Solubility enhancement of simvastatin and atorvastatin by arginine: A solvodynamics study

Accepted Manuscript Solubility enhancement of simvastatin and atorvastatin by arginine: A solvodynamics study

M.M.R. Meor Mohd Affandi, Minaketan Tripathy, A.B.A. Majeed PII: DOI: Reference:

S0167-7322(17)30367-7 doi: 10.1016/j.molliq.2017.05.003 MOLLIQ 7295

To appear in:

Journal of Molecular Liquids

Received date: Revised date: Accepted date:

27 January 2017 ###REVISEDDATE### 3 May 2017

Please cite this article as: M.M.R. Meor Mohd Affandi, Minaketan Tripathy, A.B.A. Majeed , Solubility enhancement of simvastatin and atorvastatin by arginine: A solvodynamics study, Journal of Molecular Liquids (2017), doi: 10.1016/ j.molliq.2017.05.003

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Solubility enhancement of simvastatin and atorvastatin by arginine: a solvodynamics study MMR Meor Mohd Affandi a,b . Minaketan Tripathya, b*. ABA Majeed

b

a

RI

*corresponding author, Tel: +60332584693; fax +60332584602

PT

Laboratory Fundamental of Pharmaceutics, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), 42300 Bandar Puncak Alam, Selangor, Malaysia. b Pharmaceutical and Life Sciences Core, Universiti Teknologi MARA (UiTM), 40450, Shah Alam, Selangor Darul Ehsan, Malaysia.

SC

E-mail address: [email protected] ABSTRACT

NU

Arginine (ARG) aided solubility enhancement of statin-based model drugs such as simvastatin (SMV) and atorvastatin (ATV) has been reported. Herein, both SMV and ATV

MA

are considered as a solute, whereas ARG the cosolute. The present study deals with experiments to illustrate the solute-solvent interaction, solute-cosolute interaction and the

D

thermodynamic parameters during the solubilisation of the above drug candidates in water in

PT E

the presence of ARG. The soundspeed values of ARG, Simvastatin-Arginine (SMV-ARG) and Atorvastatin-Arginine (ATV-ARG) systems were determined in water maintaining

CE

different concentrations (0.01, 0.02, 0.04, 0.09, 0.18, 0.36 and 0.73 mol dm-3) of aqueous ARG, with saturated presence of SMV (SMV-ARG) and ATV (ATV-ARG) at 298.15 K.

AC

Values of refractive index of the above system were recorded at 298.25, 303.15, 308.15, and 313.15 K. Refractive index values were used to calculate the molar refractivity and the results discussed accordingly. Values of sound speed were used to evaluate acoustic parameters such as isentropic compressibility (Ks), apparent isentropic molar compressibility (Ks), relative association (Ra), acoustic impedance (Z), internal pressure (i), and free volume (Vf). It was observed that sound velocity increased with the increase in case of ARG concentration with linear fashion (R2=0.9978). Compressibility values decreased with increase in ARG

ACCEPTED MANUSCRIPT concentration. Changers in acoustic parameters were discussed in terms of solute-solvent interaction and structural effects of water for all systems. Keywords:

arginine, statin, acoustic parameters.

1. Introduction Poor solubility is one of the main technical obstacles faced by the pharmaceutical

PT

scientist involved in the formulation of drug products. The issue is significant as 40% of new

RI

chemical entities are either poorly soluble or insoluble in water [1]. Statin molecules, well-

SC

known for their ability to compete and inhibit 3-hydroxy-3-methlyglutaryl coenzyme A (HMG-CoA) reductase are active pharmaceutical ingredients categorized as BCS Class II

NU

drugs (low solubility, high permeability). In order for drugs of this class to achieve complete absorption in the systemic circulation, they must be dissolved in the gastrointestinal fluid to

MA

release their content [2].

Arginine (ARG) is a conditional essential amino acid and a key component of protein. It

D

has various applications including promotion of nitric oxide release [3-4], alleviation of

PT E

impotence [5-6], wound healing [7] and protection against age-related degenerative diseases [8]. The role of ARG in solubility enhancement of proteins has been extensively studied [9-

CE

10]. It disrupts protein-protein and protein-surface interactions, thereby increasing protein solubility. An attempt by other researchers to solubilize the highly insoluble protein, gluten

AC

[10-11] supports the possibility for ARG to be explored as a potential solubility enhancer.

We studied the solubility enhancement of simvastatin (SMV) and atorvastatin (ATV) using ARG as a cosolute and found 12,000 and 25-fold increase in solubility respectively [12-13]. The involved thermodynamics, solute-solvent interactions and related spectral characterizations were reported in the same communication.

As a continuation of our

research we have further elucidated the molecular interactions and dynamics, hence the related structural effects upon solvation using the measurement of refractive index and sound

ACCEPTED MANUSCRIPT speed. High-precision sound speed and refractive index measurements provide valuable information about the functional properties of solutes in aqueous solutions [14]. Further, ultrasonic properties of electrolytic and non-electrolytic solutions are useful in elucidating solute-solvent and solute-solute interactions [15-18].

PT

2. Experimental

RI

2.1. Chemicals

SC

SMV and ATV were generously donated by Hovid Berhad (Ipoh, Malaysia). ARG was procured from Sigma Aldrich (St. Louis, USA). The water used was obtained from Bio O

D

2.2. Preparation of solution systems

MA

analytical grade unless otherwise stated.

NU

Purite (Oxfordshire, United Kingdom) water system. All other chemicals used were of

PT E

Solution systems of SMV and ATV in the presence of ARG was weighed on a Metler balance with a precision of ±0.001mg and dissolved in 100ml in purified water in a conical

freshly prepared.

CE

flask. ARG solutions ranging from 0.01 to 0.73 mol dm-3 (denoted as SB1 to SB7) were

AC

An excess amount of drugs (SMV or ATV), was added to each flask containing the specified molar solutions of the ARG and denoted as SM1 to SM7 and ST1 to ST7 respectively, to prepare the saturated solution. Separately, an excess amount of drug was added to only laboratory grade water to determine the respective intrinsic solubilities, denoted as (SM0 and ST0). All conical flasks were placed in a mechanical water bath shaker at temperature of 308.15 ± 0.02 K and shaken for a maximum period of 72 hours. At the end of the incubation period, the suspensions were filtered through a 0.5 µm membrane filter

ACCEPTED MANUSCRIPT (Millipore). Aliquots of the filtrates were subjected to sound speed and refractive index estimation against the respective molar solutions of ARG as blank. Each experiment was repeated at least three times and the results reported are the mean values ±SD.

2.3. Refractive index measurements

PT

The refractive indices were measured using an Abbemax digital refractometer (Misco,

RI

USA), fitted with one Microsoft windows software. The instrument was calibrated using the

SC

reference solvents, provided by the supplier. The temperature maintenance of the system was performed by the inbuilt peltier device, with a temperature uncertainty of ± 0.01K. The

NU

uncertainties in refractive indices were ± 0.000001.

MA

2.4. Sound velocity

A multifrequency electro acoustics spectrometer (Dispersion Tech Inc, USA) was used to

D

measure the sound speed through different samples at temperature 298.15 K. All the

PT E

generated data were treated to further calculate the thermo-physical parameters to interpret with respect to the solute solvent interactions and structural effects in order to provide more

CE

insights into the solution dynamics. The instrument was operated to generate six data point.

AC

3. Results and discussion

3.1. Refractive Index

The values of refractive index, D molar refractivity RD, of water and of various samples of ARG, SMV-ARG and ATV-ARG captured at 298.15,303.15, 308.15, and 313.15 K are shown in Table 1, 2, and 3 respectively. Values displayed in the table represent the average of at least three independent measurements. Values of RD of the studied systems are calculated using the Lorentz-Lorentz equation [19-21]

ACCEPTED MANUSCRIPT (1)

Where xi and Mi are the mole fraction and the molecular weight of the ith component of the solution system respectively. Values of refractive indices of water (SB0) at the four studied temperatures are lower than the ARG (SB1-SB7), SMV-ARG (SM1-SM7) and ATV-ARG

PT

(ST1-ST7) solution systems (Table 1-3). This observation is in good agreement with the

RI

literature [21]. The D shows an upward trend with increasing concentrations, whereas the reverse is the case with temperature in all three solution (Figure 1a-c). As can be seen, values

SC

of D in case of SMV-ARG are higher than those of both ATV-ARG and ARG solution

NU

systems (Figure 2a-d). This behaviour is consistent with results showing the effect of ARG concentrations on the apparent molar volume, indicating that D is directly related to the

MA

interactions in the solution [22]. The trend of RD values for the studied system is the same as that of the D values: SMV-ARG > ATV-ARG > ARG (Table 1-3). The refractive index of a

D

solution system indicates the packing of the molecules in the solvent structure [23]. These

PT E

observations are in coherence with our solubility data [12-13], whereas the cosolute ARG enhances the solubility of SMV much more than ATV. Further the variations in RD at

CE

303.15K, as a function of ARG concentrations, also in saturated presence of SMV and ATV are depicted graphically in Figure 3 (a-c). Plots in Figure 3a-c are found to increase linearly

AC

with increasing amount of ARG and ARG in the presence of SMV and ATV. The RD as a factor is directly proportional to the molecular polarizability [22]. Hence Figure 3a-c reveal that the overall polarizability of the systems under study increases with the cosolute and solute content and the different extent of tight packing resulting in the maximum solute solvent interaction of SMV-ARG >ATV-ARG>ARG.

3.2. Sound Velocity

ACCEPTED MANUSCRIPT In case of the aqueous ARG solutions, the velocity of sound increases with an increase in the concentration of the solute (Table 4). As can be seen, aqueous solutions of SMV-ARG have comparatively higher values of sound velocity as compared to the blank. This observation can be explained by the fact that, the solution system in case of SMV-ARG contains a large number of SMV molecules, which contribute to the higher sound velocity.

PT

This is consistent with the result obtained from the higher density values of the SMV-ARG

RI

[12-13].

SC

From the results of the sound velocity (U) and density (d), the isentropic compressibility,

MA

NU

Ks of the samples was calculated [15] as

(3)

PT E

D

and the internal pressure [24] as

(2)

Where Ks0 is the isentropic compressibility of water. The apparent isentropic molar

(4)

AC

CE

compressibility Ks of the samples were computed from equation [17]:

where Ks0 and d0 are the isentropic compressibility and density respectively, of water at 298.15 K. The values of density and sound velocity enable us to estimate the magnitude of relative association (Ra) from the relation [25]:

(5)

ACCEPTED MANUSCRIPT Where Uo is the sound velocity of water at 298.15 K. The acoustic impedance Z was determined from the relation [26] (Dash et al., 2007): (6)

PT

The values of the Ks, Ra, Z and Ks of the samples are given in Table 4 and 5 respectively.

(7)

SC

RI

The value of free volume, Vf was calculated from the relation [26]:

NU

Where Vm is the molar volume of the mixture and is given by

(9)

PT E

D

MA

and

(8)

Where ni is the number of moles and mi is the molecular mass of the i-th component in the

CE

mixture and d is the density of the corresponding aqueous solution systems.

AC

In equation (6), b is the Van der walls constant and obtained from the relation [27]: (10)

Where R is the universal gas constant, T (=298.15) K, and мav is the average molecular mass of the mixture as given in equation (9). The value of Vf along with that of internal pressure, πi are given in Table 5.

ACCEPTED MANUSCRIPT As can be seen from Table 4, isentropic compressibility, Ks values at a fixed temperature decrease with an increase in the concentration of solute for the systems of ARG, SMV-ARG and ATV-ARG. It is further observed that Ks is lower in the presence of SMV and ATV compared to the blank (ARG). ARG addition to water results in (i) the breaking of the 3Dpolymeric structure of water, dissociation of ARG and subsequent ion-pair formation and (ii)

PT

the formation of some complex structures/aggregates, possibly by the self-association of

RI

ARG. The tendency of aggregate formation increases in the presence of the aqueous insoluble

SC

drugs such as SMV and ATV, resulting in smaller Ks values as compared to the values of the samples containing ARG alone. Further the phenomenon of complex structure or aggregate

NU

formation can be explained in terms of (i) molecular association between ARG and SMV by the mechanism of hydrogen bonding and (ii) reorientation of ARG leading to self-association,

MA

hence forming a cage that can accommodate a hydrophobic substance, by reducing the effective hydrophobic surface in this case of ATV. It means that the presence of the aqueous

D

insoluble drugs in the aqueous ARG solutions makes the medium electrostricted as a result of

PT E

which the isentropic compressibility decreases, and the internal pressure increases. This observation is supported by Srivastava et al (1970) [24].

CE

The apparent isentropic molar compressibility, Ks of the system was irregular except for

AC

the SMV-ARG system. The presence of SMV in the system decreases the Ks .Values of Ks are negative in most of the cases, and this can be explained in terms of two different phenomena; extent of electrostriction and solvation. It means that the medium exhibits typical response, because of ion pair formation, solute-co-solute interaction and co-solute – co-solute led self-association of ARG corresponding to the systems of ARG, SMV-ARG and ARGATV respectively. This also points to the fact that the solvent loses its elasticity.

ACCEPTED MANUSCRIPT The ratio of instantaneous pressure excess on any solute/substance within the medium to its instantaneous velocity defines the phenomenon of acoustic impedance which depends upon the concentration and temperature of the system [28]. When sound travels in a medium the pressure on particles varies, from one another and is usually governed by the inertial and elastic properties of the medium. A perusal of Table 5 shows that the acoustic impendence

PT

(Z) increases with an increase in the concentration of solute and cosolute of all systems. This

RI

observation can be ascribed to the fact that the increase in solute concentration results in an

SC

increase in internal pressure as well as the cohesive energy. Strong intermolecular interaction causing an increase in acoustic impedance, due to elevation in the instantaneous pressure

MA

with the results of the internal pressure i.

NU

excess at any molecule, with the propagation of sound wave. This observation is in agreement

The internal pressure πi plays an important role in elucidating molecular interactions as

D

this represents the resultant of the forces of repulsion and attraction between the molecules

PT E

[24]. The free volume Vf is the effective volume accessible to the center of a molecule in a liquid. The structure of a liquid is determined by strong repulsive forces in the liquid with the relatively weak attractive forces providing the internal pressure which holds the liquid

CE

molecules together. The Vf seems to be conditional of the repulsive forces while the πi is

AC

more sensitive to attractive forces. These two factors together uniquely determine the entropy (i.e., disorderness) of the system. The πi, Vf and temperature are the thermodynamic variables that describe the liquid system of fixed composition. As detected, the values of πi are positive and enhanced with an increase in the concentration whereas the values of Vf , are negative and decrease with a rise in the cosolute/solute concentration. The positive value of πi indicates that there is a strong inter molecular interaction leading to the enhanced structure of water. Values of πi and isentropic compressibility complement each other. The negative value Vf signifies that there is a decrease in cohesive forces leading to the disruption of water

ACCEPTED MANUSCRIPT structure in systems containing ARG molecules and aqueous insoluble drugs such as SMV and ATV as a result of which water molecules are entrapped in voids created by the complex aggregate. Values of the relative association, Ra (Table 5) show a slight increase from unity for pure water to aqueous ARG, SMV-ARG and ATV-ARG systems, except at ST1 of ARG-ATV

PT

systems. Values of Ra of the systems show an irregular trend. When compared between

RI

systems, the presence of SMV and ATV, resulted in a dual behaviour. Relative association is

SC

influenced by two factors; (i) the breaking of associated solvent molecules on the addition of a solute to it, and (ii) the solvation of the solute molecules (here ARG and the drug). The

NU

former is predominant when the Ra value decreases and the latter, in the case of an increase in Ra values. In the present study, Ra values point to the fact that solute solvent interactions are

MA

associated with the disruption of water structure followed by solvation.

D

4. Conclusion

PT E

In this study, refractive indices and sound speed of various concentration of ARG, SMVARG and ATV-ARG system were determined at 298.15-313.15K and 298.15K respectively.

CE

The D of aqueous solutions of all systems is higher than that of water and increases with the concentration. The trend of RD values of the system is the same as that of the D values:

AC

SMV-ARG > ATV-ARG > ARG. D and RD values indicate maximum interactions and polarizability within the systems and the results are in good agreement with our solubility findings, where solubility enhancement is in the order: SMV-ARG > ATV-ARG. The ultrasonic velocity (U) increases with the concentration in all systems. Aqueous solutions of SMV-ARG and ATV-ARG have comparatively higher values of U as compared to the blank. Values of acoustic parameters such as isentropic compressibility (Ks), internal pressure (πi), acoustic impedance (Z) and free volume (Vf) complement each other. The

ACCEPTED MANUSCRIPT positive value of πi indicates that there is a strong inter molecular interaction leading to the enhanced structure of water. Values of Vf are negative and decrease with an increase in the cosolute/solute concentration. Values of Ra, in the case of the ARG systems shows a regular pattern, whereas that of SMV-ARG and ATV-ARG, exhibit an irregular correlation with concentration. When compared among the systems, the presence of SMV and ATV, resulted

PT

in a dual behaviour. Ra values suggest that the solute solvent interactions are associated with

RI

the disruption of water structure followed by solvation. As a conclusion, the present study

SC

provides the possible molecular interactions and molecular dynamic in ARG-aided solubility enhancement of SMV and ATV on the basis of refractive index and sound speed based

NU

physical measurements.

MA

Acknowledgements

We are thankful to Hovid Bhd for providing SMV and ATV drug samples and MMR Meor

D

Mohd Affandi is thankful to UiTM for study leave and financial assistance.

PT E

References

1. A. Naseem, C.J. Olliff, L.G. Martini, A.W. Lloyd, Int. J. Pharm. 269 (2004) 443-450.

CE

2. D. Hörter, J. Dressman, Adv. Drug. Deliv. Rev. 46 (2001) 75–87.

AC

3. A.J. Maxwell, J.P. Cooke, Curr. Opin. Nephrol. Hypertens. 7 (1989) 63–70. 4. G. Wu, C.J. Meininger, J. Nutr. 130 (2000) 2626–2629. 5. A. Melman, J. Urol. 158 (1997) 686-694. 6. A.W. Zorgniotti, E.F. Lizza, Int. J. Impot. Res. 6 (1994) 33–35. 7. S.J. Kirk, M. Hurson, M.C. Regan, D.R. Holt, H.L. Wasserkrug, A. Barbul, Surgery. 114 (1993) 155–159. 8. J. Yi, L.L. Horky, A.L. Friedlich, Y. Shi, J.T. Rogers, X. Huang, Int. J. Clin. Exp. Pathol 2 (2009) 211–238.

ACCEPTED MANUSCRIPT

9. A. Hirano, T. Arakawa, K. Shiraki, J. Biochem. 144 (2008) 363-369. 10. A. Arakawa, Y. Kita, A.H. Koyama, Int. J. Pharm. 355 (2008) 220-223. 11. S. Tripathy, M. Tripathy, P.V. Kar, A.B.A. Majeed, Chem. Sci. Trans. 2 (2013) 208212.

PT

12. M.M.R. Meor Mohd Affandi, M. Tripathy, S.A. Alishah, A.B.A. Majeed, Drug Des. Dev. Ther. 10 (2016) 959–969.

RI

13. M.M.R. Meor Mohd Affandi, M. Tripathy, A.B.A. Majeed, J. Adv. Pharm. Technol. Res. 7 (2016) 80–86.

SC

14. V.A. Rana, H.A. Chaube, J. Mol. Liq. 187 (2013) 66-73.

NU

15. S.S.B. Ambomase, S. Tripathy, M. Tripathy, U.N. Dash, E-J. Chem. 8 (2011) 63-70.

MA

16. W. Chanasattru, E.A. Decker, D.J. McClements, Food Hydrocolloid. 22 (2008) 14751484. 17. N. Rohman, N.N. Dass, S. Mahiuddin, J. Chem. Eng. Data. 44 (1999) 465-472.

D

18. A. Wahab, S. Mahiuddin, J. Chem. Eng. Data. 49 (2004) 126-132.

PT E

19. H.A. Lorentz, Ann. Phys. 245 (1880) 641–665. 20. L. Lorenz, Ann. Phys. 247 (1880) 70–103.

CE

21. A. Ali, S. Hyder, S. Sabir, D. Chand, A.K. Nain, J. Chem. Thermodyn. 38 (2006) 136–143.

AC

22. A. Ali, F. Nabi, F.A. Itoo, S. Tasneem, J. Mol. Liq. 143 (2008) 141–146. 23. I. Banik, M.N. Roy, J. Mol. Liq. 169 (2012) 8–14. 24. S.P. Srivastava, S. Laxmi, J. Phys. Chem. 70 (1970) S 219-223. 25. U.N. Dash, G.S. Roy, S. Mohanty, Indian J. Chem. Techn. 11 (2004) 714-718. 26. U.N. Dash, G.S. Roy, S. Mohanty, M. Ray, Indian J. Pure Ap. Phy. 45 (2007), 151156. 27. J.V. Rani, K. Kannagi, R. Padmavathy, N. Radha, JBAP.1 (2012) 96-101.

ACCEPTED MANUSCRIPT

AC

CE

PT E

D

MA

NU

SC

RI

PT

28. A. Awasthi, M. Rastogi, M. Gupta, J.P. Shukla, J. Mol. Liq. 80 (1999), 77-88.

ACCEPTED MANUSCRIPT Table 1 Refractive indices (nD) and molar refractive Indices (RD) of arginine solution (SB0 = purified water, SB1-SB7 = arginine solution system ranging from 0.01148 mol.dm-3 to 0.73478 mol.dm-3). Concent 298.15K 303.15K 308.15K 313.15K (Molar) nD RD (x10-3) nD RD (x10-3) nD RD (x10-3) nD RD (x10-3) SB0 1.3324 ± 0.000006 0 1.3317 ± 0.00001 0 1.3311 ± 0.000005 0 1.3303 ± 0.00001 0 SB1

1.3329 ± 0.000006

7.421

1.3322 ± 0.00001

7.430

1.3315 ± 0.000009

SB2

1.3333 ± 0.000006

14.847

1.3327 ± 0.00001

14.857

1.3319 ± 0.000005

14.864

SB3

1.3341 ± 0.000006

29.725

1.3335 ± 0.00001

29.750

1.3328 ± 0.000009

SB4

1.3360 ± 0.000010

59.554

1.3353 ± 0.00001

59.634

SB5

1.3391 ± 0.000006

119.410

1.3385 ± 0.00001

119.608

SB6

1.3450 ± 0.000006

239.799

1.3444 ± 0.00002

240.143

SB7

1.3583 ± 0.000006

484.225

1.3579 ± 0.00003

485.333

A

C C

T P E

D E

T P

I R

7.426

1.3308 ±0.00001

7.426

1.3312 ± 0.00001

14.864

29.755

1.3321 ± 0.00001

29.755

1.3346 ± 0.000009

59.628

1.3339 ± 0.00001

59.628

1.3378 ± 0.000001

119.607

1.3372 ± 0.00001

119.607

1.3438 ± 0.000008

240.194

1.3434 ± 0.00001

240.195

1.3576 ± 0.000005

486.696

1.3574 ± 0.00001

486.696

C S U

N A

M

ACCEPTED MANUSCRIPT

Table 2 Refractive indices (nD) and molar refractive Indices (RD) of arginine saturated with simvastatin solution system (SM0 = purified water saturated with simvastatin, SM1-SM7 = arginine saturated with simvastatin solution system ranging from 0.01148 mol.dm-3 to 0.73478 mol.dm-3). Concen 298.15K 303.15K 308.15K 313.15K -3 -3 -3 (Molar) nD RD (x10 ) nD RD (x10 ) nD RD (x10 ) nD RD(x10-3) SM0 1.3325 ± 0.000006 0.005 1.3317 ± 0.00001 0.005 1.3311 ± 0.000005 0.005 1.3303 ± 0.00001 0.005

T P

C S U

SM1

1.3331 ± 0.000006

8.290

1.3324 ± 0.00001

8.301

1.3317 ± 0.000008

8.300

SM2

1.3336 ± 0.000006

15.967

1.3330 ± 0.00002

15.974

1.3323 ± 0.000005

SM3

1.3346 ± 0.000006

32.657

1.3340 ± 0.00001

32.663

SM4

1.3367 ± 0.000010

63.506

1.3361 ± 0.00001

63.526

SM5

1.3417 ± 0.000006

127.839

1.3410 ± 0.00001

SM6

1.3508 ± 0.000012

265.968

1.3503 ± 0.00001

SM7

1.3675 ± 0.000006

560.606

1.3670 ± 0.00001

D E

A

C C

T P E

I R

1.3310 ±0.00001

8.293

15.986

1.3316 ± 0.00001

15.971

1.3333 ± 0.000005

32.710

1.3325 ± 0.00001

32.679

1.3354 ± 0.000005

63.649

1.3346 ± 0.00001

63.598

1.3405 ± 0.000012

128.129

1.3400 ± 0.00001

128.147

262.627

1.3498 ± 0.000008

266.750

1.3495 ± 0.00001

266.727

550.050

1.3670 ± 0.000017

562.876

1.3665 ± 0.00001

563.335

127.223

N A

M

ACCEPTED MANUSCRIPT

Table 3 Refractive indices (nD) and molar refractive Indices (RD) of arginine saturated with atorvastatin solution system (ST0 = purified water saturated with atorvastatin, ST1-ST7 = arginine saturated with atorvastatin solution system ranging from 0.01148 mol.dm -3 to 0.73478 mol.dm-3). Concen 298.15K 303.15K 308.15K 313.15K (Molar) nD RD (x10-3) nD RD (x10-3) nD RD (x10-3) nD RD(x10-3) ST0 1.3325 ± 0.000015 0.195 1.3318 ± 0.000020 0.195 1.3312 ± 0.000015 0.195 1.3304 ± 0.000015 0.195

T P

I R

C S U

ST1

1.3329 ± 0.000021

9.471

1.3323 ± 0.000010

9.474

1.3316 ± 0.000010

ST2

1.3333 ± 0.000026

17.025

1.3327 ± 0.000051

17.029

ST3

1.3343 ± 0.000087

32.584

1.3336 ± 0.000098

32.627

ST4

1.3358 ± 0.000031

62.810

1.3352 ± 0.000010

ST5

1.3391 ± 0.000011

122.733

1.3384 ± 0.000010

ST6

1.3453 ± 0.000017

243.225

1.3447 ± 0.000055

D E

ST7

1.3585 ± 0.000081

489.084

1.3577 ± 0.000072

A

C C

T P E

9.465

1.3308 ±0.000015

9.465

1.3320 ± 0.000040

17.031

1.3312 ± 0.000062

17.031

1.3329 ± 0.000010

32.628

1.3321 ± 0.000093

32.593

1.3345 ± 0.000036

62.838

1.3341 ± 0.000059

62.903

122.877

1.3376 ± 0.000011

122.855

1.3367 ± 0.000012

122.678

243.769

1.3440 ± 0.000012

243.812

1.3434 ± 0.000019

243.684

489.058

1.3569 ± 0.000024

488.904

1.3559 ± 0.000052

491.530

62.765

N A

M

ACCEPTED MANUSCRIPT Table 4 Values of density (ρ), ultrasonic velocity (U), isentropic compressibility (Ks) and apparent isentropic compressibility (Ksɸ) of different concentrations of arginine solution system, arginine solution system (ARG) with saturated presence of simvastatin (SMV-ARG) and arginine solution system with saturated presence of atorvastatin (ATV-ARG) Concentration (M x 10-2) Solution Ultrasonic 1.148 2.296 4.592 9.184 18.369 36.739 73.478 System Parameter (S2) (S3) (S4) (S5) (S6) (S7) Ultrasonic Velocity 1495.27 1497.11 1499.35 1504.35 1517.36 1533.16 1572.53 ARG (m/s) Density @ 298.15K 0.9971 0.9979 0.9986 1.001 1.0054 1.0136 1.032 (kg.m-3) Ks (10-7) (Pa-1) 4.4856 4.4710 4.4545 4.4144 4.3200 4.1972 3.9185 -5 Ksɸ (10 ) -4.0531 -6.0224 -3.3537 -3.2998 -3.9379 -2.3885 -2.1865 Ultrasonic Velocity 1495.56 1497.87 1500.65 1506.58 1518.54 1537.90 1578.80 SMV-ARG (m/s) Density @ 298.15K 0.9978 0.998 0.9995 1.002 1.007 1.0165 1.034 (kg.m-3) Ks (10-7) (Pa-1) 4.4807 4.4660 4.4428 4.3969 4.3064 4.1594 3.8799 Ksɸ (10-5) -12.3292 -9.0412 -7.1255 -5.8574 -5.1499 -3.8106 -2.8528 Ultrasonic Velocity 1504.70 1506.00 1511.30 1515.80 1521.50 1544.30 1584.10 ATV-ARG (m/s) Density @ 298.15K 0.9970 0.9980 0.9990 1.001 1.006 1.016 1.033 -3 (kg.m ) Ks (10-7) (Pa-1) 4.4300 4.4179 4.3826 4.3479 4.2939 4.1270 3.8577 Ksɸ (10-5) 3.1292 -1.7577 -5.6653 -3.7036 -2.1254 -2.9410 -2.2904

T P

I R

C S U

N A

D E

T P E

A

C C

M

ACCEPTED MANUSCRIPT Table 5 Values of molar volume (Vm), free volume (Vf), internal pressure (πi), acoustic impedance (Z) and relative association (Ra) data of different concentration of arginine solution system (ARG), arginine solution system with saturated presence of simvastatin (SMV-ARG) and arginine solution system with saturated presence of atorvastatin (ATV-ARG) Concentration (M x 10-2) Solution Ultrasonic 1.148 2.296 4.592 9.184 18.369 36.739 73.478 System Parameter (S1) (S2) (S3) (S4) (S5) (S6) (S7) 3 Vm (m ) 174.71 174.57 174.44 174.03 173.26 171.86 168.80 3 3 -1 ARG Vf (10 ) (m mol ) -39.632 -39.649 -39.681 -39.719 -39.890 -39.983 -40.287 -9 πi (10 ) (Pa) 0.6908 2.1497 3.7959 7.8130 17.250 29.532 57.399 2 -2 -1 Z (10 ) (kgm S ) 14.909 14.939 14.972 15.058 15.255 15.540 16.228 Ra 1.0015 1.0018 1.0020 1.0034 1.0049 1.0096 1.0193

T P

I R

SMV-ARG

ATV-ARG

Vm (m3) Vf (103) (m3 mol-1) πi (10-9) (Pa) Z (102) (kgm-2S-1) Ra

174.58 -39.612 1.2348 14.923 1.0024

174.55 -39.666 2.7076 14.949 1.0020

Vm (m3) Vf (103) (m3 mol-1) πi (10-9) (Pa) Z (102) (kgm-2S-1) Ra

174.72 -39.888 0.5304 15.002 0.9998

174.55 -39.882 1.7380 15.030 1.0005

174.29 -39.681 5.0321 14.999 1.0029

E C

C A

D E

PT 174.37 -39.984 5.2704 15.098 1.0003

173.85 -39.739 9.6218 15.096 1.0041 174.03 -40.024 8.7391 15.173 1.0014

C S U

N A

172.99 -39.858 18.6676 15.292 1.0065

171.37 -39.994 33.3641 15.633 1.0117

168.47 -40.371 61.3154 16.325 1.0201

173.16 -39.976 14.1360 15.306 1.0051

171.46 -40.181 30.0824 15.690 1.0101

168.63 -40.547 57.7564 16.364 1.0183

M

ACCEPTED MANUSCRIPT

T P

I R

C S U

N A

D E

b

M

T P E

C C

A

c Fig. 1 a-c. Refractive Indices (nD) against concentration (mol.dm-3) at various temperature for (a) Arginine solution system (b) Simvastatin-Arginine solution system (c) Atorvastatin-Arginine solution system.

ACCEPTED MANUSCRIPT

a

b

T P

I R

C S U

N A

D E

c

M

d

T P E

C C

A

Fig. 2 a-d. Refractive Indices (nD) against concentration (mol.dm-3) at various solution system (a) 298.15K (b) 303.15K (c) 308.15K (d) 313.15K

ACCEPTED MANUSCRIPT

a

T P

I R

b

C S U

c

Fig. 3 a-c. Variation of molar refractive Indices against concentration at T = 303.15K for (a) Arginine solution system(r2 = 1) (b) Simvastatin-Arginine solution system (r2 = 0.9993) (c) Atorvastatin-Arginine solution system(r2=1).

N A

D E

T P E

A

C C

M

ACCEPTED MANUSCRIPT Highlight.



Solvodynamics study of statins with the presence of arginine were highlighted.



Influences of arginine concentration on sound velocity and compressibility were discussed.



Changers in acoustic parameters in terms of solute-solvent interaction and structural effects of water were reviewed.

I R

T P

C S U

N A

D E

T P E

A

C C

M