European Journal of Pharmaceutical Sciences 37 (2009) 499507

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European Journal of Pharmaceutical Sciences

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Tempe tycompo

Ftima L aa,a LSRE/LCM - La de dob LSRE/LCM - La o, InsCampus de San

a r t i c l

Article history:Received 22 JaReceived in reAccepted 19 AAvailable onlin

Keywords:DrugsSolubilityMeasurementModelingNRTL-SACPure solvents

of druge btate,for g

analysis by HPLC. Previous literature values on the solubilities of paracetamol were used to assess theexperimental methodology employed in this work. No literature data was found for any of the otherdrugs studied in this assay. Melting properties of the pure drugs were also determined by differentialscanning calorimetry (DSC) to provide a broader knowledge about the solubilization process and also for

1. Introdu

One of ttry is to dTherefore,steps of drso hydrophbioavailabimaceutical2007; Hu emanipulatiamorphoustallizationcosolventsation and tdrugs (Blagrelatively nal., 2008; B

CorrespoE-mail add

0928-0987/$doi:10.1016/j.emodeling purposes.The solubility data as a function of temperature were used to determine the thermodynamic properties

of dissolution like, Gibbs energy, enthalpy and entropy. Theoretical work was essentially focused on theevaluation of theNonrandomTwo-Liquid Segment Activity Coefcient (NRTL-SAC)model,which has beenreferred as a simple and practical thermodynamic framework for drug solubility estimation. A satisfactoryagreement was found between experimental and calculated values: the absolute average deviation was68% for the correlation in the organic solvents and 38% for the prediction in water, where the best resultsin prediction could be related to the selected solvents.

2009 Elsevier B.V. All rights reserved.

ction

he most challenging tasks of the pharmaceutical indus-iscover new therapies or to improve existing ones.new drugs are evaluated everyday in the differentug development. Many of these drug candidates areobic that their effects in the organism, related to theirlity, are dependent on the techniques used by the phar-industry to make them more soluble (Blagden et al.,t al., 2004). These techniques include, among others,on of solid state structures (polymorph changes andforms) (Nordstrm and Rasmuson, 2006), sonocrys-

(Manish et al., 2005), salt formation, solubilization inand micellar solutions (Millard et al., 2002), complex-he use of lypidic systems for the delivery of lipophilicden et al., 2007). Pharmaceutical cocrystallization is aew technology to improve solubilization (Basavoju etlagden et al., 2007).

nding author. Tel.: +351 22 508 1653.ress: eamacedo@fe.up.pt (E.A. Macedo).

Solubility is, thus, a very important property for pharmaceuti-cal product design because it affects the drug efcacy, its futuredevelopment and formulation efforts, and also inuences thepharmaco-kinetics, such as the release, transport and the degreeof absorption in the organism. On the other hand, in the pharma-ceutical industry, themajority of active pharmaceutical ingredients(APIs) are isolated in the solid form via crystallization and so, solu-bility is important for the design of these processes.

Solubility data involving new drugs are frequently not avail-able in the literature. Although some thermodynamic models canbe used to predict drug solubility, the availability of experimentaldata is still fundamental for an appropriate model developmentand evaluation. However, there are inherent complexities withexperimental measurements: accuracy and reliability are difcultto achieve, and experiments are costly and time consuming. Thesedifculties can be related to substance purity, different solid struc-tures, pH, temperature control, and solubility measuring method.Stovall et al. (2005) and Bustamante et al. (2000) measured thesolubility of ibuprofen in ethanol, methanol, 1-pentanol and 1-octanol and the results between authors present differences in therange of 9145%, which stresses the need of a reliable experimen-tal procedure and justies why efcient methodologies to predict

see front matter 2009 Elsevier B.V. All rights reserved.jps.2009.04.009rature and solvent effects in the solubiliunds: Measurements and modeling

. Motaa, Aristides P. Carneiroa, Antnio J. Queimadboratory of Separation and Reaction Engineering, Faculdade de Engenharia, Universidaboratory of Separation and Reaction Engineering, Escola Superior de Tecnologia e Gestta Apolnia, 5301-857 Braganca, Portugal

e i n f o

nuary 2009vised form 17 April 2009pril 2009e 3 May 2009

a b s t r a c t

In this work, pure solvent solubilitiesonide,measured in the temperature ranwere water, ethanol, acetone, ethyl aceformed using the shake-ask methodm/locate /e jps

of some pharmaceutical

Simo P. Pinhob, Eugnia A. Macedoa,

Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugaltituto Politcnico de Braganca,

gs, such as paracetamol, allopurinol, furosemide and budes-etween298.2315.2K are presented. The solvents under studycarbon tetrachloride and n-hexane. Measurements were per-enerating the saturated solutions followed by compositional

500 F.L. Mota et al. / European Journal of Pharmaceutical Sciences 37 (2009) 499507

solubilities are a main research subject, with high value for drugdesign.

In spite of drugs being so complex molecules, with several func-tional grouchemical stseveral metand Macedoochemical pand themeland Duffy, 2partition cois not the ca(Millard et adict solubiliwhy these eically soundused for ph

The Sc(Prausnitzmodels moseveral moa maximumand soluteused for nranging froesters, etheet al., 1998bsolubility pand Rohanithe correlatexperimenteters. Thisparameterstoluene, beacetone, anacetateethof this modlimited pra

Some otnot all are pnot availablthe determmental dataand Rohanimation of dpredictivegstructure inpredictionmixtures (Hties being othe solute aThus, they hor from avathat the nuso high thamissing par

Another(2003, 2004methodologities of spabased on a lbecause nothe selectioparacetamonobarbital

and OConnell, 2004), with estriol and ibuprofen (Abildskov andOConnell, 2005) in ethanol/water solvent systems, and ephedrine,hydrocortisone, salicylic acid, niumic acid, diuron and monuron

solvdologany

liabilare ttitivere mrecetor-l(Kla8; Tuhe rutionct cothisre-cafor aib an. ItsoluboutudeNonodel8) ison oative, andriaoaceuafts,haveo pets bamodnts. Afor p

l ranonlymetewornideorganwas

the mcedunal gtionshe stis a

rinoloducent omidtiveseleeverhobis, kes of hd hyloridps (associating, hydrogen bonding), having differentructures or isomers, or even different solid structures,hods to represent their solubility were reviewed (Pinho, 2007). Some empirical correlations based on physic-roperties like the octanolwater partition coefcientting pointwere proposed (Huuskonen, 2001; Jorgensen002) but they are currently of little use. To calculate theefcient several reliable methods are known, but thatse for the melting point. The so-called log-linear modell., 2002) that uses the partition coefcient cannot pre-ty in systems that present maxima, and this is a reasonmpirical models should be replaced by more theoret-models such as the thermodynamic models regularly

ase equilibria.atchardHildebrand concept of regular solutionset al., 1999) has been one of the thermodynamicst used in the pharmaceutical industry, and there aredications. According to this theory, the existence of

in the solubility curve is observed when the solventsolubility parameters are the same. This model wasaproxen and sodium diclofenac in several solventsm water, alkanes, alcohols, ketones, carboxylic acids,rs, amides, benzene and its derivatives (Bustamante), proving to be suitable for determination of partial-arameters. It was also used for paracetamol (Hojjati, 2006a) but it underestimated the solubilities. Withive Hansen model (Bustamante et al., 1993), availableal data are used to estimate solute solubility param-model was successfully used to estimate solubilityusing experimental data of sulfadiazine in some esters,nzene, dioxane, alcohols, water, amides, water andd sulfamethoxypyridazine in dioxanewater and ethylanol mixtures (Bustamante et al., 1993). A drawbackel is its very simple assumptions which lead to very

ctical use in the prediction of drug solubilities.her activity coefcient models have also been used, butractical because phase equilibrium data are frequentlye and the application of thesemodels regularly requiresination of binary interaction parameters from experi-. The UNIFAC model (Fredenslund et al., 1975; Hojjati, 2006a) is one interesting approach, used in the esti-rug solubilities in pure and mixed solvents. This is aroup-contributionmodel,which requires only chemicalformation for the solutes and solvents. Itwasused in theof the solubility of paracetamol in waterisopropanolojjati and Rohani, 2006a), with overestimated solubili-btained. Additionally,whennot all groupparameters forre available, group-contributionmodels cannot be used.ave to be obtained from structurally similar substancesilable experimental data. In this way, it often happensmber of group parameters needed to be obtained ist the available database is insufcient to estimate allameters.methodology, proposed by Abildskov and OConnell, 2005), the reference solvent approach, is a simpliedy that allows the prediction of differences in solubil-

ringly soluble chemicals when the solvent is changed,imited set of experimental data. This technique is usefulpure-solute properties are needed. However, it requiresn of a reference solvent. It was already tested withl in ethyl acetate/ethanol, and in sulfanilamide, phe-and vinbarbital in water/ethanol mixtures (Abildskov

in puremethonatesmand rewhichcompestructu

Theconducnativesal., 200els is tdistriba perfetage ofonly pappliedrofecoxdictionof the scarriedmagnit

TheSAC) mal., 200sentatia deriv(1968)equilibpharmand Cr(2004)work tsolvenof thissegmesideredthe fulthat itof para

Thisbudesoat theetamolone oftal profunctiointeracAlso, tetamolAllopuacid prtreatmsulfonaconges

Thecover shydroppounddegreebic antetrachents (Abildskov and OConnell, 2003). In general, thisy cancels errors in pure-solute properties and elimi-interactionparameters, showinga satisfactoryaccuracyity. However, a strategy must be developed for solutesoo much soluble and for those that form complexes orly interactwith the solvent. Thepossible effect of soluteodications is also not taken into account.nt developments in computational chemistry yieldedike screening model (COSMO) that are promising alter-mt and Eckert, 2000; Lin and Sandler, 2002; Mullins etng et al., 2008). The main characteristic of these mod-

eduction of the molecular properties to a probabilityof the screening charges for the solvated molecule in

nductor, the sigma prole of the molecule. The advan-model is that no experimental data is required, needinglculated quantum chemical output. This model wasset ofdrugcompounds, namely lovastatin, simvastatin,d etoricoxib (Tung et al., 2008), with a reasonable pre-

implementation in the study of temperature inuenceilities of drug compounds in different solvents was also(Zilnik et al., 2007) and even if the order of solubilityis predicted, generally the results are poor.randomTwoLiquid SegmentActivityCoefcient (NRTL-(Chen and Song, 2004; Chen and Crafts, 2006; Tung etone recent and most successful model for the repre-

f drug solubility. It is based on the polymer NRTL model,of the original NRTL model of Renon and Prausnitz

has been widely applied to correlate and predict phasefhighlynonideal systems, like thosecontainingcomplextical organic electrolytes (Chen and Song, 2004; Chen2006; Kokitkar and Plocharczyk, 2008). Chen and Songshown that NRTL-SAC is a simple and practical frame-

rform solubility calculations both in pure and mixedsed on a limited set of experimental data. The essenceel consists in representing the molecules by conceptualccordingly, the experimental measurements to be con-arameter regressionmust be carefully selected to cover

ge of segments. One of the advantages of NRTL-SAC isrequires this well-chosen data to t a smaller numberrs.k focus essentially poorly water soluble drugs such as, furosemide and allopurinol, whose water solubilitiesisms temperature range from 20 to 500mg/L. Parac-also used on the experimental measurements as it isost studied drugs, allowing to validate the experimen-

re used in this work. The drugs selected have differentroups anddifferentmolecular sizes, leading to differentwith the solvents and, therefore, different properties.

udied drugs have different therapeutic effects. Parac-n active principle with analgesic/antipyretic action.is a xanthine oxidase inhibitor that decreases the uriction. Budesonide is a glucocorticoid steroid, used in thef asthmaand furosemidebelongs to a family of benzoic-e-furans, being a loop diuretic used in the treatment ofheart failure.ction of solvents used involved a careful choice toal types of surface interaction characteristics, namely,c, hydrophilic and polar. Alkanes are hydrophobic com-tones and esters are polar molecules with varyingydrophobic contents, alcohols are hybrids of hydropho-drophilic segments. In this way, n-hexane, carbone, acetone, ethyl acetate and ethanol were used as

F.L. Mota et al. / European Journal of Pharmaceutical Sciences 37 (2009) 499507 501

representative solvents, with distinctive surface interaction char-acteristics.

The main goal of this work is thus to extend the database onexperimental solubility for a group of drugs and to evaluate theuse of the NRTL-SAC model to correlate and predict the solubilityof these compounds in the different solvents. In this way, sol-ubilities were measured in a temperature range between 298.2and 315.2K in water, and at three temperatures (298.2, 310.2, and313.2K) in acetone, carbon tetrachloride, ethanol, ethyl acetate andn-hexane. Good agreement was obtained between experimentaland modeling values: the absolute average deviation was 68% forthe correlation, while it was 38% in the prediction.

2. Materials and methods

2.1. Materials

In all experiments, bi-distilled water (2.53S/cm) wasused. Ethanol, acetone, ethyl acetate, carbon tetrachlorideand n-hexane were of HPLC grade (99.8% purity). Paraceta-mol (N-(4-hydroxyphenyl)acetamide, CAS N: 103-90-2, min.99% purity), allopurinol (3,5,7,8-tetrazabicyclo[4.3.0]nona-3,5,9-trien-2-one, CAS N: 315-30-0, min. 98% purity), budesonide(16,17-(butylidenebis(oxy))-11,21-dihydroxy-,(11-,16-)-pregna-1,4-diene-3,20-dione, CAS N: 51333-22-3, min. 98% purity)and furosemide (4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoylbekindly provTheir chemwere used a

2.2. Experim

2.2.1. SolubAll the so

ical isothermmeasured aand 315.2Kacetate, carobtained atrated soluti

20mL of solvent into constant-temperature jacketed glass cells andstirring for 2 days. Temperature was maintained constant in twoways: (i) using thermostatic water in the cell jackets and (ii) plac-ing the cell0.1K) prothe cell jackelectric fanperature coaround thesampling) wperature w(Pt-100) (to an Agilensuring systedeviation othe agitatioday allowintimes werein composit

Samplesplastic syrinviously platemperaturformed, forHPLC (VWRreversed-ph

lubints,

tive s

DSC mtingnninder udelineal saencest rue of 1mintheelue ie 2,ond

ermo

solung sis purmelt

f

xs is tn, Rute mheatempecalcuNRT

originbtainzoic acid, CAS N: 54-31-9, min. 99% purity) wereided by the Portuguese pharmaceutical company Bial.ical structures are presented in Fig. 1. All chemicalss received.

ental procedure

ility measurementslubility experimentswere carried out using the analyt-al shake-ask method. The aqueous solubilities were

t ve different temperatures 298.2, 303.2, 310.2, 313.2, while for the other solvents (ethanol, acetone, ethylbon tetrachloride and n-hexane) the solubilities werethree temperatures, 298.2, 310.2 and 313.2K. Satu-

ons were prepared mixing an excess of solid solute and

Fig. 1. Chemical structures of the drugs under study.

Each sosuremerespec

2.2.2.Mel

tial scaa broafor moically sas referThe ring ratat 1K/racyofEach vain Tablcorresp

2.3. Th

Thefollowiphase iby the

ln xs =

whereof fusiothe solmolarto be tcient

Theof the( I) is os in an air bath. A circulating water bath (Grant LTC1,moted the circulation of thermostatic water throughets; and the air bath, composed by an acrylic box, anand a resistance connected to a Fuji PXR-4 PID tem-ntroller (0.1K) created a thermostatic environmentcells, so that all the measuring procedure (stirring andas performed at the same target temperature. Tem-

as monitored with 4-wire platinum resistance probes0.01K) placed in contact with solutions and connectedt 34970A data acquisition unit. This temperature mea-m was previously calibrated, presenting a maximum

f 0.06K at 303.67K. Once the equilibrium was attained,n was stopped and the solution was kept still for 1g undissolved solid to settle. The stirring and settlingdetermined by continuous sampling until no changesion were veried.of the saturated liquid phases were collected usingges coupled with polypropylene lters (0.45m) pre-ced at the air bath (in order they are at the samee as the samples). Quantitative analysis was then per-each drug, by comparisonwith a calibration curve using-Hitachi Lachrom Elite) with UvVis detection using aase C18 HPLC column (Merck Purospher star RP18e).lity value is an average of at least three different mea-which are presented in Table 1, simultaneouslywith thetandard deviations.

easurementsdata of the pure compounds were obtained by differen-g calorimetry (DSC) (Netzsch 200 F3 Maia) to providenderstanding of the solubilization process, as well asg purposes. Aluminium crucibles were used to hermet-mples (46mg)of solid andanemptycruciblewasused. The heatingwas promoted under a streamof nitrogen.n was done in a larger temperature range with a heat-0K/min and then, several runs (at least 3) were donearound the expected melting temperature. The accu-quipmentwas ascertained running an indiumstandard.s an average of at least three runs, which are presentedtogether with the number of measurements and theing standard deviations.

dynamic modeling

bility of a solid solute s in a liquid solvent is given by themplied expression, where it is assumed that the solide and that the triple point temperature can be replaceding temperature (Prausnitz et al., 1999):

usH

R

(1T

1Tm

)+ Cp

R

[TmT

1 ln(

TmT

)] lns

(1)

hemole fractionof the solute,fusH the solute enthalpythe ideal gas constant, T the absolute temperature, Tmelting temperature, Cp the difference between the

capacity of solute liquid and solid phases (consideredrature independent) and s is the solute activity coef-lated using a thermodynamic model.L-SAC model (Chen and Song, 2004) is a modicational NRTL where the activity coefcient of component I

ned from two contributions: a combinatorial term (CI )

502 F.L. Mota et al. / European Journal of Pharmaceutical Sciences 37 (2009) 499507

Table 1Experimental solubilities (s) of the studied drugs.

T (K) s (g/L)

Paracetamol Allopurinol Budesonide Furosemide

Water315 37.510.81 0.580.01 (25.760.14)103 (55.120.34)103313 32.370.59 0.550.01 (24.460.62)103 (45.480.43)103310 27.332.97 0.420.02 (24.130.20)103 (35.220.20)103303 20.710.68 0.280.01 (20.900.31)103 (30.100.05)103298 16.661.12 0.200.02 (19.040.33)103 (25.321.03)103

Acetone313 140.115.85 2.490.02 8.450.39 4.360.05310 131.472.73 1.330.05 6.960.42 3.030.10298 98.443.92 0.660.03 3.980.18 2.190.12

Carbon tetrach313310298

Ethanol313310298

Ethyl acetate313310298

n-Hexane313310298

obtained frotorial entrosum of thesegment.

lnI = lnCIThe com

lnCI = ln

x

with

rI =

i

ri,I

I =rIxIJ rJx

where xJ issegment spnumber ofcomponent

resid

ln

the a

Table 2Average meltin

Drugs

ParacetamolBudesonideAllopurinolFurosemide

a Marrero anloride(21.971.28)103 (101.530.45)103(16.681.24)103 (82.590.38)103(4.640.14)103 (66.650.41)103

242.694.27 (152.637.30)103224.353.79 (92.175.36)103188.092.34 (36.104.33)103

(31.871.43)103 (210.360.67)103(23.640.22)103 (187.403.97)103(15.490.76)103 (177.362.04)103

(12.080.69)103 (43.240.29)103(9.690.75)103 (29.630.25)103(3.930.32)103 (17.460.93)103

m the FloryHuggins approximation for the combina-py of mixing and a residual term (RI ) set equal to thelocal composition (lc) interaction contribution for each

+ lnRI (2)

The

lnRI =

wherebinatorial term is given by:

I

I+ 1 rI

J

JrJ

(3)

(4)

J(5)

the mole fraction of component J, rm,I the number ofecies m contained in component I, rI the total segmentcomponent I and I is the segment mole fraction ofI.

by:

ln lcm =

and the acticomponent

ln lc,Im =

I and J are cspecies indspecies j, xj,

g point and enthalpy of fusion of the studied drugs.

Scans Tm (K)

Exp. Group-contribution method

5 443.2 0.5 385.53 534.0 1.2 477.8 653.5 1.3 435.1 534.3 0.9 510.9

d Gani (2001).(817.2211.53)103 (1.570.18)103(612.196.28)103 (0.930.05)103(412.707.86)103 (0.280.01)103

31.371.84 16.030.4223.990.99 6.870.5114.941.16 2.250.16

8.380.06 10.681.147.260.19 9.190.322.490.08 2.970.02

(27.180.40)103 (293.200.39)106(25.880.90)103 (184.340.57)106(18.880.89)103 (128.881.73)106

ual term,

lcI =

m

rm,I(ln lcm ln lc,Im ) (6)

ctivity coefcient of segment species m ( lcm ) is givenjxjGjmjm

kxkGkm+m

xmGmmkxkGkm

(mm

jxjGjmjm

kxkGkm

)

(7)

vity coefcient of segment species m contained only inI ( lc,Im ) is expressed by:

jxj,IGjmjm

kxk,IGkm+m

xm,IGmmkxk,IGkm

(mm

jxj,IGjmjm

kxk,IGkm

)

(8)

omponent indexes, i, j, k, m and m are segment basedexes, xj the segment-based mole fraction of segmentI is the segment-basedmole fraction of segment species

fusH (kJmol1)

a Exp. Group-contribution methoda

27.6 1.1 23.634.7 1.2 57.0 38.5 48.7

F.L. Mota et al. / European Journal of Pharmaceutical Sciences 37 (2009) 499507 503

j contained only in component I, and can be calculated as follows:

xj =

JxJrj,JI

ixIri,I

(9)

xj,I =rj,Iiri,I

(10)

Gij and ij are local binary quantities related to each other by theNRTL nonrandomness parameter :

Gij = exp(ijij) (11)To account for several interactions, predened concep-

tual segments were proposed, along with their correspondingsegmentsegment binary parameters, and this is what makesthe difference between this model and the group-contributionapproaches which build molecules from a large set of predenedfunctional groups based on chemical structure. Each compound inthe system is represented by predened segments, one hydropho-bic (X), one polar-attractive (Y), one polar-repulsive (Y+) and onehydrophilic (Z). Thehydrophobic segment represents themolecularsurface area unlike to form hydrogen bonds; the hydrophilic repre-sents the area with interactions characteristic of a hydrogen-bonddonor or accharacteristequations, t(rm,I):whichsolvents usealready avaparametersbers of eachare four. Theters, and residual terare shown iwere determequilibriumused to estimodel can bsystems (Ch

The melubilizationpurposes. Ibe estimateposed by M

Table 3aNRTL-SAC mol

Solvent

AcetoneCarbon tetrachEthanolEthyl acetaten-HexaneWater

Table 3bNRTL binary p2004).

Segment 1Segment 2

122112 =21

different types of isomers and already tested with success for com-plex chemicals (Mota et al., 2008).

3. Results and discussion

The measured solubilities of paracetamol, allopurinol, budes-onide and furosemide, as a function of temperaturewere presentedin Table 1. The solubility follows the expected increasing trendwithtemperature. Paracetamol and allopurinol are the most soluble inwater, in the range of 0.238g/L, while budesonide and furosemideare the less soluble (less than 55mg/L).

Solubilities in the pure organic solvents are also listed in Table 1while Table 4 shows a solubility ranking. Solubilities are higher inthe binary systems paracetamol/ethanol and paracetamol/acetonewith the lowest being found for furosemide/carbon tetrachlorideand furosemide/n-hexane. This means that, for example, ethanoland acetone are appropriate solvents to separate and purify parac-etamol from solutions. n-Hexane is among the studied solvents theworst to solubilize all of these drugs (except for budesonide, wherewater takes its place), and thebest solvents are ethanol andacetone.

With the exception of paracetamol, among the studied drugs nosolubility d

racets, whl, thered dtamasmuat thIn thwhi

uthohern themagom dmeamearese

e 1%.dataesented bin a

ch et

y rank

Solu

>100101

110

0.11

0.01

0.00

504 F.L. Mota et al. / European Journal of Pharmaceutical Sciences 37 (2009) 499507

Fig. 2. Solubil[ (Bustamantat 298, 303 an[ (Granberg aRasmuson, 199(Jimenez and Mand 313K], eth(Perlovich et a

Furosem653.5K, rescould not b(BYU DIPPRand Crafts,point deviaMelting temfor allopurinthe values mtively). Thewith those443.2K for

For paramelting temdata (deviatpresent higonide).

DSC anature range fand singlecrystal stru

The solution of the tof dissolutientropy (

Linear soable, becauaccurately,sion and cprocess. Thare undoubture dependa more theoGibbsHelmuct in termthe followin

solH = RT

solG = R

where the molar enthalpy of dissolution is the difference betweenthe partial molar enthalpy of the compound in the solution and the

olar enthalpy at temperature T, x the solute mole fractionity, aanbtionsent

ed fro

s

le 5 sn prtiests thtionegatierablsuchhydros somthee atinololutioept fo. Bu

o 303as c

worknearnd 3kingloridpic cry sime anutios areininlorids negtrachitiveity of paracetamol in several solvents: this work vs. literature. Watere et al., 1998a) at 298 and 303K; (Granberg and Rasmuson, 1999)d 313K; (Hojjati and Rohani, 2006b) at 298, 303 and 313K], acetonend Rasmuson, 2000) at 298K], carbon tetrachloride [* (Granberg and9) at 298K], ethanol [ (Granberg and Rasmuson, 1999) at 298K; artinez, 2006) at 298 and 303K; (Romero et al., 1996) at 298, 303

yl acetate [ (Granberg and Rasmuson, 1999) at 303K], n-hexane [l., 2006) at 298 and 310K].

ide and allopurinol decompose at melting (534.3 andpectively), and because of this, their fusion enthalpiese measured. Melting data was found for paracetamol801 Thermophysical Properties Database, 1998; Chen2006; NIST Chemistry Webbook, 2007) with meltingting less than 1% and enthalpy of fusion less than 6%.peraturesof 633and479Kwere found (Jain et al., 2008)ol and furosemide respectively, that comparewellwitheasured in this work (deviations of 3 and 12%, respec-values measured in this work are in close agreementreported by Bial: melting temperatures of 512.2 andbudesonide and paracetamol, respectively.cetamol, budesonide and furosemide the calculatedperatures are ingoodagreementwith theexperimentalions below 12%) while the calculated fusion enthalpiesher deviations (15% for paracetamol and 64% for budes-

lysis of the pure drugs were performed in the tempera-rom 273 up to some K above the melting temperature,and sharp peaks were found, indicating that a single

pure msolubillution cinterac

Theobtain

solS =

Tabsolutioproperpresendissolu(and nconsidbeingwatersame iwherenegativallopurof diss

Excparisonclose tvalue win thisa nonli298.2 a

Lootetrachenthalhas vechloridcontribubilitiedetermtetrachalso habon teare poscture was being studied.bility data of the drugs under studywas plotted as func-emperature to calculate the thermodynamic propertieson, molar Gibbs energy (solG), enthalpy (solH) andsolS).lubilitytemperature plots are often considered desir-se they can be interpolated and extrapolated quitecan be treated by the usual statistics of linear regres-an provide thermodynamic data for the dissolutione original vant Hoff plot of ln (solubility) against 1/Ttedly most helpfully, however to express the tempera-ence of solubility for nearly ideal solidliquid systemsretically-based approach is adopted. It starts from theholtz equationand thedenitionof the solubilityprod-

s of the molar Gibbs energy of dissolution, from whereg equations can be obtained (Adkins, 1983):

2(

d ln xdT

)P

(12)

T ln(x)P (13)

mic.Like prev

an activityence of thesolid phaseetamol a v801 Thermcompoundscapacity, a tMarrero anperature efcapacity, a(Goodmanfound at 29furosemidebudesonidehigher (73%be used asthe Cp is ipoints (Mis(meltingpond P is the pressure. The values of the enthalpy of disso-e regardedas a reectionof thenatureof intermolecular.ropic change for the dissolution process (solS) ism the respective enthalpies and Gibbs energies:

olH solGT

(14)

ummarizes the thermodynamic functions for the dis-ocess in pure solvents. Looking at the thermodynamicin water, it is possible to observe that budesonidee smallest enthalpy of dissolution. This would favor itsrelatively to the other drugs, but because of a very highve) entropy of dissolution it is hindered as involves ae ordering of the water molecules. In fact, budesonidea large molecule requires a considerable amount ofgen bonds to be broken in order to be solubilized. Theehow found for furosemide, another large molecule,

entropy of dissolution is very close to zero or slightlythe lowest temperatures. Comparing paracetamol andit can be seen that paracetamol has a smaller enthalpyn and then it is more soluble.r paracetamol, no literature valueswere found for com-

stamante et al. (1998a) reported a solH of 22.46kJ/molK, while in this work it was found 35.61kJ/mol. This

alculated by a method slightly different from that used: in the temperature range from 278 to 343K they usedtendency, while here a linear t was adopted between15.2K.at the organic solvents (Table 5), paracetamol in carbonehas avery favorable entropic contributionbut a strongontribution, leading to smaller solubility. Budesonideilar enthalpic contributions in acetone, carbon tetra-

d ethanol; in water and n-hexane where the enthalpicns are low, but there are negative entropies, the sol-considerably lower. Furosemide has entropic effects

g its smaller dissolution in n-hexane while in carbone the enthalpic effects are more relevant. Allopurinolative entropies determining its low solubilities in car-loride and ethyl acetate. All the enthalpies of solution, meaning that the dissolution processes are endother-

iouslymentioned, to calculate solubilities it is requiredcoefcient model, melting properties, and the differ-heat capacities between the hypothetical liquid and

s. Limited data are available for Cp. Only for parac-alue was found: 32.13 J/molK at 298.2K (BYU DIPPRophysical Properties Database, 1998). For the other, the values had to be estimated. For the liquid heathree-level group-contributionmethodrstproposedbyd Gani (2001) and extended to take into account tem-fects was used (Kolsk et al., 2008). For the solid heatcorrelation based on molecular structure was selectedet al., 2004). The following estimated values were8.2K: 121.32 J/molK for paracetamol, 188.30 J/molK for, 162.01 J/molK for allopurinol and 104.34 J/molK for. In spite of, the estimated value for paracetamol being) than that found in literature, the estimated values willreference values. Frequently, in solubility calculations,gnored, specially when compounds have high meltinghra and Yalkowsky, 1992). This is the case of allopurinolint 653.5K),where theCp termwill not be considered.

F.L. Mota et al. / European Journal of Pharmaceutical Sciences 37 (2009) 499507 505

Table 5Thermodynamic properties of dissolution of the drugs under study in pure solvents: solG (kJmol1), solH (kJmol1) and solS (Jmol1 K1)).

T (K) Paracetamol Allopurinol Budesonide Furosemide

solH solG solS solH solG solS solH solG solS solH solG solS

Water315 38.48 14.14 77.23 53.67 24.77 91.71 14.78 35.98 67.27 35.34 33.28 6.55313 37.99 14.44 75.22 52.99 24.77 90.14 14.59 35.89 68.01 34.89 33.57 4.22310 37.27 14.74 72.63 51.98 25.23 86.25 14.32 35.59 68.59 34.23 33.92 0.99303 35.61 15.12 67.59 49.66 25.66 79.19 13.68 35.15 70.84 32.70 33.56 2.83298 34.44 15.41 63.82 48.04 26.15 73.43 13.23 34.80 72.36 31.63 33.44 6.06

Acetone313 18.29 7.17 35.52 59.76 17.22 135.85 40.11 17.03 73.70 33.10 18.07 48.00310 17.94 7.25 34.46 58.62 18.66 128.84 39.35 17.37 70.86 32.47 18.84 43.96298 16.58 7.65 29.94 54.17 19.70 115.63 36.36 18.08 61.30 30.01 18.91 37.21

Carbon tetrachloride313 85.20 29.08 179.21 20.50 24.82 13.79 34.16 22.39 37.59 90.25 37.98 166.93310 8 3.51 22.92 34.15 88.53 38.98 159.76298 7 0.97 23.01 26.69 81.81 40.44 138.77

Ethanol313 1 7.91 14.23 75.63 97.84 15.28 263.62310 1 7.19 14.78 72.25 95.97 17.32 253.59298 1 4.37 15.38 63.69 88.69 19.42 232.34

Ethyl acetate313 3 7.75 16.30 164.29 71.58 14.99 180.73310 3 6.46 16.51 161.03 70.22 15.23 177.30298 3 1.42

n-Hexane313 6 0.30310 5 9.91298 5 8.40

Concernparametersfunction:

F =

i

(ln

where xs isscripts exprespectively

The soludata in purein Table 2, theters publisaqueous sowas not inctual segmenabsolute avelished differbe related tfusion, andparameters

Table 6Regressed NRTbinary system

Solute name

ParacetamolBudesonideAllopurinolFurosemide

a AAD (%) =

work

corrquateFor tthanr wh3.57 29.51 174.32 20.11 25.11 16.14 37.23 31.54 153.25 18.58 24.67 20.43 3

2.31 6.40 18.89 74.19 25.08 156.82 32.08 6.52 17.91 72.78 26.14 150.36 31.16 6.67 15.05 67.25 27.45 133.49 3

6.20 28.08 25.93 7.66 22.89 48.63 65.51 28.58 22.34 7.52 22.97 49.83 62.81 28.52 14.39 6.95 22.22 51.22 6

1.07 29.84 99.70 45.49 26.25 61.45 29.90 30.12 96.01 44.63 26.97 56.92 15.36 31.20 81.03 41.24 27.24 46.95 1

ing the optimization procedure, for each system thewere estimated minimizing the following objective

xexps ln xcalcsln xexps

)2(15)

In thisonly.

Thean adeonide.highervent fothe solute solubility in mole fraction and the super-and calc refer to experimental and calculated solubility,.temodelparameterswere regressedusing the solubilitysolvents presented in Table 1, the melting data showne Cp values abovementioned and the solvent param-hed by Chen and Crafts (2006) (Tables 3a and 3b). Thelubilities will be predicted and because of that waterluded in the regression. Table 6 presents the concep-t numbers for each drug under study together with theragedeviation (AAD). ChenandCrafts (2006)havepub-ent parameters for paracetamol, but this difference cano their different melting temperature and enthalpy ofnot considering the Cp term in the estimation of the. Also, these authors used a more extensive database.

L-SAC molecular parameters (rm,I) for the studied compounds in alls except water and respective absolute average deviation (AAD).

X Y Y+ Z AAD (%)a

0.416 0.016 0.168 1.861 651.000 0.178 0.005 1.079 820.016 0.002 1.169 0.000 390.600 0.127 0.010 1.620 83

1N

i

(xexps xcalcs

xexps 100

).

while n-hexwith higherThemost somuch bette

Once thebe used tosolvents. Fig

Fig. 3. NRTL-furosemide; (18.53 143.86 64.89 17.44 159.15

30.46 32.43 38.97 41.56 8.2830.29 33.46 38.23 42.36 13.3129.90 38.56 35.33 41.61 21.08

, the parameters were regressed based in ve solvents

elation results lead to the conclusion that NRTL-SAC ismethod, with a maximum deviation of 89% for budes-his compound all solubilities are low and deviations80% were found for all solvents. Ethanol was the sol-ich lower deviations were found, in the order of 53%,

ane, carbon tetrachloride and ethyl acetate were thosedeviations, in the order of 82, 75 and 65%, respectively.luble compounds, allopurinol andparacetamol, showedr correlation results.solute model parameters are obtained, the model canpredict the solubility of the same solute in different. 3 shows the prediction of the aqueous solubilities of

SAC prediction results: () paracetamol; () budesonide; ()) allopurinol.

506 F.L. Mota et al. / European Journal of Pharmaceutical Sciences 37 (2009) 499507

Fig. 4. NRTL-Sacetate mixedwith the paramparameters ob

these compSAC providefor allopurican still beplex organiSurprisinglyduring corrvents wherof segmentnol hydrophregressed vtests were malso be obsetion, what gsolutes prewith the so

The sambility in mix(2000) reptone; Romeethanolethmixture ethfractions wagreementdeviations fIn the casean extremeagreementfor water wwhatwas fopresented iobtained wand those paverage devauthors arein this workparameterstion, and dthe differenthat for pur(absolute dfraction incethyl acetat

of 69%. As referred before, ethyl acetate was one of the solventswhere the correlation was worse, and that certainly inuences thequality of predictions. Even though, if the ideal solubilities were

ted,nsideemese reive mund

, andg thlubi

clus

thisrugide

coming tn a stetrndargendatatermon pes. TeterproNRTities.ess tdictd sorepr

wled

auo pLSR

005.D/32t froAC prediction results for paracetamol solubility in ethanolethylsolvent at 298.2K (, Romero et al. (1996); , NRTL-SAC predictions)eters estimated in this work (- - -, NRTL-SAC predictions) with the

tained by Chen and Crafts (2006).

ounds as a function of temperature. In general, NRTL-s a good prediction, with a maximum deviation of 70%nol, which for a predictive result of aqueous solubilityconsidered a good estimate, as solubilities of such com-c compounds inwater are frequently difcult to predict., allopurinol was the drug that showed lower deviationelation. However, the correlation was based in ve sol-e ethanol is the only one presenting the unique kind(hydrophilic) present in water. Moreover, the allopuri-ilic segment parameter was xed to zero because the

alue was too low and some correlation and predictionade xing it at zero and the results did not vary. It canrved that the prediction results are better than correla-enerally not happen. This can be related to the fact thatsent a broader and more complex kind of interactionslvents selected for correlation than with water.emodel parameters can also beused to predict the solu-ed solvents. For paracetamol, Granberg and Rasmuson

orted solubility data in mixtures of water and ace-ro et al. (1996) reported data for ethanolwater andyl acetate binary solvents. In the case of the binaryanolwater, a solubility peak for higher water weightas observed, where the predictions are not in good

calculathat coimprov

Thepredictsolutesresultsshowindrug so

4. Con

Insome dfurosemFor allincreassured icarbonThe staused toubilityalso debilizatipurposwere dlization

Thesolubilto regrthe prein mixetool to

Ackno

TheFundacand byEQU/2SFRH/Bsupporwith the experimental data. Even though, the averageor water weight fractions between 0.0 and 0.7 are 59%.of the binary mixture acetonewater, although this isly non-ideal system, the model predictions are in goodwith the experimental data and the average deviationseight fractions between 0.0 and 0.5 are 26%, similar tound for themixed solvent systemethyl acetate/ethanol,n Fig. 4. In this gure a comparison between the resultsith the paracetamol parameters estimated in this workroposed by Chen and Crafts (2006) is also shown. Theiations obtainedwith the parameters reported by those19%, lower than those using the parameters calculated(46%), but Chen and Crafts (2006) used ve adjustable

, a much larger set of solvents for parameter estima-id not took into account the melting properties andce in the thermal heat capacity. It can also be seene ethanol, the calculated solubility value is very goodeviation of 18%), but as long as the ethyl acetate weightreases the prediction gets worse. When it reaches puree, the correlated solubility value presents a deviation

to Bial for k

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Temperature and solvent effects in the solubility of some pharmaceutical compounds: Measurements and modelingIntroductionMaterials and methodsMaterialsExperimental procedureSolubility measurementsDSC measurements

Thermodynamic modeling

Results and discussionConclusionsAcknowledgementsReferences