Part I:

Chemical Development in

the Pharmaceutical Industry

Overview of Pharmaceutical R&D

Drug Discovery and Drug Development

What is Chemical Development?

General Aspects of Chemical Development

Part I Topics

Long Road to a New Medicine

Large Amounts ofCandidate Medicine

Synthesized

Project Team and PlansSynthesis of Compounds

Early Safety Studies

Formulations Developed

ExtensiveSafety Studies

Screening

Studies in HealthyVolunteers Phase I

Candidate Medicine Tested in 3,000-10,000 Patients (Phase III)

Studies in 100-300Patients (Phase II)

Clinical Data Analysis New

Medicine

IdeaDiscovery

Full Development

Registration

ExploratoryDevelopment

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Pharmaceutical R&D Process

IdeaIdea DrugDrug12 - 15 Years12 - 15 Years

DiscoveryDiscovery Exploratory DevelopmentExploratory Development Full DevelopmentFull Development

Phase IPhase I Phase IIPhase II Phase IIIPhase III

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7,000,000 Compounds ScreenedHigh risk: $800 million+

7,000,000 Compounds ScreenedHigh risk: $800 million+

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The Pharmaceutical R&D Process

Discovery Stage Exploratory Development Stage Full Development Stage Registration

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 individualsif 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 person’s health condition?

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.

The Discovery PhaseThe Discovery PhaseThe Discovery Stage

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

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 > 95%.

The drug candidate will be given to a variety of animals andto a large number of human subjects

Such large scale synthesis activities requires expertise in:

synthetic organic chemistry chemical engineering analytical chemistry

The Exploratory Development Stage

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

Exploratory Development StageExploratory Development Stage

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.

Exploratory Development StageExploratory Development Stage

Common Excipients

Magnesium stearateLactoseStarchTalcSucrose

Silicon dioxideTitanium dioxideCalcium phosphateEthylcelluloseGelatin

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.

Exploratory Development - SummaryExploratory Development - Summary

Large scale organic synthesisis used to produce the drug substance

The drug substance is combined with excipients to produce the formulateddrug product.

The drug product is toxicity-testedin animals for safety.

In Phase I clinical studies, the drug product is tested in humans to assess safety, and tolerability.

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%.

The Full Development StageThe Full Development Stage

A drug candidate moves into Full Developmentafter 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 thenconducted 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.

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.”

What is a “Process”?

Process – a sequence of actions; in organic synthesis, those actionstaken 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

A Typical Drug Discovery/Development Project Timeline

Phase IVPhase I Phase II Phase IIIDiscovery / Preclinical Phase

DrugCandidate

Named

INDsubmitted

NDAsubmitted

Tox LotSynthesis

(100 g – 10 kg)

Pre-LeadSynthesis(<10 g)

GeneratePh I / II / III

Batches(1 – 100’s kg)

PilotSynthesis

(1 Metric Ton)

Demo andValidation Lots

(a few MT’s)

Full ScaleManufacturing(Many MT’s)

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 > 5 years. Drug Candidate success rates vary, but 1 in 25 is typical.

How Large is “Large Scale”?

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)

Drug Discovery and Development - Summary

What is Chemical Development?

Chemistry activities required to bring a drug candidate fromthe discovery phase to the marketplace

- Synthetic organic chemistry- Analytical Chemistry- Chemical Engineering

A subset of Chemical Development is called “Process Chemistry”

Main Objectives ofChemical Development

1. 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

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

Key Criteria in Chemistry PathwayDiscovery and Optimization

1. Safety

2. Robustness

3. Cost

1. Safety

Process Safety – thermochemical hazards

Compound Safety – biological hazards

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 compound’s specifications as developed under FDA guidelines

Promoted by consistently following a set of procedures known in the industry as Good Manufacturing Practices (GMP)

3. Cost

Essentially, the fully-burdened cost of the manufacture of the compound.

Elements include prices of:

all chemicals and solventall labor utilizedall energy costsall disposal servicestax issues?

A Process Chemist seeks the Optimum Synthetic Pathway

Optimum Synthesis - The best or most efficient synthesis in terms of all cost parameters

Corollary A - ANYTHING can be made / performed better

Corollary B - It is not our job to be satisfied

Note : an optimum is defined by a point in time

Key Parameters in Process Work NotWell-Appreciated in Laboratory Scale Research

1. Heat Transport

2. Mass Transport

3. Mixing

4. Polymorphism

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.

Mass TransportCan 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.

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.

Polymorphs and Polymorphism

“a polymorph is a solid crystalline phase of a given compoundresulting from the possibility of at least two differentarrangements of the molecules of that compound in the solid state”

Different polymorphs of a given compound have differentphysical properties:

MP ColorSublimation point MorphologyHeat capacity HygroscopicityConductivity SolubilityVolume Dissolution rateDensity Chemical stability

An organic compound may exist as many polymorphs!

Allotropism vs. Polymorphism

Allotropism

Polymorphism

Particles involved

Atoms

Molecules

Particles combine to form:

Molecules or crystals

Crystals

Examples of Allotropy:

Carbon – diamond, graphite and buckminsterfullereneTin – grey and white forms (Napolean’s Buttons)

Allotropes of Tin andNapolean’s Buttons

White Tin(metallic and malleable)

Gray Tin(Powdery and brittle)

56 oF“tetragonal” “cubic”

How are polymorphs detected and measured?

Powder x-ray diffractionSingle Crystal x-ray diffractionDifferential scanning calorimetry (DSC)Solid state IR and NMRRaman SpectroscopyMicroscopyMelting point

http://hypertextbook.com/physics/matter/polymorphs/

Polymorphism in Chocolate (cocoa butter):

Why is polymorphism importantin 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 polymorphwith the lowest melting point is the most thermodynamically stable.

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

HIV Protease Inhibitors

Ritonavir (Abbott Labs) – the “Disappearing Polymorph”

Nelfinavir (Agouron Pharmaceuticals)

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Easy to detect, given the right equipment

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Polymorphism - Summary

Returning to our main topic……

What is the bottom-line purposeof Chemical Development

in the pharmaceutical and related industries?

- Process chemical yields

- Time required for synthesis

- Effort required

- Equipment required

- Process Safety

- Atom economy

- Environmental factors

- Process reliability

In the end, it all comes down to money……

These factors have a direct effect on the cost of drugs.

The Bottom Line

Process Chemistry is closer to what the average SynthesisJock does as a graduate student than is Medicinal Chemistry.

So……..

If you are more interested in the biological side of organicchemistry, you will probably enjoy Medicinal Chemistry.

If you are more interested in the strategies, mechanismsand design of organic reactions, you will probably enjoyProcess Chemistry.

Bibliography

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

Bert Spilker “Multinational Drug Companies”,Raven Press, 1989, ISBN 0-88167-463-X

Questions?????

Kim AlbizatiChief Scientific Officer

Strategic Enzyme Applications, Inc.10420 Wateridge CircleSan Diego, CA 92121

858 518-9831kalbizati@stratbiocat.com

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”