Prediction of Satranidazole Solubility in Water-Polyethylene Glycol 400 Mixtures Using Extended Hildebrand Solubility Approach

        A better approach is not to restrict the interaction term ‘W’ to a geometric mean but rather to evaluate it experimentally from the solubility of the solute in various solvent concentrations in a binary mixture employing Eq. 2. An empirical equation for ‘W’ as a function of solubility parameters of the solvent mixture remains to be discovered. Then, back-calculating ‘W’ and substituting into Eq. 2 permit the mole fraction solubility of a drug (solute) to be predicted in essentially any solvent mixture. Therefore, the present investigation pertains to the utility of EHSA in relation to the satranidazole solubility in water-PEG 400 binary solvent mixtures.

2. Materials and methods

2.1. Materials

      Satranidazole was obtained as a gift sample from Alkem Laboratories Ltd., Baddi, India, and was purified by recrystallization process. The solvent used for recrystallization of Satranidazole was acetone. Polyethylene Glycol 400 and acetone were purchased from Research Laboratory; Mumbai, India and Qualigens Fine Chemicals, Mumbai, India, respectively. Freshly prepared double distilled water was used for experimental purpose throughout the study. All chemicals and reagents used in the study were of analytical grade and used as such. Double beam UV/Vis spectrophotometer, Shimadzu model 1601 with spectral bandwidth of 2 nm, wavelength accuracy ±0.5 nm and a pair of 10 mm matched quartz cells was used to measure absorbance of the resulting solutions. Citizen balance, CX-100, was used for weighing of Satranidazole. Differential Scanning Calorimeter, Shimadzu TA-60 WS, was used for determination of melting point and heat of fusion of satranidazole.

2.2. Methods

2.2.1. Solubility measurements

      The solubility of satranidazole was determined in binary solvent mixtures of water and PEG 400. Double distilled water was used to prepare mixtures with PEG 400 in concentrations of 0-100% by volume of PEG 400. About 10 ml of PEG 400, water, or binary solvent blends were introduced into screw-capped vials containing an excess amount of satranidazole. After being sealed with several turns of electrical tape, the vials were submerged in water at 25±0.4 °C and were shaken at 150 rpm for 24 h in a constant-temperature bath. Preliminary studies showed that this time period was sufficient to ensure saturation at 25 °C [14].

Figure 1. Mole fraction solubility of satranidazole in water, PEG 400, and water-PEG 400 mixtures at 25±0.4 °C.Key: (♦) represents experimental solubilities in water-PEG 400 binary solvent system and (------) back-calculated solubilities from Extended Hildebrand Eq. 2. 

Table 1.Molar observed solubility and validation parameters of satranidazole in water-PEG 400 mixtures.

δ₁=Solubility parameter of solvent blend, V₁=molar volume of the solvent blend

       After equilibration, the solutions were microfiltered (0.45 µm) and the filtrate was then diluted with double distilled water to carry out the spectrophotometric determination at the maximum wavelength of absorption of the satranidazole (λ_max-319.80 nm). The solubility of the satranidazole was determined at least three times for this solvent mixture, and the average value was taken. The densities of the solvent mixtures and the filtrates of the saturated solutions of satranidazole were determined in triplicate at 25±0.4 °C using 10 ml specific gravity bottles. Once the densities of solutions are known, the solubilities can be expressed in mole fraction scale.

      The solubility parameters of the solvents were obtained from the literature [15, 16]. The solubility parameter of satranidazole was calculated previously by the method of Fedor [17, 18] which was confirmed by solubility analysis in dioxane-water blend.

 Figure 2. Plot of observed interaction energy versus solubility parameter of water-PEG 400 binary mixtures. Quartic expression provides relation between two variables (W obs and δ1), which has been used to back calculate Wcal.

Table 2. Comparison of observed and calculated mole fraction solubility’s of satranidazole in water-PEG 400 mixtures at 25 ±0.4 0C.

Calculation of interaction energy and mole fraction solubilities were obtained with the help of Eq. 2 and 10 as described in the text.

2.2.2. Differential scanning calorimetry

The thermogram of satranidazole was obtained with a differential scanning calorimeter [19]. The melting point and heat of fusion were measured. Sample of 8.8 mg in perforated pan was heated at a rate of 15 °C/min. under nitrogen purge. The temperature range studied was 25-225 degrees.

3. Results and discussion

3.1. Mole fraction solubility and solubility parameter

      The molar enthalpy of fusion of satranidazole was 112.30 J/g (7763.838 cal/mol) and the temperature of fusion is 461.83 °K. Neither decomposition nor polymorphic change was observed at the experimental temperature range. The ideal mole fraction solubility of satranidazole was calculated from these values (–logX₂ⁱ=1.60974602). The mole fraction solubilities of satranidazole at 25±0.4 °C in water-PEG 400 binary mixtures which cover a large range of the solubility parameter scale, from 11.30 to 23.40 (Cal/cm³)0.5, are listed in Table 1. The experimental mole fraction solubility of satranidazole at 25±0.4 °C in water-PEG 400 mixtures is plotted in Figure 1 versus the solubility parameter, δ₁, of the various mixed solvent systems. The mole fraction solubility of satranidazole (δ₂=11.30) in pure PEG 400 (δ₂=11.30), pure water (δ₁=23.4), and in the mixture of the twosolvents is represented by the solid circles in Figure 1. The maximum solubility of satranidazole in the mixture is X₂=0.010783 mol/ lit and occurs at δ₁=11.30. This value is well below the ideal solubility, X₂ⁱ=0.0245614 mol/lit, as predicted from regular solution theory. The discrepancy between the results using the original Hildebrand-Scatchard equation and experimental points demonstrates that Eq 1a and 1b cannot be used to predict drug solubility in water-PEG 400 binary solvent systems. This behavior has been dealt with the theoretical replacement of mean geometric solubility parameters (δ₁δ₂) term with the interaction energy term (W).

Figure 3. Relationship of observed and calculated mole fraction solubility of satranidazole. Comparison of 11 observed satranidazole solubilities in water-PEG 400 systems at 25±0.4 °C with solubilities predicted by extended Hildebrand approach.

3.2. Solubility prediction using regression of W versus δ₁

       Equation 2, differing from Equation 1 in that the geometric mean is not used provides an accurate prediction of solubility once ‘W’ is obtained. Although ‘W’ presently cannot be estimated based on fundamental physico-chemical properties of the solute and solvent, ‘W’ may be regressed against a polynomial in δ1 of the water -PEG 400 binary solvent mixtures (Figure 2). The following quadratic, cubic, and quartic equations were obtained using the experimental solubility data for satranidazole in water-PEG 400 mixtures:

      The ‘W’ values calculated using these expressions compared favorably with the original ‘W’ values computed using Eq. 2. The solid line plotted in Figure 1 was obtained employing the quartic expression (Eq.10). This calculated solubility curve fits the experimental data points quite well (Figures 1 and 3), predicting the solubility of satranidazole in water-PEG 400 mixtures at most points within an error of ~2.17%, a value approximating the error in experimentally determined solubility values. These polynomials are used successfully for the calculation of ‘W’, at any value of solubility parameter (δ₁), which was

subsequently employed to calculate mole fraction solubility of solute (X_2cal) in a solvent blend using backward regression. Representative data along with validation parameters are summarized in Table 1. Wcal values are indicating significant interaction of satranidazole and solvent molecules at the peak of solubility profile.

      Validation of Eq. 10 was done by comparing experimentally obtained and calculated values of mole fraction solubility by estimating residuals and percent difference (Table 2). The predictive capability of the model for satranidazole is represented in Figure 3, which indicates a very high degree of correlation coefficient (R²) 0.992 and negligible intercept (0.00003) equal to zero.

4. Conclusion

       The Extended Hildebrand Approach to solubility employs a power series(quartic) equation in δ₁ to back-calculate ‘W’, which reproduces the solubility of satranidazole in water-PEG 400 mixtures within the accuracy ordinarily achieved in experimental solubility results.

       On the basis of validation parameters, it can be expressed that the behavior of non regular solution can be quantified more precisely using EHSA. The procedure can be explored further to predict the solubility of satranidazole in pure water or PEG 400 and in any water-PEG 400 mixtures.Simultaneously, this tool may become useful in optimization problems of clear solution formulations. Thus the method has potential usefulness in preformulation and formulation studies during which solubility prediction is important for drug design.

Acknowledgement

       The author wishes to express his gratitude to M/S Alkem Laboratories Limited, Baddi for providing gift sample of Satranidazole.