estimation of the effect of nacl on the solubility of organic compounds in aqueous solutions

Estimation of the Effect of NaCl on the Solubility ofOrganic Compounds in Aqueous Solutions

NINA NI, MOHAMED M. EL-SAYED,* TAPAN SANGHVI, SAMUEL H. YALKOWSKY

College of Pharmacy, The University of Arizona, Tucson, Arizona 85721

Received 20 April 2000; revised 6 August 2000; accepted 7 August 2000

ABSTRACT: The Setschenow constant, Ksalt, of a nonelectrolyte in a NaCl solution isshown to be related to the logarithm of its octanolwater partition coefficient, log Kow,determined by Ksalt 4 A log Kow + B, where Kow is the octanolwater partition coeffi-cient of the solute and the coefficients A and B are constants. The values of A and Bwere empirically determined from literature data for 62 organic compounds and vali-dated for a test set of 15 compounds including several drugs. 2000 Wiley-Liss, Inc. andthe American Pharmaceutical Association J Pharm Sci 89: 16201625, 2000Keywords: Setschenow constant; nonelectrolyte; sodium chloride; partition coeffi-cient; solubility

INTRODUCTION

Solubility data can be used to predict pharmaceu-tically important parameters such as dissolutionrate, absorption rate, and tissue distribution rate.The presence of strong electrolyte salts can eitherincrease or decrease the solubility of organic com-pounds in water. The effect observed is dependenton the polarity of both the solute and the salt.Inorganic salts, such as NaCl, increase the polar-ity of water. As a result, they increase thesqueezing out effect of water on nonpolar sol-utes. This salting-out effect is frequently de-scribed by the Setschenow equation (eq. 1):1

log S/S0 = 1KsaltCsalt (1)

where S and S0 are the solubilities of the organicsolute in aqueous salt solution and in water re-spectively, Csalt is the molar concentration of elec-trolyte, and Ksalt is the empirical Setschenow con-stant.

Several attempts to quantitate the effect ofsalts on the solubility of organic compounds havebeen reported, including: (a) electrostatic DebyeMacAulay Theory (DMT) of Debye and MacAu-lay,2 (b) ConwayDesnoyersSmith theory(CDST) of Conway et al.,3 (c) internal pressuretheory (IPT) of McDevit and Long,4(d) scaled par-ticle theory (SPT) of Masterton and Lee,5 and (e)internal pressure theory (XIPT) modified by Xieand Yang.6

Xie and Mackay,7 in reviewing the theories justmentioned, showed that each method requires theuse of several parameters to calculate Ksalt andthe results are only fairly accurate. They also pro-posed that Setschenow constants can be simplyand more accurately determined by assumingthat they are related to the solute molar volume,V, by Ksalt 4 0.0018V. The Xie and Mackay vol-ume calculation (XMV) is based on the method ofLe Bas.8

In this paper, a simple relationship is proposedfor predicting the structural dependence of Ksaltin NaCl from the octanolwater partition coeffi-cient of the solute. Using new experimental dataand data from the literature, the results of thisrelationship are compared with those of the sixmethods just listed.

*Present address: Department of Pharmaceutics, Facultyof Pharmacy, Suez Canal University, Ismailia, Egypt

Correspondence to: S.H. Yalkowsky (Telephone: 520-626-1289; Fax: 520-626-4063)Journal of Pharmaceutical Sciences, Vol. 89, 16201625 (2000) 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association

1620 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 12, DECEMBER 2000

THEORETICAL SECTION

It is well known that cosolvents increase the solu-bility of nonpolar compounds in aqueous solution.The relationship between the drug solubility andthe cosolvent concentration can be described bythe log-linear model of Yalkowsky and cowork-ers;911 that is:

log S/S0 = sCcosol (2)

where S and S0 are the solubilities of solute incosolvent solution and in water, respectively,Ccosol is the concentration of cosolvent and s is theempirical solubilizing power of the cosolvent forthe solute. The value of s is related to both thepolarity of the solute by log Kow and the polarity ofthe solvent:9/11

s = S log Kow + T (3)

where S and T are constants that characterizeeach cosolvent. Combining eqs. 2 and 3 gives:

log S/S0 = ~S log Kow + T!Ccosol (4)

which describes both the solvating-out of polarsolutes as well as the solvating-in of nonpolarsolutes.

Cosolvents and salts mix completely with wa-ter to form homogenous solutions, but with differ-ent effects. Cosolvents decrease the polarity of thewater and reduce the ability of the aqueous sys-tem to squeeze out nonpolar solutes, which re-sults in an increase of the solubility of nonelec-trolytes. On the other hand, salts decrease thesolubility of nonelectrolytes by increasing the po-larity of the water, thereby increasing the abilityof the aqueous system to squeeze out the non-polar solutes. It can be seen that eqs. 1 and 2describe a loglinear relationship between solutesolubility and the concentration of salt or cosol-vent, respectively. By analogy, Ksalt can be ex-pected to be correlated to log Kow by:

Ksalt = A log Kow + B (5)

where A and B are constants that characterizeeach salt. Combining eqs. 1 and 5 gives:

logS/S0 = - ~A log Kow + B! Csalt (6)

The objective of this investigation is to evaluatethe validity of the proposed eq. 5 in estimating the

Table 1. Log Kow and Experimental Ksalt Values forTested Compounds

Name Log Kow Ksalt Reference

Ethylbenzene 3.17 0.234 12Isopropylbenzene 3.57 0.316 121,2,4-Trimethylbenzene 3.59 0.293 121,2,3-Trimethylbenzene 3.54 0.321 121,3,5-Trimethylbenzene 3.64 0.318 12Sec-Butylbenzene 4.10 0.288 12Tert-Butylbenzene 3.97 0.243 121-Methylnaphthalene 3.81 0.200 121-Ethylnaphthalene 4.34 0.273 12Biphenyl 4.03 0.276 12Acenaphthene 3.77 0.238 12Fluorene 4.08 0.267 12Phenanthrene 4.49 0.272 12Anthracene 4.49 0.326 122-Methylanthracene 4.99 0.336 121-Ethylanthracene 5.52 0.313 12Pyrene 4.95 0.320 12Fluroanthene 4.95 0.339 12Chrysene 5.66 0.336 121,2-Benzanthracene 5.66 0.354 12Benzo[a]-Pyrene 6.12 0.328 12o-Dichlorobenzene 3.45 0.247 12n-Pentane 3.34 0.221 12n-Hexane 3.87 0.276 12Cyclopentane 2.79 0.182 12Cyclohexane 3.35 0.277 12Cycloheptane 3.91 0.343 12Methylcyclopentane 3.31 0.273 12Methylcyclohexane 3.87 0.274 12Phenol 1.47 0.111 12o-Nitrophenol 1.85 0.136 12m-Nitrophenol 1.85 0.147 12p-Nitrophenol 1.85 0.165 12p-Nitrotoluene 2.38 0.163 12p-Toluidine 1.41 0.170 12Benzoic acid 1.88 0.177 12o-Chlorobenzoic acid 2.00 0.182 12m-Chlorobenzoic acid 2.70 0.180 12o-Hydroxylbenzoic acid 2.19 0.172 12Phenylacetic acid 1.41 0.190 12n-Hexanol 1.88 0.232 12Cyclohexanone 0.86 0.202 12Acetone 0.21 0.110 12Ethylacetate 0.71 0.172 12Phenylthiourea 0.75 0.184 12Propanoic acid 0.33 0.132 6Butanoic acid 0.79 0.166 6Hexanoic acid 1.92 0.220 6Septanoic acid 2.45 0.242 6Acetic acid 0.17 0.064 6

EFFECT OF NaCl ON ORGANIC COMPOUNDS SOLUBILITY 1621

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 12, DECEMBER 2000

Setschenow constant of NaCl for different non-electrolyte solutes from their octanolwater par-tition coefficients.

EXPERIMENTAL SECTION

Materials

All chemicals were reagent grade , purchasedfrom Aldrich, and used as received.

Solubility Determination

The solubilities of phenytoin, theophylline, andcytosine were determined in different concentra-tions of NaCl in water. Excess amounts of eachdrug were added directly into the different con-centrations of NaCl solutions. Equilibrium wasreached by end-over-end rotation for a period of 3days at room temperature. The saturated solu-tions were filtered through 0.45-mm milliporemembranes and analyzed by Beckman DUt 640,UV-VIS spectrophotometry (theophylline at 220nm and cytosine at 256 nm) or by high-performance liquid chromatography (HPLC; phe-nytoin). All experimental values are the averageof duplicate runs with a relative standard devia-tion of

determined their log Kow values with ClogPt soft-ware. Figure 1 shows the correlation between thelogarithm of the calculated octanolwater parti-tion coefficient and the published Setschenowconstant in NaCl for the compounds listed inTable 1. This relationship is described by:

Ksalt = 0.039 log Kow + 0.117 ~n = 62, r = 0.9257!(7)

Both the slope and the intercept are specific forNaCl. Combining eqs. 1 and 7 gives:

log S/S0 = - ~0.039 log Kow + 0.117!Csalt (8)

Equation 8 and Figure 1 show that if the ClogPvalue of the solute is larger than zero, the Ksaltvalue will be positive and NaCl will decrease itssolubility in water. If the ClogP value of the soluteis much less than zero (i.e., < - (0.117/0.039), theKsalt value will be negative and NaCl will increaseits aqueous solubility.

Table 2 gives the octanolwater partition coef-ficients of the 12-solute test sets along with the

Table 3. Summary of Ksalt Values for 12 Test Compounds in NaCl Solution by Different Estimation Methodsa

Solute

Method

DMT CDST IPT SPD XIPT XMV Proposed

Benzene 0.217 0.154 0.423 0.186 0.163 0.173 0.200Toluene 0.259 0.176 0.505 0.205 0.187 0.213 0.220o-Xylene 0.293 0.194 0.573 0.215 0.207 0.253 0.237m-Xylene 0.299 0.198 0.584 0.220 0.210 0.253 0.239p-Xylene 0.300 0.198 0.586 0.221 0.210 0.253 0.239Naphthalene 0.270 0.182 0.529 0.173 0.194 0.266 0.246CB 0.236 0.170 0.483 0.220 0.181 0.211 0.2281,3-DCB 0.267 0.181 0.542 0.220 0.197 0.248 0.2561,4-DCB 0.278 0.184 0.542 0.224 0.197 0.248 0.2561,2,4-TCB 0.290 0.191 0.591 0.216 0.212 0.286 0.2792,4-DCP 0.275 0.165 0.551 0.150 0.200 0.261 0.2362,4,6-TCP 0.320 0.183 0.627 0.226 0.222 0.299 0.261

a References 7, 12, and 13.

Table 4. Summary of Calculated Percentage Errorsa for 12 Test Compounds by Different Estimation Methods

Solute

Method

DMT CDST IPT SPD XIPT XMV Proposed

Benzene 11.2 21.0 116.9 4.62 16.41 11.38 2.80Toluene 13.6 22.8 121.4 10.09 17.98 6.68 3.53o-Xylene 29.0 14.5 152.4 5.29 8.81 11.33 4.63m-Xylene 20.5 20.1 135.4 11.29 15.32 1.90 3.44p-Xylene 19.5 21.1 133.4 11.95 16.33 0.68 4.60Naphthalene 22.7 17.2 140.4 21.36 11.82 20.76 12.04CB 19.1 14.1 143.9 11.11 8.58 6.56 15.421,3-DCB 18.1 19.9 139.8 2.65 12.83 9.73 13.381,4-DCB 15.8 23.3 125.8 6.67 17.92 3.33 6.761,2,4-TCB 16.0 23.6 136.4 13.60 15.20 14.40 11.702,4-DCP 26.1 24.3 152.7 31.19 8.26 19.72 8.412,4,6-TCP 40.3 19.7 175.0 0.88 2.63 31.14 14.40Average errorb 21.0 20.1 139.5 10.89 12.68 11.47 8.43

a Percentage error 4 (predicated value experimental value) ? 100/experimental value.b Average error 4 sum (ABS(percentage error))/12.



observed Setschenow constant for sodium chlo-ride.

Table 3 shows the Setschenow Ksalt values pre-dicted by the aforementioned theories and the ex-perimental NaCl data on benzene, toluene, o-, m-,and p-xylenes, naphthalene, chlorobenzene (CB),1,3-dichlorobenzene (1,3-DCB), 1,4-dichloro-benzene (1,4-DCB), 1,2,4-trichlorobenzene (1,2,4-TCB), 2,4-dichlorophenol (2,4-DCP), and 2,4,6-trichlorophenol (2,4,6-TCP). The errors associ-ated with the calculation of the Setschenowconstants by the various methods are given inTable 4. The average errors predicted by theaforementioned theories are given in the last lineof the table. It is obvious that the proposedmethod is more accurate than the other theoreti-cal and empirical methods.

Table 5 shows the data we obtained experimen-tally for phenytoin, theophylline, and cytosine inNaCl solutions along with the data predicted bythe method of Xie and Mackay and by the pro-posed equation. (The theoretical methods werenot used because they require parameters thatcould not be unambiguously determined.) In the

case of cytosine, the negative Ksalt value of theexperimental result indicates a salting-in effect.But the Ksalt value is very small, showing thatthere is no significant effect of NaCl on the solu-bility of cytosine as we predicted. Table 5 showsthat our data are much more accurate than theXMV method because the XMV method is basedsolely on volume, which cannot explain the sol-utesolute and solventsolute interactions. So,the XMV method cannot be used to predict thesalting-in of polar compounds. Furthermore, itcannot be used to distinguish among isomers oramong homomorphs that have the same molarvolume, but different polarity.

Of the theories listed in Tables 3 and 4, eqs.68 are most comparable with scaled particletheory (SPT), which treats the activity coefficientof the nonelectrolyte as the sum of free energyterms for cavity formation and interaction be-tween the solute and solvent, like eqs. 24. SPTcan be used to explain how a cosolvent increasesthe solubility of an organic compound in water.Masterton and Lee applied the SPT to a system ofthree components, giving a very complicatedequation. Our method, also based on SPT, usesonly three simple coefficients (log Kow, A, and B)to more accurately predict the Ksalt value. Thepartition coefficient reflects the effect of the inter-action between the solute and water whereas theconstants A and B account for the effect of the salton the water.

CONCLUSIONS

A linear relationship between logarithm of oc-tanolwater partition coefficient, log Kow and Set-schenow constant, Ksalt, is proposed and appliedto 77 organic solutes. This relationship provides asimple and accurate method to predict the effectof NaCl on the aqueous solubility of organic com-pounds.

Figure 1. The Ksalt values of different compounds inNaCl solution versus their log Kow values.

Table 5. Ksalt Values for Three Test Compounds by Equation 7

Solute Experimental VLe Basa Log Kow XMV Proposed

Phenytoin 0.191 263.7 2.08 0.475 0.198Theophylline 0.100 169.4 0.06 0.298 0.115Cytosine 0.005 100.8 1.65 0.181 0.053

a The calculated Le Bas molar volume is based on ref 8.

1624 NI ET AL.


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estimation of the effect of nacl on the solubility of organic compounds in aqueous solutions

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