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Fluid Phase Equilibria 318 (2012) 89–95

Contents lists available at SciVerse ScienceDirect

Fluid Phase Equilibria

jou rna l h omepage: www.elsev ier .com/ locate / f lu id

favourable solubility of isoniazid, an antitubercular antibiotic drug,n alternative solvents

ndreia Fortea, Catarina I. Meloa, Rafał Bogel-Łukasikb, Ewa Bogel-Łukasika,∗

REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, PortugalLaboratório Nacional de Energia e Geologia, I.P., Unit of Bioenergy, Estrada do Pac o do Lumiar 22, 1649-038 Lisboa, Portugal

r t i c l e i n f o

rticle history:eceived 9 December 2011eceived in revised form 13 January 2012ccepted 18 January 2012vailable online 25 January 2012

eywords:

a b s t r a c t

The sufficient solubility of isoniazid in alternative solvents obtained in this work can open newperspectives in pharmaceutical processing. Solid–liquid equilibrium (SLE) measurements have beenmade using a dynamic (synthetic) method. The melting point and the enthalpy of fusion of iso-niazid were acquired using differential scanning calorimetry (DSC). The solubility of isoniazid inbis(trifluoromethylsulfonyl)amide ionic liquids was found to be significantly lower than in the stud-ied trifluoromethanesulfonate ionic liquid. The best solvent amongst studied for this common antibiotic

soniazidonic liquidolubilityolid–liquid equilibriahermochemical propertiesrug

against tuberculosis was discovered. The solid–liquid phase equilibria were described using the six dif-ferent correlation equations which revealed relatively good description with the acceptable standarddeviation temperature range.

© 2012 Elsevier B.V. All rights reserved.

ntibiotic

. Introduction

According to the statistics of the World Health Organization,uberculosis kills more people than any other infectious diseasen the world. It causes more deaths than AIDS and malaria com-ined [1]. Tuberculosis is an infectious bacterial disease caused byycobacterium tuberculosis which most commonly affects the lungs

2]. Several drugs are needed to treat active tuberculosis. In normalreatment of tuberculosis, patients take the antibiotic drugs: isoni-zid and rifampicin (the most effective tuberculosis drug available)or a few months. A drug called isoniazid can be used as a preven-ative therapy for those who are at high risk of becoming infectedith tuberculosis. Isoniazid is available worldwide, as well as is

nexpensive and generally well tolerated. Moreover, except beingn antitubercular drug, isoniazid was one of the first antidepres-ants discovered. The Sheldon’s E-factor, defined as the mass ratiof waste to desire product indicates the highest E factor of 25–1003] for pharmaceutical industry amongst oil refining, bulk or finehemicals sectors. For this reason an attention should be focused onevelopment in pharmaceutical industry with regard to waste min-

misation and to assessing its current status in the broad contextf green chemistry and sustainability. Particularly, the pharmaceu-ical industry should search for solutions to the problem of waste

∗ Corresponding author. Tel.: +351 212948353; fax: +351 212948550.E-mail address: ewa.lukasik@fct.unl.pt (E. Bogel-Łukasik).

378-3812/$ – see front matter © 2012 Elsevier B.V. All rights reserved.oi:10.1016/j.fluid.2012.01.022

generation in chemicals manufacture. Organic hazardous solventscan be substituted by green solvents which are advantageous espe-cially in terms of volatility and flammability. Ionic liquids haveproven their sustainable applications in reactions [4,5] and sep-arations [5,6] mostly due to their unique tuneable properties, suchas a thermal stability [7,8] and a solvent power [6,9–14]. In general,ILs with a short alkyl chain appended in the imidazolium cation andwith hydrophilic anions have low toxicity [15,16]. The [C4mim] and[C6mim] cations were largely nontoxic towards Caco-2 cells [17],although a slightly higher toxicity was noticed for a surface activecation of [C8mim]. Nevertheless, the toxicity of these ionic liq-uids did not prevent their use as pharmaceutical solvents as manypharmaceutical excipients such as the non-ionic surfactants (e.g.polysorbate 80) exhibit similar toxicities to many ILs [18]. In case ofclassical solvents in operations such as granulation, blending, com-pounding and drying, volatile liquids are used, and thus flammableor explosive atmospheres can be created. The flammable solvents’use has a direct impact on a specific engineering design, featuresof pharmaceutical facilities and process equipment [19]. Due tothis it is desirable to improve manufacturing processes with sol-vents recognised as “safer” [19,20] and suitable in pharmaceuticalprocessing [21,22].

This work is focused on screening of alternative solvents in

order to open possibilities for the pharmaceutical processingby presenting the solubility data of isoniazid, a common anti-tubercular antibiotic drug, in bis(trifluoromethylsulfonyl)amideand trifluoromethanesulfonate ionic liquids. To the best of

9 e Equilibria 318 (2012) 89–95

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ur knowledge, until now there are no studies dedicatedo ionic liquids and isoniazid. In particular, the follow-ng ionic liquids were used: 1-ethyl-3-methylimidazoliumis(trifluoromethylsulfonyl)amide [C2mim][NTf2], 1-butyl--methylimidazolium bis(trifluoromethylsulfonyl)amideC4mim][NTf2], 1-hexyl-3-methylimidazoliumis(trifluoromethylsulfonyl)amide [C6mim][NTf2], 1-methyl--octylimidazolium bis(trifluoromethylsulfonyl)amideC8mim][NTf2], 1-decyl-3-methylimidazoliumis(trifluoromethylsulfonyl)amide [C10mim][NTf2], 1-decyl-3-ethylimidazolium trifluoromethanesulfonate [C10mim][OTf]

onic liquids.

. Materials and methods

.1. Chemicals

Isoniazid with the stated purity of ≥99 mass% was pur-hased from Fluka. Ionic liquids [Cnmim][NTf2] (n = 2, 4, 8,0) and [C10mim][OTf] were obtained from Iolitec, Germanyith the purity of ≥99 mass%. All ionic liquids were degassed,ried, and freed from residues of volatile compounds by apply-

ng a vacuum 0.1 Pa at moderate temperature of 60 ◦C. Allhe drying techniques were carried out for 48 h prior to thereparation of new solutions. The mass fraction of water remain-

ng in the dried samples was analysed by the coulometricarl–Fischer titration and showed the following amount of water

n the pure compounds: [C2mim][NTf2], 120 ppm; [C4mim][NTf2],10 ppm; [C6mim][NTf2], 130 ppm; [C8mim][NTf2], 120 ppm;C10mim][NTf2], 110 ppm; [C10mim][OTf], 130 ppm.

.2. Experimental procedure

A detailed description of experimental procedure utilised in thisork was presented previously [23]. Solid–liquid equilibria (SLE) of

tudied systems were obtained at pressure of 0.1 MPa and a temper-ture ranging from 251.42 K to 413.00 K using a dynamic (synthetic)ethod. Experiments were performed in a Pyrex glass cell thatas equipped with stirring. The cell could be opened/closed by a

eflon valve at the end of a long, capillary-thin (inner diameterf 0.1 mm) neck. It allowed the cell to be deeply immersed in aemperature-controlled bath, while, at the same time, diminishingosses due to evaporation. The solutions were prepared in Pyrexonical 5 mL flasks (Supelco) by weighing the pure componentsith an accuracy of 10−4 g. The mixture of solute and solvent waseated very slowly (at less 2 K h−1 near the equilibrium tempera-ure) with continuous stirring inside the Pyrex glass cell, placed in ahermostatic bath with ethanol (250–293 K), water (293–333 K) orilicon (333–413 K). The last crystal disappearance temperatures,etected visually, were measured with a calibrated DOSTMANNlectronic P600 thermometer equipped in a Pt 100 probe totallymmersed in the thermostatic liquid. The uncertainty of the tem-erature measurements was ±0.03 K and that of the mole fractionid not exceed ±0.0005.

.3. Differential scanning calorimetry

The melting point and the enthalpy of fusion of isoniazid werebtained using differential scanning calorimetry (DSC), accordingo the following procedure: a sample up to 5 mg was encapsu-ated in a 40 �L aluminium crucible. The sample was scanned in

temperature range from 273 to 573 K. All scans were performedt the heating rate of 5 K/min. The results are the average of ateast three scans. The DSC instrument (Mettler Toledo DSC 822e)

as calibrated with a sample of indium and zinc, both with the

Fig. 1. Comparison of solubilities of isoniazid in [C2mim][NTf2] (�), or[C4mim][NTf2] (�), or [C6mim][NTf2] (�), or [C8mim][NTf2] (©), or [C10mim][NTf2](�), or [C10mim][OTf] (�). Points represent the experimental results.

99.9999 mol% purity, before each scan. The indium and zinc sam-ples were selected because zinc allows for the calibration in therange of temperatures corresponding to the expected range for highmelting point compounds. The calorimetric accuracy was ±1% andthe precision was ±0.5%. In respect to melting points, the uncer-tainty was estimated at the level of ±0.5 K.

3. Results and discussion

3.1. Solid–liquid equilibria

The aim of this work was to provide the solubility data of iso-niazid, an antituberculosis drug, in alternative solvents namelyionic liquids. The chemical structure of isoniazid is illustratedin Fig. 8. The (solid + liquid) phase diagrams for isoniazid inseries of bis(trifluoromethylsulfonyl)amide ionic liquids and 1-decyl-3-methylimidazolium trifluoromethanesulfonate have beenmeasured by a dynamic method from 251.42 K to 413.00 K.

The solubility data of the studied isoniazid in aforementionedionic liquids are presented in Table 1. The table compiles the directexperimental results of the SLE, temperatures, T1 (˛1, ˛2, sta-ble crystalline forms of solute (1) and solvent (2)) versus x1, themole fraction of isoniazid in the saturated solution for the investi-gated systems. All examined systems are described by the classicalsolid–liquid phase envelopes with the eutectic point below thedetection limit. The phase envelopes of systems containing isoni-azid and studied ionic liquids are shown in Figs. 1–7. As presentedin Fig. 1, the eutectic point is strongly shifted towards the low molefraction of the solute due to a high melting point (445.84 K) and ahigh enthalpy of fusion (27.912 kJ mol−1) of isoniazid.

Considering solubilities of the studied drug inbis(trifluoromethylsulfonyl)amide ionic liquids a general con-clusion is that the solubility decreases with an increase of thealkyl chain in the ionic liquid cation as it can be observed inFig. 1. At 373.15 K the highest solubility of isoniazid was foundin [C2mim][NTf2] (x1 = 0.0497) and it decreased to x1 = 0.0357 for[C10mim][NTf2]. For explanation of such a decreasing solubilityof isoniazid in [NTf2], the affinity of the cation to form stronger

interactions with isoniazid (Fig. 8) containing carboxamide andhydrazine group can suit. Regarding the solubility of isoniazid in[C2mim][NT2] it can be remarked that an acidic H in position 2in the [C2mim] cation increases the ability of the ionic liquid to

A. Forte et al. / Fluid Phase Equilibria 318 (2012) 89–95 91Ta

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Fig. 2. Solubility of isoniazid in [C2mim][NTf2]. Points represent the experimentalresults. The dashed line demonstrates the correlation by NRTL 1 equation. The dottedline represents the ideal solubility.

interact with isoniazid leading to the higher solubility. In case oflonger alkyl chains in imidazolium cation, the proton in position 2is less acidic. It is caused by a partial compensation of the deficit ofelectrons in the imidazolium ring by a shift of the electron cloudof the alkyl chain towards the imidazolium ring. This occurrencehas an indication in the hydrogen bond donor acidity of the ionicliquid, e.g. for [C2mim][NT2] is equal to 0.627 [24] while for[C4mim][NTf2] and [C8mim][NTf2] is reduced to 0.617 [25] and0.595 [24], respectively.

To give more highlights on solubilities of isoniazid in ionicliquids, [C10mim][OTf] was selected as a representative of triflu-oromethanesulfonate ionic liquids. Commonly trifluoromethane-sulfonate ILs are recognised as better solvents for compoundscapable to form hydrogen bonds. The [OTf] ILs were reported asmuch better solvents for alcohols and polyols than [NTf2] due

to the formation of a strong hydrogen bond lattice between thehydroxyl group of alcohols and the anion [26]. Our recent sol-ubility studies of pyrazinecarboxamide in similar ionic liquidsas indicated in this work allowed to draw a similar conclusion

0.00 0.05 0.10 0.15 0.20 0.96 1.00250

300

350

400

445

450

T/K

x1

Fig. 3. Solubility of isoniazid in [C4mim][NTf2]. Points represent the experimentalresults. The dashed line demonstrates the correlation by NRTL 1 equation. The dottedline represents the ideal solubility.

92 A. Forte et al. / Fluid Phase Equilibria 318 (2012) 89–95

0.00 0.05 0.10 0.15 0.96 1.00250

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350

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Fig. 6. Solubility of isoniazid in [C10mim][NTf2]. Points represent the experimentalresults. The dashed line demonstrates the correlation by NRTL equation. The dottedline represents the ideal solubility.

300

350

400

445

450T/K

ig. 4. Solubility of isoniazid in [C6mim][NTf2]. Points represent the experimentalesults. The dashed line demonstrates the correlation by Wilson equation. The dottedine represents the ideal solubility.

27]. The solubility of pyrazinecarboxamide in [OTf] ionic liquidas at least one order of magnitude higher than in the corre-

ponding [NTf2] ionic liquids. Data presented in this work are ingreement with a general trend of solubilities in [NTf2] and [OTf]Ls. They clearly confirm a significant enhancement in solubility ofsoniazid in [C10mim][OTf] comparing with the analogous [NTf2]onic liquid. For example at 373.15 K the solubility of isoniazid inOTf] ionic liquid is almost three times higher than that of [NTf2]x1 = 0.0994 and x1 = 0.0357 for [C10mim][OTf] and [C10mim][NTf2],orrespondingly). It is obviously a consequence of the formationf a hydrogen bond between NH of carboxamide and [OTf] anionimilarly to the aforementioned work [26].

Furthermore comparing the solubility of the two drugs in ioniciquids studied in this work with our previous report [27] it can betated that isoniazid is slightly less soluble than pyrazinecarboxam-

de in all examined solvents. For example the solubility of isoniazidn [C10mim][NTf2] is equal to x1 = 0.0357, while the solubilityf pyrazinecarboxamide in the same ionic liquid is only slightlyigher (x1 = 0.0488). For better solvent such as [C10mim][OTf]

0.00 0.05 0.10 0.15 0.96 1.00

250

300

350

400

445

450

T/K

x1

ig. 5. Solubility of isoniazid in [C8mim][NTf2]. Points represent the experimentalesults. The dashed line demonstrates the correlation by NRTL equation. The dottedine represents the ideal solubility.

0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.96 1.00250

x1

Fig. 7. Solubility of isoniazid in [C10mim][OTf]. Points represent the experimentalresults. The dashed line demonstrates the correlation by UNIQUAC ASM equation.The dotted line represents the ideal solubility.

the difference between solubility of pyrazinecarboxamide andisoniazid is also small (x1 = 0.1334 and x1 = 0.0994 for pyrazinecar-boxamide and isoniazid, respectively). This small difference in thesolubility is probably caused by a basic effect of hydrazine whichconstitutes isoniazid molecule. Hydrazine is a base (pKb = 5.90 [28]),therefore the overall acidity of the proton in the carboxamide group

in isoniazid is lower than in pyrazinecarboxamide because is par-tially compensated by the basic effect of the hydrazine group.

Fig. 8. The chemical structure of isoniazid.

A. Forte et al. / Fluid Phase Equilibria 318 (2012) 89–95 93

Table 2The thermophysical properties of isoniazid obtained by the differential scanning calorimetry.

Parameter Value

In this worka Literature [29]b

Melting point, Tfus,1 (K) 445.84 ± 0.50 445.15 ± 1.00−1

3

ecsa

(fi

3

f(�cbirvtctitsee

tri

Enthalpy of fusion, �fusH1 (kJ mol ) 27.912 ± 0.28

a Standard uncertainties u are u(Tfus,1) = 0.50 K, ur(�fusH1) = 0.28.b Standard uncertainties u are u(Tfus,1) = 1.00 K, ur(�fusH1) = 0.56.

.2. Differential scanning calorimetry

The melting point, the enthalpy of fusion and correspondingnthalpy of isoniazid were obtained using differential scanningalorimetry (DSC). The thermograph of studied isoniazid is pre-ented in Fig. 9. The obtained data shown in Table 2 are in a goodgreement with the literature reported.

For temperature above 483 K the decomposition of isoniazidnot showed in Fig. 9) has been observed that can suit as a con-rmation of the previous literature studies [29].

.3. Correlation of (solid + liquid) equilibrium

The solubility of a solid in a liquid can be expressed by theollowing equation: − ln x1 = (�fusH1)/R ((1/T1) − (1/Tfus,1)) −�fusCp1)/R (ln (T1/Tfus,1) + (Tfus,1/T1) − 1) + ln �1, where x1, �1,

fusH1, �fusCp1, Tfus,1 and T1 stand for mole fraction, activityoefficient, enthalpy of fusion, difference in solute heat capacityetween the solid and liquid at the melting temperature, melt-

ng temperature of the solute (1) and equilibrium temperature,espectively. Unfortunately, there was impossible to determinealue of �fusCp1 for isoniazid, thus, the equation was used inhe calculations without the second term. The heat capacityhange at the melting temperature is needed for the accuratehermodynamic description of the SLE. But also the heat capacitys an important property from the practical point of view becausehe heat capacity is e.g. used in order to calculate a sensible heattorage density of the IL. It has a specific application for ILs as.g. heat-transfer fluid in the solar electric generating system inlectric power plants [30].

The omission of this term leads to less accurate description of

he obtained results, therefore the standard deviations of the cor-elation equations are higher than for systems with the �fusCp1ncluded [8,31].

420 430 440 450 460 470

-30

-20

-10

0

mW

T/K

Fig. 9. The thermograph of isoniazid.

28.388 ± 0.56

The equation may be used assuming the simple eutectic mix-tures with a full miscibility in the liquid and immiscibility in thesolid phases.

In this study, the six methods were used to derive the soluteactivity coefficients �1 from the so-called correlation equations thatdescribe the Gibbs excess energy (GE), the Wilson [32], UNIQUAC[33], UNIQUAC ASM [34], NRTL [35], NRTL 1 [35] and NRTL 2 [35].The exact mathematical forms of the equations were presentedelsewhere [36].

The two adjustable parameters of equations were found byan optimisation technique using Marquardt’s or Rosenbrock’smaximum likelihood method of minimisation described by the

equation: =∑n

t=1[Texpt − Tcal

t (x1i, P1, P2)]2, where is the

objective function, n is the number of experimental points, Texpi

and Tcali

denotes respectively experimental and calculated equi-librium temperature corresponding to the concentration. The x1,P1 and P2 are model parameters resulting from the minimisa-tion procedure. The root-mean-square deviation of temperature

was defined as follows: �T =√∑n

i=1((Texpi

− Tcali

)2/(n − 2)). The

pure component parameters r (volume parameter) and q (surfaceparameter) in the UNIQUAC ASM, NRTL, NRTL 1 and NRTL 2 equa-tions were obtained by means of the following simple relationships[37]: ri = 0.028281Vm, qi = ((Z − 2)ri/Z) + (2(1 − li))/Z, where Vm

is the molar volume of pure compound i at 298.15 K. The molarvolume of solute Vm1 (298.15 K) was calculated by the group con-tribution method [38] and was assumed to be 110.1 cm3 mol−1.The coordination number Z and the bulk factor li for the cyclicmolecule were assumed to be equalled to 10 and to 1, respec-tively. The calculations were carried out by the use of data set ofassociation: K = 12.5 and −�hh = 9.29 kJ mol−1 at 313.15 K for iso-niazid. To the best of our knowledge there are no association datafor isoniazid. Nevertheless, as poly(N-methyl methacrylamide)is the most similar compound to the studied solute for whichthe association data are available, thus, the self-association ofpoly(N-methyl methacrylamide) data were used in this work [39].Furthermore, the molar volume of solvents needed for the cor-relation has been taken from literature in the following order:257.9, 292.4, 326.2, 361.8 and 404.0 cm3 mol−1 for [C2mim][NT2],[C4mim][NTf2], [C6mim][NTf2], [C8mim][NTf2], [C10mim][NTf2],respectively [40]. The molar volume for [C10mim][OTf] has beenestimated at the level of 322.6 cm3 mol−1 considering the litera-ture molar volume of [C4mim][OTf] equalled to 211 cm3 mol−1 [41]and a contribution of the additional hexyl group in the alkyl chain.The Kretschmer–Wiebe model of association for the developing oftwo adjustable parameters was used [42]. In this work, the valueof parameter ˛, a constant of proportionality similar to the non-randomness constant of the UNIQUAC ASM, NRTL, NRTL 1 and NRTL2 equations was used in calculations for different binary systems.Values of model parameters obtained by fitting solubility curvesare presented in Table 3 together with the corresponding standarddeviations.

The positive deviations from ideality were found for all stud-ied systems; therefore, the solubility is lower than the ideal for allstudied [NTf2]. Additionally, it indicates that the activity coefficientof solute, �1 is higher than 1. It is important to notice that in case of

94 A. Forte et al. / Fluid Phase EquiTa

ble

3C

orre

lati

on

of

the

solu

bili

ty

dat

a,

SLE,

of

ison

iazi

d

(1) +

an

IL

(2)

by

Wil

son

, UN

IQU

AC

, UN

IQU

AC

ASM

, NR

TL, N

RTL

1

and

NR

TL

2

equ

atio

ns:

valu

es

of

par

amet

ers

and

root

-mea

n-s

quar

e

dev

iati

ons.

IL

Para

met

ers

Dev

iati

ons

Wil

son

(J

mol

−1)

UN

IQU

AC

(J

mol

−1)

UN

IQU

AC

ASM

(J

mol

−1)

NR

TL(J

mol

−1)

NR

TL

1(J

mol

−1)

NR

TL

2(J

mol

−1)

Wil

son

(K)

UN

IQU

AC

(K)

UN

IQU

AC

ASM

(K)

NR

TL(K

)N

RTL

1(K

)N

RTL

2(K

)

g 12–g

22

g 21–g

11

�u 1

2

�u 2

1

�u 1

2

�u 2

1

�g 1

2

�g 2

1

�g 1

2

�g 2

1

�g 1

2

�g 2

1

�T

c�

Tc

�T

a�

Ta

�T

a�

Ta

[C2m

im][

NTf

2]

7077

.94

−500

.18

−175

5.56

5482

.56

−202

.75

931.

43−8

71.7

617

78.0

3−1

09.6

216

89.6

8−1

71.9

591

2.50

2.27

2.91

1.96

2.20

b1.

91b

1.94

b

[C4m

im][

NTf

2]

8012

.14

−916

.46

−191

8.74

5552

.29

−279

.64

1065

.44

−107

0.61

2923

.59

−769

.87

2514

.84

−319

.42

1144

.36

4.46

6.05

4.54

4.42

b4.

26b

4.46

b

[C6m

im][

NTf

2]

8915

.77

−158

0.64

−220

4.09

6355

.88

−309

.12

1241

.60

−131

5.42

3916

.87

−135

5.65

3305

.22

−395

.99

1388

.38

4.53

6.62

5.27

4.53

b4.

77b

5.15

b

[C8m

im][

NTf

2]

9977

.37

−243

5.56

−253

5.24

7341

.04

−316

.47

1383

.88

−145

4.20

4685

.31

−300

9.88

5964

.51

−427

.18

1564

.47

4.47

7.20

6.05

4.41

b5.

15b

5.89

b

[C10

mim

][N

Tf2]

10,5

16.5

6−2

706.

28−2

637.

8977

57.4

5−3

39.0

415

49.2

9−1

452.

2649

65.9

8−3

199.

6464

88.2

2−4

77.9

917

77.0

54.

54

7.65

6.62

4.43

b5.

30b

6.42

b

[C10

mim

][O

Tf]

9872

.92

−435

5.54

−248

7.87

6204

.10

−2.1

15.

2581

6.16

−190

5.65

−3.8

19.

49−2

.12

5.27

3.02

5.47

3.71

4.82

c3.

71b

3.71

b

aA

ccor

din

g

to

equ

atio

n

�T

=

(∑n i=

1(T

iexp

−

T ica

l )2/

(n

−

2))1/

2.

bC

alcu

late

d

wit

h

the

thir

d

non

-ran

dom

nes

s

par

amet

er

˛

=

0.99

.c

Cal

cula

ted

wit

h

the

thir

d

non

-ran

dom

nes

s

par

amet

er

˛

=

0.90

.

libria 318 (2012) 89–95

[NTf2] ionic liquids, the activity coefficients of solute are very high(even higher than 7). The values of activity coefficient of solute for[C10mim][OTf] are significantly lower than for [NTf2] ionic liquidsbut are still above 1. This can be explained by the fact that the inter-action between the solute and solvent are stronger resulting in ahigher solubility of isoniazid in the studied ionic liquid.

Considering the correlation of the experimental results, theaverage standard deviation (�T) ranged from 1.91 to 7.65 K. Takinginto account complexity of systems studied here, a simplified solu-bility equation (without �fusCp1 term) and an assumption relatedto the association constants of the examined drug, the correlationequations gave acceptable �T.

4. Conclusions

Data on solubilities of systems involving the hydrazinederivative; isoniazid – a tuberculosis antibiotic, and alternativesolvents: five bis(trifluoromethylsulfonyl)amide based ionic liq-uids and 1-decyl-3-methylimidazolium trifluoromethanesulfonateionic liquid are collected in this work. The provided solubility dataare in the satisfactory range of solubilities [43] permitting to con-clude that: (1) the studied ionic liquids are appropriate solventsfor the drug manufacturing and (2) such solvents can be suitablefor pharmaceutical processing [21,22,43,44]. The binary systemscomposed of isoniazid and an ionic liquid form the solid–liquidphase equilibria with the eutectic point shifted towards ionic liq-uids rich solutions. We sought to discover the best solvent amongstthe analysed ionic liquids. 1-Decyl-3-methylimidazolium triflu-oromethanesulfonate ionic liquid ([C10mim][OTf]) was found tobe the best solvent for an antibiotic drug. Analysing solubilitiesobtained in the case of the bis(trifluoromethylsulfonyl)amide ionicliquids, it can be noticed that the solubility of the studied antituber-cular drug decreases with an increase of the alkyl chain in the cationof the ionic liquid. The solid–liquid phase equilibria were describedusing the six different correlation equations (Wilson, UNIQUAC,UNIQUAC ASM, NRTL, NRTL 1 and NRTL2) which allowed for a gooddescription with the standard deviation of temperature in the rangeof 1.91–7.65 K for the examined systems. Thermophysical proper-ties of the studied drug determined by the differential scanningcalorimetry technique are in good agreement with the literaturedata.

The favourable solubilities in alternative solvents obtainedwithin this study for the investigated drug, accompanied by theabovementioned beneficial properties of ionic liquids can allowionic liquids compete in a more “safer” mode with solvents rou-tinely used in pharmaceutical industry.

List of symbols[BF4] tetrafluoroborate[C2mim] 1-ethyl-3-methylimidazolium[C4mim] 1-butyl-3-methylimidazolium[C6mim] 1-hexyl-3-methylimidazolium[C8mim] 1-methyl-3-octylimidazolium[C10mim] 1-decyl-3-methylimidazoliumDSC differential scanning calorimetryg12–g22, g21–g11 adjustable parameters of WilsonGE Gibbs excess energyK association constantli bulk factorn number of experimental points[NTf2] bis(trifluoromethylsulfonyl)amide[OTf] trifluoromethanesulfonate

q pure component surface parameterP1 and P2 model parameters resulting from the minimisation pro-

cedurer pure component volume parameter

e Equi

RSTT

TTuVxZ˛

��

�

���

�˝

A

Ta

R

[

[

[

[

[

[

[

[[

[

[

[[

[[

[

[

[

[[

[

[

[[[[

[[[[

[

[

[[

[

[

[

[47] Y. Shimizu, Y. Ohte, Y. Yamamura, K. Saito, T. Atake, J. Phys. Chem. B 110 (2006)

A. Forte et al. / Fluid Phas

ideal gas constantLE solid–liquid equilibrium

temperatureexpi

experimental equilibrium temperaturecali

calculated equilibrium temperaturefus,1 melting temperature of isoniazid

standard uncertainty of measurementm molar volume of pure compound i at 298.15 K1 mole fraction of isoniazid

coordination number constant of the NRTL, NRTL 1 and NRTL 2 equations, or

crystallographic form of solute1 activity coefficient of isoniazidfusCp1 difference in isoniazid heat capacity between the solid

and liquid at the melting temperatureg12, �g21 adjustable parameters of NRTL, NRTL 1 and NRTL 2

equationsfusH1 enthalpy of fusion of isoniazidhh enthalpy of associationu12, �u21 adjustable parameters of UNIQUAC and UNIQUAC

ASM equationsT root-mean-square deviation of temperature

objective function

cknowledgement

This work was supported by the Fundac ão para a Ciência e aecnologia (FCT, Portugal) through grants SFRH/BPD/26356/2006nd PEst-C/EQB/LA0006/2011.

eferences

[1] http://www.worldhealthsciences.com/tuberculosis-tb.html.[2] http://www.who.int/topics/tuberculosis/en/.[3] R.A. Sheldon, Green Chem. 9 (2007) 1273–1283.[4] J.P. Hallett, T. Welton, Chem. Rev. 111 (2011) 3508–3576.[5] E. Bogel-Lukasik, S. Santos, R. Bogel-Lukasik, M. Nunes da Ponte, J. Supercrit.

Fluids 54 (2010) 210–217.[6] C.I. Melo, R. Bogel-Lukasik, E. Bogel-Lukasik, J. Supercrit. Fluids 61 (2012)

191–198.[7] H.L. Ngo, K. LeCompte, L. Hargens, A.B. Mcewen, Thermochim. Acta 357 (2000)

97–102.[8] U. Domanska, R. Bogel-Lukasik, J. Phys. Chem. B 109 (2005) 12124–12132.[9] R. Bogel-Lukasik, L.M.N. Goncalves, E. Bogel-Lukasik, Green Chem. 12 (2010)

1947–1953.10] E. Bogel-Lukasik, C. Lourenco, M.E. Zakrzewska, R. Bogel-Lukasik, J. Phys. Chem.

B 114 (2010) 15605–15609.11] A. Forte, E. Bogel-Lukasik, R. Bogel-Lukasik, J. Chem. Eng. Data 56 (2011)

2273–2279.12] R. Bogel-Lukasik, D. Matkowska, E. Bogel-Lukasik, T. Hofman, Fluid Phase Equi-

lib. 293 (2010) 168–174.13] R. Bogel-Lukasik, D. Matkowska, M.E. Zakrzewska, E. Bogel-Lukasik, T. Hofman,

Fluid Phase Equilib. 295 (2010) 177–185.

[

[

libria 318 (2012) 89–95 95

14] J.M. Crosthwaite, S.N.V.K. Aki, E.J. Maginn, J.F. Brennecke, J. Phys. Chem. B 108(2004) 5113–5119.

15] S. Stolte, M. Matzke, J. Arning, A. Boschen, W.R. Pitner, U. Welz-Biermann, B.Jastorff, J. Ranke, Green Chem. 9 (2007) 1170–1179.

16] S. Stolte, J. Arning, U. Bottin-Weber, A. Muller, W.R. Pitner, U. Welz-Biermann,B. Jastorff, J. Ranke, Green Chem. 9 (2007) 760–767.

17] V. Jaitely, A. Karatas, A.T. Florence, Int. J. Pharm. 354 (2008) 168–173.18] M. Moniruzzaman, M. Tamura, Y. Tahara, N. Kamiya, M. Goto, Int. J. Pharm. 400

(2010) 243–250.19] K.D. Tait, Pharmaceutical industry, in: J.M. Stellman (Ed.), Encyclopaedia of

Occupational Health and Safety: Chemical, Industries and Occupations, Inter-national Labour Office, 1998, p. 64.

20] S. Pareek, C. Rajsharad, R. Kirkinde, Express Pharma (2008), Nov 16–30,http://www.expresspharmaonline.com/20081130/cphiindia200805.shtml.

21] K.B. Smith, R.H. Bridson, G.A. Leeke, J. Chem. Eng. Data 56 (2011) 2039–2043.22] H. Mizuuchi, V. Jaitely, S. Murdan, A.T. Florence, Eur. J. Pharm. Sci. 33 (2008)

326–331.23] U. Domanska, E. Bogel-Lukasik, J. Chem. Eng. Data 48 (2003) 951–956.24] R. Bini, C. Chiappe, V.L. Mestre, C.S. Pomelli, T. Welton, Org. Biomol. Chem. 6

(2008) 2522–2529.25] L. Crowhurst, P.R. Mawdsley, J.M. Perez-Arlandis, P.A. Salter, T. Welton, Phys.

Chem. Chem. Phys. 5 (2003) 2790–2794.26] C.A.S. Trindade, Z.P. Visak, R. Bogel-Lukasik, E. Bogel-Lukasik, M. Nunes da

Ponte, Ind. Eng. Chem. Res. 49 (2010) 4850–4857.27] C. Lourenco, C.I. Melo, R. Bogel-Lukasik, E. Bogel-Lukasik, J. Chem. Eng. Data,

submitted for publication.28] H.K. Hall, J. Am. Chem. Soc. 79 (1957) 5441–5444.29] F.D. Freire, C.F.S. Aragao, T.F.A.D. Moura, F.N. Raffin, J. Therm. Anal. Calorim. 97

(2009) 333–336.30] M.E. Van Valkenburg, R.L. Vaughn, M. Williams, J.S. Wilkes, Thermochim. Acta

425 (2005) 181–188.31] U. Domanska, M. Zawadzki, M. Zwolinska, J. Chem. Thermodyn. 43 (2011)

775–781.32] G.M. Wilson, J. Am. Chem. Soc. 86 (1964) 127–130.33] D.S. Abrams, J.M. Prausnitz, AICHE J. 21 (1975) 116–128.34] I. Nagata, Fluid Phase Equilib. 19 (1985) 153–174.35] I. Nagata, Y. Nakamiya, K. Katoh, J. Koyabu, Thermochim. Acta 45 (1981)

153–165.36] U. Domanska, J. Rolinska, Fluid Phase Equilib. 86 (1993) 233–250.37] J.H. Vera, S.G. Sayegh, G.A. Ratcliff, Fluid Phase Equilib. 1 (1977) 113–135.38] A.F.M. Barton, CRC Handbook of Solubility Parameter, 1985, p. 64.39] C.T. Lin, S.W. Kuo, J.C. Lo, F.C. Chang, J. Phys. Chem. B 114 (2010)

1603–1613.40] J.N.C. Lopes, T.C. Cordeiro, J.M.S.S. Esperanca, H.J.R. Guedes, S. Huq, L.P.N. Rebelo,

K.R. Seddon, J. Phys. Chem. B 109 (2005) 3519–3525.41] S.N.V.K. Aki, B.R. Mellein, E.M. Saurer, J.F. Brennecke, J. Phys. Chem. B 108 (2004)

20355–20365.42] C.B. Kretschmer, R. Wiebe, J. Chem. Phys. 22 (1954) 1697–1701.43] T. Lee, C.S. Kuo, Y.H. Chen, Pharm. Technol. (2006), Oct 2,

http://www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=378746&sk=&date=.&pageID=13.

44] D.J.C. Constable, C. Jimenez-Gonzalez, R.K. Henderson, Org. Process Res. Dev.11 (2007) 133–137.

45] Y.U. Paulechka, A.V. Blokhin, G.J. Kabo, A.A. Strechan, J. Chem. Thermodyn. 39(2007) 866–877.

46] A.V. Blokhin, Y.U. Paulechka, A.A. Strechan, G.J. Kabo, J. Phys. Chem. B 112 (2008)4357–4364.

13970–13975.48] R.D. Chirico, V. Diky, J.W. Magee, M. Frenkel, K.N. Marsh, Pure Appl. Chem. 81

(2009) 791–828.49] S.V. Dzyuba, R.A. Bartsch, ChemPhysChem 3 (2002) 161–166.