Hydrolysis kinetics of diacetyl nadolol.

Diacetyl nadolol, a prodrug of nadolol and a beta-blocker, has corneal permeability approximately 20 times higher than that of its parent compound due to its higher lipophilicity. Hydrolysis studies were conducted for diacetyl nadolol at various elevated temperatures and pH values to provide stability information for its ophthalmic preparations. The apparent rate constants for diacetyl nadolol hydrolysis to acetyl nadolols and nadolol were determined. Within the neutral pH range (6.8 to 8.2), the hydrolysis of diacetyl nadolol may be proposed as specific base catalysis. Various constants for diacetyl nadolol hydrolysis to acetyl nadolols and acetyl nadolols to nadolol were respectively listed as following: activation energy, 9.78 and 11.39 kcal/mol; entropy at 25 degrees C, -9.78 and -5.86 cal/mol.deg; second-order rate constant at 75 degrees C, 3.47 X 10(4) and 2.22 X 10(4) M-1h-1. According to these kinetic constants, a diacetyl nadolol aqueous solution with pH 6.5 may be prepared as an antiglaucoma agent. The shelf-life was estimated to be only 43 d at room temperature (25 degrees C). However, when the storage temperature is lowered to 5 degrees C, the shelf-life can be extended to greater than 2 years.