Solubility of a pharmacological intermediate drug Isatin in different solvents at various temperatures

The solubility of isatin in different solvents was studied by a gravimetrical method from (298.15 to 318.15) K under atmospheric pressure and the solubility data were correlated against temperature. The solvents selected for the present study are: water, methanol, ethanol, 1-butanol, dichloromethane, dichloroethane, chloroform and carbon tetra chloride. Among chlorinated solvents, solubility is observed to be maximum in 1, 2-dichloroethane and minimum in dichloromethane whereas in alcohols, maximum solubility is observed in methanol. In water, solubility is found to be minimum. Further, some thermodynamic parameters such as Gibb’s energy ( ΔG sol ), heat of solution ( ΔH sol ) and entropy of solution ( ΔS sol ) have also been evaluated.


INTRODUCTION
Isatin or 1H-indole-2,3-dione is an indole derivative which is found in many plants. It is a yellow to red needle crystalline solid which has arose great attention in recent years due to their wide variety of biological activities and pharmacological studies as fungicides, 1 insecticides 2 , anticancer 3 , anticonvulsant 4 , anti HIV 5 , anti protozoal 6 , enzymatic 7 , antimicrobial 8 , antifungal 9 , anti-inflammatory 10 , anticonvulsant 11 and cytotoxic 12 and antioxidant 13 etc. Moreover, isatins are the synthetic precursors of some biologically important compounds 14,15 .
Because of the continuing interest about isatin and its derivatives [16][17][18][19] , the present work was undertaken to test the solubility of isatin in different solvents at different temperatures and as a result, to evaluate different thermodynamic parameters. Further, various thermodynamic parameters have been evaluated from these solubility data. The solubility data of isatin may be used in the various fields of chemistry and pharmaceutical industry.
This work is the continuation of our systematic study of solubilities of drug in different solvents. In this paper the solubility of isatin in different solvents such as water, methanol, ethanol, 1-butanol, dichloromethane, dichloroethane, chloroform and carbon tetrachloride have been determined 26 .

EXPERIMENTAL
Isatin, with a mass purity of 99.7 %, was purchased from (Loba Chemicals, Mumbai). All the solvents selected for the present study were analytical grade reagents, which were purified by fractional distillation. Their purities were checked by SHIMADZU GC-MS (Model No QP-2010) and were found to be greater than 99.70 %.
The drug was recrystallized and its melting point was determined by DSC. The observed value was found to be 472 K which is in good agreement with the reported value 20 (473 K).

1. Description of experiment
The solubilities were measured by a gravimetric method 21 . For each measurement, an excess mass of isatin was added to a known mass of solvent. Then, the equilibrium cell was heated to a constant temperature (±0.1 °C) with continuous stirring. After, 3 hours, temperature of water was constant and was recorded. The stirring was stopped and the solution was kept still for 2 hrs. A portion of this solution was filtered and by a preheated injector, 2 ml of this clear solution was taken in another weighted measuring vial (m 0 ). The vial was quickly and tightly closed and weighted (m 1 ) to determine the mass of the sample (m 1 -m 0 ). Then, the vial was covered with a piece of filter paper to prevent dust contamination. Then, the vial was placed in at room temperature to evaporate the solvent.
After the solvent in the vial had completely evaporated, the vial was dried and reweighed (m 2 ) to determine the mass of the constant residue solid (m 2 -m 0 ). All the weights were taken using an electronic balance (Mettler Toledo AB204-S, Switzerland) with an accuracy of 0.0001 g. Thus, the solid concentration of the sample solution of mole fraction, x, could be determined from equation 1.
where M 1 is the molar mass of isatin and M 2 is the molar mass of the solvent. At each temperature, the measurement was repeated three times and an average value is given in Table 1.

RESULTS AND DISCUSSION
The mole fraction solubilities x of isatin in studied solvents at different temperatures (298.15 to 318.15) are summarized in Table 1. It is evident from Table 1 that among chlorinated solvents, solubility is minimum in dichloromethane and maximum in 1,2dichloroethane whereas in alcohols, maximum solubility is observed in methanol. In water, solubility is found to be minimum. Table 2 shows dielectric constants and dipole moments of the studied solvents. It is well known fact that solubility is affected by dielectric constant and dipole moment of the solvents. Among alcohols and water, dielectric constant and dipole moments is maximum for water and minimum for 1-butanol. But, it is observed that solubility is minimum in water and maximum for 1-butanol. If water is excluded from alcohols then maximum dielectric constant and dipole moments are for methanol where solubility is higher at lower temperature but at higher temperatures, solubility is found to be greater for 1-butanol. This may be due to disruption of structure due to bulky 1-butanol as compared to other two alcohols.
Among chlorinated solvents, dielectric constant and dipole moments is maximum for 1,2-dichloroethane and minimum for carbon tetrachloride. The maximum solubility in 1,2dichloroethane can be explained due to its high dielectric constant. However, minimum solubility is observed in dichloromethane which is having dielectric constant greater than chloroform and carbon tetra chloride. When dipole moments of the four solvents are compared, it is observed that dipole moment is maximum for dichloromethane which may be the reason for less solubility in this solvent. Again, in this case also, bulky 1,2-dichloroethane may cause greater solubility as compared to other chlorinated solvents.
The variation of solubility with temperature is also shown in Figure 2. It is observed that solubility increases with increase of temperature. As shown in Figure 2, the mole fraction solubility x of isatin was correlated as a function of temperature. The temperature dependence of the drug solubility in solvents is described by the modified Apelblat equation 22 (2) where x is the mole fraction solubility of isatin, T is the absolute temperature and A, B and C are the parameters.

International Letters of Chemistry, Physics and Astronomy Vol. 17 43
The values of these parameters are given in Table 3. The calculated solubilities x ci are also reported in Table 1. The experimental solubility of isatin in the studied solvents was compared with calculated solubility (x ci ).
Further, root-mean-square deviations (RMSD), calculated by equations 3 is listed in Table 2.
where N is the number of experimental points and x ci is the solubility calculated by equation 2.
The relative deviations (RD) between the experimental and calculated values of solubilities are also calculated by equation 4 and are given in Table 1.

Relative Deviation
The heat of solution (H sol ) was calculated by modified van't Hoff equation 23,24 : where T is the experimental temperature and R is perfect gas constant (8.314 J. mole -1 .K -1 ). T hm is the mean harmonic temperature which is given as where n is the number of experimental temperatures 17 . In the present case, the T hm value obtained is only 307.79 K. The slope of the plot of ln x versus (1/T-1/307.79) gives the value of H sol .
The Gibbs energy change for the solubility process was then evaluated from the following relation 23 : ΔG sol = -RT• intercept (7) Using these evaluated H sol and G sol values, the entropy of solution S sol were obtained from equation 23 (8) All these thermodynamic parameters are given in Table 4.
It is evident from Table 4 that for all the solvents G sol and S sol values are positive. When stronger bonds are broken and weaker bonds are formed, energy is consumed. So, H sol becomes positive 24 . This indicates endothermic dissolution of compounds where the enthalpy term contributes to an unfavorable positive value of G sol . Thus, positive value of G sol indicates that the dissolution process is not spontaneous 16 . The positive S sol for dichloromethane, 1,2-dichloroethane and carbon tetrachloride confirms the complex formation. However negative S sol values in chloroform may due to absence of complex formation 25 .

CONCLUSION
In alcohols, maximum solubility is observed in 1-Butanol whereas in chloriated solvents, it is maximum in 1,2-dichloroethane. Further, solubility increases with temperature. The dissolution process is not spontaneous and is endothermic.