Propranolol-HCl (PPN-HCl, which molecular structure is presented in figure 1) is a non selective β-adrenergic blocker widely used in the treatment of hypertension, angina pectoris, and cardiac disrhythmias (1, 2). Although PPN-HCl is widely used nowadays in therapeutics, its physicochemical information about volumetric behavior and other aqueous properties is not complete at present. Furthermore, it is well known that the pharmaceutical and biopharmaceutical behavior of drugs is strongly dependent on their physicochemical properties, especially, those of thermodynamic character (3). Thus, the solution thermodynamics in aqueous media for the molecular form has been presented in the literature (4), and the thermodynamics of the transfer between organic solvents with different hydrogen-bonding capability and aqueous media has also been presented (5). In this context, the study of molar volumes of pharmaceutical relevant compounds has been carried out to facilitate the design process of dosage forms, and for explaining the transfer mechanisms of drugs across biological membranes (6).

For these reasons, as a contribution to the generation and systematization of physicochemical information about the aqueous behavior of drugs, the main goal of this study was to evaluate the effect of concentration and temperature on the apparent molar volume of PPN-HCl in water. Taking into account such purpose, an interpretation in terms of solute-solvent interactions based on the corresponding volumetric behavior was developed.

MATERIALS AND METHODS

Chemicals

Propranolol-HCl of USP quality (7) from Shenzhen Sunrising Industry Co., Ltd., China (drug purity near to 0.999 in mass fraction) and distilled water (conductivity < 2 µS cm^–1) were used in this research.

Preparation of PPN-HCl aqueous solutions

All PPN-HCl aqueous solutions were prepared by mass in quantities of 30.00 g using a Ohaus Pioneer TM PA214 analytical balance with a sensitivity of ± 0.1 mg, in drug concentrations from 0.0500 mol kg^–1 to 0.2500 mol kg^–1 in order to study nine solutions. This procedure implied an uncertainty value of ± 2 x 10^–5 in molality.

Density determination

Density was determined at temperatures of 278.15, 283.15, 288.15, 293.15, 298.15, 303.15, 308.15 and 313.15 K by using a DMA 45 Anton Paar digital density meter connected to a Neslab RTE 10 Digital Plus (Thermo Electron Company) recirculating thermostatic water bath according to a procedure previously described (6). The equipment was calibrated according to the Instruction Manual using air and water at the different temperatures studied (8). Volumes near to 3.0 cm³ were employed in all the density determinations. All volumetric properties were calculated from the experimental density values and solution compositions according to the equations presented earlier (6).

RESULTS AND DISCUSSION

The experimental densities of PPN-HCl in water at the range of 278.15 to 313.15 K are shown in table 1. The apparent molar volumes (φ_V) were calculated by using equation 1.

In this equation, M₂ is the molecular mass of the solute; ρ₀ and ρ are the densities of solvent and solution respectively, and m is the solution concentration expressed as molality.

Table 1 summarizes the results of the apparent molar volumes of PPN-HCl, their molal concentrations and their uncertainties. Uncertainty values were calculated according to the law of propagation of uncertainties (9). It is clear that φ_V values decrease as the temperature increases for the same drug concentration. Moreover, φ_V values decrease as the drug concentration increases at almost all temperatures except at 278.15 K.

The φ_V dependence regarding the drug molal concentration (at all the temperatures studied) was fitted to equations of the following type (10):

In equation 2, is the apparent molar volume at infinite dilution (equal to the partial molar volume at infinite dilution); S_V is an experimental parameter (related to the water-structure promotion or disruption), and m is the molality once again. Values of (for PPN-HCl) and S_V were obtained by means of weighted least-squares, and the numerical values together with their uncertainties are shown in table 2.

Using the principle of volume additivity, the apparent molar volume at infinite dilution of PPN-HCl can be separated into individual ionic contributions according to the following equation (11, 12):

In such equation, are the partial molar volumes of free base and HCl, respectively. Data of were taken from the literature (13). Values of (for the molecular form) obtained from equation 3 at each temperature studied are shown in table 3. values calculated from the literature data are also shown in this table.

The variation of with regard to the temperature was adjusted by the method of weighted least squares according to the following linear empiric equation (with r² equal to 0.87):

In this equation, T is the temperature in Kelvin.

Figure 2 shows the dependence of on T. Furthermore, the partial molar expansibility at infinite dilution (E_φ⁰) can be calculated from Equation 4 by differentiating it according to the temperature as follows: .

The value of E_φ⁰ is 0.346 ± 0.029 cm³ mol^–1 K^–1.

According to table 3, the data reported by Ruso et al. (14) show significant differences in compared with the data obtained in this study. However, significant similarity was found with the values reported by Iqbal et al., 1994, 1989 (12, 15) at 298.15 and 308.15 K. Nevertheless, we cannot explain the differences found between data reported in this study and the one of Iqbal et al., 1994, 1989 (12, 15) regarding the data reported by Ruso et al., 2004 (14).

The sign of the S_V parameter in equation 2 can be associated with the influence of the solute upon water. This structural influence can be described in terms of structure promotion or structure-breaking effects of the solute on the surrounding water medium (16, 17). Negative S_V values were found for some solutes such as tetraakylamonium salts, which are typical ionic surfactants, characterized by their water-structure promotion effect (17-20). In this type of solutes, the hydrophobic effect becomes dominant compared with the hydrophilic effect; therefore, solvation around of the ionic moiety decreases. According to table 3, the S_V value is negative for all temperatures, except at 278.15 K. These observations can be interpreted in terms of the structure promotion effect of PPN on the water-structure at temperatures above 278.15 K.

In figure 2, it can be seen the tendency in which PPNincreases when the temperature increases. This result could be attributed to the breakage of the solvent structure, which causes an increase in the structural molar volume (19). As it was already stated, E⁰_φ is positive and this can be explained according to the formation of ''clathrate-like'' structures as described by Wen and Saito, 1964 (17). Thus, when the concentration of PPN-HCl increases, the water cluster surrounding the ions tends to join their neighbors and form flickering cages, forcing the ions to get inside these cages. If these structures are heated, they would breakdown, leading to the expansion of the complete system (20).

CONCLUSION

From all previously discussed topics, it can be concluded that the volumetric behavior of PPN-HCl in aqueous media is dependent on both concentration and temperature. Based on the negative sign of the S_V term obtained, it can be proposed that this drug acts as a water-structure promoter due to hydrophobic effect around its non-polar moieties. Ultimately, the data presented in this report fulfills the purpose of expanding the physicochemical information about electrolyte drugs in aqueous solutions.

ACKNOWLEDGEMENTS

We would like to thank the DIB-DINAIN of the Universidad Nacional de Colombia (UNC) for the financial support, and the Department of Pharmacy of UNC for putting the required equipment and laboratories to our service.

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