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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