Solubility, Polymorphism, Crystallinity, Crystal Habit, and Drying Scheme of (R, S)-(±)-Sodium Ibuprofen Dihydrate
The racemic compound (R, S)-(±)-ibuprofen is a popular and well understood active pharmaceutical ingredient, but it has several disadvantageous formulation properties such as poor solubility, low melting point, and potential esterification with excipients containing an hydroxyl group. The authors investigate the use of an (R, S)-(±)-ibuprofen salt to evaluate these problems using various analytical methods to determine the polymorphism, crystallinity, and drying scheme.
(R, S)-(±)-sodium ibuprofen dihydrate dissolved well in nine good solvents in Classes 4 and 5: tetrahydrofuran (THF), n-butyl alcohol, isopropyl alcohol (IPA), benzyl alcohol, N,N-dimethylformamide (DMF), ethanol, dimethyl sulfoxide (DSMO), methanol, and water. The compound only slightly dissolved in
n-heptane, xylene, p-xylene, ethyl acetate, toluene, methyl-tert-butyl ether, benzene, methyl ethyl ketone, chloroform, N,N-dimethylaniline, acetone, 1,4-dioxane, nitrobenzene, and acetonitrile with a solubility of <1 mg/mL at 25 °C, giving 14 bad solvents in Classes 1, 2, and 3. Only nine solubility curves of (R, S)-(±)-sodium ibuprofen dihydrate in nine good solvents at 15, 25, 40, and 60 °C were constructed and grouped by their similar
solubility ranges for ease of comparison (see Figure 3).
If the solute and the solvent formed an ideal solution, a straight line should result when ln x was plotted against 1/T according to the van't Hoff equation (13):
in which x is the mole fraction of (R,S)-(±)-sodium ibuprofen dihydrate in the solution at a given temperature (T) measured in K, converted from the solubility curves in Figure 3, and Rg was the ideal gas enthalpy constant (8.314 J/mol • K). Any deviation from the ideal solution behavior would be reflected
from the correlation coefficient (R) of the linear fit in Figure 4. The relatively high correlation coefficients with values > 0.97 of the solvent systems, except
for the one of DMSO, indicated that the solubility measurements by gravimetric titration were quite accurate, and the deviation
of the solution from ideality was negligible. The enthalpy of dissolution (ΔHd)and the entropy of dissolution (ΔSd) were estimated from the slope and the y-intercept of the straight lines in Figure 4, respectively.