Solubility studies. Because of the expensive nature of (R, S)-(±)-sodium ibuprofen dihydrate, its solubility was determined by the gravimetric titration method that required a relatively
small amount of material (13). Although the gravimetric titration method had an inherent error of about ± 20% because the
solvent volume used was assumed to be the same as the solution volume (13) and was less accurate than the well-known UV-visible
spectroscopic technique (16) and the evaporation-weighing technique (17), it was rapid, robust, and more suited for the initial
screening. Unlike the other two techniques, the gravimetric titration method did not require establishing time-consuming calibration
curves of (R, S)-(±)-sodium ibuprofen dihydrate concentration in every solvent and did not produce any unforeseen solvates that could interfere
with the true mass of the dihydrate solids after removal of the solvents.
Solvent-miscibility studies. The miscibility tests were performed by mixing two solvents from the 23 solvents in a 20-mL scintillation vial (13). The
number of miscible and immiscible solvent pairs from the miscibility investigations and the API solubility in the 23 single
solvents from the Solubility Studies Section (13) were combined to deduce a form space. The form space is defined as the total number of solid-generation experiments in pure-solvent, cosolvent and antisolvent systems (13).
Polymorph, crystallinity, and crystal-habit studies. Solids were produced in the good solvents ferreted out by the Solubility Studies Section (13). The polymorphism, crystallinity, and crystal habit of the solids were determined by DSC, TGA, PXRD, OM, and SEM, respectively.
Scanning electron microscopy. Solids of racemic (R, S)-(±)-sodium ibuprofen dihydrate compound grown from water were filtered, rinsed with acetone, and vacuumed-dried at 40 °C
or 4 h. The anhydrous (R, S)-(±)-sodium ibuprofen solids were mounted on an aluminum stub by a double-sided carbon conductive adhesive tape (Product
number 16073, Ted Pella Inc., Redding, CA). The solid sample was sputter-coated with a 6-nm thick gold film in an Hitachi
E-1010 Auto Sputter Coater (Hitachi Ltd., Tokyo, Japan).
SEM was carried out using an Hitachi S-3500N (Hitachi Ltd., Tokyo, Japan) instrument equipped with a tungsten filament cathode
source. Gold-coated samples were examined with beam energies of 15 kV with a chamber pressure of 10-5 Pa (resolution ~3Å at these voltages).
Drying-scheme studies. Filtered solids of the racemic (R, S)-(±)-sodium ibuprofen dihydrate compound were dried by three various modes in a DOV-40 oven (Dengyng Instrument Co., Ltd.,
Taiepi, Taiwan) at 40 °C for 4 h in air, at 40 °C for 4 h under vacuum, and 90 °C for 2 h under vacuum. A vacuum of 6.7 ×
10-2 Pa was generated by the GVD-050A vacuum pump (Ulvac Kiko Inc., Yokohama, Japan).