Physicochemical characterization of nedocromil bivalent metal salt hydrates. 2. Nedocromil zinc.
Salts are usually considered as alternatives for drug delivery when the physicochemical characteristics of the acidic or basic parent drug are unsuitable or inadequate for a satisfactory formulation. The physical, chemical, and biological characteristics of nedocromil sodium, which 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 several hydration states, an octahydrate, a heptahydrate, and a pentahydrate, which itself exists in two modifications, designated as A and B. The relationships between these, NZ hydrates and the nature of the water interactions in the solid phases 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) spectroscopy, solid-state nuclear magnetic resonance (SSNMR) spectroscopy, environmental scanning electron microscopy (ESEM), water uptake at various relative humidities (RH), intrinsic dissolution rate (IDR), and solubility measurements. The integral water stoichiometries of the NZ hydrates were deduced from KFT and TGA and were confirmed by elemental analysis. For the heptahydrate, the loss of 1 mol of water at a higher temperature than for the others is attribute 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 determined. Similarly, for both pentahydrate modifications, 1 mol of water was also lost at a higher temperature than the others. Results from studies using DSC, TGA, HSM, PXRD, SSNMR, and FTIR suggested that the octahydrate contains loosely bound water in its structure and is partially amorphous. The course of the dehydration processes depended on the water vapor pressure and temperature. The octahydrate and heptahydrate underwent an apparently irreversible phase transformation to the pentahydrate at an elevated temperature and water vapor pressure. Pentahydrate modifications A and B differ in their long-range order (deduced from differences in their PXRD pattern and their thermal analytical behavior), but their short-range order (i.e., molecular environments) are identical (deduced by identical SSNMR spectra). The rank order of both IDR and solubility in water at 25 degrees C was octahydrate > heptahydrate > pentahydrate modification A approximately pentahydrate modification B, corresponding to the rank order of free energy with respect to the aqueous solution and the order of preparation according to Ostwald's rule of stages.
Zhu
H
H
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis 55455-0343, USA.
Padden
B E
BE
Munson
E J
EJ
Grant
D J
DJ
D002152:Calorimetry, Differential Scanning; D009682:Magnetic Resonance Spectroscopy; D008855:Microscopy, Electron, Scanning; D017835:Nedocromil / Q000737:chemistry*; D012492:Salts; D017550:Spectroscopy, Fourier Transform Infrared; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction; D015032:Zinc / Q000737:chemistry*
D012492:Salts; D014867:Water; D017835:Nedocromil; D015032:Zinc