Solubilization Behavior of Paracetamol in Transcutol–Water Mixtures at (298.15 to 333.15) K

Solubilization Behavior of Paracetamol in Transcutol−WaterMixtures at (298.15 to 333.15) KFaiyaz Shakeel,*,†,‡ Fars K. Alanazi,‡ Ibrahim A. Alsarra,†,‡ and Nazrul Haq†,‡

†Center of Excellence in Biotechnology Research, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia‡Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia

ABSTRACT: The solubilization behavior of paracetamol (PCT) in adiethylene glycol monoethyl ether (Transcutol)−water mixture at (298.15to 333.15) K is not reported in literature so far. Therefore, attempts weremade to investigate the solubilization behavior of PCT in monosolvents andvarious Transcutol−water mixtures at the temperature range of (298.15 to333.15) K. The mole fraction solubility of PCT was determined by reportedshake flask method. The experimental solubility data of PCT in monosolventsand various Transcutol−water mixtures were found to be correlated well withthe modified Apelblat model with the correlation coefficients in the range of0.996 to 0.999. The solubility of PCT was found to be increased significantlywith the increase in temperature and mass fraction of Transcutol. The molefraction solubility of PCT was found to be highest in pure Transcutol (0.111 at298.15 K) as compared to water and other cosolvent mixtures. The positive values of enthalpies and entropies indicated that thedissolution of PCT is endothermic. Overall, these results indicated that Transcutol could be used as a physiologically compatiblecosolvent to enhance the aqueous solubility of PCT. These preliminary studies could be useful in the formulation development ofPCT especially in terms of liquid dosage forms.

1. INTRODUCTIONThe IUPAC name of paracetamol (PCT) is N-(4-hydrox-yphenyl) acetamide, and its molecular structure is presented inFigure 1 (molecular formula,C8H9NO2; molecular weight,

151.169 g·mol−1; CAS Registry No. 8055-08-1).1−3 It is themost widely used analgesic and antipyretic drug especially forpediatric and geriatric patients.1−7 It is commercially availablein the form of tablets, capsules, syrups, and suspensions. Thesingle adult dose of PCT is usually very high (500 mg) due towhich it is preferred to administer as a solid dosage form inadult human beings. It is sparingly soluble in water according toseveral pharmacopoeias, which is the main obstacle for theformulation development of PCT especially for parenteral/

liquid dosage forms.4−7 Due to high doses, a large volume ofcosolvents is generally required to solubilize it, which is notfeasible from the medical/pharmaceutical point of view. If it issolubilized in relatively small amount of cosolvent/cosolventmixtures, the development of PCT liquid dosage forms such asinjectable formulations would be quite easy. Many cosolventssuch as ethanol, propylene glycol, ethyl acetate, and dioxanehave been used to enhance the solubility of PCT either at roomtemperature or a various range of temperatures.1−7 It has beenreported in literature that temperature-dependent solubilitydata of poorly soluble drugs in cosolvent mixtures have greatimportance because they could be extremely useful in drugdissolution/permeation studies, drug crystallization, drugpurification, preformulation studies, and formulation develop-ment.1,8−10 Various mathematical models have been developedfor correlation and calculation of solubility of such drugs, but allthese models are not suitable for the calculation of temperature-dependent solubility data.1−3,11−17 Therefore, the determina-tion of temperature-dependent solubility profile of drugs isimportant to obtain complete information regarding phys-icochemical characterization of such drugs.1 The IUPAC nameof Transcutol is diethylene glycol monoethyl ether (molecularformula C6H14O3; molecular weight 134.17 g·mol−1; CASRegistry No. 111-90-0). It has been investigated extensively asan cosolvent/cosurfactant in the development of various lipid

Received: September 22, 2013Accepted: October 29, 2013Published: November 8, 2013

Figure 1. Molecular structure of paracetamol.

Article

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based formulations such as microemulsions, nanoemulsions,self-microemulsifying drug delivery systems (SMEDDS), andself-nanoemulsifying drug delivery systems (SNEDDS).17−21

All of these lipid-based systems (microemulsions, nano-emulsions, SMEDDS, and SNEDDS) are known to enhance

the solubility and bioavailability of drugs.17−23 Nevertheless, ithas not been investigated as a cosolvent to enhance solubility ofdrugs in water−cosolvent mixtures in literature so far. Themodified Apelblat model is the commonly used model whichcan be applied for both polar as well as for nonpolar systems to

Table 1. Experimental (xe) and Calculated Mole Fraction Solubility (xmAc) of Paracetamol in Various Transcutol−WaterMixtures at (298.15 to 333.15)a and Atmospheric Pressure of 0.1 MPa

T/K 103 xe 103 xmAc AD/%

Transcutol + Water (m = 0.0)298.15 1.6 1.5 5.8303.15 1.9 1.8 5.5308.15 2.3 2.2 3.6313.15 2.7 2.6 1.7318.15 3.3 3.2 3.7323.15 4.0 3.8 6.1328.15 4.7 4.5 5.3333.15 5.5 5.3 4.8

Transcutol + Water (m = 0.1)298.15 3.7 3.7 −1.0303.15 4.2 4.4 −2.8308.15 5.2 5.2 1.1313.15 6.1 6.1 1.4318.15 7.3 7.1 2.4323.15 8.5 8.3 2.0328.15 9.7 9.7 0.2333.15 10.8 11.2 4.0

Transcutol + Water (m = 0.2)298.15 6.0 6.1 −1.0303.15 6.9 6.9 −1.0308.15 7.9 7.9 0.2313.15 8.9 8.9 0.4318.15 10.0 10.0 −0.4323.15 11.3 11.3 −0.2328.15 12.7 12.7 −0.2333.15 14.1 14.3 −1.3

Transcutol + Water (m = 0.3)298.15 10.2 10.3 −1.1303.15 11.4 11.5 −0.7308.15 12.9 12.8 0.7313.15 14.3 14.3 0.3318.15 15.8 15.8 −0.1323.15 17.6 17.5 0.3328.15 19.4 19.4 −0.0333.15 21.1 21.4 −1.5

Transcutol + Water (m = 0.4)298.15 17.2 17.1 0.4303.15 18.5 18.5 −0.0308.15 19.7 19.9 −0.8313.15 21.1 21.4 −1.3318.15 22.7 22.9 −1.1323.15 24.4 24.6 −0.6328.15 26.3 26.3 −0.1333.15 28.3 28.2 0.5

Transcutol + Water (m = 0.5)298.15 26.8 26.7 0.1303.15 27.8 27.9 −0.3308.15 29.0 29.1 −0.3313.15 30.3 30.3 0.0318.15 31.5 31.6 −0.2323.15 32.8 32.9 0.1328.15 34.1 34.2 −0.5

T/K 103 xe 103 xmAc AD/%

Transcutol + Water (m = 0.5)333.15 35.7 35.6 0.2


Transcutol + Water (m = 0.7)298.15 39.0 39.1 −0.2303.15 40.6 40.8 −0.4308.15 42.3 42.5 −0.5313.15 44.1 44.3 −0.4318.15 45.9 46.1 −0.3323.15 47.6 47.9 −0.7328.15 49.6 49.8 −0.4333.15 51.6 51.7 −0.1

Transcutol + Water (m = 0.8)298.15 50.2 50.2 −0.0303.15 52.3 52.3 −0.0308.15 54.3 54.5 −0.3313.15 56.5 56.7 −0.2318.15 58.8 58.9 −0.1323.15 60.9 61.2 −0.4328.15 63.4 63.5 −0.2333.15 66.0 65.9 0.1

Transcutol + Water (m = 0.9)298.15 68.8 69.1 −0.4303.15 71.6 72.1 −0.6308.15 74.9 75.1 −0.3313.15 78.2 78.2 −0.0318.15 81.4 81.4 −0.0323.15 84.5 84.7 −0.2328.15 87.6 88.1 −0.4333.15 91.0 91.5 −0.5


aThe relative standard uncertainty for experimental solubilities is 1.3%; the uncertainty for temperature is ± 0.26 K, distilled water (W),mass fraction of Transcutol in cosolvent mixtures (m), experimentalsolubility of paracetamol (xe), mole fraction solubility of paracetamolcalculated by the modified Apelblat model (xmAc), relative absolutedeviation between experimental and calculated solubilities (AD).

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correlate experimental solubility data with the theoreticalone.24,25 The solubilization behavior of PCT in variouscosolvent mixtures such as dioxane−water, sugar−water,propylene glycol−water, and propylene glycol−ethanol havebeen investigated in literature.1−7 However, its solubilizationbehavior in the Transcutol−water mixture at (298.15 to333.15) K has not been reported in literature so far. Therefore,the aim of this study was to investigate the solubilizationbehavior of PCT in monosolvents (distilled water andTranscutol) as well as in Transcutol−water mixtures to makecorrelation between experimental data and the modifiedApelblat model at the temperature range of (298.15 to333.15) K. These preliminary studies could be useful in drugdissolution/permeation studies, purification, preformulationstudies, and formulation development of PCT. Moreover,these studies could also be useful in the development of variousnanosized lipid based formulations of PCT such as nano-emulsions/microemulsions and SNEDDS/SMEDDS.

2. EXPERIMENTAL SYSTEM AND METHODS2.1. Materials. PCT (mass fraction purity of 0.995) was

purchased from Sigma Aldrich (St. Louis, MO). Highly purifieddiethylene glycol monoethyl ether (Tarnscutol-HP) (massfraction purity of 0.9998) was a kind gift sample from Gatefosse(Cedex, France). Distilled water was procured from distillationunit in the laboratory. All other chemicals and reagents usedwere of analytical reagent (AR grade).2.2. Measurement of PCT Solubility. The solubility of

PCT in monosolvents (distilled water and Transcutol) andvarious Transcutol−water mixtures of mass fraction ofTranscutol (m from 0.1 to 0.9) was measured by the shakeflask method at atmospheric pressure and temperature rangefrom (298.15 to 333.15) K.17 PCT in an excess amount wasadded in 5 mL of monosolvents and Transcutol−watermixtures in 10 mL capacity vials in triplicate. Each vial wastightly closed with the cap, and the solid−liquid mixture waskept in an isothermal mechanical shaker bath (Julabo, PA) atshaking speed of 100 rpm for 72 h to reach equilibrium. After72 h, all of the sample mixtures were removed from the shakerand allowed to settle drug particles for 2 h at the bottom ofvials. All of the samples were filtered through 0.45 μm filterpaper, and supernatant from each sample was taken and dilutedsuitably with respective solvent and subjected for analysis ofcontent of PCT using a UV−visible spectrophotometer(SP1900, Axiom, Germany) as reported previously.1,3 Theproposed spectrophotometric method was found to be linear inthe range of (2 to 20) μg·mL−1 with a correlation coefficient of0.999. The uncertainty in solubility was observed as 1.3 %.However, the uncertainty in temperature was observed as ±0.26 K. The experimental mole fraction solubility (xe) of PCTwas calculated using eq 1:8,17

=+ +

xm M

m M m M m M/

/ / /e1 1

1 1 2 2 3 3 (1)

where m1 is the mass of PCT (solute) and m2 and m3 are themass of Transcutol and water, respectively. M1 represents themolecular mass of PCT, and M2 and M3 represent themolecular masses of Transcutol and water, respectively.

3. RESULTS AND DISCUSSION3.1. Solubility Data of PCT. The mole fraction solubility

data of PCT in monosolvents (Transcutol and water) and

Transcutol−water mixtures at the temperature range from(298.15 to 333.15) K are listed in Table 1. The mole fractionsolubility of PCT was found to be increased exponentially withincrease in temperature in monosolvents as well as inTranscutol−water mixtures at (298.15 to 333.15) K. Themole fraction solubility of PCT was observed highest andlowest in pure Transcutol (m = 1.0) and water, respectively, ateach temperature studied (Table 1). The mole fractionsolubility of PCT in pure Transcutol was observed as 111.0× 10−3 at 298.15 K as compared to 1.6 × 10−3 in water (Table1), which was significantly higher in pure Transcutol than purewater. The effect of mass fraction of Transcutol on molefraction solubility of PCT in the temperature range from(298.15 to 333.15) K is presented in Figure 2. It was observed

that the mole fraction solubility of PCT was found to beincreased with the increase in mass fraction of Transcutol ateach temperature studied (Figure 2). It is well-known thatwater is a highly polar solvent than organic solvents such asTranscutol.26 Therefore, the lowest solubility of PCT in purewater was probably due to its highest polarity.27 The molefraction solubility of PCT in Transcutol−water mixtures wasincreased rapidly by increasing the mass fraction of Transcutolin cosolvent mixtures that was probably due to reducedpolarities in Transcutol−water mixtures.26−28 Our results ofmole fraction solubility of PCT were in agreement withprevious report of polarities in all Transcutol−water mixtures.The highest mole fraction solubility of PCT in pure Transcutolwas probably due to the lower polarity of Transcutol ascompared to water. The solubility of PCT in 26 pure solventsincluding water and various organic solvents has been reportedby Granberg and Rasmuson.29 Nevertheless, its solubility inpure Tanscutol or Transcutol−water mixtures is not reportedin literature so far. According to the Granberg and Rasmuson,the mole fraction solubility of PCT in pure water was observedas 2.0 × 10−3 at 303.15 K.29 However, in present study themole fraction solubility of PCT in pure water was found to be1.9 × 10−3 at 303.15 K which was very close to the reportedvalue. Moreover, Granberg and Rasmuson29 also reported themole fraction solubility of PCT in pure water as 1.7 × 10−3 at298.15 K which was close to the experimental value obtained inpresent study (1.6 × 10−3) at 298.15 K (Table 1). Overall, thetemperature-dependent solubility data of PCT were in good

Figure 2. Impact of mass fraction of Transcutol (m = 0 to 1.0) on theexperimental mole fraction solubility (xe) of paracetamol at temper-ature range of (298.15 to 333.15) K.



agreement with previously published data of PCT inwater.1,15,30 Based on these results, PCT could be consideredas freely soluble in pure Transcutol and sparingly soluble inpure water. Therefore, Transcutol could be utilized as aphysiologically compatible cosolvent in preformulation studiesand formulation development especially in terms of liquiddosage form of PCT. Because PCT was found to be freelysoluble in Transcutol, it can be utilized as a cosurfactant/cosolvent in the development of lipid-based formulations(nanoemulsions/microemulsions and SNEDDS/SMEDDS) ofPCT.3.2. Thermodynamic Modeling of PCT Solubility. As

mentioned in the Introduction, the modified Apelblat model isthe most commonly applied model for both polar as well as fornonpolar systems; therefore it was selected in present study tocorrelate experimental solubility data with the calculatedone.8−10,24,31 The temperature-dependent mole fraction sol-ubility of PCT can be represented by eq 2 to describe thesolid−liquid equilibrium according to the modified Apelblatmodel:25

= + +x ABT

C Tln ln( )e (2)

where xe is the experimental mole fraction solubility, T is theabsolute temperature (K), and parameters A, B, and C areadjustable equation parameters. Parameters A, B, and C weredetermined with the help of regression analysis of theexperimental data using the modified Apelblat model (eq 2).The modified Apelblat solubilities (xmAc) were calculated usingequation parameters A, B, and C. The modified Apelblatsolubilities were correlated with experimental solubilities ofPCT, and the percentage of absolute relative deviation (% AD)was calculated using eq 3. The data of experimental molefraction solubility, calculated solubility, and % AD inmonosolvents (pure water and pure Transcutol) and Trans-cutol−water mixture are listed in Table 1.

=−

·x x

xAD(%)

( )100e c

e (3)

where xe is the experimental mole fraction solubility and xc iscalculated solubility of PCT. The % AD was found to be lessthan 3 % in most of the Transcutol−water mixtures at alltemperatures studied (Table 1). The highest value of % AD wasobserved in pure water at 323.15 K which was 6.1 %. Thevalues of regressed parameters A, B, and C in water, Transcutol,and Transcutol−water mixtures are listed in Table 2. Thevalues of correlation coefficient (R2) for PCT in water andTranscutol were observed as 0.998 and 0.997, respectively(Table 2). However, R2 values for PCT in various Transcutol−water mixtures were observed in the range of 0.996 to 0.999,indicating a good fit in monosolvents as well as in cosolventmixtures.3.3. Thermodynamic Parameters for PCT Dissolution.

The dissolution of PCT into a liquid can be expressed as:17,24,31

solid + liquid = solid−liquid at an equilibrium.The molar enthalpy (ΔH0) and entropy (ΔS0) of PCT

dissolution can be calculated using eqs 4 and 5, respectively:

Δ = −⎜ ⎟⎛⎝

⎞⎠H RT C

BT

0

(4)

Δ = −⎜ ⎟⎛⎝

⎞⎠S R C

BT

0

(5)

where B and C are the adjustable parameters calculated by themodified Apelblat model. R and T are the universal gasconstant and absolute temperature, respectively. ΔH0 and ΔS0for PCT dissolution were calculated using eqs 4 and 5,respectively, at various temperatures. The results of thermody-namic parameters in monosolvents (water and Transcutol) andvarious Transcutol−water mixtures are listed in Table 3. TheΔH0 of PCT dissolution in pure water and pure Transcutol atvarious temperatures ranged from 26.7 to 29.9 and (10.0 to11.3) kJ·mol−1, respectively (Table 3). However, the ΔH0 ofPCT dissolution in various Transcutol−water mixtures rangedfrom (5.8 to 27.1) kJ·mol−1 at the same temperature range(Table 3). The ΔH0 of PCT dissolution in pure Transcutol wassignificantly decreased as compared to pure water. Thisindicated that relatively low energy is required for solubilizationof PCT in Transcutol. The rapid decline in ΔH0 values wasobserved in Transcutol−water mixtures up to mass fraction of0.5; after that only slight changes in ΔH0 values were observed.These results indicated that PCT dissolution in pure water,Transcutol, and various Transcutol−water mixtures wasendothermic because the values of ΔH0 were observed aspositive in each case. The positive values of ΔH0 were probablydue to the attraction between PCT molecules and the solventmolecules. The ΔS0 values of PCT dissolution in pure water,pure Transcutol, and various Transcutol−water mixtures werealso observed as positive values [(19.6 to 89.7) J·mol−1·K−1] ateach temperature studied, which also indicated that PCTdissolution is an endothermic and an entropy-driven process.

4. CONCLUSIONIn the present study, the solubilization behavior of paracetamolin pure water, pure Transcutol, and various Transcutol−watermixtures at temperature range from (298.15 to 333.15) K wasinvestigated. The mole fraction solubility of paracetamol wasfound to be increased exponentially with the increase intemperature in pure water, pure Transcutol, and Transcutol−water mixtures. The solubility of paracetamol in pureTranscutol was found to be significantly higher than purewater. The solubility data of paracetamol were correlated wellwith the modified Apelblat model in all samples with thecorrelation coefficients in the range of 0.996 to 0.999. Based onsolubility data of the present study, paracetamol is consideredas freely soluble in pure Transcutol and sparingly soluble inpure water. These studies indicated that Transcutol could beutilized as a physiologically compatible cosolvent in preformu-

Table 2. Modified Apelblat Parameters (A, B, and C) andCorrelation Coefficients (R2) for Paracetamol in VariousTranscutol−Water Mixturesa

m A B C R2

0.0 −62.23 57.60 10.970 0.9980.1 −55.42 43.70 9.936 0.9960.2 −41.79 36.40 7.634 0.9990.3 −35.04 32.30 6.543 0.9990.4 −22.76 28.50 4.478 0.9980.5 −11.53 21.60 2.590 0.9990.6 −11.23 23.20 2.566 0.9980.7 −10.72 22.30 2.513 0.9990.8 −10.10 25.20 2.448 0.9990.9 −10.23 27.60 2.525 0.9991.0 −19.50 45.50 4.224 0.997

aMass fraction of Transcutol in Transcutol−water mixtures (m).



lation studies and formulation development of paracetamol.Lipid-based formulations of paracetamol could also bedeveloped using current solubility data.

■ AUTHOR INFORMATIONCorresponding Author*Phone: +966-537507318. E-mail: [email protected] authors are highly thankful to Center of Excellence inBiotechnology Research (CEBR) and Department of Pharma-ceutics, College of Pharmacy, King Saud University, Riyadh,Saudi Arabia for their funding and support.NotesThe authors declare no competing financial interest.

■ REFERENCES(1) Jimenez, J. A.; Martinez, F. Thermodynamic study of thesolubility of acetaminophen in propylene glycol + water cosolventmixtures. J. Braz. Chem. Soc. 2006, 17, 125−134.(2) Martinez, F. Usefulness of the extended Hildebrand solubilityapproach in the solubility study of acetaminophen in water-propyleneglycol solvent mixtures. Rev. Acad. Colomb. Cienc. 2005, 29, 429−438.(3) Perez, D. C.; Guevara, C. C.; Cardenas, C. A.; Pinzon, J. A.;Barbosa, H. J.; Martínez, F. Solubility and displacement volumes of

acetaminophen in binary mixtures formed by propylene glycol, ethanoland at 25 °C. Rev. Colomb. Cienc. Quim. Farm. 2003, 32, 116−136.(4) Bustamante, P.; Romero, S.; Reillo, A. Thermodynamics ofparacetamol in amphiprotic and amphiprotic-aprotic solvent mixtures.Pharm. Pharm. Comm. 1995, 1, 505−507.(5) Bustamante, P.; Pena, A.; Escalera, B.; Reillo, A. Enthalpy-entropycompensation for the solubility of drugs in solvent mixtures:paracetamol, acetanilide, and nalidixic acid in dioxane-water. J.Pharm. Sci. 1998, 87, 1590−1596.(6) Etman, M. A.; Naggar, V. F. Thermodynamics of paracetamolsolubility in sugar-water cosolvent systems. Int. J. Pharmaceutics 1990,58, 177−184.(7) Grant, D. J. W.; Mehdizadeh, M.; Chow, A. H. L.; Fairbrother, J.E. Non-linear van’t Hoff solubility-temperature plots and theirpharmaceutical interpretation. Int. J. Pharmaceutics 1984, 18, 25−38.(8) Shakeel, F.; Alanazi, F. K.; Alsarra, I. A.; Haq, N.Thermodynamics-based mathematical model for solubility predictionof glibenclamide in ethanol-water mixtures. Pharm. Dev. Technol. 2014,19, 702−707.(9) Cantillo, E. A.; Delgado, D. R.; Martinez, F. Solutionthermodynamics of indomethacin in ethanol + propylene glycolmixtures. J. Mol. Liq. 2013, 181, 62−67.(10) Sunsandee, N.; Hronec, M.; Stolcova, M.; Leepipatpiboon, N.;Pancharoen, U. Thermodynamics of the solubility of 4-acetyl benzoicacid in different solvents from 303.15 to 373.15 K. J. Mol. Liq. 2013,180, 252−259.

Table 3. Thermodynamic Parameters (ΔH0 and ΔS0) for Paracetamol in Various Transcutol−Water Mixturesa

T/K

m 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15

0.0ΔH0 (kJ·mol−1) 26.7 27.1 27.6 28.0 28.5 28.9 29.4 29.9ΔS0 (J·mol−1·K−1) 89.6 89.6 89.6 89.6 89.7 89.7 89.7 89.70.1ΔH0 (kJ·mol−1) 24.2 24.6 25.0 25.5 25.9 26.3 26.7 27.1ΔS0 (J·mol−1·K−1) 81.3 81.4 81.4 81.4 81.4 81.4 81.5 81.50.2ΔH0 (kJ·mol−1) 18.6 18.9 19.2 19.5 19.8 20.2 20.5 20.8ΔS0 (J·mol−1·K−1) 62.4 62.4 62.4 62.5 62.5 62.5 62.5 62.50.3ΔH0 (kJ·mol−1) 15.9 16.2 16.4 16.6 17.0 17.3 17.5 17.8ΔS0 (J·mol−1·K−1) 53.5 53.5 53.5 53.5 53.5 53.5 53.5 53.50.4ΔH0 (kJ·mol−1) 10.8 11.0 11.2 11.4 11.6 11.7 11.9 12.1ΔS0 (J·mol−1·K−1) 36.4 36.4 36.4 36.4 36.4 36.4 36.5 36.50.5ΔH0 (kJ·mol−1) 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9ΔS0 (J·mol−1·K−1) 20.9 20.9 20.9 20.9 20.9 20.9 20.9 20.90.6ΔH0 (kJ·mol−1) 6.1 6.2 6.3 6.4 6.5 6.7 6.8 6.9ΔS0 (J·mol−1·K−1) 20.6 20.6 20.7 20.7 20.7 20.7 20.7 20.70.7ΔH0 (kJ·mol−1) 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7ΔS0 (J·mol−1·K−1) 20.2 20.2 20.2 20.3 20.3 20.3 20.3 20.30.8ΔH0 (kJ·mol−1) 5.8 5.9 6.0 6.1 6.2 6.3 6.4 6.5ΔS0 (J·mol−1·K−1) 19.6 19.6 19.6 19.6 19.6 19.7 19.7 19.70.9ΔH0 (kJ·mol−1) 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7ΔS0 (J·mol−1·K−1) 20.2 20.2 20.2 20.2 20.3 20.3 20.3 20.31.0ΔH0 (kJ·mol−1) 10.0 10.2 10.4 10.6 10.7 10.9 11.1 11.3ΔS0 (J·mol−1·K−1) 33.8 33.8 33.8 33.9 33.9 33.9 33.9 33.9

aMass fraction of Transcutol in cosolvent mixtures (m).



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Solubilization Behavior of Paracetamol in Transcutol–Water Mixtures at (298.15 to 333.15) K