PHYSICOCHEMICAL CHARACTERIZATION OF NEDOCROMIL BIVALENT-METAL SALT HYDRATES .3. NEDOCROMIL CALCIUM

A crystalline pentahydrate and a crystalline 8/3 hydrate of nedocromil calcium (NC) were prepared. The relationships between these solid pha ses and the nature of the water interactions in their structures were studied through characterization by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Karl Fischer titrimetry (KFT) , hot-stage microscopy (HSM), ambient-or variable-temperature powder X -ray diffraction (PXRD), Fourier-transform infrared (FTIR) spectroscop y, solid-state nuclear magnetic resonance (SSNMR) spectroscopy, water uptake at various relative humidities (RH), intrinsic dissolution rate (IDR) and solubility measurements. The solubility and intrinsic disso lution rate of the pentahydrate in water at 25 C are similar to 17% gr eater than the corresponding values for the 8/3 hydrate, corresponding to a greater Gibbs free energy of only 380 J.mol(-1) (91 cal.mol(-1)) for the pentahydrate. The results of DSC, TGA, and FTIR and SSNMR spe ctroscopy indicate that the water of hydration is more loosely bound i n the pentahydrate than in the 8/3 hydrate. On increasing the temperat ure in open-pan DSC and TGA, the water in the pentahydrate is released in four steps (three steps in crimped pans), whereas the water in the 8/3 hydrate is released in three steps (three steps also in crimped p ans). These three stepwise dehydrations are fundamentally explained by their different water environments in the crystal structure of the 8/ 3 hydrate, which was determined by single-crystal XRD [crystal data: t riclinic, space group P (1) over bar, a = 13.2381(3) Angstrom, b = 13. 3650(2) Angstrom, c = 17.8224(2) Angstrom, alpha = 68.202(1)degrees, b eta = 86.894(1)degrees, gamma = 82.969(1)degrees, Z = 6]. The asymmetr ic unit contains three nedocromil anions and three calcium cations ass ociated with eight water molecules. The nedocromil anions act as polyf unctional ligands to the Ca2+ ions, coordinating through both the carb onyl oxygen and the carboxylate oxygen atoms. The molecular conformati ons of the three nedocromil anions in the asymmetric unit are almost i dentical. However, the crystal structure contains two different calciu m environments, one of which has the Ca2+ ion hydrated by four water m olecules in the equatorial plane and by two carbonyl oxygens in its ax ial coordination sites. In the second environment, the Ca2+ ion has fo ur carboxylate oxygen atoms in its equatorial plane and two water mole cules in its axial coordination sites. Two of the carboxylate ligands are twisted out of the tricyclic ring, and the other two carboxylate l igands are nearly coplanar with the tricyclic ring. All of the eight w ater molecules in the 8/3 hydrate are linked to calcium and carboxylat e ions and none are linked to other water molecules.