Diclofenac Solubility: Independent Determination of the Intrinsic Solubility of Three Crystal Forms

The solubility in water of diclofenac ({2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid), a potent nonsteroidal
anti-inflammatory drug, has been investigated. The various solid forms have been characterized by
thermogravimetric analysis, differential scanning calorimetry, and X-ray diffraction. The commercially
available form of diclofenac is the anhydrous sodium salt. This was recrystallized from ethanol and precipitated
as a hydrate containing four diclofenac anions, four sodium cations, and nineteen water molecules per unit
cell. This crystal structure is similar to but different from an earlier report of the structure. Crystals of the
acid form of diclofenac were anhydrous and corresponded to an earlier crystal structure. Separate solubility
measurements on all three of these solid forms of diclofenac gave consistent results for the intrinsic solubility.
The aqueous solubility values reported in the literature for diclofenac are spread over a large range, with a
factor of 100 separating the largest and the smallest. Our value is at the smaller end of this range. It is the
only one supported by three independent procedures and rigorous characterization of the solid forms. The
experimental conditions were precisely controlled.