Journal of Molecular Liquids 188 (2013) 28–32

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Journal of Molecular Liquids

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Solubility prediction of indomethacin in PEG 400+water mixtures atvarious temperatures

Faiyaz Shakeel a,b,⁎, Fars K. Alanazi b,c, Ibrahim A. Alsarra a,b, Nazrul Haq a,b

a Center of Excellence in Biotechnology Research, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabiab Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabiac Kayyali Chair for Pharmaceutical Industries, Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia

⁎ Corresponding author at: Center of Excellence in BiotUniversity, Riyadh, Kingdom of Saudi Arabia. Tel.: +966 5

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

0167-7322/$ – see front matter © 2013 Elsevier B.V. All rihttp://dx.doi.org/10.1016/j.molliq.2013.09.013

a b s t r a c t

a r t i c l e i n f o

Article history:Received 5 April 2013Received in revised form 21 September 2013Accepted 23 September 2013Available online 9 October 2013

Keywords:IndomethacinAqueous solubilityMole fraction solubilityPolyethylene glycol 400ThermodynamicsModified Apelblat equation

The objective of this studywas to determine the equilibriumsaturated solubility aswell asmole fraction solubility ofindomethacin in distilled water, polyethylene glycol 400 (PEG 400) and PEG 400+water mixtures at the tem-perature range of 293.15 to 318.15 K. The equilibrium solubilities of indomethacin were determined by shakeflask method and resulting data were analyzed by regression analysis. The experimental data were well correlatedwith the modified Apelblat model at various temperatures studied. The solubilities of indomethacin were found tobe increased exponentially with increase in temperature inmono-solvents as well as in PEG 400+water mixtures.The equilibrium saturated solubility aswell asmole fraction solubility of indomethacinwas found to be significantlyhigher in pure PEG 400 than distilled water and PEG 400 +water mixtures. The equilibrium and mole fractionsolubility of indomethacin in pure PEG 400 at the temperature of 298.15 K were found to be 0.0831 g/g and0.093, respectively. The relative absolute deviation (AD) between experimental and theoretical mole fractionsolubility was found to be less than 1% in mono-solvents as compared to PEG 400 +water mixtures. Solubilitydata of present study indicate that PEG 400 could be successfully applied as a cosolvent in preformulation studiesand formulation development of indomethacin as an alternate cosolvent of ethanol and propylene glycol.

© 2013 Elsevier B.V. All rights reserved.

1. Introduction

The chemical name of indomethacin is 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetic acid and its molecular structure ispresented in Fig. 1 (molecular formula—C19H16ClNO4, molecular weight—357.79 g/mol, CAS registry number—53-86-1). Therapeutically, it is apotent nonsteroidal anti-inflammatory, analgesic and antipyretic drugand recommended for the management of various kinds of pain andinflammation associated with several diseases [1–3]. Currently, variousformulations of indomethacin such as tablets, capsules, gels, injections,etc. are commercially available in the market [3]. Physicochemically, itshows very poor aqueous solubility (0.937μg/ml at 298.15K) [4] and con-sidered as practically insoluble drug which is the main obstacle for theformulation development of indomethacin especially for liquid dosageformswhere high amount of drug is required to be solubilized in relative-ly small volume of solvents [3–8]. For this reason, some physicochemicaldata of drugs such as solubility, volume of solvents to solubilize the drugsand other components in solution are very important in order to facilitateformulation/drug development processes [7,8]. The solubility data ofpoorly water soluble drugs in water–cosolvent mixtures have great im-portance because these cosolvent mixtures are frequently used in drug

echnology Research, King Saud37507318.

ghts reserved.

crystallization, drug purification process, preformulation studies and for-mulation development of such drugs [8–11]. Currently, various methodsare used for calculation of solubility of drugs but all thesemethods do notconsider the impact of temperature on solubility data of drugs [6–17].Therefore, it is of utmost importance to determine systematically, thesolubility of such drugs (temperature dependent solubility) in order toget complete information about physicochemical data of these pharma-ceutical systems [8]. The temperature-dependent solubility data of poorlysoluble drugs will allow conducting respective thermodynamics analysis,which could be able to explain the molecular mechanism involved inthe solution processes [8,13–15]. Polyethylene glycol 400 (PEG 400),propylene glycol (PG) and ethanol are very commonly used cosolventsin the preformulation studies and formulation development of variouspoorly soluble drugs due to their low toxicity (environmentallyconsidered as green solvents), good solubilizing capacity and cost effec-tiveness [18]. In the recent years, the modified Apelbalt model is themost accurate and commonly used mathematical model for polar aswell as for nonpolar systems and applied successfully to make cor-relation between experimental and theoretical solubility data ofvarious drugs/pharmaceuticals [19]. Various other models such asBuchowski–Ksiazczak λH model, Wilson, non-random two-liquid(NRTL), universal quasichemical (UNIQUAC), UNIFAC, UNIQUAT,COSMOPACE, GEQUAC, cubist, PLS, Yalkowski & Valvani, Hildebrandand Abraham solvation models have also been used to calculatesolubility of drugs/pharmaceuticals/chemicals [6–24]. Solubility data

Fig. 1. Molecular structure of indomethacin.

29F. Shakeel et al. / Journal of Molecular Liquids 188 (2013) 28–32

of indomethacin in various cosolvent mixtures such as ethanol–water,ethanol–PG, 1,4 dioxane–water and ethanol–ethyl acetate using varioussolubilitymodels are reported in literature [6,24–30]. However, tempera-ture dependent solubility data of indomethacin in PEG 400 + watermixtures and its correlation with the modified Apelblat model are notreported in literature so far. Therefore, the objective of this study wasto determine the equilibrium saturated solubility as well as the molefraction solubility of indomethacin in mono-solvents (distilled waterand PEG 400) as well as in PEG 400+water mixtures by shake flaskmethod to make correlation between experimental data and the modi-fied Apelblat model at the temperature range of 293.15 to 318.15 K.These preliminary studies on solubility data of indomethacin could beuseful in purification, preformulation studies and formulation develop-ment of indomethacin.

2. Experimental

2.1. Materials

Indomethacin (molecular structure in Fig. 1, purity 99.20%) was ob-tained as a gift sample from Alfa Aesar, A Johnson Metthey Company(Ward Hill, MA). PEG 400 (purity 99.98%) was purchased from FlukaAG Chemicals (Buchs, Switzerland). All other chemicals used were of

Table 1General properties of materials used in experiment.

Materials Molecular formula M.W. (g/mol)

Indomethacin C19H16ClNO4 357.790PEG 400 H(OCH2OCH2)nOH 400.000Water H2O 18.015

Table 2Equilibrium saturated solubility (S), mole fraction solubilities (Xe), calculated solubilities (XmAc

and PEG 400) at various temperatures.

T/K S (mg/g) 103 Xe 103 XmAc

W293.15 0.00089 4.73× 10−5 4.74× 10−

298.15 0.00094 5.00× 10−5 5.001 × 10303.15 0.00100 5.31× 10−5 5.28× 10−

308.15 0.00105 5.58× 10−5 5.57× 10−

313.15 0.00110 5.85× 10−5 5.86× 10−

318.15 0.00116 6.16× 10−5 6.17× 10−

PEG 400293.15 75.124 84.196 83.825298.15 83.124 93.162 93.411303.15 92.314 103.462 103.905308.15 102.430 114.800 115.378313.15 114.350 128.160 127.901318.15 126.540 141.822 141.552

Distilledwater (W), polyethylene glycol 400 (PEG 400), mole fraction solubility of indomethacinexperimental and calculated solubility (AD), reported mole fraction solubility of indomethacin

analytical reagent (AR grade). All these chemicals were used withoutfurther purification and their general properties along with molecularformulae are listed in Table 1.

2.2. Determination of indomethacin solubility

The saturated equilibrium solubility as well as mole fraction solubil-ity of indomethacin inmono-solvents (distilledwater and PEG 400) andPEG 400+water mixtures (mass fraction w from 0.1 to 0.9) was deter-mined by shake flaskmethod at atmospheric pressure and temperaturerange from 293.15 to 318.15K. An excess amount of indomethacin wasadded in 10g of distilled water, PEG 400 and PEG 400+water mixturesin 25ml capacity conical flasks in triplicate. Each solid–liquid mixturewas vortexed properly and kept in an isothermal mechanical shakingwater bath (Julabo, PA) for mechanical shaking at 100 rpm for 24 h toreach equilibrium. Each experiment was performed at temperaturerange from 293.15 to 318.15 K. The uncertainty in experiments wasobserved around ±0.60%. After 24 h, all the samples were taken outand allowed to settle drug (solute) particles for 2h at the bottomof con-ical flasks. All the samples were subjected to centrifugation at 5000rpmfor 15 min, supernatant from each sample was taken, diluted andsubjected for analysis of indomethacin using UV-Visible spectropho-tometer at 318 nm [2,3]. From indomethacin content in each sample,equilibrium saturated solubility (mg/g) was determined. However, theexperimentalmole fraction solubility (xe) of indomethacinwas calculat-ed using Eq. (1) [19]:

xe ¼ m1=M1m1=M1þm2=M2þm3=M3

ð1Þ

Where, m1 is the mass of indomethacin (solute) and m2 and m3 arethe mass of PEG 400 and distilled water, respectively. M1 representsthe molecular mass of indomethacin and M2 and M3 represent themolecular mass of PEG 400 and distilled water, respectively.

D (g/ml) Purity (%) CAS no.

1.320 99.20 53-86-11.124 99.98 25322-68-31.000 – –

) and reported mole fraction solubility of indomethacin in mono-solvents (distilled water

AD (%) Xe* References

5 −0.2−5 −0.2 4.98 × 10−8 [4]5 0.65 0.25 −0.25 −0.0

0.4−0.2 94.144× 10−3 [35]−0.4−0.50.20.1

calculated by themodified Apelbalt equation (XmAc), relative absolute deviation betweenin mono-solvents at 298.15 K (Xe*).

Table 3Equilibrium saturated solubility (S), mole fraction solubilities (Xe) and calculatedsolubilities (XmAc) of indomethacin in PEG 400+water mixtures at various temperatures.

T/K S (mg/g) 103 Xe 103 XmAc AD (%)

PEG 400+W (w=0.1)293.15 0.550 0.282 0.279 0.8298.15 1.000 0.308 0.313 −1.6303.15 1.600 0.343 0.351 −2.1308.15 2.400 0.390 0.392 −0.3313.15 3.200 0.437 0.437 0.0318.15 4.000 0.484 0.487 −0.4

PEG 400+W (w=0.2)293.15 1.000 0.565 0.555 1.7298.15 1.800 0.618 0.626 −1.3303.15 3.000 0.697 0.705 −1.1308.15 4.400 0.789 0.792 −0.4313.15 6.000 0.894 0.888 0.6318.15 7.600 0.999 0.994 0.4

PEG 400+W (w=0.3)293.15 1.900 0.891 0.879 1.4298.15 3.100 0.981 0.990 −0.9303.15 4.500 1.086 1.114 −2.5308.15 6.400 1.228 1.250 −1.8313.15 8.600 1.392 1.401 −0.6318.15 11.200 1.586 1.567 1.2

PEG 400+W (w=0.4)293.15 3.000 1.260 1.259 0.0298.15 4.300 1.372 1.381 −0.6303.15 5.700 1.494 1.512 −1.2308.15 7.600 1.659 1.654 0.2313.15 9.4600 1.815 1.806 0.4318.15 11.000 1.953 1.970 −0.8

PEG 400+W (w=0.5)293.15 5.000 1.767 1.777 −0.5298.15 6.500 1.922 1.928 −0.2303.15 8.000 2.077 2.089 −0.5308.15 10.000 2.284 2.261 1.0313.15 11.600 2.450 2.443 0.2318.15 13.100 2.605 2.637 −1.2

PEG 400+W (w=0.6)293.15 7.100 2.413 2.387 1.0298.15 8.800 2.632 2.645 −0.5303.15 10.800 2.889 2.926 −1.2308.15 12.900 3.159 3.232 −2.3313.15 16.000 3.559 3.564 −0.1318.15 19.200 3.970 3.948 1.1

PEG 400+W (w=0.7)293.15 9.400 3.353 3.321 0.9298.15 11.000 3.626 3.696 −1.9303.15 13.400 4.036 4.106 −1.7308.15 16.100 4.497 4.455 −1.2313.15 19.200 5.026 5.041 −0.3318.15 22.400 5.572 5.573 −0.0

PEG 400+W (w=0.8)293.15 25.150 8.401 8.314 1.0298.15 31.650 10.056 10.019 0.3303.15 39.720 12.110 12.036 0.6308.15 48.280 14.289 14.416 −0.8313.15 60.120 17.303 17.217 0.4318.15 73.76 20.775 20.504 1.3

PEG 400+W (w=0.9)293.15 42.150 23.590 23.433 0.6298.15 48.650 26.881 26.807 −0.2303.15 55.720 30.461 30.599 0.4308.15 63.280 34.288 34.852 1.6313.15 73.120 39.270 39.611 0.8318.15 85.760 46.670 44.930 −1.6

Distilled water (W), polyethylene glycol 400 (PEG 400), mole fraction solubility ofindomethacin calculated by the modified Apelbalt equation (XmAc), mass fraction of PEG400 in cosolvent mixtures (w), relative absolute deviation between experimental and cal-culated solubility (AD).

30 F. Shakeel et al. / Journal of Molecular Liquids 188 (2013) 28–32

3. Results and discussion

3.1. Solubility data of indomethacin

The saturated equilibriumsolubility andmole fraction solubility dataof indomethacin in mono-solvents (distilled water and PEG 400) andPEG 400 + water mixtures at temperature range from 293.15 to318.15K are listed in Tables 2 and 3, respectively. The saturated equilib-rium solubility as well as mole fraction solubility of indomethacin wasfound to be increased exponentially with increase in temperature inmono-solvents as well as in PEG 400+water mixtures. The saturatedas well as mole fraction solubility at each temperature were observedhighest and lowest in PEG400 anddistilledwater, respectively(Table 2).The saturated solubility of indomethacin in PEG 400 was found to be83.124 mg/g at the temperature of 298.15 K (room temperature) ascompared to 0.00094mg/g in distilled water (Table 2). Around 88430fold enhancement in solubility of indomethacin in PEG 400 was ob-served as compared to its aqueous solubility at room temperature.Mole fraction solubility of indomethacin in PEG 400 was observed as0.093162 at 298.15 K (room temperature) as compared to 5 × 10−8 indistilled water (Table 2) which was significantly higher in PEG 400than its aqueous solubility. Overall, the saturated and mole fractionsolubilities of indomethacin in various PEG 400 + water mixtureswere found to be increased by increasing the mass fraction of PEG 400in cosolvent mixtures at each temperature studied (Table 3). The effectof mass fraction on mole fraction solubility of indomethacin at varioustemperatures is presented in Fig. 2. It is noticeable that water is a highlypolar solvent than PEG 400 because the dielectric constant of water at298.15 K is 78.36 as compared to 12.4 of PEG 400 [31]. The highestand lowest solubilities of indomethacin in PEG 400 and distilled waterwere probably due to their lowest and highest polarities, respectively[32]. It has been reported that the solubility of solute/solvent could beenhanced by reducing the polarity of solvents or solvent mixtures[33]. The solubility of indomethacin in PEG 400+water mixtures wasalso increased by increasing the mass fraction of PEG 400 that couldbe due to reduced polarities in PEG 400 + water mixtures [31–33].These results were in accordance with previously published solubilitydata of indomethacin in ethanol–ethyl acetate and ethanol–PGmixtures[27,34]. Moreover, experimental mole fraction solubility of indometha-cin in water (5 × 10−8) and PEG 400 (0.093162) was very close toreported mole fraction values (4.98 × 10−8 in water and 0.094144 inPEG 400) at 298.15 K [4,35]. Based on solubility data, indomethacin

Fig. 2. Experimentalmole fraction solubility (Xe) of indomethacin in various mass fraction(0–1.0) of PEG 400+water mixtures at temperature ranging from 293.15 to 318.15 K.

31F. Shakeel et al. / Journal of Molecular Liquids 188 (2013) 28–32

could be considered as soluble in PEG 400 and practically insoluble indistilled water (aqueous media). Therefore, PEG 400 could be success-fully applied as a cosolvent in preformulation studies and formulationdevelopment of indomethacin as an alternate cosolvent of ethanol andPG, etc.

3.2. Thermodynamic modeling of solubility of indomethacin

According to thermodynamic principles, many equations/models asmentioned in Introduction section have been used to correlate experi-mental solubility data with theoretical mole fraction solubility [6–23].The modified Apelblat model is the most accurate and widely usedmodel to describe experimental solubility data, therefore it was selectedin present study to correlate experimental data with data calculatedfrom themodified Apelblat model [9,22]. Moreover, this model is appli-cable to polar as well as for nonpolar systems [19,21]. According to themodified Apelblat equation, the temperature dependent mole fractionsolubilities of indomethacin at different temperatures can be represent-ed by Eq. (2) to describe solid–liquid equilibrium:

lnxe ¼ Aþ BTþ C ln Tð Þ ð2Þ

Where, xe is the experimental mole fraction solubility of indo-methacin, T is the absolute temperature (K), parameters A, B andC are adjustable equation parameters which can be obtained by fittingthe experimental mole fraction solubility data. In the present study,these adjustable parameters (A, B and C) were determined from regres-sion analysis of the experimental data using Eq. (2). The modifiedApelblat solubilities (xmAc) of indomethacin were calculated with thehelp of adjustable parameters A, B and C. The calculated mole fractionsolubilities were comparedwith experimentalmole fraction solubilitiesand the percentage of absolute relative deviation (%A D) of indometha-cin was determined using Eq. (3). The data of experimental solubility,calculated solubility and the % AD in mono-solvents and various PEG400+water mixture are listed in Tables 2 and 3, respectively.

AD %ð Þ ¼ xe−xcð Þxe

� 100 ð3Þ

Where, xe and xc are the experimental mole fraction and calculatedsolubility of indomethacin, respectively. The % ADwas found to be low-est (less than 1%) in distilled water and PEG 400 as compared to PEG400+water mixtures (Tables 2 and 3). Overall, % AD was found to beless than 2.6% in each mixture of PEG 400 + water (Table 3). Theregressed parameter values (A, B and C) of indomethacin in distilledwater, PEG 400 and PEG 400 + water mixtures are listed in Table 4.The experimental solubility data of indomethacin and its correlation

Table 4The modified Apelblat model adjustable parameters for indomethacin in mono-solventsand PEG 400+water mixtures.

Sample Modified Apelblat model

A B C R2

Distilled water −28.301 12.80 3.222 0.9980PEG 400 −32.012 22.40 6.402 0.9990PEG 400+W (w=0.1) −39.847 26.80 6.775 0.9970PEG 400+W (w=0.2) −41.092 28.20 7.114 0.9970PEG 400+W (w=0.3) −40.370 27.60 7.068 0.9940PEG 400+W (w=0.4) −30.921 18.70 5.473 0.9980PEG 400+W (w=0.5) −26.894 16.50 4.826 0.9970PEG 400+W (w=0.6) −33.710 21.60 6.075 0.9940PEG 400+W (w=0.7) −34.778 14.90 6.325 0.9960PEG 400+W (w=0.8) −60.653 34.80 11.030 0.9990PEG 400+W (w=0.9) −42.131 31.10 7.954 0.9970

Distilled water (W), polyethylene glycol 400 (PEG 400), mass fraction of PEG 400 incosolvent mixtures (w).

with the modified solubilities calculated by Apelblat model in mono-solvents (distilled water and PEG 400) and PEG 400+water mixturesare listed in Tables 2 and 3, respectively. The value of correlation coeffi-cient (R2) for indomethacin in distilledwater and PEG400was observedas 0.9980 and 0.9990, respectively (Table 4). However, the values of R2

for indomethacin in PEG 400 +water mixtures were observed in therange of 0.9940–0.9990, indicating a good fit in all samples investigated.

3.3. Thermodynamic parameters for indomethacin

According to the thermodynamic principle of the modified Apelblatmodel, the dissolution of indomethacin (solute) into a liquid can beexpressed as [13–15]:

solidþ liquid ¼ solid−liquid

With the help of modified Apelblat parameters B and C, the molar en-thalpy (ΔsolH) and entropy (ΔsolS) of dissolution can be calculatedusing Eqs. (4) and (5), respectively:

ΔsolH ¼ RT C− BT

� �ð4Þ

ΔsolS ¼ R C− BT

� �ð5Þ

Where, R is universal gas constant and T is absolute temperature.ΔsolH and ΔsolS for indomethacin were calculated at temperaturerange from 293.15 to 318.15 K using Eqs. (4) and (5), respectively.These thermodynamic parameters of indomethacin in mono-solvents(distilled water and PEG 400) and PEG 400+water mixtures are listedin Tables 5 and 6, respectively. The molar enthalpies (ΔsolH) of indo-methacin in distilledwater and PEG 400 at various temperatures rangedfrom 7.746–8.416 and 15.417–16.748 kJ mol−1, respectively (Table 5).However, ΔsolH of indomethacin in various PEG 400+water mixturesranged from 11.625 to 28.887 at same temperature range (Table 6). TheΔsolH of indomethacin in distilled water was observed as lowest ascompared to PEG 400 and PEG 400 + water mixtures that could bedue to the highest polarity of distilled water. However, the ΔsolH ofindomethacin in PEG 400 was observed higher than distilled waterthat could be due to the low polarity of PEG 400 as compared to distilledwater. Overall, these results indicate that the dissolution of indometha-cin in distilledwater, PEG 400 and PEG 400+watermixtureswas endo-thermic because the values of molar enthalpies were observed aspositive in all sample matrices. The positive values of ΔsolH in distilledwater, PEG 400 and PEG 400+water mixtures were probably due tothe formation of new bond energy of attraction between indomethacinmolecules and the solvent molecules. The ΔsolS values of indomethacinin distilled water, PEG 400 and PEG 400+watermixtures were also ob-served as positive values at each temperature range studied which alsoindicated that dissolution of indomethacin is an endothermic and anentropy-driven process (Tables 5 and 6). TheΔsolS valueswere also ob-served lowest in distilled water as compared to PEG 400 and PEG400+water mixtures as shown in Tables 5 and 6.

Table 5Thermodynamic parameters ΔsolH and ΔsolS for indomethacin in mono-solvents.

T/K Distilled water PEG 400

ΔsolH(kJmol−1)

ΔsolS(Jmol−1 K−1)

ΔsolH(kJmol−1)

ΔsolS(Jmol−1 K−1)

293.15 7.746 26.426 15.417 52.593298.15 7.880 26.432 15.684 52.604303.15 8.014 26.438 15.950 52.614308.15 8.148 26.443 16.216 52.624313.15 8.282 26.449 16.482 52.634318.15 8.416 26.454 16.748 52.643

Table 6Thermodynamic parameters ΔsolH and ΔsolS for indomethacin in PEG 400+water mix-tures.

Sample T/K

293.15 2938.15 303.15 308.15 313.15 318.15

PEG 400+W (w=0.1)ΔsolH (kJmol−1) 16.290 16.572 16.853 17.135 17.417 17.698ΔsolS (Jmol−1 K−1) 55.570 55.583 55.595 55.607 55.618 55.630

PEG 400+W (w=0.2)ΔsolH (kJmol−1) 17.105 17.400 17.696 17.992 18.288 18.583ΔsolS (Jmol−1 K−1) 58.349 58.362 58.375 58.388 58.400 58.412

PEG 400+W (w=0.3)ΔsolH (kJmol−1) 16.997 17.291 17.585 17.879 18.173 18.467ΔsolS (Jmol−1 K−1) 57.983 57.996 58.009 58.021 58.033 58.045

PEG 400+W (w=0.4)ΔsolH (kJmol−1) 13.184 13.411 13.639 13.866 14.094 14.321ΔsolS (Jmol−1 K−1) 44.973 44.983 44.992 45.000 45.008 44.016

PEG 400+W (w=0.5)ΔsolH (kJmol−1) 11.625 11.826 12.026 12.227 12.428 12.628ΔsolS (Jmol−1 K−1) 39.657 39.665 39.673 39.680 39.687 39.694

PEG 400+W (w=0.6)ΔsolH (kJmol−1) 14.627 14.880 15.132 15.385 15.637 15.890ΔsolS (Jmol−1 K−1) 49.897 49.908 49.917 49.927 49.936 49.945

PEG 400+W (w=0.7)ΔsolH (kJmol−1) 15.292 15.555 15.818 16.081 16.344 16.607ΔsolS (Jmol−1 K−1) 52.166 52.173 52.180 52.186 52.193 52.199

PEG 400+W (w=0.8)ΔsolH (kJmol−1) 26.595 27.053 27.512 27.970 28.429 28.887ΔsolS (Jmol−1 K−1) 90.721 90.738 90.754 90.769 90.784 90.799

PEG 400+W (w=0.9)ΔsolH (kJmol−1) 19.128 19.459 19.789 20.120 20.451 20.781ΔsolS (Jmol−1 K−1) 65.252 65.265 65.280 65.294 65.307 65.320

Distilled water (W), polyethylene glycol 400 (PEG 400), mass fraction of PEG 400 incosolvent mixtures (w).

32 F. Shakeel et al. / Journal of Molecular Liquids 188 (2013) 28–32

4. Conclusions

In the present study, the saturated as well as the mole fraction solu-bility of indomethacin in distilled water, PEG 400 and various PEG400 + water mixtures at temperature range from 293.15 to 318.15 Kwere measured. The solubilities of indomethacin were found to be in-creased with increase in temperature in distilled water, PEG 400 andvarious PEG 400 + water mixtures. The solubility of indomethacin inpure PEG 400 was found to be significantly higher than pure distilledwater and various PEG 400 + water mixtures. The solubility data ofdistilled water, PEG 400 and various PEG 400+water mixtures werewell correlated by the modified Apelblat model. The values of correla-tion coefficients (R2) in the range of 0.9940–0.9990 indicated that themodified Apelblat model provided good fitting of experimental solubil-ity data. Based on the solubility data, indomethacin could be consideredas soluble in PEG 400 and practically insoluble in distilled water. Thesepreliminary studies indicate that PEG 400 could be utilized as an alter-nate cosolvent of ethanol and PG in preformulation studies and formu-lation development of indomethacin.

Conflict of interest statement

The authors declare no conflict of interest related to this manuscript.The authors alone are responsible for the content and writing of thepaper.

Acknowledgements

The authors are grateful to Center of Excellence in Biotechnology Re-search (CEBR) and Department of Pharmaceutics, College of Pharmacy,King Saud University, Riyadh, Saudi Arabia for facilitating the equip-ments and laboratories used.

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