INTRODUCTION:

In the development of effective drugs, one of the main factors emphasized by formulators is the aqueous solubility. This factor is, however, a challenge for lovastatin (LVS)¹, a statin drug classified under Biopharmaceutical Classification System (BCS) Class II drugs which have low solubility despite being highly permeable^2-4. The structure of LVS is shown in Figure 1. Numerous formulation strategies such as solid dispersion, particle size reduction, forming inclusion complex and some other novel methods have been applied and investigated in order to overcome this limitation⁵.

Figure 1: Chemical structure of LVS

Arginine (ARG) is a semi-essential amino acid obtained by hydrolysis of many proteins and found particularly abundant in protamines and histones^6-8. Previous studies reported that ARG to be effective in suppressing protein aggregation and protein adsorption to a solid surface, facilitating desorption of bound proteins from various chromatographic columns, and enhancing the solubility of the highly insoluble wheat protein in phosphate buffer pH 7 as well as in water^9-13. It has been indicated that ARG also undergoes weak hydrogen bonding to the protein surface and is possibly involved in the π electron-cation interaction⁹. From these facts we assume that ARG has the potential to improve the solubility of LVS.

Previously, we reported the 43-fold solubility enhancement of LVS in the presence of ARG as a cosolute¹⁴. In recent years, most studies are centred only on the solubility improvement and leaving out the fundamental properties that are vital information to understand the enhanced solubility mechanism of the drug. In this manuscript, the related thermodynamics and solute-solvent interactions of LVS-ARG are presented. Additionally, we further investigated the molecular interactions and dynamics, as well as related structural effects during solubilization by measuring the sound velocity, density, and refractive index. Data on functional properties were obtained by determining values of sound velocity, density, and refractive index.

MATERIAL AND METHODS:

Chemicals and reagents:

Materials used to prepare our solution systems were LVS and ARG, they were used without further purification. All materials used in the current study were of analytical grade and purchased from Sigma Aldrich (St. Louis, MO, USA). The chemical name, CAS number (CAS), supplier, purification method and purity are shown in Table 1. Ultrapure water (Select Bio O Purite: Oxfordshire, United Kingdom) was used to prepare the solutions.

Table 1: Source and Purity of Chemical Reagents Used in This Work.

Chemical Name	CAS No.	Abbreviation	Supplier	Mass Fraction Purity^a
L-arginine	74-79-3	ARG	Sigma-Aldrich	≥99.5%
Lovastatin	75330-75-5	LVS	Sigma-Aldrich	≥99.5%

^a The purities of compounds are provided by the suppliers.

Preparation of Solution Systems:

ARG and LVS-ARG solution systems were prepared according to the method described by Higuchi and Connors¹⁵. Chemicals were weighed on a Metler balance with a precision of 0.001mg and dissolved in 100mL purified water in a conical flask. ARG solutions with various concentrations (0.01-0.8 mol.dm^-3) denoted as SB1 to SB7 were freshly prepared.

An excess amount of LVS was added to each flask containing the specified molar solutions of the ARG, denoted as SD1 to SD7 respectively. Separately, an excess amount of LVS was added to laboratory grade water to determine the respective intrinsic solubility, denoted as SD0. All conical flasks were placed in a mechanical water bath shaker at temperature of 308.15± 0.02K and shaken for a maximum period of 72 h. At the end of the incubation period, the suspensions were filtered through a 0.5µm membrane filter. Aliquots of the filtrates were subjected to viscosity estimation against the respective molar solutions of ARG as the blank. Each experiment was repeated at least three times and the results reported were the average values.

Refractive Index Measurement:

A 7 Abbemax digital refractometer (Misco, USA) was used to measure the refractive index. It is fitted with Microsoft windows software and the instrument was calibrated using reference solvents, provided by the supplier. The temperature of the system was maintained by the inbuilt peltier device, with a temperature uncertainty of ±0.01K. Meanwhile, uncertainties in refractive indices were ±0.000001.

Volumetric Study:

Density determination of the solutions (both blank and solutions containing saturated concentrations of LVS at four different temperatures ranging from 298.15K and 313.15K) was carried out by using Anton Paar digital density meter (Model DMA 60/602; Anton Paar, Austria). The temperature of water around the density meter cell was controlled by temperature bath (± 0.02K). Calibration of the density meter was done using dry air and pure water. All density measurements of the solutions were made with respect to pure water. Densities of pure water at the experimental temperatures were obtained from the literature¹⁶.

Sound Velocity:

The sound velocity through different samples at temperature 298.15 K was measured using a multifrequency electroacoustics spectrometer (Dispersion Tech Inc, USA) at frequency of 2 Mhz. The accuracy of the ultrasonic velocity measurement is within ± 0.5m/s. All the generated data were used to further calculate the thermo-physical parameters. The data were to be interpreted with respect to the solute solvent interactions and structural effects in order to provide more insights into solution dynamics.

RESULTS:

Refractive Index:

Triplicate measurements of refractive index (η_D) were taken and the values were averaged. Table 2 and Table 3 show the values of η_D and molar refractivity (R_D) respectively, of water as well as varying molar concentrations of ARG and LVS-ARG recorded at 298.15, 303.15, 308.15 and 313K. To obtain the values of R_D, Lorentz-Lorentz equation^16-18 was used for calculation:

R_D = [(n_D²–1)/(n_D²+1)](∑³_i₌₁ x_iM_i/ρ) (1)

Where x_i is the mole fraction while M_i is the molecular weight of the i^th component of the mixture.

Table 2: Refractive Indices (n_D) and Molar Refractive Indices (R_D) of ARG Solution.

Sample/ mol.dm^-3	T/K
	298.15		303.15		308.15		313.15
	*n_D*	*R_D* (x 10^-3)	*n_D*	*R_D* (x 10^-3)	*n_D*	*R_D* (x 10^-3)	*n_D*	*R_D* (x 10^-3)
SB0	1.3326 ± 0.0003	0	1.3319 ± 0.0001	0	1.3312 ± 0.0001	0	1.3304 ± 0.0001	0
SB1 (0.01)	1.3329 ± 0.0019	6.4084	1.3312 ± 0.0019	6.4463	1.3306 ± 0.0016	6.4478	1.3300 ± 0.0012	6.4409
SB2 (0.03)	1.3336 ± 0.0001	19.3876	1.3330 ± 0.0001	19.4204	1.3323 ± 0.0001	19.4164	1.3315 ± 0.0001	19.3761
SB3 (0.09)	1.3358 ± 0.0002	58.3309	1.3351 ± 0.0002	58.3404	1.3343 ± 0.0002	58.4703	1.3335 ± 0.0002	58.2304
SB4 (0.27)	1.3414 ± 0.0004	175.7754	1.3407 ± 0.0004	175.7126	1.3400 ± 0.0004	177.0282	1.3393 ± 0.0003	175.4011
SB5 (0.50)	1.3489 ± 0.0007	327.0939	1.3482 ± 0.0007	327.2028	1.3473 ± 0.0007	330.0117	1.3461 ± 0.0006	326.3160
SB6 (0.70)	1.3542 ± 0.0008	458.7044	1.3535 ± 0.0009	458.9417	1.3528 ± 0.0007	462.2153	1.3522 ± 0.0004	458.4722
SB7 (0.80)	1.3552 ± 0.0031	522.5150	1.3561 ± 0.0025	524.8786	1.3551 ± 0.0025	526.5028	1.3538 ± 0.0026	523.0518

SB0 = purified water, SB1-SB7 = ARG solution ranging from 0.1 to 0.8 mol dm^-3.

Table 3: Refractive Indices (n_D) and Molar Refractive Indices (R_D) of ARG Solution Saturated with LVS.

Sample/ mol.dm^-3	T/K
	298.15		303.15		308.15		313.15
	*n_D*	*R_D* (x 10^-3)	*n_D*	*R_D* (x 10^-3)	*n_D*	*R_D* (x 10^-3)	*n_D*	*R_D* (x 10^-3)
SD0	1.3326 ± 0.0001	1.7143	1.3319 ± 0.0001	1.7143	1.3313 ± 0.0002	1.7137	1.3306 ± 0.0001	1.7111
SD1(0.01)	1.3329 ± 0.0001	6.5943	1.3323 ± 0.0001	6.5966	1.3316 ± 0.0001	6.5906	1.3310 ± 0.0003	6.5828
SD2(0.03)	1.3336 ± 0.0001	20.1223	1.3330 ± 0.0001	20.1279	1.3323 ± 0.0001	20.1478	1.3315 ± 0.0001	20.0741
SD3(0.09)	1.3360 ± 0.0118	59.2752	1.3351 ± 0.0001	59.2817	1.3343 ± 0.0002	59.3858	1.3335 ± 0.0002	59.2489
SD4(0.27)	1.3416 ± 0.0001	176.6848	1.3409 ± 0.0002	176.7785	1.3401 ± 0.0002	178.2674	1.3390 ± 0.0008	176.2886
SD5(0.50)	1.3493 ± 0.0010	328.3082	1.3480 ± 0.0010	328.1923	1.3472 ± 0.0007	332.4537	1.3462 ± 0.0005	341.4808
SD6(0.70)	1.3542 ± 0.0016	460.2231	1.3544 ± 0.0017	461.4931	1.3536 ± 0.0019	467.1890	1.3529 ± 0.0024	460.4983
SD7(0.80)	1.3581 ± 0.0009	528.3047	1.3568 ± 0.0007	527.9455	1.3554 ± 0.0010	526.9387	1.3541 ± 0.0010	525.7482

SD0 = purified water, SD1-SD7 = ARG solution saturated with LVS ranging from 0.1 to 0.8 mol dm^-3.

Volumetric Studies:

To get insight to solute-solvent interactions, it is crucial to evaluate limiting apparent molar volume (Φ_V⁰) and limiting apparent molar expansibility (Φ_E⁰) of ARG and LVS-ARG solution systems at 298.15, 303.15, 308.15 and 313.15 K by thorough analysis of the experimental data. The following relationships derived from experimentally measured densities were used to evaluate data given in Table 4:

Φ_V = 1000 (Cd₀) –1(d₀ – d) + M₂/d₀ (2)

Φ_E = αΦ_V⁰ + (α – α₀)1000/C (3)

where C is the molar concentration of the solute, d₀ is the density of pure water, d is the density of the solution, M₂ is the molecular mass of the solute and α₀ and α are the coefficients of expansion of the solvent and solution (with or without drug), respectively, and determined by means of the relation available in the literature.

Values of Φ_V calculated by means of Eq. (2) were fitted by a method of least squares to Masson equation to obtain Φ_V⁰ (limiting apparent molar volume) and the slope, S_V

Φ_V= Φ_V⁰ + S_VC^1/2 (4)

Values of Φ_E from Eq (3) were also fitted by using least square method to get limiting apparent expansibility, ΦE⁰, and the slope S_E.

Φ_E = Φ_E⁰ + S_E/C (5)

The standard partial molar volumes, Δ_tΦ_V⁰ were experimentally determined parameter using the following equation:

Move the equation number to the end of the line as such:

ΔtΦV0 = ΦV0 (in aqueous arginine solutions) – ΦV0 (in

water)

Table 4: Limiting Apparent Molar Volume (Φ_v⁰), Standard Partial Molar Volume (Δ_tΦ_V⁰), Limiting Apparent Molar Expansibility (Φ_E⁰), S_V and S_E Constant of ARG, and LVS-ARG Systems.

System	Temperature (K)	S_V (cm³.mol^-1)	Φ_V⁰ (cm^9/2.mol^-3/2)	Δ_tΦ_V⁰ (cm^9/2.mol^-3/2)	S_E (cm³.mol^-1K)	Φ_E⁰ (cm^9/2.mol^-3/2K^-1)
ARG	298.15	11.68	503.54	298.45	-312.38	952.69
LVS-ARG	298.15	22.44	345.61	140.52	0.70	13.80
ARG	303.15	6.18	359.03	153.94	-320.46	1025.80
LVS-ARG	303.15	8.55	357.26	152.17	0.32	8.24
ARG	308.15	3.96	361.07	155.98	-241.95	765.21
LVS-ARG	308.15	5.18	403.36	198.27	0.45	9.74
ARG	313.15	6.96	359.49	154.40	-234.62	721.68
LVS-ARG	313.15	19.52	369.75	164.66	0.51	10.25

Table 5: Values of Sound Velocity (U), Density (ρ), Isentropic Compressibility (K_s) and Apparent Isentropic Compressibility (K_s^Φ) of Different Concentrations of ARG and LVS-ARG at 298.15 K.

Solution system	Ultrasonic parameter	Concentration/ mol.dm^-3
Solution system	Ultrasonic parameter	0.01 (S1)	0.03 (S2)	0.09 (S3)	0.27 (S4)	0.50 (S5)	0.70 (S6)	0.80 (S7)
ARG	Sound velocity/m.s^-1	1494.45	1493.65	1498.20	1520.05	1543.00	1560.30	1570.05
	Density @298.15 K/ kg.m^-3	0.9970	0.9990	1.0010	1.0083	1.0193	1.0277	1.0320
	K_S (10^-7)/Pa^-1	4.4910	4.4868	4.4507	4.2922	4.1205	3.9970	3.9309
	K_SΦ/10^-5)	-15.3210	-4.2635	-1.1826	-2.2352	-2.0086	-1.4851	-1.3846
LVS-ARG	Sound velocity/m.s^-1	1494.85	1494.25	1498.80	1521.57	1543.87	1564.20	1570.65
	Density @298.15 K/ kg.m^-3	0.9960	0.9980	1.0007	1.0090	1.0197	1.0277	1.0310
	K_S (10^-7)/Pa^-1	4.4931	4.4877	4.4486	4.2808	4.1145	3.9771	3.9317
	K_SΦ (10^-5)	-12.1111	-3.5964	-.1.6227	-2.8912	-2.2224	-1.8140	-1.3563

Table 6: The Molar Volume (V_m), Free Volume (V_f), Internal Pressure (π_i), Acoustic Impedance (Z) and Relative Association (R_A) of Different Concentrations of ARG and LVS-ARG.

Solution system	Ultrasonic parameter	Concentration/ mol.dm^-3
Solution system	Ultrasonic parameter	0.01 (S1)	0.03 (S2)	0.09 (S3)	0.27 (S4)	0.50 (S5)	0.70 (S6)	0.80 (S7)
ARG	V_m /m³	174.72	174.37	174.03	172.76	170.90	169.51	168.80
	V_f (10³) /m³mol^-1	-39.6321	-39.6497	-39.6818	-39.7207	-39.8930	-39.9859	-40.2878
	Π_i (10^-9) /Pa	1.8681	2.2869	5.8991	21.7469	38.9151	51.2695	57.8758
	Z (10²)/kgm^-2S^-1	14.8997	14.9216	14.9970	15.3272	15.7283	16.0347	16.2029
	R_A	1.0005	1.0027	1.0037	1.0061	1.0120	1.0165	1.0187
LVS-ARG	V_m /m³	174.90	174.55	174.08	172.65	170.84	169.51	168.96
	V_f (10³) /m³mol^-1	-39.6116	-39.6658	-39.6808	-39.7405	-39.8607	-39.9956	-40.3710
	Π_i (10^-9) /Pa	2.0004	2.5407	6.4499	23.2279	39.8549	53.6028	58.1378
	Z (10²) /kgm^-2S^-1	14.8887	14.9126	14.9980	15.3526	15.7423	16.0748	16.1934
	R_A	0.9993	1.0014	1.0031	1.0063	1.0121	1.0156	1.017

The R_D values for the studied system show the same trend as that of the η_D values where those of the LVS-ARG system are higher as compared to ARG. The refractive indices increase with an increase in the concentration of ARG molecules. An efficient packing of ions in the solution systems and the ion arrangement resulted in high refractive index values which proves that solubility for LVS in LVS-ARG system is enhanced in the presence of ARG²⁴.

Since graphs of R_D values against concentration gives out similar trend at all experimental temperature, only R_D values at 303.15 K were illustrated to represent the relationship in (Fig. 3) and (Fig. 4) as a function of ARG and LVS-ARG systems, respectively.

Fig. 3: Molar Refractive Indices (R_D) against Concentration (mol.dm^-3) of ARG System.

Fig. 4: Molar Refractive Indices (R_D) against Concentration (mol.dm^-3) of LVS-ARG System.

Plots in (Fig. 3) and (Fig. 4) display a linear upward trend with an increase in ARG concentration in both solution systems. The slopes of the lines in both plots were very similar, thus indicating that the rate of change of molar refraction was almost identical. R_D is directly proportional to the molecular polarizability¹⁷. This relation could be seen in (Fig. 3) and (Fig. 4) which revealed that the general polarizability of the ARG and LVS-ARG solution increased with the cosolute and solute content. Additionally, varying degree of tight packing resulted LVS-ARG to have maximum solute-solvent interaction as compared to ARG.

Volumetric Studies:

From Table 4 values of Φ_V⁰ are observed to be positive at all experimental temperatures. It is a measure of solute-solvent interaction for LVS-ARG system and ion-solvent interaction for ARG system where the positive value indicates strong solute-solvent and ion-solvent interactions. With increase in temperature for both systems, the ion-solvent and the solute-solvent interactions also increase except at 311.15K. This phenomenon promotes the structure-making effects of the LVS in aqueous ARG systems.

The values of S_V are observed to be negative at all experimental temperatures except at higher temperature for LVS-ARG system which indicated absence of ion-ion or solute-solute interaction in the system. S_V values of ARG-LVS system were smaller as compared to that of ARG system. This suggested that the structure of the solvent was enhanced in presence of LVS, which follows our previous assumption.

At all experimental temperatures, the values of Δ_tΦ_V⁰ are observed to be positive (Table 4). They however decrease as the temperature increases. Strong interactions between LVS and the solvent (water) are indicated by the positive values of Δ_tΦ_V⁰. It could also be due to water molecules being withdrawn from ions (the cation and anion of the ARG) and drug (LVS) molecules. The values are decreased as the temperature increased indicating lesser net solvation caused by overlapping cospheres, effectively destroying the interactions. This might enlarge the drug (solute) volume and cause ARG to lose its effect on the water structure due to the strong interaction between LVS and ARG.

In Table 4, Φ_E⁰ values for both ARG and ARG-LVS systems at all experimental temperatures are listed. From observation, values of S_E were negative in ARG system without LVS and positive for ARG system with abundant LVS. Negative values of Φ_E⁰ provide an indication of insignificant caging or packing effect, which indicate that the structure of solvent was enhanced.

Sound velocity:

Table 5 shows that the sound velocity, (U) increased with an increase in the concentration of the solute for both solution systems. The sound velocity value was, however, slightly higher in LVS-ARG compared to ARG solution. This indicated that there was higher presence of molecules and intermolecular hydrogen-bonding in the LVS-ARG solution system, the magnitude of the speed of sound through the liquid system was enhanced^25,26. This could be supported by the higher density values of the LVS-ARG.

Table 5 also deduces that at a fixed temperature, K_S values show a declining pattern with an increase in concentration of ARG in both ARG and LVS-ARG system. Since K_S values are summation of contribution from solvent intrinsic and solute intrinsic, solute intrinsic which is dominant over solvent intrinsic gives the combined effect of solvation of ions and breaking of the structure of LVS molecules²⁷. K_S values for ARG were slightly higher than LVS-ARG except for S1, S2 and S7. It could be due to the dissociation of ARG and the following ion-pair formation and due to complex structure formation in the presence of LVS. K_S also reflects the compactness of the hydration layers around the core of the solute, hence the isentropic compressibility may be decreased due to the reorientation of ARG molecules which then leads to self-association and formation of a cage that can fit a hydrophobic molecule, by reducing the effective hydrophobic surface, in this case the LVS molecule. In short, the presence of water insoluble LVS causes electrostriction on the medium as a result of decreased isentropic compressibility and internal pressure increase²⁸. The apparent isentropic molar compressibility, K_S^Փ of the system is presented in Table 5. The values were negative for both systems. The negative values are associated with the strong attractive interactions between the solute and solvent due to solvation of the solute.

Acoustic impedance is the ratio of the instantaneous pressure excess on any solute/substance to its instantaneous velocity. When sound wave travels in a medium, variations of pressure from one particle to another occur. This occurrence is controlled by inertial and elastic properties of the medium²⁹. Table 5 shows the calculated values of acoustic impedance, Z where the value increased with an increase in the concentration of ARG for both systems. This indicated that increase in concentration elevated the internal pressure and molecular interactions became stronger due to closer packing structure of solute and solvent molecules by the formation of H-bond in solutions²⁹. This observation complied with the results of the internal pressure π_i.

Table 6 also gives the values of internal pressure and free volume of the ARG and LVS-ARG solution system. The internal pressure is a parameter of solute-solvent interactions and indicates both the attractive and repulsive molecular interactions. Meanwhile, free volume is the effective volume accessible to the centre of a molecule in a liquid. Strong repulsive forces in the liquid along with the relatively weak attractive forces (which provide the internal pressure that holds the molecules together) are two factors that determine the structure of a liquid.

Internal pressure, π_i is sensitive to attractive forces while free volume, V_f is responsive to the repulsive forces. Together, these factors determine the entropy (i.e., disorderliness) of the system. The values of π_iwere found to be positive and increased with an increase in the concentration. On the other hand, the values of V_f, were negative and decreased with an increase in ARG concentration for both systems. Strong intermolecular interaction is indicated by the positive values of π_iwhich enhance the structure of water. Values of π_i and isentropic compressibility correspond with each other. Meanwhile, V_f results showed negative values which suggested the weakening of cohesive forces that later caused disruption of the structure of water in systems that contains ARG molecules and LVS due to entrapment of water molecules in spaces created by aggregation of the LVS-ARG complex³⁰.

The extent of association in solutions could be analysed using the relative association (R_A) parameter. Generally R_A values are governed by two factors that increase or decrease the value which are (i) breaking up solvent structure upon the addition of a solute which causes a declining pattern in R_A values and (ii) successive solvation of solutes by solvent molecules will result in an inclining pattern in R_A values. Table 6 shows R_A values in both solution systems. It is known that slight addition of additive, i.e., structure breakers will increase the cohesion between molecules by breaking the open structure²⁹. Hence in this case R_A values rose with the increase in ARG concentration in both systems suggesting that the solute-solvent interaction is associated by solvation of solutes by solvent molecules.

CONCLUSION:

In this study, sound velocity was determined at 298.15 K (Table 5) and refractive index of various concentrations of ARG and LVS-ARG was determined at 298.15-313.15 K (Table 3 and Table 4). The n_D of aqueous solutions of all systems was higher than that of water and increased with the concentration. The trend of R_D values of the system was the same as that of the n_D values where in the case of LVS-ARG was larger than ARG. n_D and R_D values indicated maximum interactions and polarizability within the systems and the results were in agreement with our solubility findings, where solubility of LVS was noticeably enhanced. The positive value of Φ_V⁰ illustrates a strong solute-solvent and ion-solvent interaction in both ARG systems. The value of S_V indicated solute-solvent interactions that prevail at the highest temperature for LVS-ARG system (Table 4).

The ultrasonic velocity (U) increased with the concentration in all systems. Aqueous solutions of LVS-ARG have higher values of U compared to ARG solution. Values of acoustic parameters such as isentropic compressibility (K_S), internal pressure (π_i), acoustic impedance (Z) and free volume (V_f) complement each other. The positive value of π_i indicated that there was a strong intermolecular interaction leading to the enhanced structure of water. Values of V_f are negative and decrease with an increase in the cosolute/solute concentration. Values of R_A in the case of ARG systems showed a regular pattern whereas that of LVS-ARG exhibited an irregular correlation with concentration. When compared among the systems, the presence of LVS, resulted in an increase of R_A values suggesting that the solute solvent interactions were associated with the solvation of solutes by solvent molecules.

ACKNOWLEDGEMENT:

The authors are thankful to Faculty of Pharmacy, University Teknologi Mara (UiTM) for support and cooperation in the completion of this study. This study was supported by the Fundamental Research Grant Scheme (600-IRMI/FRGS 5/3 (19/2016)), Ministry of Higher Education, Government of Malaysia.

CONFLICT OF INTEREST:

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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Received on 13.08.2020 Modified on 16.10.2020

Research J. Pharm. and Tech. 2021; 14(7):3631-3638.

DOI: 10.52711/0974-360X.2021.00628