Dr. Dhananjay Sathe Vice President-CRD - NCLwcip.ncl.res.in/uploads/presentation/flow...

API PROCESS DEVELOPMENT: Transition from batch processes to continuous flow!!?

Dr. Dhananjay Sathe

Vice President-CRD

20 December 2011 1CONFIDENTIAL

UNICHEM

• Indian Generic Company

• Annual sales of about 1000 Cr

• Business includes APIs, FDFs for domestic as well as export markets

• R&D and Corporate office at Jogeshwari, Mumbai

• API Plants at Roha and Indore

• FDF plants at Goa, Gaziabad and Sikkim


API

• Active pharmaceutical ingredients

– Small molecules: mw 400-600

– Macromolecules: Scerolimus, Tacrolimus

– Peptides, nucleosides, nucleotides

• Glatiramer Acetate

• Eptifibatide

– Carbohydrates: Levonox

– Polymers: Sevelamer


API

• Categories

– General: Diabetese, Cardiovascular, CNS etc

– Oncology: Anticancers

– Steroids

– Antiinfectives: Antibiotics, Antivirals, Antifungals

– Natural or semi synthetic


API Business

• Markets: US, EU, Japan, ROW• Strategy

– API selection– Growth: New Products, New Customers, New Markets– Operation: Supply Chain, Continuous Development– PIV or PIII entry

• Commoditized– Entry barrier

• Chemistry: Chiral, Organometallic etc• Technology: TFF, SMB etc

• Is Micro Tubular Reactor an enabling technology which can create entry barrier?


Challenges

• Local

– Waste management

– Safety issues

– Supply chain

• Global

– Intense competition from other generic players

– Complicated IPR scenario: PIII, PIV

– Regulatory issues: ICH Guideline

– The window of opportunity is short lived


API Processes

• Encompass entire range of Synthetic Organic Chemistry

• Single step to Multistep Synthesis

• Multi component reactions

• Batch Processes

• Batch sizes ranging from Multigram to Multiton

• Homogenous or Heterogenous


API Processes

• Temperatures ranging from -70oC to +200oC

• Pressures ranging from Atmospheric to 100 bar

• Biphasic reactions

• Telescopic reactions


Bottlenecks

• Hazardous reactions/reagents– Hydrazoic acid, Diborane, EO

– Nitration, Azidation

• Cryogenic reactions– Swern Oxidation, Butyl Lithium

• Lower batch sizes– Low yields

– Time consuming reactions

– Dilute reactions


Flow Chemistry

• Where does it fit in?• Which chemistries can it handle?• Is it a laboratory technique?• Are the standard protocols available?• Are the prototype equipments available?• Can it be scaled up?• Is there a technology barrier?• Can it be patented?• Can it be validated?


Prior Art

• Stoicheometric Reactions• C-C Bond formation: Grignard, Wittig, Evans Auxillary

• Oxidation/Reduction: Swern Oxidation, Hydride Reductions

• Heterocyclic ring formations: Pyrrols, Pyridones, Indoles?

• Condensation reactions: Amide, Ester synthesis

• Fluorination

• Nitration

• Diazotization

• Polymerization


Prior Art

• Catalytic Reactions• C-C bond formation: Heck, Suzuki, Kumada

• Oxidation/Reductions

• Organocatalysis: CBS Catalysts

• Enzymatic


C-C Bond Formation

• Oxazolidone Chiral Auxillary

• Batch Reaction:• 31% Yield, 85:15 de, >10% Byproduct

• >50% Byproduct at higher temperature

• Flow Reaction• 41% Yield, 91:9 de, No Byproduct

20 December 2011 13

N O

CH3

OO

CH3N O

CH3

OO

CH3

N O

CH3

OO

CH3+NaHMDS, THF, -100

oC

Br

+

N O

CH3

O

Ph

CONFIDENTIAL

Aliskiren Building Blocks

20 December 2011 14

NH NH2

O

CH3CH3

O

OHCH3 CH3

NH2

CH3CH3O

CH3

OOCH3

CH3CH3O

CH3

OOCH3

O

OHN O

O

Ph

O

CH3 CH3

Cl

O

CH3

OR

+

N O

O

Ph

O

CH3 CH3

OH

O

CH3 CH3

ClClCl +

CONFIDENTIAL

Swern Oxidation

• Batch Process:• 19% Product, 72% Byproducts

• Cryogenic conditions

• Microreactor Process• 88% Product

• RT

20 December 2011 15

OH O O

S

CH3

O

O

FF

F

+ +DMSO/TFAA

TEA/-200C

CONFIDENTIAL

API Building Blocks

20 December 2011 16

NO

OCH3

CH3

O

N

O

N

OH

Swern Oxidation

Donepezil

O O

O

OROH

O O

O

ORO

Swern Oxidation

CONFIDENTIAL

Nitration

• Batch Process• Highly exothermic and explosive• Significant decarboxylated byproduct formation• Longer reaction time >12 Hrs

• Microreactor• >73% Product formation, in 35 min residence time• No byproduct formation

20 December 2011 17

NH

N

SN

N

N

N

CH3

O

CH3

O

OO

CH3

CH3

O2N

N

N

CH3

CH3

O2N

N

N

CH3

CH3

O

OH

N

N

CH3

CH3

O

OH

+HNO3/H2SO4

90-100

oC

CONFIDENTIAL

Condensation Reaction

– Eli Lilly potent NK1 Antagonists 2 & 3

20 December 2011 18

N

N N

N

FF

F

F

F

F

Cl

O

CH3 N N

N

N

O

FF

F

F

F

F

O

N

O

CH3

Cl

FF

F

F

F

F

N

N+

N-

23

NK1 Antagonists

1-Azidomethyl

-3,5

-trifluoromethyl benzene

CONFIDENTIAL

Batch Process

• DMSO/Water/NaN3/RT

• Longer reaction time ~48 hrs

• Side reaction

• Hydrazoic acid vapor formation in the head space

• Explosive

20 December 2011 19

FF

F

F

F

F

N

N+

N-

FF

F

F

F

F

Cl

NaN3

FF

F

F

F

F

OH

+

CONFIDENTIAL

Flow Process

• SS 316 coil placed in GC oven with T joint outside oven for injecting reagents– Dia 2.16mm

• Temperatures 50, 70 and 90oC• Residence time 60 min• Back pressure 200 psig• Only 64% conversion

– Dia 1 mm• Temperature 60oC• Residence time 20 min • Back pressure 200 psig• Conversion >99%, Purity 98.5%


Azide Chemistry

• Reacts with metals and forms metal azides which can detonate

• Liberates low boiling hydrozoic acid in contact with water which lowers BP and is explosive

• Wide application in API industry• Converting Alkyl Halides or Tosylate/Mesylates to Amines

– Linezolid– Aliskiren

• Converting Nitriles to Tetrazoles– Valsartan, Irbesartan, Olmesartan, Losartan etc

• Converting Alkynes to Triazoles : Click Chemistry• Converting Carboxylic Acids to Amines: Curtius

Rearrangement


Sartans

• Angeotensin II receptor antagonists• Clinically used as anti hypertensives• Doses are in the range of 40-400 mg

20 December 2011 22

N NH

N N

R

R=

CH3

N

O OH

CH3

CH3O

Valsartan

N

N

O

CH3

Irbesartan

N

N

CH3

O

OO

O

CH3

O

OH

CH3

CH3

Olmesartan modoxamil

N

N

CH3

OH

Cl

Losartan

CONFIDENTIAL

Sartans

• Tetrazole formation is the last step in the sartan synthesis

• It is a time consuming reaction• Energy demanding• Generally high yielding• Generates toxic and explosive hydrazoic acid

during the work up

20 December 2011 23

N NH

N N

RR

N

NaN3/TEA.HCl

Xylene/140oC

24-48Hrs

CONFIDENTIAL

Sartans

• Losartan sales are $3.6 bn, Kilo consumption is ~500 MT

• Irbesartan sales are $3 bn, Kilo consumption is ~700 MT

• Valsartan sales are $8.9 bn, Kilo consumption is ~1000 MT

• Olmesartan sales are $3.9 bn, Kilo consumption is ~75 MT


Polymerization

• Peptide Homopolymers and Copolymers

• L-Lysine, L-Alanine, L-Leucine, L-Glutamic acid

• Low PDI in the range of 1.19-1.32

• Molecular wt distrebution is tunable

• Function of residence time, monomer ratios, monomer/base ratios

20 December 2011 25

NH

O

O

O

R

N-

O

O

O

R

NH

O

O

O

R

+N

O

O

O

R

O

R

NH2

NCA

Base

Active Monomer NCA Peptide

Chain Reaction

CONFIDENTIAL

Copaxone

• It is a $3bn molecule invented by TEVA• Clinically used for the treatment of RRMS• It’s a “complex” copolymer of L-Lysine, L-Alanine, L-Tyrosine,

L-Glutamic acid• Average MW is in the range of 5-9KDa• Its PDI is about 1.6• It’s a 2 stage process:

• Copolymerization to 40 Kda• Cutting down to desired MW range of 5-9 KDa

• Final step is TFF purification to remove low molecular wt fractions.

• Batch size is limited by TFF capacity, and TFF systems are very expensive


Conclusion

• It has to make a commercial sense

• To debottleneck API processes

• To free capacity for new products

• If it is a technology barrier

• If it can be exclusive


Bibliography

• Chem. Rev. 2007, 107, 2300-2318

• Organic Process Research & Development 2009, 13, 152-160

• References therein


THANK YOU


Dr. Dhananjay Sathe Vice President-CRD - NCLwcip.ncl.res.in/uploads/presentation/flow...

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