INTRODUCTION:
An irregular solution is one in which self-association of solute or solvent, solvation of the solute by the solvent molecules, or complexation of two or more solute species are involved.1 Polar systems exhibit irregular solution behaviour and are commonly encountered in pharmacy.2 The extended Hildebrand solubility approach (EHS) a modification of the Hildebrand-Scatchard equation, permits calculation of the solubility of polar and nonpolar solutes in solvents ranging from nonpolar hydrocarbons to highly polar solvents such as water, ethanol, and glycols.3,4 The solubility parameters of solute and solvent were introduced to explain the behaviour of regular and irregular solutions.
Solubility parameter, δT, is an intrinsic physicochemical property of a substance, and is expressed as square root of the cohesive energy density of the substance.5 The cohesive energy density itself is defined as the ratio of the energy of vaporization to the molar volume at the same temperature.6
This has been used to explain drug action, structure activity relationship, drug transport kinetics, in situ release of drug, gas solid chromatography.7-11 Therefore, the precise value of the solubility parameter of a drug is of interest.
Different methods are available to determine the solubility parameter of drugs. Firstly, group contribution methods (theoretical methods) such as Fedors, Hoy, and partial solubility parameters methods are used to determine the solubility parameter of the drugs.12,13 Secondly, Hildebrand regular solution theory according to which, peak solubility technique is used to obtain the solubility parameter of a solute. In non-regular solutions, the peak solubility does not approximate the ideal solubility. Therefore, a criterion X2 (experimental solubility) = X2i (ideal mole fraction solubility) is selected to decide the δT value. At present, for predicting the solubility, the extended hildebrand solubility approach (EHS) 14, 15 has evoked considerable interest. This approach is largely empirical and permits the estimation of solubility parameter also.16, 17
Satranidazole:
Satranidazole, 1-methylsulphonyl-3-(1-methyl-5-nitro-2-imidazolyl)-2-midazolidinone, is one of the large series of nitroimidazoles with a potent antiprotozoal activity, against E. hystolytica, T.vaginalis and giardia .18 It is not official in IP, USP and BP till date.19, 20 Though the molecule is found to be effective against these microorganisms, its therapeutic efficacy is hindered due to its poor aqueous solubility.21 The drugs with low aqueous solubility i.e., less than 1 mg/ml usually suffer oral bioavailability problems because of limited gastrointestinal transit time of the undissolved drug particles and limited solubility at the absorption site.22 The poor aqueous solubility and wettability of satranidazole give rise to difficulties in pharmaceutical formulations meant for oral or parenteral use, which may lead to variation in bioavailability.23
A perusal to the structure of Satranidazole indicates that the molecule is highly aromatic and the functional groups may not contribute much to the aqueous solubility. The solution behaviour of satranidazole in different solvents and total solubility parameter of satranidazole is not reported, therefore this candidate is chosen for the study.
Therefore, the present communication reports the behavior of satranidazole solubility in the context of existing theories of solutions such as ideal, regular, and irregular solutions. Furthermore, the solubility parameter of satranidazole is determined using Fedor’s group contribution method and solubility of satranidazole in methanol-water system was investigated to highlight the irregular solution behaviour. This allows further to test the reliability and validity of the models.
MATERIALS AND METHODS:
Materials:
Satranidazole, obtained as gift sample (Alkem Laboratories Ltd., Baddi, India) and used as received. Methanol was purchased from Dipa Chemical Industries, Pvt., Ltd., Aurangabad. Double distilled water was prepared in the laboratory using all glass distillation apparatus and used for experimental purpose throughout the study. Double beam UV/Vis spectrophotometer, Shimadzu model 1601 with spectral bandwidth of 2 nm, wavelength accuracy ±0.5 nm and a pair of 1 cm matched quartz cells was used to measure absorbance of the resulting solutions. Differential Scanning Calorimeter, Shimadzu TA-60 WS, was used for determination of melting point and heat of fusion of satranidazole.
Solubility Determination:
The solubility of satranidazole was determined in mixed solvents as well as individual solvents. About 10 ml of methanol, water, or mixed solvent blends were placed into screw-capped vials containing excess of satranidazole. The vials were agitated in a cryostat constant temperature reciprocating shaker bath at room temperature (25 ± 1°C) for at least 72 h in order to obtain equilibrium. Preliminary studies showed that this period was sufficient to ensure saturation at 25oC.24
After 72 h of equilibrium, aliquots were withdrawn, filtered (0.22 µm pore size), diluted, and analyzed at 319.80 nm on Shimadzu UV/Vis spectrophotometer. All solubility experiments were conducted in triplicate and the average value was reported.
Heat of Fusion:
The heat of fusion of satranidazole was determined by using Differential Scanning Calorimeter. The thermogram is shown in Fig. 1. The heat of fusion is 112.30 J/g (7763.838 cal/mol).
Solubility Parameter of Mixed Solvents:
The solubility parameter, δ1, for the mixture of two solvents methanol and water was calculated from the relationship25;
Where δMTH and δW are the solubility parameters of individual solvents in the blend, respectively, and Ф1=ФMTH + ФW is the total volume fraction of two solvents.
Volume Fraction and Mean Molar Volume in Mixed Solvents:
The volume fraction for a solvent blend (Ф1) was calculated either by an iteration procedure (Martin and Mauger, 1988) or by using the experimental mole fraction solubility (X2).26, 27
Where, X2 is the mole fraction solubility of the solute in the mixed solvent, V1 and V2 are the molar volumes of the solvent blends and the solute (Satranidazole), respectively. An iteration procedure was used for the analysis in binary solvents and Eq. 2 was used for the data in individual solvents. For each mixed solvent composed of MTH and water in various proportions: 28
Where, X and M are the mole fraction and molecular weight of the particular solvent in the mixture, respectively, and ρ1 is the density of the solvent mixture at the experimental temperature (25oC).
The mean molar volume of the solvent blend (V1) is calculated by the equation,
V1 = VMTH ФMTH + VW ФW ----------------- (4)
Where, VMTH and VW are the molar volumes of the respective solvents.
Solubility Parameter and Molar Volume of Satranidazole:
Group contribution method was used to calculate the total solubility parameter (δ2) and molar volume of satranidazole (Table 1.). In present investigation, the total solubility parameter of satranidazole was calculated by the methods of Fedor’s. The molar volume of satranidazole taken as a supercooled liquid at 25oC is also calculated by using the Fedor’s group contribution method. For the rest of the work, the molar volume of satranidazole was determined experimentally by the floatation technique by immersion of the solid in methanol (δ = 14.5 H).29 The solubility parameter of the methanol and water are collected from the literature.30,31
Table 1. Calculation of solubility parameter of satranidazole by Fedor’s Group Contribution Methiod
|
Drug fragments |
No. of Fragments |
Cohesive Energy (Cal/mol) |
Molar Volume (Cm3/mol) |
|
=CH |
[1] |
1030 |
13.5 |
|
=C< |
[3] |
1690 |
6.5 |
|
-CH3 |
[2] |
1125 |
33.5 |
|
-NO2 |
[1] |
3670 |
32.0 |
|
-SO2 |
[1] |
3700 |
23.8 |
|
>N- |
[3] |
2800 |
5.0 |
|
-CH2- |
[2] |
1180 |
16.1 |
|
=N- |
[1] |
2800 |
5.0 |
|
Conjugation |
[2] |
400 |
-2.2 |
|
Ring Closure |
[2] |
250 |
16 |
|
|
Total |
30580 |
235.6 |
|
|
δ2 (Cal/cm3)0.5 |
=(30580/235.6)0.5 |
=11.3928 |
Table 2. Absorbance data of satranidazole in MTH-Water mixtures
|
Concentration (μg/ml) |
Absorbance |
Concentration (μg/ml) |
Absorbance |
|
5 |
0.162 |
30 |
0.968 |
|
10 |
0.325 |
35 |
1.126 |
|
15 |
0.498 |
40 |
1.296 |
|
20 |
0.642 |
45 |
1.432 |
|
25 |
0.805 |
50 |
1.594 |
Calculation of Ideal Solubility:
The ideal mole fraction solubility (X2i) of crystalline solids in polar and non-polar solvents is calculated from32
The entropy of fusion, ΔSf, is evaluated by using the relationship33
ΔHf = T0. ΔSf ----------- (6)
Where, ΔHf is heat of fusion, T0 is the melting point of solute in absolute scale, T is working temperature of solutions in Kelvin at which the solubility was determined, and R is the real gas constant. The DSC of satranidazole is given in Fig. 1.
Fig. 1. Differential scanning calorimetry of satranidazole.
RESULTS AND DISCUSSION:
The absorption spectrum of satranidazole in methanol solution was obtained (λmax - 319.80 nm, Fig. 2.). Lambert-Beer’s law obeys in the concentration range of 5–50 μg/ml (R2 = 0.9997) as shown in Table 2 and the calibration curve (Fig. 3) was constructed. The ΔHf value of 7763.838 cal/mol and T0 value of 461.83 K were obtained. Then ΔSf was calculated to yield a value of 16.811 cal/mol/degree. The ideal mole fraction solubility of satranidazole is 0.0245614 (– logX2i = 1.60974602).34 The experimental molar volume of satranidazole obtained is 271.3497 cm3/mol. The molar volume from Fedors group contribution method is 235.6 cm3/mol. The experimentally determined mole fraction solubilities of satranidazole at 25oC in the solvent series are found in the Table 3 together with the molar volumes and solubility parameters of solvent mixtures. The (log γ2)/A (obs) values are also found in the Table 4.
Fig. 2. UV spectrum of satranidazole.
The experimental mole fraction solubility of satranidazole in the solvent series is recorded in Fig. 4. The δ value of satranidazole was determined by measuring the solubility in different solvent blends.35 The experimental mole fraction solubility of satranidazole shows peak solubility and the δ value of solvent blend at peak solubility is taken as the solubility parameter of satranidazole. According to regular solution theory, when δ1 = δ2, the experimental mole fraction solubility is equal to the ideal mole fraction solubility. In regular solutions, maximum solubility occurs when δ of the solvent is approximately equal to δ of the solute. The peak solubility for satranidazole in the methanol-water series is observed (Fig.4.) at the δ value of solvent blend 15.39 H which is nearer to the 11.39 H value calculated by Fedor’s Group Contribution Method.
Fig. 3. Lambert-Beer plot of satranidazole.
Fig. 4. Mole fraction solubility of satranidazole in MTH-water binary mixtures.
In irregular solutions, these relations do not apply exactly as in regular solutions. It appears that the condition X2 = X2i is still valid, although the peak solubility technique was disregarded. In case of the solubility of satranidazole in a dioxane-water system, the solute and solvent (Lewis acid-base) interaction might have unduly lowered the δ2 value.36 Therefore; the peak solubility does not provide the δ value of solute in irregular solutions.
Observed solubility data was then subjected to the evaluation of interaction energy. The interaction term W can be calculated from Eq. (7) at each experimental point (X2, δ1). The results are also presented in Table 3. Experimental values of interaction energy (Wobs) were regressed against solubility parameter to obtain Wcal (Fig. 5.), which was then used to back calculate the mole fraction solubility (X2cal).
Fig. 5. Plot of observed interaction energy versus solubility parameter of MTH-water binary mixtures.
The EHS approach was proposed to understand the non-regular behavior of solutions. This involves regression of W values against a power series, namely quartic, of the solvent solubility parameter.37
In our case, the following fit was obtained:
Wcal = -226.46176099 + 58.87254598 δ1 – 3.98276898 δ12 + 0.14952617 δ13 – 0.00185420 δ14
(n = 11, R2=0.99999989)
Validation of this equation has been done by comparing experimentally obtained and calculated values of mole fraction solubility by estimating residuals and percent difference (Table 4).
The predictive capability of the model for satranidazole is represented in Fig. 6., which indicates a very high degree of correlation coefficient (R2) 0.9995 and negligible intercept equal to zero.
CONCLUSIONS:
The Extended Hildebrand Solubility Parameter Approach applied to the solubility data of satranidazole in MTH-water mixtures leads to an expansion of the W interaction term as a fourth degree power series in δ1 which reproduces the satranidazole solubility within the accuracy ordinarily achieved in such measurements.