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

Experimental thermodynamics studies and quantum chemical reaction path calc ulations on the hydrolytic degradation of Poly-vephyllinemalate microsphere s in acidic and basic media were performed. It was possible to make a concl usion on the release mechanism of free Vephylline (R) as follows: a hydroly tic cleavage of the ester bonds between molecular fragments of R,S-malic ac id takes place and leads to a soluble oligoester fraction. Then, further hy drolysis of the ester bonds between the xanthine fragment and R,S-malic aci d leads to the release of Vephylline (R) as free base. The hydrolytic proce ss 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 (R). In basic solution both st eps of the hydrolysis are fast processes leading to a complete release of f ree Vephylline (R) within 1 h. The process of Vephylline (R) release is und er entropic control. The experimental results are well correlated to the re sults obtained after kinetics investigation and after AMI quantum chemicall y calculated energy barriers in the reaction path leading to the tetrahedra l intermediates of the hydrolytic reactions. This conclusion is in good acc ordance with an indirect study on the release mechanism of Vephylline (R) f rom its polymeric prodrug, paying attention to the biological response, rep orted previously. (C) 1999 Elsevier Science B.V. All rights reserved.