Process Chem Talk

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Part I Chemical Development in the
Pharmaceutical Industry
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Part I Topics

• Overview of Pharmaceutical RD
• Drug Discovery and Drug Development
• What is Chemical Development?
• General Aspects of Chemical Development

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Long Road to a New Medicine
Registration
Clinical Data Analysis
New Medicine
Full Development
Candidate Medicine Tested in 3,000-10,000
Patients (Phase III)
Studies in 100-300 Patients (Phase II)
Large Amounts of Candidate Medicine Synthesized
ExtensiveSafety Studies
Studies in Healthy Volunteers Phase I
Exploratory Development
Formulations Developed
Screening
Project Team and Plans
Early Safety Studies
Discovery
Idea
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Pharmaceutical RD Process
7,000,000 Compounds Screened High risk 800
million
Preclinical Pharmacology
Clinical Pharmacology Safety
Preclinical Safety
Products
Exploratory Development
Discovery
Full Development
Phase I
Phase II
Phase III
0
15
5
10
Drug
Idea
12 - 15 Years
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The Pharmaceutical RD Process

• Discovery Stage
• Exploratory Development Stage
• Full Development Stage
• Registration

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The Discovery Stage
It all starts with an Idea to address a disease
through an associated Therapeutic Target.
Example perhaps we can find a treatment for
HIV-infected individuals if we could inhibit an
enzyme which is crucial for replication of the
virus. This leads to some questions..

• Can we design and chemically synthesize a small
  organic molecule (i.e., a drug)
• which can fit into the active site of the
  enzyme and inhibit its function?
• Can we find a way to administer this drug to
  humans?
• Is the drug safe for humans to take?
• Does the drug have the desired effect on a
  persons health condition?

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The Discovery Phase
The Discovery Stage

• The main goal of the Discovery Stage is to
  identify
• a single discrete organic molecule as a good
  candidate
• to become an effective, marketable drug.
• The Discovery Stage can take up to 7 years, but
  rarely
• takes less than 3 years.
• The candidate compound then passes into the
  Exploratory
• Development Stage where the potential of that
  
• drug candidate to become a drug is evaluated.

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The Exploratory Development Stage

• Consists of Three Phases
• Preclinical Phase - animal testing
• Toxicity
• Phase I - initial testing in healthy humans
• Toxicity
• Phase II - testing in humans with the disease
• Toxicity
• Establish dosing parameters
• Initial indications of efficacy

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The Exploratory Development Stage
The drug candidate will be given to a variety of
animals and to a large number of human subjects
Therefore, the need for much larger quantities
of the drug becomes acute. The drug must be
chemically synthesized, usually in multi-kilogram
amounts and the drug purity must be very high
-- generally gt 95.

• Such large scale synthesis activities requires
  expertise in
• synthetic organic chemistry
• chemical engineering
• analytical chemistry

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Exploratory Development Stage
Once prepared, the drug substance must be
formulated, i.e., prepared in such a way that it
can easily enter living tissue and make its way
to the site(s) of drug action.

• This generally requires that the drug substance
  be combined with other organic and
• inorganic compounds (called excipients) which are
  used to
• Control the release of the drug substance in the
  human body
• Improve the assimilation process and
  bioavailability
• Enhance drug dissolution
• Extend the stability and shelf life of the drug
  substance
• Aid in the manufacturing process (e.g.,
  production of tablets and capsules)
• Mask an unpleasant taste

Once formulated the drug substance is called the
drug product.
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Exploratory Development Stage
Common Excipients
Magnesium stearate Lactose Starch Talc Sucrose
Silicon dioxide Titanium dioxide Calcium
phosphate Ethylcellulose Gelatin
Example Prozac (an antidepressant drug) is
formulated with starch, gelatin, silicone,
titanium dioxide and iron oxide,
among other excipients.
Once it has been formulated, the drug product is
ready for administration to animals and humans.
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Exploratory Development - Summary
Large scale organic synthesis is used to produce
the drug substance
The drug substance is combined with excipients
to produce the formulated drug product.
In Phase I clinical studies, the drug product is
tested in humans to assess safety, and
tolerability.
The drug product is toxicity-tested in animals
for safety.
In Phase II clinical studies, the drug product is
tested in humans to determine the dose range and
to collect information on efficacy.
Success rates in Exploratory Development are low
-- around 10 - 25.
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The Full Development Stage
A drug candidate moves into Full
Development after enough information has been
gathered which gives a strong indication that
the candidate will be successful in treating the
disease.
Phase III clinical studies in humans are
then conducted to confirm the efficacy of the
drug in a large population of patients.
Many more activities must go on at this time to
prepare to launch the drug.
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Pre-Launch Activities
Drug Substance a large scale, inexpensive and
robust
manufacturing process for the
drug substance must be developed. Drug
Product a large scale, inexpensive and robust
formulation process for
the drug product must
be developed.
The Key Terms here are Large Scale and
Process.
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What is a Process?
Process a sequence of actions in organic
synthesis, those actions taken in performing a
chemical reaction or series of chemical
reactions may refer to a synthesis composed of
several steps Another term you may run
into API active pharmaceutical ingredient
another term for the drug substance
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How Large is Large Scale?
A Typical Drug Discovery/Development Project
Timeline
Phase IV
Phase I
Phase II
Phase III
Discovery / Preclinical Phase
Drug Candidate Named
IND submitted
NDA submitted
Tox Lot Synthesis (100 g 10 kg)
Pre-Lead Synthesis (lt10 g)
Generate Ph I / II / III Batches (1 100s kg)
Pilot Synthesis (1 Metric Ton)
Demo and Validation Lots (a few MTs)
Full Scale Manufacturing (Many MTs)

• Time from Drug Candidate to IND is 12 18
  months - gating item is drug synthesis.
• Time from Drug Candidate to NDA approval varies
  by therapeutic area but gt 5 years.
• Drug Candidate success rates vary, but 1 in 25
  is typical.

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Drug Discovery and Development - Summary
Drug Discovery - the process of designing,
synthesizing and
demonstrating the potential of
molecules as drug candidates.
(Medicinal Chemistry)
Drug Development - the process of making drug
candidates
available in large
quantities by organic synthesis for
purposes of further
evaluation and
eventual marketing.
(Chemical Development)
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What is Chemical Development?
Chemistry activities required to bring a drug
candidate from the discovery phase to the
marketplace
- Synthetic organic chemistry - Analytical
Chemistry - Chemical Engineering
A subset of Chemical Development is called
Process Chemistry
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Main Objectives ofChemical Development

• THE OPTIMIZATION OF THE CHEMICAL SYNTHESIS
• OF DRUG CANDIDATES IN ORDER TO INCREASE
• THEIR SUPPLY AND TO MINIMIZE THEIR
• COST OF PRODUCTION
• 2. ENSURING THAT THE DRUG SUBSTANCE CAN BE
• MADE REPRODUCIBLY AND IN HIGH PURITY

DESIRED RESULT PRODUCE THE DRUG SUBSTANCE IN
THE MOST
COST EFFECTIVE MANNER POSSIBLE

INCREASED PROFITS
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Process Chemistry - the discovery, optimization
and scaleup of the most efficient synthetic
pathway (i.e., a process) to a drug substance
pathway discovery - How to synthesize the drug
substance from
inexpensive starting materials pathway
optimization - How to get the best chemical
yields along
the pathway and minimize costs and
waste efficiency - defined in terms of all cost
parameters, including cost of
materials, equipment and labor
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Key Criteria in Chemistry Pathway Discovery and
Optimization

• Safety
• Robustness
• Cost

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1. Safety
Process Safety thermochemical hazards Compound
Safety biological hazards
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2. Robustness
Reproducibility chemistry/process must work
the same way EVERY TIME

• Purity (or impurity) profiles must fall within a
  very narrow range
• or the drug is not usable strictly defined
  by a compounds
• specifications as developed under FDA
  guidelines
• Promoted by consistently following a set of
  procedures known
• in the industry as Good Manufacturing
  Practices (GMP)

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3. Cost

• Essentially, the fully-burdened cost of the
• manufacture of the compound.
• Elements include prices of
• all chemicals and solvent
• all labor utilized
• all energy costs
• all disposal services
• tax issues?

A Process Chemist seeks the Optimum Synthetic
Pathway
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Optimum Synthesis - The best or most efficient
synthesis
in terms of all cost parameters
Note an optimum is defined by a point in time
Corollary A - ANYTHING can be made / performed
better Corollary B - It is not our job to be
satisfied
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Key Parameters in Process Work Not Well-Appreciate
d in Laboratory Scale Research

• Heat Transport
• Mass Transport
• Mixing
• Polymorphism

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Heat Transport
In a brisk wind, does a gnat cool off faster than
an elephant?

• Heating and cooling a chemical reaction is
  primarily
• a surface phenomenon.
• As a reaction vessel becomes larger the surface
  area volume
• ratio decreases.
• Therefore, heating and cooling rates must be
  carefully
• studied reaction parameters.

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Mass Transport
Can you move a gnat from point A to point B
faster than you can move an elephant?

• In most chemical reactions you are physically
  combining
• (adding, mixing) one discrete chemical to
  another to cause a
• chemical reaction to occur.
• It takes longer to combine (add) 100 liters of
  one chemical
• to a reaction mixture than it does to add 1
  mL to a
• smaller reaction mixture
• Therefore, addition rates must also be carefully
  studied
• reaction parameters.

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Mixing

• It may be hard to believe, but hand stirring and
  magnetic stirring
• are incredibly inefficient ways to mix
  reactants.
• Large scale chemistry uses impellers which may
  spin at
• several hundred RPM.
• Mixing is even more important in heterogeneous
  reactions.
• This is yet another factor, taken for granted at
  the lab scale,
• which must be carefully studied at large
  scale.

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Polymorphs and Polymorphism
a polymorph is a solid crystalline phase of a
given compound resulting from the possibility of
at least two different arrangements of the
molecules of that compound in the solid state
Different polymorphs of a given compound have
different physical properties MP Color Sublim
ation point Morphology Heat capacity Hygroscopi
city Conductivity Solubility Volume Dissolutio
n rate Density Chemical stability
An organic compound may exist as many polymorphs!
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Allotropism vs. Polymorphism
Particles involved Atoms Molecules
Particles combine to form Molecules or
crystals Crystals
Allotropism Polymorphism
Examples of Allotropy
Carbon diamond, graphite and buckminsterfulleren
e Tin grey and white forms (Napoleans Buttons)
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Allotropes of Tin andNapoleans Buttons
White Tin (metallic and malleable)
Gray Tin (Powdery and brittle)
56 oF
cubic
tetragonal
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How are polymorphs detected and measured?
Powder x-ray diffraction Single Crystal x-ray
diffraction Differential scanning calorimetry
(DSC) Solid state IR and NMR Raman
Spectroscopy Microscopy Melting point
Polymorphism in Chocolate (cocoa butter)
http//hypertextbook.com/physics/matter/polymorphs
/
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Why is polymorphism important in the production
of pharmaceuticals?

• Interconversion among polymorphs can occur
  during
• crystallization processes
• physical handling (milling, grinding
  and tabletting)
• Solubility and dissolution rate affect a drugs
  bioavailability

In general, in a series of polymorphs of a
compound, the polymorph with the lowest melting
point is the most thermodynamically stable.
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What factors are important in polymorphism?

• Hydrogen bonding ability
• Presence of solvents
• Degree of rigidity or floppiness of a molecule

How widespread is polymorphism?

• Estimated to be at least 50
• Some people believe that .most organic
  compounds, when
• studied carefully, exist in more than one
  crystalline form.
• - J.W. Mullin in Crystallization (4th Edition)
• 
  Oxford Univ. Press. 2001

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HIV Protease Inhibitors
Ritonavir (Abbott Labs) the Disappearing
Polymorph
Nelfinavir (Agouron Pharmaceuticals)
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Polymorphism - Summary

• Polymorphism in organic compounds is
• Unpredictable
• Easy to detect, given the right equipment
• Critically important to the pharmaceutical
  industry
• Not well appreciated by graduating chemistry
  students

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Returning to our main topic
What is the bottom-line purpose of Chemical
Development in the pharmaceutical and related
industries?
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In the end, it all comes down to money
- Process chemical yields - Time required for
synthesis - Effort required - Equipment required
- Process Safety - Atom economy - Environmental
factors - Process reliability
These factors have a direct effect on the cost of
drugs.
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The Bottom Line
Process Chemistry is closer to what the average
Synthesis Jock does as a graduate student than is
Medicinal Chemistry.
So.. If you are more interested in the
biological side of organic chemistry, you will
probably enjoy Medicinal Chemistry. If you are
more interested in the strategies, mechanisms and
design of organic reactions, you will probably
enjoy Process Chemistry.
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Bibliography
Bert Spilker Multinational Drug
Companies, Raven Press, 1989, ISBN 0-88167-463-X
Rick Ng Drugs From Discovery to Approval,
John Wiley and Sons, 2004, ISBN 0-471-60150-0
Bert Spilker and Pedro Cuatrecasas Inside the
Drug Industry, Prous Science, 1990, ISBN
84-86973-22-8
The WetFeet Insider Guide to Careers in Biotech
and Pharmaceuticals, WetFeet Inc., 2003, ISBN
1-58207-316-3
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Questions?????
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Kim Albizati Chief Scientific Officer Strategic
Enzyme Applications, Inc. 10420 Wateridge
Circle San Diego, CA 92121 858 518-9831 kalbizati_at_
stratbiocat.com
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Chemical Development vs. Medicinal Chemistry
Chemical Development - primary
interest is obtaining information - main
synthetic goal is to design the most efficient
pathway to a single compound - optimize
strategy, tactics and execution of a
synthesis - knowledge of mechanistic principles
and chemical reactivity are important -
generally engaged in problem solving in
organic synthetic chemistry
Medicinal Chemistry - primary
interest is obtaining compounds - main synthetic
goal is to design a flexible pathway to a large
number of structurally similar compounds -
optimize of similar compounds accessible
from a synthesis route - knowledge of organic
structure and biochemistry are important -
generally engaged in problem solving in drug
design