THERMODYNAMICS OF ALLOXAN SOLUBILITY IN VARIOUS SOLVENTS AT DIFFERENT TEMPERATURES

The solubility of Alloxan in methanol, ethanol, ethane-1, 2-diol, water, acetone, and tetrahydrofuran was measured by gravimetric method over a temperature range (293.15 to 323.15) K at atmospheric pressure. The solubility increases non-linearly with temperature in all the studied solvents. Further, in protic solvents, solubility is maximum in methanol and minimum in ethane-1, 2 diol whereas in the selected nonprotic solvents, solubility is greater in tetrahydrofuran than in acetone. The experimental data were correlated with modified Apelblat and Buchowski-Ksiazczak equations. The calculated results show good agreement with the experimental data. Some thermodynamic parameters such as dissolution enthalpy, Gibb’s free energy, and entropy of mixing have also been calculated. The evaluated thermodynamic parameters are found to be positive. The positive enthalpy and Gibb’s free energy indicate endothermic and spontaneous dissolution of compounds. The positive entropy suggests entropy-driving dissolution process.


Introduction
Diabetes mellitus has been considered as one of the major health concerns all around the world today. 1,2[5][6] Alloxan is an oxygenated pyrimidine derivative, and its IUPAC name is 2,4,5,6-pyrimidinetetrone. Figure 1 shows the structure of alloxan.

Figure 1. The structure of alloxan
It causes selective necrosis of the β-cells of pancreatic islets.In pharmaceutical industries, the crystallization process is a critical method for both drug intermediates and final drugs.The solubility data is essential for the selection of the proper solvent for the crystallization process and in pre-formulation studies. 7Further, phenomenological treatment of drug delivery, transport and distribution are dependent on knowledge of solubility. 8The transportation through membranes and the topical activity of drugs can also be predicted by solubility data. 91][12] Thus, in the present work, the solubilities of alloxan have been determined in various solvents; methanol, ethanol, ethane-1,2-diol, water, tetrahydrofuran and acetone over a temperature range 293.15K to 323.15 K by a gravimetric method.The experimental solubility data were correlated with modified Apelblat and Buchowski-Ksiazczak models.Further, some thermodynamic parameters such as enthalpy of dissolution, Gibb‫׳‬s energy, and entropy of solutions have been evaluated.

Materials
Alloxan was purchased from Loba Chemie Pvt. Ltd.The polymorph used in this study was monohydrate.The melting point of alloxan was determined measured by Differential Scanning Calorimeter (Shimadzu-DSC-60) and was found to be 254 0 C.All of the solvents used for the present study were of analytical grade and supplied by Loba Chemie Pvt. Ltd.These solvents were purified by drying over anhydrous sodium sulfate and were fractionally distilled.The solvents were stored over molecular sieves.The purities of the solvents were confirmed by GC-MS (SHIMADZU-Model No.-QP-2010) equipped with column (DB-5MS, 25 m in length, 0.20 mm internal diameter and 0.33μm film) and were found be greater than 99.8 %.

Solubility measurement
The solubility of alloxan was determined by the gravimetric method.For each measurement, an excess mass of drug was added to a known mass of solvent.The equilibrium cell was heated to a constant temperature with continuous stirring for about 5 hours (the temperature of the water bath approached the constant value, and then the actual value of the temperature was recorded).After 5 hours, stirring was stopped, and the solution was kept for 2 hours to approach equilibrium.The equilibrium time of 2 hours is optimized by checking the concentration of solution at different intervals of time.After 2 hours, the change in concentration was less than 1 %, so the saturated solution was assumed to be equilibrium.The upper portion of this clear solution was filtered through a membrane (0.22 μm) and was kept in a weighed vial.The vial with the solution was quickly weighed to determine the mass of the sample.When the mass of the residue reached constant value, the final mass was recorded.All of the masses were taken using an electronic balance (Mettler Toledo AB204-S, Switzerland) with an uncertainty of ±0.0001 g.At each temperature, the measurement was conducted three times, and an average value was used to determine the mole fraction solubility.The saturated mole fraction solubility (xi) of the drug in each solvent can be calculated by using equation ( 1). ( where M1 is the molar mass of solvent and M2 is the molar mass of alloxan.m1 and m2 are the mass of the solvent and solute (alloxan), respectively.
At each temperature, the measurement was conducted three times.By using the average value, mole fraction solubility of alloxan in selected solvents was calculated.

Results and discussion
The mole fraction solubilities xi of alloxan in the selected solvents are presented in Table 1 at different temperatures (293.15 to 323.15 K) with an uncertainty of ±0.1 K and more visually given in Fig. 2. It is observed that the solubility of alloxan increases nonlinearly with temperature.Further, in protic solvents, solubility is maximum in methanol and minimum in ethane-1,2-diol.The order of solubility is: methanol > water > ethanol > ethane-1,2 diol.In the selected nonprotic solvents, solubility is greater in tetrahydrofuran than in acetone.The results are compared with dielectric constants and dipole moments of the solvents, which was given in Table 2.For protic solvents, solubility was maximum in methanol and minimum in ethane-1,2-diol which is of reverse order of dipole moment.The dipole moment of ethane-1,2-diol is highest among studied protic solvents whereas that of methanol is lowest.In nonprotic solvents, solubility was found to be in higher in tetrahydrofuran (THF) than in acetone.The dipole moment of acetone is higher than that of THF.So, the solubility of alloxan was increasing with decreasing of dipole moment.
The temperature dependence of alloxan solubility in pure solvents was described by the modified Apelblat model. 13)   The values of λ and h are evaluated using experimental solubility data and are reported in Table 4. Using these values of adjustable parameters, solubility (x b ci) is calculated using equation ( 3).These values are also plotted against temperature along with experimental mole fraction solubility (xi) as shown in Figure 3.It is observed that the calculated solubilities by Buchowski-Ksiazczak (λh) model are in good agreement with experimental solubility in all the solvents.
The root-mean-square deviations (RMSD) and average relative deviations (ARD) are also calculated for both Apelblat and Buchowski-Ksiazczak models using following equations: (4) (5)   where N is the number of experimental points.3 and 4 for Apelblat and Buchowski-Ksiazczak models respectively.
From these solubility data, some thermodynamic parameters such as enthalpies of solution (Hsol), Gibb's energy of dissolution (ΔGsol) and entropy of solutions (Ssol) have also been evaluated.The enthalpies of solution (Hsol) was calculated by modified van't Hoff equation, i.e., from the slope of the plot of lnx versus (1/T -1/Thm).where T is the experimental temperature, and R is gas constant.Thm is the mean harmonic temperature Thm is is given as (7)   where n is the number of experimental temperatures.
In the present case, the Thm value obtained is only 307.83 K. From the intercepts of these plots, Gibbs energy change (ΔGsol) for the solubility process was evaluated by the following relation: (8)   Using these evaluated Hsol and Gsol values, the entropies of solutions (Ssol) were obtained from the following equation: (9)   Table 5 summarizes these thermodynamic parameters.It is found that enthalpy of dissolution (Hsol) is positive for all the solvents indicating the thereby endothermic behavior of dissolution.This suggests that there may be strong interactions between drug and solvent molecules that those between the solvent molecules and the newly formed bond energy between drug and solvent molecule is not powerful enough to compensate the energy needed for breaking the original association bond in various solvents. 15The Gibbs energy of dissolution (Gsol) is positive for the studied solvents suggesting that the dissolution process is spontaneous.
Further, the order of Gsol values is the reverse of solubility data.The Gibb's energy of dissolution is minimum for methanol and maximum for acetone whereas solubility is maximum for methanol and minimum for acetone.Further, the entropy of dissolution (Ssol) is found to be positive in all the solvents.The positive entropy change indicates that the entropy of solubilization is unfavorable for the solute in solution. 14The entropy depends on the functional groups present in the drug as well as in the solvent.Owing to the Alloxan molecule containing groups of different nature like -NH-, -C=O, there may exist various forces such as electrostatic force, hydrogen bond, hydrophobic interaction and stereoscopic effect in the dissolving process.

    Conclusion
In protic solvents, solubility is maximum in methanol and minimum in ethane-1,2-diol.The order of solubility is: methanol > ethanol >water > ethane-1,2-diol.In the selected nonprotic solvents, solubility is greater in THF than in acetone.The positive Gibb's energy and enthalpy of dissolution suggest dissolution process be endothermic and spontaneous.

Table 1 .
Experimental and calculated mole fraction solubilities (xi) of alloxan in different studied solvents at different temperatures.

Table 2 .
Dipole moments and Dielectric constants of the studied solvents

Table 3 .
Parameters A, B and C of Apelblat model in studied solvents *ARD=average relative deviation, RMSD=root mean square deviation

Table 4 .
Parameters of Buchowski-Ksiazczak h equation in the studied solvents