The hydrolysis kinetics of monobasic and dibasic aminoalkyl esters of ketorolac

Abstract

Six aminoethyl and aminobutyl esters of ketorolac containing 1-methylpiperazine (MPE and MPB), N-acetylpiperazine (APE and APB) or morpholine (ME and MB), were synthesized and their hydrolysis kinetics were studied. The hydrolysis was studied at pH 1 to 9 (for MPE, APE and ME) and pH 1 to 8 (for MPB, APB and MB) in aqueous phosphate buffer (0.16 M) with ionic strength (0.5 M) at 37°C. Calculation of k_obs, construction of the pH-rate profiles and determination of the rate equations were performed using KaleidaGraph^® 4.1. The hydrolysis displays pseudo-first order kinetics and the pH-rate profiles shows that the aminobutyl esters, MPE, APB and MB, are the most stable. The hydrolysis of the ethyl esters MPE, APE and ME, depending on the pH, is either fast and catalyzed by the hydroxide anion or slow and uncatalyzed for the diprotonated, monoprotonated and nonprotonated forms. The hydrolysis of the butyl esters showed a similar profile, albeit it was also catalyzed by hydronium cation. In addition, the hydroxide anion is 105 more effective in catalyzing the hydrolysis than the hydronium cation. The hydrolysis pattern of the aminoethyl esters is affected by the number and pKa of its basic nitrogen atoms. The monobasic APE and ME, show a similar hydrolysis pattern that is different than the dibasic MPE. The length of the side chain and the pKa of the basic nitrogen atoms in the aminoethyl moiety affect the mechanism of hydrolysis as the extent of protonation at a given pH is directly related to the pKa.

Keywords::

• Ester prodrugs
• hydrolysis kinetics
• ketorolac
• pH-rate profile
• stability

Acknowledgments

The authors would like to thank Mr. Eyad Hamzeh and Mr. Farouq Al-Zoughoul for their help with the HPLC analysis and Al-Hikma Pharmaceuticals for providing ketorolac.

Declaration of interest

This work was funded by a grant from the Deanship of Research at Jordan University of Science and Technology. The authors report no conflict of interest.