PHYSICAL CHARACTERIZATION OF NEDOCROMIL SODIUM HYDRATES

Nedocromil sodium, which is used in the treatment of reversible obstru ctive airway diseases, such as asthma, is found to exist in the follow ing hydrate phases: the heptahemihydrate, the trihydrate, a monohydrat e, and an amorphous phase which contains variable amounts of water (1. 5-3.0 mol). An anhydrate phase is formed from the trihydrate at zero h umidity at greater than or equal to 150 degrees C, but is rapidly hydr ated under ambient conditions. The physical and thermodynamic properti es of the four hydrate phases were characterized using differential sc anning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-r ay diffraction (PXRD) at ambient and elevated temperatures, hot-stage microscopy (HSM), solid phase interconversion at various relative humi dities (RH), intrinsic dissolution rate (IDR), equilibrium solubility measurements, and critical RH measurements. Below 100 degrees C in ope n pan TGA, the heptahemihydrate and the amorphous forms lose virtually all their water, the monohydrate loses negligible amounts of water, w hereas the trihydrate loses the first two moles of water. From 130 deg rees C to 200 degrees C in open pan TGA the trihydrate and the monohyd rate lose their last mole of water to form the anhydrate. In crimped p an DSC, the thermal events observed are analogous to those observed in open pan TGA, but the temperatures are increased by about 75 degrees C for all except the heptahemihydrate, for which the thermal events ar e more complex. When the heptahemihydrate is healed in a crimped pan, a melting endotherm is observed at about 75 degrees C followed by thre e dehydration endotherms. For the crystalline hydrate phases at 22 deg rees C, the ranges of stability are as follows. the monohydrate from 0 to 6.4% RH; the trihydrate from 6.4 to 79.5% RH; the heptahemihydrate above 80% RH. A microbalance study showed that the heptahemihydrate i s kinetically stable over the range 11 to 79.5% RH. The IDR in water a t 25 degrees C under constant hydrodynamic conditions decreases in the rank order: monohydrate > trihydrate > heptahemihydrate, correspondin g to the rank order of free energy with respect to the aqueous solutio n. The equilibrium aqueous solubility of the heptahemihydrate at 25.0 +/- 0.2 degrees C is 0.956 +/- 0.010 M.