Chemical Papers 67 (11) 1442–1452 (2013) DOI: 10.2478/s11696-013-0404-y ORIGINAL PAPER Temperature-dependent volumetric and viscometric properties of amino acids in aqueous solutions of an antibiotic drug a Suvarcha Chauhan*, a Poonam Chaudhary, a Kundan Sharma, a Kuldeep Kumar, b Kiran a Department of Chemistry, Himachal Pradesh University, Summerhill, Shimla-171005, India b Mata Gujri College, Department of Chemistry, Fatehgarh Sahib-140406, Punjab, India Received 30 December 2012; Revised 1 March 2013; Accepted 6 March 2013 Volumetric and viscometric properties of glycine and methionine (amino acids) in a 0.2 vol. % amikacin sulphate (antibiotic drug) aqueous solution with the molality range of 0.025 mol kg −1 – 0.25 mol kg −1 were measured over the temperature range of 20 ◦ C – 40 ◦ C at the interval of 5 ◦ C. Different parameters like apparent molar volume (φV), apparent molar adiabatic compression (φκ), isentropic compression (κS) along with other acoustical parameters were calculated. Parameters like viscous relaxation time (τ ), free volume (VF), internal pressure (ΠI ), and molar cohesive energy (MCE) were calculated from dynamic viscosity measurements. The φV values are positive in both cases, but with higher magnitude observed in methionine. These positive values of φV are indicative of strong solute–solvent interactions at all temperatures. In case of methionine there is a sharp initial increase in the φV values which become almost constant with further additions of the amino acid. Structural differences in the two amino acids studied are clearly reflected in the different nature of the plots of different parameters. In case of an amino acid–drug system, dynamic viscosity increase has been attributed to the increase in the hydrophilic–ionic and hydrophilic–hydrophilic interactions with the increase in the amino acid concentration which in turn may cause more frictional resistance to the flow of the solution. All other parameters are discussed in terms of solute–solvent and solvent– solvent interactions. c 2013 Institute of Chemistry, Slovak Academy of Sciences Keywords: amikacin sulphate, apparent molar adiabatic compression, apparent molar volume, glycine, leucine Introduction Drug–macromolecule interactions are an impor- tant phenomenon in physiological media, such as blood, membranes, and intra- and extra-cellular flu- ids. Processes of drug transport, protein-binding, and anaesthesia are some of the examples where drug and bio-macromolecules interact in an important and vitally significant manner. In biophysical chemistry, drug–macromolecule interactions are an important phenomenon involving a complex mechanism (Iqbal & Siddiquah, 2006). Also thermodynamic properties are very useful for the understanding of the ionic, hy- drophilic and hydrophobic interactions in different so- lutions media as they provide information elucidat- ing the solute–solute and solute–solvent interactions in the solution phase (Iqbal & Verrall, 1989). Systematic knowledge of the drug behaviour in a solution can thus be of great significance for the un- derstanding of their physiological action (Chauhan et al., 2010). The addition of certain molecules to protein solutions can result in the stabilisation or destabilisa- tion of the proteins (Castellanos et al., 2003; Arnold & Zhang, 1994). The conformation adapted by a pro- tein under the given solvent environment depends on its interaction with the surrounding solvent molecules *Corresponding author, e-mail: chauhansuvarcha@rediffmail.com
Transcript
Chemical Papers 67 (11) 1442–1452 (2013)DOI: 10.2478/s11696-013-0404-y
ORIGINAL PAPER
Temperature-dependent volumetric and viscometric propertiesof amino acids in aqueous solutions of an antibiotic drug
Drug–macromolecule interactions are an impor-tant phenomenon in physiological media, such asblood, membranes, and intra- and extra-cellular flu-ids. Processes of drug transport, protein-binding, andanaesthesia are some of the examples where drugand bio-macromolecules interact in an important andvitally significant manner. In biophysical chemistry,drug–macromolecule interactions are an importantphenomenon involving a complex mechanism (Iqbal& Siddiquah, 2006). Also thermodynamic propertiesare very useful for the understanding of the ionic, hy-
drophilic and hydrophobic interactions in different so-lutions media as they provide information elucidat-ing the solute–solute and solute–solvent interactionsin the solution phase (Iqbal & Verrall, 1989).Systematic knowledge of the drug behaviour in a
solution can thus be of great significance for the un-derstanding of their physiological action (Chauhan etal., 2010). The addition of certain molecules to proteinsolutions can result in the stabilisation or destabilisa-tion of the proteins (Castellanos et al., 2003; Arnold& Zhang, 1994). The conformation adapted by a pro-tein under the given solvent environment depends onits interaction with the surrounding solvent molecules
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Fig. 1. Structure of amikacin.
Fig. 2. Zwitterionic structure of glycine and methionine.
(Ramahlo & da Cunha, 2011; Shulgin & Ruckenstein,2005; Rubinstein & Sherman, 2004). Mechanisms ofthese molecular processes are not yet clearly under-stood. Therefore, attempts are being made to un-derstand these interactions through properties likepartial molar volume and partial molar compression,and through dynamic viscosity studies (Jahagirdar etal., 1998; Surdo et al., 1978). Various concepts re-garding molecular processes in solutions such as elec-trostriction (Harned & Owen, 1943), hydrophobic hy-dration (Tanford, 1980), micellisation (Wyn-Jones &Gormally, 1983) and co-sphere overlap during solute–solute interactions (Gurney, 1954) have been derivedand interpreted from the partial molar volume data ofmany compounds.In the present case, the antibiotic drug – amikacin
sulphate, which is a semi-synthetic aminoglycosidederived from kanamycin, was used. Molecular struc-ture of amikacin sulphate with the molecular formulaC22H43N5O13 · 2H2SO4 is shown in Fig. 1.Among amino acids, glycine used in this study has
the smallest molecule and it is a non-essential aminoacid with the structural formula HOOCCH2NH2. Inan aqueous solution, at or near neutral pH, glycineexists predominantly in form of zwitterions (Fig. 2),which are neutral molecules that bear an equal num-ber of positive and negative charges. The iso-electricpoint or iso-electric pH of glycine is centered be-tween the pKas values of the two ionisable groups, theamino group and the carboxylic acid group. Anotheramino acid used is methionine with the structural for-
mula HOOCCH(NH2)CH2CH2SCH3. It is an essen-tial amino acid containing sulphur whose side chain isquite hydrophobic and is usually found buried withinproteins. The structure of glycine and methionine isshown in Fig. 2.
Experimental
Aqueous stock solutions of amino acids of differ-ent molality in the range of 0.025 mol kg−1 – 0.25mol kg−1 were prepared by adding small aliquots ofconcentrated stock solutions of amino acids to 10 mLof 0.2 vol. % amikacin sulphate as a solvent mediumover a wide temperature range (20–40◦C) at the inter-val of 5◦C. Uncertainties in the mass and concentra-tions were ± 2 × 10−4 g mol−1 and ± 0.01 mol kg−1,respectively.Water was the main solvent in the present study
and it was purified using a Millipore Elix distillationunit; and it was subjected to further distillation onacidified KMnO4 in a ≈ 750 mm long fractionatingcolumn. Different fractions of distilled water were col-lected and their conductivity, κ/(S cm−1) and pH weredetermined. The sample of the κ value < 1 × 10−6S cm−1 was collected for further use. However, the pHvalue of thus collected water remained in the rangeof 6.5–6.9. Both these parameters were measured atroom temperature. The purified water so obtainedwas used within two days. Glycine and methioninehaving the purity of ≈ 99.9 %, were purchased fromCALBIOCHEM (Germany), and Sd Fine-Chem (In-dia), respectively. Amikacin sulphate was supplied byAristo Lab (India) (2 mL of amikacin sulphate con-tains 500 mg of Amikacin) in injection form. The molefractions with the purity of dioxane and dimethylsul-foxide of > 0.995 and > 0.997, respectively, were pur-chased from Sisco Research Laboratories (India).All measurements were carried out in an automatic
digital temperature controlled high precision waterthermostat supplied by Harco ltd. maintained at thetemperature of (25.00 ± 0.02)◦C. Temperature of thewater thermostat was controlled at the desired tem-perature in such a way that the heat losses due toradiation and other factors were exactly compensatedby the input voltage of electric bulbs. Using this tech-nique, the temperature was controlled within± 0.02◦Cduring the measurements. Any change in the temper-ature reading required only a slight adjustment in thetoluene regulator.A Jackted Ostwald (Harco, India) viscometer with
the flow time of 475 s for pure water at 25◦C wasused for all dynamic viscosity measurements. The vis-cometer was cleaned with warm chromic acid, rinsedwith distilled water followed by rectified spirit andacetone before use. After drying under vacuum, theviscometer was filled with the solution studied (fil-tered using Whatman 41 filter paper) and clampedvertically near the thermostat. The viscometer was
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Table 1. Experimental and literature values of densities and viscosities for solvents used at different temperatures
a) Palaioglu et al. (2002); b) Tsierkezos and Molinou (1998); c) Kapadi et al. (1997); d) Papanastasiou and Ziogas (1992); e) Ottaniet al. (2002); f) Contreras (2001); g) Oswal and Patel (1995).
kept at thermostatically controlled conditions by cir-culation of thermostatic water for about half an hourusing a water circulator from Riviera Glass (Mum-bai, India) fitted with a temperature control device.The solution was gently extracted into the upperbulb and the cycle was repeated until the precisionof ± 0.01 s was obtained for three determinationsusing a 1/100 s electronic timer. Dynamic viscos-ity was calculated using the density of the solutionmeasured with the help of a high precision densityand sound velocity analyser 5000 (DSA-5000, An-ton Paar, Austria). The viscometer was subjectedto calibration before use at all temperatures usingwater, dioxane and dimethylsulfoxide; experimentaland literature values are reported in Table 1. Ex-perimental values of viscosity for water, 1,4-dioxane,and DMSO are very close to the literature valuesat all temperatures (Table 1). The dynamic vis-cosity values were found to be reproducible within± 0.01 %.Density and sound velocity of the solutions un-
der examination were measured using a Density andSound Analyzer, DSA-5000 (Anton Paar, Austria)which is an oscillating U-tube density and velocitysound meter measuring to the highest accuracy in awide temperature range. The DSA-5000 measures thespeed and density of the solution at the resolutionof 1 × 10−1 ms−1 and 1 × 10−6 g cm−3, respectively.Calibration of the DSA was done with doubly distilledwater over the temperature range of 20◦C – 40◦C andthe values are reported in Table 1. The density valuesagreed well with the literature ones. DSA was ther-mostated within ± 0.002◦C using a Peltier heatingdevice.
Results and discussion
Density and sound velocity measurements
Density (d) and sound velocity (v) for amino acids(glycine and methionine) in the molality range of 0.025mol kg−1 – 0.25 mol kg−1 were measured in aqueoussolution of 0.2 mass % amikacin sulphate over the tem-perature range of 20◦C – 40◦C with the interval of 5◦C.The data are summarised in Tables 2 and 3. A surveyof these data revealed that the density increases withthe amino acid concentration and decreases with theincrease in the temperature. However, the sound veloc-ity increases both with the increase in the temperatureand the amino acid concentration.From the density and sound velocity values, vari-
ous parameters like apparent molar volume (φV), ap-parent molar adiabatic compression (φK), isentropiccompressibility (κS), relative association (RA), freelength (LF), specific acoustic impedance (Z), and mo-lar sound number (U) were obtained using the rela-tions given below (Chauhan et al., 2012; Syal et al.,2005a, 2005b):
φV = (d0 − d)/mdd0 +M/d (1)
φK = (κs − κ0)/md0 + φVκS (2)
κS = 1/v2d (3)
RA = (d/d0)(v/v0)1/3 (4)
LF = K(κS)1/2 (5)
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U = (v − v0)/(v0m) (6)
Z = vd (7)
where m/(mol kg−1) is the molality of the solution,M/(kg mol−1) is the molecular mass of amino acids,v0/(m s−1), d0/(kg m−3), κ0/(TPa−1), v/(m s−1),d/(kg m−3), κS/(TPa−1) are the velocities, densities,and compressibilities of the solvent (aqueous solutionof amikacin sulphate) and the solution, respectively,and K = 10−8(93.875 + 0.375)T refers to the temper-ature dependent constant.The compressibility data are summarised in Tables
2 and 3 from which it is clear that the κS values de-crease with an addition of the amino acid in both cases(Fig. S1 (supplementary data)). This decrease canbe attributed to the electrostatic interactions aminoacid–drug (Syal et al., 1995a, 1995b) which makesthe solution rather incompressible. Also, the decreasein the κS value with the increase in the amino acidconcentration is indicative of the presence of solute–solvent interactions. This observation is characteris-tic of the electrolytic behaviour as found in literature(Kawaizumi & Zana, 1974; Singh et al., 1994; Syalet al., 1992, 1995a, 1995b, 1998). The reduction inthe κS values is more pronounced in methionine thanin glycine, which seems to be in accordance with thehigher basicity of the —NH2 group in methionine asit is evident from its lower pK2 value.Further insight into the type and extent of the
amino acid interactions in an aqueous solution of drugwas obtained from the behaviour of the apparent mo-lar volume, φV, and the apparent molar adiabaticcompression, φK. The apparent molar volume, φV,of methionine and glycine in an aqueous solution ofamikacin sulphate are presented in Table 4.Different types of interactions which could occur in
an amino acid–drug system are: i) hydrophilic–ionicinteractions between the polar group of the drug andthe zwitterion of the amino acid, and ii) hydrophilic–hydrophilic interaction between the polar group of thedrug and the polar group of the amino acid.These electrostatic types of interactions, i.e. i) and
ii), result in the reduction of the electrostriction ef-fect and in enhanced overall structure of water. Thesepositive values of φV are indicative of strong solute–solvent interactions with increase in the concentrationof glycine as well as methionine at all temperatures(Kumar & Kaur, 2012). However, in case of methio-nine there is a sharp initial increase in the φV valuewhich becomes almost constant with further additionsof the amino acid. The φK data reported in Table 4describe the behaviour of φK in glycine and methion-ine, respectively. The φK values are negative in bothcases at all studied temperatures. Negative φK val-ues indicate the presence of electrostatic, hydrophilicor ionic interactions solute–solute, solute–solvent, andsolvent–solvent (Syal et al., 2005b; Chauhan et al.,
2012), and show that water molecules around the so-lute are less compressible than those in the bulk whichis attributed to strong attractive interactions (Kumarand Kaur (2012), Fig. S3).Functional diversity exhibited by this class of
biomolecules is directly related to the combinatorialpossibilities of the monomeric units. Amino acids areimportant bioactive molecules, constituents of pro-teins and they can take part in various physiologicalprocesses and perform structural, hormonal, and cat-alytic functions (Sakami & Harrington, 1963). At thepH of 7, the carboxyl group of an amino acid is in itsconjugate base form (COO−) and the amino group isin its conjugate acid form (NH+3 ). Thus, each aminoacid can behave as either an acid or a base. The termamphoteric is used to describe this property.Tables 4 and 5 report the LF values of glycine and
methionine. The LF values decrease with the increasein the amino acid concentration, which is similar tobehaviour of κS. The decrease in the free length indi-cates that there is a significant interaction betweenthe solute and solvent molecules affecting also thestructural arrangement of the molecule. The Z val-ues are reported Tables 5 and 6. Their variation withthe amino acid is similar to those of the density andsound velocityCalculated values of the relative association (RA)
for the studied system are presented in Tables 5 and6, which show that the RA values are all positive andhigher than unity. RA is influenced by two factors:i) breaking of solvent aggregates on the addition ofa solute, resulting in a decrease in the RA values,and ii) subsequent solvation of ions by the free sol-vent molecules, which results in an increase in the RAvalue.In the present case, relative association increases
with the increasing amino acid concentration whichis indicative of hydrophilic interactions between thesolute and the solvent (Dhote et al., 2012; Sonar &Pawar, 2012).The molar sound number (U) provides another
piece of evidence explaining the intermolecular inter-actions or structural changes taking place in the solu-tion system (Tables 5 and 6). These values are positiveat all temperatures in both amino acid; however, themagnitude is higher in methionine as compared to thatin glycine. In the present case, a non-linear variationin U is indicative of various interactions among thespecies present in the solution.
Viscometric studies
Dynamic viscosity studies offer important evidenceon the structure and molecular interactions in solu-tions. Dynamic viscosity was calculated using the for-mula:
η = dStSηS/d0t0 (8)
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Fig. 3. Free volume versus molality of glycine (a) and methionine (b) in aqueous solution of amikacin sulphate (0.2 vol. %) at20◦C ( ), 25 ◦C (◦), 30◦C (�), 35◦C (�), 40◦C (�).
where dS/(kg m−3), tS/(s), ηS/(m Pa s), d0/(kg m−3),and t0/(s) are the density of the solution, flow time ofthe solution, dynamic viscosity of the solution (aque-ous solution of amikacin sulphate), density of the sol-vent, and flow time of the solvent, respectively.Dynamic viscosity values are reported in Table 7.
Dynamic viscosity increases with the increasing aminoacid concentration; however, it shows a decrease withthe increasing temperature for both amino acids.These observations are the result of the presence ofdifferent kinds of interactions in the system (Iqbal &Chaudhry., 2009; Aswale et al., 2012; Dhondge et al.,2012). In addition, there are certain parameters viz:viscous relaxation time (τ), relative viscosity (ηR), freevolume (VF), internal pressure (ΠI) and molar cohe-sive energy (MCE) calculated by combining the vis-cosity data with the density and ultrasonic velocitydata.The viscous relaxation time (τ) was calculated us-
ing the following formula (Syal et al., 2005a):
τ = 4η/3v2d (9)
where η/(mPa s), d/(kg m−3), and v/(m s−1) are thedynamic viscosity, density, and sound velocity of thesolution, respectively.Viscous relaxation time is directly proportional to
dynamic viscosity and inversely related to adiabaticcompressibility of the solution system. From Table 7it is clear that viscous relaxation time increases withthe increase in the amino acid concentration (Sharmaet al., 2008). However, the increase in τ with the in-creasing solute concentration can be attributed to thesolute–solvent interactions (Fig. S4).Free volume can be defined as the average vol-
ume in which the central molecule can move insidethe hypothetical cell due to the repulsion of surround-
ing molecules. Free volume can also be referred to asthe void space between the molecules i.e. the volumepresent as holes of monomeric size, due to the irregularpacking of molecules.Free volume (VF) was calculated using the given
formula (Syal et al., 2005a):
VF = (Mv/K ′η)3/2 (10)
M =M12 = x1M1 + x2M2 (11)
M123 =M12 +mass of solute (12)
where η/(mPa s) and v/(m s−1) are the dynamicviscosity and the sound velocity of the solution; K ′
= 4.28 × 109 is a constant independent on the na-ture of the liquid; M12 and M123 are the averagemolecular masses of the solution; M1/(kg mol−1) andM2/(kg mol−1) are the molecular masses of the sol-vents.
VF values in general decrease in magnitude withthe increasing amino acid concentration (Fig. 3). Anincrease in the temperature also increases the magni-tude of VFInternal pressure (ΠI) is a result of forces of at-
traction and repulsion between the solute and solventmolecules of the solution and is calculated using theformula (Syal et al., 2005a):
ΠI = bRT (K ′η/v)1/2(d2/3/M7/6) (13)
where η/(mPa s), d/(kg m−3), v/(m s−1), and M(kgmol−1) are the dynamic viscosity, density, velocity,and the average molecular mass of the solution. Pack-ing factor (b) is assumed to be 2 in liquid systems.From Fig. 4 it is evident that the ΠI values de-
crease with the increasing temperature. The increase
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Fig. 4. Internal pressure versus molality of glycine (a) and methionine (b) in aqueous solution of amikacin sulphate (0.2 vol. %)at 20◦C ( ), 25◦C (◦), 30◦C (�), 35◦C (�), 40◦C (�).
Fig. 5. Molar cohesive energy versus molality of glycine (a) and methionine (b) in aqueous solution of amikacin sulphate (0.2vol. %) at 20◦C ( ), 25◦C (◦), 30◦C (�), 35◦C (�), 40◦C (�).
of ΠI with the concentration indicates an increase inthe intermolecular interactions due to the formation ofsolvent molecules aggregates around the solute, whichaffects the structural arrangement of the solution sys-tem. This can also be attributed to the solute–solventinteractions.Molar cohesive energy (MCE) of a liquid system
can be defined as the molar energy required to dis-rupt all the molecular interactions and is a fundamen-tal tool to explain properties such as surface tension,conductance and miscibility point It is expected toplay a key role in the kinetics of chemical reactionsand physical processes MCE of a liquid medium is acharacteristic energy function of the medium and it
is almost equal to ∆G; it may correspond to the ofthe entire medium but with a slightly different conno-tation from the sense in which it is used in the solidstate.However, MCE explains the free energy state of the
liquid system related to the escaping tendency, whichis a result of totality of the contributions of all its con-stituent molecules in what ever state of aggregation,ions etc.Molar cohesive energy (MCE) was calculated using
the formula (Sharma et al., 2008):
MCE = ΠIVM (14)
S. Chauhan et al./Chemical Papers 67 (11) 1442–1452 (2013) 1451
where ΠI/(Pa) and VM/(m3 mol−1) are the internalpressure and the molar volume of the solution, respec-tively.From Fig. 5 it is clear that with the increas-
ing amino acid concentration, the cohesive energy in-creases while it decreases with the increasing temper-ature (Sharma et al., 2008). These results of dynamicviscosity are in good agreement with the volumetricand acoustical studies discussed earlier.All the above experiments regarding the interac-
tions in amino acid–drug systems are highly usefulfrom the physiological point of view as many solute–solvent interactions occur among the drug moleculesand the amino acid moieties. These interactions arealso important for the stabilisation or destabilisationof proteins as well as the drug target ability.
Conclusions
From the results obtained, the amino acid–ami-kacin system studied showed significant concentra-tion and temperature dependence of the measuredphysico–chemical parameters. Volumetric and com-pressibility measurements clearly revealed the pres-ence of electrostatic, hydrophilic or ionic interactionsbetween solute–solute, solute–solvent, and solvent–solvent molecules. Dynamic viscosity increased withthe increasing amino acid concentration and decreasedwith the increasing temperature for both amino acidsThe increase in the temperature can result an increasein the kinetic energy of the molecules and ions presentin the solution, which in turn decreases the number ofthe solute–solvent interactions. Thus a decrease in thenumber of interactions seems to be responsible for thedecrease in the dynamic viscosity with the increasingtemperature. All other parameters evaluated from theviscosity measurements are in good agreement withthe acoustical studies.
Acknowledgements. S. Chauhan thanks the UGC for thefinancial support under the project (F.No.32-237/2006/SR)Kundan Sharma and Kuldeep Kumar thank the UGC, NewDelhi for meritorious fellowship (No.F.4-1/2006 (BSR)/7-75/2007) (BSR) and (No. F-7-75/2007 (BSR), respectively.
Supplementary data
Supplementary data associated with this articlecan be found in the online version of this paper (DOI:10.2478/s11696-013-0404-y).
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