**15. In vitro intraconverion of Paracetamol ProD 1 to the parent drug paracetamol**

carboxylic free acid form and since only the carboxylate anion form undergoes Bruice's

The quantum mechanics (QM) calculations in different methods revealed that the acidcatalyzed hydrolysis efficiency of processes **34**-**42**, atenolol **ProD 1**-**ProD 2**,amoxicillin **ProD1** and cephalexin **ProD 1** is significantly sensitive to the pattern of substitution on the carboncarbon double bond and nature of the amine leaving group. The linear correlation found between the reaction rate and strain energy difference between the intermediate and the reactant (Es INT-GM) supports the notion that the reaction is governed by strain effects. Furthermore, the linear correlation of the calculated DFT and experimental EM values reinforce the credibility of using DFT methods for energy and rate predictions for the kind of

Comparisons of the calculated DFT properties for processes **34**-**40**andatenolol prodrugs **ProD1**-**ProD2** with the calculated DFT properties for the acid-catalyzed hydrolysis of acyclovir prodrugs and cefuroxime (Figure 19) demonstrate that while for processes **34**-**40** and atenolol prodrugs **ProD 1**-**ProD 2,** the rate-limiting step was the collapse of the tetrahedral intermediate in the processes of cefuroxime prodrugs and acyclovir prodrugs the rate-limiting step was the tetrahedral intermediate formation. This is might attributed to the nature of the amine leaving

**O**

**N**

**O**

**O**

**O**

**S H**

**O**

**O**

Prodrugs for Masking the Bitter Taste of Drugs

http://dx.doi.org/10.5772/58404

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**R1**

**R2**

**Cefuroxime Prodrugs**

**O**

**NH**

**O**

**OH**

**O**

**NH**

**N**

**OH**

cyclization the hydrolysis rate in 1N HCl is almost negligible or zero.

**16. Conclusions and future directions**

group involved in the tetrahedral intermediate collapse step. **<sup>H</sup>**

**N**

**O**

**OH**

**R1, R2 = H, CH3**

Comparison of the calculated t 1/2 value (63.2 hours) for atenolol **ProD 1** to the experimental value (3.82 hours) indicates that while the B3LYP/6-31G (d,p) value is overestimated (about 17

**<sup>N</sup> <sup>N</sup>**

**Figure 19.** Chemical structures for acyclovir and cefuroxime prodrugs.

processes reported in this section.

**N**

**Aciclovir Prodrugs**

**N H**

**OH**

**O**

**R2**

**R1**

**O**

**O**

The hydrolysis of paracetamol **ProD 1** was studied in four different media; 1N HCl, buffer pH 3, buffer pH 6.6 and buffer pH 7.4. The prodrug hydrolysis was monitored using HPLC analysis. At constant pH and temperature the release of paracetamol from its prodrug was followed and showed a first order kinetics. *kobs* **(h-1)** and t1/2 values for the intraconversion of paracetamol **ProD 1** was calculated from regression equation obtained from plotting log concentration of residual of paracetamol **ProD 1** vs. time. The kinetics results in the different media are summarized in Table 4 and Figure 18.


**Table 4.** The observed *k* value and *t*1/2 of paracetamol **ProD 1** In 1N HCl and buffers pH 3and 7.4.

As shown in Table 4 the hydrolysis rate of paracetamol **ProD 1** at pH 7.4 was the fastest among all media, followed by pH 6.6 medium. In 1N HCl no conversion of the prodrug to the parent dug was observed.

**Figure 18.** First order hydrolysis plot of paracetamol **ProD 1** in (a) buffer pH 3 and (b) buffer pH 7.4.

At pH 7.4 and 6.6 paracetamol **ProD 1** is mainly exists as the carboxylate anion form which is expected to undergo fast hydrolysis according to Bruice's mechanism shown in Figure 16. At pH 3, the prodrug exists in both form, the carboxylate anion and the carboxylic free acid forms since the pKa of the prodrug is about 3. In 1N HCl, the prodrug is entirely exists as the carboxylic free acid form and since only the carboxylate anion form undergoes Bruice's cyclization the hydrolysis rate in 1N HCl is almost negligible or zero.
