1.

0 PHARMACEUTICAL CHEMISTRY/CHEMICALS
➢ Pharmaceutical Chemistry is a branch of chemistry that deals with the chemical,
biochemical and pharmacological aspects of drugs. It includes synthesis/isolation,
identification, structural elucidation, structural modification, Structural Activity
Relationship (SAR) studies, study of the chemical characteristics, biochemical changes after
drug administration and their pharmacological effects.
➢ Pharmaceutical inorganic chemistry: deals with the study of both non-essential and
essential elements - their preparation, standards of purity, test for identification, limit tests
to be performed for determining the quality and extent of purity, storage, different
formulations and their storage conditions and therapeutic uses.
➢ Pharmaceutical organic chemistry deals with the study of preparation, structure and
reactions of organic compounds related to life processes.
➢ ‘A Pharmaceutical’: is a term is used for any chemical substance useful in preventive or
therapeutic or which finds use in the preparation of medicament. Some find use only in the
laboratory during the preparation but may not be present in the final product, these are
also incorporated under pharmaceuticals.
➢ Quality of all pharmaceuticals must be carefully controlled.
➢ The descriptions of pharmaceuticals are reported in the pharmacopoeia.

Pharmacopoeia:

➢ It’s a book containing directions for the identification of samples and the preparation of
compound medicines.
➢ It is published by the authority of a government or a medical or pharmaceutical society. For
this reason, Pharmacopoeia is a legislation of a nation which sets standards and mandatory
quality indices for drugs, raw materials used to prepare them and various pharmaceutical
preparations.
➢ Examples: British Pharmacopoeia (BP), United States Pharmacopoeia (USP), International
Pharmacopoeia (IP), European Pharmacopoeia (EP), Union of Soviet Socialist Republics
Pharmacopoeia (USSRP) Indian Pharmacopoeia (IND.P./IP/PI).
Pharmacopoeia Description/Presentation

➢ Most of the Pharmacopoeias consist of the three major sections namely:

(a) Introduction including general notices
(b) Monographs of the official drugs
(c) Appendices.
(a) Introduction: It is a useful pointer to pharmaceutical progress since last edition. It
summarizes the different changes including additions/deletions in the current edition
compared to last edition. To avoid misinterpretation and misunderstanding of later parts
of the text, attention should be paid to general notices at the outset.
(b) Monographs: The general monographs for dosage forms of active pharmaceutical
ingredients (APIs) are grouped together at the beginning of volume II in the
Pharmacopeia. They are followed by the monographs for the APIs, pharmaceutical aids
and individual dosage forms all in alphabetical order. Monographs for other articles of a
special nature such as vaccines and immunosera for human use, herbs and herbal
products, blood and blood related products, biotechnology products, veterinary products
are given in separate sections in volume III.

Monograph

➢ Monographs are descriptions of pharmaceutical preparations.

➢ It is a reference work for pharmaceutical drug specifications. It is a complete description
of a specific pharmaceutical, which includes chemical formulae, atomic and molecular
weight, definition, statement of content, category, dose, usual strength, description,
solubility, identification tests, assay, other test, limits of impurities, quantities, and
conditions for storage. The appendices include standards for apparatus, reagents and
solutions, indicators, reference substances, test animals, calculation of results, other
chemicals techniques, processes etc. of the concerned pharmaceuticals.

Part I: Generally the drugs that have similar use or actions are bringing together by part I of
Pharmacopoeia. In related chapters to guide reader the cross references is used to find out the
drug that may be of interest. The common actions of the groups of drugs are provided as
background information in many of the chapters.
Part II: Monographs of new drugs, drugs under investigation, drugs which are not easily classified
and obsolescent drugs still of interest are presented in part II of Pharmacopoeia. It also provides
details regarding effects of required drug therapy.
Part III: Composition of the proprietary medicines that are advertised to the public in different
countries are documented with omission of herbal medicine in part III of Pharmacopoeia.
2.0 DRUG DISCOVERY AND DEVELOPMENT
➢ Drug discovery is a process of identifying and/or designing a compound which is
therapeutically useful in treating and curing disease.
➢ It is the mission of pharmaceutical research companies to take the path involves
understanding a disease and bringing a safe and effective new treatment to patients.
➢ Scientists work to piece together the basic causes of disease at the level of genes, proteins
and cells. Out of this understanding emerge “targets,” which potential new drugs might
be able to affect.
➢ Researchers work to:
i) Validate the targets,
ii) Discover the right molecule (potential drug) to interact with the target chosen,
iii) Test the new compound in the lab and clinic for safety and efficacy
iv) Gain approval and get the new drug into the hands of doctors and patients.
➢ Drug discovery encompasses a series of essential stages, known as the “five pillars of drug
discovery”. These pillars are:
i) Target identification and validation.
ii) Lead discovery.
iii) Lead optimization.
iv) Preclinical testing.
v) Clinical trials.
➢ Drug development process must ensure the medicine is safe, effective, and has achieved
all regulatory requirements for approval.

2.1 The Discovery Process

1. Pre-discovery - Understand the disease
➢ Involves understanding fully the disease to be treated and to unravel the underlying cause
of the condition.
➢ In this stage, the scientist seeks to understand
i) How the genes are altered,
ii) How the alteration affects the proteins they encode
 iii) How those proteins interact with each other in living cells,
iv) How those affected cells change the specific tissue they are in
v) How the disease affects the entire patient.
➢ This knowledge forms the basis of treating the problem.

2. Target Identification - Choose a molecule to target with a drug

➢ Pharmaceutical researchers select a “target” for a potential new medicine.
➢ “Target”: is generally a single molecule, such as a gene or protein, involved in a particular
disease.
➢ The target should be “drugable,” i.e., one that can potentially interact with and be
affected by a drug molecule.

3. Target Validation - Test the target and confirm its role in the disease
➢ It must be proved that the target chosen is actually involved in the disease and can be
acted upon by a drug.
➢ Target validation helps scientists avoid research paths that look promising, but ultimately
lead to dead ends.
➢ Researchers demonstrate that a particular target is relevant to the disease being studied
through complicated experiments in both living cells and in animal models of disease.

4. Drug Discovery - Find a promising molecule (a “lead compound”) that could become a
drug
➢ Scientists search for a molecule, usually called “lead compound,” that may act on their
target to alter the disease course.
➢ If successful over long odds and years of testing, the lead compound can ultimately
become a new medicine.
➢ Ways of finding a lead compound:
a) Nature/natural products:
➢ Nature hosts interesting compounds for fighting disease.
➢ Examples: bacteria found in soil and mouldy plants both led to important new
treatments.
b) De novo:
➢ This where scientists create molecules from scratch.
➢ They can use sophisticated computer modelling to predict what type of molecule may
work.
c) High-throughput Screening:
➢ Is the most common process of finding leads compounds.
➢ Advances in robotics and computational power allow researchers to test hundreds of
thousands of compounds against the target to identify any that might be promising.
➢ Based on the results, several lead compounds are usually selected for further study.
d) Biotechnology:
This is where scientists genetically engineer living systems to produce disease-fighting
biological molecules.
5. Early Safety Tests - Perform initial tests on promising compounds
➢ Lead compounds go through a series of tests to provide an early assessment of the safety
of the lead compound.
➢ Scientist’s test: Absorption, Distribution, Metabolism, Excretion and Toxicological
(ADME/Tox) properties, or “pharmacokinetics,” of each lead compound.
➢ Successful drugs must be:
i) Absorbed into the bloodstream,
ii) Distributed to the proper site of action in the body,
iii) Metabolized efficiently and effectively,
iv) Successfully excreted from the body and
v) Demonstrated to be not toxic.
➢ ADME/Tox studies are performed in living cells, in animals and via computational models.
➢ These studies help researchers prioritize lead compounds early in the discovery process.
6 Lead Optimization - Alter the structure of lead candidates to improve properties
➢ Lead compounds that survive the initial screening are then “optimized,” or altered to
make them more effective and safer.
➢ By changing the structure of a compound, scientists can give it different properties.
➢ For example, they can make it less likely to interact with other chemical pathways in the
body, thus reducing the potential for side effects.
➢ Hundreds of different variations or “analogues” of the initial leads are made and tested.
Teams of biologists and chemists work together closely:
The biologists test the effects of analogues on biological systems
The chemists take this information to make additional alterations that are then
retested by the biologists. The resulting compound is the candidate drug.
➢ At this stage, researchers consider:
How the drug will be made i.e. the formulation (the recipe for making a drug,
including inactive ingredients used to hold it together and allow it to dissolve at the
right time),
Delivery mechanism (the way the drug is taken – by mouth, injection, inhaler)
Large-scale manufacturing (how to make the drug in large quantities).
7. Preclinical Testing - Lab and animal testing to determine if the drug is safe enough for
human testing
➢ Optimized compounds are tested extensively to determine if they should move on to
testing in humans.
➢ Scientists carry out in vitro and in vivo tests.
In vitro tests are experiments conducted in the lab, usually carried out in test tubes
and beakers (“vitro” is “glass” in Latin)
In vivo studies are carried out in living cell cultures and animal models (“vivo” is
“life” in Latin).
➢ Scientists try to understand how the drug works and its safety profile.
Regulators e.g. The U.S. Food and Drug Administration (FDA) requires extremely
thorough testing before the candidate drug can be studied in humans.
➢ During this stage researchers also must work out how to upscale production – to get
enough quantities of the drug for clinical trials. Techniques for making a drug in the lab
on a small scale do not translate easily to larger production.
 ➢ The drug will need to be scaled up even more if it is approved for use in the general patient
population.
➢ NB: After starting with approximately 5,000 to 10,000 compounds, scientists winnow the
group down to between one and five molecules, “candidate drugs,” which will be studied
in clinical trials.

2.2 The Development Process

1. Investigational New Drug (IND) Application and Safety - File IND with the FDA before
clinical testing can begin; ensure safety for clinical trial volunteers through an Institutional
Review Board
➢ Before any clinical trial can begin, the researchers must file an Investigational New Drug
(IND) application with the relevant authority e.g. Kenya Pharmacy & Poisons Board, FDA.
➢ The IND application includes:
The results of the preclinical work,
Chemical structure of the candidate drug
How the candidate drug is thought to work in the body,
A listing of any side effects
Manufacturing information.
A detailed clinical trial plan that outlines how, where and by whom the studies
will be performed.
➢ The relevant body reviews the application to make sure people participating in the clinical
trials will not be exposed to unreasonable risks.
➢ Also, all clinical trials must be reviewed and approved by the Institutional Review Board
(IRB) at the institutions where the trials will take place. This process includes the
development of appropriate informed consent, which will be required of all clinical trial
participants.
➢ Data obtained is constantly monitored by statisticians.
➢ The regulatory authority or the sponsor company can stop the trial at any time if problems
arise. For instance, a study may be stopped because the candidate drug is performing so
 well that it would be unethical to withhold it from the patients receiving a placebo or
another drug.
➢ The company sponsoring the research must provide comprehensive regular reports to the
regulating authority and the IRB on the progress of clinical trials.
➢ IND has three phases:
Phase 1 Clinical Trial - Perform initial human testing in a small group of healthy volunteers
➢ The candidate drug is tested in people for the first time.
➢ These studies are usually conducted with about 20 to 100 healthy volunteers. The main
goal of a Phase 1 trial is to discover if the drug is safe in humans.
➢ Researchers look at the drugs:
Pharmacokinetics: How is it absorbed? How is it metabolized and
eliminated from the body?
Pharmacodynamics: Does it cause side effects? Does it produce desired
effects?
➢ These closely monitored trials are designed to help researchers determine what the safe
dosing range is and if it should move on to further development.
Phase 2 Clinical Trial - Test in a small group of patients
➢ Researchers evaluate the candidate drug’s effectiveness in about 100 to 500 patients with
the disease or condition under study, and examine the possible short-term side effects
(adverse events) and risks associated with the drug.
➢ They also strive to answer these questions: Is the drug working by the expected
mechanism? Does it improve the condition in question? Researchers also analyze optimal
dose strength and schedules for using the drug.
➢ If the drug continues to show promise, they prepare for the much larger Phase 3 trials.
Phase 3 Clinical Trial - Test in a large group of patients to show safety and efficacy
➢ In Phase 3 trials researchers study the drug candidate in a larger number (about 1,000-
5,000) of patients to generate statistically significant data about safety, efficacy and the
overall benefit-risk relationship of the drug.
➢ This phase of research is key in determining whether the drug is safe and effective. It also
provides the basis for labelling instructions to help ensure proper use of the drug (e.g.,
information on potential interactions with other medicines).
➢ Phase 3 trials are both the costliest and longest trials. Hundreds of sites over wide area
sometimes in different countries or continents are selected to participate in the study to
get a large and diverse group of patients. Coordinating all the sites and the data coming
from them is a monumental task.
➢ During the Phase 3 trial (and even in Phases 1 and 2), researchers are also conducting
many other critical studies, including plans for full-scale production and preparation of
the complex application required for approval.
2. New Drug Application (NDA) and Approval - Submit application for approval to FDA
➢ Once all three phases of the clinical trials are complete, the sponsoring company analyses
all of the data. If the findings demonstrate that the experimental medicine is both safe
and effective, the company files a New Drug Application (NDA) — which can run 100,000
pages or more — with the regulator/authority to request approval to market the drug.
➢ The NDA includes all of the information from the previous years of work, as well as the
proposals for manufacturing and labelling of the new medicine.
➢ FDA experts review all the information included in the NDA to determine if it
demonstrates that the medicine is safe and effective enough to be approved
➢ “How does the authority decide to approve a new drug?”
BENEFIT VS. RISK
➢ The regulatory authority uses the information in the NDA to try to address three major
concerns:
1) Because no drug has zero risk, the regulatory authority must determine whether the
benefits of the drug outweigh the risks, i.e., is the drug effective for its proposed use,
and has an acceptable balance between benefits and risks been achieved?
2) Based on its assessment of risk and benefit, what information should be contained in
the package insert to guide physicians in the use of the new drug.
 3) Are the methods used to manufacture the drug and ensure its quality adequate to
preserve the drug's identity, strength and purity.
➢ Following rigorous review, the regulatory can either
1) Approve the medicine
2) Send the company an “approvable” letter requesting more information or studies
before approval can be given.
3) Deny approval.
➢ Review of an NDA may include an evaluation by an advisory committee, an independent
panel of Regulatory Authority - appointed experts who consider data presented by
company representatives and FDA reviewers. Committees then vote on whether the FDA
should approve an application, and under what conditions. The FDA is not required to
follow the recommendations of the advisory committees, but often does.
3. Manufacturing
➢ Going from small-scale to large-scale manufacturing is a major undertaking. In many
cases, companies must build a new manufacturing facility or reconstruct an old one
because the manufacturing process is different from drug to drug. Each facility must meet
strict guidelines for Good Manufacturing Practices (GMP).
➢ Making a high-quality drug compound on a large scale takes great care.
4. Ongoing Studies and Phase 4 Trials
➢ Research on a new medicine continues even after approval. As a much larger number of
patients begin to use the drug, companies must continue to monitor it carefully and
submit periodic reports, including cases of adverse events, to the Regulatory Authority.
➢ In addition, the authority sometimes requires a company to conduct additional studies
on an approved drug in “Phase 4” studies. These trials can be set up to evaluate long-term
safety or how the new medicine affects a specific subgroup of patients.
Take away:
➢ The discovery and development of new medicines is a long, complicated process where
each success is built on many, many prior failures.
 ➢ Advances in understanding human biology and disease are opening up exciting new
possibilities for breakthrough medicines.
➢ Researchers face great challenges in understanding and applying these advances to the
treatment of disease. These possibilities will grow as our scientific knowledge expands
and becomes increasingly complex.
➢ Research-based pharmaceutical companies are committed to advancing science and
bringing new medicines to patients.

2.3 Primary and Secondary Metabolites

Primary Metabolites
➢ Primary metabolites are considered essential to microorganisms for proper growth.
➢ Primary metabolites are involved in growth, development, and reproduction of the
organism.
➢ Primary metabolites are typically formed during the growth phase as a result of energy
metabolism.
➢ Examples of primary metabolites include alcohols such as ethanol, lactic acid, and certain
amino acids. In industrial microbiology, alcohol is one of the most common primary
metabolites used for large-scale production.
➢ other, primary metabolites such as amino acids– including L-glutamate and L-lysine,
which are commonly used as supplements– are isolated via the mass production of a
specific bacterial species, Corynebacteria glutamicum.
➢ Citric acid, produced by Aspergillus niger, is one of the most widely used ingredients in
food production. It is commonly used in pharmaceutical and cosmetic industries as well.
Secondary Metabolites
➢ Secondary metabolites do not play a role in growth, development, and reproduction, and
are formed during the end or near the stationary phase of growth.
➢ They are typically organic compounds produced through the modification of primary
metabolite synthases.
➢ Secondary metabolites do not play a role in growth, development, and reproduction like
primary metabolites do, and are typically formed during the end or near the stationary
 phase of growth. Many of the identified secondary metabolites have a role in ecological
function, including defence mechanism(s), by serving as antibiotics and by producing
pigments. Examples of secondary metabolites with importance in industrial microbiology
include atropine and antibiotics such as erythromycin and bacitracin.
➢ Atropine, derived from various plants, is a secondary metabolite with important use in
the clinic. Atropine is a competitive antagonist for acetylcholine receptors, specifically
those of the muscarinic type, which can be used in the treatment of bradycardia.
➢ Antibiotics such as erythromycin and bacitracin are also considered to be secondary
metabolites. Erythromycin, derived from Saccharopolyspora erythraea, is a commonly
used antibiotic with a wide antimicrobial spectrum. It is mass produced and commonly
administered orally. Lastly, another example of an antibiotic which is classified as a
secondary metabolite is bacitracin.
➢ Bacitracin, derived from organisms classified under Bacillus subtilis, is an antibiotic
commonly used a topical drug. Bacitracin is synthesized in nature as a nonribosomal
peptide synthetase that can synthesize peptides; however, it is used in the clinic as an
antibiotic.
➢ These metabolites can be used in industrial microbiology to obtain amino acids, develop
vaccines and antibiotics, and isolate chemicals necessary for organic synthesis.

2.4 Pharmaceutical Microbiology

➢ The study of microorganisms that are related to the production of antibiotics, enzymes,
vitamins, vaccines, and other pharmaceutical products.
➢ Pharmaceutical microbiology also studies the causes of pharmaceutical contamination
and spoil.