Solubility, Polymorphism, Crystallinity, Crystal Habit, and Drying Scheme of (R, S)-(±)-Sodium Ibuprofen Dihydrate - Pharmaceutical Technology

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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.


Pharmaceutical Technology


Hansen parameters fine-tune the total Hildebrand value (δt) into three contributions: a dispersion-force component (δd); a polar component (δp); and a hydrogen-bonding component (δh) (15) as expressed in the following equation:










Dispersion forces are the induced attractions by the random polarities of two molecules in proximity. They are called London dispersion forces or induced dipole-induced dipole forces, and the number of temporary dipoles increases with the molecule's size. Polar forces are created when electrons are unequally shared between the individual atoms in a molecule. The charge distribution is related to the atomic composition, geometry, and size of a molecule. When polar molecules arrange themselves head-to-tail and positive-to-negative, the molecular network leads to a further increase in intermolecular interaction. These temperature-dependent dipole–dipole forces collectively create the Keesom orientation effect. A particularly strong type of polar interaction occurs when hydrogen's sole electron is drawn toward such electronegative atoms as oxygen, nitrogen, and fluorine, leaving the positively charged hydrogen nucleus exposed. The exposed positive nucleus exerts a considerable attraction on electrons in other molecules, forming a proton bridge, which is called hydrogen bonding.

Materials and methods


Table I: Total Hildebrand value and Hansen parameters for solvents at 25 8C.
Solvents. Table I lists the 23 solvents from five different classes in the ascending order of Hildebrand parameters (13). Two other solvents n-propanol (CH3(CH2)2OH, ACS grade, 99.98%, boiling point of 97 C, molecular weight of 60.1 g/mole, Lot 909065 Tedia Company, Fairfield, NJ) and cyclohexane (C6H12, ACS grade, 99.9%, boiling point of 80.7 C, molecular weight of 84.16 g/mol, Lot k24470166, Merck KGaA, Darmstadt, Germany) were used to verify the solubility sphere in the three-dimensional (3-D) Hansen plot.


Figure 2
Active pharmaceutical ingredient. Ibuprofen sodium salt (C13H17NaO2, molecular weight of 228.29 g/mol, batch number 015K0586) purchased from Sigma-Aldrich Corporation (St. Louis, MO) was a dihydrate of racemic (R, S)-()-sodium 2-(4-isobutylphenyl) propionate with a molecular formula of C13H17NaO2•2H2O and a molecular weight of 264.29 g/mol. The amount of the stoichiometric water was determined by the thermogravimetric-use test showing about 13% water loss by weight near the boiling point of water (see Figure 2).


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