Solubility of N‑(4-Chlorophenyl)-2-(pyridin-4-ylcarbonyl)-hydrazinecarbothioamide (Isoniazid Analogue) inTranscutol + Water Cosolvent Mixtures at (298.15 to 338.15) KFaiyaz Shakeel,*,† Mashooq A. Bhat,‡ and Nazrul Haq†

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

ABSTRACT: The solubility of N-(4-chlorophenyl)-2-(pyridin-4-ylcarbonyl)-hydrazinecarbothioamide (isoniazid analogue) in various diethylene glycolmonoethyl ether (Transcutol) + water cosolvent mixtures was measured at(298.15 to 338.15) K using the shake flask method. In order to investigatethe influence of temperature on solubility, the experimental solubilities of theisoniazid analogue were correlated with the Apelblat equation. To investigatethe influence of cosolvent mixtures on solubility, the log−linear model ofYalkowsky was used. For the Apelblat equation, the root-mean-squaredeviations (RMSDs) were observed in the range of 0.004 to 0.033. For theYalkowsky model, the RMSDs were observed in the range of 0.021 to 0.114.The correlation coefficients were observed in the range of 0.996 to 0.999.These results indicated the good fitting of experimental solubilities withthe Apelblat equation and Yalkowsky model. The solubility of isoniazidanalogue was found to be highest and lowest in pure Transcutol (4.23·10−2

at 298.15 K) and pure water (5.17·10−7 at 298.15 K), respectively. Thermo-dynamic parameters such as molar enthalpies and entropies were observed aspositive values in all cosolvent mixtures, indicating that the dissolutionprocess for the isoniazid analogue is endothermic and entropy-driven. Based on the solubility data of the current study, the isoniazidanalogue has been considered as freely soluble in Transcutol and practically insoluble in water.

1. INTRODUCTIONMost of the new drug candidates discovered by pharmaceuticalindustries today and many of the marketed/approved moleculesare poorly water-soluble.1,2 Poorly water-soluble compoundspresent several formulation development hindrances.2 TheIUPAC name of isoniazid is pyridin-4-carbohydrazide (Figure 1a)

which is one of the antitubercular drugs for the treatment oftuberculosis (TB).3,4 The high dose and oral administration ofisoniazid are associated with several adverse effects.5 In order toreduce the dose and adverse effects of isoniazid, variousanalogues of isoniazid have been evaluated for the effectivetreatment of TB.5−11 Some of the isoniazid analogues have alsobeen investigated as potential anticancer and anti-Candidalagents.6,9−14 The IUPAC name of the isoniazid analogue used

in this study is N-(4-chlorophenyl)-2-(pyridin-4-ylcarbonyl)-hydrazinecarbothioamide.14 The molecular formula and molec-ular mass of this analogue are C13H11ClN4OS and 306.77 g·mol

−1,respectively (molecular structure is presented in Figure 1b). Thisanalogue was synthesized, purified, characterized, and investigatedfor anti-Candidal activity in the literature.14 Anti-Candidal agent isused to treat invasive fungal infections caused by Candida albicans.Nevertheless, the literature lacks solubility data of such analogueswhich creates great challenges in their recrystallization/purificationand formulation development processes. Cosolvent technique isone of the simple techniques used for solubility enhancement ofpoorly water-soluble compounds.15−17 The molecular formula andmolecular mass of Transcutol are C6H14O3 and 134.17 g·mol−1,respectively.18 Recently, Transcutol has been investigated as aneffective cosolvent for solubility enhancement of several poorlywater-soluble compounds such as paracetamol, diclofenac sodium,glibenclamide, risperidone, olmesartan medoxomil, and tadala-fil.18−23 In order to correlate experimental solubilities with calc-ulated ones and to investigate the influence of temperature onsolubility, the Apelblat equation is commonly used.24−26 However,the log−linear model of Yalkowsky is helpful in evaluating the

Received: March 15, 2014Accepted: April 23, 2014Published: April 30, 2014

Figure 1. Molecular structure of isoniazid (a) and the isoniazidanalogue (b).

Article

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influence of cosolvent mixtures on solubility of solutes/drugs.27

The temperature-dependent solubility data of the isoniazid analogueare not available in literature. Therefore, the aim of this study was tomeasure the temperature-dependent solubilities of the isoniazidanalogue in monosolvents (pure water and pure Transcutol) andvarious Transcutol + water cosolvent mixtures at (298.15 to338.15) K using the shake flask method. For pharmaceuticalapplications, the solubilities at room temperature (298.15 K) orbody temperature (310.15 K) are useful. Therefore, the temperaturerange of (298.15 to 338.15) K was selected. This temperature rangecould help in the determination of solubility of the isoniazid analogueat room temperature or body temperature either directly or indirectly.The shake flask method is the most accurate and commonly usedmethod for the measurement of solubilities of drugs/pharmaceut-icals.28 The experimental solubilities were correlated with theApelblat equation and log−linear model of Yalkowsky in order toinvestigate the influence of temperature and cosolvent mixtures,respectively, on the solubility of the isoniazid analogue. Thesolubility data of this study could be useful in formulationdevelopment of isoniazid analogues in pharmaceutical industries.

2. EXPERIMENTAL SYSTEM AND METHODS2.1. Materials. Tarnscutol (IUPAC name-diethylene glycol

monoethyl ether) was a kind gift from Gattefosse (Lyon, France).The isoniazid analogue was synthesized, purified and characterizedin the laboratory of Pharmaceutical Chemistry, King SaudUniversity, Riyadh, Saudi Arabia.14 All other chemicals/reagentsused were of analytical/pharmaceutical grades. The generalproperties of materials used in the experiment are listed in Table 1.2.2. Measurement of Isoniazid Analogue Solubility.

The solubility of isoniazid analogue in various Transcutol +water cosolvent mixtures (mass fraction [m] of Transcutol incosolvents mixtures was 0.0 to 1.0) was measured from (298.15to 338.15) K at atmospheric pressure using the shake flaskmethod.28 The excess amount of drug was added in 5 g of eachcosolvent mixture in triplicate. These mixtures were tightlyclosed and transferred to a water shaker bath (Julabo, PA) at

100 rpm for 72 h. For the optimization of equilibrium time, thesolubility of the isoniazid analogue was measured at (12, 24, 36,48, 72, 96, and 120) h. The solubility of the isoniazid analoguewas found to be increase for up to 72 h. After 72 h, only negligiblechanges were observed in the solubility of the isoniazid analogue.Hence, 72 h was chosen as the optimum equilibrium time in thepresent study. After 72 h, the samples were removed from theshaker and allowed to settle solute particles for 2 h (it has beenreported as being enough time for complete settling of soluteparticles).19−21 The samples were then centrifuged at 5000 rpmfor 20 min. The supernatants from each mixture were taken,diluted and analyzed for drug content using UV−visiblespectrophotometer (SP1900, Axiom, Germany) at 276 nm. Thestandard uncertainty for the temperatures u(T) was observed as± 0.27 K. However, the relative standard uncertainty in solubilityur(xe) for isoniazid analogue was observed as 1.8 %. Theexperimental mole fraction solubilities (xe) of the isoniazidanalogue were calculated using the reported formula.21−23

3. RESULTS AND DISCUSSION3.1. Solubility Data of Isoniazid Analogue. The

solubilities of isoniazid analogue in various Transcutol + watercosolvent mixtures from (298.15 to 338.15) K and atmosphericpressure of 0.1 MPa are listed in Table 2. Because, the isoniazidanalogue was newly synthesized in the laboratory, its solubilitydata is not available in the literature. Moreover, the temperature-dependent solubilities of any of the isoniazid analogues are alsonot available in the literature so far. The solubility of the isoniazidanalogue was found to increase with an increase in temperaturein all cosolvent mixtures. The mole fraction solubilities wereobserved highest in pure Transcutol (m = 1.0) (4.32·10−2 at298.15 K) as compared to pure water (m = 0.0) (5.17·10−7 at298.15 K) and other cosolvent mixtures from (298.15 to 338.15)K (Table 2). The solubility of the isoniazid analogue in pureTranscutol was significantly higher than its aqueous solubilityfrom (298.15 to 338.15) K. The lowest solubilities of theisoniazid analogue in pure water from (298.15 to 338.15) K were

Table 1. General Properties of Isoniazid Analogue and Solvents Used in the Experiment

material molecular formula molecular mass (g·mol−1) purity (mass fraction) analysis method source

isoniazid analogue C13H11ClN4OS 306.77 > 0.99 GC synthesizedTranscutol C6H14O3 134.17 ≥ 0.99 GC Gattefossewater H2O 18.01

Table 2. Experimental Mole Fraction Solubilities (xe) of Isoniazid Analogue against Mass Fraction of Transcutol (m) inTranscutol + Water Cosolvent Mixtures in the Absence of Solute at Temperatures T = (298.15 to 338.15) K and Pressurep = 0.1 MPaa

xe

m T = 298.15 T = 308.15 T = 318.15 T = 328.15 T = 338.15

0.0 5.17·10−7 5.93·10−7 7.05·10−7 8.28·10−7 9.75·10−7

0.1 1.54·10−6 1.93·10−6 2.38·10−6 2.96·10−6 3.47·10−6

0.2 5.04·10−6 5.68·10−6 6.46·10−6 7.24·10−6 8.10·10−6

0.3 1.51·10−5 1.90·10−5 2.38·10−5 2.86·10−5 3.41·10−5

0.4 4.85·10−5 5.66·10−5 6.47·10−5 7.28·10−5 8.08·10−5

0.5 1.50·10−4 1.86·10−4 2.27·10−4 2.69·10−4 3.20·10−4

0.6 4.56·10−4 5.25·10−4 6.11·10−4 6.96·10−4 7.81·10−4

0.7 1.49·10−3 1.64·10−3 1.83·10−3 2.02·10−3 2.26·10−3

0.8 4.56·10−3 5.04·10−3 5.55·10−3 6.08·10−3 6.72·10−3

0.9 1.60·10−2 1.73·10−2 1.88·10−2 2.03·10−2 2.18·10−2

1.0 4.23·10−2 4.68·10−2 5.14·10−2 5.65·10−2 6.07·10−2

aThe standard uncertainty for the temperatures u(T) is ± 0.27 K, the relative standard uncertainty in solubility ur(xe) for isoniazid analogue is 1.8 %.

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probably due to its highest polarity and lower molecular weightas compared to pure Transcutol and other cosolvent mixtures.18

Based on solubility data of this study, the isoniazid analogue hasbeen considered as freely soluble in Transcutol and practicallyinsoluble water. Because, Transcutol enhanced the solubility ofisoniazid analogue in water significantly, it could be used as aphysiologically compatible cosolvent in preformulation studiesand formulation development of the isoniazid analogue.3.2. Correlation of Experimental Solubilities with the

Apelblat Equation. To investigate the influence of temper-ature on solubility of isoniazid analogue, Apelblat equation wasused.24−26 According to this equation, the temperature-dependent solubilities of the isoniazid analogue can becalculated using eq 1:24,25

= + +x ABT

C Tln ln( )(1)

where x and T represent the calculated solubilities of theisoniazid analogue and absolute temperature (K), respectively.The coefficients A, B, and C are Apelblat coefficients whichwere determined by multivariate regression analysis ofexperimental solubilities listed in Table 2.22,23 The calculated/Apelblat solubilities (xAc) were calculated using Apelblat coefficientsA, B, and C. The root-mean-square deviations (RMSDs)between experimental and Apelblat solubilities were calculatedusing eq 2.23 The correlation between experimental andApelblat solubilities in various Transcutol + water cosolvent mixturesfrom (298.15 to 338.15) K is presented in Figure 2a−c.Figure 2a−c represents the lower, middle, and higher solubilitycurve, respectively.

∑=−

=

⎡⎣⎢⎢

⎛⎝⎜

⎞⎠⎟

⎤⎦⎥⎥N

x xx

RMSD1

i

N

1

Ac e

e

2 1/2

(2)

Figure 2. Correlation and curve fitting of experimental mole fraction solubilities (xe) of isoniazid analogue in various Transcutol + water cosolventmixtures from (298.15 to 338.15) K; (a) m = 0.0 to 0.2 (blue diamond, m = 0.0; red square, m = 0.1; green triangle, m = 0.2); (b) m = 0.3 to 0.6(blue diamond, m = 0.3; red square, m = 0.4; green triangle, m = 0.5; ×, m = 0.6) and (c) m = 0.7 to 1.0 (blue diamond, m = 0.7; red square, m = 0.8;green diamond, m = 0.9; ×, m = 1.0) [solid lines represent Apelblat solubilities].

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where N is the number of experimental data points. TheRMSDs in pure water (m = 0.0) and pure Transcutol (m = 1.0)were observed as 0.013 and 0.018, respectively (Table 3).However, the RMSD values in other cosolvent mixtures wereobserved in the range of 0.004 to 0.033. The highest value ofRMSD was observed at m = 0.2 of Transcutol (0.033).However, the lowest one was observed at m = 0.3 of Transcutol(0.004). The values of Apelblat coefficients A, B, and C alongwith correlation coefficients (R2), standard errors (SE), andRMSDs in various Transcutol + water cosolvent mixtures arelisted in Table 3. The R2 values for the isoniazid analogue inpure water and Transcutol were observed as 0.998. However,the R2 values for the isoniazid analogue in various Transcutol +water cosolvents were observed in the range of 0.996 to 0.999.These results indicated good fitting of experimental data withthe Apelblat equation.3.3. Correlation of Experimental Solubilities with the

Log−Linear Model of Yalkowsky. In order to evaluate theimpact of cosolvent mixtures on the solubility of isoniazidanalogue, the log−linear model of Yalkowsky was used becauseit is one of the cosolvency model for this purpose.27 Accordingto this model, the solubilities of the isoniazid analogue inTranscutol + water cosolvent mixtures can be calculated usingeq 3:

= +S w S w Slog log logm 1 1 2 2 (3)

where Sm is the solubility of isoniazid analogue in cosolventmixtures; S1 and S2 are the solubility of isoniazid analogue inneat solvents 1 (Transcutol) and 2 (water), respectively; and w1and w2 are the mass fractions of Transcutol (solvent 1) and

water (solvent 2) in the absence of solute (isoniazid analogue).The experimental solubilities of isoniazid analogue werecorrelated with Sm (Yalkowsky solubilities) and RMSDs valueswere calculated using eq 2.The logarithmic solubilities of isoniazid analogue along with

RMSDs in various Transcutol + water cosolvents mixtures from(298.15 to 338.15) K are listed in Table 4. The RMSD values invarious Transcutol + water cosolvent mixtures were observed in

Table 3. Apelblat Coefficients (A, B, and C) along withCorrelation Coefficients (R2), Root Mean Square Deviations(RMSDs), and Standard Errors (SE) for Isoniazid Analoguein Various Tanscutol + Water Cosolvent Mixtures (m)

m A B C R2 RMSDs SE

0.0 −81.41 1809.09 10.68 0.998 0.013 0.0110.1 18.31 −3227.93 −3.66 0.998 0.017 0.0120.2 −179.17 −29.92 3.21 0.999 0.033 0.0040.3 55.16 −4840.83 −8.78 0.997 0.004 0.0060.4 49.27 −3859.13 −8.12 0.996 0.005 0.0010.5 27.29 −3296.54 −4.39 0.998 0.025 0.0070.6 7.42 −1865.54 −1.55 0.998 0.006 0.0060.7 −67.92 1991.09 9.60 0.998 0.029 0.0040.8 −40.88 849.33 5.73 0.999 0.005 0.0020.9 −18.07 −17.38 2.45 0.999 0.031 0.0021.0 16.51 −1698.66 −2.45 0.998 0.018 0.004

Table 4. Logarithmic Solubilities of Isoniazid Analogue (log Sm) Calculated by Log−Linear Model of Yalkowsky in VariousTranscutol + Water Cosolvent Mixtures (m) at Temperatures T = (298.15 to 338.15) K and Pressure p = 0.1 MPa

log Sm

m T = 298.15 T = 308.15 T = 318.15 T = 328.15 T = 338.15 RMSDs

0.1 −5.79 −5.73 −5.66 −5.59 −5.53 0.1120.2 −5.30 −5.24 −5.17 −5.11 −5.05 0.0460.3 −4.81 −4.75 −4.69 −4.63 −4.57 0.1490.4 −4.32 −4.26 −4.20 −4.14 −4.09 0.0300.5 −3.83 −3.77 −3.72 −3.66 −3.61 0.1640.6 −3.33 −3.28 −3.23 −3.18 −3.13 0.0430.7 −2.84 −2.79 −2.74 −2.69 −2.65 0.0300.8 −2.35 −2.30 −2.26 −2.21 −2.17 0.0210.9 −1.86 −1.81 −1.77 −1.73 −1.69 0.114

Table 5. Thermodynamic Parameters (ΔH0 and ΔS0) forDissolution of Isoniazid Analogue in Various Tanscutol +Water Cosolvent Mixtures (m)

T/K

m 298.15 308.15 318.15 328.15 338.15

0.0ΔH0/kJ·mol−1 11.43 12.32 13.20 14.09 14.98ΔS0/J·mol−1·K−1 38.34 39.98 41.52 42.96 44.310.1ΔH0/kJ·mol−1 17.76 17.46 17.15 16.85 16.54ΔS0/J·mol−1·K−1 59.58 56.66 53.92 51.35 48.930.2ΔH0/kJ·mol−1 9.44 9.71 9.98 10.24 10.51ΔS0/J·mol−1·K−1 31.68 31.52 31.37 31.22 31.090.3ΔH0/kJ·mol−1 18.48 17.75 17.02 16.29 15.56ΔS0/J·mol−1·K−1 61.99 57.61 53.50 49.65 46.020.4ΔH0/kJ·mol−1 11.95 11.28 10.60 9.32 9.25ΔS0/J·mol−1·K−1 40.10 36.61 33.34 30.26 27.370.5ΔH0/kJ·mol−1 16.52 16.16 15.79 15.43 15.06ΔS0/J·mol−1·K−1 55.42 52.44 49.65 47.02 44.550.6ΔH0/kJ·mol−1 11.66 11.53 11.41 11.28 11.15ΔS0/J·mol−1·K−1 39.13 37.44 35.86 34.38 32.980.7ΔH0/kJ·mol−1 7.24 8.04 8.83 9.63 10.43ΔS0/J·mol−1·K−1 24.29 26.09 27.78 29.36 30.860.8ΔH0/kJ·mol−1 7.14 7.61 8.09 8.57 9.04ΔS0/J·mol−1·K−1 23.95 24.72 25.44 26.12 26.750.9ΔH0/kJ·mol−1 6.21 6.42 6.62 6.82 7.03ΔS0/J·mol−1·K−1 20.85 20.83 20.82 20.81 20.791.0ΔH0/kJ·mol−1 8.05 7.84 7.64 7.43 7.23ΔS0/J mol−1·K−1 26.99 25.46 24.02 22.66 21.39

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the range of 0.021 to 0.114 from (298.15 to 3338.15) K (Table 4).These results also indicated good correlation of experimentalsolubilities with the log−linear model of Yalkowsky. The impact ofmass fraction of Transcutol on the solubility of the isoniazidanalogue from (298.15 to 338.15) K is presented in Figure 3. Thesolubility of the isoniazid analogue was found to increase rapidlywith an increase in the mass fraction of Transcutol in cosolventmixtures from (298.15 to 338.15) K (Figure 3).3.4. Thermodynamic Parameters for Dissolution of

Isoniazid Analogue. Thermodynamic parameters such asmolar enthalpy (ΔH0) and entropy (ΔS0) of isoniazid analoguedissolution were calculated using eqs 4 and 5:23,26,29

Δ = −⎜ ⎟⎛⎝

⎞⎠H RT C

BT

0

(4)

Δ = −⎜ ⎟⎛⎝

⎞⎠S R C

BT

0

(5)

where B and C are Apelblat coefficients calculated bymultivariate regression analysis of experimental solubilitiesusing eq 1. R and T are the universal gas constant and absolutetemperature (K), respectively. The values of ΔH0 and ΔS0 invarious Transcutol + water cosolvent mixtures from (298.15 to338.15) K were calculated using eqs 4 and 5, respectively. Thevalues of ΔH0 for dissolution of isoniazid analogue in purewater and pure Transcutol were observed in the range of(11.43 to 14.98) kJ·mol−1 and (7.23 to 8.05) kJ·mol−1,

respectively from (298.15 to 338.15) K (Table 5). However,the ΔH0 values for the dissolution of the isoniazid analogue invarious cosolvent mixtures were observed in the range of(6.21 to 18.48) kJ·mol−1. The ΔS0 values for dissolution ofisoniazid analogue in pure water and pure Transcutol wereobserved in the range of (38.34 to 44.31) J·mol−1·K−1 and (21.39 -to 26.99) J·mol−1·K−1 from (298.15 to 338.15) K, respectively(Table 5). The ΔH0 and ΔS0 values for dissolution of theisoniazid analogue in pure Transcutol were significantly reduced ascompared to pure water. These results of thermodynamicparameters clearly indicated that relatively low energy is requiredfor dissolution/solubilization of isoniazid analogue in pureTranscutol as compared to pure water.18 The positive values ofΔH0 and ΔS0 indicated that the dissolution of isoniazid analoguewas endothermic and an entropy-driven in all cosolvent mixtureswith the experimental temperature range (298.15 to 338.15) Kinvestigated.18,22,23

4. CONCLUSION

In the present study, the solubilities of the isoniazid analogue invarious Transcutol + water cosolvent mixtures were measuredfrom (298.15 to 338.15) K using the shake flask method. Thesolubility was found to increase nonlinearly with an increase intemperature in all cosolvent mixtures. The solubility ofisoniazid was much higher in pure Transcutol as compared toits solubility in pure water. The experimental solubilities werecorrelated well with the Apelblat equation and log−linear

Figure 3. Impact of mass fraction of Transcutol (m) on mole fraction solubilities (xe) of isoniazid analogue from (298.15 to 338.15) K; bluediamond, 298.15 K; red square, 308.15 K; green triangle, 318.15 K; purple ×, 328.15 K; and blue ×, 338.15 K.

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model of Yalkowsky in all cosolvent mixtures from (298.15 to338.15) K. Based on these results, the isoniazid analogue hasbeen considered as practically insoluble in water and freelysoluble in Transcutol. Therefore, Transcutol could be used as aphysiologically compatible cosolvent to enhance aqueoussolubility of the isoniazid analogue.

■ AUTHOR INFORMATIONCorresponding Author*Phone: +966-537507318. E-mail: faiyazs@fastmail.fm.

NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSThe authors are thankful to Deanship of Scientific Research andResearch Center, College of Pharmacy, King Saud University.

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dx.doi.org/10.1021/je5002522 | J. Chem. Eng. Data 2014, 59, 1727−17321732