3rd IGCW-2013 SGM/AZ - PDB1

Sulur G Manjunatha

Principal scientist

Pharmaceutical Development

AstraZeneca India Pvt. Ltd.

Bangalore, India

Route and Process Design

to

Drug Substance Manufacture

A Sustainable approach to reduce Carbon foot print

3rd IGCW-2013 SGM/AZ - PDB2

IND filed

NDA filed

DMF

2-3Kg

Research Focus and Major outcome

3rd IGCW-2013 SGM/AZ - PDB3

Focus Outcome Environ

Impact

Drug Design and

Development

Drug substance manufacturing

process and supply

High

Formulation Design

development

Drug product manufacturing

process and supply

Low to Medium

Clinical Research Phases of clinical studies and

supporting data

Low

4

Environment Impact

EB = P x A x T

EB: Environmental Burden

P: Population

A: Affluence(Consumption)

T: Technology/Process

Technology/Process need for minimizing EB:

a) efficient(Yield and atom efficiency)

b) safe(nature of Hazard)

c) no pollution or minimum pollution(quantity generated per Kg

out put)

3rd IGCW-2013 SGM/AZ - PDB

5

Technology Efficiency Measurement

Ti = Ei x Si x Hi

Ti = Overall Technology/Process efficiency

Ei = Efficiency factor

Yield, cost, Selectivity Etc.

Si = Sustainability factor

Waste (PMI), Energy etc.

Hi = Process Hazard, material hazard.

3rd IGCW-2013 SGM/AZ - PDB

Drug Substance – Recent Trends

3rd IGCW-2013 SGM/AZ - PDB6

Structure:

- Complex structure with increasing molecular weight

- increasing number of hetero atom

- Increasing number of chiral center

Synthesis:

- Number of synthetic steps and many possible routes

- Too many possible processes

- Complex Raw materials and their availability

- increasing cost and delivery time

AZ marketed Drug molecules

Examples for complex structures

3rd IGCW-2013 SGM/AZ - PDB7

Rosuvastatin(Crestor)

Ticagrelor(Brilinta)Esomeprazole(Nexium)

Gefitinib(Iressa,)

Meropenem(Monan)

Quetiapine(Seroquel)

Source: Wikipedia

Development of a sustainable

process needs investment in

time, resources and money

Challenges to RD/PD during developmental stage

3rd IGCW-2013 SGM/AZ - PDB8

• Cost of initial development v/s Attrition Rate and development time

• How much to do(Route selection v/s delivery)

• Fit for the purpose

• Chemistry develops over a period - New Ideas

• Frequent change in Route/Process not preferred as this impacts

• impurity profile(Route/Process related)

• regulatory documentation(Physical, Pharmacological and toxicological)

Danger of getting fixed with inefficient process

• Route/Process improvement will have positive impact on SHE, Cost

and efficiency.

Ambition is to have the best synthetic route and sustainable process

as early as possible to support manufacture/market

How do we do it?

3rd IGCW-2013 SGM/AZ - PDB9

Route and Process

Route: A path to sequentially build the intermediate that leads to

target molecule through chemical transformation

A B C D E F G

Linear Route

G

A B C

G H I

G

A B C

G H I

Convergent Route

Process: A set of reaction parameters, reagents and activities

that is used to bring chemical transformation of one intermediate

to other leading to target molecule

3rd IGCW-2013 SGM/AZ - PDB10

Reagents, solvents, temp., pressure

Phases of Process Development

Route Design

Process Design

Process Optimization

• Retrosynthesis, and Evaluation of various

possible routes

• Prioritization of routes for lab trials

• Route selection from SELECT

• Solvent and reagent selection

(Solvent/Reagent selection guide)

• Understanding influencing factors

• Developing appropriate workup procedure

• Identification of impurities

• Analytical method development

• Isolation/teliscoping of steps

• Reagents and solvents quantity optimization

• Optimizing process parameters

• Specification for raw materials, intermediates

and final molecules.

• Process and analytical method validation

113rd IGCW-2013 SGM/AZ - PDB

Manufacture

SHE

assessment

SHE

assessment

SHE

assessment

SHE

assessment

SHE

assessmentAll impurities are fixed at the early stage of development

Enables long term

route selection

Enables long term

solvent and reagent

selection

Sustainable process

Route / Process Selection - SELECT Guidance

3rd IGCW-2013 SGM/AZ - PDB12

Safety Are there any toxic reagents/intermediates, including PGI’s?

Are there any operational hazards (potential explosives, highly flammables etc.)?

Environmental Is there significant waste generated? What type of waste generated?

Does the process require significant energy consumption (temperature

extremes, long processes etc)?

Are there any emissions or solvents/reagents of concern?

Legal Is there freedom to operate?

Is there existing patent protection?

Are there any IP opportunities?

Economics Are there any expensive reagents/starting materials?

Are there high operational costs (long routes/processes)?

Does the route meet long term cost targets?

Control Are there controlled isolation points with stable intermediates?

Is there good control of processes and impurities?

Are processes robust and reproducible with respect to yield and quality?

Is there a robust supply chain?

Throughput Are the processes efficient and high yielding?

Is the route convergent?

Are any of the processes high dilution?

Chemical Reviews 2006 July edition

Expectation is to reach a safe, efficient and sustainable process

N

N

NN

N

F

FF

ON

N

OCOOH

HOOC

AZD3514 Maleate

Selective Androgen Receptor Down regulator

Route DesignEvolution in synthetic routes for AZD3514

3rd IGCW-2013 SGM/AZ - PDB13

DIPEA

DMF

K2CO3

DMF

DMA

MsCl

Et3N

DCM

Hydrogen

5% Pd/C

MeOH

AZD3514

MeOH

Chloro TAP Pip phenolTriazopehnol

AZD3514 Maleate

DIPEA

DMF

K2CO3

DMF

DMA

MsCl

Et3N

DCM

Hydrogen

5% Pd/C

MeOH

AZD3514

MeOH

Chloro TAP Pip phenolTriazopehnol

AZD3514 Maleate

SYNTHETIC ROUTE 1 – 1st Generation Route (Med chem)

3rd IGCW-2013 SGM/AZ - PDB14

Highlights: Diverse oriented synthesis

Drawbacks: Linear with 6 stages, Low yield(27%), use of MsCl(corrosive)

Low yielding step

DIPEA

DMF

K2CO3 DMF

DMA

MsCl

Et3N

DCM

5% Pd/C

EtOH

AZD3514MeOH

Chloro TAP Pip phenolTriazopehnol

AZD3514 Maleate

TPNAP70oC

DIPEA

DMF

K2CO3 DMF

DMA

MsCl

Et3N

DCM

5% Pd/C

EtOH

AZD3514MeOH

Chloro TAP Pip phenolTriazopehnol

AZD3514 Maleate

TPNAP70oC

SYNTHETIC ROUTE – 2nd Generation Route

Overall yield : 24.5%

3rd IGCW-2013 SGM/AZ - PDB15

No. of stages : 6

Low yielding step

chloroTAP PipPhenol HBr Triazophenol

TPNAP

AZD3514

DMAc

TEA DIAD

MeOH,

DCM/ TPP

H2/1Pd/C

Methanol

Ethylacetate

HBr

chloroTAP PipPhenol HBr Triazophenol

TPNAP

AZD3514

DMAc

TEA DIAD

MeOH,

DCM/ TPP

H2/1Pd/C

Methanol

Ethylacetate

HBr

SYNTHETIC ROUTE – 3rd Generation route

(Mitsunobu Route)

SHE Assessment:

• DMAC needs to be avoided.

• Mitsunobu – not a green reaction

Highlights:

• convergent route

• 4 synthetic steps only

• yield improved to 58% from 27%

Mitsunobyu Rn

chloroTAP PipPhenol HBr

CENAP. HCl

Triazophenol TPNAP

AZD3514

IPA

H2O

TEA aq. NaOH/Diopxane

MeOH

H210%Pd/C

Methanol

Ethylacetate

chloroTAP PipPhenol HBr

CENAP. HCl

Triazophenol TPNAP

AZD3514

IPA

H2O

TEA aq. NaOH/Diopxane

MeOH

H210%Pd/C

Methanol

Ethylacetate

SYNTHETIC ROUTE – 4th Generation route

Advantage:

• No DMAC; No Mitsunobu reaction

• 4 stages only; Yield improved to 67%

• Greener route and process

RATIONAL FOR route SELECTION

Synthetic route Product Remarks

1 Generation(Med

chem approach)

Yes No. of stages : 6; Overall yield : 27.6%

More number of stages and low yield

2nd Generation Yes No. of stages : 6; Overall yield : 24.5%

More number of stages and low yield

3rd Generation Yes No. of stages : 4; Overall yield : 58.4%

High effluent & use of hazardous chemicals

4th Generation Yes No. of stages : 4; Overall yield : 67.1%

3rd IGCW-2013 SGM/AZ - PDB18

Route and Process related impurities defined.

Process optimisation is the next step

Synthetic Routes to AZD 1981

3rd IGCW-2013 SGM/AZ - PDB19

AZD1981 AZD1981

AZD1981 Thioether

AZD1981 Nitro EsterAZD1981 Amino ester

AZD1981 Amino ester AZD1981

(27%)

(85%)

(60%)

(78%)

1. NaOH, THF then acid

2. EtOH (76%)

Discovery Route

slow reaction

impurities

hazards /

handling

SHE

20 3rd IGCW-2013 SGM/AZ - PDB

Low Yielding

AZD1981 Route for Pre-clinical to Phase 2b Campaigns

NH

NO2

N

S ClNO2

O

OEt

N

S ClNH

O

OH

O

S S ClCl

NH

S ClNO2

N

S ClNH

O

O

OEt

NO2

NH2

1. Pt/C, H2, EtOAc

2. AcCl, Et3N, EtOAc

(93%)

NaOMe / MeOH

BrCH2CO2Et, K2CO3,

MeCN, water (89%)

1M NaOH, n-PrOH

then MIBK / acid (~95%)

Thioether

Nitro ester Amide ester AZD1981

Nitro indole

Me2CO, KOtBu

DMSO, air(24 - 48%)

Makosza

Delivered Drug Substance for clinical trials (30-500 kg)

21

Energetic Intermediate

Hazardous reaction

conditionsLacrymatry

Need for an alternate safe, efficient and

sustainable process3rd IGCW-2013 SGM/AZ - PDB

AZD1981- Are there any better ways of making?

3rd IGCW-2013 SGM/AZ - PDB22

• The Semmler-Wolff reaction

Conversion of cyclohexenone oximes to anilines or acetanilides• W. Semmler, Ber. Dtsch, Chem. Ges., 1892, 25, 3352

• L. Wolff, Annalen der Chemie, 1902, 322, 351

AZD 1981 – 3rd Generation Route

3rd IGCW-2013 SGM/AZ - PDB23

Semmler Wolffs Aromatisation

3rd IGCW-2013 SGM/AZ - PDB

New Route (Semmler - Wolff Rearrangement) - Advantages

• The Semmler - Wolff route is highly efficient, robust, and

safe for the synthesis of AZD1981.

• Safe as this does not go through energetic Nitroindole

intermediate

• Process hazard involving the synthesis of Nitroindole is also

avoided

• Route goes through cheap, readily available building

blocks, and is suitable for large-scale manufacture.

• Semmler−Wolff aromatisation, has been found to proceed

under relatively mild reaction conditions

Org. Process Res. Dev. 2012, 16, 1746−1753

Route SelectionSELECT Guidance

25

Criteria Gassman Route Makozsa’s Route Semmler Wolff Route

Safety Use of hazardous tert-butyl hypochlorite

NaH – Hazardous reagent

Hydrogenation reaction

Reaction in air above

acetone flash point

Energetic intermediate

Hydrogenation reaction

Safe reactions

Avoided

Environ-

mental

Use of lachrymatricreagent

MDC solvent

Use of lachrymatricreagent

Avoided

Safe solvents

Legal No Issues No Issues New oppurtunity

Economics No issue No Issue No issue

Control Less control on key

reaction

Less control on key

reaction

Good control

Throughput Low yield Low yield High yield3rd IGCW-2013 SGM/AZ - PDB

CONCUSION

3rd IGCW-2013 SGM/AZ - PDB26

1. Route Design enables

• understanding of nature of possible intermediates

• the selection of best synthetic route with safe intermediates

• fixes the route related impurities(RD).

2. Process Design enables selection of

• environmental friendly solvents and reagents

• fixes the process related impurities(PD)

5. This approach gives flexibility for the development of a sustainable

manufacturing process for the drug substance

4. Extends right kind of supports to manufacturing and Regulatory team

3. Ensures right kind of substance for clinical and formulation studies

Supports the organization in reducing the

carbon foot print

Managing our environmental

3rd IGCW-2013 SGM/AZ - PDB

Managing our environmental impact is a key

aspect of being a responsible business

http://www.astrazeneca.com/Responsibility/The-environment

ACS GCI Pharmaceutical Roundtable

ACS GCI Pharmaceutical Roundtable

To catalyze the implementation of green chemistry and

engineering in the pharmaceutical industry globally

Informing & Influencing

the Research Agenda

Educating

Leaders

Developing Tools

for Innovation

Collaborating

Globally

ACKNOWLEDGEMENT

3rd IGCW-2013 SGM/AZ - PDB30

AZD1981

Parhalad Sharma, Ravi R,

Ravi Naidu, Eric Merifield,

Duncan Gill, Adrian Clarke,

Colin Thomson, Michael

Butters, Sreekanth Bachu, Colin

H. Benison, Nagaraju D, Emily

R. Fong, David R. J. Hose,

Gareth P. Howell, Siobhan E.

Mobberley, Simon C. Morton,

Alexander K. Mullen, Jayan

Rapai and Bharathi Tejas

AZD3514

Harikrishna Tumma

Partha Prathim Bishi

Srinivasa Rao

Vidya Nandita

Veerababu K

Ranganayakulu N

AstraZeneca India Pvt. Ltd.

Diorazio, Louis J – Member of ACS DCIPR

3rd IGCW-2013 SGM/AZ - PDB31

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