Route and Process Design

to
Drug Substance Manufacture

A Sustainable approach to reduce Carbon foot print

Sulur G Manjunatha
Principal scientist
Pharmaceutical Development
AstraZeneca India Pvt. Ltd.
Bangalore, India

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3rd IGCW-2013 SGM/AZ - PDB
 DMF

NDA filed

IND filed
2-3Kg

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Research Focus and Major outcome

Focus Outcome Environ

Impact

Drug Design and Drug substance manufacturing High

Development process and supply

Formulation Design Drug product manufacturing Low to Medium

development process and supply

Clinical Research Phases of clinical studies and Low

supporting data

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 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)
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 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.

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 Drug Substance – Recent Trends
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

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 AZ marketed Drug molecules
Examples for complex structures

Rosuvastatin(Crestor)
Meropenem(Monan)

Esomeprazole(Nexium) Ticagrelor(Brilinta)

Development of a sustainable
process needs investment in
Gefitinib(Iressa,) time, resources and money Quetiapine(Seroquel)
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Source:3rdWikipedia
IGCW-2013 SGM/AZ - PDB
 Challenges to RD/PD during developmental stage

• 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

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 How do we do it?

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 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
A B C
G
G H I
Reagents, solvents, temp., pressure

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

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Phases of Process Development
SHE
assessment
• Retrosynthesis, and Evaluation of various
Route Design possible routes
• Prioritization of routes for lab trials
SHE Enables long term
• Route selection from SELECT
assessment route selection
• Solvent and reagent selection
(Solvent/Reagent selection guide)
Process Design • Understanding influencing factors
• Developing appropriate workup procedure
Enables long term
• Identification of impurities
SHE
solvent and reagent • Analytical method development
assessment
selection • Isolation/teliscoping of steps

Process Optimization • Reagents and solvents quantity optimization

• Optimizing process parameters
SHE Sustainable process
• Specification for raw materials, intermediates
assessment and final molecules.
Manufacture • Process and analytical method validation

SHE
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assessment
All impurities are fixed at3rdthe early stage of development
IGCW-2013 SGM/AZ - PDB
 Route / Process Selection - SELECT Guidance

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?

Expectation is to reach a safe, efficient and sustainable process

Chemical Reviews 2006 July edition
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 Route Design
Evolution in synthetic routes for AZD3514

O
N
N

N O
COOH
N
N N
HOOC
N
F
F
F
AZD3514 Maleate

Selective Androgen Receptor Down regulator

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

DIPEA Hydrogen
DMF 5% Pd/C
MeOH

Pip phenol K2CO3

Chloro TAP Triazopehnol
DMF

MsCl
Et3N
DCM

DMA
Low yielding step

MeOH

AZD3514 AZD3514 Maleate

Highlights: Diverse oriented synthesis

Drawbacks: Linear with 6 stages, Low yield(27%), use of MsCl(corrosive)
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 SYNTHETIC ROUTE – 2nd Generation Route

DIPEA
DMF

K2CO3
DMF MsCl
Chloro TAP Pip phenol Et3N
Triazopehnol DCM

5% Pd/C
EtOH

70 o C TPNAP DMA

Low yielding step

MeOH
AZD3514
AZD3514 Maleate

No. of stages : 6 Overall yield : 24.5%

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 SYNTHETIC ROUTE – 3rd Generation route
(Mitsunobu Route)

TEA DIAD
DCM/ TPP
HBr DMAc

chloroTAP PipPhenol HBr

Triazophenol
TPNAP
Mitsunobyu Rn

H2/1Pd/C
MeOH,

Methanol

Highlights:
• convergent route Ethylacetate
AZD3514
• 4 synthetic steps only
• yield improved to 58% from 27%

SHE Assessment:
• DMAC needs to be avoided.
• Mitsunobu – not a green reaction
SYNTHETIC ROUTE – 4th Generation route

TEA aq. NaOH/Diopxane

IPA
H2O
chloroTAP PipPhenol HBr
Triazophenol
TPNAP
CENAP. HCl

H210%Pd/C
MeOH

Methanol

Ethylacetate
AZD3514

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

chem approach) 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%

Route and Process related impurities defined.
18 Process optimisation
3rd IGCW-2013 is the next step SGM/AZ - PDB
 Synthetic Routes to AZD 1981

AZD1981

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 Discovery Route

hazards /
AZD1981 Thioether handling
Low Yielding (27%)

(85%)

(60%)

slow reaction
AZD1981 Amino ester impurities AZD1981 Nitro Ester

SHE
(78%)

1. NaOH, THF
then acid

2. EtOH
(76%)
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AZD1981 Amino ester AZD1981
 AZD1981 Route for Pre-clinical to Phase 2b
Hazardous reaction
Campaigns
conditions
Lacrymatry
Energetic Intermediate

NO2 Makosza NO2

NO2 S Cl
Me2CO, KOtBu Cl S S Cl BrCH2CO2Et, K2CO3,

NH2 DMSO, air N NaOMe / MeOH MeCN, water

H N
(24 - 48%) H Thioether (89%)
Nitro indole
O
O
NO2 S Cl NH S Cl NH
1. Pt/C, H2, EtOAc S Cl
1M NaOH, n-PrOH

N O 2. AcCl, Et3N, EtOAc N O then MIBK / acid N O

(93%) (~95%)
OEt OEt
Nitro ester Amide ester AZD1981 OH

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

Need for an alternate safe, efficient and

21 sustainable process
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 AZD1981- Are there any better ways of making?

• 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

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 AZD 1981 – 3rd Generation Route

Semmler Wolffs Aromatisation

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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

3rd IGCW-2013 SGM/AZ - PDB

 Route Selection
SELECT Guidance
Criteria Gassman Route Makozsa’s Route Semmler Wolff Route

Safety Use of hazardous tert- Reaction in air above Safe reactions

butyl hypochlorite acetone flash point
Avoided
NaH – Hazardous Energetic intermediate
reagent

Hydrogenation Hydrogenation reaction

reaction
Environ- Use of lachrymatric Use of lachrymatric Avoided
mental reagent reagent
Safe solvents
MDC solvent
Legal No Issues No Issues New oppurtunity

Economics No issue No Issue No issue

Control Less control on key Less control on key Good control

reaction reaction
Throughput Low yield Low3rdyield High yield
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 CONCUSION

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)

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

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

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

manufacturing process for the drug substance

Supports the organization in reducing the

carbon foot print
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Managing our environmental

Managing our environmental impact is a key

aspect of being a responsible business

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

3rd IGCW-2013 SGM/AZ - PDB

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

Collaborating Educating
Globally Leaders

Developing Tools
for Innovation
 ACKNOWLEDGEMENT

AZD1981
Parhalad Sharma, Ravi R,
AZD3514 Ravi Naidu, Eric Merifield,
Harikrishna Tumma Duncan Gill, Adrian Clarke,
Partha Prathim Bishi
Srinivasa Rao
Colin Thomson, Michael
Vidya Nandita Butters, Sreekanth Bachu, Colin
Veerababu K H. Benison, Nagaraju D, Emily
Ranganayakulu N R. Fong, David R. J. Hose,
Gareth P. Howell, Siobhan E.
Mobberley, Simon C. Morton,
Alexander K. Mullen, Jayan
Rapai and Bharathi Tejas

Diorazio, Louis J – Member of ACS DCIPR

AstraZeneca India Pvt. Ltd.

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T: +44(0)20 7604 8000, F: +44 (0)20 7604 8151, www.astrazeneca.com

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