Interactions of amino acids and peptides with the drug pentoxifylline in aqueous solution at various temperatures: A volumetric approach

J. Chem. Thermodynamics 54 (2012) 288–292

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Interactions of amino acids and peptides with the drug pentoxifylline in aqueous solution at various temperatures: A volumetric approach Amalendu Pal ⇑, Nalin Chauhan Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India

a r t i c l e

i n f o

Article history: Received 19 January 2012 Received in revised form 3 May 2012 Accepted 8 May 2012 Available online 16 May 2012 Keywords: Amino acids Peptides Pentoxifylline, Partial molar volume

a b s t r a c t Pentoxifylline is used to improve blood flows through peripheral blood vessels. The density of three amino acids and two peptides (glycine, L-alanine, L-valine, glycylglycine, and glycylglycylglycine) are measured using DSA 5000 instrument at T = (293.15, 298.15, 303.15, and 308.15) K in aqueous solution of this compound. The apparent molar volume, (V/), partial molar volume, (V/0), transfer partial molar volume, (DV/0), and partial molar expansibility, (E20), thermal expansion coefficient, (a2), and Hepler’s constant, (o2V/0/oT)2 are calculated from the density data. The above parameters are used to interpret the solute–solute and solute–solvent interactions of amino acids/peptides in aqueous pentoxifylline solution. The dependence of these parameters upon concentration and temperature clearly suggest the role of amino acids/peptides and pentoxifylline in solute–solvent interactions. Ó 2012 Elsevier Ltd. All rights reserved.

Transfer properties Partial molar expansibility

1. Introduction Most biochemical processes occur in aqueous media; therefore, studies on the physicochemical properties of biomolecules like amino acids, peptides, sugars, and drugs in aqueous solution provide useful information which is important to understand the complex mechanism of molecular interactions [1]. Thermodynamic properties are very useful in understanding the ionic, hydrophilic, and hydrophobic interactions in different solutions media, as they provide convenient parameters for the elucidation of solute– solvent and solute–solute interactions in the solution phase [2]. Characterization of drugs in aqueous solutions has been a subject of interest because they exert their activity by interaction with biological membrane. Further, physicochemical properties of drugs are of interest to know during action at the molecular level. The action of a drug must be regarded as the vital outcome of physicochemical interactions between the drug and functionally important molecules in the living organism. But due to the complicated structure of proteins containing many miscellaneous functional groups, the study protein–drug interactions are somewhat difficult. Therefore, for a better understanding of the hydration behaviour of proteins, one useful approach is to study simpler model compounds such as amino acids and small peptides. From the literature survey we found that there are extensive studies of drugs in aqueous and aqueous additive solutions [3–9], but the study of amino acids ⇑ Corresponding author. Tel.: +91 1744 239765; fax: +91 1744 238277. E-mail address: [email protected] (A. Pal). 0021-9614/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jct.2012.05.009

and peptides in aqueous drug solution are scare [10,11]. Pentoxifylline (figure 1) is used to treat intermittent claudication resulting from obstructed arteries in the limbs, and vascular dementia [12]. It has also been used to treat nausea and headaches in the mountains (altitude sickness). Despite various explanations of the phenomenon, the role of this drug remains uncertain, we therefore planned to carry out the volumetric study of different amino acids/peptides in aqueous drug solution at different temperatures. The main goal of this study is to evaluate the effect of molality and temperature on the physico-chemical behaviour of this drug in the presence of amino acids/peptides. With that purpose, the density of pentoxifylline in aqueous solutions of glycine, L-alanine, L-valine, glycylglycine, glycylglycylglycine at different molalities (0.03 to 0.30) mol  kg1 and at different temperatures, T = (293.15, 298.15, 303.15, and 308. 15) K, are determined. A number of useful parameters namely, apparent molar volumes, partial molar volumes, partial molar volumes of transfer and partial molar expansions have been reported. We have also calculated the group contribution to transfer volume for different group at different temperatures. All these parameters are discussed in terms of various interactions occurring in these solutions. 2. Experimental The following materials were used (source in parentheses): glycine (AR Grade, S.D. Fine-Chemicals, Mumbai); L-alanine, L-valine (mass fraction > 0.99, HiMedia, Mumbai); glycylglycine (G 1002, Sigma Chemicals Co); glycylglycylglycine (G 1377, Sigma Chemi-

A. Pal, N. Chauhan / J. Chem. Thermodynamics 54 (2012) 288–292

O

O N

N

O

N

N

FIGURE 1. Structure of pentoxifylline drug.

cals Co.) and Pentoxifylline (mass fraction > 0.99, HiMedia, Mumbai). All the chemicals were used as such without further purification (See table 1). Before use, these were dried for 72 h under reduced pressure at T = 298.15 K and then stored over P2O5 in desiccators. Doubly distilled deionized water which has been freshly degassed was used for the preparation of the aqueous solutions. Stock solutions of drug (approximate: 0.1 mol  kg1) were prepared by mass on the molality concentration scale. Solutions of glycine, L-alanine, L-valine, and glycylglycine (0.05 to 0.30) mol  kg1 and of glycylglycylglycine (0.03 to 0.10) mol  kg1 were made by mass on the molality concentration scale with an accuracy of ±1  105. The weighing were done on an A&D Company, Limited electronic balance (Japan, Model GR-202) with a precision of ±0.01 mg. The uncertainties in the solution molalities were in the range ±2  105 mol  kg1. All solutions were prepared afresh before used. Solution densities were measured simultaneously and automatically, using an Anton Paar DSA 5000 instrument that was precalibrated with doubly distilled deionized water and dry air for the temperature range investigated. Density is extremely sensitive to temperature, so it is controlled to ±1  102 K by a built- in-solid state thermostat. The sensitivity of the instrument corresponded to a precision in density measurements of ±1  106 g  cm3. The reproducibility of density was found to be better than ±5  106 g  cm3.(See table 2). 3. Results and discussion

289

The V/ value is sensitive to solute–solvent interactions occurring in the solution. The variation of V/ is found to be linearly dependent on the molality, mA in the concentration range studied, in all the cases with a positive slope (except for glycylglycylglycine at T = 308.15 K). A sample plot for glycine in 0.1 mol  kg1(approximate) of drug solutions at different temperatures is shown in figure 2. A similar plot of all the amino acids/peptides in 0.1 mol  kg1 (approximate) of drug solutions at T = 298.15 K are shown in figure 3. Figures 2 and 3 show that, the apparent molar volume, V/ increases with increase in the molality of the amino acids/peptides. This indicates that the solute–solvent interactions are increasing with increase in the amount of amino acids/peptides in the aqueous drug solution. This also suggests that, as the concentration of amino acids/peptides is increased, there is a significant decrease in the amount of bound drug. This type of binding appears to involve unusual and complex mechanism. For the/ dilute solutions used in the present study, the variation of V/ with molality can be represented by the following equation:

V / ¼ V 0/ þ SV ; m

ð2Þ

V/0

where is the limiting value of partial molar volume (i.e. apparent molar volume at infinite dilution) and SV is the experimental slope indicative of solute–solute interactions. The observed value of apparent molar volume at infinite dilution and their experimental slope are given in table 3 along with standard errors of the fit for equation (2). The partial molar volumes of a solute at infinite dilution, V/0 reflect the effects of solute–solvent interactions [13]. Table 3 shows that the V/0 values increase with increase in temperature for all the amino acids and peptides in aqueous drug solution. It indicates that solute /cosolute–solvent interactions are increasing with increase in temperature. The V/0 results of all the amino acids/peptides in water show that for each amino acids/peptide, at any particular temperature, in general, V/0 decreases except with glycylglycylglycine as evident from table 3. It indicates that, at any particular temperature, the solute amino acids/glycylglycine– solvent interactions decrease in presence of drug solution. Further, V/0 increases with increase in the molar mass and hydrophobicity of the alkyl side chain of the amino acids. The V/0 values increase in the order:

3.1. Partial molar volumes The values of the density of the amino acids and peptides (glycine, L-alanine, L-valine, glycylglycine, and glycylglycylglycine) in aqueous solutions of pentoxifylline (approximate: 0.1 mol  kg1) measured using DSA 5000 instrument at T = (293.15, 298.15, 303.15, and 308.15) K are given in table 2. From these values, the apparent molar volume V/ of theamino acids and peptides in water and in pentoxifylline solutions, (mB = approximate: 0.1 mol  kg1), where mB is the molality of pentoxifylline at temperatures T = (293.15, 298.15, 303.15, and 308.15) K, have been determined from the experimentally measured densities using the following equation:

V / ¼ ðM=qÞ  f1000ðq  q0 Þ=mA q; q0 g;

ð1Þ

where M amd mA are the molar mass and molality of the solute, that is, amino acids/peptides in solutions, and q0, and q are the densities of pure solvent and solution, respectively. TABLE 1 List of chemicals, their provenance and purity values. Chemical

Provenance

Purity

Glycine L-alanine, L-valine

S.D. Fine-Chemicals, Mumbai HiMedia, Mumbai

AR Grade Mass fraction > 0.99

Glycylglycine Glycylglycylglycine Pentoxifylline

Sigma Chemicals Co Sigma Chemicals Co HiMedia, Mumbai

G 1002 G 1377 Mass fraction > 0.99

glycylglycylglycine > L-valine > glycylglycine > Lalanine > glycine A similar increase in the value of V/0 has been observed by many authors [14,15]. The SV value obtained by least square fitting of equation (2) is influenced by a number of effects [16] and also these values are not statistically significant. The V/0 values in water and in aqueous drug solutions have been used to calculate /the partial molar volume of transfer at infinite dilution using equation:

DV 0/ ¼ V 0/ ðamino acids=peptides in aqueous drug solutionÞ  V 0/ ðamino acids=peptides in waterÞ:

ð3Þ

The resultant values of DV/0 are given in table 4 and are illustrated in figures 4 and 5. The V/0 of amino acids/peptides in water at T = (293.15, 298.15, 303.15 and 308.15) K were taken from the literatures [17–19]. The various group contributions have also been calculated from the difference in DV/0 values of the homologous series of amino acids and are reported in table 5. The DV/0 of a peptide backbone unit (–CH2CONH–)n from water to aqueous drug solution reported in table 5, have been calculated from the difference in the DV/0 values of successive glycine oligopeptides. It can be seen from table 5 that DV/0 for the peptide backbone unit (–CH2CONH–) is positive except at T = 298.15 K and the

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A. Pal, N. Chauhan / J. Chem. Thermodynamics 54 (2012) 288–292

44.2

TABLE 2 The density (q/kg  m3) of amino acids and peptides in aqueous drug solutions as a function of concentrations of amino acids/peptides from T = (293.15 to 308.15) K T = 303.15 K

T = 308.15 K

q  103/

q  103 / (kg  m3)

q  103/

q  103/

(kg  m3)

(kg  m3)

(kg  m3)

1

0 0.0613 0.1079 0.1565 0.21 0.2492 0.2939

Glycine in aqueous drug solutions, mB = 0.09736 mol  kg 1.003773 1.0025 1.001023 0.999319 1.005737 1.0045 1.002945 1.001231 1.007218 1.0059 1.004396 1.002673 1.008744 1.0074 1.005895 1.004163 1.010413 1.0091 1.007533 1.005788 1.011627 1.0103 1.008727 1.006971 1.012992 1.0116 1.01007 1.008306 L-alanine

0 0.0631 0.105 0.1516 0.2013 0.2351 0.3023

in aqueous 1.003813 1.005625 1.006818 1.008136 1.009526 1.010465 1.012326

44.0

43.8 -1

T = 298.15 K

drug solutions, mB = 0.09842 mol  kg1 1.0026 1.001058 0.999356 1.0043 1.002839 1.001127 1.0055 1.004012 1.002293 1.0068 1.005308 1.003582 1.0082 1.00668 1.004949 1.0091 1.007607 1.005871 1.011 1.009438 1.007691

in aqueous drug, mB = 0.09760 mol  kg1 0 1.003775 1.0025 1.001021 0.999320 0.049 1.005074 1.0038 1.002295 1.000585 0.0936 1.006244 1.005 1.003443 1.001725 0.1454 1.007586 1.0063 1.004759 1.003031 0.201 1.009002 1.0077 1.006146 1.004410 0.2506 1.010252 1.0089 1.007372 1.005626 0.2711 1.010762 1.0094 1.007873 1.006125 Glycylglycine in aqueous drug solutions, mB = 0.10119 mol  kg1 0 1.003967 1.0027 1.001211 0.999508 0.0555 1.007078 1.0058 1.004270 1.002548 0.1047 1.009794 1.0085 1.006948 1.005210 0.1508 1.012317 1.011 1.009427 1.007673 0.1931 1.014608 1.0132 1.011676 1.009909 0.2631 1.018306 1.0169 1.015336 1.013551 0.2901 1.019745 1.0183 1.016742 1.014947 Glycylglycylglycine in aqueous drug solutions mB = 0.09851 mol  kg1 0.00000 1.003834 1.0026 1.001081 0.999381 0.05550 1.007026 1.0057 1.00422 1.002497 0.10469 1.007732 1.0064 1.004916 1.003195 0.15076 1.008434 1.0071 1.005607 1.003889 0.19310 1.009372 1.0081 1.006533 1.004820 0.26310 1.01014 1.0088 1.007291 1.005584 0.29012 1.010173 1.0088 1.007324 1.005618

43.6

3

T = 293.15 K

6

m A/ (mol  kg1)

Vφ x 10 / m mol

a

43.4

43.2

43.0

42.8

0.05

0.10

0.15

0.20

mA/ mol kg

0.25

0.30

-1

L-valine

a m stands for the molalities of peptide in aqueous and aqueous solutions of glucose which represents that the solutions of amino acids/peptide in water and (water + drug) were prepared on the molal basis (i.e. no. of moles of amino acids/ peptides dissolved in 1000 g of the aqueous and aqueous solution of drug). Subscripts A stands for amino acid/peptides and B stands for the pentoxifylline drug. The mA is the molality of the amino acids/peptides in aqueous drug solution and mB is the molality of solvent (i.e. aqueous drug solution). Uncertainty in the values of molality and density are ±2  105 mol  kg1 and ±5106 g  cm3, respectively.

contribution of methylene group is large. Therefore, it may be concluded that the positive contribution of –CH2– to DV/0 in (– CH2CONH–) is greater than the contribution of –CONH– to DV/0. The less positive DV/0 of the –CONH– group can be rationalized in terms of a reduction in the hydrogen bonding interactions with water as a result of its interaction with the aqueous drug solution. The observed DV/0 of amino acids and peptides from water to 0.1 mol  kg1 (approximate) aqueous drug solution are in the following order: (i) L-alanine > glycine > L-valine, and (ii) glycylglycylglycine > glycylglycine > glycine

FIGURE 2. Apparent molar volumes V/, as a function of molality mA of glycine in 0.1 mol  kg1 of pentoxifylline drug at T = h, 293.15 K; s, 298.15 K; D, 303.15 K;r, 308.15 K.

90

70

6

3

Vφ x 10 / m mol

-1

80

60

50

40 0.05

0.10

0.15

0.20

mA / mol kg

0.25

0.30

-1

FIGURE 3. Apparent molar volumes V/, as a function of molality mA of amino acids/ peptides in 0.1 mol  kg1 of pentoxifylline drug at T = 298.15 K: h, glycine; s, glycylglycine; D, L-alanine; r, L-valine.

the drug leads to a reduction in the volume of transfer. The observed higher values of DV/0 of glycylglycylglycine than glycylglycine in 0.1 mol  kg1 (approximate) aqueous drug solution are due to the release of more number of water molecules from glycylgycylglycine due to domination of ionic-hydrophilic and ionic– hydrophobic interactions. The observed increase in DV/0 values for glycylglycylglycine in 0.1 mol  kg1 (approximate) aqueous drug solution with an increase of temperature may be attributed to the corresponding decrease in the number of electrostricted water molecules. 3.2. Partial molar expansions

The lower values of DV/0 of the amino acid L-valine from water to 0.1 mol  kg1 (approximate) aqueous drug solution as compared to glycine and L-alanine (table 4) is due to the –CH(CH3)2 group. Increased hydrophobic–hydrophobic interactions between the hydrophobic group of L-valine and the hydrophobic group of

The temperature dependence of V/0 can be represented by the equation:

V 0/ ¼ a þ bðT  T m Þ þ cðT  T m Þ2 ;

ð4Þ

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A. Pal, N. Chauhan / J. Chem. Thermodynamics 54 (2012) 288–292

TABLE 3 The apparent molar volume at infinite dilution (V/0/m3  mol1) and experimental slope (SV/m3  L1/2  mol3/2) of amino acids and peptides in aqueous drug solutions from T = (293.15 to 308.15) K. Amino acid/peptide

T = 293.15 K

298.15 K

303.15 K

308.15 K

293.15 K

V/0  106/(m3  mol1) Glycine in water

42.90 (±0.01) [17] 42.80 (±0.005) 59.97 (±0.004) [17] 60.09 (±0.01) 90.54 (±0.004) [17] 90.19 (±0.003) 75.59 [18]

Glycine L-alanine

in water

L-alanine L-valin

in water

L-valine

Glycylglycine in water

Glycylglycine

43.24 (±0.01) [17] 43.19 (±0.005) 60.36 (±0.02) [17] 60.39 (±0.01) 90.87 (±0.004) [17] 90.56 (±0.01) 76.22 (±0.01) [18] 76.13 (±0.02) 111.56 (±0.04) [19] 111.84 (±0.01)

75.58 (±0.04) 110.76 (±0.04) [19] 111.21 (±0.03)

Glycylglycylglycine in water

Glycylglycylglycine

298.15 K

303.15 K

308.15 K

SV  106/(m3  L1/2  mol3/2) 43.66 (±0.004) [17] 43.53 (±0.003) 60.69 (±0.005) [17] 60.69 (±0.003) 91.22 (±0.004) [17] 90.88 (±0.005) 76.62 [18]

43.88 (±0.004) [17] 43.70 (±0.003) 60.97 (±0.03) [17] 60.91 (±0.003) 91.48 (±0.004) [17] 91.18 (±0.003) 77.04 (±0.02) [18]

76.57 (±0.02) 112.27 (±0.03) [19] 112.72 (±0.04)

1.53 (±0.02)

1.35 (±0.03)

1.15 (±0.02)

1.37 (±0.02)

0.72 (±0.05)

0.69 (±0.03)

0.46 (±0.01)

0.38 (±0.01)

1.11 (±0.01)

1.03 (±0.04)

1.11 (±0.02)

1.08 (±0.01)

76.96 (±0.01) 112.64 (±0.04) [19]

3.02 (±0.21)

2.78 (±0.12)

2.74 (±0.09)

2.60 (±0.07)

113.75 (±0.002)

11.65 (±0.45)

14.87 (±0.23)

8.6 (±0.68)

2.18 (±0.03)

TABLE 4 Transfer partial molar volume (DV/0/m3  mol1) and limiting partial molar expansions (E20/m3  mol1  K1) of amino acids and peptides in aqueous drug solutions from T = (293.15 to 308.15) K. Amino acid/peptide

T = 293.15 K

298.15 K

303.15 K

308.15 K

293.15 K

DV/0  106/(m3  mol1) Glycine

298.15 K

303.15 K

308.15 K

E20  106/(m3  mol1  K1)

L-alanine

0.10 0.12

0.05 0.03

0.13 0.00

0.18 0.06

0.094 0.067

0.072 0.059

0.050 0.051

0.028 0.043

L-Valine

0.35

0.31

0.34

0.30

0.076

0.069

0.062

0.055

Glycylglycine Glycylglycylglycine

0.01 0.45

0.09 0.28

0.05 0.45

0.08 1.110

0.116 0.110

0.100 0.150

0.084 0.190

0.068 0.230

1.2 0.1

1.0

0.8

ΔVφ x 10 / m mol

0.6

6

3

-0.1

6

3

ΔVφ x 10 / m mol

-1

-1

0.0

0.4

0

0

-0.2

-0.3

0.2

0.0

-0.2

-0.4 292

294

296

298

300

302

304

306

308

310

T/K FIGURE 4. Plots of partial molar volume of transfer at infinite dilution of amino acids in aqueous drug solutions at different temperatures: h, glycine; s, L-alanine; D, L-valine.

292

294

296

298

300

302

304

306

308

310

T/K FIGURE 5. Plots of partial molar volume of transfer at infinite dilution of amino acid and peptides in aqueous drug solutions at different temperatures: h, glycine; s, glycylglycine; D, glycylglycylglycine.

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A. Pal, N. Chauhan / J. Chem. Thermodynamics 54 (2012) 288–292

TABLE 5 Group contribution to transfer volumes from T = (293.15 to 308.15) K.

a b c d

Group

Water ? 0.1 mol  kg1 drug solution

–CH2–a (CH3)2C–b –NH–CO–CH2–c (–NH–CO–CH2–)2d

T = 293.15 K 0.22 0.25 0.09 0.55

298.15 K 0.08 0.26 0.04 0.33

303.15 K 0.13 0.21 0.08 0.58

308.15 K 0.12 0.12 0.10 1.29

Ala-gly. Val-gly. Digly-gly. Trigly-gly.

a2 ¼ 1=V 0/ ½@V 0/ =@T:

TABLE 6 Coefficients of equation 4 for the amino acids and peptides in aqueous drug solution. Amino acid/ peptide

a/ (m3  mol1)

b/ (m3  mol1  K1)

c/ (m3  mol1  K2)

Glycine

43.37 (±0.02)

0.0608 (±0.0024)

L-alanine

60.54 (±0.01)

0.0552 (±0.0016)

L-valine

90.72 (±0.005) 76.36 (±0.01)

0.0658 (±0.0006)

112.25 (±0.02)

0.1700 (±0.002)

0.0022 (±0.0005) 0.0008 (±0.0003) 0.0007 (±0.0001) 0.0016 (±0.0003) 0.0040 (±0.0005)

Glycylglycine Glycylglycylglycine

0.0916 (±0.0012)

(o2V0/oT2)P/ (m6  mol2  K2)

a2/K

L-alanine

T = 293.15 K 298.15 K 303.15 K 308.15 K 0.00220 0.00167 0.00115 0.00064 0.0044 0.00111 0.00098 0.00084 0.00071 0.0016

L-valine

0.00085

0.00076 0.00068 0.00060 0.0014

Glycylglycine 0.00153 Glycylglycylglycine 0.00099

0.00131 0.00110 0.00036 0.0032 0.00134 0.00169 0.00202 0.0080

Glycine

ð6Þ

The calculated values of a2 are included in table 7. The highest value of a2 is obtained in glycine among amino acids and in glycylglycylglycine among peptides. The a2 values decrease with an increase in temperature except with glycylglycylglycine indicating that amino acids/peptides–water binding is weakened. Further, the values of E20 and a2 are higher in glycylglycylglycine than for glycine owing to the greater molar mass of glycylglycylglycine. 4. Conclusions

TABLE 7 Values of (o2V0/o T2)P, and a2 of amino acids and peptides in aqueous drug solution from T = (293.15 to 308.15) K. Amino acids/ peptides

of table 7 reveals that positive (o2V/0/oT2) values are associated with the structure-making nature of the glycylglycylglycine molecule in 0.1 mol  kg1 drug solution because of the increase of molar mass. Negative values of (o2V/0/oT2) associated with the structure-breaking solutes are observed for other amino acids/glycylglycine. This feature is similar to that observed for sulpha drugs in aqueous solution of sodium chloride [4] and glycine [22]. The isobaric thermal expansion coefficient a2 is calculated using the following equation:

In this paper, we have presented the volumetric properties of amino acids/peptides in aqueous drug solution at different temperatures. The partial molar volume values are positive in aqueous drug solution, indicating the presence of strong solute–solvent interactions. The increasing negative values of transfer partial molar volume from glycine to L-alanine, indicates the strengthening of hydrophobic–hydrophobic interactions due to the increase in the alkyl chain length of amino acids. The positive contribution of transfer partial molar volume from glycine to glycylglycylglycine shows greater interaction between the peptides and drug molecules in aqueous solution. Acknowledgement

where Tm represents the midpoint temperature of the range used (Tm = 300.65 K), was fitted to the V/0 data using a leastsquares procedure. The polynomial coefficients of equation (4), together with their uncertainties obtained from the least-squares analysis, are given in table 6. Differentiation of equation (4) with respect to temperature at constant pressure gives/

E02 ¼ ð@V 0/ =@TÞP ¼ b þ 2cðT  T m Þ:

ð5Þ E20,

The partial molar isobaric expansion at infinite dilution, derived from the polynomial coefficients are given in table 4. The E20 values for any solute ought to be a sensitive measure of solute–solvent interaction. It can be seen from table 4 that partial molar expansion, E20 values decrease with increase in the temperature (except for glycylglycylglycine) in aqueous drug solution. Furthermore, the E20 values are positive for amino acids/peptides in aqueous drug solution, which again indicates the presence of solute– solvent interactions in the ternary mixture of the present study as reflected by the partial molar volume data. This may be due to the release of electrostricted water from the loose solvation layers of the amino acids/peptide that is, the predominance of hydrophobic hydration over the ele/ctrostriction of water molecules around the solute amino acids/peptide molecules. Qualitative information on the hydration of the solute molecules can be obtained from the values of the Hepler’s constant (o2V/0/oT2) [20,21]. The (o2V/0/oT2) values calculated from equation (5) are given in table 7. Inspection

Financial support for this project (sanction letter no.01 (2187)/ 07/EMR –II) by the Government of India through the Council of Scientific and Industrial Research (CSIR), New Delhi is gratefully acknowledged. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]

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JCT-12-26