MEDICINE

The Pharmaceutical
Industry
By:
Vince Neil Balaguer
Renz Jonnar Subida
 Pathology
Pharmacognosy
Therapeutics
Pharmacy
Physiology Pharmacology
Toxicology

MEDICINE
Marketing
Biotechnology Chemistry Biochemistry
Chemical Engineering
Molecular BiologyStatisticsResearch
 History of the
Pharmaceutical
Industry
Mid-1800s 1945: From botanicals to the first synthetic drugs
Epinephrine, norepinephrine, and amphetamine
1897: epinephrine and norepinephrine was identified
1929: amphetamine was developed
Discovery and development of the barbiturates
1903: diethylbarbituric acid was developed
1912: discovery of phenobarbitals potent anti-epilectic activity
Insulin
early 1900s: understanding of diabetes
1869: removal of pancreas in dogs induce diabetes
1921: injection of pancreatic extracts; development of pure insulin
Early anti-infective research
1911: arsphenamine was developed as effective treatment for syphilis
1920s: sulfonamides were developed as less toxic antibiotic
 History of the
Pharmaceutical

Industry
Unsafe Drugs and Early Industry Regulation
The Biologics Act of 1902
Pure Food and Drugs Act of 1908
The Elixir of Sulfanilamide Phenomenon, 1937
_ Federal Food, Drug, and Cosmetic Act of 1938

1945 1970: The post-war years

Further advances in anti-infective research
1943: streptomycin was developed as a treatment for tuberculosis
1954: development of the polio vaccine
1962: development of the measles vaccine
1967: development of the mumps vaccine
Development and marketing of antihypertensive drugs
1952: hydrazaline was developed as an antihypertensive drug
mid 1950s: chlorothiazide was developed and remains to be used today
 What is a
drug?
A drug is a chemical substance
that interacts with a living system
and produces a biological
response.
A pharmaceutical drug
is a drug used to
diagnose, cure, treat, or
prevent disease.
 How do drugs
work?

Drug
Enzyme/Receptor Binding Biological Response

AGONIST binds and

activates
ANTAGONIST binds and
blocks
PARTIAL AGONIST induces a partial
response
 Purine salvage pathway

free purine

phosphoester
sugar

Purine nucleoside phosphorylase inhibition

Purine nucleoside
phosphorylase
(PNP)

PNP inhibitor
 What makes a good
drug?
Lipinskis Rules (Chris Lipinski, 1997)
In general, an orally active drug will meet most of the
following:
Not more than 5 hydrogen bond donors (nitrogen or
oxygen atoms with one or more hydrogen atoms)

Not more than 10 hydrogen bond acceptors (nitrogen or

oxygen atoms)

Molecular weight under 500 grams per mole

An octanol-water partition coefficient log P of less than 5

 Major Therapeutic
Targets
CNS
Metabolic
Cardiovascular
Anti-infectives
Respiratory
Gentio-urinary
Musculoskeletal
Oncology
 Drug Discovery and Drug
Design
Traditional Drug Discovery (Forward
Pharmacology)
relies on trial-and-error testing of chemical
substances on cultured cell or animals and matching
the apparent effects to treatments

Rational Drug Design (Reverse Pharmacology)

the inventive process of finding new medications
based on the knowledge of a biological target
 Pharmaceutical
Formulation
Enteral Formulations
Tablet (10% active ingredient, 90% excipients)
Capsule (active ingredient enclosed in gelatinous envelope)

Parenteral Formulations
Liquid
Lyophilized (freeze-dried)

Topical Formulations
Cream (emulsion of 1:1 proportion of oil and water)
Ointment (emulsion of 4:1 proportion of oil and water)
Gel (liquefies upon contact with skin)
Paste (suspension of powder in an emulsion of 4:1 proportion of oil and water)
Powder (finely-subdivided solid substance)
 Pre-Clinical
Trials
Pharmacological
Assessments
Pharmacokinetic Profile
What is the fate of the drug in the body?

Pharmacodynamic Profile
How does the drug bring about its characteristic effects?

Bioavailability
What proportion of the drug actually reaches the site of action?

Bioequivalence
Does modification of delivery systems yield the same safety and efficacy?
 Pre-Clinical
Trials
Toxicological
Assessments
Acute and Chronic Toxicity
Does the drug exhibit any short-term or long-term toxicity?
Reproductive Toxicity and Tetratogenicity
Does the drug cause fertility hazards and fetal developmental abnormalities?
Mutagenicity
Is the drug capable of inducing DNA damage?
Carcinogenicity
Are the active ingredients or the excipients capable of being carcinogenic?
Immunotoxicity
Does the drug induce allergic or hypersensitive responses?
Local Tolerance
Is there any associated toxicity at/surrounding the site of administration?
 Clinical Trials
Trial Number
Average
Phas Evaluation of
Duration
e Patients
I Safety testing in healthy human volunteers 20-100 1 year
Efficacy and safety testing in small number of
II 100-200 2 years
patients
Large-scale efficacy and safety testing in
III 1000-6000 3 years
substantial numbers of patients
Several
IV Post-marketing safety surveillance (varies)
years
The aims of the clinical trial studies are largely to establish:
The pharmacological properties of the drugs in humans (including
pharmacokinetic and pharmacodynamics considerations);
The toxicological properties of the drugs in humans (with establishment of
the maximally tolerated dose); and
The appropriate route and frequency of administration of the drug to
humans.
 INTRODUCTION TO LEAD
AND ANALOGUE SYNTHESIS
Linear Synthesis one step in the synthetic
pathway is immediately followed by another

Convergent Synthesis two or more sections of the

molecule are synthesized separately before being
combined to form the target structure
General considerations when selecting chemical
reactions of the proposed synthetic pathway:
The yields of reaction should be high. This is particularly
important when the synthetic pathway involves a large
number of steps.

The products should be relatively easy to identify, isolate,

and purify.

Reactions should be stereospecific, as it is often difficult

and expensive to separate enantiomers. This is a condition
that is often difficult to satisfy.

The reactions used in the research stage of the synthesis

should be adaptable to large scale production methods.
Asymmetry in Syntheses
 The Use of Non-Stereoselective Reactions to
Produce Stereospecific Centers

Non-stereoselective reactions produce either a mixture of

diastereoisomers or a racemic modification.

The separation of a racemic modification into its constituent

enantiomers is normally achieved by converting the
enantiomers in the racemate into a pair of diastereoisomers by
reaction with a pure enantiomer.
The Use of Non-Stereoselective Reactions to
Produce Stereospecific Centers
 The Use of Stereoselective Reactions to
Produce Stereospecific Centers

Stereoselective reactions are those that result in the

selective reaction of one of the stereoisomers of the product.

Enantiomeric (e.e.)/Diasteroisomeric (d.e.) Excess

records the extent of the selectivity of the reaction

 The Use of Stereoselective Reactions to

Produce Stereospecific Centers

The stereochemistry of the

product of a reaction will be
influenced by the structures of
the reagent and substrate and
the mechanisms by which they
react.
 The Use of Stereoselective Reactions to
Produce Stereospecific Centers

A stereoselective reaction is most likely to occur when steric hindrance at

the reaction center restricts the approach of the reagent to one direction.
 General Methods of Asymmetric
Synthesis
Methods that use catalysts to obtain stereoselectivity
Enzyme-Controlled Stereospecific Reactions
Non-Enzyme Catalysed Stereospecific Reactions

Methods that do not use catalysts to obtain

stereoselectivity
Using chiral building blocks
Using a chiral auxiliary
Using achiral reagents and substrates
 Methods that Use Catalysts to Obtain
Stereoselectivity
Enzyme-Controlled Stereospecific Reaction
 Methods that Use Catalysts to Obtain
Stereoselectivity
Non-Enzyme
Catalysed
Stereoselective
Reaction
 Methods That Do Not Use Catalysts To Obtain
Stereoselectivity
Using chiral building blocks
 Methods That Do Not Use Catalysts To Obtain
Stereoselectivity
Using a chiral
auxiliary
 Methods That Do Not Use Catalysts To Obtain
Stereoselectivity
Using achiral reagents and substrates
 Designing Organic Syntheses

The Disconnection Approach or Retrosynthetic Analysis

The usual synthetic approach is to work back from the target
structure in a series of steps until cheap commercially
available materials are found.

In all cases, the final pathway should contain a minimum of

stages, in order to keep costs to a minimum and overall
yields to a maximum.
 Designing Organic Syntheses

In the disconnection approach, bonds are usually disconnected by either

homolytic or heterolytic fission. However, some bonds may be
disconnected by a reverse pericyclic mechanism.
 Designing Organic Syntheses
In the cases of both linear and convergent syntheses, the
design of a synthetic pathway using the disconnection
approach must take into account the following:

The order of disconnection that could influence the ease and

direction of subsequent reactions;

The need to protect a reactive group in a compound by the

use of suitable protecting agent; and

The need to incorporate chiral centers into the structure.