Volumetric and optical properties of ACE inhibitor captopril in aqueous-alcoholic mixtures

Peer review under responsibility of Taibah University.

Abstract

Captopril is an angiotensin-converting enzyme (ACE) inhibitor that is used for the treatment of hypertension and congestive heart failure. This article addresses the accurate measurements of densities and refractive indices of solutions containing captopril in pure solvents such as water, methanol, ethanol and 1-propanol and aqueous mixtures of methanol, ethanol and propan-1-ol of 30%, 50% and 70% by volume in a wide range of drug concentration at 26 °C. This article also includes the evaluation of apparent molar volume, partial molar volume at infinite dilution and transfer volumes. The concentration dependence of the refractive indices studied and respective fitting parameters have been reported. Different properties are interpreted in terms of intermolecular interactions, effect of drug on structure of solvent/solvent mixture and overall structural fittings in solutions.

Keywords:

• Drug
• Solvation
• Molecular interactions
• Alcohols

1 Introduction

Water-co-solvent mixtures are widely used in the pharmaceutical sciences to enhance the solubility of drugs. These mixtures are highly non-ideal due to the existence of intermolecular interactions. The drug solutions in these water-co-solvent systems have applications in drug solubility and the design of homogeneous pharmaceutical dosage forms such as syrups and elixirs. Therefore, the physicochemical behaviour of the drug captopril (CPT) in water-co-solvent mixtures is highly significant in view of its pharmaceutical applications.

Table 1 Density, ρ (g cm⁻³) and refractive index data for CPT in pure solvents at 26 °C.

c	ρ				n
	H2O	MeOH	EtOH	1-PrOH	H2O	MeOH	EtOH	1-PrOH
0.005	0.9969	0.7850	0.7994	0.7975	1.3318	1.3306	1.3615	1.3812
0.010	0.9970	0.7854	0.7999	0.7982	1.3320	1.3309	1.3617	1.3818
0.030	0.9976	0.7871	0.8017	0.8003	1.3327	1.3316	1.3620	1.3830
0.050	0.9984	0.7891	0.8037	0.8023	1.3334	1.3321	1.3622	1.3835
0.070	0.9992	0.7913	0.8057	0.8044	1.3340	1.3327	1.3625	1.3840

Table 2 Density, ρ (g cm⁻³) and refractive index data for CPT in aqueous-alcoholic mixtures at 26 °C.

c	ρ			n
	MeOH + H2O	EtOH + H2O	1-PrOH + H2O	MeOH + H2O	EtOH + H2O	1-PrOH + H2O
30 vol%
0.005	0.9576	0.9592	0.9559	1.3365	1.3435	1.3505
0.010	0.9581	0.9595	0.9563	1.3367	1.3443	1.3507
0.030	0.9593	0.9606	0.9581	1.3375	1.3464	1.3515
0.050	0.9604	0.9617	0.9597	1.3383	1.3480	1.3520
0.070	0.9615	0.9628	0.9614	1.3390	1.3490	1.3535
50 vol%
0.005	0.9275	0.9320	0.9227	1.3390	1.3545	1.3615
0.010	0.9279	0.9322	0.9232	1.3393	1.3550	1.3620
0.030	0.9289	0.9331	0.9251	1.3402	1.3555	1.3622
0.050	0.9301	0.9342	0.9269	1.3410	1.3560	1.3630
0.070	0.9311	0.9354	0.9287	1.3415	1.3565	1.3632
70 vol%
0.005	0.8874	0.8944	0.8755	1.3400	1.3592	1.3697
0.010	0.8877	0.8946	0.8761	1.3403	1.3595	1.3700
0.030	0.8888	0.8956	0.8778	1.3410	1.3600	1.3708
0.050	0.8900	0.8968	0.8796	1.3416	1.3605	1.3714
0.070	0.8917	0.8983	0.8815	1.3421	1.3610	1.3721

The study of molecular interactions in solutions containing alcohols is of great interest, as alcohols are –OH group-containing highly polar organic molecules and self-associate through hydrogen bonding [1–3]. They are polar compounds in which hydrogen bonding or dipole-dipole Van der Waals forces are present. The hydrophobic character of alcohols increases with chain length; therefore, hydrophobic effects are studied using alcohol solvents.

Studies on physicochemical properties of drugs in aqueous-alcoholic mixtures are of interest due to peculiar results in different solvent systems. Volumetric data from drug studies can provide clues to the interactions occurring in cellular fluids. A survey of the literature reveals that studies on volumetric properties of drugs are of increasing interest by a number of workers in this field of research.

Drugs are the organic molecules containing hydrophobic and hydrophilic groups. Pharmacological properties of drug molecules are highly dependent on their solution behaviour [4,5]. Drugs may break or preserve the structure of the solvent or solvent mixture through interactions due to the presence of hydrophobic and hydrophilic groups. These interactions are specific and electrostatic interactions. Drug transport, anaesthesia and protein binding are important processes where drug and biomacromolecules interact, which affects their physicochemical behaviour.

Volumetric properties are dependent on different interactions such as solute-solute, solute-solvent and solvent-solvent interactions and structural effects due to volume difference among different components of solution [6]. Systems containing hydrogen bonds are of great interest due to the vital role of these bonds in chemical, physical and biological processes [7]. Pure and mixed (with water) alcohols are widely used in fields such as the pharmaceutical industry, ecology, cosmetics, and energy source [7,8]. Density, refractive index and viscosity and derived properties are useful in collecting analytical information required for industrial purposes [9]. The study of refractive indices of different systems containing various solutes has been carried out by many researchers [10–15]. Knowing the densities and refractive indices of drug solutions is helpful for understanding molecular interactions and structural fittings in solution. Molecular interactions in solution are understood from studies based on measurements of refractive indices of solutions [16–19].

Therefore, in continuation of our earlier work in understanding the solution behaviour of different systems [20–24], the systematic study of volumetric and refractometric properties of CPT drug in water, alcohols and in alcohol-water mixtures of different volume ratios is carried out in the present work.

2 Experimental

Captopril (CPT) was received as a gift from Wockhardt Ltd. Aurangabad (MS) India, and it was used as is. Deionized distilled water (HPLC grade, pH = 6.91) obtained from a Millipore prefiltration kit (Direct-Q™ system series) was used. Methanol (MeOH, Merck, 99.0%), ethanol (EtOH, SD fine, 99.9%) and 1-propanol (1-PrOH, SD fine, 99.0%) were used. Solutions of drugs having different concentrations were prepared in pure solvents and solvent mixtures of different volume ratios. Density of solutions was measured using a single capillary calibrated pycnometer. The pycnometer was calibrated by ethanol at experimental temperature. Weight was measured on a single pan electronic balance (±0.001 g). The refractive index of solutions was measured using a thermostatically controlled Cyber LAB-Cyber Abbe Refractometer (Amkette Analytics, ±0.0002, 1.3000 to 1.7000). Averages of three readings of density and refractive index are reported.

CPT has different interaction sites as shown in Fig. 1. It has hydrophilic and hydrophobic parts (functional groups) along with a hydrogen bonding site. The amide (–CONH) group can undergo hydrogen bond interactions with polar molecules, and the acid (–COOH) group is polar and ionic; therefore, CPT shows interesting interactions with polar solvent molecules.

Fig. 1 Hydrophilic, hydrophobic and hydrogen bonding sites in CPT.

3 Results and discussion

Experimental densities of drug in pure solvent and solvent mixtures are reported in Tables 1 and 2. It is seen that the density increased with drug concentration in any given solvent system, and density largely decreased with increase in volume ratios of MeOH, EtOH and PrOH for a given drug concentration, which is consistent with the densities of these alcohols. Behaviour density with drug concentration indicates a change in volume, strengthening of drug-solvent interactions and modification of structural orientation in solution.

The apparent molar volume (φ_v, AMV) of drug in different solvent systems is calculated from accurately measured densities of solution [25] using Eq. (1)(1) ${\phi }_v=\frac{M_2}{\rho }+\frac{1000}{c{\rho }_0}({\rho }_0-\rho )$(1) as follows:(1) ${\phi }_v=\frac{M_2}{\rho }+\frac{1000}{c{\rho }_0}({\rho }_0-\rho )$(1) where c is molar concentration, Μ₂ = molecular weight of solute, ρ₀ = density of solvent and ρ = density of solution. AMV values of drug in pure solvents and aqueous-alcoholic mixtures with different composition are presented in Figs. 2 and 3.

Fig. 2 Plots of φ_v (cm³ mol⁻¹) as a function of drug concentration in different pure solvents.

Fig. 3 Plots of φ_v (cm³ mol⁻¹) as a function of drug concentration in different solvent mixtures.

It is seen that AMV decreases with drug concentration in each solvent/solvent mixture and increases with increase in volume ratio of alcohols in the respective systems. A decrease in AMV with increasing drug concentration is attributed to solvophobic hydration between the polar groups of CPT and the solvent and compression in volume due to modified mean distance [26]. Increase in AMV with increased volume ratio of alcohols is due to relative weakening of drug-solvent interactions and reduction in electrostriction. The AMVs of drug in pure MeOH, EtOH and PrOH are greater than in water due to the presence of additional alkyl groups (–CH₃, –CH₂CH₃ and –CH₂CH₂CH₃ respectively) in these alcohols. The AMV is the sum of the geometric volume of solute molecules, and changes in volume occurred due to the interaction of solute with solvent [27]. A survey of the literature on model compounds revealed that the volumes of the water-soluble compounds are generally smaller in aqueous medium compared to non-aqueous medium.

AMV data is fitted to Masson’s relation [28,29] Eq. (2)(2) ${\phi }_v={\phi }_v^0+S_v\sqrt{c}$(2) :(2) ${\phi }_v={\phi }_v^0+S_v\sqrt{c}$(2)

The φ^o_v (partial molar volume, PMV) and S_v are determined as the intercept and slope of the linear plots for drug + pure alcohols and drug + mixed solvents. Values of φ^o_v and S_v are obtained from the graph by linear fitting and are reported in Table 3.

Table 3 The φ^o_v (cm³ mol⁻¹), S_v (cm³ dm^3/2 mol^−3/2) and transfer volumes, Δ_trφ⁰_v (cm³ mol⁻¹) of CPT in pure solvents and aqueous-alcoholic mixtures.

Binary/ternary system	PMV, φ^ov	Experimental slope, −Sv	Transfer volume, Δtrφ^0v
Pure solvents
H2O	205.25	85.36	–
MeOH	255.82	208.71	50.57
EtOH	257.17	249.67	51.92
1-PrOH	232.24	189.38	26.99
MeOH + H2O
30 vol%	211.93	179.64	6.68
50 vol%	220.29	151.91	15.04
70 vol%	232.33	171.81	27.08
EtOH + H2O
30 vol%	214.89	169.33	9.64
50 vol%	222.32	140.75	17.07
70 vol%	235.50	173.12	30.25
1-PrOH + H2O
30 vol%	207.65	253.67	2.40
50 vol%	212.80	253.52	7.55
70 vol%	220.99	213.08	15.74

The φ^o_v is independent of solute-solute interactions in solution; its values for CPT are positive and large in all the solvent systems due to strong drug-solvent interactions because of reduction in the electrostriction, change in the volume and solvation behaviour of drug The φ^o_v values in MeOH-H₂O and EtOH-H₂O are nearly the same but greatly differ from the values in 1-propanol-water. Positive φ^o_v values also suggest no restriction on the molecular motion in solution [30]. The trend of φ^o_v values with solvent composition is: MeOH-H₂O ≈ EtOH-H₂O > 1-PrOH-H₂O as shown in Fig. 4. This observation suggests that relatively more of the structure is disrupted in aqueous solutions of 1-PrOH due to the hydrophobic chain of alcohols [25]. The φ^o_v increased with alcohol content and is attributed to the solvation behaviour of drug and change in volume due to reduction in the electrostriction and migration of solvent from the second layer around the drug to bulk solvent.

Fig. 4 Plot of φ⁰_v (cm³ mol⁻¹) vs. vol % of alcohol content in different systems.

S_v values are negative (negative slopes) for all the solvent systems, which indicates the presence of weak ion-ion or solute-solute interactions and insufficient counter ion binding of the drug molecule due to its hydrophobic nature [26]. At infinite dilution, the drug molecules are far away from each other and cannot interact strongly, which results in the negative slopes and weak drug-drug interactions and strong drug-solvent interactions. A negative S_v value also suggests that the drug molecule tries to occupy the empty space of the solvents. There is no appreciable change in the S_v with solvent composition, even from water to 1-propanol.

Partial molar volume of transfer (standard transfer volume of drug, Δ_trφ⁰_v) from aqueous solution to aqueous-alcoholic solutions is calculated [31] from the following Eq. (3)(3) ${\mathrm{\Delta }}_{tr}{\phi }_v^0={\phi }_v^0(Aqueous)-{\phi }_v^0(Water)$(3) and is reported in Table 3.(3) ${\mathrm{\Delta }}_{tr}{\phi }_v^0={\phi }_v^0(Aqueous)-{\phi }_v^0(Water)$(3) In all cases, the Δ_trφ⁰_v values are positive. Δ_trφ⁰_v increased with increase in alcohol content. These values are large and positive in pure solvents such as MeOH, EtOH and 1-PrOH. Δ_trφ⁰_v values are smaller in 1-PrOH-H₂O solutions compared to MeOH-H₂O and EtOH-H₂O. The trend of Δ_trφ⁰_v values with solvent composition is: MeOH-H₂O ≈ EtOH-H₂O < 1-PrOH-H₂O.

The hydration number (the number of water molecules hydrating drug) of the drug decreases in the presence of alcohol in aqueous drug solution and further decreases with increase in the alcohol content in solution due to the existence of drug-alcohol polar-hydrophilic interactions and intermolecular interactions (intermolecular hydrogen bonding) between water and alcohol [32]. Positive Δ_trφ⁰_v values are attributed to decrease in volume of shrinkage because of interactions between drug and alcohols, the existence of hydrophilic-hydrophilic and ion-hydrophilic interactions, and the reduction in the electrostriction (less hydration of drug in presence of alcohol) due to intermolecular hydrogen bonding between water and alcohol. These effects increase with increase in the alcohol content of the solution. This result also suggests the presence of dominating hydrophilic-hydrophilic interactions in solution. The increase in the values of φ⁰_v and positive Δ_trφ⁰_v values are due to strong-drug-solvent interactions and decrease in the shrinkage volume of water by the drug in presence of alcohols, i.e., alcohols have a dehydrating effect on the hydrated drug [33]. Apart from the interactions of -OH groups with polar/hydrophilic/ionic groups of the drug, additional interactions between hydrophobic alkyl groups (–CH₃, –CH₂CH₃ and –CH₂CH₂CH₃) of MeOH, EtOH and PrOH and the hydrophobic part of the drug molecule occur in aqueous-alcoholic solutions.

The experimental refractive indices of drug in pure and mixed solvents are reported in Tables 1 and 2. The refractive index increases with drug concentration in each solvent system. It also increases with volume ration of MeOH, EtOH and 1-PrOH for a given drug concentration. In pure MeOH, the refractive index values are small compared to H₂O and aqueous-MeOH mixtures. However, in the case of aqueous-EtOH and aqueous-1-PrOH, the refractive index values increased with an increase in alcohol content for a given drug concentration.

In general, the refractive index data in different aqueous-alcoholic mixtures follows the following trend: Aqueous-1-PrOH > Aqueous-EtOH > Aqueous-MeOH. In pure solvents, the refractive index data follows the following trend: 1-PrOH > EtOH > H₂O > MeOH. Refractive index trends in various systems are in accordance with the refractive indices of the respective solvents and solvent composition. The relationship between refractive index and concentration of solute depends on the nature of the solute, solvent, temperature and wavelength. The dependence on temperature and wavelength is eliminated by using a thermostat and monochromatic light, respectively. The linear relationship between refractive index and concentration of drug is checked [34] using the following Eq. (4)(4) $n_D=K\times c+n^0$(4) and graphical parameters, namely, refractive index at infinite dilution, n^o and constant, K which depends on nature of solute are determined graphically and are reported in Table 4 along with r² values of the respective plots:(4) $n_D=K\times c+n^0$(4) where n = refractive index of solution, n⁰ = infinite dilution refractive index and K = constant.

Table 4 Graphical parameters of concentration dependence of n, {n = K (dm³ mol⁻¹) × c (mol dm⁻³) + n⁰} for CPT in pure solvents and aqueous-alcoholic mixtures.

Binary/ternary system	Infinite dilution refractive index, n^0	Constant, K	r^2
Pure solvents
H2O	1.3317	0.0340	0.9987
MeOH	1.3305	0.0313	0.9909
EtOH	1.3615	0.0144	0.9788
1-PrOH	1.3813	0.0414	0.9340
MeOH + H2O
30 vol%	1.3363	0.0388	0.9992
50 vol%	1.3389	0.0389	0.9859
70 vol%	1.3399	0.0319	0.9897
EtOH + H2O
30 vol%	1.3434	0.0849	0.9750
50 vol%	1.3546	0.0285	0.9698
70 vol%	1.3592	0.0266	0.9923
1-PrOH + H2O
30 vol%	1.3502	0.0433	0.9626
50 vol%	1.3616	0.0251	0.9350
70 vol%	1.3696	0.0361	0.9943

The refractive index at infinite dilution increases with the volume ratio of MeOH, EtOH and 1-PrOH for a given drug concentration except in the case of pure MeOH. The r² values of various plots indicate that the relationship between refractive index and concentration of drug is linear in most cases [35]. Further, the linear relationship between refractive index and density of solutions is checked. From the r² values of various plots, the relationship between refractive index and density of solutions seems to be linear.

4 Conclusions

From the volumetric and refractometric properties of CPT in pure solvents and solvent mixtures of different compositions, it is concluded that strong drug-solvent interactions are present in each solution. The large positive values of φ^o_v confirm the reduction in electrostriction, change in volume and solvation behaviour of CPT. Relatively more structure disruption is observed in aqueous solutions of 1-PrOH due to the hydrophobic chain. Drug-drug interactions are weak in all aqueous-alcoholic systems and are not greatly affected by the nature of alcohol. A standard transfer volume, Δ_trφ⁰_v, indicates reduction in hydration number of the drug with increase in alcohol content. Hydrogen bonding interactions and ionic/hydrophilic-hydrophilic interactions between drug (–C=O, amide group and –COOH, acid group) and solvent/co-solvent (–OH) exists in solution. Refractive index data suggests that the packing of drug molecules becomes tighter with increases in concentration of drug in each system due to strengthening of drug-solvent interactions and structural cause of change in density and existence and modification of molecular interactions. The present work is helpful for prediction of absorption and permeability of CPT through membranes, which has applications in the field of medicinal and pharmaceutical chemistry.

Acknowledgements

The authors are thankful to Wockhardt Ltd. Aurangabad Ltd. Aurangabad (MS) India for the generous gift of the drug sample.

Notes

Peer review under responsibility of Taibah University.