**2.2 Prodrug**

Prodrug is the chemically modified inactive derivative of active form with optimized properties and better in vivo performance. Almost one-tenth of the pharmaceutical products are used as prodrug with main aim of improving bioavailability by avoiding first-pass metabolism, improved drug absorption, and organ selective transport. So prodrug can be defined as inactive form that undergoes biotransformation and converted to active form to elicit its pharmacological effect. Development of prodrug depends on specific property of drug that needs improvement and mostly with respect to stability, improving bioavailability [2].

In recent times, science has moved to "cod drugs," "hard drugs," and "soft drugs," where cod drug consists of two pharmacologically active components, which are complexed to form a single molecule (e.g., sulfasalazine, Levodopa-Entacapone). Soft drugs are the modified derivatives with predetermined metabolism, so that after exerting pharmacological action for suitable time, its metabolite can be eliminated from body. Main aim of developing soft drugs is to avoid toxicity associated with formed metabolites. Hard drugs are opposite to soft drugs, where the modifications are made in such a way that its original properties are retained but are not prone to chemical or biological transformation to avoid generation of metabolites or to increase the biological activity.

Apart from abovementioned classification, there are two main broad classes of prodrug that are carrier-linked prodrug and bioprecursor prodrug. In carrier-linked prodrug, the drug is linked to a carrier moiety by a temporary covalent linkage. Cleavage of a carrier prodrug generates a molecular entity of increased bioactivity (drug) and at least one side product, the carrier, which may be biologically inert. Carrier molecule or functional group can be easily removed in vivo, usually by hydrolytic cleavage [3]. There are several criteria for being a carrier-linked prodrug, which are as follows:


**7**

*Preformulation Studies: An Integral Part of Formulation Design*

Several goals of developing prodrug are as follows:

Improving unfavorable physical properties:

• Improvement in organoleptic characteristic.

Improving unfavorable pharmacokinetic properties:

• Improving penetration power through membrane.

Classical example of target-specific drug delivery in selective metastatic colon cancer is capecitabine which is prodrug of 5-fluorouracil. Capecitabine requires triplephase transformation to be converted to its active form 5-fluorouracil. The first metabolism takes place in liver by action of enzyme carbonyl esterase. This transformed form then enters the tumor cells by selective uptake and is again transformed by deamination by action of enzyme cytidine deaminase. This form in tumor cell is converted to 5-fluorouracil by enzyme thymidine phosphorylase, which is only present in the tumor cells. The other example of target-specific delivery is release of sulfasalazine in colon by action of bacterial reductase where sulfasalazine is converted to sulfapyridine

One of the best ways to improve the lipophilicity is the esterification of the molecule. For example, terbutaline is orally active beta-2-agonist and is indicated in bronchial asthma. It requires significantly higher dose due to lower lipophilicity. Its prodrug bambuterol has improved lipophilicity as well as chemical stability and

Determination of chemical properties indicates the absorption behavior as well as stability of a molecule in the body. One of the most widely determined chemical properties includes partition coefficient (Log P), dissociation constant (pKa or pKb), and stability of molecule under a variety of conditions. Each property has

Partition coefficient (Log P) value is defined as ratio of unionized drug distributed between aqueous and organic phase. Oil-water partition coefficient gives the idea about drug's ability to cross the lipidic membrane. Lipophilic/hydrophilic balance is one of the most important contributing factors for optimum drug

and 5-amino salicylic, where the later formed is the active molecule.

thus requires considerably lower dose than terbutaline [5].

**3. Determination of chemical properties**

significant value in development of formulation.

**3.1 Partition coefficient**

*DOI: http://dx.doi.org/10.5772/intechopen.82868*

• Improvement in water solubility.

• Improvement in chemical stability.

• Improvement in lipophilicity.

• Improving bioavailability.

• Improved first-pass metabolism.

• Target-specific drug delivery.

Bioprecursor prodrug results from a molecular modification of the active principle. In vivo transformation of drug generates a new metabolite [4].

*Preformulation Studies: An Integral Part of Formulation Design DOI: http://dx.doi.org/10.5772/intechopen.82868*

Several goals of developing prodrug are as follows:

Improving unfavorable physical properties:


*Pharmaceutical Formulation Design - Recent Practices*

metabolites or to increase the biological activity.

**2.2 Prodrug**

bioavailability [2].

which are as follows:

nontoxic.

• Increased patient compliance can be obtained by converting a molecule to a salt form. For instance, injection of cephalosporin generates the pain at site of application. However, when it is administered as morpholine salt, the pain at the site of application was reduced to many folds. In similar way, salt form can improve the taste adaptability by masking the taste and odor. Piperazine can be

improved organolaptically by converting into salt with adipic acid [1].

Prodrug is the chemically modified inactive derivative of active form with optimized properties and better in vivo performance. Almost one-tenth of the pharmaceutical products are used as prodrug with main aim of improving bioavailability by avoiding first-pass metabolism, improved drug absorption, and organ selective transport. So prodrug can be defined as inactive form that undergoes biotransformation and converted to active form to elicit its pharmacological effect. Development of prodrug depends on specific property of drug that needs improvement and mostly with respect to stability, improving

In recent times, science has moved to "cod drugs," "hard drugs," and "soft drugs," where cod drug consists of two pharmacologically active components, which are complexed to form a single molecule (e.g., sulfasalazine, Levodopa-Entacapone). Soft drugs are the modified derivatives with predetermined metabolism, so that after exerting pharmacological action for suitable time, its metabolite can be eliminated from body. Main aim of developing soft drugs is to avoid toxicity associated with formed metabolites. Hard drugs are opposite to soft drugs, where the modifications are made in such a way that its original properties are retained but are not prone to chemical or biological transformation to avoid generation of

Apart from abovementioned classification, there are two main broad classes of prodrug that are carrier-linked prodrug and bioprecursor prodrug. In carrier-linked prodrug, the drug is linked to a carrier moiety by a temporary covalent linkage. Cleavage of a carrier prodrug generates a molecular entity of increased bioactivity (drug) and at least one side product, the carrier, which may be biologically inert. Carrier molecule or functional group can be easily removed in vivo, usually by hydrolytic cleavage [3]. There are several criteria for being a carrier-linked prodrug,

• Link between drug and a carrier molecule must be a covalent linkage.

• The prodrug, as well as the in vivo released transport moiety, must be

prodrug metabolism or gradual drug inactivation.

ciple. In vivo transformation of drug generates a new metabolite [4].

• Carrier-linked prodrug is inactive or less active than the parent compound.

• The linkage between the drug and the carrier molecule must be broken in vivo.

• The generation of the active form must take place with rapid kinetics to ensure effective drug levels at the site of action and to minimize either alternative

Bioprecursor prodrug results from a molecular modification of the active prin-

**6**


Improving unfavorable pharmacokinetic properties:


Classical example of target-specific drug delivery in selective metastatic colon cancer is capecitabine which is prodrug of 5-fluorouracil. Capecitabine requires triplephase transformation to be converted to its active form 5-fluorouracil. The first metabolism takes place in liver by action of enzyme carbonyl esterase. This transformed form then enters the tumor cells by selective uptake and is again transformed by deamination by action of enzyme cytidine deaminase. This form in tumor cell is converted to 5-fluorouracil by enzyme thymidine phosphorylase, which is only present in the tumor cells.

The other example of target-specific delivery is release of sulfasalazine in colon by action of bacterial reductase where sulfasalazine is converted to sulfapyridine and 5-amino salicylic, where the later formed is the active molecule.

One of the best ways to improve the lipophilicity is the esterification of the molecule. For example, terbutaline is orally active beta-2-agonist and is indicated in bronchial asthma. It requires significantly higher dose due to lower lipophilicity. Its prodrug bambuterol has improved lipophilicity as well as chemical stability and thus requires considerably lower dose than terbutaline [5].
