Chemical stability of prostacyclin (PGI2) in aqueous solutions

The rate constant for the hydrolysis of prostacyclin (PGI₂) to 6-keto-PGF_1α was measured by monitoring the UV spectral change, over a pH range 6 to 10 at 25°C and the total ionic strength of 0.5 M. The first-order rate constant (k_obs) extrapolated to zero buffer concentration follows an expression, k_obs = k_H+ (H+), where k_H+ is a second-order rate constant for the specific acid catalyzed hydrolysis. The value of k_H+ obtained (3.71 × 10⁴ sec⁻¹ M⁻¹) is estimated approximately 700-fold greater than a k_H+ value expected from the hydrolysis of other vinyl ethers. Such an unusually high reactivity of PGI₂ even for a vinyl ether is attributed to a possible ring strain release that would occur upon the rate controlling protonation of C₅. A Brønsted slope (α) of 0.71 was obtained for the acid (including H₃O+) catalytic constants, from which a pH independent first-order rate constant for the spontaneous hydrolysis (catalyzed by H₂O as a general acid) was estimated to be 1.3 × 10⁻⁶ sec⁻¹. An apparent activation energy (E_a) of 11.85 Kcal/mole was obtained for the hydrolysis at pH 7.48, from which a half-life of PGI₂ at 4°C was estimated to be approximately 14.5 min. when the total phosphate concentration is 0.165 M (cf. 3.5 min. at 25°C).