PHYSICOCHEMICAL CHARACTERIZATION OF NEDOCROMIL BIVALENT-METAL SALT HYDRATES .1. NEDOCROMIL MAGNESIUM

Nedocromil sodium is used in the treatment of reversible obstructive a irways diseases, such as asthma. The physicochemical, mechanical, and biological characteristics of nedocromil sodium can be altered by its conversion to other salt forms. In this study, three crystalline hydra tes, the pentahydrate, heptahydrate, and decahydrate, of a bivalent me tal salt, nedocromil magnesium (NM), were prepared. The relationships between these hydrates were studied through their characterization by differential scanning calorimetry (DSC), thermogravimetric analysis (T GA), Karl Fischer titrimetry (KFT), hot stage microscopy (HSM), ambien t or variable temperature powder X-ray diffraction (PXRD), Fourier-tra nsform infrared (FTIR) spectroscopy, solid-state nuclear magnetic reso nance (SSNMR) spectroscopy, scanning electron microscopy (SEM), water uptake at various relative humidities (RH), intrinsic dissolution rate (IDR), and solubility measurements. The pentahydrate showed two dehyd ration steps, corresponding to two binding states of water, a more tem perature-sensitive tetramer and a more stable monomer, deduced from th e crystal structure previously determined. The heptahydrate and decahy drate each showed a dehydration step with a minor change in slope at a bout 50 degrees C, which was analyzed by derivative TGA and confirmed by DSC. HSM and variable temperature PXRD also confirmed the thermal d ehydration behavior of the NM hydrates. The decahydrate underwent an a pparently irreversible phase transformation to the pentahydrate at 75 degrees C at an elevated water vapor pressure. The PXRD, FTIR, and SSN MR of the decahydrate were similar to those of the heptahydrate, sugge sting that the three extra water molecules in the decahydrate are loos ely bound, but were significantly different from those of the pentahyd rate. The rank order of both IDR and solubility in water at 25 degrees C was heptahydrate approximate to decahydrate > pentahydrate, corresp onding to the rank order of free energy with respect to the aqueous so lution.