Process Chemistry

Alex Joseph

Outline

What is Process Chemistry?

Drug Development Timeline and Cost

General Considerations

What is Process Chemistry?

Process chemistry- refers to development work that is carried out in the pharmaceutical industry in pursuit of safe, efficient, economical, and environmentally friendly syntheses of complex molecules for use in treating human disease. The mission of process chemistry in the pharmaceutical industry is to provide documented, controlled synthetic processes for the manufacture of an active pharmaceutical ingredient (API) or the drug.

Safe Environmentally friendly

Efficient Economical ($ and atom)

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Why is synthesis and process research needed since there already exists a synthesis established by discovery chemistry about the way to find the clinical candidate?
Synthetic strategies: Discovery chemistry vs Synt. & Proc. Research Diversity vs target orientation

The goal of discovery chemistry the task of medicinal chemists is to synthesize as many new compounds as quickly as possible, which will then be tested by biologists against the chosen biological target.- diversity oriented process After the identification of a new clinical candidate. The task now is to develop a specific synthetic process for a large-scale production process which should be safe, efficient, economical, and environmentally friendly.
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Drug Development Timeline

Average of 12-15 yrs

Process research begin as soon as a hit compound is found till after launch if necessary. Two time periods process chemistry can significantly shorten are the period between the lead candidate optimization to the clinical trials and the time at the end of the clinical trials to the launch of the drug on the market. Reduced timeline of process research would allow for an early launch into the market with minimal costs.
Target Screen(s) Hit Lead Candidate
CLINICAL
P A T E N T

Patent Launch Expiration

D I S C O V E R Y SAFETY/PHARMACEUTICAL STUDIES

P R O C E S S R E S E A R C H 4.5 yrs 200-300 gms 2 yrs 8.2 years < 100 kg

100-2000 kg

Need For Efficient Process Chemistry

Patent protection for 20 years

Generic drug application: Abbreviated New Drug Application (ANDA)

http://www.fda.gov/cder/index.html

Presidential Green Chemistry Challenge Award

Established in 1995 by the US-EPA For innovations in cleaner, cheaper and smarter Sertraline hydrochloride chemistry
O HN H2N N O HO Cl N
O O

HN

HCl
CF3

N
N CF3 F N

Ganciclovir

OH Cl
O

H N

HN

Aprepitant

Cytovene 2000 Roche Corp. Reduced liquid waste: 1120 metric tons / year Reduced solid waste: 25 metric tons / year

Zoloft 2002 Pfizer, Inc. Reduced waste: HCl (conc): 150 metric tons / year TiO2: 440 metric tons / year

Emend Anti-emitic 2005 Merck Reduced waste: 340,000 L / metric ton

Principles of process and green Chemistry

1. Prevention. (waste)

2. Atom Economy. 3. Less Hazardous Chemical Synthesis. 4. Designing Safer Chemicals. 5. Safer Solvents and Auxiliaries. 6. Design for Energy Efficiency. Energy requirements should be minimized 7. Use of Renewable raw material. A raw material or feedstock should be renewable rather than depleting 8. Reduce Derivatives. Unnecessary derivatization. 9. Catalysis. Catalytic reagents (as selective as possible) are superior to stoichiometric reagents. 10. Design for Degradation. Chemical products should be designed so that at the end of their function they do not persist in the environment and instead break down into harmless degradation products. 11. Real-time Analysis for Pollution Prevention. in-process monitoring and control prior to the formation of hazardous substances. 12. Inherently Safer Chemistry for Accident Prevention. Substance used in a chemical process should be chosen so as to minimize the potential for chemical accidents, including releases, explosions.

General Considerations for Process Chemistry

Avoid column chromatography Seeding helps crystallization Avoid desiccants, use azeotrope Avoid solvents with flash point < 15 C

Ether, hexanes, DCM

Temperature range -40 to 120 C Avoid protecting groups Impurities of > 0.1% must be analyzed
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1. Prevention
It is better to prevent waste than to treat or clean up waste after it is formed.

2. Atom Economy
Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product.

Organic Chemistry & Percent Yield

Epoxidation of an alkene using a peroxyacid
O O O OH

+
Cl

100% yield

Percent yield:
Percent yield: % yield = (actual yield/theoretical yield) x 100 What is missing?
What co-products are made? How much waste is generated? Is the waste benign waste? Are the co-products benign and/or useable? How much energy is required? Are purification steps needed? What solvents are used? (are they benign and/or reusable? Is the catalyst truly a catalyst? (stoichiometric vs. catalytic?)

Balanced Reactions
Balanced chemical reaction of the epoxidation of styrene

O O O OH O OH

+
Cl

+
Cl

Atom Economy
% AE = (FW of atoms utilized/FW of all reactants) X 100

Balanced chemical reaction of the epoxidation of styrene

Assume 100% yield. 100% of the desired epoxide product is recovered. 100% formation of the co-product: m-chlorobenzoic acid A.E. of this reaction is 43%. 57% of the products are waste.

3. Less Hazardous Chemical Synthesis

Whenever practicable, synthetic methodologies should be designed to use and generate substances that possess little or no toxicity to human health and the environment.

Less Hazardous Chemical Synthesis

Polycarbonate Synthesis: Phosgene Process
O

O
HO

OH

NaOH
Cl * O

Cl

Disadvantages phosgene is highly toxic, corrosive requires large amount of CH2Cl2 polycarbonate contaminated with Cl impurities

Less Hazardous Chemical Synthesis

Polycarbonate Synthesis: Solid-State Process
HO

OH O

+
O O O

Advantages diphenylcarbonate - synthesized without phosgene eliminates use of CH2Cl2 higher-quality polycarbonates

4. Designing Safer Chemicals

Chemical products should be designed to preserve efficacy of the function while reducing toxicity.

Designing Safer Chemicals: Case Study: Antifoulants

Antifoulants are generally dispersed in the paint as it is applied to the hull. Organotin compounds have traditionally been used, particularly tributyltin oxide (TBTO). TBTO works by gradually leaching from the hull killing the fouling organisms in the surrounding area TBTO and other organotin antifoulants have long halflives in the environment (half-life of TBTO in seawater is > 6 months). They also bioconcentrate in marine organisms (the concentration of TBTO in marine organisms to be 104 times greater than in the surrounding water). Organotin compounds are chronically toxic to marine life and can enter food chain. They are bioaccumulative.

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Designing Safer Chemicals: Case Study: Antifoulants

Sea-Nine 211 Rohm and Haas Presidential Green Chemistry Challenge Award, 1996 The active ingredient in Sea-Nine 211, 4,5-dichloro-2-n-octyl-4isothiazolin-3-one (DCOI), is a member of the isothiazolone family of antifoulants.

Designing Safer Chemicals: Case Study: Antifoulants

Sea-Nine 211 works by maintaining a hostile growing environment for marine organisms. When organisms attach to the hull (treated with DCOI), proteins at the point of attachment with the hull react with the DCOI. This reaction with the DCOI prevents the use of these proteins for other metabolic processes. The organism thus detaches itself and searches for a more hospitable surface on which to grow. Only organisms attached to hull of ship are exposed to toxic levels of DCOI. Readily biodegrades once leached from ship (half-life is less than one hour in sea water).

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5. Safer Solvents and Auxiliaries

The use of auxiliary substances (solvents, separation agents, etc.) should be avoided whenever possible and, when used,should be used judiciously.

Safer Solvents
Solvent Substitution Water as a solvent New solvents

Ionic

liquids Supercritical fluids

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Solvent Selection
Preferred Water Acetone Ethanol 2-Propanol 1-Propanol Ethyl acetate Isopropyl acetate Methanol Methyl ethyl ketone 1-Butanol t-Butanol Useable Cyclohexane Heptane Toluene Methylcyclohexane Methyl t-butyl ether Isooctane Acetonitrile 2-MethylTHF Tetrahydrofuran Xylenes Dimethyl sulfoxide Acetic acid Ethylene glycol Undesirable Pentane Hexane(s) Di-isopropyl ether Diethyl ether Dichloromethane Dichloroethane Chloroform Dimethyl formamide N-Methylpyrrolidinone Pyridine Dimethyl acetate Dioxane Dimethoxyethane Benzene Carbon tetrachloride

Red Solvent

Reason

Pentane Hexane(s) Di-isopropyl ether Diethyl ether Dichloromethane Dichloroethane Chloroform Dimethyl formamide N-Methylpyrrolidinone Pyridine Dimethyl acetate Dioxane Dimethoxyethane Benzene Carbon tetrachloride

Very low flash point, good alternative available. More toxic than the alternative heptane Very powerful peroxide former, good alternative ethers available. Very low flash point, good alternative ethers available. High volume use, regulated by EU solvent directive Carcinogen Carcinogen Toxicity, strongly regulated by EU Solvent Directive Toxicity, strongly regulated by EU Solvent Directive. Carcinogenic/mutagenic/reprotoxic carcinogen, toxicity, very low threshold limit value (TLV) for worker exposures. Toxicity, strongly regulated by EU Solvent Directive. carcinogen carcinogen, toxicity. Avoid use toxic to humans and environment, very low TLV (0.5 ppm), strongly regulated in EU. Avoid use: carcinogen, toxic, ozone depletor, not available for large-scale use, strongly regulated in the EU.

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Solvent replacement table

Undesirable Solvent Pentane Hexane(s) Di-isopropyl ether or diethyl ether Dioxane or dimethoxyethane Chloroform, dichloroethane or carbon tetrachloride Dimethyl formamide, dimethyl acetamide or N-methylpyrrolidinone Pyridine Dichloromethane (extractions) Dichloromethane (chromatography) Benzene

Alternative Heptane Heptane 2-MeTHF or tert-butyl methyl ether 2-MeTHF or tert-butyl methyl ether Dichloromethane Acetonitrile Et3N (if pyridine is used as a base) EtOAc, MTBE, toluene, 2-MeTHF EtOAc/heptane Toluene

Safer solvents: Supercritical fluids

A SCF is defined as a substance above its critical temperature (T C) and critical pressure (PC). The critical point represents the highest temperature and pressure at which the substance can exist as a vapor and liquid in equilibrium.

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6. Design for Energy Efficiency

Energy requirements should be recognized for their environmental and economic impacts and should be minimized. Synthetic methods should be conducted at ambient temperature and pressure.

Energy in a chemical process

Thermal (electric) Cooling Distillation Equipment (lab hood) Microwave

Source of energy: Power plant coal, oil, natural gas

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Energy usage
Chemicals and petroleum industries account for 50% of industrial energy usage. ~1/4 of the energy used is consumed in distillation and drying processes.

Alternative energy sources: Photochemical Reactions

Two commercial photochemical processes (Caprolactam process & vitamin D3) Caprolactam process NOCl NO + Cl (535nm)
+ Cl + HCl

NO

+ NO

NO

NOH.2HCl

+ 2 HCl

NOH.2HCl

O N

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Alternative Energy Sources: Microwave chemistry

Wavelengths between 1 mm and 1 m More directed source of energy Heating rate of 10C per second is achievable Possibility of overheating (explosions) Solvent-free conditions are possible Interaction with matter characterized by penetration depth

7. Use of Renewable Feedstocks

A raw material or feedstock should be renewable rather than depleting whenever technically and economically practical.

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Polymers from Renewable Resources:

Fermentation of glucose in the presence of bacteria and propanoic acid (product contains 5-20% polyhydroxyvalerate) Similar to polypropene and polyethene Biodegradable (credit card)

OH O OH R O

HO OH

Alcaligenes eutrophus OH propanoic acid

R = Me, polydroxybutyrate R = Et, polyhydroxyvalerate

Raw Materials from Renewable Resources: The BioFine Process

Paper mill sludge

HO

Agricultural residues, Waste wood

Levulinic acid Green Chemistry Challenge Award 1999 Small Business Award

Municipal solid waste and waste paper

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Levulinic acid as a platform chemical

O
OH HO
O

OH HO

butanediol
HO

Succinic acid
O
O

Acrylic acid
O

HO

MTHF (fuel additive)

CH3 HO C C H2 C H2 O

THF
O
O OH

OH

H2N O

Diphenolic acid gamma butyrolactone

DALA (-amino levulinic acid) (non-toxic, biodegradable herbicide)

8. Reduce Derivatives
Unnecessary derivatization (blocking group, protection/deprotection, temporary modification of physical/chemical processes) should be avoided whenever possible.

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Protecting Groups
2 synthetic steps are added each time one is used Overall yield and atom economy will decrease Protecting groups are used because there is no direct way to solve the problem without them.

9. Catalysis
Catalytic reagents (as selective as possible) are superior to stoichiometric reagents.

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Heterogeneous vs Homogenous

Distinct solid phase Readily separated Readily regenerated & recycled Rates not as fast Diffusion limited Lower selectivity Long service life High energy process Poor mechanistic understanding

Same phase as rxn medium Difficult to separate Expensive and/or difficult to separate Very high rates Not diffusion controlled High selectivity Short service life Mild conditions Mechanisms well understood

Biocatalysis

Enzymes or whole-cell microorganisms Benefits

Substrate specificity: Only one specific reaction step is normally catalyzed by an enzyme. Site specificity (regiospecificity Stereospecificity and selectivity Rection in water Naturally occurring Moderate conditions Possibility for tandem rxns (one-pot)

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10. Design for Degradation

Chemical products should be designed so that at the end of their function they do not persist in the environment and instead break down into harmless degradation products.

11. Real-time Analysis for Pollution Prevention

Analytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances.

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Real time analysis for a chemist is the process of checking the progress of chemical reactions as it happens.

Knowing when your product is done can save a lot of waste, time and energy!

12. Inherently Safer Chemistry for Accident Prevention

Substance and the form of a substance used in a chemical process should be chosen so as to minimize the potential for chemical accidents, including releases, explosions, and fires. Chemists try to avoid things that explode, light on fire, are air-sensitive, etc.

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