −113.70

3.408 3.444 3.188 3.462,b 3.508c 3.195,b 3.518c

+

a

Distance R is the central aromatic ring distance between monomers (see Figure S1). bDistance R1 is the central aromatic ring distance between monomers (see Figure S1). cDistance R2 is the central aromatic ring distance between monomers (see Figure S1).

Table 4. Pharmacokinetics Parameters of Chrysin and Cocrystal 1 after the Oral Administration to Rats at the Dose of 24 mg/kg Chrysina parameters

chrysin

cocrystal 1

Cmax (μg/L) Tmax (h) AUC0−24h (h·μg/L)

10.18 ± 1.21 2.03 ± 0.91 70.73 ± 1.19

14.97 ± 1.61 2.04 ± 0.73 120.69 ± 5.85

Data are expressed as the mean ± SD (n = 6). Cmax, maximum plasma concentration; Tmax, time to reach the maximum concentration; AUC0−24h, area under the concentration−time curve.

a

cocrystal has a modest improvement of Cmax and AUC compared with pure chrysin.

Figure 5. DVS isotherm plots for cocrystal 1 at 25 °C.

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CONCLUSIONS A novel salt cocrystal of chrysin (ChrH) with berberine (BerbOH), [Berb+−Chr−]−2ChrH (1), was prepared and characterized. Crystal structure analysis shows charge-assisted strong hydrogen-bonding interactions between phenolic anion and hydroxyl groups of chrysin dominate the structure of cocrystal 1. Density functional theoretical calculations indicate that the 1:3 stoichiometry of berberine and chrysin is more stable than other ratios due to its largest interaction energies. The bioavailability of chrysin in the form of cocrystal 1 in rats is about 1.7 times that of pure chrysin. Cocrystal 1 represents the first salt cocrystal based on flavonoid anion and its parent flavonoid. Cocrystal 1 is also a class of novel drug−drug cocrystal based on two kinds of natural products. Since both alkaloid and flavonoid are greatly diverse natural products, this work could provide a new strategy for designing drug−drug cocrystals based on alkaloids and flavonoids through chargeassisted strong hydrogen-bonding interactions.

value (1.6%) corresponds to one water molecule uptaken by one cocrystal unit [Berb+−Chr−]−2ChrH, which indicated that cocrystal 1 is slightly hygroscopic. In Vivo Pharmacokinetic Study. Like chrysin, cocrystal 1 is practically insoluble in water. An in vivo bioavailability study was performed on pure chrysin and chrysin in the form of cocrystal 1. The mean plasma concentrations of chrysin versus time profiles for chrysin and cocrystal 1 are shown in Figure. 6.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.8b00696. Figure 6. Mean plasma concentrations versus time profiles of chrysin and cocrystal 1.

Density functional theory calculations (PDF) Accession Codes

The pharmacokinetic parameters are listed in Table 4. It shows chrysin in the form of cocrystal 1 has a higher Cmax and AUC compared with pure chrysin. The AUC0−24h results show that the relative bioavailability of cocrystal 1 (calculated as AUCtot of the cocrystal divided by AUCtot of chrysin) is about 1.7 times that of pure chrysin. It can be found that the salt

CCDC 1841595 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. E



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AUTHOR INFORMATION

Corresponding Author

*Tel: +86-591-83761630. E-mail: [email protected]. ORCID

Benyong Lou: 0000-0001-6300-5843 Author Contributions #

R.S. and Y.Z. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to the support from the National Natural Science Foundation of China (21503105), the Natural Science Foundation of Fujian Province (2015J01599, 2017J05025, and 2018J01434), and Project for Outstanding Young Talents of Fujian Provincial Universities (2016).

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