The racemic compound (R,S)-(±)-ibuprofen or (R, S)-(±)-2-(4-isobutylphenyl) propionic acid is a popular active pharmaceutical ingredient (API) in analgesic, anti-inflammatory,
and antipyretic therapies (1) with abundant information about the compound provided in the literature (2–11). Ibuprofen is
marketed as a racemate. The enantiomer (S)-(+)-ibuprofen is the active agent and the other enantiomer, (R)-(–)-ibuprofen, is partially converted into (S)-(+)-ibuprofen in humans. (R,S)-(±)-ibuprofen has several disadvantageous formulation properties such as poor water solubility of less than 1 mg/mL at 25
°C, a low melting point of 77 °C, and possible esterification with excipients containing a hydroxyl group (1). These problems
can be easily overcome by using an (R,S)-(±)-ibuprofen salt such as the racemic compound (R,S)-(±)-sodium 2-(4-isobutyl–phenyl) propionate dihydrate or (R, S)-(±)-sodium ibuprofen dihydrate (see Figure 1), whose potential values over (R,S)-(±)-ibuprofen make the study of its solubility, polymorphism, crystallinity, crystal habit, and drying scheme meaningful
In this study, the solubility of (R, S)-(±)-sodium ibuprofen dihydrate solids at 25 °C was determined in 23 solvents using a robust and scalable initial solvent-screening
method (13). Good solvents were identified, and the solubility curves of the solids in various good solvents were constructed.
Good solvents were defined as solvents in which the solubility of racemic (R, S)-(±)-sodium ibuprofen dihydrate had a solubility of < 1 mg/mL at 25 °C. All solids were produced from the supersaturated
solution of the good solvents by temperature cooling from 60–25 °C.
Differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and powder X-ray diffraction (PXRD) determined
the polymorphism, crystallinity, and drying scheme of the solid samples (14). Optical microscopy (OM) and scanning electron
microscopy (SEM) were used for crystal-habit imaging. The solids' solubilities and crystal habits were related to the solvent
microscopic properties of dispersion forces (δd) polar forces (δp), and hydrogen bonding (δh) by the Hansen model adopted from the paint industry at 25 °C (15).
Solvent liquids generally are held together by van der Waals forces, which are electromagnetic interactions among molecules.
The strength of van der Waals forces is directly reflected by the heat of vaporization (ΔHv). ΔHv can be translated into a correlation between vaporization and the solubility behavior because the types of intermolecular
attractive forces needed to be overcome to vaporize a solvent liquid are the same as those that must be overcome to dissolve
it. The Hildebrand numerical value (δt[Pa1/2 ]) of the solvency behavior of a specific solvent was invented as a function of ΔHv (15) in the following:
in which R is the gas constant (8.314 J/mol • K), T is the temperature (measured in K), and Vm is the molar volume (measured in m3 /mol).