Thermodynamic solubility, solvent effect and preferential solvation analysis of rebamipide in aqueous co-solvent mixtures of propylene glycol, n-propanol, isopropanol and ethanol

Journal Pre-proofs Thermodynamic solubility, solvent effect and preferential solvation analysis of rebamipide in aqueous co-solvent mixtures of propylene glycol, n-propanol, isopropanol and ethanol Wanxin Li, Ali Farajtabar, Rong Xing, Yiting Zhu, Hongkun Zhao, Rongguan Lv PII: DOI: Reference:

S0021-9614(19)31057-2 https://doi.org/10.1016/j.jct.2019.106045 YJCHT 106045

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J. Chem. Thermodynamics

Received Date: Revised Date: Accepted Date:

11 December 2019 27 December 2019 30 December 2019

Please cite this article as: W. Li, A. Farajtabar, R. Xing, Y. Zhu, H. Zhao, R. Lv, Thermodynamic solubility, solvent effect and preferential solvation analysis of rebamipide in aqueous co-solvent mixtures of propylene glycol, npropanol, isopropanol and ethanol, J. Chem. Thermodynamics (2019), doi: https://doi.org/10.1016/j.jct. 2019.106045

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Thermodynamic solubility, solvent effect and preferential solvation analysis of rebamipide in aqueous co-solvent mixtures of propylene glycol, n-propanol, isopropanol and ethanol Wanxin Lia, Ali Farajtabarb, Rong Xinga, Yiting Zhua, Hongkun Zhaoc*, Rongguan Lva* a School

of Chemistry and Environmental Engineering, Yancheng Teachers University, Yancheng, Jiangsu

224002, People’s Republic of China b Department

c College

of Chemistry, Jouybar Branch, Islamic Azad University, 4776186131, Jouybar, Iran

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).

Tel: + 86 515 88258980; Fax: + 86 515 88628866. E-mail address: [email protected] (Rongguan Lv).

ABSTRACT Mole fraction solubility of rebamipide (R- and S-enantiomer mixtures with a mole ratio of 50:50) in mixtures of propylene glycol (PG, 1) + water (2), n-propanol (1) + water (2) , isopropanol (1) + water (2) and ethanol (1) + water (2) was reported at temperature range from (273.15 to 318.15) K. All experiments were made by the use of the isothermal saturation technique under ambient pressure of 101.2 kPa. At the same mass fraction proportions of PG, n-propanol, isopropanol or ethanol and temperature, the rebamipide solubility was highest in the PG (1) + water (2) mixture. 1

The solubility data were correlated mathematically through the Jouyban-Acree model, attaining RAD values lower than 6.35 % and RMSD values lower than 6.7310-6. Quantitative values for local mole fraction of PG (n-propanol, isopropanol or ethanol) and water adjacent the rebamipide were determined by means of the Inverse Kirkwood–Buff integrals method applied to the determined solubility data. The preferential solvation parameters were negative in the water-rich mixtures but positive in the co-solvent compositions from 0 to 0.20 in mole fraction of n-propanol/PG, and from 0 to 0.25 in mole fraction of ethanol/isopropanol, respectively. It was conjectured that the preference of rebamipide in water-rich mixtures could be the result from the higher basic behaviour of rebamipide molecules interacting with the proton-donor functional groups of the water. In addition, the solubility variation over the composition range was analysed by KAT-LSER model to distinguish the main factors that explained solvent effect on solubility of rebamipide in the PG (n-propanol, isopropanol or ethanol) + water mixtures. It was found that the rebamipide solubility variation was mainly due to the change in the hydrogen bond acidity and cavity term for the ethanol (isopropanol, n-propanol) mixtures and the cavity term for the PG + water mixture.

Keywords: Rebamipide; Solubility; Jouyban-Acree; Preferential solvation; Solvent effect

1. Introduction Presently, the knowledge on drugs solubility attracts much attention in the pharmaceutical industry, because the drugs solubility in solutions, specifically in aqueous co-solvents solutions is one of the essential physicochemical properties which play a vital role in many biological processes pertaining to raw material purification and understanding the mechanisms concerning the physical and chemical stability of a solid dissolutions [1-6]. In addition, the solid solubility is needed in controlling the yield, supersaturation, particle size and polymorphicform. Co-solvency is an effective and common technique used to solubilize poorly soluble drugs, as aqueous co-solvent solutions are usually used as the crystallization solvents for purification process and medium of 2

synthesis reaction of lots of drugs [1,5]. Poor aqueous solubility is expected to result in low bioavailability or formulation difficulty in the clinical improvement [1,7]. Moreover, the drugs solubility in solutions is employed to perform the thermodynamic analysis to deeply insight the molecular mechanisms pertaining to the drug dissolution and preferential solvation estimation of the drugs by solvent components in solvent mixtures [8-11]. Rebamipide (R- and S-enantiomer mixtures with a mole ratio of 50:50; molar mass, 370.79 g·mol−1; CAS number, 90098-04-7, structure shown in Figure 1), which IUPAC name is 2-(4-chlorobenzamido)-3-[2(1H)-quinolinon-4-yl]propionic acid, is a white crystalline powder. It is a gastro-protective antiulcer drug clinically used for treating the gastric ulcers and amelioration of gastric mucosal lesions caused by the serious exacerbation period of acute chronic gastritis and gastritis [12,13]. Rebamipide is developed by the Otsuka Pharmaceutical Co., Ltd. and is commercially accessible as an ophthalmic suspension launched in Japan in January 2012. In terms of the biopharmaceutical classification system (BCS), rebamipide is classified as a class IV drug due to its poor oral bioavailability (< 10 %) in humans, low permeability and solubility [14-16]. A lot of methods including nano-emulsions, amorphous solid dispersions, inclusion complexes with cyclodextrins, lipid-based formulations, nanocrystals and co-crystals have been employed to improve the oral delivery, dissolution properties and solid solubility of rebamipide [16-24]. Nevertheless a little consideration has been made on the physico-chemical property of the drug rebamipide in mixed solvents, especially in aqueous co-solvent mixtures. A comprehensive literature review reveals that only the rebamipide solubility in several neat solvents is reported by Ha and co-workers up to yet [25]. In terms of the literature results, rebamipide shows up to approximately (102 to 103)-fold rise in solubility in going from neat water to several neat alcohols [25]. This case suggests the presence of preferential solvation of rebamipide in aqueous co-solvent mixtures of alcohols [10,11]. This stimuluses our research group to deeply perform examination about the rebamipide solubility and study on thermodynamic analysis of rebamipide in some aqueous mixtures. Additionally, even though the solvent mixtures have been expansively employed

3

in pharmacy field for many years [5], just at present the mechanisms regarding the decrease or increase of the drugs solubility start to be studied from a thermodynamic point of view, comprising the preferential solvation analysis of solute by the solvent components in mixed solvents [8-11]. Furthermore, the analysis of solvent effect with the help of linear solvation energy relationships, LSER, provides a convenient way to distinguish the main factors controlling the solubility variation when solvent changes. For a given solute, the solubility variation depends on the change in energy of various solute-solvent and solvent-solvent interactions in different solvents. LSER divides these interactions into two subclasses of non-specific (dispersion, dipole-induced dipole and dipole-dipole) and specific (hydrogen bonding) ones, and defines their energy terms based on suitable solvent properties. This gives a linear combination of different interaction modes to model the Gibbs energy changes induced by solvent effect [26]. In LSER model developed by Kamlet, Abboud, Abbraham and Taft, KAT-LSER, the solvent is characterized by three parameters involving the hydrogen bond basicity,  the dipolarity/polarizability, * and hydrogen bond acidity,  [26-29]. These parameters are determined under certain conditions from direct measurement of energy change attributable to each interaction mode at molecular level and thus their combination provides a reliable quantitative description for the solvent polarity. Though the KAT-LSER method, one can determine the relative importance of the main parameters that govern the solvent effect on a variety of chemical properties such as the solubility in neat and mixed solvents [30-33]. It is well-known that isopropanol is a colourless compound with strong odour. It may dissolve a extensive range of non-polar compounds. Isopropanol presents lower non-toxic compared to the alternative solvents. It is frequently used merely or in mixed solvents with other solvents for different purposes

including

in

penetration-improving

pharmaceutical

compositions

for

transepidermal and percutaneous uses [34,35]. Ethanol is a common organic solvent in the pharmaceutical liquid formulations. Its solubilization power is very high, so it is commonly used in the liquid formulations at concentrations lower than 50 %. In addition, ethanol has crucial effect on 4

the drug’s excretion, distribution, absorption and metabolism [36]. Propylene glycol (PG) is also a commonly used co-solvent in pharmacy [37]. In contrast, even though n-propanol is not extensively employed as a co-solvent for the liquid medicine design, it has been used as a solvent for resins and cellulose esters in the pharmaceutical industry [38]. In terms of the points mentioned above, the main purposes of the present contribution are to report the solubility of rebamipide in aqueous co-solvent solutions of PG, ethanol, n-propanol and isopropanol under local atmospheric pressure and obtain the respective thermodynamic quantities of the four mixtures, as well as the preferential solvation analysis of the rebamipide by the co-solvents.

2. Theoretical considerations In the present work, the Jouyban−Acree model [39,40] is used to describe the rebamipide solubility in the four aqueous co-solvent solutions of PG, ethanol, n-propanol and isopropanol. Furthermore, the KAT-LSER model [26] is implemented on experimental data to detect the factors explaining the solvent effect upon the rebamipide solubility. 2.1. Jouyban-Acree model The expression of this model is described as Eq. (1), which is normally applied to mathematically describe for solute solubility dependence upon both temperature and solvent compositions for mixtures studied [39,40].

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 solute solubility in mole fraction in the aqueous co-solvent mixtures at temperature T/K; w1 and w2 are mass fraction proportions of the co-solvent 1 (PG, ethanol, n-propanol or isopropanol) and the solvent 2 (water) in the absence of solute (rebamipide), respectively; x1,T and x2,T are the solute solubility in mole fraction scale in neat solvents; and Ji stand for the parameters of the Jouyban-Acree model. 2.2. Kamlet and Taft Linear Solvation Energy Relationship model

5

To treat solvent effect, KAT-LSER model considers a multi-parameter expression that relates the free energy of solvent-dependent properties to different interaction modes [26]. Applied to the solid solubility, this model is expressed as Eq. (2) [26,30-32]. V 2 ln x  c0  c1 * c2   c3  c4 ( s H ) 100 RT

(2)

here, x refers to the solid solubility in mole fraction scale in mixtures, and therefore its logarithm denotes the Gibbs energy of solubility. This quantity is a summation over four energy terms defined for various intermolecular interactions on the right hand side of the Eq. (2). The three terms c1*, c2 and c3 belong to non-specific and specific solute-solvent interactions, while the last term in Eq. (2) accounts for all solvent-solvent interactions. The c1* determines the energy contribution from the dispersion, induction and electrostatic interactions in term of * of solvent. The c2 and c3 correspond to energy term for solute-solvent interactions where solvent act as hydrogen bond acceptor and donor, respectively [26-32]. Finally, the last term is the cavity term that reflects the energy needed for breaking solvent-solvent interactions for the solute’s accommodation in solvent. Vs is the molar volume of solute,  refers to the Hildebrand solubility parameter and R represents the universal gas constant. The coefficients ci=1-4 are the solute-dependent constant that convey information on the relative contribution from each interaction mode to the solubility in the system under study; c0 stands for the intercept of this model at ==*=H=0. Eq. (3) is the objective function used in the regression. e c F   ln xw,T  ln xw,T 

2

(3)

i=1

Moreover, with the object of presenting the error of the Jouyban-Acree model, the relative average deviation (RAD) and root-mean-square deviation (RMSD) are also employed herein, which are expressed as Eqs. (4) and (5). 1 RAD  N

c e  xw,T  xw,T   x e w,T 

   

(4)

6

RMSD 



N i 1

c e  xw,T ( xw,T )2

(5)

N e

herein, N is the number of data points; xw,T stands for the solubility in mole fraction scale obtained c

through experiment in this work; and xw,T , through computation via the solubility model. 2.3. Preferential solvation The method of inverse Kirkwood–Buff integrals (IKBI) is powerful in describing the local composition nearby a solute with respect to components in mixtures. This handling is based on the values of standard molar Gibbs energy of transfer of the solute (compound 3) from neat water (compound 2) to the co-solvent (compound 1) + water (compound 2) mixture and the excess molar Gibbs energy of mixing for the mixture in the absence of the solute. In view of that, this handling is of very importance in the pharmaceutical and chemical sciences to deeply insight the solute-solvent interactions. The general form of the IKBI method can be described as [8-11,37,41]: Gi ,3  

rcor

0

( gi ,3  1)4 r 2 dr

(6)

here, r denotes the distance between the molecule centers of rebamipide (3) and that of co-solvent (1) or water (2); gi,3 refers to the pair correlation function for the solvent i molecule in co-solvent (1) + water (2) mixture nearby the rebamipide (3); rcor is the correlation distance, wherein gi,3 (r>rcor) is approximately equal to 1. Consequently, the integral value is essentially zero for r>rcor. The preferential solvation parameter (δx1,3) of rebamipide (3) by the co-solvent (1) in the mixture of co-solvent (1) + water (2) is expressed as Eqs. (7) [8-11,37,41]. L  x1,3  x1,3  x1   x2,3

(7)

L Here x1,3 denotes local mole fraction proportion of the co-solvent (1) nearby the solute rebamipide

(3); and x1, bulk mole fraction proportion of the co-solvent (1) in initial aqueous solutions of the co-solvent. If the values of δx1,3 are greater than zero, the solute rebamipide (3) is preferentially solvated by the co-solvent (1); whereas if they are smaller than zero, then the solute rebamipide (3)

7

is said to be preferentially solvated by the water (2). The δx1,3 values can be available from the method of IKBI for individual solvent compositions [8-11,37,41].

 x1,3 

x1 x2  G1,3  G2,3 

(8)

x1G1,3  x2G2,3  Vcor

with G1,3  RT  T  V3 

x2 V2 D Q

(9)

G2,3  RT  T  V3 

x1V1 D Q

(10)



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



1/3

 0.085 

3

(11)

where, κT denotes the isothermal compressibility of the solutions of co-solvent (1) + water (2). V 1 and V 2 refer to the partial molar volumes of the co-solvent (1) and water (2), respectively, in the mixtures; and V 3 , the partial molar volume of rebamipide in the solutions. The function D described as Eq. (12) is the derivative of standard molar Gibbs energy of transfer of rebamipide from neat water (2) to the solutions of co-solvent (1) + water (2) with respect to the co-solvent proportion. The function Q expressed as Eq. (13) is the second derivative of excess molar Gibbs energy of mixing of the two solvents ( G1Exc  2 ) with respect to water composition in the co-solvent solution. Vcor refers to the correlation volume; and r3, the molecular radius of rebamipide calculated via Eq. (14), wherein NAv is the Avogadro’s number. o   tr G(3,2  1 2) D   x1  T , P

(12)

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

(13)

r3 

3

3 1021V 3 4 N AV

(14)

8

Because the κT values depend upon the solvent compositions, thus they are not known for the four mixtures investigated. On the other hand, the contribution of the term RTκT to IKBI is very slight, hence, the values of κT may be approximately estimated by means of considering an additive property through the solution compositions and the available values for pure solvents by [10,37,41]: o o  T  x1 T,1  x2 T,2

(15)

o Here xi refers to the mole fraction of component i in the aqueous co-solvent mixtures;  T,i denotes

the isothermal compressibility of the neat component i. The standard molar Gibbs energies of transfer of rebamipide from neat water (2) to isopropanol (1) + water (2), PG (1) + water (2), n-propanol (1) + water (2) and ethanol (1) + water (2) mixtures may be calculated by Eq. (16) from the determined solubility data and mathematically correlated with the empirical equations {Eqs. (17) and (18)}, wherein A0, A1, A2, t1 and t2 refer to the empirical equation parameters.

 x3,2  0  tr G3,2  1 2  RT ln  x  3,1 2 

 tr G

o 3,2 1 2

 tr G

o 3,2 1 2

 A0  A1e



x1 t1



x1 t1

 A0  A1e

 A2 e

(16)



x1 t2

(17)

(18)

The definitive correlation volume requires iteration since it depends upon the local mole fractions nearby the solute. The iteration process can be carried out by substituting δx1,3 and Vcor in L Eqs. (7), (8) to (11) to recalculate x1,3 until a non-variant Vcor value is attained.

3. Experimental 3.1. Materials Rebamipide was purchased from the Yuhan Pharm. Co., Ltd, China with a mass fraction purity of 0.992, which was confirmed by the use of a high-performance liquid chromatography (HPLC, Agilent 1260). Moreover, the R- and S-enantiomer ratio for the rebamipide was determined in our

9

laboratory on an amylase derivative chiral stationary phase by using the high performance liquid chromatography (JASCO 2000), which was equipped with a UV detector and a circular dichroism detector. The mole ratio of the R- and S-enantiomers was 50:50. The organic solvents including isopropanol, ethanol, PG and n-propanol were provided by Sinopharm Chemical Reagent Co., Ltd., China, the mass fraction compositions of which were all higher than 0.994, which were checked by using Smart (GC-2018) gas chromatography. The twice-distilled water used in this contribution had a conductivity of less than 2µS·cm-1, which was prepared in our laboratory located in Yangzhou university. The details of these solvents and rebamipide were tabulated in Table 1. 3.2. Solubility measurement During the experimental process, we use the analytical balance having a type BSA224S to prepare the aqueous co-solvent mixtures. The mixture used in each experiment was around 25 ml, and the relative standard uncertainty of which was assessed to be no greater than 0.0002. The mass fraction proportions of organic solvent in the mixtures covered the range from 0 to 1.The ambient atmospheric pressure was approximately 101.2 kPa. The solid-liquid equilibrium of rebamipide dissolved in the co-solvent mixtures of (isopropanol + water), (ethanol + water), (PG + water) and (n-propanol + water) was constructed by using a saturation shake-flask technique [42,43]. The apparatus reliability was verified through the solubility of benzoic acid in neat toluene [43]. The Agilent-1260 HPLC was employed to determine the solubility of rebamipide in equilibrium liquor [25]. The experiments for rebamipide solubility were performed at temperature range from “T = 278.15 K” to “T = 318.15 K” at intervals of 5 K and pressure “p=101.2 kPa”. Excess amount of rebamipide was added into each mixture of 25 ml in triplicates. The rebamipide solutions were entirely mixed and then transferred into a thermostatic shaker, which was purchased from the Tianjin Ounuo Instrument Co. Ltd., China. The solutions were shaken by means of the shaker at a shaking speed of 100 rpm. In an attempt to acquire the equilibration time, 0.5 ml of liquor was withdrawn by using a 2 mL of syringe every 1 h and then analysed via the Agilent 1260 HPLC. 10

Analysis showed that 12 h was adequate for all the studied solutions to arrive at equilibrium. Then all the mixtures were removed from the shaker and allowed to settle the undissolved rebamipide particles for no less than 1 h. The upper clear liquid was taken out carefully, diluted (if necessary) and then analysed by the Agilent 1260 HPLC. 3.3. Analysis method The content of rebamipide in equilibrium liquor was analysed by the use of the Agilent 1260 HPLC, which consisted of a quaternary pump and an UV detector (G1314F). The separation was performed by using a reverse phase column (250 mm × 4.6 mm, 5 μm) having a model of Waters C18, which was provided by the “Waters (Waters Inc., Bedford, MA, USA)”. The mobile phase consisted of methanol and water with a volume ratio of 70:30, which flow rate was 1.2 mL·min−1. Before examination, it was adjusted to pH 2.6 by using acetic acid. The absorption wavelength of solutions was set to 327 nm [25]. The Agilent 1260 HPLC system was calibrated by using standard solutions in advance. The calibration curve was constructed between the rebamipide concentration and the HPLC area (not shown in this work). Each test was repeated for three times. The solubility was the average value of three tests. The relative standard uncertainty was no greater than 0.062 for the solubility in mole fraction scale. 3.4. X-ray powder diffraction With the aim of confirming the absence of solvate formation or polymorph transformation of rebamipide in determination process, the equilibrated solids were identified by the use of X-ray powder diffraction (XRD). All tests were carried out upon a DX-2700B (HaoYuan, China) instrument at ambient temperature by using Cu Ka radiation (λ=0.154184 nm). During the determination process, the scan speed was 6 degmin−1. The tube voltage and tube current were set to at 40 kV and 30 mA, respectively. The data were collected covering the range from 5° to 60° (2-Theta) under ambient pressure.

4. Results and discussion 4.1. Results of X-ray powder diffraction 11

The typical XRD scans of equilibrated solids with their corresponding liquors and raw rebamipide are graphically shown in Figure S1 of Supporting material. It can be seen from the obtained XRD spectra of raw and equilibrated rebamipide that the sharp characteristic peaks appear at different 2θ values (Figure S1). In addition, the XRD spectra of equilibrated solids with their corresponding liquors are very similar with that of the raw rebamipide and the equilibrated solids with neat solvents [25], suggesting that rebamipide presents in neat crystalline state and no transform to polymorphic form or solvate formation takes place in all experiments. 4.2. Solubility data The mole fraction solubility of rebamipide determined in mixtures of (ethanol + water), (n-propanol + water), (isopropanol + water) and (PG + water) is presented in Tables 2-5, respectively. What’s more, the relationship between the mole fraction solubility and co-solvent compositions and temperature is plotted in Figure 2. It can be observed that for these mixtures studied, the rebamipide solubility is a function of the solvent compositions and temperature. The solubility of rebamipide rises with increasing temperature and mass fractions of PG (isopropanol, ethanol or n-propanol) for the PG (isopropanol, ethanol or n-propanol) + water mixtures. The maximum value of solubility of rebamipide is observed in the neat PG (isopropanol, ethanol or n-propanol). In addition, the rebamipide solubility in (PG + water) mixture is larger than that in the other three co-solvent mixtures at the same co-solvent compositions and temperature. The rebamipide solubility in neat PG, ethanol, isopropanol, n-propanol and water obtained in this contribution as well as those reported in the publication [25] is graphically shown in Figure S2 of Supporting material for comparison. It may be observed that the mole fraction solubility of rebamipide determined in this work is close to that reported by Hao and co-workers [25]. The maximum values of relative average deviation (RAD) are 2.95 %, 1.75 %, 1.99, 1.37 and 9.16 % for the solvent of ethanol, n-propanol, isopropanol, PG and water, respectively. Additionally, the solubility of rebamipide in ethanol at 298.2 K is estimated as 0.56 mg ml−1 (converted to 8.82 × 10−5 12

in mole fraction, not shown in Figure S2) [14]; in this work, the mole fraction solubility of rebamipide in ethanol at 298.15 K is determined as 9.659×10−5. The solubility value of rebamipide in ethanol determined in this work is similar to the previously reported. The small difference may be caused by many factors, such as analysis method, purity, determination method, equilibration time, sampling and so forth. 4.3. Analysis of solvent effect on solubility of rebamipide The solvent descriptors , , * and  are available over the all composition ranges of PG + water, isopropanol + water, ethanol + water and n-propanol + water mixtures from previous studies [44,45], and presented in Table S1 of Supporting material. A value of Vs (219 cm3mol−1) for rebamipide is taken from the Ref. [25], which is calculated by using a Fedors's method. The rebamipide solubility data is introduced to KAT-LSER model and correlations are examined by the multiple linear regression analysis. Eq. (2) represents the four-parametric KAT-LSER model. Therefore, for a full analysis, data is also fitted to other KAT-LSER expressions including single, dual and triple-parametric models. The obtained results are summarized in Tables S2-S5 in Supporting Materials. In the case of analysis of solvent effect on solubility, any acceptable KAT-LSER model should have positive ci=1-3 and negative c4, because solute-solvent interactions favor while solvent-solvent interactions disfavour the solute solubility. Among these, the model that gives highest F-statistic is mathematically the best descriptive model as bolded in Tables S2-S5. Tables S2-S5 show that the solubility of rebamipide depends strongly on  and cavity term in the ethanol + water, isopropanol + water and n-propanol + water. This means the hydrogen-bonding solute-solvent interaction and solvent-solvent interactions determines the solubility variation in these mixtures. According to coefficients ci=3,4 the sensitivity of solubility to  and cavity term is 13

36.6 and 63.4 % in ethanol (1) + water (2) mixture, 41.89 and 58.11 % in n-propanol (1) + water (2) mixture, and 46.89 and 53.11 % in isopropanol (1) + water (2) mixture. Resultes show that the term

 does not have a significant effect on the solubility variation in these mixtures. As evident in Figure 1, rebamipide has several hydrogen bonding acceptor sites that facilitate its interactions with hydrogen bond donor solvents. The solute can also undergo specific interactions with solvent through its acidic hydrogens. However, it seems that such types of interaction do not vary notable over the composition range; leading to the absence of  in KAT-LSER model. Results also show that KAT-LSER model with single variable cavity term gives excellent correlation particularly in (water + PG) mixtures. The dominant effect of cavity term is expectable because rebamipide has a large size and its accommodation within the solvent is accompanied with large cavity formation energy. Accordingly, the solubility of rebamipide increases when cavity term declines with increasing in mole fraction of co-solvent in aqueous mixtures studied in this work. As a conclusion, KAT-LSER analysis demonstrates that solvent-solvent and solute-solvent interactions have the main contribution to the solvent effect on the solubility of rebamipide in binary mixtures studied. However, it is worthy to consider the possible occurrence of the preferential solvation of rebamipide with the purpose of studying upon the other aspect of solvent effect in the binary mixtures. 4.4. Preferential solvation of rebamipide The standard molar Gibbs energies of transfer of rebamipide from water (2) to PG (1) + water (2), isopropanol (1) + water (2), ethanol (1) + water (2) and n-propanol (1) + water (2) mixtures are computed by using the Eq. (16) from the determined solubility at 298.15 K and tabulated in Table S6 of Supporting material. In addition, these values are graphically shown in Figure S3 of o Supporting material. The computed values of trG3,2 12 are mathematically correlated with the

empirical Eqs. (17) and (18). The regressed equation coefficients, A0, A1, t1, A2 and t2 are tabulated 14

in Table S7 of Supporting material. As a result, the values of D presented in Tables S8-S11 of Supplementary material are acquired from the first derivative of Eq. (12) solved based on the mixture compositions varying by 0.05 in mole fraction of PG (1), ethanol (1), isopropanol (1) and n-propanol (1). Because values of partial molar volumes of rebamipide (3) in these solutions are not accessible in the publications, herein these values are regarded as similar to that of the neat rebamipide [10,11,37,41,44-46]. Therefore, the solute radius value (r3) is calculated with Eq. (14) as 0.443 nm. In addition, the values of RTκT and partial molar volumes of two neat solvents in the PG (1) + water (2), isopropanol (1) + water (2), n-propanol (1) + water (2) and ethanol (1) + water (2) mixtures as well as the Q values at 298.15 K have been reported [11,46]. Consequently, the values of G1,3 and G2,3 in the mixtures studied may be obtained and tabulated in the Tables S8-S11. The attained values of Vcor and δx1,3 through iteration are also tabulated in the Tables S8-S11 for ethanol (1) + water (2), n-propanol (1) + water (2), isopropanol (1) + water (2) and PG (1) + water (2) mixtures, respectively. Furthermore, the dependence of δx1,3 upon the solvent compositions is graphically shown in Figure 3. It shows that the δx1,3 values non-linearly vary with the co-solvent (1) compositions in all the aqueous mixtures. In terms of the Figure 3, addition of ethanol (n-propanol, isopropanol or PG) (2) makes negative the δx1,3 values of rebamipide (3) from neat water (1) up to x1 = 0.20 mole fractions of ethanol and isopropanol, and x1 = 0.25 mole fraction of n-propanol and PG. In these regions, the local mole fractions of PG (n-propanol, isopropanol or ethanol) (1) are smaller than that of the mixtures and as a result the δx1,3 values are negative, which illustrates that rebamipide is preferentially solvated by water. Perhaps the structuring of water molecules adjacent the nonpolar aromatic group of rebamipide (i.e. hydrophobic hydration of aromatic ring group) contributes to lowering the net δx1,3 values to be negative in the PG (n-propanol, isopropanol or ethanol) mixtures. Miniimum negative values are attained with the composition x1 = 0.10 with δx1,3 = −1.480×10−2 for the ethanol (1) + water (2), x1 = 0.05 with δx1,3 = −1.106×10−2 for the n-propanol (1) + water (2), x1 = 0.10 with δx1,3 = −1.441×10−2 for the

15

isopropanol (1) + water (2) and x1 = 0.10 with δx1,3 = −1.704×10−2 for the PG (1) + water (2) mixtures. In the ethanol/isopropanol (1) + water (2) mixtures with compositions 0.25 < x1 < 1, and n-propanol/PG (1) + water (2) mixtures with compositions 0.20 < x1 < 1, the local mole fractions of PG (n-propanol, isopropanol or ethanol) are higher than those of the co-solvent mixtures and therefore the δx1,3 values are positive, which specifies that the rebamipide is preferentially solvated by the PG (n-propanol, isopropanol or ethanol). The co-solvent action to increase the rebamipide solubility may be relation to the breaking of ordered structure of water around the polar moiety of rebamipide which increases the solvation having maximum values near to x1 = 0.65 with δx1,3 = 4.896×10−2 for the ethanol (1) + water (2), x1 = 0.50 with δx1,3 = 2.130×10−2 for the n-propanol (1) + water (2), x1 = 0.60 with δx1,3 = 11.74×10−2 for the isopropanol (1) + water (2) and x1 = 0.45 with δx1,3 = 1.958×10−2 for the PG (1) + water (2) mixtures. According to a structural and functional group analysis, rebamipide can act as a Lewis acid in solution due to the ability of the acidic hydrogen atom in its nitrogen atom of >N- and oxygen atom of -COOH (Figure 1) to establish hydrogen bonds with proton-acceptor functional groups of the co-solvents (oxygen atom in –OH group). In addition, rebamipide can also act as a Lewis base because of the free electron pairs in nitrogen atoms of >NH and oxygen atoms of C=O, 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 ethanol/isopropanol and 0.20 < x1 < 1 for n-propanol/PG, rebamipide is acting as a Lewis acid with ethanol, isopropanol, n-propanol or PG molecules, because these co-solvents are more basic than water, as described by the Kamlet–Taft hydrogen bond acceptor parameters, i.e. β = 0.75 for ethanol, β=0.86 for n-propanol, β=0.84 for isopropanol, β=0.83 for PG and β = 0.47 for water [27,47]. In contrast, in water-rich mixtures, where rebamipide is preferentially solvated by water, rebamipide could be acting mainly as a Lewis 16

base in front to water because the Kamlet–Taft hydrogen bond donor parameters are, α = 0.76 for isopropanol, α = 0.90 for PG, 0.86 for ethanol, 0.84 for n-propanol and 1.29 for water [28,47]. 4.5. Solubility modelling Based on the solubility data determined, the model parameters of Eq. (1) are attained through Mathcad software. The obtained values of model parameters are tabulated in Table S12 of the Supporting material together with the RAD and the RMSD values. Additionally, the solubility of rebamipide in these mixtures is evaluated on the basis of the regressed parameters’ values and graphically shown in Figure 2. It can be observed from the Table S12 that the values of relative average deviations (RAD) are 2.00 % for (ethanol + water) mixture, 4.65 % for (n-propanol + water) mixture, 2.32 % for (isopropanol + water) mixture and 6.35 % for (PG + water) mixture. Additionally, the maximum RMSD value is 6.73ⅹ10-6, which is obtained for (PG + water) mixture. On the whole, the Jouyban-Acree model provides satisfied correlation results for the four co-solvent mixtures.

4. Conclusions The equilibrium solubility of rebamipide in four co-solvent mixtures of PG (1) + water (2), ethanol (1) + water (2), isopropanol (1) + water (2) and n-propanol (1) + water (2) was experimentally determined through the isothermal saturation method within the temperature range from 278.15 K to 318.15 K under 101.2 kPa. At the same temperature and mass fraction of PG (n-propanol, isopropanol or ethanol), the mole fraction solubility of rebamipide was larger in (PG + water) than those in the other three mixtures. The values of preferential solvation parameters (δx1,3) for PG, ethanol, isopropanol or n-propanol were positive in the ethanol/isopropanol mixtures with compositions 0.25 < x1 < 1, and n-propanol/PG mixtures with compositions 0.20 < x1 < 1, which showed that rebamipide was preferentially solvated by co-solvent. In addition, the drug’ solubility was mathematically correlated by the Jouyban-Acree model obtaining average relative deviations lower than 6.35 %. KAT-LSER model gives an excellent correlation between the solubility 17

variation and different interaction modes. As a result, the solubility changes due to the change mainly in solvent-solvent interactions and a significant effect of hydrogen-bonding solute-solvent interactions.

Acknowledgments The authors express sincere thanks to National Natural Science Foundation of China (Project number: 41877118), Natural Science Foundation of Jiangsu Province Higher Education (Grant No.11KJD480002), Natural Science Foundation of the Jiangsu Higher Education Institutions of China (Project number: 17KJB610013), Natural Science Foundation of Jiangsu Province of China (Project number: BK20181479) and Jiangsu Province Education Department Major Project (19KJA140003) for their financial support.

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23

Figure 1. Chemical structure of rebamipide.

24

150

150

(a)

(b)

100 6

6

10 x

10 x

100

50

50

0 320

310

300

T/K 290 280

0.0

0.2

0.4

0 320

1.0 0.8 0.6

310

w

300

T/K 290 280

125 (c)

0.0

0.2

0.4

1.0 0.8 0.6

w

(d)

300

10 x

75

6

6

10 x

100

50

100

25 0 320

200

310

300

T/K

290

280

0.0

0.2

0.4

0 320

1.0 0.8 0.6

w

310

300

T/K

290

280

0.0

0.2

0.4

1.0 0.8 0.6

w

Figure 2. Determined solubility (x) of rebamipide in mole fraction in (a) ethanol (w) + water (1-w), (b) n-propanol (w) + water (1-w), (c) isopropanol (w) + water (1-w) and (d) PG (w) + water (1-w) solutions with various mass fractions at different temperatures: w, mass fraction; ■, w = 0; ●, w = 0.1000; ▲, w = 0.2000; ◆, w = 0.3000; ▼, w = 0.4000; ★, w = 0.5000; △, w = 0.6000; ○, w = 0.7000; ☆, w = 0.8000; ◀, w = 0.9000; □，w = 1. —, calculated curves by the Jouyban−Acree model.

25

12

 x1,3

8

4

0 0.0

0.2

0.4

x1

0.6

0.8

1.0

Figure 3. δx1,3 values of rebamipide (3) in ethanol (1) + water (2), n-propanol (1) + water (2), isopropanol (1) + water (2) and PG (1) + water (2) mixtures at 298.15 K. ■, ethanol (1) + water (2); ●, n-propanol (1) + water (2); ▲, isopropanol (1) + water (2); ▼, PG (1) + water (2).

26

Table 1 Detailed aspects of rebamipide and the solvents used in the work. Chemicals

CAS Reg. No.

Molar mass /g·mol−1

Rebamipide (R- and S-enantiomer mixtures with a mole ratio of 50:50)

90098-04-7

370.79

isopropanol

67-63-0

60.10

n-propanol

71-23-8

60.10

PG

57-55-6

76.09

ethanol

64-17-5

46.07

water

7732-18-5

18.02

Source

Yuhan Pharm. Co., Ltd.

Sinopharm

Final mass fraction purity

Purification method

Analytical method

0.992

none

HPLCa

0.995

none

GCb

0.996

none

GC

0.994

none

GC

0.995

none

GC

Double distilled

GC

Chemical

a

Reagent

Co.,

Ltd.

High-performance liquid phase chromatography.

b Gas

chromatography.

27

Table 2 e Mole fraction solubility ( xT,W 106 ) of rebamipide in the ethanol (w) + water (1-w) mixture within the

temperatures ranging from 278.15 to 318.15 K under p = 101.2 kPa.a e xT,W 106

W T/K 0

0.1000

0.2000

0.3000

0.4000

0.5000

0.6000

0.7000

0.8000

0.9000

1

278.15

0.3463

0.5615

0.8886

1.472

2.613

4.746

8.233

14.61

23.66

38.31

62.57

283.15

0.4257

0.6747

1.092

1.831

3.140

5.496

9.426

16.83

26.58

42.97

69.18

288.15

0.5293

0.8785

1.390

2.263

3.816

6.492

10.90

19.12

29.97

47.77

76.47

293.15

0.6836

1.105

1.691

2.726

4.589

7.549

12.50

22.05

33.70

53.73

86.11

298.15

0.8675

1.313

2.030

3.328

5.499

8.803

14.45

25.26

38.10

60.63

96.59

303.15

1.079

1.595

2.468

4.074

6.545

10.18

16.89

28.82

42.93

67.23

107.1

308.15

1.299

1.917

2.965

4.900

7.735

12.00

19.22

32.61

48.66

76.17

118.4

313.15

1.557

2.357

3.562

5.811

8.921

14.07

22.17

37.08

54.68

86.31

130.6

318.15

1.868

2.816

4.355

7.051

10.66

16.87

26.69

42.71

62.42

96.51

143.1

a Relative

standard uncertainty ur is ur (x) = 0.062 and ur(w) = 0.0002; Standard uncertainties u are u(p) = 0.45 kPa

and u(T) = 0.02 K. w refers to the mass fraction composition of ethanol in ethanol (w) + water (1-w) mixture free of rebamipide.

28

Table 3 e Mole fraction solubility ( xT,W 106 ) of rebamipide in the n-propanol (w) + water (1-w) mixture within the

temperatures ranging from 278.15 to 318.15 K under p = 101.2 kPa.a e xT,W 106

W T/K

0

0.1000

0.2000

0.3000

0.4000

0.5000

0.6000

0.7000

0.8000

0.9000

1

278.15

0.3463

0.5242

0.8295

1.343

2.225

3.773

5.970

9.892

15.30

25.35

42.54

283.15

0.4257

0.6594

1.043

1.690

2.736

4.533

7.174

11.69

17.62

30.36

50.82

288.15

0.5293

0.8391

1.330

2.251

3.562

5.971

8.921

14.01

21.09

35.93

60.01

293.15

0.6836

1.061

1.706

2.832

4.585

7.383

11.42

16.85

25.51

42.16

70.33

298.15

0.8675

1.357

2.077

3.522

5.671

8.821

13.64

20.86

30.61

50.58

81.04

303.15

1.079

1.688

2.659

4.355

6.852

10.62

16.87

25.06

37.66

60.07

93.83

308.15

1.299

2.069

3.283

5.354

8.472

13.18

20.62

30.11

45.51

71.89

107.3

313.15

1.557

2.565

4.112

6.553

10.54

15.84

24.35

37.02

54.96

85.94

122.9

318.15

1.868

3.158

5.126

8.452

13.11

19.25

29.62

44.74

67.23

102.2

140.2

a Relative

standard uncertainty ur is ur (x) = 0.062 and ur(w) = 0.0002; Standard uncertainties u are u(p) = 0.45 kPa

and u(T) = 0.02 K. w refers to the mass fraction composition of n-propanol in n-propanol (w) + water (1-w) mixture free of rebamipide.

29

Table 4 e Mole fraction solubility ( xT,W 106 ) of rebamipide in the isopropanol (w) + water (1-w) mixture within the

temperatures ranging from 278.15 to 318.15 K under p = 101.2 kPa.a e xT,W 106

W T/K 0

0.1000

0.2000

0.3000

0.4000

0.5000

0.6000

0.7000

0.8000

0.9000

1

278.15

0.3463

0.5363

0.8295

1.374

2.175

3.522

5.323

8.424

11.89

17.16

24.13

283.15

0.4257

0.6786

1.043

1.729

2.674

4.232

6.354

10.12

14.95

21.59

30.21

288.15

0.5293

0.8295

1.284

2.101

3.325

5.262

8.045

12.44

18.59

26.85

38.71

293.15

0.6836

1.038

1.595

2.557

4.115

6.471

10.21

15.56

22.70

34.56

48.01

298.15

0.8675

1.313

1.936

3.148

4.969

7.863

12.55

19.25

28.21

42.97

59.25

303.15

1.079

1.623

2.382

3.793

5.912

9.341

15.31

23.39

35.01

52.27

73.13

308.15

1.299

1.939

2.903

4.565

7.002

11.22

18.66

28.25

42.72

62.16

89.08

313.15

1.557

2.291

3.482

5.402

8.393

13.49

22.34

33.77

51.05

75.14

107.4

318.15

1.868

2.881

4.456

6.735

10.42

16.48

26.69

40.35

60.98

92.18

129.4

a Relative

standard uncertainty ur is ur (x) = 0.062 and ur(w) = 0.0002; Standard uncertainties u are u(p) = 0.45 kPa

and u(T) = 0.02 K. w refers to the mass fraction composition of isopropanol in isopropanol (w) + water (1-w) mixture free of rebamipide.

30

Table 5 e Mole fraction solubility ( xT,W 106 ) of rebamipide in the PG (w) + water (1-w) mixture within the temperatures

ranging from 278.15 to 318.15 K under p = 101.2 kPa.a e xT,W 106

W T/K 0

0.1000

0.2000

0.3000

0.4000

0.5000

0.6000

0.7000

0.8000

0.9000

1

278.15

0.3463

0.5694

1.014

1.854

3.389

6.359

12.33

24.88

48.88

102.5

182.0

283.15

0.4257

0.7210

1.251

2.286

4.291

8.267

14.91

30.20

58.23

115.7

191.8

288.15

0.5293

0.9190

1.553

2.914

5.614

10.54

18.52

36.87

69.84

130.5

206.8

293.15

0.6836

1.177

2.000

3.615

7.251

13.00

23.06

45.25

82.87

146.9

225.4

298.15

0.8675

1.481

2.536

4.526

8.943

15.81

28.28

55.35

95.90

165.4

246.8

303.15

1.079

1.835

3.156

5.616

10.89

19.16

34.53

66.26

110.9

183.8

269.3

308.15

1.299

2.198

3.854

6.971

13.08

22.99

42.45

79.43

128.1

206.6

293.1

313.15

1.557

2.624

4.797

8.542

15.62

28.36

51.89

94.43

147.0

231.5

319.2

318.15

1.868

3.237

5.917

10.54

18.76

35.21

63.53

108.9

172.1

256.5

349.9

a Relative

standard uncertainty ur is ur (x) = 0.062 and ur(w) = 0.0002; Standard uncertainties u are u(p) = 0.45 kPa

and u(T) = 0.02 K. w refers to the mass fraction composition of PG in PG (w) +water (1-w) mixture free of rebamipide.

Highlights

► Rebamipide solubility in four aqueous co-solvent mixtures of alcohols was determined and correlated. ► Solvent effect was studied in terms of solvent-solvent and solute-solvent interactions. ► Preferential solvation of rebamipide in four mixtures were derived through IKBIs method.

31

Graphic abstract

12

150

8

100

 x1,3

6

10 x

ethanol (w) + water (1-w) 50

0 320

310

300

T/K 290 280

0.0

0.2

0.4

1.0 0.8 0.6

isporopanol (1) + water (2) n-propanol (1) + water (2) ethanol (1) + water (2) PG (1) + water (2)

4

0

w

0.0

0.2

0.4

x1

0.6

0.8

1.0

Author statement

Wanxin Li: Methodology, Writing-Original Draft. Ali Farajtabar: Formal analysis, Data Curation. Rong Xing: Investigation. Yiting Zhu, Data Curation ， Resources. Hongkun Zhao: Conceptualization, Supervision. Rongguan Lv: Project administration.

The authors declared that they have no conflicts of interest to this work. We declare that we do not have any commercial or associative interest that repres ents a conflict of interest in connection with the work submitted.

32