Organic Pharmaceutical Chemistry IV

1st Semester, Year 5 (2016-2017)

Lecture 1

Organic Pharmaceutical Chemistry:

Prodrugs

Dr Asim A. Balakit
Pharmaceutical Chemistry Dept.,
College of Pharmacy,
Babylon University

This lecture is mainly based on:

http://shodhganga.inflibnet.ac.in/bitstream/10603/3457/10/10_chapter%201.pdf
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History & Basic Concept

The prodrug concept was first proposed by Albert in 1958.

Albert and his co-workers described prodrugs as pharmacologically

inactive chemical derivatives that could be used to alter the
physicochemical properties of drugs, in a temporary manner, to
increase their usefulness and/or to decrease associated toxicity.

This included both compounds that are designed to undergo a

transformation to yield an active substance and those that were
discovered by serendipity to do so.

These two situations were distinguished by Harper, who in 1959

introduced the term drug Iatentiation to refer to drugs that were
specifically designed to require bioactivation.
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Another two terms hard drugs and soft drugs were also introduced

Hard drugs are compounds that are designed to contain the structural
characteristics necessary for pharmacological activity but in a form that is
not susceptible to metabolic or chemical transformation. In this way, the
production of any toxic metabolite is avoided, and there is increased
efficiency of action. Since the drug is not inactivated by metabolism, it may
be less readily eliminated.

Soft drugs are active compounds that after exerting their desired
pharmacological effect are designed to undergo metabolic inactivation to
give a nontoxic product. Thus soft drugs are considered to be the opposite
of prodrugs.

Ideally, the prodrug is converted to the original drug as soon as the

derivative reaches the site of action, followed by rapid elimination of the
released derivatizing group without causing side effects in the process.

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 B
i
o
Drug l Pro Drug
o
g
i
c Enzymatic or Chemical
a Transformation
Derivatization “In Vivo”
“In the Lab” l

B
a
r
Pro Drug r Pro Drug
i
e

Schematic Representation of Prodrug Concept 4

The Applications of Prodrugs:
The various applications of prodrug approach are:

1. Improved physicochemical properties (e.g., better solubility in the intended

formulation).
2. Enhanced delivery characteristics and/or therapeutic value of the drug.
3. To improve drug penetration through biological membranes.
4. To increase site specificity of the drug.
5. To improve the drug’s stability and solubility.
6. To increase duration of pharmacological activity.
7. To decrease the drug’s toxicity and adverse effects.
8. To improve patient acceptance.

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Ideal Requirements of Prodrugs
An ideal prodrug must meet the following requirements:

1. The prodrug is inactive or less active than the parent compound.

2. The linkage between the drug and the carrier must be cleaved in vivo.
3. The carrier molecule released in vivo must be non-toxic.
4. The metabolic fragments of carrier molecule, apart from the drug should be
non toxic.

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Barriers to Drug Action
Administration of a prodrug is one of the avenues when attempting to
control drug delivery and generate predictable drug concentration vs. time
profiles at specific drug receptors.

The rationale behind the prodrug approach is that the prodrug is capable
of overcoming one or more of the barriers to drug delivery more efficiently
than the parent drug. Some of the potential barriers related to the
pharmaceutical and pharmacokinetic phase, respectively.

The pharmaceutical phase comprises:

I. Incorporation of a potential drug entity into a convenient drug
delivery system or a dosage form.
II. Release of the active drug from the formulation.

Whereas the pharmacokinetic phase embraces the absorption,

distribution, metabolism, and excretion of the drug. 7
 Pharmaceutical Phase
Drug

Manufacture
Pharmacokinetic Phase
Release Drug in Sol. at
Dosage form Elimination
Admin Site

Absorption
Drug in Various
Distribution Drug in
Body Elimination
Blood
Compartments

Transport

Elimination Drug in Target

Pharmacodynamic phase
Organ

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 THE PHARMACEUTICAL PHASE
There are two barriers identified in the development phase of
commercially usable drug products are:

A. Aesthetic properties such as odour, taste (in case of

paediatric use or when intended for oral administration),
pain upon injection, gastrointestinal (GI) irritability of the
new molecule

B. Drug formulation problems such as stability profile,

undesirable physicochemical properties like solubility,
polarity, partition coefficient and pKa values due to which
precludes its incorporation into a specific drug delivery
system.
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 THE PHARMACOKINETIC PHASE

This phase can be considered as the phase involving absorption,

distribution, metabolism and excretion of the drug.

The pharmacokinetic studies provide valuable information regarding the

in vivo properties of a drug’s limitation such as poor absorption, too rapid
elimination and pre systemic metabolism.

If these properties can be related back to the physicochemical and

dosage form properties of the system, then corrections will require
prodrug interventions.

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What are the principal barriers which identified in
the pharmacokinetic?!

1. Incomplete absorption of the drug from the delivery system or

across biological barriers such as the gastrointestinal mucosal cells
and the blood brain barrier.

2. Incomplete systemic delivery of an agent due to pre-systemic

metabolism in the gastrointestinal lumen mucosal cells and liver.

3. Toxicity problems associated with local irritation or distribution into

tissue other than the desired target organ.

4. Poor site specificity of the drug.

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HOW CAN WE USE PRODRUGS TO OVERCOME THE
PHARMACEUTICAL BARRIERS ?!

1- Masking Taste or Odour

The undesirable taste arises due to adequate solubility and

interaction of drug with taste receptors.

So, what we have to do?!!

The answer is:

We can overcome this problem by lowering the solubility of drug or

prodrug in saliva.

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Example 1 : “ The undesirable test”

Chloramphenicol which produces a bitter taste when given as the parent

drug.
The hydrophobic palmitate ester does not dissolve to any appreciable
extent in the mouth, so there is little chance for interaction with taste
receptors.

The ester moiety is subsequently hydrolyzed in the GI tract, and the

agent is absorbed as chloramphenicol.
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Example 2 : “The malodour”

Odour is another aesthetic concern for some drugs, that are often volatile liquid or
solids with significant vapour pressure that makes them difficult to formulate.

How can we use organic chemistry to sort out this problem?

A classic example is the volatile mercaptans used as tuberculostatic agents for the
treatment of leprosy.

The ethyl mercaptan has a boiling point of 25ºC and a strong disagreeable odour.

On the other hand, diethyl dithio isophthalate, a prodrug of ethyl mercaptan has a
higher boiling point and is relatively odourless.

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2- Minimizing Pain at Site of Injection

Pain caused by intramuscular injection is mainly due to the weakly acidic nature or
poor aqueous solubility of drugs.

So, it is the problem of poor aqueous solubility of drugs!!

What we have to do?!

We can find the answer in the following examples:

Intramuscular injection of antibiotic like clindamycin and anticonvulsant drug like

phenytoin was found painful due to poor aqueous solubility and could be
overcome by making phosphate ester prodrugs respectively and maintaining the
formulations at pH 12

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Clindamycin–2 dihydrogen phosphate- prodrug of clindamycin

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Phenytoin and its prodrug
3- Alteration of Drug Solubility

The prodrug approach can be used to increase or decrease the solubility of a

drug, depending on its ultimate use.

For example, chloramphenicol succinate and chloramphenicol palmitate, ester

prodrugs of chloramphenicol, have enhanced and reduced aqueous solubility
respectively.

On the basis of altered solubility, chloramphenicol sodium succinate prodrug is

found suitable for parenteral administration.

Administration of a drug parenterally may cause pain at the site of injection,

especially if the drug begins to precipitate out of solution and damage the
surrounding tissue.

This situation can be remedied by preparing a drug with increased solubility in

the administered solvent. Since chloramphenicol has low water solubility, the
succinate ester was prepared to increase the water solubility of the agent and
facilitate parenteral administration.
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The succinate ester itself is inactive as an antibacterial agent, so it must
be converted to chloramphenicol for this agent to be effective. This
occurs in the plasma to give the active drug and succinate. The ester
hydrolysis reaction can be catalysed by esterases present in large
amounts in the plasma.

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The prodrug approach is also made useful for better gastrointestinal
absorption.

It was observed that sulindac, a prodrug of sulindac sulfide being more

water soluble with sufficient lipophilicity, makes this drug suitable for
oral administration.

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4- Enhancement of Chemical Stability

Chemical stability is a most extreme necessary parameter for every

therapeutic agent to bring out its pharmacological activity for a longer
duration.

A shelf life of at least 2 years is desirable except for vaccines, cytotoxic

agents and other life saving drugs.

Although chemical unstability can be solved to a greater extent by

appropriate formulations, its failure necessitates the use of prodrug
approach.

How this work?!

The prodrug approach is based on the modification of the functional
group responsible for the instability or by changing the physical properties
of the drug resulting in the reduction of contact between the drug and the
media in which it is unstable.
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Example:
This approach was successfully used to inhibit the auto aminolysis, which
occur due to capability of NH2 group of side chain to attach β–lactam ring
of other molecule, in ampicillin molecule in concentrated solution it
generates polymeric species of ampicillin.

By making hetacillin, a prodrug of ampicillin formed by the reaction of

acetone and ampicillin „ties up‟ the amine group and thus inhibits auto
aminolysis.

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The other advantage of this modification is it decreases the basicity of the
α-amino group and reduces protonation in the small intestine so that the
agent is more lipophilic.

In this manner, the absorption of the drug from the small intestine is
increased after oral dosing, and chemical hydrolysis after absorption
regenerates ampicillin.

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References:

http://shodhganga.inflibnet.ac.in/bitstream/10603/3457/10/10_chapter%201.pdf (this is the

main reference).

Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, 11th ed.,
2004, Lippincott Williams & Wilkins, USA.

Kuei-Meng Wu, A New Classification of Prodrugs: Regulatory Perspectives, Pharmaceuticals

2009, 2, 77-81; doi:10.3390/ph2030077.

R. R. Nadendla, Principles of Organic Medicinal Chemistry, 2005, New Age International (P)
Ltd., Publishers, India.

Thomas L. Lemke, David A. Williams, Foye's Principles of Medicinal Chemistry, 7th ed., 2013,
Lippincott Williams & Wilkins, USA.

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