Wen Yu*, Yiyang Bo, Yiling Luo, Xiyan Huang, Rixiang Zhang, Jiaheng Zhang*

Research Centre of Printed Flexible Electronics, School of Materials Science and Engineering, Harbin Institute of Technology, Shenzhen 518055, China

Keywords:

ABSTRACT

1. Introduction

Curcumin (CUR) is a polyphenol extracted from the turmeric rhizome of Zingiberaceae plants.It has significant biological activities that beneficial for the treatment of various diseases, particularly anti-inflammatory and antioxidant properties [1]. Moreover,preclinical and clinical curcumin therapeutic activities have shown limited adverse effects,even for high doses[2].Despite its multiple pharmacological activities, the practical applications of curcumin are hindered by its low aqueous solubility(11 ng?ml-1),instability,poor bioavailability (0.05 μg?ml-1, less than 1%), and photodegradation[3–5],which need to be overcome to improve the utilization of CUR in practical applications. Among the multiple strategies to overcome the solubility issues, addition of additives is simple and frequently used in pharmaceutical industry. However, the reported additives, such as surfactants [6,7], cyclodextrin [8], and polymers [9] (gelatin, whey-protein, etc.), offer good efficacy but require complex synthesis process or use organic compounds,lead to high cost or present a risk to human health at some doses [4].Therefore, extensive pharmaceutical research has been oriented to CUR aqueous solubility enhancement using relatively safe and environmentally friendly solvents. In this context, deep eutectic solvents (DESs) are excellent candidates for green chemistry and processing owing to their high solubilization capacity, simple preparation, tunable properties, and reusability [10,11].

DESs are obtained by mixing hydrogen bond acceptors (HBA)and hydrogen bond donors (HBD), with a melting point much lower than any of the pure component. Owing to the low vapor pressure, cost-efficient synthesis, negligible toxicity profiles, and environmental benign, DESs are promising solvents for extraction,dissolution, and functional materials [12–15]. Previous investigation showed that the DESs would undergo volatility at high temperature and/or vacuum pressure, and they might toxic, nonbiocompatible,and flammable[16].For the pharmaceutical industrial application of DESs, choosing cheap,biocompatible and natural raw materials are effective strategies to tune the properties of DESs, increase the greenness, and reduce the cost. Particularly,choline chloride (ChCl) is one of the most widely used HBA for preparation of DESs for several applications owing to its high wide availability, low toxicity, and biocompatibility [17–19]. Polyols[18,19], such as ethylene glycol (EG), 1,2-propandiol (1,2-PDO),1,3-propandiol (1,3-PDO) and glycerol (G), are used as hydrogen bond donor (HBD) due to their wide availability as well as their renewable, low toxic and biodegradable nature. DESs comprising of ChCl and glycerol (molar ratio 1:1) allow CUR dissolution(7.25 mg?g-1turmeric powder at 293.15 K) and prevention from photodegradation [15]. Nevertheless, DES inherent high viscosity hampers the extraction and dissolution process. Water addition causes a DES viscosity decrease, which is beneficial to the mass transfer of drugs to solution. Furthermore, the solubility of solute in DESs can be tuned by adjusting water content [20]. DESs increase the aqueous solubility of several water-insoluble drugs,such as acetaminophen [21], mesalazine [22], naproxen [23],paracetamol [24], and cefixime trihydrate [25]. More recently, a new category of ChCl-based DESs improved CUR solubility in water with the order of ChCl/EG>ChCl/G>ChCl/urea[26].Nevertheless,limited reports described the effect of ChCl-based DESs on CUR aqueous solubility enhancement. Some important semi-empirical and activity coefficient models have been used to predict solubility of drugs in solvent mixtures [25,26]. However, the availability of complementary experimental data is still fundamental to pharmaceutical researches.

Understanding the interactions between DESs and drugs are crucial in view of designing DESs with suitable properties for an effective dissolution. Extensive investigation has been devoted to the intermolecular interactions between solute and solvents by estimating the thermodynamic properties of the dissolution process[27–29].Results pointed out the key role of the strong interactions between DESs and drugs in the dissolution process.Recently,density functional theory (DFT) has been applied to mass transfer process (such as separation [19], gas capture [18], and dissolution[30]), which helps to understand the solute–solvent interaction at the molecular level.Through DFT calculations,the major contribution in the dissolution process of cellobiose and xylan in solvents(water, methanol, and ionic liquids) was observed to be interand intramolecular hydrogen bonding [30]. The dissolution mechanism of SiO2in ionic solutions as investigated by Stritto et al.[31]majorly involved proton transfer occurring due to ion-induced stronger H-bonding between terminal hydroxyl groups and bridging oxygen atom.The dissolution mechanism of α-cyclodextrin and chitobiose in 1-ethyl-3-methyl-imidazolium acetate was examined using DFT and major interactions involved were noncovalent interactions in which hydrogen bonding interactions were predominant[32].However,to the best of our knowledge,the effects of the DES structure on both CUR solubility and DES-CUR interactions at the atomic level have not been deeply examined so far. To expand the applications of DESs in dissolution and utilization of drugs in water, it is extremely importance to investigate the enhancing effect of ChCl-based DESs on the aqueous solubility of drugs.

In this work, aiming to selecting proper DES to be used as cosolvent,the solubility of CUR in aqueous ChCl-based DESs solutions was measured.The polyols,including 1,3-PDO,1,2-PDO,EG,and G,were selected as HBDs, owing to their importance in industrial food and pharmaceutical applications[33].The effects of DES components, temperatures, and concentrations were investigated. The empirical solubility models included the modified Apelblat equation, λh (Buchowski) equation, and Yalkowsky model were employed to correlate the experimental solubility results.Furthermore,the density in the aqueous DES mixtures was measured and the results were used to calculate the volumetric properties to define solute–solvent interactions. Finally, the interactions between ChCl-based DESs and CUR,and the effect of different DESs on CUR aqueous solubility at an atomic level were explored through quantum chemistry calculations for the first time. The interaction energy between DESs and CUR was also calculated using density functional theory(DFT).This work intends to provide a valuable reference to design efficient DESs for the utilization of CUR and contribute to a deeper insight into the interactions between DES and drugs for future pharmaceutical purposes and green processes.

2. Methodology

2.1. Materials

1,3-PDO (purity > 98.0%), G (purity > 99.0%), 1,2-PDO(purity > 98.0%), and EG (purity > 99.0%) were purchased from Demas-beta Chemicals Inc. and used as received. The analytical reagent grade chemicals were used as received. ChCl (purity > 99.0%) was kept in a vacuum glove box. Doubled-distilled water was prepared in the lab (conductivity < 1 μS?cm-1).

Although curcumin generally refers to 1,7-bis(4-hydroxy-3-me thoxyphenyl)-1,6-heptadiene-3,5-dione, which is also known as‘‘curcumin I” [2], with a crystalline yellow-orange color, melting temperature of 456.15 K, the commercial curcumin usually contains two additional compounds demethoxycurcumin and bisdemethoxycurcumin, with significant difference in their melting points (441.15 K and 497.15 K, respectively), which are known as‘‘curcumin II” [2]. So there has some difference in melting points of curcumin with different compound ratios in the literatures(e.g.,449.15–450.15 K[34],456.15 K[4]).In this work,the melting point of curcumin was measured with a differential scanning calorimeter (DSC 3 STARe System) whose melting point was 454.35 K,which was similar to the melting point of curcumin I[2].

2.2. Preparation of DESs

Considering the strong hygroscopicity of ChCl,the weighing and mixing of ChCl and polyols were performed in vacuum glove box to avoid moisture. DESs were prepared through mixing designed amounts of ChCl and polyol (AW 220, GR220, Shimadzu, precision of 1×10-4g)in a jacketed glass vessel and then moved outside the vacuum box and stirred under a stirrer rate of 350 r?min-1at 353.15 K,until a homogeneous solution was obtained.The primary experiments were conducted to determine the optimum molar ratio for the homogenous and stable DESs. The HBA/HBD molar ratio of 1:1-1:5 were tested for preparing ChCl/polyol DESs.ChCl/EG DES was not homogeneous liquid at HBA/HBD molar ratio of 1:1, and the rest combinations were liquid, while ChCl/G at all molar ratios were liquid and stable. Higher ratio of G (4:1)increased the solvent viscosity significantly which minimizing the mass transfer of compounds into the extracting solvent,glycerol-based DESs have much higher solubility of solutes at lower ratio of G to ChCl (2:1) [33]. Thus, the ChCl/EG and ChCl/G DESs with HBA/HBD molar ratio of 1:2-1:5 was used in this study.The ChCl/1,2-PDO DESs were liquid at HBA/HBD molar ratio of 1:2-1:5 at 353.15 K, but precipitation were observed with molar ratio of 1:2 and 1:3 at lower temperature, while the rest of the DESs combinations were found to be stable in nature. Thus, The ChCl/1,2-PDO with HBA/HBD molar ratio of 1:4 was used, and ChCl/1,3-PDO DES with HBA/HBD molar ratio of 1:4 was prepared for comparison. The prepared DESs were connected to a vacuum pump to dry completely. The Karl-Fischer titration was used to analyze the water content of the prepared DESs.The water content of ChCl/1,2-PDO(1:4),ChCl/1,3-PDO(1:4),ChCl/EG(1:2),and ChCl/G (1:2) was 0.03%, 0.04%, 0.02%, and 0.04%, respectively. To check the structures and the formation of H-bonding of the four ChClpolyol DESs,these DESs were characterized using1H NMR(Bruker AVANCE 400 spectrometer) and FTIR (Bruker Vertex 70). The TGDTA(NETZSCH STA449 F3)was used to determine the thermal stabilities of the prepared DESs. The characterization results of the prepared ChCl-polyol DESs are presented in Figs.S1-S9 of the Supplementary Material.

2.3. CUR solubility measurement

Designed amounts of DESs and water were mixed to obtain solvent mixtures.In a typical solubility measurement of CUR in aqueous DES solution,an excess amount of CUR powder was added into each solvent mixture and then kept the mixtures in a water bath thermostat(ED,Julabo Co.,with an accuracy of±0.01 K)for 5 days under stirring to reach equilibrium. When the saturated solution was obtained, the undissolved CUR powder was removed by centrifugation (Heraeus Multifuge X1R, Thermo Fisher Scientific Inc.,Germany) followed by filtration (Dura pore?Millipore membrane filters, 0.45 μm). Due to the reduced viscosity of the aqueous system,the centrifugation was usually finished in five min.In order to keep the temperature constant for a few minutes and do not alter CUR solubility during this process, the centrifuge tube containing solutions was placed in homemade bushings that matching the centrifuge to keep the temperature constant during centrifugation.So, the change of temperature and the error of experimental solubility data could be minimized.

The transparent solutions were diluted using water to different mass fraction and then analyzed using a high performance liquid chromatography (HPLC, Agilent 1260 Infinity II). CUR solubility(mole fraction, x1, uncertainty of 0.5%) in CUR (1) + water(2) + DES (3) ternary systems was calculated using Eq. (1):

where wiand Miwere the mass fraction and molecular mass of component i in the each ternary solution, respectively.

Each experimental was repeated more than 3 times. The average experimental data was calculated and recorded in this work.The solutions were placed in sealed glass vials. The density of the solutions was measured with a pycnometer(Micromeritic AccuPyc II 1340) with a precision of 0.03%.

2.4. Correlation models

Three empirical solubility equations, including the modified Apelblat equation [35], λh equation [36], and Yalkowsky model[37], have been applied to correlate the CUR solubility. The modified Apelblat model, as shown in Eq. (2), could be applied to both polar and nonpolar systems:

where A and B were two constants that reflecting the changes of activity coefficient of solution, indicating the effect of the nonideal solution on solubility of solute. C was a constant indicating the temperature effect on fusion enthalpy.

The Buchowski-Ksiazczak model, also called λh-equation, have been applied to correlate the solubility data of several solid–liquid equilibria systems [21,38]. Thus, it was used to correlate the solubility data of CUR in DES + water solutions (Eq. (3)):

where Tmtwas CUR melting temperature, λ value was the approximate average binding number of solute,indicating the non-ideality of system, and h represents the excess mixing enthalpy of solution[36].

The Yalkowsky equation could describe the exponential enhancement in the solubility of solute with a linear increase in the concentration of co-solvent [39], as shown in Eq. (4):

where ln x1,mixand ln x1,H2Owere the solubility of solute in water + co-solvent mixture and water, respectively. w3was the mass fraction of co-solvent in the water + co-solvent mixture. σ was the solubilization capacity of co-solvent.

2.5. Theoretical calculation and method

Cluster conformation search process was performed by Molclus Program [40]. We used GNF2-xTB method to generate 2000 kinds of cluster conformations by xtb and crest [41,42]. After removing duplicates, optimization and single point energy was calculated at same level. The following DFT process was executed by ORCA program [43–47]. The structure optimization were performed for 10 structures with the lowest energy in hundreds of independent cluster conformations using B97-3c functional[48].The final structure optimization and frequency analysis for 3 structures with lowest energy were performed using B3LYP-D3 functional[49]with 6-311G** basis set [50] to obtain reliable structure and thermal correction. There was no imaginary frequency, which ensured the existence of a minimum. And the single point energy was calculated by PWPB95-D3 functional with def2-TZVPP basis set[51,52].The thermal vibrational correction,thermal rotational correction, thermal translational correction, ZPE correction, thermal enthalpy correction and entropy correction were calculated by frequency analysis.And the electronic energy was obtained from single point calculation. The final structure of molecular clusters had lowest Gibbs free energy, which was sum of single point energy and thermal correction. Multiwfn program [53–55] and VMD program [56] were used to perform reduced density gradient (RDG)[54] and electrostatic potential (ESP) analyses [55].

3. Results and Discussion

3.1. Experimental solubility and Correlations

Aqueous solubility of CUR in DES+water systems with different mass fractions of ChCl-based DESs with polyols as HBDs was measured at different temperatures. The modified Apelblat equation,λh equation, and Yalkowsky model were applied to correlate the CUR solubility results. The experimental results and correlated data are presented in Fig. 1 and Tables S1-S4 in Supplementary Material. The calculated mean relative deviation summarized in Tables S1-S4 confirm that the correlation results are in good agreement with the experimental results, that is, these equations are suitable for correlation of CUR solubility in the prepared aqueous solutions with DESs as co-solvent. Moreover, to evaluate the performance of used models for the investigated systems,the average relative deviation percent (ARD) were calculated and the details of the calculation and results are presented in Table S5.As shown in Table S5, compared with λh equation and Yalkowsky model, the Apelblat model exhibits better accordance with the experimental data of CUR aqueous solubility.

CUR aqueous solubility in these systems is higher than that in water [4], indicating DES efficiency as co-solvents. Specifically, a maximum CUR aqueous solubility of 19.20 μg?ml-1was obtained in ChCl/1,2-PDO + water with a wDESof 0.8 at 318.15 K, which is approximately 1700-fold higher than that in water[4].In addition,the CUR solubility in DES aqueous solutions are all higher than that obtained with aqueous solution of individual counterparts(ChCl or polyols), as shown in Fig. S10, indicating that these DESs have the ability to enhance the aqueous solubility of CUR relative to the individual counterparts. DES mass fraction (wDES) effect on CUR solubility (x1) was further investigated. Fig. 1(a) and (b) shows the changes in CUR solubility in the aqueous DESs over wDESat 303.15 K and 313.15 K.For all solvents,x1increases with increasing wDESdue to the intermolecular forces between CUR and DES. Shekaari et al. [25] also reported similar observations and found that the solubility of drugs such as cefixime trihydrate, CUR [26], and acetaminophen [39] in aqueous solutions increased with increasing co-solvent amount as a result of intermolecular H-bonding between solvent and solute.

Additionally, for all wDES, CUR solubility at 313.15 K is higher than that measured at 303.15 K. An increasing difference in CUR solubility in the four types of aqueous DES solutions is observed at higher wDES,especially at wDES=0.8.CUR solubility at wDES=0.8 and 313.15 K followed the trend ChCl/1,2-PDO>ChCl/1,3-PDO>C hCl/EG > ChCl/G. Compared with the results reported by Shekaari et al. [25], the same trend of ChCl/EG > ChCl/G for enhancing CUR solubility in water is obtained. Furthermore, two more efficient DESs ChCl/1,2-PDO and ChCl/1,3-PDO for enhancing CUR solubility in water are developed. An important factor affecting the solvent power is the structure of the HBD employed to form each DES[14,57],which affects not only the overall solvent viscosity but also the solvent capacity to interact through hydrogen bonding with the different drugs.Though glycerol has three—OH groups as compared with the two —OH groups of other diols, which would enhancing the solvent ability to form specific interactions with the solutes, the lowest CUR solubility in ChCl/G aqueous solution than that of diols-based DES aqueous solution are obtained in this study. According to the cosphere overlap model as developed by Friedman and Krishnan [58,59], there is competition among various interaction occurring among solute and co-solvent molecules.And the —OH group interactions within ChCl/G predominate over CUR and DES molecules might be the reason for the relative low CUR solubility in ChCl/G aqueous solution.

The reason for the higher CUR solubility in aqueous ChCl/1,2-PDO, compared to the other solvents, is ascribable to structural basis. The relatively weak internal interactions of OH groups in 1,2-PDO allow a better interaction with CUR, compared to the other three ChCl-based DESs, characterized by strong OH internal interactions that reduce their ability to react with CUR,and its consequent solubility.Moreover,as shown in Fig.1(c),the experimental CUR mole fraction solubility in ChCl/1,2-PDO+water solution at w3of 0.8 at all experimental temperatures is higher than the result obtained with ethanol, which is typically used as a co-solvent(ethanol mass fraction of 0.8) [60]. The result designates this type of DESs a promising green solvents.

Fig.1. Relationships between CUR solubility,x1,and DES mass fraction,wDES,in various aqueous DESs at 303.15 K(a)and 313.15 K(b).Relationships between CUR solubility,x1, and temperature at wDES of 0.8 (c). The solid lines were calculated curves using Apelblat model.

DESs was regenerated by mixing with more water to precipitate CUR. The CUR was filtered out and dried in a vacuum over. The DES-water mixture was separated with a rotary evaporator at 333.15 K and vacuum pressure to remove water. Finally, the obtained DESs were dried in a vacuum oven at 343.15 K for 3 h for reuse.Chen et al.[61]mentioned that vacuuming to regenerate DESs would lead to easy volatile due to volatility or the decomposition of the DESs.So,it is necessary to analysis the thermal stability of the prepared DESs in this study.In order to judge whether the DESs prepared in this work evaporated or decomposed during the regeneration process, the thermal stability of DESs have been tested and the TG-DTA results are shown in Fig. S9. The results show that the first decomposition temperature for ChCl/1,2-PDO,ChCl/1,3-PDO, ChCl/EG, and ChCl/G DESs are 161.4 °C, 161.0 °C,153.2 °C, and 174.9 °C, respectively, which are much higher than that of the regeneration temperature. These results verify that the DESs will not be decomposed in the regeneration process.Moreover,the mass of DESs before and after regenerated have been tested and there is no detectable change in the mass of DESs after regeneration at 60 °C in vacuum. The water were collected and analyzed for traces of CUR and DES using HPLC-MS. It is observed that no CUR or DES is detected in the collected water,further indicating that the CUR is completely separated and the DESs are not evaporated during the regeneration process.These results demonstrate that the prepared DESs exhibit excellent thermal stability and the collected water is clean and could be used as solvent for subsequent runs.

The results of CUR solubility using aqueous solution of the original and the regenerated DESs at w3of 0.8 and 313.15 K are shown in Fig. S11. The CUR solubility using ChCl/1,2-PDO and ChCl/1,3-PDO are much higher than that of using ChCl/EG and ChCl/G in each run. After the fifth cycle, the CUR solubility using ChCl/1,2-PDO aqueous solution and ChCl/1,3-PDO aqueous solution only decrease 1.9% and 3.3%, respectively, as shown in Fig. S11. The experimental results verify the good reusability of these DESs,which is essential for industrial applications. It is worth mentioning that compared with the methods of using other additives(such as surfactant and polymers, etc.), DESs are easier to be recovered,then regenerated by simply removing the water, and finally to be reused for next runs, thus showing great application prospect in pharmaceutics. In particular, DESs could be considered a better option for enhancing dissolution or extracting drugs insoluble in water since DESs had lower price, desirable environmental impact compared to organic solvents, and be separated completely from drugs without residue and meet the medicinal product quality criteria.

3.2. Volumetric properties

CUR density in water and DES + water systems was measured.The apparent molar volume,Vφ, was calculated using Eq. (5):

where M was molar mass of CUR.m was CUR molality in water or in(DES + water) solutions. ρ0was the density of solvent. ρ was the density of solution. Density and Vφvalues of the solutions under investigation are presented in Fig. 2 and Table S5.

Density of these aqueous DES solutions increase with increasing wDESand temperature. The positive values of Vφindicate the existence of strong solute–solvent interactions. Additionally, with the increase of temperature, the interactions of solvent with CUR molecules are weakened due to the effect of the water thermal kinetic energy [39,62], the number of the water molecules gather to CUR molecules through H-bonding interactions reduced at higher temperature, thereby decreasing Vφ[39].

The standard partial molar volume,, was calculated using least-squares fitting method (Eq. (6)):

where m was CUR molality in solvent. SVwas the experimental slope that reflecting the solute–solute interactions.values reflected the solute–solvent interactions.Thevalues for DES+water solutions at 0.4,0.6,and 0.8(mass ratio)were calculated and the results were shown in Fig. 3. Due to the enhanced interactions of solute–solvent, the positivevalues considerably increase for higher mass fraction of ChCl/1,2-PDO and ChCl/1,3-PDO and higher temperatures. This trend demonstrates that strong interactions existed between DESs and CUR, which are strengthened at higher concentrations of ChCl/1,2-PDO or ChCl/1,3-PDO in the ternary solutions and higher temperatures. Similar trends are observed for the ChCl/EG + water and ChCl/G + water solvent systems(Figs. S12 and S13). The results demonstrate that these DESs with ChCl HBA and polyol HBD have an important effect on the solute–solvent interactions.

3.3. Structure, ESP and RDG analysis

The formation of ChCl-based DESs with 1,2-PDO, 1,3-PDO, EG,and G as HBDs and the interaction energy between these DESs and CUR were studied through quantum chemistry calculations.The interaction energy of each cluster was computed as the difference among the whole cluster and the monomers [63–65], which was calculated as follows:

where ΔEintwas the interaction energy of cluster,E were the Gibbs free energies of clusters or monomers,Xiwas the monomer in cluster. The Gibbs free energies were calculated as a sum of electronic energy and thermal correction.Fig.4(a)and(b)show the optimized configurations of ChCl/1,2-PDO???CUR and ChCl/1,2-PDO, respectively. Introducing CUR only elongates the hydrogen bonds of ChCl/1,2-PDO slightly.Thus,the structure of the ChCl/1,2-PDO DESs do not change with the introduction of CUR,indicating its stability,independently from the presence of CUR.Noticeably,the configurations of the other three ChCl-based DESs are also not affected by the presence of CUR (Figs. S14-S16), denoting the overall structure stability.

ESP analysis was performed to describe the configurations involving ChCl/1,2-PDO and CUR qualitatively. The ESP of ChCl/1,2-PDO???CUR and ChCl/1,2-PDO are mapped onto their electron densities with an isovalue of 0.05 in Fig. 4(c) and (d), respectively. According to the ESP of ChCl/1,2-PDO in Fig. 4(d), the electronegative region remains at the hydroxyl group of 1,2-PDO,whereas the electropositive region is around choline group. The leaving chloride anion is stabilized by 1,2-PDO via van der Waals attractive interaction, as revealed by the broad green in Fig. 4(f).As shown in the main view of Fig.4(c),the CUR molecule interacts with ChCl through its electronegative part, and with 1,2-PDO through its electropositive part. Similar results are obtained for ChCl/1,3-PDO???CUR, ChCl/EG???CUR, and ChCl/G???CUR (Figs. S14–S16). These interactions efficiently stabilize the system.

To distinguish among the possible types of interactions in reduced gradient space, noncovalent interactions were studied via RDG analysis.Fig.4(f)clearly shows hydrogen bonding marked in blue. Moreover, the two large flakes in green between 1,2-PDO and ChCl reflect the van der Waals(vdW)interactions,demonstrating the existence of vdW interactions in ChCl/1,2-PDO monomer.Within the monomer, RDG analysis indicates the coexistence of vdW interactions and H-bonding, which are the reasons for its low freezing points and the formation of ChCl/1,2-PDO DESs with stable structures. Similar results are obtained for ChCl/1,3-PDO,ChCl/EG, and ChCl/G (Figs. S14(f), S15(f) and S16(f), respectively).Furthermore,Fig.4(e),Fig.S14(c),Fig.S15(c),and Fig.S16(c)show that vdW attraction interactions are the main intermolecular interactions between the prepared DESs and CUR molecule,as revealed by the broad green in Fig.4(e).For ChCl/1,2-PDO???CUR,in Fig.4(e),the largest vdW surfaces are observed between the ChCl/1,2-PDO and the CUR molecule than that between other DESs and CUR (as shown in Figs. S14(c), S15(c), and S16(c)). Besides, for H2O + DES???CUR, it is found in Figs. S17 to S20 that most of water molecules are around DES monomer, other than around CUR molecules.RDG analysis results in Figs.S17(c)to S20(c)show hydrogen bonding marked in blue between water molecules and DESs,while vdW attractions are the main intermolecular interactions between the prepared DESs and CUR molecule. These results further indicate the significant role of DES in enhancing dissolution of CUR in aqueous solution.

Fig. 2. Density and apparent molar volume for CUR in different DES +water solutions at T = 303.15–318.15 K. (a) ChCl/1,2-PDO; (b) ChCl/1,3-PDO; (c) ChCl/EG; (d) ChCl/G.

Fig. 3. The V0φ of CUR in ChCl/1,2-PDO + water solutions (a) and in ChCl/1,3-PDO + water solutions (b) at different temperatures. w3 = 0.400 (-■), 0.600 (-●), 0.800 (-▲).

3.4. Energetic interactions analysis

The interaction energy between the molecules could reflect dissolution effect. A low interaction energy between the molecules suggests the stability of system, and a satisfactory dissolution effect [66]. In this section, the interaction energy between CUR and the prepared DESs were calculated quantitatively using DFT.The results are shown in Table 1.The interaction energies between CUR and ChCl-based DESs are smaller than those of the individual DESs,indicating that the addition of ChCl-based DESs are beneficial to stabilizing the system and enhancing the dissolution capacity.The enhancing effect of ChCl/EG (1:2) is higher than that of ChCl/G (1:2) under the same conditions (Table 1, entries 1 and 2). This can be reasonably explained considering the internal H-bond strength of DESs and the competitive interaction network of DESs-CUR.The internal H-bond strength in ChCl/EG(1:2)is weaker than that in ChCl/G(1:2)(Table 1,entries 5 and 6),allowing strong H-bond network between CUR and HBA (ChCl) and reducing the ability of HBD to bind to HBA. The same effect is observed for ChCl/1,3-PDO(1:4)and ChCl/1,2-PDO(1:4).The interaction energy of the ChCl/1,2-PDO???CUR system is the lowest (Table 1, entry 4,-12.59 kcal?mol-1, 1 kcal?mol-1=4.18 kJ?mol-1), indicating that the ChCl/1,2-PDO???CUR system is the most stable and reflect a satisfactory dissolution effect,as backed by experimental and correlation results.

4. Conclusions

In this study, DESs with ChCl as HBD and polyols 1,2-PDO, 1,3-PDO,EG,and G as HBDs were prepared for enhancing aqueous solubility of CUR. The experimental solubility results indicated that the four DESs have a considerable enhancing effect on the aqueous solubility of CUR.The CUR solubility in the studied solvent systems increased with increasing mass fraction of ChCl-polyol DESs and temperature owing to the intermolecular H-bonding between CUR and solvent. When compared to the reported results with ethanol as co-solvent (mass fraction of 0.8), the CUR aqueous solubility using ChCl/1,2-PDO as co-solvent (mass fraction of 0.8)was higher at all experimental temperatures, designates the ChCl/1,2-PDO DES a promising green alternative to organic solvents.

Fig. 4. Optimized structures of ChCl/1,2-PDO???CUR (a) and ChCl/1,2-PDO (b).Molecular surface ESP diagrams of ChCl/1,2-PDO???CUR (c) and ChCl/1,2-PDO (d).Red areas indicate positive ESP. Blue areas indicate negative ESP. RDG diagrams of ChCl/1,2-PDO???CUR (e) and ChCl/1,2-PDO (f), with blue for strong attractive interactions, red for strong steric repulsions, and green for typical van der Waals interactions.

Table 1 Interaction energies between CUR and the prepared ChCl-polyol DESs calculated by DFT

The correlation results using modified Apelblat equation showed better agreement with the experimental solubility of CUR than using Buchowski equation and Yalkowsky equation.That was, the modified Apelblat equation was more recommended to predict CUR solubility in the proposed solvent systems. The positive Vφvalues derived from volumetric measurements revealed a strong solute–solvent interaction. Moreover, the standard partial molar volume Vφ0values increased substantially with increasing ChCl-polyol DESs mass fraction and temperature, indicating that interactions between DES and CUR were stronger at higher concentrations of ChCl-polyol DESs and higher temperatures. Further,owing to CUR being insoluble in water, CUR could be precipitated via diluting of solutions and separated from solutions.After removing water,it was then possible to regenerate the DES as co-solvent for further dissolution of target drugs. Owing to the low vapor pressure of DES, the recovered water was clean and could be reused, too. It can therefore be conducted that through the use of green ChCl/polyol DES as co-solvent for enhancing CUR aqueous solubility could satisfy the criteria of green chemistry for sustainable process.

The effects of the DES structure on CUR solubility and DES-CUR interactions were investigated through quantum chemistry calculations to give a deep insight into the interactions between CUR and DESs. RDG analysis revealed the coexistence of hydrogen bonding and vdW interactions in the structure of ChCl-polyol DESs.The main interactions between DESs and CUR were vdW interactions,which efficiently stabilize the system.The lowest interaction energy in the ChCl/1,2-PDO???CUR system indicated that DES based on ChCl and 1,2-PDO are appropriate co-solvent for enhancing aqueous solubility of CUR,which also was confirmed by the experimental and correlation results. It can therefore be concluded that the use of DESs based on choline chloride and polyols, especially ChCl/1,2-PDO, are hopefully to be green candidates for efficient dissolution and utilization of curcumin in medical and pharmaceutical application.The results are useful in understanding the interaction of DES and drugs and helpful to develop the performance in the emerging and mature sustainable applications of industry.

Data Availability

Data will be made available on request.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (21905069, U21A20307, 22208073),the Shenzhen Science and Technology Innovation Committee(ZDSYS20190902093220279, KQTD20170809110344233, GXWD-20201230155427003-20200821181245001, GXWD2020123015-5427003-202008211 81809001, ZX20200151), the Department ofScienceandTechnologyofGuangdongProvince(2020A1515110879).

Supplementary Material

Supplementary data to this article can be found online at https://doi.org/10.1016/j.cjche.2023.01.005.

Nomenclature