PHYSICOCHEMICAL CHARACTERIZATION OF NEDOCROMIL BIVALENT-METAL SALT HYDRATES .2. NEDOCROMIL ZINC

Salts are usually considered as alternatives for drug delivery when th e physicochemical characteristics of the acidic or basic parent drug a re unsuitable or inadequate for a satisfactory formulation. The physic al, chemical, and biological characteristics of nedocromil sodium, whi ch is used in the treatment of reversible obstructive airways diseases such as asthma, can be altered by its conversion to other salt forms. Nedocromil zinc (NZ), a bivalent metal salt, was found to exist in se veral hydration states, an octahydrate, a heptahydrate, and a pentahyd rate, which itself exists in two modifications, designated as A and B. The relationships between these NZ hydrates and the nature of the wat er interactions in the solid phases were studied through characterizat ion by differential scanning calorimetry (DSC), thermogravimetric anal ysis (TGA), Karl Fischer titrimetry (KFT), hot-stage microscopy (HSM), ambient- or variable-temperature powder X-ray diffraction (PXRD), Fou rier-transform infrared (FTIR) spectroscopy, solid-state nuclear magne tic resonance (SSNMR) spectroscopy, environmental scanning electron mi croscopy (ESEM), water uptake at various relative humidities (RH), int rinsic dissolution rate (IDR), and solubility measurements. The integr al water stoichiometries of the NZ hydrates were deduced from KFT and TGA and were confirmed by elemental analysis. For the heptahydrate, th e loss of 1 mol of water at a higher temperature than for the others i s attributed to an identifiable water molecule that is linked directly to the zinc and to two carboxylate oxygen atoms but not to the other water molecules, as deduced from the crystal structure previously dete rmined. Similarly, for both pentahydrate modifications, 1 mol of water was also lost at a higher temperature than the others. Results from s tudies using DSC, TGA, HSM, PXRD, SSNMR, and FTIR suggested that the o ctahydrate contains loosely bound water in its structure and is partia lly amorphous. The course of the dehydration processes depended on the water vapor pressure and temperature. The octahydrate and heptahydrat e underwent an apparently irreversible phase transformation to the pen tahydrate at an elevated temperature and water vapor pressure. Pentahy drate modifications A and B differ in their long-range order (deduced from differences in their PXRD pattern and their thermal analytical be havior), but their short-range order (i.e., molecular environments) ar e identical (deduced by identical SSNMR spectral. The rank order of bo th IDR and solubility in water at 25 degrees C was octahydrate > hepta hydrate > pentahydrate modification A approximate to pentahydrate modi fication B, corresponding to the rank order of free energy with respec t to the aqueous solution and the order of preparation according to Os twald's rule of stages.