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

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

ABSTRACT: The aim of the present investigation was to measure and correlate the solubility of N-(4-chlorophenyl)-2-(pyridin-4-ylcarbonyl)hydrazinecarbothioamide [isoniazid (INH) analogue] in five different pure solvents, namely, ethanol, ethyleneglycol (EG), propylene glycol (PG), polyethylene glycol-400 (PEG-400), and isopropyl alcohol (IPA) at (298.15 to 338.15) Kusing the shake flask method. The experimental solubilities of INH analogue were regressed with Apelblat equation with root-mean-square deviations in the range of (0.22 to 4.42) %. The correlation coefficients were observed in the range of 0.996 to0.999, indicating good fitting of experimental data. The solubility of INH analogue was found to increase with an increase intemperature in each solvent investigated. The mole fraction solubility of INH analogue was found to be highest in PEG-400 (1.08× 10−1 at 298.15 K) followed by EG (7.70 × 10−3 at 298.15 K), PG (7.38 × 10−3 at 298.15 K), IPA (1.13 × 10−3 at 298.15 K),and ethanol (6.47 × 10−4 at 298.15 K). Dissolution thermodynamic studies indicated nonspontaneous and endothermicdissolution of INH analogue in each solvent investigated. Based on these results, INH analogue has been considered as freelysoluble in PEG-400, soluble in IPA, EG, and PG, and slightly soluble in ethanol. The solubility data of this study could be usefulin crystallization/purification and formulation development of INH analogue.

1. INTRODUCTION

Isoniazid (INH) (pyridin-4-carbohydrazide) is a well-knownantitubercular drug used for the treatment of tuberculosis (TB)caused by pathogenic microorganism Mycobacterium tuberculosis(M. tuberculosis).1,2 The oral administration of INH producedseveral adverse effects.3 Therefore, the demand for new, potent,and safe anti-TB drugs is increasing day by day around theglobe. Nevertheless, no new anti-TB drugs have been approvedby the Food and Drug Administration for the treatment of TBover the past 40 years.4,5 Recently, various analogues of INHhave been investigated for the effective treatment of TB andvarious cancers with an attempt to reduce adverse effects and toenhance therapeutic efficacy of the treatment.3−11 Morerecently, the N-(4-chlorophenyl)-2-(pyridin-4-ylcarbonyl)-hydrazinecarbothioamide analogue of INH (INH analogue)was recently synthesized, characterized, and investigated forpotent anti-Candidal activity.12 The molecular structure of thisanalogue (INH analogue) is presented in Figure 1 (molecular

formula, C13H11ClN4OS; molecular mass, 306.77). In ourrecent work, we have reported the temperature-dependentsolubility data of this analogue in 2-(2-ethoxyethoxy)ethanol +water cosolvent mixtures from (298.15 to 338.15) K.13 Severalphysiologically compatible pure solvents such as ethanol,propylene glycol (PG), polyethylene glycol-400 (PEG-400),

Received: May 27, 2014Accepted: July 25, 2014Published: August 5, 2014

Figure 1. Molecular structure of N-(4-chlorophenyl)-2-(pyridin-4-ylcarbonyl)hydrazinecarbothioamide (INH analogue).

Article

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© 2014 American Chemical Society 2660 dx.doi.org/10.1021/je500457p | J. Chem. Eng. Data 2014, 59, 2660−2664

and 2-(2-ethoxyethoxy)ethanol have been investigated success-fully to enhance the solubility of various poorly water-solubledrugs in literature.12−21 Temperature-dependent solubility dataof drugs are very useful in drug recrystallization/purificationand formulation development of these drugs.15−19 Apelblatequation is a simple and commonly used thermodynamic-basedmathematical equation for correlation of experimentalsolubilities with calculated ones.20−23 Therefore, the aim ofthe current study was to measure the temperature-dependentsolubility data of INH analogue in five physiologicallycompatible pure solvents, namely, ethanol, isopropyl alcohol(IPA), ethylene glycol (EG), PG, and PEG-400 at (298.15 to338.15) K. The experimental solubilities of INH analogue werecorrelated with Apelblat equation. These preliminary studiescould be useful in recrystallization/purification and formulationdevelopment of INH analogues in chemical and pharmaceuticalindustries.

2. MATERIALS AND METHODS2.1. Materials. INH analogue (mass fraction purity of

>0.99) was synthesized, purified, and characterized in thelaboratory of Pharmaceutical Chemistry, College of Pharmacy,King Saud University, Riyadh, Saudi Arabia.12,13 PG (IUPACname, propane-1,2-diol) and PEG-400 [IUPAC name, poly-(oxyethene)] were from Fluka Chemicals (Buchs, Switzerland),ethyl alcohol (IUPAC name, ethanol) from Sigma-Aldrich (St.Louis, MO, USA), and EG (IUPAC name, ethane-1,2-diol) andIPA (IUPAC name, 2-propanol) from Winlab Laboratory(Leicestershire, U.K.) were used in the present study. Thegeneral properties along with molar mass, source, and massfraction purity of these materials are listed in Table 1.24

2.2. Measurement of Solubility of INH Analogue. Thesolubility of INH analogue in five pure solvents, namely,ethanol, IPA, EG, PG, and PEG-400, was measured from(298.15 to 338.15) K at atmospheric pressure using the shakeflask method.25 The excess amount of INH analogue was addedin 5 g of each pure solvent in conical flasks in triplicate. Eachflask was tightly closed, and resultant mixtures were kept in anisothermal shaker bath (Julabo, Allentown, PA, USA) at 100rpm for 72 h. After 72 h (optimized equilibrium time),13 all ofthe samples were taken out from the shaker. The samples wereleft on the laboratory bench for 2 h in order to allow completesettling of drug particles at the bottom of the flasks.19−22 Thesupernatants from each sample were taken, diluted, andsubjected to analysis for quantification of INH analoguecontent using a UV−visible spectrophotometer (SP1900,Axiom, Berlin, Germany) at 276 nm.13 The proposed analyticalmethod was observed to be linear in the range of (2 to 20) μg·g−1 with a correlation coefficient of 0.998. The standarduncertainty for the temperatures u(T) was found to be ± 0.16K. The relative standard uncertainty in solubility ur(xe) of INHanalogue was observed as 1.55 %. The experimental mole

fraction solubility (xe) of INH analogue was calculated asreported previously.18,19

3. RESULTS AND DISCUSSION

3.1. Solubility Data of INH Analogue. The mole fractionas well as mass fraction solubilities of INH analogue in ethanol,IPA, EG, PG, and PEG-400 at (298.15 to 338.15) K are listedin Table 2. The temperature-dependent solubility data of INHanalogue in 2-(2-ethoxyethoxy)ethanol + water cosolventmixtures have been reported in our recently publishedwork.13 The mole fraction solubility of INH analogue in purewater and pure 2-(2-ethoxyethoxy)ethanol was observed as4.32·10−2 at 298.15 K and 5.17·10−7 at 298.15 K, respectively.13

The solubility of INH analogue was found to increase withtemperature in all solvents investigated. The mole fractionsolubilities of INH analogue were observed to be higher inPEG-400 as compared to ethanol, IPA, EG, and PG at (298.15to 338.15) K (Table 2). The mole fraction solubility of INHanalogue was found to be highest in PEG-400 (1.08·10−1 at298.15 K) followed by EG (7.70·10−3 at 298.15 K), PG (7.38·10−3 at 298.15 K), IPA (1.13·10−3 at 298.15 K), and ethanol(6.47·10−4 at 298.15 K) at (298.15 to 338.15) K. The solubilityof INH analogue in PEG-400 was significantly higher than itsreported solubility in water.13 The highest solubility of INHanalogue in PEG-400 was probably due to its lower polarity andhighest molecular weight as compared to other solvents.14

Based on these results, INH analogue has been considered asfreely soluble in PEG-400 soluble in IPA, EG, and PG andslightly soluble in ethanol. The solubility data of this studycould be useful in crystallization/purification and formulationdevelopment of INH analogue.

3.2. Correlation of INH Analogue Solubility. In thepresent study, the solubility data of INH analogue werecorrelated by the Apelblat equation.21−23 According to thisequation, the temperature-dependent solubility of INHanalogue can be represented by23

= + +x ABT

C Tln ln( )(1)

where x is the calculated mole fraction solubility of INHanalogue, T is the absolute temperature (K), and coefficients A,B, and C are Apelblat coefficients. Apelblat coefficients A, B,and C were determined by nonlinear multivariate regressionanalysis of experimental solubilities listed in Table 2 using eq1.20,22 The calculated (Apelblat solubilities; x) were thencalculated using Apelblat coefficients. The root-mean-squaredeviations (RMSD) between experimental and calculatedsolubilities of INH analogue were calculated using eq 2.18,20

The correlation and curve fitting between experimental andcalculated solubilities at (298.15 to 338.15) K is presented inFigure 2.

Table 1. General Properties of INH Analogue and Pure Solvents

molecular mass

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

INH analogue C13H11ClN4OS 306.77 0.996 GC synthesized in the laboratoryethanol C2H5OH 46.06 0.999 GC Sigma-AldrichPG C3H8O2 76.09 0.995 GC Fluka ChemicalsPEG-400 H(OCH2CH2)nOH 400.00 0.999 GC Fluka ChemicalsEG C2H6O2 62.07 0.996 GC Winlab LaboratoryIPA C3H8O 60.10 0.997 GC Winlab Laboratory

Journal of Chemical & Engineering Data Article

dx.doi.org/10.1021/je500457p | J. Chem. Eng. Data 2014, 59, 2660−26642661

∑=−

=

⎡⎣⎢⎢

⎛⎝⎜

⎞⎠⎟

⎤⎦⎥⎥N

x xx

RMSD1

i

N

1

e

e

2 1/2

(2)

where N represents the number of experimental data points(which were 5 in this study). The RMSD in all pure solventswere observed in the range of (0.22 to 4.42) % (Table 3). Thehighest value of RMSD was observed in EG (4.42 %).However, the lowest one was observed in IPA (0.22 %). Thevalues of RMSD were significantly different among puresolvents which could be due to different solubilization behaviorof solute in different solvents. The values of standard errors(SE) were observed in the range of 0.000 to 0.009. The valuesof Apelblat coefficients A, B, and C in ethanol, IPA, EG, PG,and PEG-400 are listed in Table 3. The values of correlationcoefficients (R2) for INH analogue were observed in the rangeof 0.996 to 0.999 in all solvents investigated, indicating goodfitting of experimental data (Table 3).

3.3. Thermodynamic Parameters for Dissolution ofINH Analogue. Various thermodynamic parameters such asenthalpy change (ΔH°), Gibbs function (ΔG°), and molarentropy change (ΔS°) for the dissolution of INH analoguewere measured. The ΔH° values for the dissolution of INHanalogue in all solvents were determined by van’t Hoffanalysis.26,27 According to the van’t Hoff analysis, the ΔH°values for the dissolution of INH analogue can be calculated atmean harmonic temperature (Thm) with the help of eq 3 (Thmwas 317.52 K in the current study).

∂

∂ −= − Δ °

⎛

⎝

⎜⎜⎜

⎞

⎠

⎟⎟⎟( )x H

Rln

T Tp

1 1

hm (3)

Here, R is the universal gas constant, and its value is equal to8.314 J·mol−1·K−1. The ΔH° values for the dissolution of INHanalogue were obtained by plotting ln xe against (1/T) − (1/Thm) using eq 3. The Van’t Hoff plots for solubilities of INHanalogue in five pure solvents are presented in Figure 3. Theseplots for solubilities of INH analogue were observed to belinear with R2 values in the range of 0.994 to 1.000 in allsolvents investigated (Table 4).The ΔG° values for the dissolution of INH analogue in five

pure solvents were determined using the approach of Krug etal. using28

Δ ° = ×G RT intercepthm (4)

in which the value of the intercept was obtained from the Van’tHoff plots of INH analogue presented in Figure 3.The ΔS° values for the dissolution of INH analogue at Thm

were calculated with the help of ΔH° and ΔG° using

Δ ° = Δ ° − Δ °S

H GThm (5)

The values of ΔH°, ΔG°, and ΔS° along with R2 values for thedissolution of INH analogue in ethanol, EG, PG, PEG-400, andIPA are listed in Table 4. The ΔH° values for the dissolution ofINH analogue were observed as positive values in all solventsinvestigated, indicating endothermic dissolution of INHanalogue in all of these solvents. The ΔH° value for thedissolution of INH analogue in ethanol, EG, PG, PEG-400, andIPA was observed as 5.8 kJ·mol−1, 6.2 kJ·ol−1, 6.0 kJ·mol−1, 4.1kJ·mol−1, and 5.6 kJ·mol−1, respectively (Table 4). The ΔG°T

able

2.Experim

entalMoleFraction

Solubilities(x

e)andMassFraction

Solubilities(S

m)of

Crystallin

eIN

HAnaloguein

Various

PureSolvents

(S)at

temperaturesT=

(298.15to

338.15)KandPressurep=0.1MPaa

x eS m/(kg·kg−

1 )

ST=298.15

KT=308.15

KT=318.15

KT=328.15

KT=338.15

KT=298.15

KT=308.15

KT=318.15

KT=328.15

KT=338.15

K

ethanol

6.47·10−

46.93·10−

47.43·10−

47.92·10−

48.34·10−

44.31·10−

34.62·10−

34.95·10−

35.28·10−

35.56·10−

3

IPA

1.13·10−

31.21·10−

31.21·10−

31.29·10−

31.38·10−

35.80·10−

36.20·10−

36.64·10−

37.10·10−

37.60·10−

3

EG7.70·10−

38.41·10−

38.94·10−

39.61·10−

31.04·10−

23.84·10−

34.19·10−

34.46·10−

34.80·10−

35.24·10−

3

PG7.38·10−

37.89·10−

38.48·10−

39.09·10−

39.87·10−

33.00·10−

23.20·10−

23.45·10−

23.70·10−

24.02·10−

2

PEG-400

1.08·10−

11.14·10−

11.20·10−

11.26·10−

11.31·10−

19.32·10−

29.91·10−

21.04·10−

11.10·10−

11.16·10−

1

aThe

standard

uncertaintyforthetemperaturesu(T)is±

0.16

K;therelativestandard

uncertaintyin

solubilityu r(x

e)of

INH

analogue

is1.55

%.

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values for the dissolution of INH analogue were also observedas positive values in all solvents investigated, indicating that thedissolution of INH analogue was nonspontaneous in all of thesesolvents. The ΔG° value for the dissolution of INH analogue inethanol, EG, PG, PEG-400, and IPA was observed as 19.0 kJ·mol−1, 12.4 kJ·mol−1, 12.5 kJ·mol−1, 5.5 kJ·mol−1, and 17.5 kJ·mol−1, respectively (Table 4). The positive values of ΔH° andΔG° indicated the stronger interactions between the moleculesof INH analogue and the solvent molecules as compared withthose between INH analogue−INH analogue molecules andsolvent−solvent molecules. The ΔS° values for the dissolutionof INH analogue were observed as negative values in allsolvents investigated, indicating that the dissolution of INHanalogue was not an entropy-driven process in all of thesesolvents (Table 4). The values of ΔH° and ΔG° for thedissolution of INH analogue in ethanol, EG, PG, PEG-400, andIPA were significantly lower as compared to their reportedvalues in water which indicated that relatively low energy isutilized for the solubilization of INH analogue in ethanol, EG,PG, PEG-400, and IPA as compared to water.13

Figure 2. Correlation and curve fitting of experimental mole fraction solubilities (xe) of crystalline INH analogue in (a) fx1 IPA and fx2 ethanol and(b) fx3 EG, fx4 PG, and fx5 PEG-400 at (298.15 to 338.15) K (solid lines represent the solubilities calculated by the Apelblat equation).

Table 3. Apelblat Parameters (A, B, and C) along with Correlation Coefficients (R2), Root-Mean-Square Deviations (RMSD),and Standard Errors (SE) for Crystalline INH Analogue in Various Pure Solvents (S)

Apelblat params

S A B C R2 RMSD/% SE

ethanol 5.06 −1126.65 −1.51 0.998 2.25 0.002IPA −34.45 724.65 4.43 0.999 0.22 0.000EG −43.15 1159.17 6.03 0.996 4.42 0.009PG −61.65 2047.97 8.75 0.996 1.94 0.002PEG-400 −0.72 −486.17 0.02 0.999 1.48 0.002

Figure 3. Van’t Hoff plots for experimental solubilities of INHanalogue in fx6 ethanol, fx7 IPA, fx8 EG, fx9 PG, and fx10 PEG-400.

Table 4. Thermodynamic Parameters and R2 Values for Dissolution of INH Analogue in Different Pure Solvents

params ethanol PG PEG-400 EG IPA

ΔH°/(kJ·mol−1) 5.8 6.0 4.1 6.2 5.6ΔG°/(kJ·mol−1) 19.0 12.5 5.5 12.4 17.5ΔS°/(J·mol−1·K−1) −42.9 −20.5 −4.6 −19.3 −37.3R2 0.999 0.994 1.000 0.994 0.998

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4. CONCLUSION

In the present study, the solubilities of INH analogue inethanol, IPA, EG, PG, and PEG-400 were measured at (298.15to 338.15) K using the shake flask method. The solubility ofINH analogue was found to increase with temperature in allsolvents investigated. The solubility of INH analogue wassignificantly higher in PEG-400 as compared to ethanol, IPA,EG, and PG. The experimental solubilities of INH analoguewere correlated well with Apelblat equation in all solvents at(298.15 to 338.15) K with the correlation coefficients in therange of 0.996 to 0.999. Based on the solubility data of thisstudy, INH analogue has been considered as slightly soluble inethanol, soluble in IPA, EG, and PG, and freely soluble in PEG-400.

■ AUTHOR INFORMATION

Corresponding Author*Phone: +966-537507318. E-mail: faiyazs@fastmail.fm.

FundingThe authors would like to extend their sincere appreciation tothe Deanship of Scientific Research at King Saud University forits funding this research group no. RG 1435-006.

NotesThe authors declare no competing financial interest.

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