**Author details**

times larger than the experimental) the one obtained by mpwpw91/6-31+G(d,p) was much more closer (6.3 hours). The discrepancy between the calculated B3LYP/6-31G (d,p) and experimental values might be attributed to (i) B3LYP/6-31 G(d,p) is a DFT method without dispersion corrections and (ii) PCM solvation model (calculations in presence of solvent) is not

The experimental t 1/2 value for atenolol **ProD 1** at pH 5 was 133 hours and at pH 7.4 no hydrolysis was observed. The lack of the hydrolysis at the latter pH might be due to the fact that at this pH atenolol **ProD 1** exists mainly in the ionized form (*pKa* about 3-4). As mentioned before the free acid form is a mandatory requirement for the acid-catalyzed hydrolysis to

In a similar manner to that observed in the intraconversion of atenolol **ProD 1, the** acidcatalyzed hydrolysis of both, amoxicillin **ProD 1**and cephalexin **ProD 1** was much faster in 1N HCl than in pH 2.5 and 5 (Figures13 and 14). At 1N HCl the t ½ values for the intraconversion of amoxicillin **ProD 1**and cephalexin **ProD 1**was in both cases about2.5hours. On the other hand, in pH 7.4, both amoxicillin **ProD 1**and cephalexin **ProD 1** were entirely stable and no intraconversion to the parent drugs was detected. The salient points emerged from our study on Bruice's system are as follows: (i) the cyclization rate of Bruice's system was found to be dependent on the difference in the strain energies of the intermediate and reactant, and no relationship was found between the reaction rate and the distance between the nucleophile and the electrophile. (ii) The reactions of strained di-carboxylic semi-esters are more efficient than the less strained ones, and the reactivity extent was linearly correlated with the strain energy difference between the intermediate and reactant. (iii) The activation energy required to give a stable transition state for a strained di-carboxylic semi-ester is less than that for the unstrained semi-ester, since the conformational change from the reactant to the transition state in the former is smaller, and (iv) based on the linearity found between the relative rate, the activation energy and the difference in strain energies of the intermediate and reactant for Bruice's di-carboxylic semi-esters we have proposed two paracetamol prodrugs, which were synthesized and their in vitro kinetics was studied. Future strategy to achieve more efficient atenolol prodrugs capable of increasing the liquid formulation stability, eliminating atenolol bitterness and releasing the parent drug in a programmable manner is synthesis of atenolol prodrugs having *pKa* around 6 (intestine pH). At the pH of the intestine the planned prodrugs will exist mainly in the acidic form which has the capability to undergo an acid-catalyzed

The author would like to acknowledge funding by the German Research Foundation (DFG, ME 1024/8-1). Special thanks are also given to Nardene Karaman, Angi Karaman, Donia

capable of handling calculations in acidic aqueous solvent.

434 Application of Nanotechnology in Drug Delivery

hydrolysis to provide the active drug, atenolol.

Karaman, and Rowan Karaman for technical assistance.

**Acknowledgements**

proceed.

Rafik Karaman1,2\*

Address all correspondence to: dr\_karaman@yahoo.com

1 Bioorganic Chemistry Department, Faculty of Pharmacy, Al-Quds University, Jerusalem, Palestine

2 Department of Science, University of Basilicata, Potenza, Italy
