**8. Bitterless atenolol prodrugs based on Kirby's maleamic acids enzyme model**

Atenolol is a relatively polar hydrophilic compound with water solubility of 26.5 mg/mL at 37 0 C and a log partition coefficient (octanol/ water) of 0.23. Atenolol is a selective ß1-adrenoceptor antagonist, applied in the treatment hypertension, angina, acute myocardial infarction, supraventricular tachycardia, ventricular tachycardia, and the symptoms of alcohol with‐ drawal. The net effect of atenolol on controlling both the heart rate and blood pressure is the reduction in myocardial work and oxygen requirement which reduces cardiovascular stress, thereby preventing arrhythmia and angina attacks.

Atenolol has a pKa of 9.6; it undergoes ionization in the stomach and intestine thus its oral bioavailability is low due to inefficient absorption through membranes.

**N**

Atenolol is available as 25, 50 and 100 mg tablets for oral administration. However, most of these medicines are not formulated for easy or accurate administration to children for the migraine indication or in elderly patients who may have a difficulty swallowing tablets. Attempts to prepare a liquid formulation was challenging because atenolol is unstable in solutions. Studies showed that the degradation rate of atenolol is dependent on the tempera‐ ture, indicating higher stability at 4 ºC. Atenolol syrup is stable only for 9 days. Furthermore, oral doses of atenolol are incompletely absorbed (range 46-62%), even when formulated as a solution. Furthermore, atenolol bitterness is considered as a great challenge to health sector when used among children and geriatrics [125]. The main problem in oral administration of bitter drugs such as atenolol is incompliance by the patients [1] and this can be overcome by masking the bitterness of a drug either by decreasing its oral solubility on ingestion or eliminating the interaction of drug particles to taste buds [2].Thus the development of bitterless and more lipophilic prodrug that is stable in aqueous medium is a significant challenge. Improvement of atenolol pharmacokinetic absorption properties and hence its effectiveness may increase the absorption of the drug *via* a variety of administration routes. The aims of the study described in this section were: (1) design of atenolol prodrugs that can be (i) formulated in aqueous solutions and be stable over a long period of time, (ii) bitterless compounds having the capability to convert in physiological environment to the parent active drug, atenolol, in a controlled manner and (2) synthesis, characterization and *in vitro* kinetic study of the conver‐ sion of the designed prodrugs to their parent drug in different pHs (physiological media).

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The proposed atenolol prodrugs that were designed based on the acid-catalyzed hydrolysis

As shown in Figure 7, the only difference exists between the proposed atenolol prodrugs and their parent drug is that the amine group of atenolol was replaced with an amide moiety. Replacing the free amine in atenolol with an amide is expected to increase the stability of the prodrug thus formed due to general chemical stability for tertiary alcohols over amine alcohols. In addition, recent stability studies on atenolol esters have demonstrated that the esters were more stable than their corresponding alcohol, atenolol, when formulating in aqueous solu‐ tions. Furthermore, kinetic study on atenolol and propranolol demonstrated that increasing the lipophilicity of the drug leads to an increase in the stability of its aqueous solutions. Based on that, it is expected that atenolol prodrugs shown in Figure 7 will have the potential to be more resistant to heat or/oxidation when formulated in aqueous solutions [128-131]. Atenolol's bitter-taste can be masked by using the prodrug chemical approach. For example, paracetamol (**30**), a widely used pain killer found in the urine of patients who had taken phenacetin has a very unpleasant bitter taste. Phenacetin (**31**), on the other hand, lacks or has very slight bitter taste. The difference in the structural features of both drugs is only the group in the *para* position of the benzene ring. While in the case of paracetamol the group is hydroxyl, in phenacetin it is ethoxy. On the other hand, acetanilide (**32**)is a bitterless compound with a chemical structure similar to that of paracetamol and phenacetin but lacks the group in the *para* position of the benzene ring. These facts suggest that the presence of the hydroxyl group on the *para* position of the benzene ring is the major contributor for the bitterness of parace‐ tamol. It is likely that paracetamol bitterness is a result of interactions *via* hydrogen bonding

reactions of N-alkyl maleamic acids **34-42** (Figure 5)are depicted in Figure 7.

**NHR = atenolol, acyclovir, cefuroxime, tranexamic acid or methyl R1 and R2; H, methyl or trifluoromethyl**

**Figure 6.** Proposed mechanism for the acid-catalyzed hydrolysis of maleamic acids.

The bioavailability of atenolol is 45%-55% of the given dose and is not increased by adminis‐ tration of the drug in a solution form [123-125].About 50% of administered atenolol is absorbed; however, most of the absorbed quantity reaches the systemic circulation. Atenolol peak blood levels are reached within two to four hours after ingestion. Differently from propranolol or metoprolol, atenolol is resistant to metabolism by the liver and the absorbed dose is eliminated by renal excretion. More than 85% of I.V. dose is excreted in urine within 24 hours compared with 50% for an oral dose. Only 6-16% is protein-bound resulting in relatively consistent plasma drug levels with about a four-fold inter-patient variation. The elimination half-life of atenolol is between 6 to 7 hours and there is no alteration of kinetic profile of a drug by chronic administration.

Atenolol is one of the most important medicines used for prevention of several types of arrhythmias in childhood, but unfortunately it is still unlicensed [126]. On the other hand, atenolol is indicated as a first-step therapy for hypertension in elderly patients, who have difficulty in swallowing and, thus, tablets and capsules are frequently avoided.

Atenolol is available as 25, 50 and 100 mg tablets for oral administration. However, most of these medicines are not formulated for easy or accurate administration to children for the migraine indication or in elderly patients who may have a difficulty swallowing tablets. Attempts to prepare a liquid formulation was challenging because atenolol is unstable in solutions. Studies showed that the degradation rate of atenolol is dependent on the tempera‐ ture, indicating higher stability at 4 ºC. Atenolol syrup is stable only for 9 days. Furthermore, oral doses of atenolol are incompletely absorbed (range 46-62%), even when formulated as a solution. Furthermore, atenolol bitterness is considered as a great challenge to health sector when used among children and geriatrics [125]. The main problem in oral administration of bitter drugs such as atenolol is incompliance by the patients [1] and this can be overcome by masking the bitterness of a drug either by decreasing its oral solubility on ingestion or eliminating the interaction of drug particles to taste buds [2].Thus the development of bitterless and more lipophilic prodrug that is stable in aqueous medium is a significant challenge. Improvement of atenolol pharmacokinetic absorption properties and hence its effectiveness may increase the absorption of the drug *via* a variety of administration routes. The aims of the study described in this section were: (1) design of atenolol prodrugs that can be (i) formulated in aqueous solutions and be stable over a long period of time, (ii) bitterless compounds having the capability to convert in physiological environment to the parent active drug, atenolol, in a controlled manner and (2) synthesis, characterization and *in vitro* kinetic study of the conver‐ sion of the designed prodrugs to their parent drug in different pHs (physiological media).

**N**

**HR**

416 Application of Nanotechnology in Drug Delivery

**O H** **NHR**

**O H**

**NHR**

**O**

**O**

**H N H Me** **NHR**

**O**

**OH**

**O**

**O**

**INT3**

**O**

**O**

**O**

**O**

**OH**

**R1**

**R2**

**R1**

**R2**

**R1**

**R2**

**An amine An anhydride**

**OH RHN**

**H**

**O O**

**R1**

**R2**

**R1**

**R2**

**TS2 INT2**

**N-Alkylmaleamic acid TS1 INT1**

**NHR**

**NHR**

**O**

**OH**

**O**

**H**

**O**

**OH**

The bioavailability of atenolol is 45%-55% of the given dose and is not increased by adminis‐ tration of the drug in a solution form [123-125].About 50% of administered atenolol is absorbed; however, most of the absorbed quantity reaches the systemic circulation. Atenolol peak blood levels are reached within two to four hours after ingestion. Differently from propranolol or metoprolol, atenolol is resistant to metabolism by the liver and the absorbed dose is eliminated by renal excretion. More than 85% of I.V. dose is excreted in urine within 24 hours compared with 50% for an oral dose. Only 6-16% is protein-bound resulting in relatively consistent plasma drug levels with about a four-fold inter-patient variation. The elimination half-life of atenolol is between 6 to 7 hours and there is no alteration of kinetic profile of a drug by chronic

Atenolol is one of the most important medicines used for prevention of several types of arrhythmias in childhood, but unfortunately it is still unlicensed [126]. On the other hand, atenolol is indicated as a first-step therapy for hypertension in elderly patients, who have

difficulty in swallowing and, thus, tablets and capsules are frequently avoided.

**O**

**TS4**

**R1**

**Intermediate Collapse <sup>H</sup>**

**NHR = atenolol, acyclovir, cefuroxime, tranexamic acid or methyl**

**Figure 6.** Proposed mechanism for the acid-catalyzed hydrolysis of maleamic acids.

**R1 and R2; H, methyl or trifluoromethyl**

administration.

**R1**

**Proton Transfer**

**R2**

**R2**

**O O**

**Intermediate Formation**

**R1**

**R2**

The proposed atenolol prodrugs that were designed based on the acid-catalyzed hydrolysis reactions of N-alkyl maleamic acids **34-42** (Figure 5)are depicted in Figure 7.

As shown in Figure 7, the only difference exists between the proposed atenolol prodrugs and their parent drug is that the amine group of atenolol was replaced with an amide moiety. Replacing the free amine in atenolol with an amide is expected to increase the stability of the prodrug thus formed due to general chemical stability for tertiary alcohols over amine alcohols. In addition, recent stability studies on atenolol esters have demonstrated that the esters were more stable than their corresponding alcohol, atenolol, when formulating in aqueous solu‐ tions. Furthermore, kinetic study on atenolol and propranolol demonstrated that increasing the lipophilicity of the drug leads to an increase in the stability of its aqueous solutions. Based on that, it is expected that atenolol prodrugs shown in Figure 7 will have the potential to be more resistant to heat or/oxidation when formulated in aqueous solutions [128-131]. Atenolol's bitter-taste can be masked by using the prodrug chemical approach. For example, paracetamol (**30**), a widely used pain killer found in the urine of patients who had taken phenacetin has a very unpleasant bitter taste. Phenacetin (**31**), on the other hand, lacks or has very slight bitter taste. The difference in the structural features of both drugs is only the group in the *para* position of the benzene ring. While in the case of paracetamol the group is hydroxyl, in phenacetin it is ethoxy. On the other hand, acetanilide (**32**)is a bitterless compound with a chemical structure similar to that of paracetamol and phenacetin but lacks the group in the *para* position of the benzene ring. These facts suggest that the presence of the hydroxyl group on the *para* position of the benzene ring is the major contributor for the bitterness of parace‐ tamol. It is likely that paracetamol bitterness is a result of interactions *via* hydrogen bonding

of the phenolic group in paracetamol with the bitter taste receptors. Similarly, it is expected that blocking the amine group in atenolol with a suitable linker might inhibit the hydrogen bonding between the amine group in atenolol and its bitter taste receptors and hence masking the drug's bitterness [132].

molarity parameter. The effective molarity is defined as the rate ratio (kintra/kinter) for corre‐ sponding intramolecular and intermolecular processes driven by identical mechanisms. Ring size, solvent and reaction type are the major factors affecting the EM value. Ring-closing reactions *via* intramolecular nucleophilic addition are much more efficient than intramolecular

lecular processes occurring through nucleophilic addition. Whereas for proton transfer processes values of less than 10 M were measured for proton transfer processes until recently where values of 1010 was documented by Kirby on the hydrolysis of some enzyme models

For obtaining the EM values for processes **34**-**42** and atenolol **ProD1**-**2** the kinetic and ther‐ modynamic parameters for their corresponding intermolecular process, **Inter** (Figure 8) were

Using equations 1-4, equation 5 was derived, and describes the EM term as a function of the difference in the activation energies of the intra-and the corresponding inter-molecular processes. The calculated EM values for processes **34**-**42** and **ProD 1**-**2** were calculated using

ln EM =-(ΔG‡

Where T is the temperature in Kelvin and R is the gas constant.

**NHCH3**

**Figure 8.** Acid catalyzed hydrolysis for process **Inter**.

**CH3**

intra - ΔG‡

**Inter**

**H2O**

**CH3COOH OH**


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EM = k /k intra inter (1)

‡ ΔG = -RT ln k inter inter (2)

‡ ΔG = -RT ln k intra intra (3)

inter)/RT (5)

**O**

**CH3**

**NH2CH3**

‡ ‡ ΔG - ΔG = -RT ln k /k intra inter intra inter (4)

proton transfer reactions. EM values in the order of 109

[60,78-84].

calculated.

equation 5.

**O**

The proposed atenolol prodrugs, atenolol **ProD 1** and atenolol **ProD 2**, have a hydroxyl and carboxylic acid groups (hydrophilic moiety) and the rest of the prodrug molecule is a lipophilic moiety (Figure 7), where the combination of both groups ensures a moderate hydrophilic lipophilic balance (HLB).

It is worth noting that the HLB value of atenolol prodrug will be largely determined on the pH of the physiological environment by which the prodrug is exposed to. For example, in the stomach pH, the atenolol prodrugs, **ProD 1** and **ProD 2,** will exist in the free carboxylic acid form whereas in the blood circulation the carboxylate form will be dominant. It was planned that atenolol **ProD 1**-**ProD 2** (Figure 7) will be formulated as sodium salts since the carboxylate form is expected to be quite stable in neutral aqueous medium. However, upon dissolution in the stomach (pH less than 3) the proposed prodrugs will exist mainly as a carboxylic acid form **O**thus enabling the acid-catalyzed hydrolysis to commence.

**Figure 7.** Acid-catalyzed hydrolysis for atemolol ProD 1 and atenolol ProD 2.
