A. Roy
Jul 12, 1996
Citations
1
Influential Citations
8
Citations
Journal
International Journal of Pharmaceutics
Abstract
Abstract Cyclopentolate hydrochloride (Cy.HCl) undergoes degradation to give α-(1-hydroxycyclopentyl)-benzeneacetic acid (a β-hydroxy acid, by the expected normal ester hydrolysis pathway) and phenylacetic acid (by an unusual cyclic mechanism). These two products are formed simultaneously by parallel mechanisms. The interaction between cyclopentolate (Cy) and cyclodextrins (CDs) results in the formation of a 1:1 stoichiometric complex. β-CD and its substituted analogs exhibit the greatest degree of stabilization of Cy against hydrolysis. In the presence of CDs, the parallel mechanism still operates, but the proportion of the reaction proceeding by the two pathways is altered. For the β-hydroxy acid formation pathway, the complexed drug degrades at a rate ≈ 1 10 as rapid as that of the uncomplexed drug in solution, while the decrease in rate constant for the phenylacetic acid formation pathway is substantially less. Apart from the stabilization effect, evidence for complex formation is available from NMR and molecular modeling studies. The optimum structure of the complex is obtained when the aromatic ring of the Cy molecule enters the CD cavity. When this occurs, the rate of normal ester hydrolysis is reduced. The hydroxycyclopentyl group apparently does not penetrate deeply into the CD cavity because of the presence of an intramolecular bond which can form between the hydroxyl group and the carbonyl oxygen. When interaction with CD occurs on the hydroxycyclopentyl end of the molecule the cyclic hydrolysis mechanism is affected, but not appreciably.