Challenges in Scale-Up: Developing a process for the large scale manufacture of a pharmaceutical...

Challenges in scale-up:Developing a process for the large scale manufacture of a pharmaceutical intermediate

Greg Briner

Introduction to AstraZeneca

A multi-national pharmaceutical company

Formed in 1999

Zoladex (cancer), Seroquel (schizophrenia), Bricanyl (asthma)

Process Research & Development

Role in product timeline:

Introduction to PR&D

Target Identification

Hit Identification

Lead Identification

Lead Optimisation

CD Prenomination

Concept Testing

Development for Launch

Launch Phase

Product Maintenance

PR&D

PR&D at Macclesfield

Analytical Chemistry

Process Chemistry

Process Safety Group

Process Engineering

Process Chemistry

http://www-bioc.rice.edu/

Safe Robust Commercially viable

Process Chemistry

AstraZeneca Products

Respiratory andInflammation

Neuroscience

Infection

Gastrointestinal

Cardiovascular

Cancer

Therapy Areas

AZD2171

A vascular endothelial growth factor (VEGF) signalling inhibitor

Phase II / III trials for lung cancer and colorectal cancer

AZD2171

AZD2171 Reaction Scheme

AZD2171 Chloropyrrolidine free base

N Cl

N

N

O

RO

BnO

Ar

AZD2171 BQ Indole

N

N

O

RO

O

Ar

N

AZD2171 Crude

H2 / Pd

NMP K2CO3

N

N

O

RO

OH

Ar

AZD2171 Indolphenol

NH

+Cl

R

AZD2171 Chloropyrrolidine salt

Pyrrolidine

RH

Br Cl MTBEN


NH

+Cl

R


Pyrrolidine

RH

Br ClN

20 g 200 g

Reaction scaled-up

Heat:

17°C exotherm observed

L

Volume L3

Surface Area L2

∞

∞

NH

+Cl

R


Pyrrolidine

RH

Br ClN


AZD2171 Reaction Scheme


N Cl

N

N

O

RO

BnO

Ar

AZD2171 BQ Indole

N

N

O

RO

O

Ar

N

AZD2171 Crude

H2 / Pd

NMP K2CO3

N

N

O

RO

OH

Ar

AZD2171 Indolphenol

NH

+Cl

R


Pyrrolidine

RH

Br Cl MTBEN

AZD2171 Crude Work-up


N Cl

N

N

O

RO

O

Ar

N

AZD2171 Crude

K2CO3

N

N

O

RO

OH

Ar

AZD2171 Indolphenol

Anti-solvents:

Different volumes of water

Water / Methanol

Water / Acetonitrile

AZD2171 Crude Work-up

1:1 Water / Methanol Anti-solvent

Liquors

Product

Conclusions


N Cl

N

N

O

RO

BnO

Ar

AZD2171 BQ Indole

N

N

O

RO

O

Ar

N

AZD2171 Crude

H2 / Pd

NMP K2CO3

N

N

O

RO

OH

Ar

AZD2171 Indolphenol

NH

+Cl

R

AZD2171 Chloropyrrolidine

salt

Pyrrolidine

RH

Br Cl MTBEN

Acknowledgements

Mike Senior

Matt Evans

Martin Jones

Challenges in Scale-Up: Developing a process for the large scale manufacture of a pharmaceutical...

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