Cocrystals of Natural Products: Improving the Dissolution Performance

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Cite This: Cryst. Growth Des. 2019, 19, 3851−3859

Cocrystals of Natural Products: Improving the Dissolution Performance of Flavonoids Using Betaine Zhijie Zhang,†,‡ Duanxiu Li,† Chun Luo,† Chunxiang Huang,§ Ruchen Qiu,‡ Zongwu Deng,† and Hailu Zhang*,† †

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Laboratory of Magnetic Resonance Spectroscopy and Imaging, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, P. R. China ‡ School of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, P.R. China § Crystal Pharmaceutical (Suzhou) Co., Ltd., Suzhou Industrial Park, Suzhou 215123, P. R. China S Supporting Information *

ABSTRACT: Flavonoids are a class of important natural chemicals that can be isolated from a wide range of plants. Flavonoids exhibit diverse pharmacological activities, although most of them are slightly soluble or insoluble in water, resulting in low bioavailability after oral administration. To improve the dissolution performance of these compounds, we selected a natural sweetener, betaine (BTN), to form cocrystals with flavonoids. In this study, cocrystallization trials between BTN and three flavonoid compounds, baicalein (BAI), phloretin (PHL), and quercetin (QUE), were successfully performed. These three newly obtained cocrystals were characterized by a range of analytical methods. All cocrystal forms exhibit improved equilibrium solubilities relative to their parent compounds. The compounds used in this investigation belong to flavone, dihydrochalcone, and flavonol subclasses of flavonoids, respectively. Such results indicate BTN might show potential as a promising coformer to form performance-enhancing cocrystals with flavonoids.

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INTRODUCTION Flavonoids are a class of natural products that are abundant in nature and have a variety of biological activities.1−5 All flavonoids possess a general structure of a 15-carbon skeleton (Scheme 1a), containing two phenyl rings (A and B) and a 3carbon chain (C). Flavonoids can be divided into different subclasses based on the degree of oxidation and whether a ring structure is formed for the 3-carbon moiety (C), as well as the conjunction position (e.g., C2 or C3 position on the 3-carbon moiety) of the B ring. The basic molecular structures of flavanone (Scheme 1c), flavone (Scheme 1e), dihydrochalcone (Scheme 1g), and flavonol (Scheme 1i) compounds are shown in Scheme 1. Although the positive protective effects against various diseases have been confirmed by animal experiments and clinical evidence,4−10 the low solubility and the resulting unfavorable bioavailability of flavonoids severely limit their application as active pharmaceutical ingredients (APIs) or health-promoting supplements. Various solubilization approaches have been used to solve the solubility issue of flavonoids. Some of these approaches include particle size reduction or amorphization.11−19 However, such thermodynamically metastable species often require large amounts of surfactants or polymers as stabilizers. The formation of crystalline salts is another traditional solubiliza© 2019 American Chemical Society

tion pathway for APIs. Unfortunately, the weakly acidic phenolic hydroxyl groups inherent to many flavonoid molecules are not easy to deprotonate. Because of this fact, few pharmaceutical salts of flavonoids have been reported in the literature.20−24 Cocrystals, another kind of multicomponent crystalline complex, can also modulate various physicochemical properties, including solubility, of APIs in a rationally designed way. A pharmaceutical cocrystal consists of the API and cocrystal former (coformer) in a definite stoichiometric ratio held together via noncovalent interactions. This solid form provides important opportunities to improve the performance of weakly ionizable and nonionizable APIs. For flavonoids, our preliminary literature survey shows that dozens of cocrystals have been reported (Table S1) and improved properties can be obtained. The often employed coformers include nicotinamide, isonicotinamide, proline, caffeine, and pyridine analogues.25−36 In fact, these coformers are also the ones mostly used for other APIs. New popular and promising coformers for flavonoids are yet to be discovered. Received: March 7, 2019 Revised: May 29, 2019 Published: June 7, 2019 3851

DOI: 10.1021/acs.cgd.9b00294 Cryst. Growth Des. 2019, 19, 3851−3859

Crystal Growth & Design

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Scheme 1. Chemical Structures of (a) Flavane Nucleus, (b) Betaine, (c) Flavanones, (d) Naringenin, (e) Flavones, (f) Baicalein, (g) Chalcones, (h) Phloretin, (i) Flavonols, and (j) Quercetin

Single-crystal sample of cocrystal cannot be obtained using 1:1 starting ratio due to the obviously different solubility (leading to an incongruently saturating system) of BAI and BTN in the solvent. Powder samples of BAI-BTN can be obtained by using the liquidassisted grinding method: 81.1 mg (0.3 mmol) of BAI and 35.1 mg (0.3 mmol) of BTN were combined along with 35 μL of methanol in a 10 mL stainless steel jar with one 15 mm stainless steel grinding ball. The sample was ground for 20 min at a frequency of 40 Hz using a Pulverisette 23 (Fritsch, Germany) ball mill. The resulting solid was dried overnight at 40 °C. Preparation of the 1:1 PHL-BTN Cocrystal. PHL (27.4 mg, 0.1 mmol) and BTN (23.4 mg, 0.2 mmol) were dissolved in 0.5 mL of methanol. The solution was collected by filtration in a 25 mL glass vial and 9.5 mL of dichloromethane was added as antisolvent. The resulting solution was left for evaporation at room temperature. Colorless block-shaped crystals of PHL-BTN were harvested after 24 h. Single-crystal sample of this cocrystal also cannot be obtained using 1:1 starting ratio. Bulk samples of PHL-BTN can be obtained by using the liquidassisted grinding method. 82.3 mg (0.3 mmol) of PHL and 35.1 mg (0.3 mmol) of BTN were cogrinded in a 10 mL stainless steel jar with the assistance of 46 μL of methanol. One 15 mm stainless steel grinding ball was used and sample was ground at 40 Hz for 20 min. The resulting solid was dried at 40 °C overnight. Preparation of the 1:2 QUE-BTN Cocrystal. Sixteen and ninetenths milligrams of QUE·2H2O (0.05 mmol) and 11.7 mg (0.1 mmol) of BTN were dissolved in 7.5 mL of ethanol/ethyl acetate (1:4, v/v) mixture. The solution was filtered through a 0.22 μm PTFE filter and left to slowly evaporate at room temperature. Yellow blockshaped crystals of QUE-BTN were obtained after 7 days. Powder samples of QUE-BTN can be harvested through the slurry method. The mixture of QUE·2H2O (67.6 mg, 0.2 mmol) and BTN (46.8 mg, 0.4 mmol) was suspended in 2 mL of methanol-ethyl acetate(v/v, 1:4) solvent and stirred for 3 days. The resulting solids were isolated by centrifugation and allowed to dry at 40 °C overnight. 2.3. Single-Crystal X-ray Diffraction (Single-Crystal XRD). The single-crystal XRD data of BAI-BTN and QUE-BTN were collected on a Bruker APEX-II CCD diffractometer at 296 K with a Mo−Kα (λ=0.71073 Å) radiation. The data for PHL-BTN was obtained on an Agilent Xcalibur Atlas Gemini diffractometer with Cu−Kα (λ=1.54184 Å) radiation at 213 K. All crystal structures were solved by direct methods and refined on F2 by full-matrix least-squares using SHELXL-2017.46 All non-hydrogen atoms were refined with

Recently, we obtained cocrystals of naringenin (NAR, Scheme 1d) with betaine (BTN, Scheme 1b).33 BTN is known as trimethylglycine. It is a natural sweetener that is widely distributed in microorganisms, plants, and animals, and is currently used as dietary supplement, food sweetener, as well as cosmetic humectant. This compound also has significant physiological functions in human organisms, such as preventing and treating many chronic diseases.37−41 Using BTN as a coformer can not only modify physicochemical properties of APIs, but also provide pleasant taste and positive health benefits to patients. Such a promising coformer42 is not currently prominent in the field of crystal engineering. Only five pharmaceutical cocrystals of BTN have thus far been reported.33,42−44 Carboxylate should be the main hydrogen bonding interaction group in BTN. Since a robust hydroxyl··· carboxylate intermolecular interaction (supramolecular synthon)28,44,45 was observed in NAR-BTN cocrystals, we want to know whether this small molecule can also form cocrystals with other (other types of) hydroxyl-rich flavonoids. NAR is a flavanone compound. In this contribution, cocrystallization trials between BTN and another three flavonoid compounds, baicalein (BAI, Scheme 1f), phloretin (PHL, Scheme 1h), and quercetin (QUE, Scheme 1j) were performed. These three flavonoid compounds belong to flavone, dihydrochalcone, and flavonol subclasses of flavonoids, respectively.

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EXPERIMENTAL SECTION

Materials. BAI (≥98%), PHL (≥97%), and BTN (≥99%) were purchased from Dalian Meilun Biotechnology Co., Ltd. QUE dihydrate (QUE·2H2O, ≥ 98.7%) was purchased from Aladdin LLC. All analytical-grade solvents were obtained from Sinopharm Chemical Reagent Co., Ltd. Preparation. Preparation of the 1:1 BAI-BTN Cocrystal. BAI (27.0 mg, 0.1 mmol) and BTN (23.4 mg, 0.2 mmol) were dissolved in 10 mL of mixed solvent of methanol and ethyl acetate (1:9, v/v). The solution was filtered through a 0.22 μm PTFE filter and allowed to slowly evaporate at room temperature. Yellow block crystals of the BAI-BTN cocrystal in 1:1 stoichiometry were obtained after 3 days. 3852



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anisotropic thermal parameters. Hydrogen atoms associated with carbon atoms were placed in geometrically calculated positions, and position of O bonded hydrogen atoms were located from difference electron density maps. Crystallographic data for cocrystals are summarized in Table 1 and hydrogen-bond parameters are listed in Table S2.

at 276, 289, and 360 nm for BAI, PHL, and QUE, respectively. A mixture of acetonitrile/water (50:50, v/v) was used as the mobile phase with a flow rate of 1 mL·min−1 at 37 °C. Dissolution Experiment. Sieved samples with particle size ranges of 75−125 μm were used in powder dissolution experiments. 100 mg (or corresponding to for cocrystals) of powdered flavonoids were added to dissolution vessels containing 40 mL phosphate buffer (pH 6.8, simulated intestinal condition) at 37 ± 0.2 °C. For BAI (and BAIBTN), 0.5% Tween 80 was added to the buffer to improve the wettability of BAI. The dissolution studies were conducted with a rotation speed of 350 rpm (magnetic stirring). One-half a milliliter of solution was withdrawn at the predetermined time points to measure the concentration value by HPLC after filtration through 0.22 μm MCE filter. Each dissolution test was performed in duplicate. The apparent solubility values of flavonoids and cocrystals were measured using a shake-flask method using similar parameters to the powder dissolution experiments. After 72 h, 1 mL of each sample was filtered through 0.22 μm MCE filter for concentration measurement. Each solubility test was performed in triplicate. The residual solids after solubility tests were measured by powder XRD to check the possible phase changes. Dynamic Vapor Sorption (DVS). DVS experiments were conducted using an intrinsic dynamic gravimetric water sorption analyzer (SMS Ltd., UK) at 25 °C. About 25 mg of each cocrystal sample was placed in a quartz sample holder and studied over relative humidity (RH) range from 0% to 95% with a step size of 5%. The equilibration criterion for each humidity step is either dm/dt ≤0.002 min−1 or a maximum hold time of 3 h. Moisture Stability. Moisture stability of cocrystals was tested under 60, 75, 85, and 95% RH conditions at 25 °C for 7 days. The resulting solids were measured by powder XRD measurements to monitor possible phase transformation.

Table 1. Crystallographic Data and Details of Refinement for the Cocrystals name formula formula weight T (K) cryst syst space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z Dcalcd (g cm−3) total no. of reflns unique no. of reflns Rint no. of observations no. of parametersΔρmax/ Δρmin (e Å−3) F(000) GOF R1[I > 2σ(I)] wR2 (all data) CCDC

BAI-BTN

PHL-BTN

QUE-BTN

C20H21NO7 387.38 296(2) monoclinic P21/c 17.4249(14) 8.7329(8) 12.2482(10) 90 94.153(3) 90 1858.9(3) 4 1.384 36 155 42 660.0901

C20H25NO7 391.41 213(2) orthorhombic Pbca 9.0233(9) 17.4574(13) 25.0837(18) 90 90 90 3951.3(6) 8 1.316 28 417 40 380.1120

C25H32N2O11 536.52 296(2) monoclinic P21/c 9.4180(11) 18.705(2) 14.4714(16) 90 94.962(4) 90 2539.8(5) 4 1.403 23 673 45 960.0721

2660 2680.220/0.258 816.0 1.027 0.0544 0.1245 1900681

2171 2690.208/0.232 1664.0 0.995 0.0629 0.1785 1900682

3286 3630.207/0.240 1136 1.024 0.0482 0.1109 1900683

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RESULTS AND DISCUSSION Crystal Structure Analysis. BAI-BTN. BAI-BTN crystallizes in the P21/c space group of the monoclinic system. Each unit cell contains four asymmetric units (Z = 4) and each asymmetric unit contains one molecule each of BAI and BTN (Z’ = 1, Figure 1a). BAI has three − OH groups (Scheme 1f), among them − O3H forming an intramolecular hydrogen bond with the adjacent O2 site (2.562 Å, Figure 1a). The other − OH groups in different BAI molecules are connected by O7 of BTN via O4−H4···O7 (2.638 Å) and O5−H5···O7 (2.5494 Å) hydrogen bonds (Figure 1a, b), forming a 1D molecular chain infinitely extended along the c axis (Figure 1b). The other carboxylate O atom (O6) of BTN does not interact with any proton donor group in this structure. Along the c axis, each molecular chain is packed as two-armed hanging rings (Figure 1c). And upright and inverted rings are further arranged alternately along the b axis (Figure 1c, d, Figure S1), forming a 3D layered module. The whole crystal structure of BAI-BTN is then constructed by the regular stacking of the 3D modules along the a axis (Figure S1). PHL-BTN. The crystal structure of PHL-BTN has the symmetry of space group Pbca, and each asymmetric unit contains one PHL and one BTN (Z′ = 1). Similar to the BAIBTN structure, an intramolecular hydrogen bond between O2H and O1 of PHL is also present in the structure (2.469 Å, Figure 2a). The difference, however, is that both of the carboxylate O atoms (O6 and O7) of BTN are involved in intermolecular hydrogen bonding interactions. PHL and BTN are connected into a zigzag molecular chain via O5−H5···O6 (2.659 Å) and O3−H3···O7 (2.654 Å) along the crystallographic b axis (Figure 2a). Along the c axis, different molecular chains are connected via O4−H4···O7 (2.639 Å, Figure 2a), forming a corrugated 3D structure (Figure 2b). Such 3D

Powder XRD. Powder XRD measurements were conducted using a Bruker D8 Advance X-ray diffractometer equipped with a LynxEye detector. The diffractometer was operated using Cu−Kα radiation, and the voltage and current of the generator were set to 40 kV and 40 mA, respectively. The data was recorded over the 2θ range from 3 to 40° with a scanning step size of 0.0194°. Solid State Nuclear Magnetic Resonance (solid state NMR). All solid state 13C NMR spectra were collected using a Bruker AVANCE III-500 WB spectrometer equipped with a 4 mm double resonance MAS probe. To avoid the interference of the spinning sidebands on the signals, a total sideband suppression (TOSS) frame was embedded into the conventional cross-polarization (CP/MAS) pulse sequence. For PHL, 13C CP/MAS spectrum was also collected to identify some weak signals on the corresponding CP/MAS TOSS spectrum caused by the fast transverse relaxation effect. All spectra were collected with a MAS spinning frequency of 8 kHz and a contact time of 2.0 ms. Recycle delay times for BAI, PHL, QUE·2H2O, BTN, BAI-BTN, PHL-BTN, and QUE-BTN were 60, 60, 15, 8, 8, 8, and 8 s, respectively. The reported chemical shifts were externally referenced to tetramethylsilane. Differential Scanning Calorimetry (DSC). DSC experiments were performed using a DSC Discovery250 system (TA Instruments). Samples weighing 3−5 mg were heated in a hermetically sealed aluminum pan from 25 °C at a heating rate of 10 °C min−1 under a nitrogen gas flow of 50 mL min−1 until the sample melting/ decomposition was observed. High Performance Liquid Chromatography (HPLC) Analysis. The concentration values of flavonoids were analyzed using Waters 2535 HPLC system with a C18 HPLC column (GraceSmart RP C18, 4.6 mm × 250 mm, 5 μm) and a photodiode array detector 3853



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Figure 1. Crystal structure of BAI-BTN. (a) Asymmetric unit. (b) Intermolecular hydrogen bonding interactions and the 1D chain structure. (c, d) Molecular packing representation of two adjacent chain structures viewed along the c axis and b axis, respectively. In b−d, H atoms not involved in hydrogen-bonding interactions are omitted for clarity.

modules extend along the a axis via O4−H4···O7 interactions to form the whole packing arrangement (Figure S2). QUE-BTN. The crystal structure was solved and refined using monoclinic P21/c space group with one QUE and two BTN in each crystallographic asymmetric unit (Z′ = 1, Figure 3a). These two nonequivalent BTN molecules provide one and two carboxylate O atoms as proton acceptors, forming O6−H6··· O9 (2.595 Å), O7−H7···O9 (2.682 Å), O5−H5···O8A (2.602 Å), and O2−H2···O9A (2.631 Å) interactions, respectively (Figure 3a, b). The O9 atom of one BTN is bifurcated, which is not seen in the other two structures. This interaction mode also leads to a short intramolecular (O6)H6···H7(O7) distance (1.94 Å). Two asymmetric units form an R44(24) dimeric structure through two O2−H2···O9A (2.631 Å) hydrogen bonds (Figure 3b). The dimeric units are arranged in a parallel and head-to-tail staggered distribution, forming the layered structure in the ac-plane (Figure 3c). No hydrogen bonding interaction is observed among these dimer blocks. The layered structures and the reverse ones are further packed alternately along the b axis, forming the 3D arrangement of this crystal structure (Figure 3d). These three crystal structures reveal and confirm that all cocrystals share the robust hydroxyl···carboxylate supramolecular synthon. Although the same synthon was observed and the flavonoid compounds used in this study possess similar molecular structure, three cocrystals exhibit different packing arrangements. In cocrystals, hydroxyl groups of flavonoid compounds are all involved in intramolecular or intermolecular hydrogen bonding interactions. For BTN, the carboxylate

group may provide either one or two O sites as proton acceptors. Powder XRD and Thermal Analysis. Powder XRD patterns of these three cocrystal samples and all starting materials were collected. Each characteristic pattern of cocrystal sample is different from those of either BTN or the corresponding flavonoid compound and is in line with the simulated one derived from the solved structure (Figure 4), confirming the successful preparations of the pure and distinct powder cocrystal products. The DSC curves of all cocrystal samples and their individual compounds are present in Figure 5. QUE·2H2O gives one broad endothermic peak at 131.9 °C, which corresponds to the release of the lattice water.47 No dehydration or desolvation signal was detected for other samples. The melting points (Tms) of BAI, PHL, QUE, and BTN are 269.2, 270.6, 322.9, and 307.1 °C, respectively. Tm values of BAI-BTN, PHL-BTN, and QUE-BTN are 203.1, 185.9, and 221.5 °C, respectively. Though the Tm of each cocrystal is lower than that of either corresponding flavonoid compound or coformer BTN, the relatively high values can ensure their thermodynamic stability. Solid -State 13C NMR. Solid-state NMR is another commonly used method for the characterization of solid pharmaceuticals. The 13C CP/MAS TOSS NMR spectra of three cocrystals and their starting materials are show in Figure 6. The chemical shift assignments for BTN, BAI, and QUE· 2H2O can be found in ref 33 48, and 49, respectively. Signals of PHL were assigned experientially. For this compound, some C atoms on the B ring only give very weak resonance peaks on 3854



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the CP/MAS TOSS spectrum, which should originate from their fast transverse relaxation. These signals are enhanced in the CP/MAS spectrum (Figure 6) because of the reduction in the time interval between CP and signal acquisition. Relative to the starting materials, each cocrystal sample demonstrates slightly altered 13C signals due to the changes of chemical environments, confirming the formation of new crystalline form. Relative to BTN, C11 in each cocrystal sample displays insignificant position change on the NMR spectra. Since the carboxylate group is the strongest proton acceptor in BTN, such result indicates in each cocrystal sample no proton is completely transferred from flavonoid compound to the carboxylate group of BTN, i.e., cocrystals rather than salts were obtained. Powder Dissolution and Equilibrium Solubility. Solubility is a very important parameter for pharmaceutical development, because low solubility often results in low in vivo bioavailability. Since cocrystal formation is widely used for solubilization,50,51 improved solubility is also desired for the current three cocrystals of flavonoids. The dissolution tests were performed in phosphate buffer (pH 6.8) at 37 °C. The powder dissolution profiles and equilibrium solubility values of BAI, PHL, QUE·2H2O, and three cocrystals are shown in Figure 7/Figure S4 and Figure 8, respectively. All samples except QUE·2H2O (undetectable) can achieve their maximum apparent solubilities very quickly (Figure 7). For BAI or PHL, concentration can be maintained stably after the initial fast release. For all cocrystal samples, the rapid concentration decreases (“spring” effect) can be observed, which can be attributed to the formation of less soluble solids of corresponding flavonoids (Figure S5). After the concentration

Figure 2. Crystal structure of PHL-BTN. (a) PHL-BTN molecular chains. Three adjacent chains are shown in different colors. (b) Molecular chains in a viewed along the c axis.

Figure 3. Crystal structure of QUE-BTN. (a) The asymmetric unit. (b) Two asymmetric units formed R44(24) dimeric structure. (c) 2D layered structure in the ac plane. Each dimeric structure in c is displayed in a different color. (d) 3D packing structure viewed along the c axis. In d, adjacent molecular layers are displayed in different colors. 3855



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Figure 5. DSC curves of BAI-BTN, PHL-BTN, QUE-BTN, and their starting materials.

Figure 6. 13C CP/MAS TOSS NMR spectra of BAI-BTN, PHL-BTN, QUE-BTN, and their starting materials. 13C CP/MAS NMR spectrum (138−108 ppm) of PHL is also provided as inset. The full assignments of these spectra can be found in Figure S3.

Figure 4. Experimental and simulated powder XRD patterns of (a) BAI-BTN, (b) PHL-BTN, (c) QUE-BTN, and their starting materials. The 2θ values of the main XRD peaks are summarized in Table S3.

decreases, the supersaturation of flavonoids can remain unchanged even after 72 h (Figure S4 and Figure 8). Such “hover” phenomenon of supersaturated flavonoids may be ascribed to the complexation of flavonoids with BTN in the solutions.52,53 After 72 h, the equilibrium solubilities of these three cocrystals are increased by 1.73, 1.59, and 3.67 times, respectively. Hygroscopicity and Moisture Stability. Anhydrous BTN is a hygroscopic substance and easily converts to the monohydrate form even at very low RH conditions (>12%).54 Thus, it is necessary to know whether the cocrystals are also sensitive to the moisture. The vapor sorption isotherms of cocrystals are shown in Figure 9. BAI-BTN is nonhygroscopic

Figure 7. Powder dissolution profiles of flavonoids and cocrystals in phosphate buffer at 37 °C within 6 h. Concentration values of QUE are undetectable during the dissolution process of QUE·2H2O.

when the RH is below 70%. Above this critical humidity, the mass of absorbed moisture by this sample is significantly increased. For PHL-BTN and QUE-BTN, the critical RHs are 90 and 80%, respectively. 3856



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compounds are involved in intramolecular or intermolecular hydrogen-bonding interactions, whereas for BTN, carboxylate group may provide either one or two O sites as proton acceptors. Compared with the pure form of flavonoids, all cocrystals exhibit improved apparent solubilities. Additionally, though BTN is very sensitive to the moisture even under very low RH conditions, three flavonoid-BTN cocrystals demonstrated enhanced physical stability under middle-high (70%− 85%) RH conditions. BTN cocrystals with four different subclasses of flavonoids have been obtained in this (flavone, dihydrochalcone, and flavonol) and our previous (flavanone) study, indicating that BTN may be a promising coformer to form cocrystals with this kind of natural product.

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Figure 8. Equilibrium solubilities of flavonoids and cocrystals in phosphate buffer at 37 °C.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.9b00294. Experimental and simulated powder XRD patterns of the cocrystals, powder XRD patterns of the residual solids, and preliminary literature survey for the cocrystals of flavonoid compounds (PDF) Accession Codes

CCDC 1900681−1900683 contain 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.

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Figure 9. Vapor sorption isotherms of cocrystals at 25 °C.

Moisture absorption on samples may cause deliquescence or phase transition. To choose the suitable storage conditions, the physical stability of cocrystals were examined under different RH conditions for 1 week. As shown in Table 2, BAI-BTN,

Corresponding Author

*E-mail: [email protected]. Tel: +86-512-62872713. Fax: +86-512-62603079. ORCID

Zongwu Deng: 0000-0002-9564-3740 Hailu Zhang: 0000-0001-6936-9197

Table 2. Physical Stability of Cocrystals under Different RH Conditions at 25 °Ca 60%

75%

85%

95%

√ √ √

√ √ √

× √ ×

× × *

Notes

The authors declare no competing financial interest.

a

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PHL-BTN, and QUE-BTN may keep their crystal phases under RH less than 75, 85, and 75%, respectively. Phase transformation or deliquescence will occur if the samples are exposed to higher humidity. According to the hygroscopicity and moisture stability results, these three cocrystals should be stored in an environment with RH below 70% (BAI-BTN), 85% (PHL-BTN), and 75% (QUE-BTN), respectively.

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BAI-BTN PHL-BTN QUE-BTN

AUTHOR INFORMATION

ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21874148), the Youth Innovation Promotion Association of CAS (2012242), and the China Postdoctoral Science Foundation and the CAS jointly funded outstanding postdoctoral project (2017LH045). H.L.Z. also thanks Dr. Robert M. Wenslow and Prof. Hong Wang for revising the manuscript.

√, stable; ×, transformed into raw materials; *, deliquescence.

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REFERENCES

(1) Pietta, P. G. Flavonoids as Antioxidants. J. Nat. Prod. 2000, 63, 1035−1042. (2) Verma, A. K.; Pratap, R. The Biological Potential of Flavones. Nat. Prod. Rep. 2010, 27, 1571−1593. (3) Š kerget, M.; Kotnik, P.; Hadolin, M.; Hraš, A. R.; Simonič, M.; Knez, Ž . Phenols, Proanthocyanidins, Flavones and Flavonols in Some Plant Materials and Their Antioxidant Activities. Food Chem. 2005, 89, 191−198. (4) Raffa, D.; Maggio, B.; Raimondi, M. V.; Plescia, F.; Daidone, G. Recent Discoveries of Anticancer Flavonoids. Eur. J. Med. Chem. 2017, 142, 213−228.

CONCLUSIONS The usage of BTN, a natural sweetener, as pharmaceutical coformer was explored in this contribution. Three new cocrystals of BTN with flavonoid compounds, BAI-BTN, PHL-BTN, and QUE-BTN were successfully synthesized and characterized. The crystal structures reveal and confirm that all cocrystals share a typical hydroxyl···carboxylate supramolecular synthon. In cocrystals, all hydroxyl groups of flavonoid 3857



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Cocrystals of Natural Products: Improving the Dissolution Performance

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