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. 2020 Apr 6;5(14):8283–8292. doi: 10.1021/acsomega.0c00692

Solubility and Stability Advantages of a New Cocrystal of Berberine Chloride with Fumaric Acid

Dezhi Yang †, Junzi Cao †, Lingtai Jiao †, Shiying Yang †, Li Zhang †, Yang Lu †,*, Guanhua Du ‡,*
PMCID: PMC7161028  PMID: 32309739

Abstract

graphic file with name ao0c00692_0011.jpg

BBC is a drug with a variety of activities but poor solubility. Cocrystal technology is an effective method to improve the solubility and stability of this type of compound. In this work, the cocrystal of BBC with fumaric acid was obtained at a stoichiometric ratio of 2:1. Studies on stabilities and solubilities were carried out using BBC dihydrate and tetrahydrate as reference materials. Results showed that this new cocrystal did not only significantly improve the dissolution rate of BBC but also highly improved the stability in high humidity and temperature. Given that the cocrystals formed by BBC as the host molecule were few, different techniques were applied for characterization and structural analyses. Moreover, theoretical calculations were performed on weak interactions, such as hydrogen bonding and π–π stacking interactions, which provided the research data for the study of this kind of cocrystal.

1. Introduction

Berberine (BB) is a natural isoquinoline alkaloid extracted from traditional Chinese medicine Rhizomacoptidis and Cortex phellodendri. The earliest discovery in modern pharmacological studies is that BB has inhibitory effects on a variety of gram-positive and gram-negative bacteria and it is effective in treating intestinal infection and bacterial dysentery.1,2 With increasing research, BB was found to have a wide range of pharmacological activities, such as antimicrobial, antioxidant,3,4 antidiabetic,5,6 anti-inflammatory,8,9 and antitumor activities,10,11 heart protection,7 and modulation of lipid and glucose metabolism.12,13 The discovery of these new effects endows BB with new significance and value and makes it a good development prospect.

BB is generally administered as a chloride for the treatment of diarrhea in clinical applications in China and Japan. However, low bio-availability due to low water solubility seriously limits its further clinical use. Many methods have been adopted to solve this problem, among which nanotechnology and formation of a salt or cocrystal are the most popular. Nanodrug preparation is a hot research topic and it aims to enhance drug-release performance, target action, and bio-availability and improve drug compliance of patients. BB can be prepared into nanoparticles or combined with nanocarriers to improve solubility and bio-availability.14,15 Salt formation is also an effective approach to improve the drug’s physicochemical properties. The clinical application of BB is mostly as a chloride salt, that is, BB chloride (BBC), but the actual solubility is still not ideal. Furthermore, given the shortcomings of instability of BBC in high humidity, some studies have introduced organic acid ions to replace chloride ions to improve the stability against high humidity. However, the solubility of these salts was reduced.16−18

Cocrystal formation is a recent research focus that seeks to improve the solubility of insoluble or slightly soluble drugs. Cocrystals can not only improve the solubility but also have a positive impact on stability by introducing an appropriate cocrystal former (CCF).19,20 According to the survey of existing crystal structures in the Cambridge Structural Database (CSD), a total of 33 related crystal structures of BB were retrieved. Only six cocrystals are of BBC, and the rest are BB salts and their hydrates. All these cocrystals did not improve the solubility of BBC.21−24 Therefore, the selection of a CCF is crucial.

Different BBC hydrates are also reported in the CSD, which are the states of medicinal substances stipulated by the Chinese and Japanese pharmacopoeia. The Chinese pharmacopoeia specifies dihydrates of BBC as bulk pharmaceutical chemicals, whereas the Japanese pharmacopoeia does not specify the amount of crystalline water. The amount of crystalline water varies among anhydrate, dihydrate, and tetrahydrate with humidity and temperature in the process of drug production or transportation, and these changes seriously affect the drug quality control and clinical treatment effect. Therefore, the stability of BBC also needs to be addressed.

In this study, a cocrystal of BBC with fumaric acid (FA) was developed. FA is a typical CCF which is commonly used as pharmaceutical excipient in pharmaceutical field and has a much better solubility than BBC. BBC dihydrate (BCD) and BBC tetrahydrate (BCT) were also prepared as reference materials to compare solubility and stability. Dynamic vapor sorption (DVS) analysis was carried out to investigate stability in high humidity, and the intrinsic dissolution rate (IDR) method was applied to evaluate solubility. Results showed that the stability and solubility of this new cocrystal significantly improved. In addition, different technical methods were performed for the characterization and structural analysis of this new cocrystal, such as single-crystal X-ray diffraction (SXRD), powder X-ray diffraction (PXRD), thermogravimetry (TG), and differential scanning calorimetry (DSC), because the cocrystals formed by BBC as host molecule were few. Interactions between the active pharmaceutical ingredient (API) and coformer moieties were explored by density functional theory (DFT) calculations.

2. Materials

BBC raw material was purchased from Sichuan Xieli Pharmaceutical, Co., Ltd. FA raw material was purchased from Wuhan Far Cheng Co-creation Technology Co., Ltd. All solvents used for crystallization were of analytical grade and purchased from Sinopharm Chemical Reagent Beijing Co., Ltd.

2.1. Synthesis and Crystallization

Cocrystal of BBC with FA (BBC-FA). The slurry method and recrystallization were chosen in this study. A mixture of BCD (408 mg, 1 mmol) and FA (58 mg, 0.5 mmol) was added into 5 mL of methanol and stirred for 4 h at a speed of 350 rpm. The solution was filtered and left to stand under 20 °C for approximately 2 weeks. Yellow needle crystals were obtained.

BCD. BBC raw material (∼408 mg) was added into 50 mL of 95% ethanol and completely dissolved at 60 °C by stirring at a speed of 350 rpm. The solution was filtered and allowed to stand for crystallization overnight at 4 °C. The solid obtained from the solution was dried to a constant weight in a vacuum oven at 30 °C.

BCT. BBC raw material (∼408 mg) was added into 35 mL of distilled water and completely dissolved at 75 °C by stirring at a speed of 350 rpm. The solution was filtered and allowed to stand for crystallization overnight at 4 °C. The solid obtained from the solution was dried to a constant weight in a vacuum oven at 30 °C.

2.2. Characterization

2.2.1. SXRD Analysis

SXRD experiments were carried out on a Rigaku MicroMax-002+ CCD diffractometer with Cu Kα radiation (λ = 1.54178 Å; Rigaku Americas, the Woodlands, TX, USA). The intensity data of the cocrystals were collected at 293 K. Absorption correction and integration of the collected data were performed using the CrystalClear software package (Rigaku Americas).23 The crystal structures of the analytes were then solved by the direct method followed by Fourier syntheses with SIR2008.24 Subsequent refinement through the full-matrix least-squares procedure using SHELXL was performed on F2 with anisotropic displacement parameters for non-hydrogen atoms on the Olex2 crystallography software platform.25,26 Hydrogen atoms were refined isotropically with isotropic atomic displacement parameters (Uiso) = 1.2-fold the value of the parent atom. The hydrogen atoms of the methyl or hydroxyl groups were assigned 1.5-fold the value of the parent atom. Hydrogen atoms were placed in ideal positions and refined using the riding model, and hydrogen atoms involved in hydrogen bonding were detected in the experimental electron density map and refined freely. The refinement of disorders with restraints was introduced to help data convergence.27

2.2.2. PXRD Analysis

PXRD experiments were performed using a Rigaku D/MAX-2550 diffractometer with Cu Kα radiation (Rigaku, Tokyo, Japan). Finely pulverized samples were scanned continuously with a coverage of 3–40° at a constant rate of 8°/min. Data were further processed using JADE software (Rigaku). Simulated XPRD patterns were calculated using Mercury software (Version 4.1.0, Cambridge Crystallographic Data Center, UK)28 with a starting angle of 3°, a final angle of 40°, a step size of 0.02°, and a full width at half maximum of 0.15°.

2.2.3. TG Analysis

TG analysis was performed on a DSC/TGA 1 analyzer (Mettler Toledo, Switzerland) and STARe Evaluation software 13.0. Approximately, 10 mg of the sample was added to an alumina crucible and heated at a constant rate of 5 °C/min over the temperature range of 30–500 °C under a nitrogen flux of 50 mL/min.

2.2.4. DSC Analysis

DSC thermograms were recorded with a DSC 1 (Mettler Toledo, Switzerland) and STARe Evaluation software 13.0. Approximately, 5–8 mg of the sample was weighed into an aluminum crucible and heated at a constant rate of 10 °C/min over the temperature range of 30–320 °C under a nitrogen flux of 50 mL/min.

2.3. Stability Test

2.3.1. Stress Test

The stabilities of cocrystal were studied with a ZWS-100 drug stability test chamber (ZENSAN, China) under high temperature (60 ± 1 °C), high humidity (95 ± 5%), and strong illumination (4500 ± 500 lx) tests, following the request of ICH Q1A(R2) guidelines.29 Materials were randomly selected and exposed to high temperature, high humidity, and strong illumination conditions. The storage times were 0, 5, and 10 days. After the indicated storage periods, the materials were assessed immediately by PXRD.

2.3.2. DVS Analysis

DVS was carried out using a Surface Measurement Systems DVS Resolution (SMS, England) at 25 °C. The relative humidity (RH) at 25 °C was calibrated against the deliquescence point of LiCl, Mg(NO3)2, and KCl. The nitrogen flow rate was 200 mL/min. The sample equilibrated at each step with the equilibration criteria of either dm/dt ≤ 0.002% or a maximum equilibration time of 3 h. When one of the criteria was met, the RH was changed to the next target value, following the 0–90–0% sorption and desorption cycle with a step size of 10% RH.

2.4. Solubility Experiment

2.4.1. Equilibrium Solubility Test

The equilibrium solubilities of the cocrystal BBC-FA, BCD, and BCT were determined at 37 °C in pure water. About 1 mmol sample powders were added to 900 mL of water and stirred at 160 rpm. An aliquot of 1 mL was sampled at each time point, and the same volume was replenished with water maintained at 37 °C. Sample concentrations were measured after filtration by reversed-phase HPLC (Agilent, New York, NY, USA) with a C18 column (4.6 × 250 mm, 5.0 μm, Agilent, New York, NY, USA). The mobile phase consisted of phosphate buffer (a mixed solution of 0.05 mol/L potassium dihydrogen phosphate, 0.05 mol/L sodium heptanesulfonate, and 0.5% trimethylamine; the pH was adjusted to 3.0 with phosphoric acid) and acetonitrile (40:60, v/v) with a flow rate of 1.0 mL/min and an injection volume of 10 μL. The PDA detector was set at 345 nm. The sink conditions were maintained during the entire dissolution experiment, and each test was performed in triplicate.

2.4.2. IDR Test

IDR measurements are important during the development of a new chemical entity because it may predict potential bioavailability problems and be useful for characterizing compendial articles such as excipients or drug substances.30 In this work, IDR was measured by the rotating disk method, which was applied to distinguish the dissolution properties of the cocrystal BC-FA, BCD, and BCT. Compacts of 8 mm diameter were prepared by compacting 100.0 mg (the mass was converted to the amount containing BBC) of the above samples using a pressure machine (FU KESI, China) with flat-faced round punches. Disc intrinsic dissolution was performed at 300 rpm in 700.0 mL of distilled water as a dissolution medium at 37 ± 1 °C for 120 min. The BB concentration in solution was measured using an online real-time measurement system FODT-101G (FU KESI, China) at 350 nm. The sink conditions were maintained during the entire dissolution experiment, and each test was performed in triplicate.

2.5. Computational Studies

Interactions between API moieties and coformer moieties were explored with DFT calculations. The M06-2X (GD3) functional was employed for molecular electrostatic potential energy analysis. The TZVP and def2-TZVP basis sets were used for all the hydrogen atom geometry optimizations and single-energy calculations, respectively. The B3LYP (GD3)/6-31G* level was employed for reduced density gradient (RDG) analysis. The Gaussian 16 package was utilized for all calculations.31 The Multiwfn 3.6 program was employed for all wave function analyses.32

3. Results and Discussion

3.1. Characterization

3.1.1. SXRD Analysis

Yellow needle-shaped crystals of BBC-FA suitable for crystal structure determination by SXRD were obtained by slow evaporation. The SXRD results showed that the cocrystal BBC-FA was crystallized in the triclinic space group P1̅ and possessed 2 formula units per unit cell (Z = 2). An asymmetric unit containing API and CCF with the ratio 2:1 emerged for this cocrystal. The crystallographic data for this cocrystal were deposited at CCDC. Table 1 summarizes the crystal parameters, data collection, and refinement details of the cocrystal.

Table 1. Crystallographic Data and Refinement Details for the Cocrystal BBC-FA.
  cocrystal BCC-FA
formula (C20H18NO4Cl)2·C4H4O4
crystal size (mm) 0.09 × 0.23 × 0.29
description needle
crystal system triclinic
space group P1̅
unit cell parameters a = 7.589(3)
  b = 14.368(4)
  c = 18.561(5)
(Å, deg) α = 72.261(10)
  β = 85.40(3)
  γ = 88.99(3)
volume (Å3) 1921.2(11)
Z 2
density (g/cm3) 1.486
theta range for data collection 3.434 <θ < 72.493
independent reflections 6984
reflections with I > 2σ(I) 6200
completeness 93.3
R(I > 2σI) R = 0.0648
  wR2 = 0.1824
goodness-of-fit on F2 1.046
CCDC deposition no. 1,973,683
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The D(10) motif was found in this cocrystal using the Etter and Bernstein’s graph set notation.33,34 The hydroxyl groups of the two carboxylic acid groups in FA formed hydrogen bonds with the chlorine ion of the two BBC molecules (O5···Cl1A: 3.008 and O7···Cl1B: 3.021 Å). The CCF molecule linked two API molecules and this pattern repeated indefinitely. Furthermore, we observed π–π stacking interactions, which helped us construct their 3D unlimited aggregated structures. The hydrogen-bonding scheme and a view of the packing of the structure are shown in Figure 1.

Figure 1.

Figure 1

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Molecular structural formula (i), hydrogen bond schemes, (ii) and packing of cocrystal structures (iii).

3.1.2. PXRD Analysis

PXRD is a powerful and fundamental tool to identify solid states of compounds or complexes by comparing their own characteristic powder patterns. In particular, simulated powder patterns calculated from SXRD data can act as a reference to ascertain the pure phases by comparing them with experimental ones. In this work, the PXRD patterns for API and CCF showed significant differences from that of the cocrystal, thereby indicating the formation of new phases. The simulated pattern of the cocrystal BBC-FA exhibited a good fit with its experimental pattern, which was obtained by suspension agitation (Figure 2i).The patterns of CCF, API, physical mixture, and cocrystal obtained from the experiment and simulations were marked in purple, green, blue, black, and red, respectively. PXRD patterns for different hydrates of BBC were also depicted and indicated that BCD and BCT prepared with experiments were pure phases (Figure 2ii). The simulated powder patterns of BCD and BCT were calculated using the SXRD data from CSD, which were in red and blue, respectively. The corresponding experimental patterns were in black and green.

Figure 2.

Figure 2

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PXRD patterns for the cocrystal BBC-FA (i) and different hydrates of BBC (ii).

3.1.3. TG Analysis

TG analysis was applied to investigate the dehydration process of BBC hydrates and the decomposition process of these hydrates and the cocrystal (Figure 3i). On the basis of the results of TG analysis, the cocrystal BBC-FA did not contain solvent or water. During the dehydration process of hydrates, the start temperatures were almost the same but the end temperature differed. The temperature interval was approximately from 30 to 130 °C. BCD and BCT obtained from the experiments had two molecules and four molecules of water, respectively. The mass loss of water was 9.1 and 15.8%; these values were basically consistent with the theoretical calculation values of 8.8 and 16.2%. During the decomposition process, the temperatures of the starting decomposition of BCD and BCT were 181.40 and 176.33 °C, respectively, whereas that of the cocrystal was 224.07 °C. The cocrystal presented an improvement in thermodynamic stability.

Figure 3.

Figure 3

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TG graphics of the cocrystal and different hydrates of BBC (i) and DSC profiles of the cocrystal and the corresponding API and CCF (ii).

3.1.4. DSC Analysis

The thermal behavior of the cocrystal was assessed by DSC, as shown in Figure 3ii. BBC-FA exhibited a melting endothermic peak at 235.35 °C falling in between the melting endothermic peak of BCD (200.02 °C) and FA (295.33 °C), thereby indicating that the introduction of FA improved the stability of BBC. The cocrystal BBC-FA and BCD melted and at the same time decomposed.

3.2. Stability Test

3.2.1. Stress Testing

Stress testing was carried out in the stability studies to investigate whether the physical state of the cocrystal changes under the designed conditions. No significant trends occurred in all conditions (Figure 4i) and this observation indicated that the formation of the cocrystal improved the stability of BBC in high temperature and humidity. BCD was unstable under both high humidity (95 ± 5%) and temperature (60 ± 1 °C). It would transform to BCT or dehydrate in corresponding conditions (Figure 4ii). BCT was unstable under high temperature (60 ± 1 °C) and transformed to BCD or further dehydrate depending on the duration (Figure 4iii). Thus, BBC could undergo solid-state transformations among anhydrate, dihydrate, and tetrahydrate depending on the RH and temperature.

Figure 4.

Figure 4

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Results of stress testing of the cocrystal BBC-FA (i), BCD (ii), and BCT (iii).

3.2.2. DVS Analysis

DVS can measure how much and how soon water can be absorbed into a sample and be desorbed from a sample. From Figure 5i, the cocrystal BBC-FA presented a low moisture of 0.16% of water at 90% RH, thereby indicating that the cocrystal was nonhygroscopic. The low moisture uptake may only correspond to surface absorption. In Figure 5ii, the desorption curve was close to the absorption curve for the cocrystal, thereby indicating that the absorption and desorption processes were reversible. However, different things happened in hydrates of BBC. BCD and BCT presented a high moisture of 13.36 and 13.81% of water at 90% RH, respectively, which indicated that both were hygroscopic. Similar desorption and absorption curves showed the transformation of different hydrates and implied that more hydrates formed during this process.

Figure 5.

Figure 5

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DVS change in mass plot (i) and DVS isotherm plots (ii) for the cocrystal BBC-FA, BCD, and BCT at 25 °C.

3.3. Solubility Experiment

3.3.1. Equilibrium Solubility Test

The equilibrium solubility of the cocrystal BC-FA was slightly better than that of BCD and much better than that of BCT. Although the equilibrium solubility difference between BCD and the cocrystal was not significant, the dissolution rate of the cocrystal was obviously enhanced. The solution equilibrium was reached within 15 min for the cocrystal, whereas the BCD and BCT needed about 2 h (Figure 6i). Thus, BBC could directly form a cocrystal with CCF with good solubility to improve the solubility or dissolution rate.

Figure 6.

Figure 6

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Results of equilibrium solubility (i) and IDR test (ii).

3.3.2. IDR Test

As an important physicochemical parameter to a certain extent, IDR can reflect in vivo dissolution and bioavailability of drugs and provide necessary reference for the research of preparation technology. In this work, BCD and BCT held on IDR of 0.3258 and 0.3214 mg·cm–2·min–1, respectively, as reference materials. However, IDR of the cocrystal BBC-FA significantly increased to 1.0397 mg·cm–2·min–1 and it was about three-fold more than that of the reference materials. These findings indicated that the cocrystal BBC-FA had predictable good in vivo absorption than BCD and BCT, which are used in clinical settings.

3.4. Theoretical Calculation

The Hirshfeld surface (HS) can visualize the hydrogen-bond contacts and show the area highlighted with bright-red spots.35,36Figure 7 shows the HS mapped with dnorm, 2D fingerprint plots, and percentage contributions to the HS area, where (i) is for BBC in the cocrystal and (ii) is for FA in the cocrystal. The HS showed that O–H···Cl hydrogen-bonding contacts occurred between FA and BBC. In the 2D fingerprint plots, the lower longest spike (de < di) in Figure 7i indicated that the chloride ion acted as the hydrogen bond acceptor and the longest upper spike (de > di) in Figure 7ii indicated that FA functioned as the hydrogen bond donor. Percentage contributions to the HS area for the various close intermolecular contacts for molecules in the cocrystal are given using pie charts.

Figure 7.

Figure 7

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Hirshfeld surface (mapped with dnorm) and fingerprint plots for (i) API and (ii) CCF.

After computation, the global maxima values of the ESP on the surface in FA were +59.78 and +59.35 kcal/mol, which corresponded to hydroxyl groups. The local maxima values were +16.50 kcal/mol. The global minima values of the ESP on the surface were −31.01 and −31.56 kcal/mol, which corresponded to carbonyl groups. In BBC, the global and secondary maxima values of the ESP on the surface were +52.65 and +41.14 kcal/mol, respectively. The global and secondary minima values were −79.99 and −42.10 kcal/mol, which corresponded to the chloride-ion region and 1,3-dioxolan region, respectively. The electrostatic potential surface of different molecules in the cocrystal BBC-FA is depicted in Figure 8i. On the basis of the hierarchical organization of the functional group interaction theory,37,38 the main site of interaction in the cocrystal should first occur pairwise in the minima and maxima of the ESP on the surface, followed by the secondary ones. The dominating site of interaction formed in the real cocrystal by this rule, that is, the O–H···Cl hydrogen-bonding contacts occurred. The plane of FA rotated to make the regions apart because of repulsion between the global minima site in FA and the secondary minima site in BBC. Furthermore, this operation made the local maxima site in the carboxyl group in FA come into contact with the secondary minima site in BBC (Figure 8ii).

Figure 8.

Figure 8

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Electrostatic potential surface of different molecules in the cocrystal (i) and interaction sites occurred pairwise in the minima and maxima of the EPS on the surface of the cocrystal BBC-FA (ii).

RDG is a way of visually understanding noncovalent interactions and a powerful tool to reveal noncovalent interactions, such as hydrogen bonding and electrostatic and van der Waals interactions.39 In this work, RDG was used to analyze the hydrogen bonds and π–π interactions in the cocrystal BBC-FA, BCD, and BCT. According to the RDG theory, a scatter diagram of sign (λ2) ρ versus RDG was drawn, from which the location, strength, and type of weak interactions were revealed. In Figure 9, red fusiform regions were present in each ring of the BB structure and reflected a strong steric effect, corresponding to a spike between +0.01 and +0.03 on the right of the scatter diagram. The existence of aromatic rings suggested a possible π–π stacking interaction. The RDG contour surface between the hydroxide radical and chloride ion in blue and red suggested H-bond and steric hindrance, corresponding to the left-most and right-most spikes, respectively. In the interior of the BB molecule and between BB and FA, some RDG contour surfaces were observed with colors ranging from light green to earthy yellow, representing the existence of van de Waal forces and corresponding to a spike between −0.015 and +0.01.

Figure 9.

Figure 9

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RDG analysis of the cocrystal BBC-FA.

BCD and BCT structures were extracted to further study the π–π stacking interactions between BB molecules and the minimal repeating stacking units of BB molecules in the cocrystal BBC-FA. π–π stacking interactions are important noncovalent intermolecular forces similar to hydrogen bonding. The general criteria for identifying π–π stacking interactions are as follows: the centroid–centroid distance is between 3.3 and 3.8 Å and the dihedral angle of aromatic rings is less than 20.40−42 π–π stacking interactions of the offset face-to-face type were noted in the cocrystal, BCD, and BCT on the basis of the calculations from the SXRD data. However, some differences were present among them. According to the criteria, π–π stacking interactions always exist between two BBC molecules in the cocrystal and BCT. However, π–π stacking interactions in BCD were not continuous but on an interval (Figure 10ii) because the centroid–centroid distance exceeded 3.8 Å (4.026 Å, marked in blue). This case is thought to still belong to π–π stacking interactions but a weak one.

Figure 10.

Figure 10

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π–π stacking interactions of (i) BBC-FA, (ii) BCD, and (ii) BCT.

4. Conclusions

BB has a variety of biological activities. However, its poor solubility and low bio-availability limit its further development for clinical application. The cocrystal of BBC with FA was discovered for the first time in this work. Structural analysis showed that the cocrystal was composed of a stoichiometric ratio of 1:2 amounts of FA and BBC. One molecule of FA through the O–H···Cl hydrogen bond linked two molecules of BBC, and π–π stacking interactions were noted between the BB molecules to link them. The combination of both interactions dominated the unlimited aggregated 3D structure of the cocrystals in space. The solubility of the cocrystal BBC-FA was greatly improved in comparison with that of BCD and BCT through equilibrium solubility and IDR tests. Furthermore, the stability of the cocrystal in high humidity or high temperature was enhanced as evidenced by the stress test, DVS test, and thermal analysis. Thus, this cocrystal, as an advantageous solid state, provides the material basis for the further development of this drug.

Acknowledgments

The authors acknowledge the National Key Research and Development Plan (grant 2016YFC1000905), the Drug Innovation Major Project (grant 2018ZX09711001-001-015), and the CAMS Innovation Fund for Medical Sciences (grant 2016-I2M-3-007) for financing this work.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c00692.

  • The cif file (CCDC code 1973683) contains the supplementary crystallographic data for this paper. These data can also be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033 (CIF)

Author Contributions

§ D.Y. and J.C. made equal contributions to this work.

The authors declare no competing financial interest.

Supplementary Material

ao0c00692_si_001.cif (2.7MB, cif)

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