Equilibrium solubility investigation and thermodynamic aspects of biologically active gimeracil (form P) dissolved in aqueous co-solvent mixtures of isopropanol, N,N-dimethylformamide, ethylene glycol and dimethylsulfoxide

Accepted Manuscript Equilibrium solubility investigation and thermodynamic aspects of biologically active gimeracil (form P) dissolved in aqueous co-solvent mixtures of isopropanol, N,N-dimethylformamide, ethylene glycol and dimethylsulfoxide Wentian Li, Hu Lin, Nan Song, Gaoquan Chen, Xinbao Li, Hongkun Zhao PII: DOI: Reference:

S0021-9614(19)30075-8 https://doi.org/10.1016/j.jct.2019.01.026 YJCHT 5701

To appear in:

J. Chem. Thermodynamics

Received Date: Accepted Date:

17 January 2019 28 January 2019

Please cite this article as: W. Li, H. Lin, N. Song, G. Chen, X. Li, H. Zhao, Equilibrium solubility investigation and thermodynamic aspects of biologically active gimeracil (form P) dissolved in aqueous co-solvent mixtures of isopropanol, N,N-dimethylformamide, ethylene glycol and dimethylsulfoxide, J. Chem. Thermodynamics (2019), doi: https://doi.org/10.1016/j.jct.2019.01.026

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Equilibrium solubility investigation and thermodynamic aspects of biologically active gimeracil (form P) dissolved in aqueous co-solvent mixtures of isopropanol, N,N-dimethylformamide, ethylene glycol and dimethylsulfoxide Wentian Lia, Hu Lina, Nan Songa, Gaoquan Chenb, Xinbao Lia, Hongkun Zhaob,*

a

School of Environmental & Municipal Engineering, North China University of Water Resources and Electric

Power, ZhengZhou, He’nan 450011, People’s Republic of China b

College of Chemistry & Chemical Engineering, YangZhou University, YangZhou, Jiangsu 225002, People’s

Republic of China Corresponding author. Tel: + 86 514 87975568; Fax: + 86 514 87975244. E-mail address: [email protected] (Hongkun Zhao).

ABSTRACT Solubilities of gimeracil (form P) in aqueous co-solvent mixtures of isopropanol, N,N-dimethylformamide (DMF), ethylene glycol (EG) and dimethylsulfoxide (DMSO) were investigated via the isothermal dissolution equilibrium method at (283.15 to 328.15) K under ambient pressure p=101.2 kPa. Experimental solubility was increased with increasing temperature and mass fraction of each co-solvent. The largest solubility was found in neat co-solvents. The solids equilibrated with liquid phase were characterized by X-ray power diffraction, indicating no polymorphic transformation, solvate formation or crystal transition according to the spectral data. The Jouyban-Acree model was adopted to correlate the obtained solubility. The highest RAD and RMSD values were, respectively, 2.61×10-2 and 14.96×10-4. Quantitative values for the local mole fraction of DMF (EG, DMSO or isopropanol) and water around gimeracil (form P) were acquired 1

by using the Inverse Kirkwood–Buff integrals method. The preferential solvation parameters for isopropanol were positive in the isopropanol mixtures in intermediate and isopropanol-rich compositions, which indicated that gimeracil (form P) was preferentially solvated by isopropanol. Gimeracil (form P) could act mainly as a Lewis acid interacting with proton-acceptor functional group of isopropanol. Within the same region, gimeracil (form P) was not preferentially solvated by DMF, EG and DMSO. Furthermore, the method of linear solvation energy relationships was performed with a suitable combination of solvent polarity descriptors to explain the nature of intermolecular interactions resulting in the solubility variation in the co-solvent mixtures. Keywords: Gimeracil; Solubility; Jouyban-Acree model; Inverse Kirkwood–Buff integrals; Preferential solvation; Solvent effect

1. Introduction The drug solubility in co-solvent solutions is crucial significant for raw material purification, design of liquid dosage forms and understanding of the mechanisms concerning the physical and chemical stability of pharmaceutical dissolutions [1,2]. As a result, the solubility of active ingredients in co-solvent mixtures is an important physicochemical property because it influences efficacy and pharmacokinetic and biopharmaceutical properties of the drugs [3,4]. Alternatively, the solubility dependence upon temperature allows carrying out a thermodynamic analysis to deeply insight into the molecular mechanisms regarding the drug dissolution process. Moreover, drug solubility in co-solvent mixtures is used in evaluating the preferential solvation of the solute by solvent components in solutions [5-7]. Gimeracil (CAS No, 103766-25-2; IUPAC name, 5-chloro-4-hydroxy-1H-pyridin-2-one; molecule structure shown in Figure 1) is an important component of anti-cancer drug S-1 (trade name Teysuno in Japan), which is commonly used for treatment of the advanced gastric cancer. As one of the medicinal fluoropyrimidine derivatives, recently, S-1 has also been used in combination 2

with cisplatin to treat other kinds of cancers, such as head and neck cancer, colorectal cancer and non-small-cell lung cancers in several countries [8-14]. Within the drug, the molar ratio of tegafur, gimeracil and oteracil is 1:1:0.4 [8,9,14]. Particularly, among the three essential components, gimeracil is a potent reversible inhibitor of dihydropyrimidine ehydrogenase in order to improve the antitumor activity of the fluoropyrimidines. Aqueous solubility of gimeracil is practically water-insoluble that would be a key drawback to decrease significantly the drug bioavailability . Although gimeracil has been known for over 60 years, the physic-chemical properties of gimeracil in aqueous and organic solutions have not yet been studied systemically in the previous works. gimeracil Thus this work tries to give an idea about the relative stabilization of gimeracil in aqua-organic mixtures with respect to water and the comprehensive solute−solvent and solvent−solvent interactions therein. Many semiempirical and theoretical models have been employed to predict drug solubility in co-solvent mixtures [16], however the availability of experimental data is still fundamental for the pharmaceutical scientists [1]. The solubility of gimeracil in neat water is low. Although co-solvency as the solubilizing technique has been widely employed in pharmacies long ago, recently the mechanisms involving in increase or decrease in drugs’ solubility start to be approached from a deep thermodynamic point of view, including the preferential solvation analysis of solute by the components of mixtures [5-7,17,18]. As a generalized method, the linear solvation energy relationships, LSER, treats the solvent effect by dividing the solute-solvent interactions into two types of non-specific (dipole-dipole, dipole-induced dipole and dispersion) and specific (hydrogen bonding) interactions. In addition, each of interaction terms has a linear contribution to Gibbs energy of solvent dependent properties [19]. The empirical scale provides a convenient way to characterize the ability of solvent interacting with solute, defined as polarity of the solvent, at the molecular level. Kamlet, Abboud and Taft (KAT) [19,20] introduce an extensively used solvent scales through the solvatochromic studies of pairs of probing molecules in the set of solvents with 3

different interacting properties. These scales comprise the dipolarity/polarizability (*), the hydrogen bond basicity ( and the hydrogen bond acidity (, which are directly measured of the energy changes resulting from corresponding intermolecular solvent-solute interactions. So, the study of solvent effect in terms of LSER reveals the nature and extent of solute-solvent interaction affecting a solvent-dependent property. The KAT-LSER method has shown notable success in explaining a wide range of chemical phenomena, including the solubility in pure and mixed solvents [21,22]. It is well-known that N,N-dimethylformamide (DMF) is an important co-solvent to study the interrelation between drug solubility and medium polarity [23]. Water‑DMF mixtures show strongly non-ideal and can act in the solute‑solvation process via hydrophobic interactions and preferential solvation [24,25]. Isopropanol is a strong odor. It is miscible with ethanol, water, ether and chloroform, and dissolves a lot of non-polar compounds. It is relatively non-toxic, compared to alternative solvents. Isopropanol is used solely or in mixtures for diverse aims [26,27] including in penetration-enhancing pharmaceutical compositions for topical transepidermal and percutaneous uses. Drug solubility in dimethyl sulfoxide (DMSO) is one of the important parameters considered by pharmaceutical companies during early drug discovery [28]. It dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water. It is chosen to obtain further broader insight about chemistry aqueous solutions for drug solvation. DMSO possesses two hydrophobic methyl groups with +I effect, and the hydrogen atoms of two CH3groups are of acidic character. Ethylene glycol (EG) is a pharmaceutically acceptable and safe neat solvent for industrial applications [29,30]. Therefore, considering the points-of-view mentioned above, the objectives of this work are to study the equilibrium solubility of gimeracil (3) in binary mixtures of isopropanol (1) + water (2), DMF (1) + water (2), EG (1) + water (2) and DMSO (1) + water (2) at (283.15 to 328.15) K under atmospheric conditions and evaluate the respective thermodynamic quantities of the solution and also to gain information regarding the main factors 4

contributing to the solvent effect.

2. Theoretical consideration 2.1. Jouyban−Acree model Here, the Jouyban−Acree model [16,17] is used to correlate the solubility of gimeracil in co-solvent mixtures of (DMF + water), (EG+ water), (DMSO + water) and (isopropanol + water) at various temperatures. This model describing as Eq. (1) provides accurate mathematical description for the solute solubility dependence on both temperature and solvent composition for binary co-solvent mixtures. ln xw,T  w1 ln x1,T  w2 ln x2,T 

w1w2 2 i J i  w1  w2   T / K i=0

(1)

where xw,T refers to the mole fraction solubility of gimeracil in co-solvent mixtures at absolute temperature T; w1 and w2 are the mass fraction of co-solvent 1 (DMF, EG, DMSO or isopropanol) and 2 (water) free of gimeracil, respectively; x1,T and x2,T are the gimeracil solubility in mole fraction in neat solvents; and Ji are the Jouyban-Acree model parameters. 2.2. KAT-LSER model Kamelt and co-workers suggest a well-known empirical model in terms of the linear solvation energy relationship concept to study the solvent effect [19]. This model, abbreviated KAT-LSER hereafter, divides the total change in free energy induced by the solvent into some separated intermolecular interaction energy terms, which account for both specific (e.g. hydrogen bonding) and non-specific electrostatic (such as Keesom dipole-dipole, Debye dipole-induced dipole and London instantaneous induced dipole-dipole dispersion) interactions that might occur between solute and solvent molecules. Three empirical solvent parameters named *,  and  have been introduced to describe the feature of the solvent at the molecular level. * denotes dipolarity/polarizability as a scale to characterize the solvent’s ability for non-specific interactions;

 and  symbolize the capacity of solvent to act as a hydrogen-bond acceptor and hydrogen-bond donor in specific interactions, respectively [19-22]. KAT parameters are derived by the 5

solvatochromic comparison method from a direct measurement of a change in the solute’s electronic transition energy due to corresponding solvent effect. Therefore, a linear correlation is expected between interaction energy terms defined by KAT parameters with the change induced by the solvent in Gibbs energy of a property (e.g. solubility). The KAT-LSER model delivers an opportunity to obtain detailed information about the significance and nature of different solvation components playing in the solvent effect [19-22]. The general form of KAT-LSER model relating to the Gibbs energy of solvation of a given solute (expressed as lnx) is expressed as Eq. (2) [19-22]. V2 ln x  c0  c1 * c2   c3  c4 ( s H ) 100 RT

(2)

herein, Vs, H, R and T denote, respectively, the solute’s molar volume, Hildebrand solubility parameter, the universal gas constant and absolute temperature. The product Vs  H2 accounts for solvent-solvent interactions, and represents the amount of energy consumed for breaking solvent cohesive forces to create cavities for a proper accommodation of the solute. c0 is the intercept value for ==*=H=0; ci=1-4 stand for the sensitivity of the solid solubility to each corresponding interaction energy term. 2.3. Preferential solvation of gimeracil The inverse Kirkwood-Buff integral equation is expressed as: rcor

Gi,3   ( gi,3  1)4 r 2 dr

(3)

0

where, gi,3 is the pair correlation function for molecules of solvent i in the co-solvent (1) + water (2) mixtures around the gimeracil (3); r is to the distance between the centers of molecules of gimeracil (3) and those of co-solvent (1) or water (2); and rcor signifies a correlation distance for which gi,3 (r>rcor) ≈ 1. As a result, for all distances r>rcor up to infinite, the integral value is essentially zero. The preferential solvation parameter of gimeracil (compound 3) by the co-solvent (compound 1) in co-solvent (1) + water (2) mixtures is expressed as [5,6,17,18]: 6

 x1,3  x1L，3  x1   x2,3

(4)

L

here x1，3 refers to the local mole fraction of co-solvent (1) in the environment around gimeracil (3) and x1 is the bulk mole fraction composition of co-solvent (1) in the initial co-solvent mixtures. If δx1,3 > 0 then gimeracil is preferentially solvated by co-solvent (1); on the contrary, if this parameter is < 0 gimeracil is preferentially solvated by water (2). Values of δx1,3 are obtainable from the inverse Kirkwood-Buff integrals for the individual solvent components analysed according to a set of thermodynamic quantities expressed as Eqs. [5,6,17,18]:  x1,3 

x1 x2  G1,3  G2,3 

(5)

x1G1,3  x2G2,3  Vcor

with

G1,3  RT  T  V3 

x2V2 D Q

(6)

G2,3  RT  T  V3 

x1V1 D Q

(7)



L L Vcor  2522.5 r3  0.1363 x1,3 V 1  x2,3 V2 



1/3

 0.085 

3

(8)

here, κT refers to the isothermal compressibility of the co-solvent (1) + water (2) mixtures; V 1 and

V 2 refer to the partial molar volumes of the solvents in mixtures; and V 3 is the partial molar volume of gimeracil in these mixtures. The function D {Eq. (9)} is the derivative of standard molar Gibbs energies of transfer of gimeracil from neat water (2) to co-solvent (1) + water (2) mixtures with respect to the solvent composition. The function Q {Eq. (10)} involves the second derivative Exc

of the excess molar Gibbs energy of mixing of the two solvents ( G1+2 ) with respect to the water proportion in the co-solvent solutions. Vcor is the correlation volume and r3 is the molecular radius of gimeracil evaluated by Eq. (11) with NAv as the Avogadro’s number. o   tr G(3,2  1 2) D   x1  T , P

(9)

7

Exc   2G1+2  Q  RT  x1 x2  2   x2 T , p

r3  3

3 1021V3 4 N AV

(10)

(11)

Due to the dependence of κT upon composition, this term is not known for all the systems investigated. In addition, due to minor contribution of RTκT to the inverse Kirkwood-Buff integral, the κT dependence on composition will be approximated by Eq. (12) [5,6,17,18], which is calculated as an additive property via the mixtures compositions and the reported values for neat solvents. o o  T  x1 T,1  x2 T,2

(12)

o where, xi is the mole fraction of component i in co-solvent mixtures; and  T,i , the isothermal

compressibility of pure component i. Because the definitive correlation volume depends on the local mole fraction near to the solute, it needs iteration. The process is performed by replacing δx1,3 and Vcor in the Eqs. (4), (5) and (8) to L recalculate x1,3 until a non-variant value of Vcor is obtained.

3. Experimental 3.1. Materials and experimental apparatus The gimeracil was provided by Shanghai Energy Chemical Co., Ltd. with a mass fraction of more than 0.996 in mass fraction, which was confirmed by a high-performance liquid phase chromatograph (HPLC, Agilent-1260) without additional treatment. All organic solvents (isopropanol, DMF, EG and DMSO) were purchased from Aladdin Reagent Co., Ltd., Shanghai with the purity of no less than 0.994 in mass fractions confirmed by gas chromatography (GC, FULI 9790, China). Para-nitroaniline (PNA), para-nitroanisole (PNAS) and Reichardt’s dye (RD) were used as solvatochromic probes, and were obtained from Sigma-Aldrich Co, Iran. These substances were used in experiment without additional treatment. Distilled deionized water (conductivity < 1 μS∙cm-1) obtained via distillation in our laboratory was used for solubility determination. The detailed aspects of the above chemicals were listed in Table 1. 8

In this work, the experimental apparatus employed for the solubility measurement was given in Figure S1 of Supporting material, which comprised a 100 mL jacketed glass vessel with a magnetic stirrer and a circulating water system used to keep the system temperature. The temperature of circulating water was regulated by a thermostatic water bath (Model: QYHX-1030) having a standard uncertainty of 0.05 K, which was purchased from Shanghai Joyn Electronic Co., Ltd., China. A mercury glass micro thermometer (standard uncertainty: 0.02 K) inserted in the inner chamber of the vessel displayed the real temperature of mixtures. A condenser was connected with the glass vessel to prevent the solvent from escaping. An analytical balance having a model of BSA224S (standard uncertainty, 0.0001 g) was provided by Satorius Scientific Instrument (Beijing), which was employed in determining the mass of the solute, solvent, and saturated solution. So as to check the accuracy of measurement method, the reliability of apparatus was verified by determining the solubility of benzoic acid in toluene [31]. 3.2. Preparation of aqueous co-solvent mixtures The co-solvent mixtures were prepared by using the analytical balance (model: BSA224S). The mixed solvents in the glass vessel were about 60 mL, and the standard uncertainty of which was evaluated to be 0.0001 g. The mass fractions of (isopropanol, DMF, EG and DMSO) in the co-solvent mixtures covered the range from 0 to 1.0. The glass vessel was covered with a stopper to prevent the solvent from escaping during the preparation process of solvent mixtures. 3.3. Solubility measurement The equilibrium solubility of gimeracil in the four co-solvent mixtures of {isopropanol (1) + water (2)}, {DMF (1) + water (2)}, {EG (1) + water (2)} and {DMSO (1) + water (2)} was determined via isothermal dissolution equilibrium method [17,31], and the high-performance liquid phase chromatograph (HPLC, Agilent-1260) was employed to determine the solubility of gimeracil in equilibrium liquor. Saturated solutions of gimeracil were prepared in the glass vessel for each experiment. An excess gimeracil was introduced into the jacketed vessel filled with about 60 mL solvent mixtures. 9

Continuous stirring was made through a magnetic stirrer to mix the suspension rigorously. The mixture was kept at a desired temperature by circulating water from the smart thermostatic bath through the outer jacket. So as to obtain the equilibration time of the studied solution systems, about 1 ml liquor was extracted every one hour using a 2 mL of preheated syringe equipped with a pore syringe filter (PTFE 0.2 μm), and then analysed by using the HPLC. In addition, two types of experiments were carried out to ensure that sampling was performed at equilibrium conditions, one starting from a supersaturated solution, in which the solid phase precipitated to reach equilibrium and the other starting from a non-saturated solution, in which solid dissolved to arrive at equilibrium. The results showed that it took about 24 h to arrive at equilibrium for all the investigated systems. Once the solution arrived at equilibrium, the stirrer was turned off to allow any undissolved solute to be precipitated from the solutions. One hour later, the upper liquor was taken out with the 2 mL of preheated or precooled syringe attached with a filter (PTFE 0.2 μm), and transferred speedily to a 25 mL pre-weighed volumetric flask. The volumetric flask filled with sample was weighed again with the analytical balance. Subsequently, the sample was diluted to 25 mL with methanol, and 1 μL of the solution was withdrawn for analysis through the HPLC. The local atmosphere pressure was about 101.2 kPa in the experiment. 3.4. Analysis method The gimeracil concentration was analysed through Agilent-1260 high-performance liquid chromatography (HPLC). The chromatographic column used here was a reverse phase column with a type of LP-C18 (250 mm × 4.6 mm), the temperature of which was about 303 K. The wavelength of the UV-vis detector was 225 nm [32]. The mobile phase was pure methanol with a flow rate of 0.8 mL·min−1. The experiment was conducted for triple times to attain the average value. The relative standard uncertainty of mole fraction solubility was estimated to be 0.046. 3.5. XPRD characteristic of solid phase With the purpose of illustrating the existence of solvate formation or polymorph transformation of gimeracil in experiment, X-ray powder diffraction (XPRD) patterns of equilibrated liquid were 10

determined at room temperature. The experiments were performed on a Bruker AXS D8 Advance (Bruker, Germany) instrument with Cu Ka radiation (λ=0.154184 nm). The tube voltage and current were, respectively, set at 40 kV and 30 mA. The data were gathered from 5° to 80° (2-Theta) at a scan speed of 5°·min-1 under atmospheric pressure. 3.6. KAT parameters determination Dilute solutions of PNA (0.05 mM), PNAS (0.1 mM) and RD (0.1 mM) were prepared in binary mixtures of water and EG. The mass fraction of binary mixtures was in the range of 0 to 1.0 with 0.1 intervals. The UV-vis adsorption spectrum of solutions was recorded on PG instruments t80 UV-vis spectrophotometer at constant temperature 298.15 K. The wavelength of maximum absorbance, max, of each solvatochromic probe was obtained by mathematical peak fitting of the experimental UV-vis spectrum. KAT parameters *,  and  were calculated from max data as explained previously [33-36].

3. Results and discussion 3.1. XPRD analysis The patterns of raw material and all solids equilibrating with corresponding liquor are given in Figure S2 of Supporting material. It is confirmed by XPRD pattern that all patterns of solid phase of gimeracil in equilibrium with its solution have the same characteristic peaks with the raw material. Obviously, there was no existing polymorph transformation or solvate formation during the experiment process. In addition, the XPRD patterns of gimeracil is very consistent with that of gimeracil (form P) reported in the previous works [37,38]. 3.2. Solubility values The experimental mole fraction solubility (x) of gimeracil (form P) in pure isopropanol, DMF, EG, DMSO and water within the temperature at (283.15–328.15) K are presented in Tables 2–5, and shown graphically in Figure 2. As can be seen from the Figure 2, the solubility of gimeracil (form P) increases with increasing temperature. It is highest in DMF, and lowest in water. Furthermore, the dissolving capacity of gimeracil (form P) in neat solvents are DMF > DMSO > 11

EG > isopropanol > water. Gimeracil (form P) is found to exhibit up to near 102-fold increase in mole fraction solubility in going from water to DMF and DMSO. For example, if the temperature increases from 293.15 K to 328.15 K, the mole fraction solubility of gimeracil (form P) in DMSO increases from 3.81710-2 to 9.22910-2; while in water, it increases from 0.0168410-2 to 0.0247310-2. Meanwhile, it makes the comparison of gimeracil (form P) solubility in water determined in this work with that reported in the publication [15], which is shown graphically in Figure S3 of Supporting material. Based on the aqueous solubility reported in the previous works and determined by us, the largest relative error is calculated to be 1.69 % resulting from some differences of experimental instruments and conditions. The mole fraction solubility of gimeracil (form P) in binary co-solvent mixtures of {isopropanol (1) + water (2)}, {DMF (1) + water (2)}, {EG (1) + water (2)} and {DMSO (1) + water (2)} are also listed in Tables 2, 3, 4 and 5. Furthermore, the relationship between the measured solubility and temperature and solvent composition are demonstrated graphically in Figs. 3-6. It can be seen from Tables 2-5 that the gimeracil (form P) solubility data is a function of temperature and solvent composition for the all co-solvent mixtures. The mole fraction solubility of gimeracil (form P) increases with increasing temperature and mass fraction of isopropanol, DMF, EG and DMSO for aqueous co-solvent solutions. Apparently, the solubility of gimeracil (form P) in (DMF + water) is greater than those in (isopropanol + water), (DMF+ water) and (DMSO + water) at the same temperature and co-solvent composition. 3.3. Solvent effect on solubility KAT-LSER model was performed on solubility data of gimeracil (form P) determined in four co-solvent mixtures at 298.15 K in order to elucidate the main contributors to the solvent effect. Vs =

93.2

cm3mol-1

was

used

according

to

SciFinder

database

(https://scifinder.cas.org/scifinder/view/scifinder/scifinderExplore.jsf). The KAT parameters , ,

* for (DMF + water), (DMSO + water) and (isopropanol + water) were collected from different 12

sources [39-44]. While the KAT parameters for EG + water mixtures were determined in this work. Due to the fact that these parameters are taken from different sources, so as to make an analogous tabulation, data is corrected with respect to the accepted literature data for pure solvent [45] by a procedure explained previously [36], and then tabulated in Table S1 of supporting material. Data H for pure solvents is obtained from Hansen [46]. Then, H for binary mixtures (Table S1 of Supporting material) is calculated by as a function of the volume fraction for solvent i,

i, in the mixture [6]. Eq. (2) presents the general form of KAT-LSER model having all molecular descriptors. In practice, a variety of 15 equations are made up of molecular descriptors for different mixtures. These equations are correlated to experimental solubility data of gimeracil (form P) in binary co-solvent mixtures through the multiple linear regression analysis. The regressed results are presented in Tables S2-S5 of Supporting material. In fact that any solute-solvent interaction has a positive effect on the solubility, so the coefficient value of ci for ,  and * is expected to be positive in KAT-LSER model. On the other hand, solvent-solvent interactions do play negative role in the solute solubility, because the creation of the hole within the solvent is an energy-consuming step in the solubilization process, and therefore c4 is expected to be negative in a proper KAT-LSER model. Considering these physical constraints, a model is judged as the best solvent-effect expression that shows statistically the highest F-statistic and squared correlation coefficient, r2, and lowest standard deviations [47]. The best KAT-LSER model for each binary mixture is bolded in Tables S2-S5 of Supporting material. As is seen from Table S2, the solubility of gimeracil (form P) correlates well with *, and cavity terms in isopropanol + water mixture. This model explains 98 % of variation in the solubility. The coefficienst of variables indicate that the effect of hydrogen-bond donor is 1.57 times and 1.73 times higher than that of dipolarity/polarizability term and cavity term, respectively. The KAT-LSER modelling on the solubility of gimeracil (form P) (Table S3) shows that 13

dipolarity/polarizability and hydrogen-bond donor play an important role on the solubility. In this respect, hydrogen-bond acidity of solvent is of a little significance, whereas hydrogen-bond basicity plays the main role. This observation is in support of the molecular structure of gimeracil (form P) in Figure 1. As is pointed out above, the solute undergoes hydrogen-bonding interactions with the solvent through the acidic hydrogen of amine group in its structure. The contribution of specific solute-solvent interactions is prevailing over others. Table S4 reveals that the solvent effect is mainly explained by solute-solvent interactions in terms of combined H and * descriptors in EG + water mixtures. Analysis of ci indicates that * and H explain 52.8 % and 47.2 % of variation in the solubility of gimeracil (form P), respectively. Table S5 shows that the solvent effect is mainly attributed to all KAT parameters  and * of DMSO + water mixtures. Changes in  and * describe respectively 61.9 % and 38.1 % of variation in the solubility, which means that dipolarity/polarizability of solvent is of 1.63 times more significance than hydrogen-bond basicity. The obtained coefficient for in all models is negative, indicating that hydrogen-bond donor capacity of solvent shows insignificant effect on the solubility, and thus gimeracil (form P) acts most likely as a hydrogen-bond donor solute. 3.4. Solubility correlation and calculation The experimental solubility of gimeracil (form P) in the selected co-solvent mixtures is correlated and calculated with Eq. (1). During the regression process, the objective function is defined as

F    ln xie  ln xic 

2

(13)

i=1

In addition, in order to evaluate the selected models, the relative average deviation (RAD) and root-mean-square deviation (RMSD) are also employed as Eqs. (14) and (15). 1 RAD  N

RMSD 

c e  xw,T  xw,T   xe w,T 



N i 1

   

(14)

c e ( xw,T  xw,T )2

(15)

N

14

e where N denotes the number of experimental data points. xw,T stands for the mole fraction

c solubility determined in this work; and xw,T , calculated with the corresponding solubility model.

Based on the experimental data, the parameters of Eq. (1) can be calculated by the Mathcad software. The achieved values of model parameters are listed in Table S6 of Supporting material, together with the RAD and the RMSD values. The back-calculated solubility of gimeracil (form P) in binary mixtures of (isopropanol + water), (DMF + water), (EG + water) and (DMSO + water) using the Jouyban−Acree model is shown graphically in Figs. 3-6. Table S6 shows that for the selected aqueous co-solvent solutions, the maximum value of RAD between the calculated and experimental values is 2.61 %, which is obtained for the system of (DMF + water). The RMSD values are no more than 14.96×10-4. As a result, the Jouyban-Acree model provides satisfactory correlation results for the solubility of gimeracil (form P) in the aqueous mixtures of co-solvents (isopropanol, DMF, EG and DMSO). 3.5. Preferential solvation of gimeracil (form P) The standard molar Gibbs energies of transfer of gimeracil (form P) at 298.15 K from neat water (2) to DMF (1) + water (1), EG (1) + water (1), isopropanol (1) + water (1) and DMSO (1) + water (2) mixtures are computed from the solubility data via Eq. (9). These values are tabulated in Table S7 and shown in Figure S4 of Supporting material. 0 The values of  tr G3,2 1 2 are correlated using Eq. (16) for the four co-solvent + water mixtures.

 tr G

0 3,21 2

 A0  A1e



x1 t1

 A2e



x1 t2

(16)

here A0, A1, A2, t1 and t2 are equation parameters. The obtained equation coefficients are presented in Table S8 of Supporting material. Thus, D values are calculated from the first derivative of Eq. (16) solved according to the co-solvent mixture composition varying by 0.05 in mole fraction of co-solvent (1) and reported in Tables S9-S12 of Supporting material. Because no partial molar volumes of gimeracil (form P) (3) in these mixtures are available in the 15

literature, in this work this property is considered as similar to that for the pure compound as a good approximation. From this volume value, solute radius value (r3) is calculated using Eq. (11) as 0.333 nm. In addition, the RTκT values and the partial molar volumes of both solvents in the DMF (1) + water (1), isopropanol (1) + water (1) and DMSO (1) + water (2) mixtures as well as the Q -1 values at 298.15 K have been presented in Refs. [5,18]. The G1Exc  2 values (in J·mol ) at 298.15 K

are calculated according Eq. (17) for the EG (1) + water (2) solvent mixtures [6]. 2   G1Exc  2  x1 (1  x1 )  558  164(1  2 x1 )  189(1  2 x1 ) 

(17)

The partial molar volumes of both solvents in the EG + water mixtures are calculated from the reported density values of the solvent mixtures at 298.15 K under study by Egorov [48] using Eqs. (18) and (19). Here V is the molar volume of the mixtures calculated as V =(x1·M1 + x2·M2)/ρ. Here, M1 is 62.07 g·mol–1 for EG and M2 is 18.01 g·mol–1 for water.

V1  V  x2

dV dx1

(18)

V2  V  x1

dV dx1

(19)

Therefore, the values of G1,3 and G2,3 in the four binary co-solvent mixtures can be obtained and shown in Tables S9-S12 of Supplementary material. It can be seen that the G1,3 and G2,3 values are negative in all cases. This behavior shows that gimeracil (form P) exhibit affinity for the solvents in these mixtures. The iterated values of correlation volume Vcor and δx1,3 are tabulated in Tables S9 to S12 of Supporting material for gimeracil (form P) in DMF (1) + water (2), DMSO (1) + water (2), isopropanol (1) + water (2) and EG (1) + water (1) mixtures, respectively. Furthermore, the plots of δx1,3 values versus co-solvent 1 (DMF, DMSO, isopropanol and EG) compositions are shown graphically in Figure 7. It demonstrates that the dependence of δx1,3 values on the co-solvent (1) proportion in the co-solvent mixtures is non-linear. According to Figure 7, addition of co-solvent (DMF, isopropanol, EG and DMSO) makes negative the δx1,3 values of gimeracil (form P) (3) from 16

neat water up to x1 = 0.25 mole fraction of the co-solvents. Maximum negative values are obtained with the composition x1 = 0.05 with δx1,3 = −2.606×10−2 for the isopropanol (1) + water (2), δx1,3 = −5.323×10−2 for the DMF (1) + water (2), δx1,3 = −2.971×10−2 for the EG (1) + water (2) and δx1,3 = −7.707×10−2 for DMSO (1) + water (2) mixtures, respectively. Probably the structuring of water molecules around the gimeracil (form P) contributes to lowering of the net δx1,3 to negative values in the four co-solvent mixtures. In the isopropanol (1) + water (2) mixture with composition 0.25 < x1 < 1, the local mole fractions of isopropanol are higher than those of the mixtures and therefore the δx1,3 values are positive indicating preferential solvation of gimeracil (form P) by the co-solvent. The co-solvent action to increase the solute solubility may be related to the breaking of the ordered structure of water around the gimeracil (form P) which increases the solvation having maximum values in x1 = 0.60 with δx1,3 = 5.350×10−2 for isopropanol (1) + water (2) mixture. It is important to note that the in the region of 0.25 < x1 < 1.00, absolute values of δx1,3 are lower than 1.0×10−2 for the EG (1) + water (2), DMF (1) + water (2) and DMSO (1) + water (2) mixtures. The result is a consequence of the effect of uncertainties propagation instead of the preferential solvation [49]. On the basis of a structural and functional group analysis, gimeracil (form P) can act as a Lewis acid in solution due to the ability of the acidic hydrogen atom in its –NH- and –OH groups (Figure 1) to establish hydrogen bonds with proton-acceptor functional groups of the co-solvents (oxygen atoms in –OH group). In addition, gimeracil (form P) can also act as a Lewis base because of the free electron pairs in nitrogen atoms of >NH, =O and -OH (Figure 1), which interact with acidic hydrogen atoms of water. According to the preferential solvation results, it is conjecturable that in the region of 0.25 < x1 < 1.00 for isopropanol, gimeracil (form P) is acting as a Lewis acid with the isopropanol molecules, because isopropanol is more basic than water, as described by the Kamlet–Taft hydrogen bond acceptor parameters, i.e. β=0.84 for isopropanol and β = 0.47 for water [45]. On the other hand, in water-rich mixtures, where gimeracil (form P) is preferentially solvated by water, gimeracil (form P) could be acting mainly as a Lewis base in front to water because the 17

Kamlet–Taft hydrogen bond donor parameters are, α = 0.90 for EG, 0.76 for isopropanol, 0 for DMSO and DMF, and 1.17 for water [45].

4. Conclusion The equilibrium solubility of the gimeracil (form P) in four co-solvent mixtures of (isopropanol, DMF, EG and DMSO) plus water was obtained via the isothermal equilibrium method between 283.15 K and 328.15 K under 101.2 kPa. For the studied aqueous co-solvent mixtures, the mole fraction solubility of gimeracil (form P) increased with increasing temperature and mass fraction of isopropanol, DMF, EG and DMSO for the four solution systems, and the maximum solubility of gimeracil (form P) was observed in pure DMF. The dependence of gimeracil (form P) solubility upon temperature and co-solvent composition was correlated with the Jouyban-Acree model. The RAD and RMSD were no more than 2.61×10-2 and 14.96×10-4, respectively. KAT-LSER model was employed to study the solvent effect on the solubility variation of gimeracil (form P) in mixtures studied. The significant effect of *,  and cavity term in isopropanol + water, * and in DMF + water, the cavity term and * in EG + water and  and * in DMSO + water mixtures was observed from multiple linear regression analysis. Gimeracil (form P) was preferentially solvated by isopropanol for the isopropanol mixtures in intermediate and isopropanol-rich compositions. It is conjecturable that in this region gimeracil (form P) could be acting mainly as a Lewis acid in front to isopropanol. Nevertheless, gimeracil (form P) is not preferentially solvated by DMF, EG and DMSO in the intermediate and DMF, EG and DMSO-rich compositions.

References [1] A. Jouyban, Handbook of Solubility Data for Pharmaceuticals, CRC Press, BocaRaton, FL, 2010. [2] J.T. Rubino, Cosolvents and Cosolvency, in: J. Swarbrick, J.C. Boylan (Eds.), Encyclopedia of Pharmaceutical Technology, 3, Marcel Dekker, New York, NY, 1988. 18

[3] A. Avdeef, Absorption and Drug Development, Solubility, in: Permeability and Charge State, Wiley-Interscience, Hoboken, NJ, 2003. [4] M.E. Aulton, Pharmaceutics. The Science of Dosage Forms Design, second ed., Churchill Livingstone, London, 2002. [5] A. Jouyban, W.E. Acree Jr., F. Martínez, Modelling the solubility and preferential solvation of gallic acid in cosolvent + water mixtures, J. Mol. Liq. 224 (2016) 502–506. [6] Y. Marcus, Solvent Mixtures: Properties and Selective Solvation, Marcel Dekker, Inc., New York, NY, 2002. [7] Y. Marcus, Preferential Solvation in Mixed Solvents, in: P.E. Smith, E. Matteoli, J.P. O’Connell (Eds.), Fluctuation Theory of Solutions: Applications in Chemistry, Chemical Engineering, and Biophysics, CRC, Press, Taylor & Francis Group, BocaRaton, FL, 2013. [8] X.J. Li, H.T. Zhu, L. Zhan, T. Liu, G. Cheng, N. Liu, S.B. Yu, H. Li, Y. Luo, F. Yang, J. Tang, A convenient synthesis of gimeracil, J. Chem. Res. 42 (2018) 33–34. [9] J. Itou, H. Tsukihara, M. Nukatsuka, M. Toi, T. Takechi, 5-Chloro-2,4-dihydroxypyridine, CDHP, prevents lung metastasis of basal-like breast cancer cells by reducing nascent adhesion formation, Cancer Med-US. 7 (2018) 463–470. [10] T. Wang, S.F. Zhang, M.Q. Qiu, Q.L. Li, Efficacy and safety of S-1 (tegafur, gimeracil, and oteracil potassium) concurrent with 3-dimensional conformal radiotherapy for newly diagnosed squamous cell carcinoma of the lung in elderly patients, Cancer/Radiothérapie 20 (2016) 181–186. [11] K. Sakata, M. Someya, Y. Matsumoto, H. Tauchi, M. Kai, M. Toyota, M. Takagi, M. Hareyama, M. Fukushima, Gimeracil, an inhibitor of dihydropyrimidine dehydrogenase, inhibits the early step in homologous recombination, Cancer Sci. 102 (2011) 1712–1716. [12] M. Takagi, K. Sakata, M. Someya, H. Tauchi, K. Iijima, Y. Matsumoto, T Torigoe, A. Takahashi, M. Hareyama, M. Fukushima, Gimeracil sensitizes cells to radiation via inhibition of homologous recombination, Radiother Oncol. 96 (2010) 259–266. [13] M. Fukushima, K. Sakamoto, M. Sakata, F. Nakagawa, H. Saito, Y. Sakata, Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo, Oncol. Rep. 24 (2010) 1307–1313. 19

[14] M. Kobayakawa, Y. Kojima, Tegafur/gimeracil/oteracil (S-1) approved for the treatment of advanced gastric cancer in adults when given in combination with cisplatin: a review comparing it with other fluoropyrimidine-based therapies, Onco Targets Terapy. 4 (2011) 193–201. [15] B. Yao, Study on synthesis of components of anticancer drug S-1, Thesis for master degree, Southeast University, 2013. (Chinese) [16] A. Jouyban, Review of the cosolvency models for predicting solubility of drugs in water-cosolvent mixtures, J. Pharm. Pharmaceut. Sci. 11 (2008) 32–58. [17] J. Chen, G.Q. Chen, Y. Cong, C.B. Du, H.K. Zhao, Solubility modelling and preferential solvation of paclobutrazol in co-solvent mixtures of (ethanol, n-propanol and 1,4-dioxane) + water, J. Chem. Thermodyn. 112 (2017) 249–258. [18] F. Martínez, A. Jouyban, W.E. Acree Jr., Preferential solvation of etoricoxib in some aqueous binary cosolvent mixtures at 298.15 K, Phys. Chem. Liq. 55 (2016) 291–303. [19] R.W. Taft, J.L.M. Abboud, M.J. Kamlet, M.H. Abraham, Linear solvation energy relations, J. Solution Chem. 14 (1985) 153–186. [20] R.W. Taft, M.J. Kamlet, The solvatochromic comparison method. 2. The alpha.-scale of solvent hydrogen-bond donor (HBD) acidities, J. Am. Chem. Soc. 98 (1976) 2886–2894. [21] M.J. Kamlet, R.M. Doherty, J.L.M. Abboud, M.H. Abraham, R.W. Taft, Linear solvation energy relationships: 36. Molecular properties governing solubilities of organic nonelectrolytes in water, J. Pharm. Sci. 75 (1986) 338–349. [22] M.J. Kamlet, J.L.M. Abboud, M.H. Abraham, R.W. Taft, Linear solvation energy relationships. 23. A comprehensive collection of the solvatochromic parameters, pi.*, .alpha., and .beta., and some methods for simplifying the generalized solvatochromic equation, J. Org. Chem. 48 (1983) 2877–2887. [23]

P.B.

Rathi,

V.K.

Mourya,

Solubility

prediction

of

satranidazole

in

aqueous

N,N-dimethylformamide mixtures using extended hildebrand solubility approach, Indian J. Pharm. Sci. 74 (2012) 254–258. 20

[24] A.G. Asuero, M.A. Herrador, A.G. Gonzalez, Estimation of pH and autoprotolysis constants in mixtures of aliphatic amides with water: Medium effect on the 4‑aminoazobenzene system, Talanta 40 (1993) 479–484. [25] R.J. Sindreu, M.L. Moya, B.F. Sanchez, A.G. Gonzalez, Solvent effects on the dissociation of aliphatic carboxylic acids in water-N,N-dimethylformamide mixtures: Correlation between acidity constants and solvatochromic parameters, J. Solution Chem. 23 (1994) 1101–1109. [26] G.D. Maia, M. Giulietti, Solubility of acetylsalicylic acid in ethanol, acetone, propylene glycol, and 2-propanol, J. Chem. Eng. Data 53 (2008) 256–258. [27] M. Mohammadzade, M. Barzegar-Jalali, A. Jouyban, Solubility of naproxen in 2-propanol + water mixtures at various temperatures, J. Mol. Liq. 206 (2015)110–113. [28] K.V. Balakin, DMSO solubility and bioscreening, Curr. Drug Discov. 8 (2003) 27−30. [29] S.H. Yalkowsky, S.C. Valvani, G.L. Amidon, Solubility of nonelectrolytes in polar solvents IV: nonpolar drugs in mixed solvents, J. Pharm. Sci. 65 (2010) 1488–1494. [30] F. Shakeel, M.F. Alajmi, N. Haq, N.A. Siddiqui, P. Alam, A.J. Al-Rehaily, Solubility and thermodynamic function of a bioactive compound bergenin in various pharmaceutically acceptable neat solvents at different temperatures, J. Chem. Thermodyn. 101 (2016) 19–24. [31] S. Han, L. Meng, C.B. Du, J. Xu, C. Cheng, J. Wang, H.K. Zhao, Solubility measurement and thermodynamic modelling of 4-nitrophthalimide in twelve pure solvents at elevated temperatures ranging from (273.15 to 323.15) K, J. Chem. Eng. Data 61 (2016) 2525–2535. [32] S. Li, Determination of three components in Tegafur, Gimeracil and Oteracil Potassium Tablets by HPLC, China Pharmacist 22 (2008) 984–986. (Chinese) [33] R.J. Xu, M. Zheng, A. Farajtabar, H.K. Zhao, Solubility modelling and preferential solvation of adenine in solvent mixtures of (N,N-dimethylformamide, N-methyl pyrrolidone, propylene glycol and dimethyl sulfoxide) plus water, J. Chem. Thermodyn. 125 (2018) 225–234. [34] Q.C. He, Y. Cong, M. Zheng, A. Farajtabar, H.K. Zhao, Solubility of L-tyrosine in aqueous solutions of methanol, ethanol, n-propanol and dimethyl sulfoxide: Experimental determination and 21

preferential solvation analysis, J. Chem. Thermodyn. 124 (2018) 123–132. [35] R.J. Xu, Y.Q. Du, J. Wang, A. Farajtabar, H.K. Zhao, Solubility modelling, solvent effect and preferential solvation of carbendazim in aqueous co-solvent mixtures of N,N-dimethylformamide, methanol, ethanol and n-propanol, J. Chem. Thermodyn. 128 (2019) 87–96. [36] X.B. Li, S. Feng, A. Farajtabar, N. Zhang, G.Q. Chen, H.K. Zhao, Solubility modelling, solvent effect and preferential solvation of 6-chloropurine in several aqueous co-solvent mixtures between 283.15 K and 328.15 K, J. Chem. Thermodyn. 127 (2018) 106–116. [37] P.H. Wang, Y. Liu, Y.M. Ding, Q.W. Hang, Preparation and identification of gimeracil polymorphs, Chin. J. Med. Chem. 18 (2008) 44–47. (Chinese) [38] S.L. Wang, J. Cai, Z.F. Yan, Gimeracil crystal form and preparation method thereof, CN Patent 101607936, Dec 23, 2009. [39] U. Buhvestov, F. Rived, C. Rafols, E. Bosch, M. Roses, Solute–solvent and solvent–solvent interactions in binary solvent mixtures. Part 7. Comparison of the enhancement of the water structure in alcohol–water mixtures measured by solvatochromic indicators, J. Phys. Org. Chem. 11 (1998) 185–192. [40] M. Roses, U. Buhvestov, C. Ràfols, F. Rived, E. Bosch, Solute–solvent and solvent–solvent interactions in binary solvent mixtures. Part 6. A quantitative measurement of the enhancement of the water structure in 2-methylpropan-2-ol–water

and propan-2-ol–water mixtures

by

solvatochromic indicators, J. Chem. Soc. Perkin Trans. 2 (1997) 1341–1348. [41] Y. Migron, Y. Marcus, Polarity and hydrogen-bonding ability of some binary aqueous–organic mixtures, J. Chem. Soc. Faraday Trans. 87 (1991) 1339–1343. [42] A. Duereh, Y. Sato, R.L. Smith, H. Inomata, F. Pichierri, Does synergism in microscopic polarity correlate with extrema in macroscopic properties for aqueous mixtures of dipolar aprotic solvents? J. Phys. Chem. 121 B (2017) 6033–6041. [43] R.D. Skwierczynski, K.A. Connors, Solvent effects on chemical processes. Part 7. Quantitative description of the composition dependence of the solvent polarity measure E(30) in binary aqueous–organic solvent mixtures, J. Chem. Soc. Perkin Trans. 2 (1994) 467–472. 22

[44] T.M. Krygowski, P.K. Wrona, U. Zielkowska, C. Reichardt, Empirical parameters of lewis acidity and basicity for aqueous binary solvent mixtures, Tetrahedron 41 (1985) 4519–4527. [45] Y. Marcus, The properties of organic liquids that are relevant to their use as solvating solvents, Chem. Soc. Rev. 22 (1993) 409–416. [46] C.M. Hansen, Hansen Solubility Parameters: A User's Handbook, CRC press, 2007. [47] A. Farajtabar, F. Gharib, Spectral analysis of naringenin deprotonation in aqueous ethanol solutions, Chem. Papers 67 (2013) 538–545. [48] G.I. Egorov, D.M. Makarov, A.M. Kolker, Volumetric properties of the water-ethylene glycol mixtures in the temperature range 278–333.15 K at atmospheric pressure, Russ. J. Gen. Chem. 80 (2010) 1577–1585. [49] Y. Marcus, Solubility and solvation in mixed solvent systems, Pure Appl Chem. 62 (1990) 2069–2076.

23

OH Cl N H

O

Figure 1. Molecular structure of gimeracil.

24

0.105 0.084 0.063

x

0.042 0.012 0.008 0.004 0.000 280

290

300

310

320

330

T/K Figure 2. Mole fraction solubility of gimeracil (form P) in pure solvents at different temperatures: ●, DMF; ▼, DMSO; ☆, EG; ▲, isopropanol; ◆, water.

25

0.0105 0.0090 0.0075

x

0.0060 0.0045 0.0030 0.0015 330

320

0.6 310

T/K

0.4 300

0.2 290

1.0 0.8

w

0.0 280

Figure 3. Mole fraction solubility (x) of gimeracil (form P) in isopropanol (w) + water (1-w) solutions with various mass fractions at different temperatures: w, mass fraction of isopropanol; ☆, w = 1; △, w = 0.9012; ○, w = 0.8002; □, w = 0.6987; ★, w = 0.6000; ◇, w = 0.5002; ◆, w = 0.3989; ▼, w = 0.3007; ▲, w = 0.2003; ●, w = 0.1000; ■, w = 0; —, calculated curves by the Jouyban−Acree model.

26

0.10 0.08

x

0.06 0.04 0.02 330

320

1.0 0.8 0.6

310

T/K

0.4

300

0.2

290 280

0.0

w

Figure 4. Mole fraction solubility (x) of gimeracil (form P) in DMF (w) + water (1-w) solutions with various mass fractions at different temperatures: w, mass fraction of DMF; ☆, w = 1; △, w = 0.9009; ○, w = 0.8000; □, w = 0.7001; ★, w = 0.5999; ◇, w = 0.5006; ◆, w = 0.3990; ▼, w = 0.3000; ▲, w = 0.2011; ●, w = 0.1006; ■, w = 0; —, calculated curves by the Jouyban−Acree model.

27

0.0125

x

0.0100 0.0075 0.0050 0.0025 330

320

0.6

310

0.4

300

T/K

1.0 0.8

0.2

290 280

w

0.0

Figure 5. Mole fraction solubility (x) of gimeracil (form P) in EG (w) + water (1-w) solutions with various mass fractions at different temperatures: w, mass fraction of EG; ☆, w = 1; △, w = 0.8962; ○, w = 0.7995; □, w = 0.7003; ★, w = 0.5980; ◇, w = 0.4999; ◆, w = 0.4012; ▼, w = 0.3003; ▲, w = 0.1998; ●, w = 0.0995; ■, w = 0; —, calculated curves by the Jouyban−Acree model.

28

0.10 0.08

x

0.06 0.04 0.02 1.0 0.8 0.6

330 320 310

T/K

300

0.2

0.4 w

0.0

Figure 6. Mole fraction solubility (x) of gimeracil (form P) in DMSO (w) + water (1-w) solutions with various mass fractions at different temperatures: w, mass fraction of DMSO; ☆, w = 1; △, w = 0.8990; ○, w = 0.8001; □, w = 0.7013; ★, w = 0.6000; ◇, w = 0.4990; ◆, w = 0.4001; ▼, w = 0.3018; ▲, w = 0.2000; ●, w = 0.1010; ■, w = 0; —, calculated curves by the Jouyban−Acree model.

29

6 4

x1,3

2 0 -2 -4 -6 -8 0.0

0.2

0.4

0.6

0.8

1.0

x1

Figure 7. δx1,3 values of gimeracil (form P) (3) in isopropanol (w) + water (1-w), DMF (w) + water (1-w), EG (w) + water (1-w) and DMSO (w) + water (1-w) mixtures at 298.15 K. ■, isopropanol (1) + water (2); ●, DMF (1) + water (2); ▲, EG (1) + water (2); ▼, DMSO (1) + water (2).

30

Table 1 Chemicals, purity and properties of the drug and reagents employed in this work. Chemicals

Molar mass -1

/(g·mol )

Gimeracil (P- form)

145.54

Ethanol

46.07

Isopropanol

60.06

Shanghai Energy Chem. Co., Ltd.

Aladdin Industrial (Shanghai)

DMF

73.10

Ethylene glycol

62.07

Para-nitroaniline

138.12

para-nitroanisole

153.14

Reichardt’s dye

551.68

Water

18.02

Mass

Source

Sigma-Aldrich Co, Iran

b

Gas chromatography.

Analytical

purity

method

method

0.996

None

HPLCa

0.994

None

GCb

0.995

None

GC

0..995

None

GC

0.996

None

GC

0.995

None

HPLC

0.995

None

HPLC

9.996

None

HPLC

Conductivity

Our lab

High-performance liquid chromatography.

Purification

Co.,

Ltd.

a

fraction

< 1 µS·cm-1

31

Distillation

Conductivity meter

Table 2 e

Equilibrium mole fraction solubility (100 xT,w ) of gimeracil (form P) in isopropanol (w) + water (1-w) mixture with different mass fractions ranging from T = (283.15 to 328.15) K under 101.2 kPa.a e

Mole fraction solubility (100 xT,w ) T/K

w 0

0.1000

0.2003

0.3007

0.3989

0.5002

0.6000

0.6987

08002

0.9012

1

283.15 0.01718

0.05070

0.08533

0.1187

0.1411

0.1570

0.1720

0.1906

0.2082

0.2249

0.2418

288.15 0.01781

0.05247

0.08929

0.1297

0.1518

0.1719

0.1915

0.2196

0.2407

0.2644

0.2882

293.15 0.01864

0.05483

0.09416

0.1380

0.1680

0.1889

0.2138

0.2523

0.2810

0.3154

0.3427

298.15 0.01937

0.05689

0.1026

0.1426

0.1810

0.2070

0.2381

0.2806

0.3237

0.3717

0.4076

303.15 0.02027

0.05925

0.1041

0.1480

0.1948

0.2264

0.2642

0.3114

0.3760

0.4333

0.4791

308.15 0.02102

0.06131

0.1123

0.1562

0.2075

0.2447

0.2933

0.3534

0.4195

0.5061

0.5543

313.15 0.02184

0.06367

0.1097

0.1654

0.2182

0.2660

0.3266

0.3941

0.4788

0.5751

0.6472

318.15 0.02265

0.06603

0.1226

0.1825

0.2367

0.2879

0.3576

0.4295

0.5390

0.6379

0.7497

323.15 0.02354

0.07222

0.1276

0.1919

0.2517

0.3101

0.3894

0.4814

0.6012

0.7260

0.8580

328.15 0.02473

0.07546

0.1344

0.2040

0.2626

0.3370

0.4118

0.5265

0.6783

0.8386

0.9872

a

Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45 kPa; Relative standard uncertainty ur is ur (x) = 0.046.

Solvent mixtures were prepared by mixing various masses of the solvents with relative standard uncertainty ur(w) = 0.0002. w represents the mass fraction of isopropanol in solvent mixtures of isopropanol + water mixture.

32

Table 3 e

Equilibrium mole fraction solubility (100 xT,w ) of gimeracil (form P) in DMF (w) + water (1-w) mixture with different mass fractions ranging from T = (283.15 to 328.15) K under 101.2 kPa.a e

Mole fraction solubility (100 xT,w ) T/K

w 0

0.1006

0.2011

0.3000

0.3990

0.5006

0.5999

0.7001

0.8000

0.9009

1

283.15 0.01718

0.2513

0.9925

1.719

1.864

1.892

1.995

2.332

2.662

2.940

3.151

288.15 0.01781

0.2536

0.9971

1.744

1.963

2.031

2.137

2.572

2.962

3.348

3.624

293.15 0.01864

0.2588

1.014

1.792

2.069

2.096

2.332

2.789

3.465

3.922

4.233

298.15 0.01937

0.2622

1.023

1.865

2.140

2.209

2.532

3.023

3.903

4.435

4.838

303.15 0.02027

0.2675

1.038

1.905

2.219

2.330

2.742

3.270

4.367

5.018

5.488

308.15 0.02102

0.2710

1.049

1.980

2.297

2.456

2.928

3.428

4.839

5.657

6.264

313.15 0.02184

0.2751

1.060

2.017

2.374

2.581

3.070

3.826

5.281

6.340

7.072

318.15 0.02265

0.2791

1.072

2.054

2.454

2.713

3.307

4.092

5.812

7.084

7.997

323.15 0.02354

0.2838

1.086

2.094

2.536

2.847

3.548

4.524

6.355

7.838

8.969

328.15 0.02473

0.2918

1.112

2.196

2.649

3.018

3.959

5.105

7.084

8.591

10.14

a

Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45 kPa; Relative standard uncertainty ur is ur (x) = 0.046.

Solvent mixtures were prepared by mixing various masses of the solvents with relative standard uncertainty ur(w) = 0.0002. w represents the mass fraction of DMF in solvent mixtures of DMF + water mixture.

33

Table 4 e

Equilibrium mole fraction solubility (100 xT,w ) of gimeracil (form P) in EG (w) + water (1-w) mixture with different mass fractions ranging from T = (283.15 to 328.15) under 101.2 kPa.a e

Mole fraction solubility (100 xT,w ) T/K

w 0

0.0995

0.1998

0.3003

0.4012

0.4999

0.5980

0.7003

0.7995

0.8962

1

283.15 0.01718

0.05890

0.1218

0.1799

0.2193

0.2449

0.2689

0.3013

0.3270

0.3517

0.3671

288.15 0.01781

0.06084

0.1265

0.1890

0.2338

0.2652

0.2959

0.3371

0.3861

0.4095

0.4320

293.15 0.01864

0.06906

0.1323

0.1996

0.2501

0.2877

0.3256

0.3763

0.4378

0.4700

0.5044

298.15 0.01937

0.06569

0.1379

0.2160

0.2674

0.3123

0.3590

0.4216

0.4980

0.5534

0.5934

303.15 0.02027

0.06846

0.1443

0.2278

0.2914

0.3385

0.3944

0.4696

0.5621

0.6381

0.6898

308.15 0.02102

0.07622

0.1554

0.2438

0.3087

0.3638

0.4350

0.5188

0.6346

0.7209

0.7953

313.15 0.02184

0.08422

0.1609

0.2548

0.3268

0.3904

0.4725

0.5711

0.7125

0.8140

0.9111

318.15 0.02265

0.08675

0.1668

0.2716

0.3462

0.4188

0.5184

0.6287

0.7980

0.9239

1.044

323.15 0.02354

0.08928

0.1731

0.2838

0.3659

0.4488

0.5613

0.6902

0.8793

1.036

1.190

328.15 0.02473

0.09854

0.1866

0.2986

0.3895

0.4827

0.6035

0.7578

0.9795

1.155

1.350

a

Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45 kPa; Relative standard uncertainty ur is ur (x) = 0.046.

Solvent mixtures were prepared by mixing various masses of the solvents with relative standard uncertainty ur(w) = 0.0002. w represents the mass fraction of EG in solvent mixtures of EG + water mixture.

34

Table 5 e

Equilibrium mole fraction solubility (100 xT,w ) of gimeracil (form P) in DMSO (w) + water (1-w) mixture with different mass fractions ranging from T = (293.15 to 328.15) K under 101.2 kPa.a e

Mole fraction solubility (100 xT,w ) w T/K 0

0.1010

0.2000

0.3018

0.4001

0.4990

0.6000

0.7013

0.8001

0.8999

1

293.15 0.01864

0.2150

0.8628

1.814

2.350

2.521

2.536

2.827

3.081

3.394

3.817

298.15 0.01937

0.2185

0.8722

1.845

2.423

2.644

2.710

3.102

3.532

3.843

4.359

303.15 0.02027

0.2237

0.8890

1.892

2.518

2.794

2.880

3.419

3.958

4.363

5.005

308.15 0.02102

0.2273

0.8995

1.962

2.599

2.932

3.077

3.773

4.374

4.806

5.705

313.15 0.02184

0.2316

0.9124

2.002

2.687

3.079

3.290

4.082

4.787

5.337

6.487

318.15 0.02265

0.2354

0.9234

2.035

2.767

3.218

3.498

4.413

5.300

5.912

7.300

323.15 0.02354

0.2401

0.9377

2.114

2.859

3.373

3.692

4.745

5.848

6.575

8.231

328.15 0.02473

0.2473

0.9236

2.173

2.969

3.549

3.905

4.916

6.415

8.153

9.229

a

Standard uncertainties u are u(T) = 0.02 K, u(p) = 0.45 kPa; Relative standard uncertainty ur is ur (x) = 0.046.

Solvent mixtures were prepared by mixing various masses of the solvents with relative standard uncertainty ur(w) = 0.0002. w represents the mass fraction of DMSO in solvent mixtures of DMSO + water mixture.

35

Highlights ► Solubility of gimeracil (form P) in four co-solvent mixtures was determined and correlated. ► Solvent effect analysis was performed according to experimental solubility data. ► Preferential solvation of gimeracil (form P) were derivatived by IKBI method.

36

Graphic abstract 0.0105

6 OH

0.0090 0.0075

isopropanol (w) + water (1-w)

4

Cl N H

2

O

x1,3

x

0.0060 0.0045 0.0030

-2

isopropanol (1) + water (2) DMF (1) + water (2) EG (1) + water (2) DMSO (1) + water (2)

-4

0.0015 330

0

320

1.0 0.8 0.6 310

T/K

0.4 300

0.2 290

w

-6 -8 0.0

0.0

0.2

0.4

0.6

x1

280

37

0.8

1.0