Journal of Atoms and Molecules

Research Article Journal of Atoms and Molecules An International Online Journal ISSN 2277 1247 ULTRASONIC STUDIES IN THE SOLUTIONS OF THREE HYDRATE DRUGS IN METHANOL N. Jayamadhuri 1, J. Glory 2, P. Subramanyam Naidu* 3, K. Ravindra Prasad 2 1 NBKR Institute of Science and Technology, Vidyanagar 524413, A.P., India. 2 Department of Physics, VSU PG Center, Kavali-52421 (A.P.) India. 3 Department of Physics, J.B.Degree & P.G. College, Kavali-52421 (A.P.) India. Received on: 18-3-213 Revised on: 25-3-213 Accepted on: 12 4 213 ABSTRACT: Ultrasonic velocity, density and viscosity have been measured experimentally in the solutions of hydrates in non aqueous medium i.e., methanol at two temperatures 3 and 4 o C. From the derived parameters like internal pressure, adiabatic compressibility, free volume etc., the solute-solvent and solute-solute interactions are estimated. Also in all the three hydrates in methanol, apparent molar volume and apparent molar compressibility are computed and the limiting / partial molar volumes and compressibiltiies have been obtained to reveal the nature of interactions. Jones Dole constants also evaluated are of high value in estimating the nature of interactions. On the whole, dominance of solute-solute interactions in the solutions of levofloxacin hemi hydrate is observed. In the solutions of tacrolimus monohydrate, mostly solute-solute interactions and strong solutesolvent interactions in the solutions of lisinopril di hydrate are found to be dominant. KEY WORDS: solute-solute interactions, hydrates, methanol, apparent molar volume, apparent molar compressibility * Corresponding author Dr.P.S.Naidu, Email: psnaidujb@yahoo.co.in Tel: +91-9247853495 INTRODUCTION: Studies of drugs and other compounds having medicinal value have been made by several workers [1-11]. Ultrasonic velocity, density and viscosity measurements have been of immense use in estimating solute-solute and solute-solvent interactions. Study of various drugs in aqueous media as well as non aqueous media have been well carried out in understanding the molecular interactions. In the present investigation, the drugs chosen are levofloxacin hemi hydrate, tacrolimus mono hydrate and lisinopril di hydrate owing to their importance in medicine, research and pharmaceutical industry. Ultrasonic velocity, All rights reserved 211 www.jamonline.in 492

density and viscosity measurements have been carried out in the systems of methanol with the three hydrate compounds levofloxacin hemi hydrate, tacrolimus mono hydrate and lisinopril di hydrate at two temperatures 3 and 4 o C. From the computed derived parameters like adiabatic compressibility, internal pressure etc., along with apparent molar volume (Φv ) and compressibility (Φk ), solute solute and solute solvent interactions have been estimated. Φv and Φk have been fitted to square root concentration to obtain limiting apparent molar volumes and molar compressibilities. Solvation numbers and Jones-Dole constants have also been computed to assess the nature of intermolecular interactions. Solute solute interactions in the solutions of levofloxacin and tacrolimus with methanol while in the system lisinopril + methanol at low concentrations strong solute solvent interactions are estimated. EXPERIMENTAL: Ultrasonic velocity, density and viscosity have been measured experimentally in the solutions of the three hydrate compounds employing the single crystal variable path ultrasonic interferometer, a double stem bicapillary type pyknometer and Ostwald viscometer with uncertainties +.5%, 2 parts in 1 5 and +.1% respectively. The chemicals hydrate compounds are of technical grade obtained from M/s Bioserve Clinical Research (Pvt) Ltd., Hyderabad. Methanol is of analar grade. Standardization of the equipment has been made using triple distilled water as reference liquid. THEORETICAL: From the measured velocity, density and viscosity, the following parameters can be calculated using the following expressions. Adiabatic Compressibility 1 β = U 2 ρ exp exp Internal pressure π = Free volume V f Kη brt U MU = Kη 3/2 Apparent molar volume 1/2 ρ M 2/3 7/6 (1) (2) (3) φv =(1( ρ- ρ)/ C ρ)+m eff / ρ (4) Apparent molar compressibility φk =(1(βρ-β ρ)/cρ ρ)+m eff β/ ρ (5) Solvation number S n Vβ 1 n Vβ = n n (6) Apparent molar volume (Φv ) and Apparent molar compressibility (Φk) can be fitted to square root of to obtain limiting molar volume (Φv o ) and limiting molar compressibility (Φk o ). ΦV = ΦV + S ΦK = ΦK + S V K C C (7) (8) Jones Dole Constants A and B can also be evaluated through the relation η 1 r = A + B C C (9) All the parameters have been explained else where [12,13 ]. All rights reserved 211 www.jamonline.in 493

RESULTS AND DISCUSSION: Ultrasonic velocity, density and viscosity have been measured in the three systems : i) Levofloxacin hemi hydrate +methanol, ii) tacrolimus monohydrate + methanol and iii) lisinopril dihydrate + methanol at low concentrations of the solute (hydrate) at 3 and 4 o C and are presented in Table 1. From the table, it is observed that velocity decreases with concentration of levofloxacin, increases with of tacrolimus and decreases with in the third system with lisinopril. From the measured data, thermodynamic parameters like adiabatic compressibility (β ), internal pressure (π), free volume (Vf) and enthalpy (H) have been computed and presented in Table 2. In levofloxacin system, β increases with concentration and temperature while π decreases with and temperature. Vf is opposite to that of π while H is similar to π. As observed from Table 2 in the solutions of tacrolimus, β, π and H decrease with of tacrolimus while Vf is opposite to π. In the third system i.e methanol + lisinopril also, β, π and H decrease with concentration, β curve is slightly nonlinear. From these observations, weak solute-solvent interactions and dominant solute-solute interactions in lisinopril and tacrolimus systems are indicated while in the first system levofloxacin though both types of interactions are indicated,solute-solvent interactions are very weak. In all the three systems, apparent molar volumes (Φv) and apparent molar compressebilities (Φk) also have been computed and presented in Figs. 2-3. They are fitted to square root concentration through the Masson s and Gucker equations to obtain the key parameters- limiting/partial molar volume (Φv o ) and compressibility (Φk o ) (shown in Table 3), which also speak of the nature of molecular interactions. The decrease of Φv and Φk confirm weak solute solvent and strong solute solute interactions at both the temperatures 3 and 4 o C (except at 3 o from Φv o positive). Decrease of solvation numbers as shown in Fig.4 suggests the existence of weak solute-solvent interactions. From the Jones-Dole constants, negative A suggests solute-solute interactions while positive B indicates strong solute-solvent interactions in the levofloxacin system. In the solutions of tacrolimus in methanol, Φv are positive and high and decrease with concentration as well as temperature. The decrease with temperature is also very large. Φk are negative and negative Φk decrease with both temperature and concentration. From Φv and Φk decreasing, strong solute-solute interactions are indicated. Φv o and Φk o are negative and positive respectively which confirms the existence of strong solutesolvent interactions except at 4 o. From Sv also strong solute-solvent interactions are noticed. Positive B also confirms strong solute-solvent interactions. Solvation numbers are positive and decrease with concentration of the drug. From the variation of majority of the parameters, it is suggested that there is a dominance of the solute-solute interactions even though very weak solute-solvent interactions are also observed. In the solutions of lisinopril in methanol, Φv is negative at 3 o C and positive at 4 o C. Φv decreases at both the temperatures. Φk o is negative at both the temperatures and decreases nonlinearly with at 3 and 4 o C. Φv o are positive and Φk o are negative at both the temperatures. Sv and Sk are negative and positive respectively. Jones-Dole constants suggest strong solute solvent interactions. It may be understood from the variation of majority of parameters despite a small chance of having solute-solute interactions, mostly strong solute-solvent interactions are indicated. All rights reserved 211 www.jamonline.in 494

The results of previous workers is cited here for comparison to substantiate our results and interpretations. From the density, ultrasonic velocity and viscosity measurements of four pharmacologically sufficient drugs in methanol at 25 C, Φv, Φk etc., are computed. Φv and B show different solute-solvent interactions while Φk show that drugs suppress the solvent to the same extent. The same is supported by solvation numbers [1]. Acoustical properties of four drugs in methanol at 25 C and some sympathomimetic drugs in their aqueous solutions [2] at four temperatures are studied. Meshran and Narwada [3] have studied ultrasonically some substituted pyrazolines (drugs) in acetone water mixture and observed specific molecular interactions. Paradkar et al. [4] have also contributed to the study of drugs. Baluja and Oza [5] have studied the ultrasonic behavior (also thermodynamic) of some organic compounds in both aqueous and non aqueous media. From a theoretical calculation of sound velocities in the binary solutions of tartaric acid in water, methanol and ethanol [6], the theories NR, IDR and JUNJIE appear to suit well. Sharma et al. have made viscosity and velocity studies of drugs tramacip and parvodex in binary mixtures of alcohol + water [7]. From computed parameters β, Lf, Фv, Фk, Z, RA, Sn, Jones - Dole constants A and B, molecular interactions are estimated in the solutions of Digoxin and Thiabenzadole (two drugs) in 1,4 dioxane at 33.15K. Weak solute-solvent interactions in digoxin-1,4 dioxane and strong solute-solvent interactions in thiabenzadole system are indicated [8]. Aswale et al. [9] have studied molecular interactions in coumaran-3- Ones in polar and non polar solvents from ultrasonic velocity measurements. Solute-solvent interactions have been indicated in the solutions of coumaran-3-ones in acetone and dioxane from β, Фv, Фk, Lf, Z etc. Roumana et al [1] from their investigation of Doxycycline hyclate with Ricinoleic acid, have indicated that the doxycycline hyclate exhibits liphophilic interaction effectively and turns to be monomeric form at physiological temperature from its dimer form. The inactivation of doxycycline molecules will result due to the molecular interactions with ricinoleic acid. Behaviour of L-Arginine with urea (Aq) solvent has been studied from β, Фv and Фk by Rita Mehra and Shilpi Vats [11]. Solute solvent interactions are observed to be dominant and the amino acid L-Arginine behaves as a structure maker in the system. On comparison of the three drugs (hydrates) in methanol, it is observed that from the variation of majority of parameters, dominant solute solute interactions and very weak solute - solvent interactions are suggested in the solutions of levofloxacin hemihydrate at low concentrations. In the solutions of tacrolimus monohydrate in methanol, solutesolute interactions are suggested predominantly while weak solute-solvent interactions are also observed at some concentrations. But in the third system, i.e. methanol + lisinopril dihydrate at low concentrations, unlike in the other two systems, mostly strong solute solvent interactions are indicated. ACKNOWLEDGEMENTS: The authors thank the authorities of V.S. University P.G. Centre, Kavali for providing facilities to carry out this work in the department of Physics. One of the authors (J. Glory) acknowledges the financial support from the University Grants Commission as RGNF (senior). All rights reserved 211 www.jamonline.in 495

Tables: Table 1(i). Velocity, density and viscosity data for the mixture: Levofloxacin + methanol Molarity of Levofloxacin Velocity (ms -1 ) Density (kg m -3 ) Viscosity (milli Pa.s).162 1118.4 782.63.46916.432 1115.6 784.41.4596.621 1112.3 782.87.46722.877 111. 782.54.46764.18 118. 782.16.4683.135 112. 781.85.46882.166 198. 781.36.46879.162 187.2 778.28.43348.432 185.2 778.64.4214.621 184. 775.74.42459.877 183. 775.63.42685.18 182. 775.42.4289.135 181. 774.63.4286.166 18. 773.16.4292 All rights reserved 211 www.jamonline.in 496

Table 2(i). Thermodynamic parameters for the mixture: Levofloxacin + methanol Molarity of Levofloxavin Adiabatic compressibility (1-1 N -1 m 2 ) Internal Pressure (atms) Free Volume (m 3 ) Enthalpy (KJ mole -1 ).162 1.22 114476.17 711.432 1.24 828266.22 685.621 1.32 74115.25 681.877 1.37 6426.3 668.18 1.41 586.34 659.135 1.53 513712.4 65.166 1.62 452451.47 639.162 1.87 996526.18 696.432 1.91 86629.24 667.621 1.97 717479.28 66.877 1.99 6226.33 648.18 1.12 561829.38 64.135 1.15 495957.44 63.166 1.19 435887.52 619 All rights reserved 211 www.jamonline.in 497

Table 3(i). Partial/apparent molar volumes, molar compressibilities and Jones- Dole constants for the mixture: Levofloxacin + methanol Temperature ΦV ΦK Sv Sk Jones- Dole Constants 193.98-4.88E-5-949.18.133-3474.53-6.18E-5 98486.2.165 A= -11. B= 219.4 A= -8.61 B= 164.82 Table 1 (ii) Velocity, density and viscosity Tacrolimus + Methanol Molarity of Tacrolimus Velocity (ms -1 ) Density (kg m -3 ) Viscosity (milli Pa.s).15 111.2.78148.479.32 118..78112.46925.52 1118..7854.46358.76 113..7839.46129.83 1144..77981.45668.95 116..77929.45129.19 1188..77879.44746.15 167..77461.42954.32 174..77421.4265.52 192.5.77416.41925.76 1112.6.77387.41738.83 1125..77352.41563.95 115..77337.4129.19 1164..77348.4839 All rights reserved 211 www.jamonline.in 498

Table 2(ii). Thermodynamic parameters for the mixture: Tacrolimus + Methanol Molarity of Tacrolimus Adiabatic compressibility (1-1 N -1 m 2 ) Internal Pressure (atms) Free Volume (m 3 ) Enthalpy (KJ mole -1 ).15 1.55 9661.19 76.32 1.43 72997.27 678.52 1.25 55193.37 649.76 1.4 437424.51 624.83.98 4877.57 613.95.95 366464.67 597.19.91 324362.8 578.15 1.13 88347.21 688.32 1.12 681921.29 659.52 1.8 53164.41 627.76 1.4 41932.57 61.83 1.2 393136.63 591.95.98 35859.75 573.19.95 31318.88 56 Table 3 (ii) Partial/apparent molar volumes, molar compressibilities and Jones- Dole Constants for the mixture: Tacrolimus + Methanol Temperature ΦV ΦK Sv Sk 17531.14-1.47E-5-42425 -1.42E-4 12.38-5.62E-6 21874-5.29E-4 Jones- Dole Constants A= -1.71 B= 21.7 A= -9.6 B= 16.83 All rights reserved 211 www.jamonline.in 499

Table 1 (iii) Velocity, density and viscosity Lisinopril + Methanol Molarity of Lisinopril Velocity (ms -1 ) Density (kg m -3 ) Viscosity (milli Pa.s).28 1126.4 783.9.45855.5 1122.8 783.19.45993.77 1117. 783.33.46229.113 118.4 783.53.4644.143 11.2 783.84.4667.195 196. 784.18.46971.226 191. 784.37.47146.28 1128. 772.82.3952.5 1125.8 773.14.39836.77 1123. 773.38.4357.113 1118.5 773.49.4933.143 1113.1 773.59.4125.195 116.1 773.7.41386.226 11.2 773.78.41523 All rights reserved 211 www.jamonline.in 5

Table 2 (iii). Thermodynamic parameters for the mixture: lisinopril + Methanol Molarity of Lisinopril Adiabatic compressibility (1-1 N -1 m 2 ) Internal Pressure (atms) Free Volume (m 3 ) Enthalpy (KJ mole -1 ).28 1.6 877381.21 688.5 1.13 744161.26 674.77 1.23 623325.32 66.113 1.39 51536.41 644.143 1.54 444582.48 635.195 1.62 359646.63 619.226 1.71 321893.72 611.28 1.17 814977.26 642.5 1.21 691711.32 629.77 1.25 58212.39 618.113 1.33 47618.5 65.143 1.43 414242.59 596.195 1.56 334568.77 581.226 1.68 299345.88 574 Table 3(iii) Partial/apparent molar volumes, molar compressibilities and Jones- Dole constants for the mixture: Lisinopril + Methanol Temperature ΦV ΦK Sv Sk Jones- Dole Constants 675-3.81E-5-3143 8.88E-4 A= -1.2 B= 173.5 111-7.33E-5-224122.159 A= 12.38 B= 223.1 All rights reserved 211 www.jamonline.in 51

Figures: 112 1115 111 16 14 12 velocity (ms -1 ) 115 11 195 19 solvation number 1 8 6 4 185 18..2.4.6.8.1.12.14.16.18 Fig.1(i). Variation of velocity with of levofloxacin in the mixture: Levofloxacin + methanol 2..2.4.6.8.1.12.14.16.18 Fig. 4(i). Variation of solvation number with of levofloxacin in the mixture: Levofloxacin + methanol Φ v (L mole -1 ) 4-12 -16-2..2.4.6.8.1.12.14.16.18-4 -8 velocity (ms -1 ) 12 118 116 114 112 11-24 18-28 16 Fig. 2(i). Variation of apparent molar volume with of levofloxacin in the mixture: Levofloxacin + methanol..2.4.6.8.1.12 Fig. 1(ii). Variation of velocity with of tacrolimus in the mixture: Tacrolimus + methanol Φ k (m 2 N -1 mole -1 )...2.4.6.8.1.12.14.16.18 -.1 -.2 -.3 -.4 Φ V (L mole -1 ) 16 14 12 1 8 6 -.5 4 2 -.6 Fig. 3(i). Variation of apparent molar compressibility with of levofloxacin in the mixture: Levofloxacin + methanol..2.4.6.8.1.12 Fig. 2(ii). Variation of apparent molar volume with of tacrolimus for the mixture: Tacrolimus + methanol All rights reserved 211 www.jamonline.in 52

1-1.1..2.4.6.8.1.12-1.2-1.3-1.4-1.5 8 6 3 c 4 c Φ K (m 2 N -1 mole -1 ) -1.6-1.7-1.8-1.9-2. -2.1-2.2-2.3 Φ V (L mole -1 ) 4 2-2.4.2.4.6.8.1.12.14.16.18.2.22 Fig. 3(ii). Variation of apparent molar compressibility with of tacrolimus for the mixture: Tacrolimus + methanol Fig. 2(iii). Variation of apparent molar volume with of lisinopril in the mixture: Lisinopril + methanol 18 solvation number 16 14 12 1 8 6 4 Φ K (m 2 N -1 mole -1 ). -.1 -.2 -.3 -.4.2.4.6.8.1.12.14.16.18.2.22 C 3 c 4 c 2 -.5..2.4.6.8.1.12 Fig. 4(ii). Variation of solvation number with of tacrolimus in the mixture: Tacrolimus + methanol -.6 Fig. 3(iii). Variation of apparent molar compressibility with of lisinopril in the mixture: Lisinopril + methanol 113 1125 112 9 8 7 6 3 c 4 c velocity (ms -1 ) 1115 111 115 solvation number 5 4 3 11 2 195 1 19..5.1.15.2.25 Fig. 1(iii). Variation of velocity with of lisinopril for the mixture: Lisinopril + methanol..5.1.15.2.25 Fig. 4(iii). Variation of solvation number with of lisinopril in the mixture: Lisinopril + methanol All rights reserved 211 www.jamonline.in 53

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