Biodegradable cross-linked prodrug of the bronchial dilator Vephylline. 2. Kinetics and quantum chemical studies on the release mechanism.

ABSTRACT

Experimental thermodynamics studies and quantum chemical reaction path calculations on the hydrolytic degradation of Poly-vephyllinemalate microspheres in acidic and basic media were performed. It was possible to make a conclusion on the release mechanism of free Vephylline as follows a hydrolytic cleavage of the ester bonds between molecular fragments of R,S-malic acid takes place and leads to a soluble oligoester fraction. Then, further hydrolysis of the ester bonds between the xanthine fragment and R, S-malic acid leads to the release of Vephylline as free base. The hydrolytic process takes place in acidic solution with rapid degradation of the ester bonds between the malic acid monomers and by far slower degradation of the ester bonds between the malic acid and Vephylline. In basic solution both steps of the hydrolysis are fast processes leading to a complete release of free Vephylline within 1 h. The process of Vephylline release is under entropic control. The experimental results are well correlated to the results obtained after kinetics investigation and after AM1 quantum chemically calculated energy barriers in the reaction path leading to the tetrahedral intermediates of the hydrolytic reactions. This conclusion is in good accordance with an indirect study on the release mechanism of Vephylline from its polymeric prodrug, paying attention to the biological response, reported previously.