Volumetric, acoustic and viscometric studies of l -histidine in aqueous solutions of non-steroid anti-inflammatory drug ketorolac tromethamine at different temperatures

Accepted Manuscript Volumetric, acoustic and viscometric studies of l-histidine in aqueous solutions of non-steroid anti-inflammatory drug ketorolac tromethamine at different temperatures

Mukesh Kumar, Neha Sawhney, Amit K. Sharma, Meena Sharma PII: DOI: Reference:

S0167-7322(17)31995-5 doi: 10.1016/j.molliq.2017.08.001 MOLLIQ 7709

To appear in:

Journal of Molecular Liquids

Received date: Revised date: Accepted date:

7 May 2017 31 July 2017 1 August 2017

Please cite this article as: Mukesh Kumar, Neha Sawhney, Amit K. Sharma, Meena Sharma , Volumetric, acoustic and viscometric studies of l-histidine in aqueous solutions of non-steroid anti-inflammatory drug ketorolac tromethamine at different temperatures, Journal of Molecular Liquids (2017), doi: 10.1016/j.molliq.2017.08.001

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ACCEPTED MANUSCRIPT Volumetric, acoustic and viscometric studies of L-Histidine in aqueous solutions of nonsteroid anti-inflammatory drug ketorolac tromethamine at different temperatures. Mukesh Kumar, Neha Sawhney, Amit K Sharma and Meena Sharma* Email. [email protected] Department of Chemistry, University of Jammu, Jammu-180006, India

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Abstract

In this investigation density, speed of sound and viscosity of L-Histidine (0.015-0.135) mol

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kg-1 in aqueous ketorolac tromethamine solutions (0.1-0.7) mol kg-1 at various temperatures

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(293.15, 298.15, 303.15, 308.15 and 308.15) K and at atmospheric pressure were studied. These data were further used to calculate apparent molar volume, VΦ, limiting apparent molar

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volume, VoΦ, limiting apparent molar volume of transfer, VoΦ,tr, apparent molar isentropic compression, KΦ,S, limiting molar isentropic compression, KoΦ,S, limiting apparent molar isentropic compression of transfer, KoΦ,S,tr, hydration number, nH, Jones-Dole coefficient-B,

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B, viscosity B-coefficients of transfer, Btr and the activation parameters, o#1 and o#2. The results obtained from all these thermodynamic parameters were discussed in terms of solute-

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the transition state theory.

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solute interactions and solute-solvent interactions on the basis of co-sphere overlap model and

Keywords

Apparent molar volume, apparent molar isentropic compression, transfer properties, viscosity

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1. Introduction

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B-coefficient, activation parameters.

Non-steroidal anti-inflammatory drugs are frequently known as NSAIDs show antipyretic, anti-inflammatory, analgesic, antithrombotic and platelet inhibitory properties [1]. The clotting of blood vessels is usually inhibited by NSAIDs and thus helps in the prevention of colon cancer and heart attack [2]. Structure of ketorolac tromethamine is related to indomethacin is a member of the 5-membered hetero-aryl acetic acid non-selective group of cyclo-oxygenase inhibitors [3]. Drugs that enter the human body have a tendency to excite certain receptors, ion channels and act on enzymes or transport proteins. Drugs interact with receptors by bonding at specific binding sites. Most receptors in human body are made up of

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ACCEPTED MANUSCRIPT proteins and due to the complex nature of proteins, drugs can therefore interact with the amino acids to change the conformation of the receptor proteins [4]. Thus in order to understand the nature of molecular interactions of drugs in aqueous solutions by using thermodynamic studies, a lot of experimental work has been carried out by many researchers, as drugs involve the interaction with biological membrane [5,6]. Due to existence of variety of functional groups present in proteins, their interactions in aqueous solutions are

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difficult to study. Thus in order to understand drug-protein interactions in aqueous and in mixed-aqueous solutions, a useful approach is to study interactions of low molecular weight model compounds of proteins such as amino acids, peptides and their derivatives [7-9].

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The physico-chemical and rheological properties of amino acids in aqueous solutions are very

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helpful to understand the type of interactions i.e. solute-solute and solute-solvent interactions in these systems. The stabilization of native conformation of proteins is associated with these

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types of molecular interactions [10-14]. Thus, study of drug-protein interactions develop into an imperative concern for drug development and its efficacy [15]. Since L-histidine is an essential amino-acid and has many vital functions within the body and

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is involved in the synthesis of haemoglobin, tissue repair and strengthening of immune system therefore a systematic study of its interactions with drugs should be done.

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Although different researchers have studied the physicochemical and thermodynamic studies of amino acids in aqueous-drug solutions but so far to best of our knowledge no volumetric,

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acoustic and rheological studies of L-Histidine (basic amino acid) in aqueous ketorolac tromethamine solution have been reported [16-18]. Thus we decided to work on volumetric, acoustic and rheological studies of L-Histidine in aqueous solution of NSAID ketorolac

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tromethamine at a wide range of temperatures and concentrations for better understanding about the type of interactions present in these systems.

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2. Experimental

2.1. Materials and methods L-Histidine (Sigma Aldrich, India, mass fraction >0.99) and drug ketorolac tromethamine (Ranbaxy laboratories Ltd., mass fraction >0.99) were dried in vacuum over P2O5 in desiccators at room temperature for 48 hours. The deionised distilled water having specific conductance <1  10-6 S cm-1 was used for the preparation of solutions. The weighing of samples was done on an electronic single pan five digit analytic balance (Mettler Toledo, Model: ML204) with an uncertainty of 0.01 mg. The density of the prepared solutions was measured by using U-tube densimeter (Anton Paar DMA 5000M, Austria) with an uncertainty

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ACCEPTED MANUSCRIPT of 0.150 kg m-3 and the temperature was automatically kept constant with its built in thermostat with in 0.003 K. The speed of sound in solutions were measured using single-crystal variable path multifrequency ultrasonic interferometer (Model: M-82S, Mittal enterprises, India) which is made up of stainless steel sample cell with digital micrometer functioning at fixed frequency of 6 MHz. The uncertainty in speed of sound measurements was found to be 0.5 m s-1. The

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temperature was maintained to a precision of 0.01 K using an electronic controlled thermostatic water bath (Model: TIC-4000N, Thermotech, India).

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The viscosity measurement of solutions was done by using an Ubbelohde type suspended level viscometer. The viscometer containing test liquid was vertically immersed in

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thermostatic water bath for 45 minutes so that thermal fluctuation in viscometer was minimized. The viscometer was calibrated with deionised distilled water at different

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temperatures (293.15-313.15 K). The efflux time of solutions were recorded three times with digital stop watch with an accuracy of 0.01 s. The average of three sets of flow time for each

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solution was considered as the final efflux time for each sample and can be used for calculation of viscosity. The accuracy in viscosity measurements was found to be 0.01 mPa s. Table 1

Source

name L-Histidine

Mass fraction

Structure

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Chemical

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Provenance and purity of chemical samples studied

purity

Sigma

>0.99

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Aldrich, India

Ranbaxy

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Ketorolac

tromethamine

>0.99

laboratories Ltd.

3. Results and discussion The experimental determined values of density, ρ and speed of sound, u of L-Histidine solutions in water and in aqueous ketorolac tromethamine (0.01, 0.04 and 0.07 mol kg-1) as a function of L-Histidine concentration and temperature are reported in Table S1. Fig. 1(a) and 3

ACCEPTED MANUSCRIPT 1(b) show comparison of experimental density data and speed of sound data of L-histidine in water with available literature data at different temperatures, respectively. Fig. 2 shows representative 3D-plot of density, ρ versus (a): molality, m of L-Histidine and (b): molality, mket of ketorolac tromethamine in water as a function of temperature which reveals that the density increases with molality of L-histidine but decreases with increasing temperature.

a

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1004 1003 1002

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1001

999

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 /kg m

3

1000

998 997

995 0.02

0.04

0.06

0.08 -1

1532

1524

1516

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u /m s

-1

1520

1512 1508

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1504

1496

b

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1528

1500

0.12

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m /mol kg

0.10

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994 0.00

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996

0.00

0.02

0.04

0.06

0.08

0.10

0.12

-1

m /mol kg

Fig. 1. (a) Comparison of experimental density data of L-histidine in water with available literature data at temperatures, T/K =∎ 298.15 (present work); work);

298.15, Ref [19];

303.15 (present work);

303.15, Ref [19]; 303.15, Ref [20];

308.15 (present

308.15, Ref [19].

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ACCEPTED MANUSCRIPT (b) Comparison of experimental speed of sound data of L-histidine in water with available literature data at temperatures, T/K =∎ 298.15 (present work); work);

298.15, Ref [19];

303.15, Ref [19];

303.15 (present work);

308.15 (present

308.15, Ref [19].

3.1. Volumetric studies By using experimentally determined values of density, ρ, the apparent molar volume, VΦ, is

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calculated using equation: (1)

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where, M denotes the molecular mass (kg mol-1) of solute, ρ and ρo are densities (kg m-3) of pure solution and solvent (aqueous ketorolac tromethamine), respectively and m denotes

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molality (mol kg-1) of solute. The data obtained by using equation 1 for the investigated systems are reported in Table S2 (supplementary file). The linear variation of apparent molar

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volume against molal concentration of L-Histidine in water as well as in aqueous ketorolac tromethamine solutions at different concentrations and at different temperatures are shown in

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Fig. 3.

Fig. 2. Plot of density, ρ, versus (a): molality, m, of L-Histidine and (b): molality, mket, of ketorolac tromethamine in water as a function of temperature.

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ACCEPTED MANUSCRIPT

Fig. 3. Plot of apparent molar volume, VΦ, versus molality, m of (a) L-Histidine in water, (b) L-

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Histidine in 0.01 mol kg-1 aqueous ketorolac tromethamine, (c) L-Histidine in 0.04 mol kg-1 aqueous temperatures: ∎ 293.15 K,

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ketorolac tromethamine, (d) L-Histidine in 0.07 mol kg-1 aqueous ketorolac tromethamine at 298.15 K,

303.15 K,

308.15 K and

313.15 K.

(2)

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equation [21]:

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The limiting apparent molar volume, VoΦ, is obtained from linear Redlich-Meyer type

where, slope, Sv, is the characteristics of interactions between solute molecules and intercept, VoΦ, (obtained through least square fitting) shows existence of solute-solvent interactions. The values of VoΦ, slope, Sv, along with standard deviation, , for L-Histidine in water and in aqueous ketorolac tromethamine solutions over a range of temperatures are reported in Table S3. The values of VoΦ of L-Histidine in water at temperatures are found to be in closed agreement with those obtained from literature [19]. Clearly, from Table S3 the values of VoΦ are positive implying the existence of strong solute-solvent interactions in the system. The VoΦ values also increases with increase in temperature. This increase in VoΦ values with temperature can be explained by considering the size of primary and secondary solvation 6

ACCEPTED MANUSCRIPT layers around zwitterions of L-Histidine in aqueous ketorolac tromethamine. At higher temperatures, the solvent molecules from the secondary solvation layers of L-histidine zwitterions are released into the bulk of the solvent, rather than binding to the charged end groups which result expansion of the solution. Fig. 4 clearly indicates the larger VoΦ values at

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higher temperatures [22-23].

Fig. 4. Plot of limiting apparent molar volume, VoΦ, versus molality, mket, of ketorolac tromethamine

303.15 K,

308.15 K and

313.15 K.

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3.2. Compressibility studies

298.15

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K,

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for L-Histidine in (water + ketorolac tromethamine) solutions at temperatures: ∎ 293.15 K,

By using experimentally determined values of speed of sound the apparent molar isentropic compression, KΦ,S, is calculated using equation:

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(3)

where, ks and koS are isentropic compressibilities of solution and solvent (aqueous ketorolac

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tromethamine), respectively.

The isentropic compressibility, kS, is calculated by using equation: (4) The kS values obtained by using equation (4) for L-Histidine in water and in aqueous ketorolac tromethamine solutions are reported in Table S4 (supplementary file). The kS values decreases with increase in concentrations of L-Histidine in water and in aqueous ketorolac tromethamine solutions as well as with increase in temperature (Fig. 5).

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Fig. 5. Plot of isentropic compressibility, kS, vsersus (a): molality, m, of L-Histidine and (b): molality, mket, of ketorolac tromethamine in water as a function of temperature.

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The data obtained by using equation 3 is reported in Table S2, the KΦ,S values are negative at all concentrations and at all temperatures. The negative KΦ,S values indicates that water

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molecules in the bulk solution are more compressible than the water molecules around the ionic charged group of L-Histidine. This indicates the existence of strong solute-solvent

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interactions between ions of drug and amino acid in this system. Fig. 6 shows the linear variation of KΦ,S against molal concentration of L-Histidine in water as well as in aqueous

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ketorolac tromethamine solutions at different concentrations and at different temperatures.

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ACCEPTED MANUSCRIPT

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Fig. 6. Plot of apparent molar isentropic compression, KΦ,S, versus molality, m, of L-Histidine in water and in ketorolac tromethamine + water solutions: (a) L-Histidine in water, (b) L-Histidine in 0.01 mol

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kg-1 aqueous ketorolac tromethamine, (c) L-Histidine in 0.04 mol kg-1 aqueous ketorolac tromethamine, (d) L-Histidine in 0.07 mol kg-1 aqueous ketorolac tromethamine at temperatures: ∎ 298.15 K,

303.15 K,

308.15 K and

313.15 K.

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293.15 K,

The limiting apparent molar isentropic compression, KoΦ,S, and slope, Sk, is obtained by using

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following equation:

(5)

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where, slope, Sk, gives information regarding solute-solute interactions and the intercept,

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KoΦ,S, measures solute-solvent interactions. The values of KoΦ,S, slope, Sk along with standard deviation, , for L-Histidine in water and in aqueous ketorolac tromethamine solutions over a range of temperatures are reported in Table S3. The KoΦ,S values for L-Histidine in water and

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in aqueous ketorolac tromethamine solutions are negative and the values become less negative with the increase in concentration of ketorolac tromethamine as well as temperature (Fig. 7).

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The KoΦ,S values becomes less negative (i.e. increases) which shows the existence of strong solute-solvent interactions and the positive Sk values results weak solute-solute interactions in these systems. With the rise in temperature the KoΦ,S values increases, which explains that as temperature increases the electrostriction reduces and as a result of this some water molecules released into the bulk, thus making solution more compressible. These results obtained from compressibility studies are in accordance with the results obtained from volumetric studies.

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ACCEPTED MANUSCRIPT

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Fig. 7. Plot of limiting apparent molar isentropic compressibility, KoΦ,S, versus molality, mket, of ∎ 293.15 K,

298.15 K,

303.15 K,

308.15 K and

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ketorolac tromethamine for L-Histidine in (water + ketorolac tromethamine) solutions at temperatures: 313.15 K.

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3.3. Effect of temperature on the volumetric properties of the considered systems Fig. 8 shows plot of limiting molar volume versus temperature. The

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increase in temperature.

values increase with

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Fig. 8. Plot of limiting apparent molar volume, VoΦ, versus temperature, T at different concentrations of ketorolac tromethamine: ∎L-Histidine in water, tromethamine

L-Histidine in 0.01 mol kg-1 aqueous ketorolac

L-Histidine in 0.01 mol kg-1 aqueous ketorolac tromethamine

L-Histidine in 0.01

mol kg-1 aqueous ketorolac tromethamine. 3.3.1. Temperature dependent partial molar properties

The variation of apparent molar volume at infinite dilution, VoΦ, with respect to temperature can be manifested through following equation: (6)

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ACCEPTED MANUSCRIPT where, coefficients a, b and c are evaluated by least-square data analysis, T is the temperature in Kelvin and Tref is the midpoint temperature range, Tref =303.15 K. The values of these constants for L-Histidine in aqueous ketorolac tromethamine solutions are reported in Table S5. The first derivative of equation (6) with respect to temperature at constant pressure gives limiting apparent molar expansibility, EoΦ, which can be calculated by using following

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equation:

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(7)

The limiting apparent molar expansibility, EoΦ, of solute is an important parameter for

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determining the existence of solute-solvent interactions present in solutions [24]. The observed EoΦ values are reported in Table 2. From the perusal of Table 4 it is seen that the EoΦ

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values for L-Histidine in aqueous ketorolac tromethamine are positive and these values increases with increase in temperature. The positive EoΦ values for L-Histidine in aqueous

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drug solutions indicate the existence of solute-solvent interactions in these systems. A perusal of Table 2 reveals that, with the increase in temperature molecular motion increases as a result of this some water molecules can be released from hydration layer (i.e. at high temperature

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they remain loosely bound to solute molecules) resulting expansion in volume, thus results

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increase in EºΦ values. The result obtained from limiting apparent molar expansibility, EoΦ, values also coincides with the above discussion of limiting apparent molar volume, VoΦ.

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Table 2

Limiting apparent molar expansivity, EoΦ, and temperature derivative of limiting apparent of L-Histidine in water and in aqueous ketorolac

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molar expansivity,

tromethamine solutions at different temperatures and at pressure, p = 101 kpa. T /(K)

mket



293.15 K

298.15 K

303.15 K

308.15 K

313.15 K

-1

/(mol kg ) o

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Φ

mol-1 K-2)

 10 /(m mol K ) 6

3

-1

109 /(m3

-1

0.00

0.2589

0.2594

0.2600

0.2606

0.2611

0.1140

0.01

0.2571

0.2585

0.2600

0.2614

0.2628

0.2857

0.04

0.2588

0.2594

0.2600

0.2606

0.2611

0.1140 11

ACCEPTED MANUSCRIPT 0.07

0.1694

0.1697

0.1700

0.1703

0.1706

0.0571

Standard uncertainities, s, are s(p) is 1.0 kpa, s(mb) is 0.002, s(T) is 0.01 K, s(EoΦ) is 0.0001 × 10-6 m3 mol-1 K-1 and is 0.004 × 10-9. mb is the molality of ketorolac tromethamine in water.

As EoΦ values gives information regarding solute-solvent interactions. Hepler gave a thermodynamic term (which is second derivative of limiting apparent molar volume with

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respect to temperature), which gives information regarding structure maker or structure breaker ability of solute when dissolved in solvent. The thermodynamic term given by Hepler

(8)

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used is as follows [25]:

Hepler proposed that, if the sign of

is positive, then the solute is structure maker

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and if it is negative then solute is structure breaker [26]. It is evident from the Table S4, the values are positive suggests that L-Histidine shows structure maker behaviour

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in aqueous ketorolac tromethamine solutions. 3.4. Transfer properties

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Limiting apparent molar properties of transfer gives significant information about solute-

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solvent interactions without considering the effects of solute-solute interactions [27,28]. Limiting apparent molar volume of transfer, VoΦ,tr, of L-Histidine from water to aqueous

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ketorolac tromethamine was calculated by using following equation: (9)

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where, VoΦ (in water) is the limiting apparent molar volume of L-Histidine in water, VoΦ of amino acid can be represented by using equation [29]: (10)

where, Vvw is the vander waals volume, Vvoid is the associated void volume and Vshrinkage is the shrinkage in volume due to solute-solvent interactions. It has been assumed that the contribution of Vvw and Vvoid remains approximately same in water and in mixed aqueous solutions and the decrease in shrinkage volume results positive volume of transfer.

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ACCEPTED MANUSCRIPT The presence of ketorolac tromethamine in water decreases the extent of electrostriction this results decreasing shrinkage in volume. Transfer volume explains the interaction between solute and solvent molecules at infinitely dilute solutions, as solute-solute interactions are almost negligible. The VoΦ,tr values are reported in Table 3 and are positive which increases with increase in concentration of ketorolac tromethamine. Positive value indicates existence of strong ion-ion interactions i.e. drug-amino acid interactions.

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Table 3

Partial molar volume of transfer, VoΦ,tr, and partial molar isentropic compression of transfer,

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KoΦ,S,tr, of L-Histidine in water and in aqueous ketorolac tromethamine solutions at different

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temperatures and at pressure, p = 101 kpa. T /(K) 293.15 K

298.15 K

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/(mol kg-1)

303.15 K

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mket

VoΦ,tr  106 /(m3 mol-1)

308.15 K

313.15 K

0.16

0.12

0.13

0.10

0.09

0.04

0.79

0.76

0.79

0.74

0.75

0.07

2.91

2.66

2.13

1.51

1.30

1.33

1.60

1.54

1.15

1.33

3.33

3.38

3.23

3.16

3.34

5.24

5.54

5.13

5.20

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0.01

0.01 0.04

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0.07

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KoΦ,S,tr  1015 /(Pa-1 m3 mol-1)

b

5.12 o

Standard uncertainities, s, are s(p) is 1.0 kpa, s(m ) is 0.002, s(T) is 0.01 K, V m3 mol-1 and KoΦ,S,tr is ×10-15 Pa-1 m3 mol-1. mb is the molality of ketorolac tromethamine in water.

Φ,tr

is 0.03 × 10-6

In general, on the basis of co-sphere overlap model various types of interactions occurring between drugs and amino acids and can be classified as [30-33]: (i)

Ionic-hydrophillic interactions between polar groups of ketorolac tromethamine and zwitter-ions of L-Histidine.

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ACCEPTED MANUSCRIPT (ii)

Hydrophilic-hydrophillic

interactions

between

polar

groups

of

ketorolac

tromethamine and polar group of L-Histidine. (iii)

Ionic-hydrophobic interaction between ionic group of ketorolac tromethamine/LHistidine and non polar group of L-Histidine / ketorolac tromethamine.

(iv)

Hydrophobic-hydrophobic interaction between non polar group of ketorolac

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tromethamine and non polar group of L-Histidine. In accordance with this model, if A and B species are ionic or hydrophilic, the overlap of their and if A and B species are

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co-spheres always give positive transfer values i.e.

hydrophobic or if one is hydrophilic and other is hydrophobic the overlap of their co-spheres . Thus the positive values of VoΦ,tr shows

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always give negative transfer values i.e.

that interactions of type (i) and (ii) are dominating over interaction of type (iii) and (iv) and

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these values also increases with increase in concentration of drug.

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Limiting apparent molar isentropic compression of transfer, KoΦ,S,tr, of L-Histidine from water to aqueous ketorolac tromethamine was calculated by using following equation:

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(11)

where, KoΦ,S (in water) is the limiting apparent molar isentropic compression of L-Histidine in

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water. The KoΦ,S values for the investigated solutions are positive and are presented in Table 3. The observed positive KoΦ,S,tr values which increase with increase in drug concentration indicates the dominance of charged end groups i.e. ionic-hydrophilic group interactions in

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these system. The increasing trend of KoΦ,S,tr values with concentration of drug, results increase of these type of interactions. The electrostricted water becomes less compressible

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than bulk water and results large decrease in the compressibility with increase in concentration of ketorolac tromethamine. The negative KoΦ,S values and the positive KoΦ,S,tr values shows the existence of strong solute-solvent interactions which results decrease in compressibility [34]. Results obtained from compressibility studies (i.e. KoΦ,S and KoΦ,S,tr values) further supports our earlier conclusion obtained from volumetric studies (VoΦ and VoΦ,tr). 3.5. Hydration number

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ACCEPTED MANUSCRIPT The number of water molecules hydrated, nH, to amino acids can be estimated by method proposed by Millero. There are two different ways used to determine the nH: (i) electrostriction partial molar volume and (ii) electrostriction partial molar compressibility [35]: (12) Vo(elect.) is the electrostriction partial molar volume due to hydration of amino acid, VoΦ,e is the

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molar volume of electrostricted water and VoΦ,b is the molar volume of bulk water. The at 298.15 K, 303.15 K and 308.15 K in the literature are -

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reported values of

3.3 cm3 mol-1, -3.7 cm3 mol-1 and -4.0 cm3 mol-1, respectively [36].

(13)

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The partial molar volume of amino acid, VoΦ, can be represented by following equation:

where, VoΦ(int.) is the intrinsic partial molar volume of amino acid and can be calculated by

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using equation:

(14)

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where, 0.7 is the packing density of molecules in organic crystal, 0.634 is the packing density

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of random packing spheres and VoΦ(crystal)=M/ρ(crystal). For L-Histidine the value of crystal density (ρ(crystal)) can be obtained from literature [37]. The number of water molecules hydrated to amino acids by electrostriction partial molar

(15)

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compressibility, KoΦ,S(elect), can be determined by using following equation:

where, KoΦ,S,b is the isothermal compressibility of bulk water. The estimated value of (VoΦ,b.KoΦ,S,b) is 8.1  10-15 m5 N-1 mol-1.The values of KoΦ,S(elect.) can be calculated from experimentally determined KoΦ,S values by using following equation: (16) where, KoΦ,S(int.) is KoΦ,S(isomer) and its value for L-Histidine is 3  10-6 m5 N-1 mol-1. Since KoΦ,S(int.) is expected to be less than 5  10-6 m5 N-1 mol-1 for ionic crystals and many organic

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ACCEPTED MANUSCRIPT solutes in water, so we suppose KoΦ,S(int.) value to be zero [38]. Thus, reduced form of equation 15 is as follows: (17) Equation 15 can be expressed as:

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 The nH values based on volumetric and compressibility models for the investigated solutions

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are presented in Table 4.

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Table 4

Hydration number, nH, of L-Histidine in water and in aqueous ketorolac tromethamine

Volumetric method, nH

/(mol kg-1) T /(K) 303.15 K

0.00

7.03

5.89

0.01

6.99

0.04

6.80

0.07

6.22

308.15 K

303.15 K

308.15 K

5.12

4.23

3.79

3.40

5.85

5.10

4.03

3.60

3.26

5.67

4.94

3.82

3.39

3.01

5.31

4.74

3.55

3.15

2.76

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Compressibility method, nH

298.15 K

D

298.15 K

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mket

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solutions at different temperatures and at pressure, p = 101 kpa.

Standard uncertainities, s, are s(p) is 1.0 kpa, s(mb) is

0.002, s(T) is 0.01 K, s(nH) by volumetric

AC

method is 0.04 and s(nH) by compressibility method is 0.02. mb is the molality of ketorolac tromethamine in water.

As clearly seen from the Table 4, the nH values decreases with increase in concentration of drug and are smaller than that of water, this suggests there occurs strong interactions between zwitter-ions of L-Histidine and ions of ketorolac tromethamine with increase in concentration of drug. With increase in concentration of ketorolac tromethamine, water molecules present in solution are replaced by ketorolac tromethamine molecules due to its dehydration effect on LHistidine. The nH values also decreases with increase in temperature of solution (Fig. S1), this results decrease in electrostriction with increase in temperature.

16

ACCEPTED MANUSCRIPT 3.6. Analysis of viscosity data The experimentally determined values of viscosity, η, for L-Histidine in pure water and in aqueous solutions of ketorolac tromethamine at different temperature are reported in Table 4. Fig.11 shows the comparison of experimental viscosity data of L-histidine in water with available literature data at different temperatures. Fig. 9 shows the representative 3D-plot of viscosity, η, versus (a): molality, m, of L-Histidine in 0.01 mol kg-1 ketorolac tromethamine

PT

and (b): molality, mket, of ketorolac tromethamine in water as a function of temperature. The viscosity increases with increase in concentration of L-Histidine and also increases with

RI

increase in concentration of ketorolac tromethamine in aqueous solutions and follows decreasing trend with increase in temperature. This increase in values with increase in

SC

concentration is due to increase of solute-solvent interactions with concentration, which cause more frictional resistance to flow of solutions. With the increase in temperature random

NU

motion increases and the force of attraction between them decreases, thus decreases in

MA

viscosity of solutions [39].

0.96 0.93

D

0.90

PT E

3

 x 10 /Pa s

0.87 0.84 0.81 0.78

0.72 0.69

0.02

AC

0.00

CE

0.75

0.04

0.06

0.08

0.10

0.12

-1

m /mol kg

Fig. 8. Comparison of experimental viscosity data of L-histidine in water with available literature data at temperatures, T/K =∎ 298.15 (present work); 303.15 (present work); 308.15 (present work); 298.15, Ref [19]; 303.15, Ref [19]; 303.15, Ref [20]; 308.15, Ref [19].

17

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ACCEPTED MANUSCRIPT

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Fig. 9. Plot of viscosity, η, versus (a): molality, m, of L-Histidine and (b): molality, mket, of ketorolac

SC

tromethamine in water as a function of temperature.

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The viscosity data were analysed by using Jones-Dole equation of the form [40]: (18)

where, ηr denotes the relative viscosity of the solution (Table S6 and Fig. 8), η and ηo are the

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viscosities of solution (L-Histidine + water + ketorolac tromethamine) and solvent (ketorolac tromethamine + water), respectively and m is the molality of L-Histidine. Falkenhagen

D

coefficient A, represents solute-solute interactions and Jones-Dole coefficient B also known as viscosity B-coefficient, signifies the contribution arising from the shape, size and structural

PT E

modifications induced by solute-solvent interactions [41-42]. The values of coefficients A and B can be obtained using plot between

vs. m1/2 by least square fitting, slope

AC

CE

gives the values of B and intercept gives the values of A.

18

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ACCEPTED MANUSCRIPT

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Fig. 10. Plot of relative viscosity, nr, versus molality, m, of L-Histidine in water and in ketorolac tromethamine + water solutions: (a) L-Histidine in water, (b) L-Histidine in 0.01 mol kg-1 aqueous

SC

ketorolac tromethamine, (c) L-Histidine in 0.04 mol kg-1 aqueous ketorolac tromethamine and (d) LHistidine in 0.07 mol kg-1 aqueous ketorolac tromethamine at temperatures: ∎293.15 K, 308.15 K and

313.15 K.

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303.15 K,

298.15 K,

The values of A and B coefficients are reported in Table 5. A close perusal of Table 5 reveals

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that values of both coefficients are positive; however the A-coefficients are smaller than Bcoefficients. The negligible values of A-coefficient suggest weak solute-solute interactions. The observed values of viscosity B-coefficient increases with increase in concentration

D

indicate existence of strong solute-solvent interactions in these solutions. The increase in

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viscosity B-coefficient with increase in concentration of co-solute (ketorolac tromethamine) (Fig. 11), this is due to the increase in friction that prevent water flow at increased ketorolac tromethamine concentration.

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Table 5

AC

Falkenhagen coefficient, A, viscosity B-coefficient, B, and standard deviations, σ, of LHistidine in water and in aqueous ketorolac tromethamine solutions at different temperatures and at pressure, p = 101 kpa. T /(K) Property

293.15 K

298.15 K

303.15 K

308.15 K

313.15 K

L-Histidine in water A  103

0.0565

0.0523

0.0461

0.0392

0.0322

/(kg1/2 mol-1/2)

(0.0024)

(0.0011)

(0.0011)

(0.0018)

(0.0026)

19

ACCEPTED MANUSCRIPT B  103

0.1583

0.1441

0.1337

0.1282

0.1234

/(kg mol-1/2)

(0.0088)

(0.0040)

(0.0041)

(0.0066)

(0.0096)



0.0019

0.0001

0.0001

0.0014

0.0020

L-Histidine in 0.01 mol kg-1 aqueous ketorolac tromethamine 0.0589

0.0535

0.0473

0.0405

0.03412

/(kg1/2 mol-1/2)

(0.0034)

(0.0023)

(0.0027)

(0.0031)

(0.0028)

B  103

0.1595

0.1448

0.1352

/(kg mol-1/2)

(0.0123)

(0.0084)

(0.0100)



0.0026

0.0018

0.0213

PT

A  103

0.1243

(0.0112)

(0.0103)

RI

0.1296

0.0022

0.0477

0.0422

0.03512

(0.0025)

(0.0024)

(0.0023)

0.1383

0.1335

0.1264

SC

0.0024

L-Histidine in 0.04 mol kg-1 aqueous ketorolac tromethamine 0.0594

0.0539

/(kg1/2 mol-1/2)

(0.0032)

(0.0024)

B  103

0.1604

0.1459

/(kg mol-1/2)

(0.0116)

(0.0089)

(0.0090)

(0.0089)

(0.0084)



0.0025

0.0019

0.0019

0.0019

0.0018

D

MA

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A  103

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L-Histidine in 0.07 mol kg-1 aqueous ketorolac tromethamine 0.0596

0.0544

0.0481

0.0430

0.0355

/(kg1/2 mol-1/2)

(0.0034)

(0.0026)

(0.0029)

(0.0028)

(0.0024)

B  103

0.1616

0.1467

0.1401

0.1345

0.1298

(0.0125)

(0.0095)

(0.0106)

(0.0104)

(0.0088)

0.0027

0.0020

0.0026

0.0022

0.0019



AC

/(kg mol-1/2)

CE

A  103

Standard uncertainities, s, are s(p) is 1.0 kpa, s(mb) is 0.002, s(T) is 0.01 K, s(A) is 0.002 × 10-3 and s(B) is 0.002 × 10-3. mb is the molality of ketorolac tromethamine in water.

20

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ACCEPTED MANUSCRIPT

L-Histidine in 0.01 mol kg-1 ketorolac tromethamine,

-1

kg ketorolac tromethamine

-1

L-Histidine in 0.04 mol

L-Histidine in 0.07 mol kg ketorolac tromethamine.

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Histidine in water,

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Fig. 11. Plot of viscosity B-coefficient, B, versus temperature, T, at various concentrations: ∎ L-

An important relationship between viscosity B-coefficient and temperature can be expressed

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as derivative form of dB⁄dT, this gives information regarding solute-solvent interactions in terms of structure maker (kosmotropic) or structure breaker (chaotropic) behaviour [43].

MA

Generally, the positive dB⁄dT value shows structure breaker behaviour while negative dB⁄dT value shows structure maker behaviour. The values of dB⁄dT are reported in Table 5 are negative and this indicates that L-Histidine shows structure making behaviour in water as well

D

as in aqueous solutions of ketorolac tromethamine. Structure making behaviour of L-Histidine

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in pure water and in aqueous metformin hydrochloride has also been observed by Chauhan et al. [19]. The results obtained from dB⁄dT values (i.e. kosmotropic behaviour) supports our

CE

earlier conclusion obtained from Hepler’s constant. The viscosiy B-coefficient of transfer, Btr, can be calculated by using equation:

AC

(19)

where, B (in water) is the viscosity B-coefficient of L-Histidine in water. The Btr values are reported in Table 6. From the Table, it is observed that the viscosity B-coefficient of transfer values increases with increase in concentration of ketorolac tromethamine. Table 6 Viscosity B-coefficients of transfer, Btr, and temperature coefficient, dB/dT, of L-Histidine in water and in aqueous ketorolac tromethamine solutions at different temperatures and at pressure, p = 101 kpa.

21

ACCEPTED MANUSCRIPT T /(K) mket

293.15 K

298.15 K

303.15 K

308.15 K

313.15 K

-1

/(mol kg ) Btr --

--

--

--

--

-0.0017

0.01

0.0012

0.0007

0.0015

0.0014

0.0009

-0.0017

0.04

0.0021

0.0018

0.0046

0.0053

0.0030

-0.0016

0.07

0.0033

0.0026

0.0064

0.0063

0.0064

-0.0015

PT

0.00

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Standard uncertainities, s, are s(p) is 1.0 kpa, s(mb) is 0.002, s(T) is 0.01 K, s(Btr) is 0.0004 and s( ) is 0.0005. mb is the molality of ketorolac tromethamine in water.

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3.7. Thermodynamics of viscous flow

On the basis of Feakin’s transition state theory, Gibb’s free energy (or chemical potential) of

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activation per mole of solvent, o#1, and Gibb’s free energy (or chemical potential) of activation per mole solute, o#2, can be determined by knowing the values of viscosity B-





(20)

is the partial or apparent molar volume of solvent (water +

D

where,

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coefficient [44]:

PT E

ketorolac tromethamine) (Table S3), ρo, is the density of solvent mixtures, xi and Mi denotes the mole fraction and molecular weight of water and ketorolac tromethamine in solvent mixtures, respectively.

CE

at infinite dilution.

is the limiting partial or apparent molar volume of solute

AC

Gibb’s free energy (or chemical potential) of activation per mole of solvent, o#1, can be calculated by using following equation [45]:



(21)

where, R is the gas constant, ηo is the viscosity of solvent, h is the Plank’s constant and N is the Avogadro’s number. Thus, on rearranging equation 20, Gibb’s free energy (or chemical potential) of activation per mole of solute, o#2, can be calculated as follows:





(22)

22

ACCEPTED MANUSCRIPT The calculated values of o#1 and o#2 are reported in Table 7. As these values, depends on Feakin’s transition state theory, on the basis of this if a solute is completely coordinated in the ground state solvent, transition state formed involves solute-solvent bond breaking and reduction in coordination number of solute takes place. A perusal of Table 7, the o#2 values are positive and greater than that of o#1 values. As o#2>o#1 suggests strong solutesolvent interactions in ground state are stronger than that in the transition state [46]. With the

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increase in temperature these values decreases which results decrease in solute solvent interaction with temperature.

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Table 7

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Gibb’s free energy of activation per mole of solvent, o#1, Gibb’s free energy of activation per mole of solute, o#2, entropy of activation per mole of solute, TSo#2 and enthalpy of

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activation per mole of solute, Ho#2 of L-Histidine in water and in aqueous ketorolac tromethamine solution at different temperatures and at pressure, p = 101 kpa.

L-Histidine in water

o#1

303.15 K

308.15 K

313.15 K

9.16

9.04

8.93

8.83

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9.29

298.15 K

D

293.15 K

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T /(K) Property

o#2

41.31

39.93

39.07

38.74

38.54

/(kJ mol-1)

CE

/(kJ mol-1)

40.25

40.92

41.60

42.27

80.88

80.18

79.99

80.34

80.81

TSo#2

39.57

Ho#2

AC

/(kJ mol-1) /(kJ mol-1)

L-Histidine in 0.01 mol kg-1 aqueous ketorolac tromethamine

o#1

9.38

9.26

9.15

9.06

8.97

41.48

40.11

39.27

39.10

38.76

/(kJ mol-1)

o#2 /(kJ mol-1)

23

ACCEPTED MANUSCRIPT TSo#2

37.82

38.46

39.11

39.75

40.40

79.30

78.57

78.38

78.85

79.16

9.19

9.12

/(kJ mol-1)

Ho#2 /(kJ mol-1)

o#1

9.48

9.37

9.28

41.53

40.17

39.66

33.42

33.99

34.56

74.95

74.16

74.22

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L-Histidine in 0.04 mol kg-1 aqueous ketorolac tromethamine /(kJ mol-1)

TSo#2

SC

/(kJ mol-1) /(kJ mol-1)

39.02

35.13

35.70

74.62

74.72

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Ho#2

39.49

RI

o#2

MA

/(kJ mol-1)

o#1

9.58

9.48

9.39

9.32

9.26

41.79

D

L-Histidine in 0.07 mol kg-1 aqueous ketorolac tromethamine

39.95

39.59

39.56

31.60

32.13

32.66

33.19

72.02

72.08

72.25

72.75

/(kJ mol-1)

40.42

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o#2 /(kJ mol-1) TSo#2

31.07

CE

/(kJ mol-1)

72.86

Ho#2

AC

/(kJ mol-1)

Standard uncertainities, s, are s(p) is

kpa, s(mb) is

mol-1, s(o#2) is 0.11 kJ mol-1, s(TSo#2) is

0.002, s(T) is 0.01 K, s(o#1) is 0.01 kJ

53 kJ mol-1, s(Ho#2) is

44 kJ mol-1.

mb is the molality of ketorolac tromethamine in water.

The values of activation entropy, So#2, and activation enthalpy, Ho#2, for viscous flow of LHistidine in water and aqueous ketorolac tromethamine can be determined by using following equation:





(23) 24

ACCEPTED MANUSCRIPT 





(24)

The calculated values of activation parameters Ho#2 and TSo#2 at different concentrations and temperatures recorded in Table 7 and the So#2 values are given in Table S7. The values of these said parameters are positive, which indicates that transition state for viscous flow is related to bond breaking and decreases in order. Thus the conclusions obtained from B and

o#2 values are in close agreement with those obtained from Voϕ and Koϕ,S.

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4. Conclusions

The current work leads to systematic experimental measurements of density, ρ, speed of

RI

sound, u, and viscosity, η, of solutions of L-Histidine in water and in aqueous ketorolac

SC

tromethamine at different temperatures and at atmospheric pressure. From the experimental data, various thermodynamic and activation parameters were calculated and the results were discussed in terms of solute-solvent (i.e. ionic-hydrophilic) interactions. Positive transfer

NU

values of Voϕ,tr, Koϕ,S,tr and Btr shows the dominance of ionic-hydrophilic and hydrophilichydrophilic interactions over ionic-hydrophobic and hydrophobic-hydrophobic interactions.

MA

The results obtained from Hepler’s thermodynamic relation and temperature derivative of viscosity B-coefficient are in good agreement with each other. Both these relation show structure making behaviour (i.e. kosmotropic behaviour) of L-Histidine in water and in

D

aqueous ketorolac tromethamine. Moreover, o#2 values are larger than that of o#1 values

PT E

indicate existence of strong solute-solvent interactions in these systems which suggest that formation of transition state is less favoured in presence of L-Histidine. The transition state is accompanied by rupture and distortion of bonds and this can be confirmed by positive values

CE

of Ho#2. The thermodynamic study for the investigated system plays a very significant role in

AC

medicinal and pharmaceutical chemistry.

25

ACCEPTED MANUSCRIPT Acknowledgements The authors are thankful to the Department of Chemistry, University of Jammu, Jammu, for providing the necessary facilities for the completion of this work. Appendix A. Supplementary data Supplementary data contains apparent molar volume, VΦ, and apparent molar isentropic compression, KΦ,S, Table S2, isentropic compressibility, kS, Table S3, values of coefficients

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of a, b and c Table S5, variation of hydration number, nH, versus molality, mket, of ketorolac tromethamine for L-Histidine in (water + ketorolac tromethamine) solutions Fig. S1 and , and activation entropy per mole of solute, So#2.

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apparent molar volume of solvent,

[1]

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Aqueous K2SO4/KNO3 Systems at (298.15 to 323.15) K, J. Chem. Eng. Data 57 (2012) 7. [39] H. Kumar, M. Singla, R. Jindal, Interactions of amino acids in aqueous triammonium citrate solutions at different temperatures: A viscometric approach, J Mol. Liq. 199 (2014)

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ACCEPTED MANUSCRIPT Research highlights 

Physicochemical studies of L-histidine in aqueous ketorolac tromethamine solutions were obtained. These studies show the effect of concentration and temperature on these solutions.

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There is existence of drug-amino acid interactions in these systems.

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Volumetric and viscometric studies show kosmotropic behaviour of L-histidine.

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