Journal of Molecular Liquids 207 (2015) 274–278

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Journal of Molecular Liquids

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Thermodynamics of solubility of isatin in Carbitol +watermixed solventsystems at different temperatures

Faiyaz Shakeel a,⁎, Nazrul Haq a, Mounir M. Salem-Bekhit a,b

a Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabiab Department of Microbiology and Immunology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt

⁎ Corresponding author.E-mail address: faiyazs@fastmail.fm (F. Shakeel).

http://dx.doi.org/10.1016/j.molliq.2015.03.0380167-7322/© 2015 Elsevier B.V. All rights reserved.

a b s t r a c t

a r t i c l e i n f o

Article history:Received 15 February 2015Received in revised form 18 March 2015Accepted 20 March 2015Available online 2 April 2015

Keywords:Apelblat modelIsatinSolubilityThermodynamicsVan't Hoff modelYalkowsky model

Thermodynamics of solubility of natural pharmacologically active compound isatin in various Carbitol + watermixed solvent systemswas studied. The solubilities of isatinweremeasured at T=(298.15 to 338.15) K at atmo-spheric pressure using an isothermalmethod. Themeasured solubility data of isatinwas correlated and regressedby three semiempirical models. The values of root mean square deviations were observed less than 0.040 by allthree semiempiricalmodels. Themole fraction solubility of natural isatinwas found to be highest in pure Carbitol(5.20 × 10−1 at 298.15 K) and lowest in pure water (5.13 × 10−5 at 298.15 K) at T= (298.15 to 338.15) K. Theresulting data of Van't Hoff and Krug analyses showed an endothermic, spontaneous and an entropy-driven dis-solution of isatin in all Carbitol + water mixed solvent systems.

© 2015 Elsevier B.V. All rights reserved.

1. Introduction

The chemical name of isatin has been proposed as indoline-2,3-dione and its molecular structure is presented in Fig. 1 [1,2]. It occursas a yellow to red needle crystalline powder [3,4]. It is a pharmacologi-cally active natural bioactive compound which showed broad range oftherapeutic effects [3–7]. The mole fraction solubility of isatin in waterhas been reported as 5.13 × 10−5 at T = 298.15 K [1]. According tothe literature solubility of isatin, it has been considered as poorlywater-soluble bioactive compoundwhich is themain barrier for formu-lation development of these bioactive compounds [1,2]. In order to en-hance the solubilization and stabilization of poorly water-solublebioactive compounds in aqueous media, various approaches have beeninvestigated in literature [8,9]. Among these approaches, cosolvency ap-proach is one of the simplest and the commonly used approachwhich re-quires simple cosolvents for the solubilization and stabilization of poorlywater-soluble compounds [8,10–12]. Recently, Carbitol has been investi-gated as a potential cosolvent for solubility enhancement of various poor-ly water-soluble compounds [13–19]. Although, various temperature-dependent semiempirical models have been reported for correlation ofsolubility data of solutes, the modified Apelblat and Van't Hoff modelsare commonly used models for this purpose [2,10,18–20]. However,Yalkowsky model is commonly used cosolvency model for correlation ofsolubility data of solutes [21]. Liu et al. reported the solubility data of

crystalline isatin in nine different pure solvents such as water, di-chloromethane (DCM), toluene, acetone, ethyl acetate (EA), 1,4-di-oxane, N,N-dimethylformamide, tetrahydrofuran and acetonitrile atT= (278.15 to 333.15) K and p= 0.1 MPa [2]. Baluja et al. also reportedthe solubility data of isatin in DCM, water, 1,2-dichloroethane, chloro-form, carbon tetrachloride, methanol, ethanol and 1-butanol at T =(298.15 to 318.15) K and p= 0.1 MPa [1]. The solubility data of isatin invarious biosolvents such as water, ethanol, butanol-2, Carbitol, EA, ethyl-ene glycol, isopropyl alcohol, propylene glycol and polyethylene glycol400 (PEG 400) and various PEG 400 + water mixed solvent systems atT=(298.15 to 338.15) K and p=0.1MPa have also been reported in lit-erature [10,22]. However, the solubility data of crystalline isatin in variousCarbitol + water mixed solvent systems are not available in literature.Therefore, the thermodynamics and solvation behavior of solubilities ofcrystalline isatin in various Carbitol + water mixed solvent systemswere investigated in this work. The solubilities were measured at T =(298.15 to 338.15) K and p= 0.1 MPa using an isothermal method [23].The solubility data of this work could be extremely useful in purification,crystallization, separation/extraction, preformulation studies and formu-lation development of isatin in chemical and pharmaceutical industries.

2. Experimental

2.1. Materials

Isatin was obtained from E-Merck (Hamburg, Germany). Carbitol(IUPAC name: diethylene glycol monoethyl ether) was obtained as a

Fig. 1.Molecular structure of isatin.

275F. Shakeel et al. / Journal of Molecular Liquids 207 (2015) 274–278

kind gift sample from Gattefosse (Lyon, France). The water was collect-ed from Milli-Q water purification unit (Millipore Corporation, Berlin,Germany). The detailed information about all thesematerials is present-ed in a sample Table 1. All the materials were used without any furtherpurification because of their high purity.

2.2. Measurement of isatin solubility

The solubility of isatin against mass fraction of Carbitol (m = 0.0 to1.0) in various Carbitol + water mixed solvent systems was measuredat T = (298.15 to 338.15) K and atmospheric pressure of 0.1 MPausing an isothermal method [23]. The excess amount of isatin wasadded in known amounts of Carbitol + water mixed solvent systems.The concentrated suspensions of isatin in each Carbitol + watermixed solvent system were shaken continuously in a biological shaker(Julabo, PA) at 100 rpm for 72 h [10,22]. All the experiments were re-peated in triplicates. After 72 h, all the concentrated suspensions weretaken out from the shaker and allowed to settle isatin particles for 2 h[17–19]. The upper layer of each sample was taken and centrifugedfurther at 5000 rpm for 15 min in order to remove any fine particles.The supernatants from each sample were taken, diluted suitably withrespective cosolvent mixture and subjected for the analysis of isatincontent usingUV–Visible spectrophotometer at 240nm [22]. The exper-imental mole fraction solubilities (xe) of crystalline isatin in eachCarbitol + water mixed solvent systems were calculated as reportedpreviously [10,22].

3. Results and discussion

3.1. Measured solubility data of isatin

The measured solubilities of crystalline isatin in variousCarbitol + water mixed solvent systems at T = (298.15 to338.15) K and atmospheric pressure of 0.1 MPa are presented inTable 2. The mole fraction solubility data of isatin in pure water(m= 0.0) and pure Carbitol (m= 1.0) at T = (298.15 to 338.15) K andatmospheric pressure are available in literature [22]. However, its solubil-ity data in various Carbitol+watermixed solvent systems are not report-ed in previous literature. The xe values of isatin in water and Carbitol at298.15Khavebeen reported as 5.14×10−5 and5.23×10−1, respectively[22]. In this work, the xe values of isatin in water and Carbitol at 298.15 Kwere recorded as 5.13 × 10−5 and 5.20 × 10−1, respectively. The graphi-cal comparison between experimental and literature solubilities of isatin

Table 1A sample table for drug (isatin) and materials used in the experiment.

Material Molecular formula Molar mass (g·mol−1) Purity (mass fracti

Isatin C8H5NO2 147.13 0.998Carbitol C6H14O3 134.17 0.999Water H2O 18.01 –

High performance liquid chromatography (HPLC); gas chromatography (GC).

in water and Carbitol is presented in Fig. 2 at T = (298.15 to 338.15) K.Fig. 2 showed good correlation between experimental and literature sol-ubilities of isatin at T=(298.15 to 338.15) K. Overall, these results indi-cated good agreement of the results of this work with reportedsolubility data of isatin in water and Carbitol at T = (298.15 to338.15) K. Generally, the xe values of crystalline isatin were found tobe increasing with the rise in temperature and mass fraction of Carbitolin Carbitol + water mixed solvent systems. The xe values of crystallineisatin were observed highest in pure Carbitol (5.20 × 10−1 at 298.15 K)at T= (298.15 to 338.15) K. However, the lowest xe values of crystallineisatin were observed in pure water (5.13 × 10−5 at 298.15 K) at T =(298.15 to 338.15) K. The highest xe values of crystalline isatin in pureCarbitol were probably due to lower polarity of Carbitol as comparedto pure water [17,18]. The impact of mass fraction of Carbitol onmolefraction solubility of crystalline isatin at T = (298.15 to 338.15) K ispresented in Fig. 3. The solubility of crystalline isatin was increasingcontinuously with increase in mass fraction of Carbitol inCarbitol + water mixed solvent systems at T = (298.15 to 338.15)K (Fig. 3). Overall, these results were in good agreement with previ-ously published solubility data of other natural bioactive compoundssuch as reserpine in Carbitol + water, isatin in PEG 400 +water andsilymarin in PEG 400 + water mixed solvent systems [10–12]. Com-pared with previously published solubility data of isatin in variouspure solvents and cosolvent mixtures, Carbitol was found to be thebest cosolvent for solubility enhancement of isatin [1,2,10,22].Based on solubility data of this work, isatin has been considered aspoorly soluble in water and very soluble in Carbitol.

3.2. Correlation of experimental solubilities with Van't Hoff model

According to the Van't Hoff model, the mole fraction solubility ofcrystalline isatin in various Carbitol + water mixed solvent systemscan be calculated with the help of Eq. (1) [2,10]:

ln xVan0t ¼ aþ b

T: ð1Þ

In which, xVan't is the Van't Hoff model solubility of crystalline isatinand T represents the absolute temperature (K). Parameters a and b arethe Van't Hoff model parameters. Parameters a and bwere determinedby regression analysis of ln xe against 1/T. For the correlation of xe withxVan't, the root mean square deviations (RMSD) were calculated in eachcosolvent mixture using Eq. (2).

RMSD ¼ 1N

XNi¼1

xVan0t−xexe

!224

35

12

ð2Þ

Inwhich,N represents the number of temperature points used in theexperiment. The graphical correlations between xe and xVan't of isatin invarious Carbitol+watermixed solvent systems are presented in Fig. S1.

The values ofmodel parameters a and b, correlation coefficients (R2)and RMSD in various Carbitol + water mixed solvent systems are listedin Table S1. The RMSD values in various Carbitol +watermixed solventsystems were obtained in the range of 0.002 to 0.031. The R2 values forisatin were obtained as 0.9951 to 0.9997. These data indicated good

on) Purification method Analysis method Source

None HPLC E-MerckNone GC GattefosseNone – Milli-Q purification unit

Table 2Experimentalmole fraction solubilities (xe) of crystalline isatin againstmass fraction of Carbitol (m) in variousCarbitol+water cosolventmixtures in the absence of solute at temperaturesT = (298.15 to 338.15) K and pressure p = 0.1 MPaa (the values in parentheses are standard deviations of three measurement).

m xe

T = 298.15 K T = 308.15 K T = 318.15 K T = 328.15 K T = 338.15 K

0.0 5.13 (0.03) × 10−5 8.06 (0.04) × 10−5 1.13 (0.05) × 10−4 1.51 (0.07) × 10−4 2.00 (0.08) × 10−4

0.1 1.34 (0.01) × 10−4 1.90 (0.02) × 10−4 2.63 (0.02) × 10−4 3.43 (0.03) × 10−4 4.50 (0.04) × 10−4

0.2 3.49 (0.04) × 10−4 4.71 (0.05) × 10−4 6.22 (0.06) × 10−4 7.83 (0.08) × 10−4 9.62 (0.07) × 10−4

0.3 8.11 (0.05) × 10−4 1.07 (0.06) × 10−3 1.39 (0.07) × 10−3 1.80 (0.08) × 10−3 2.23 (0.09) × 10−3

0.4 2.00 (0.01) × 10−3 2.71 (0.02) × 10−3 3.29 (0.03) × 10−3 3.99 (0.05) × 10−3 4.86 (0.04) × 10−3

0.5 5.35 (0.02) × 10−3 6.58 (0.04) × 10−3 7.92 (0.03) × 10−3 9.41 (0.05) × 10−3 1.07 (0.01) × 10−2

0.6 1.28 (0.01) × 10−2 1.52 (0.01) × 10−2 1.78 (0.02) × 10−2 2.08 (0.02) × 10−2 2.44 (0.03) × 10−2

0.7 3.31 (0.03) × 10−2 3.85 (0.02) × 10−2 4.40 (0.01) × 10−2 5.02 (0.02) × 10−2 5.58 (0.03) × 10−2

0.8 8.19 (0.04) × 10−2 9.32 (0.03) × 10−2 1.02 (0.05) × 10−1 1.13 (0.06) × 10−1 1.25 (0.06) × 10−1

0.9 2.08 (0.03) × 10−1 2.25 (0.02) × 10−1 2.43 (0.01) × 10−1 2.56 (0.04) × 10−1 2.73 (0.03) × 10−1

1.0 5.20 (0.00) × 10−1 5.36 (0.01) × 10−1 5.57 (0.01) × 10−1 5.79 (0.02) × 10−1 5.94 (0.03) × 10−1

a The standard uncertainties u are u(T) = 0.10 K, ur(m) = 0.1%, u(p) = 0.003 MPa and ur(xe) = 1.20%.

276 F. Shakeel et al. / Journal of Molecular Liquids 207 (2015) 274–278

correlation of measured solubility data of crystalline isatin with Van'tHoff model.

3.3. Correlation of experimental solubilities with the modified Apelblatmodel

According to this model, the mole fraction solubility of crystallineisatin can be calculated using Eq. (3) [20]:

ln xApl ¼ Aþ BTþ C ln Tð Þ: ð3Þ

Inwhich, xApl is themole fraction solubility of isatin calculated by themodified Apelblat model. The parameters A, B and C are the modelcoefficients which were calculated by multivariate regression analysis[10,22]. The graphical correlations between xe and xApl in variousCarbitol + water mixed solvent systems are presented in Fig. S2.

The values of the modified Apelblat parameters along with R2 andRMSD values in various Carbitol+watermixed solvent systems are pre-sented in Table S2. The RMSD values in various Carbitol + water mixedsolvent systemswere observed in the range of 0.002 to 0.016. However,the R2 values in various Carbitol + water mixed solvent systems wereobtained as 0.9967 to 0.9999. The data of R2 and RMSD indicated againgood correlation of experimental solubility data of isatin with the mod-ified Apelblat model.

Fig. 2. Comparison of experimental mole fraction solubilities (xe) of crystalline isatin withliterature values at T= (298.15 to 338.15) K; Carbitol and water (solid lines repre-sent the literature values of isatin taken from reference 22).

3.4. Correlation of experimental solubilities with Yalkowsky model

According to the log-linear model of Yalkowsky, the solubility ofcrystalline isatin in various Carbitol + water mixed solvent systemscan be calculated using Eq. (4) [21]:

LogxYal ¼ m1 logS1 þm2 logS2: ð4Þ

In which, xYal is the Yalkowsky model solubility of crystalline isatinin Carbitol + water mixed solvent systems; S1 and S2 are the solubilityof isatin in pure solvent 1 (Carbitol) and pure solvent 2 (water), respec-tively; and m1 and m2 are the mass fractions of solvents 1 and 2 in theabsence of solute (isatin). For the correlation of xewith xYal, RMSD valueswere calculated again using Eq. (2).

The log xYal values of crystalline isatin along with RMSD valuesin various Carbitol + water mixed solvent systems at T = (298.15to 338.15) K are listed in Table S3. The RMSD values in variousCarbitol + water mixed solvent systems were obtained as 0.014 to0.033 which indicated good correlation of measured solubility data ofisatin with the Yalkowsky model.

3.5. Thermodynamic parameters for isatin dissolution

The dissolution enthalpy (ΔsolH0) for crystalline isatin in various

Carbitol + water mixed solvent systems was determined by well-known Van't Hoff analysis [24,25]. Hence, the ΔsolH

0 values were

Fig. 3. Impact of mass fraction of Carbitol (m) onmole fraction solubility (xe) of crystallineisatin at T=(298.15 to 338.15) K; 298.15 K, 308.15 K, 318.15 K, 328.15 K and

338.15 K.

Fig. 4. ΔsolH0 versus ΔsolG

0 enthalpy–entropy compensation plot for the dissolution ofcrystalline isatin in Carbitol + water cosolvent mixtures at mean harmonic temperatureof 317.52 K.

277F. Shakeel et al. / Journal of Molecular Liquids 207 (2015) 274–278

calculated at mean harmonic temperature (Thm = 317.52 K) usingEq. (5):

∂ ln x

∂ 1�T−1

�Thm

� �0@

1A

P

¼ −ΔsolH0

R: ð5Þ

In which, R represents the universal gas constant. The ln xe values ofcrystalline isatin were plotted against 1

�T−1

�Thm

. These plots were ob-

served linear with R2 values in the range of 0.9950 to 0.9990 (Table S4).The ΔsolH

0 values in Carbitol + water mixed solvent systems weredetermined from the slope of each plot presented in Fig. S3. The Gibbsfree energies (ΔsolG

0) in various Carbitol + water mixed solvent sys-tems were determined at Thm = 317.52 K using Krug analysis withthe help of Eq. (6) [26]:

ΔsolG0 ¼ −RThm � intercept: ð6Þ

In which, the intercept values in each cosolvent mixtures were de-termined from Fig. S3.

The dissolution entropies (ΔsolS0) in various Carbitol +watermixed

solvent systems were calculated using Eq. (7):

ΔsolS0 ¼ ΔsolH

0−ΔsolG0

Thm: ð7Þ

The values ofΔsolH0,ΔsolG

0,ΔsolS0 and R2 in various Carbitol+water

mixed solvent systems are listed in Table S4.TheΔsolH

0 values in various Carbitol+watermixed solvent systemswere observed as positive values in the range of (2.88 to 28.10)kJ·mol−1. The ΔsolH

0 value was observed highest in pure water (m =0.0) (28.10 kJ·mol−1). However, the lowest one was observed in pureCarbitol (m=1.0) (2.88 kJ·mol−1). TheΔsolG

0 valueswere also record-ed as positive values in the range of (1.54 to 24.13) kJ·mol−1. TheΔsolG

0

value was also observed highest in pure water (24.13 kJ·mol−1) andlowest in pure Carbitol (1.54 kJ·mol−1). The positive values of ΔsolH

0

and ΔsolG0 in all Carbitol + water mixed solvent systems indicated an

endothermic and spontaneous dissolution of crystalline isatin in all bi-nary solventmixtures investigated. TheΔsolS

0 valueswere also recordedas positive values in the range of (4.21 to 12.52) J·mol−1·K−1, indicat-ing an entropy-driven dissolution of isatin. The positive values of ΔsolH

0

for the dissolution of crystalline isatinwere probably due to the strongermolecular interactions between isatin and the solvent molecules ascompared to those between the solvent–solvent and isatin–isatin mol-ecules [10,22].

3.6. Enthalpy–entropy compensation of isatin solution

The purpose of studying the enthalpy–entropy compensation effect ofisatin solution was to evaluate the mechanism of co-solvent action [24,27]. Theweighted plots ofΔsolH

0 as a function ofΔsolG0 at permits the ob-

servation of similarmechanism for solvation process according to the ten-dencies obtained Thm [28]. The results of enthalpy–entropy compensationeffects for isatin solvation behavior are presented in Fig. 4. From Fig. 4, itwas observed that crystalline isatin in Carbitol + water mixed solventsystems presents nonlinearΔsolH

0 vs.ΔsolG0 curvewith a variable positive

slope value (less than 1) for up to m = 0.3 (where the maxima werereached). Beyond this Carbitol proportion, a positive slope value of greaterthan 1 was obtained. Hence, the driving mechanism for solvation behav-ior of isatin was proposed as an entropy-driven in former case that wasprobably due to water-structure loosening. However, in latter case (sec-ond case), the driving mechanism was proposed as enthalpy-driven,that was probably due to better solvation of crystalline isatin in Carbitolmolecules [29].

4. Conclusion

The solubilities of pharmacologically active natural bioactive com-pound isatin in various Carbtol + water mixed solvent systems weremeasured at T=(298.15 to 338.15) K. Generally, the solubilities of crys-talline isatin were found to be increased with the rise in temperatureandmass fraction of Carbitol in Carbitol+watermixed solvent systems.The highest solubility of isatin was observed in pure Carbitol and lowestone was observed in pure water. The measured solubility data of isatinwere correlated well with all three mathematical models. Van't Hoffand Krug analyses showed endothermic, spontaneous and an entropy-driven dissolution of isatin in all Carbitol + water mixed solvent sys-tems investigated. Enthalpy–entropy compensation studies indicatedan entropy-driven mechanism for isatin solvation from m = 0.0 to 0.3and an enthalpy-driven mechanism from m = 0.4 to 1.0.

Conflict of interest

The authors report no conflict of interest relatedwith thismanuscript.

Acknowledgment

The authors would like to extend their sincere appreciation to theDeanship of Scientific Research at King Saud University for funding thework through the research group project no. RGP-VPP-202.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in theonline version, at http://dx.doi.org/10.1016/j.molliq.2015.03.038.

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