Physical characterization of nedocromil sodium hydrates

Abstract

Nedocromil sodium, which is used in the treatment of reversible obstructive airway diseases, such as asthma, is found to exist in the following hydrate phases: the heptahemihydrate, the trihydrate, a monohydrate, 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 humidity at ≥ 150°C, but is rapidly hydrated under ambient conditions. The physical and thermodynamic properties of the four hydrate phases were characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X‐ray diffraction (PXRD) at ambient and elevated temperatures, hot‐stage microscopy (HSM), solid phase interconversion at various relative humidities (RH), intrinsic dissolution rate (IDR), equilibrium solubility measurements, and critical RH measurements. Below 100°C in open pan TGA, the heptahemihydrate and the amorphous forms lose virtually all their water, the monohydrate loses negligible amounts of water, whereas the trihydrate loses the first two moles of water. From 130°C to 200°C in open pan TGA the trihydrate and the monohydrate lose their last mole of water to form the anhydrate. In crimped pan DSC, the thermal events observed are analogous to those observed in open pan TGA, but the temperatures are increased by about 75°C for all except the heptahemihydrate, for which the thermal events are more complex. When the heptahemihydrate is heated in a crimped pan, a melting endotherm is observed at about 75°C followed by three dehydration endotherms. For the crystalline hydrate phases at 22°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 is kinetically stable over the range 11 to 79.5% RH. The IDR in water at 25°C under constant hydrodynamic conditions decreases in the rank order: monohydrate > trihydrate > heptahemihydrate, corresponding to the rank order of free energy with respect to the aqueous solution. The equilibrium aqueous solubility of the heptahemihydrate at 25.0 ±0.2°C is 0.956 ±0.010 M.