process intensification in the manufacturing of ...process intensification in the manufacturing of...

Ulrich Onken

IPL Functional Interfaces Workshop

Brugg, 23 September 2015

Process intensification in the manufacturing of pharmaceutical intermediates

Overview

Process Intensification

Definition

Metrics for process intensity

Factors that trigger process intensification

Three examples from industrial practise

Summary

2 | IPL Functional Interfaces Workshop | Ulrich Onken | 23 September 2015 | Process Intensification in Pharma | Business

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Process Intensification: Definition

No unique, generally accepted definition

Ullmann’s Encyclopedia of Industrial Chemistry (2011)

• Holistic view of the process

• Significant, “drastic” process improvement rather than just process optimization

• Equipment elements:

- Reactors

- Work-up equipment

• “Method” elements:

- Combination of unit operations

- Continuous vs. batch operation


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Process Intensity Metrics

No generally accepted metrics for process intensity

• Use of raw materials, utilities, energy (quantities)

• Utilization of equipment (volume, time)

Metrics in pharmaceutical industry

• Material consumption: Process Mass Intensity (PMI) PMI = Quantity of all input materials [kg] / Product quantity [kg]

• Equipment utilization: Space-time yield

- Scientific literature: mol product / (reactor volume * time) in mol / (m3 h) or in 1 / h

- Novartis: Product output per main equipment volume and day [kg / (m3 * days)]


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Metrics for materials

Mass allocation of a benchmark Pharma process ACS GCIPR 2011

Solvents

Water

Reactants

Others

5% 7%

32% 56%


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APIs obtained in a multi-step

chemical synthesis

Solvents to facilitate

chemical transformations

Solvents needed to purify intermediates

(crystallization, liquid-liquid-extraction,

chromatography)

Metrics for materials

Process Mass Intensity (PMI) at Novartis

• PMI is tracked for campaigns in chemical process R&D

Measure Calculation Purpose Remarks

Atom economy MW (product) / [MW

(starting materials)]

Very simple comparison

of synthesis routes

Impacts of yields,

reagents and solvents

not considered

E factor

(Environmental factor)

[kg waste] /

kg product

Waste quantities per

product quantity

Defined by R.A.

Sheldon (1992)

PMI

(Process mass intensity)

[kg input materials] /

kg product

Material use per product

quantity for late phases

Industry standard

PMI = E-factor + 1

R factor

(Novartis)

[kg input materials

excl. water & solvents]

/ kg product

Material use per product

quantity for early phases

(route selection)

R factor = PMI without

process water and

solvents


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Factors that trigger process intensification

Demand-driven process intensification

• Chemical manufacturing of pharmaceutical intermediates in multi-purpose equipment with limited capacity

• Actual demand may exceed previous predictions

• Duplication of equipment may be impractical

Cost-driven process intensification

• Continuous pressure on manufacturing costs

• Contributions of materials (PMI) and of processing costs (space-time yield)

• In particular relevant for the manufacture of high-volume products

Cost-benefit evaluation if process intensification requires investment


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Examples for process intensification

Potentials for intensification in pharmaceutical manufacturing

• Synthetic route: Efficient, fast transformations; make use of shortcuts

• Processes: Adapt concepts from other industries (e.g. continuous mode)

• Equipment: Novel reactors or work-up equipment; use of process analytical devices


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Example Approach Process change Equipment

change

Benefit

Overcome acetonitrile

shortage

Solvent recovery with

azeotrope split

Batch continuous

Recycle of azeotrope

(Standard batch to

conti columns)

Yield

Throughput

Scale-up of reaction

sequence

Series of conti

reactors at optimal

residence time

Semibatch

continuous,

2 coupled reactors

(microstructured

reactors)

Yield

Scaling up the drying of

a sensitive intermediate

Monitoring of residual

solvent in dryer

Skip sampling NIR probe Throughput,

robustness

Example 1 Continuous process

Acetonitrile as chemical process solvent

• Polar aprotic solvent useful in chemical synthesis

• Low viscosity, high dipole moment, moderate toxicity

• Manufactured as a by-product of acrylonitrile synthesis

Acetonitrile shortage in 2008-2009

• Caused by economic crisis (polyacrylonitrile demand from car industry) and by shut-down of acetonitrile production plants in China and Texas

• Severe impact on supply of acetonitrile as a chemical process solvent (availability, price)


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Example 1 Compensate acetonitrile shortage

Batch recovery of acetonitrile from waste solvent

• Waste solvent mixture: 91% acetonitrile, 8% ethanol, 1% water

• Acetonitrile recovery by batch rectification (limited capacity)

• Waste: Acetonitrile/ethanol/water azeotrope; distillation residue

• Only 70-80% of acetonitrile recovered (10% are lost as azeotrope)


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Acetonitrile (ACNL) / Ethanol (EtOH)

• Required specifications for acetonitrile: max. 0.1% EtOH, max. 0.1% water

• Azeotropic composition depends on pressure:

Technical development of a recovery process for acetonitrile

• Develop technical concept “in-silico”: Simulation model (ASPEN) for the main components

• Confirmation of technical feasibility by piloting trials: Elucidate the fate of trace impurities, use tests to confirm quality

T-xy for ACNL/ETOH

Liquid/Vapor Molefrac ACNL

Tem

pera

ture

C

0 0.2 0.4 0.6 0.8 1

55

56

57

58

59

60

61

62

T-x 0.5 bar

T-y 0.5 bar

T-xy for ACNL/ETOH

Liquid/Vapor Molefrac ACNL

Tem

pera

ture

C

0 0.2 0.4 0.6 0.8 1

110

115

120

125

T-x 3.0 bar

T-y 3.0 bar


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Continuous recovery process with 3 columns

• Continuous rectification process with 3 columns

• Pre-distillation of mixture to remove heavy impurities (not shown)

• Azeotrope split using two rectification columns at 0.5 and 3 bar

• Yield > 90%.

• Considerable investment: Attractive for high volumes only

FEED

FEED1B

TOP1

BOTTOM1

FEED2

TPO2

BOTTOM2

K1

W2K2

W3

B1

1

2

Heat and Material Balance Tab le

Stream ID 1 2 BOTTOM1 BOTTOM2 FEED FEED1B FEED2 TOP1 TPO2

Temperature C 1 05.6 1 05.6 1 20.4 60 .9 1 16.9 1 06.3 54 .2 1 05.6 53 .5

Pressure bar 3 .0 00 3 .0 00 3 .0 00 0 .5 00 3 .0 00 3 .0 00 0 .5 00 3 .0 00 0 .5 00

Vapor Frac < 0.00 1 < 0.00 1 0 .0 00 0 .0 00 0 .0 00 0 .0 00 0 .0 00 0 .0 00 0 .0 00

Mole Flow kmol/hr 0 .0 34 0 .3 09 2 .2 78 0 .1 10 2 .4 22 0 .1 99 0 .3 09 0 .3 43 0 .1 99

Mass Flow kg /h r 1 .5 20 13.77 6 93.53 0 4 .9 50 10 0.000 8 .8 26 13.77 6 15.29 6 8 .8 26

Volume Flo w l/min 0 .0 38 0 .3 47 2 .3 49 0 .1 13 2 .5 07 0 .2 21 0 .3 15 0 .3 83 0 .2 01

En th alp y MMkcal/hr -0 .0 01 -0 .0 12 0 .0 28 -0 .0 07 0 .0 19 -0 .0 05 -0 .0 13 -0 .0 13 -0 .0 05

Mass Flow kg /h r

ACNL 0 .4 57 4 .1 45 93.51 1 0 .0 32 94.00 0 4 .1 12 4 .1 45 4 .6 02 4 .1 12

ETOH 0 .9 61 8 .7 08 0 .0 01 4 .8 38 5 .8 00 3 .8 71 8 .7 08 9 .6 69 3 .8 71

W ATER 0 .0 21 0 .1 89 trace 0 .0 79 0 .1 00 0 .1 10 0 .1 89 0 .2 10 0 .1 10

TBME 0 .0 81 0 .7 33 0 .0 18 0 .0 01 0 .1 00 0 .7 32 0 .7 33 0 .8 14 0 .7 32

Mass Frac

ACNL 0 .3 01 0 .3 01 1 .0 00 0 .0 06 0 .9 40 0 .4 66 0 .3 01 0 .3 01 0 .4 66

ETOH 0 .6 32 0 .6 32 12 PPM 0 .9 77 0 .0 58 0 .4 39 0 .6 32 0 .6 32 0 .4 39

W ATER 0 .0 14 0 .0 14 9 PPB 0 .0 16 0 .0 01 0 .0 12 0 .0 14 0 .0 14 0 .0 12

TBME 0 .0 53 0 .0 53 19 3 PPM 21 1 PPM 0 .0 01 0 .0 83 0 .0 53 0 .0 53 0 .0 83

Mole Flow kmol/hr

ACNL 0 .0 11 0 .1 01 2 .2 78 0 .0 01 2 .2 90 0 .1 00 0 .1 01 0 .1 12 0 .1 00

ETOH 0 .0 21 0 .1 89 < 0.00 1 0 .1 05 0 .1 26 0 .0 84 0 .1 89 0 .2 10 0 .0 84

W ATER 0 .0 01 0 .0 11 trace 0 .0 04 0 .0 06 0 .0 06 0 .0 11 0 .0 12 0 .0 06

TBME 0 .0 01 0 .0 08 < 0.00 1 < 0.00 1 0 .0 01 0 .0 08 0 .0 08 0 .0 09 0 .0 08

Recovered ACNL

0.5 bar, 55 °C

3 bar, 110 °C

Ethanol/water (waste)Ethanol/T BME/water (waste)


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Example 2 Scale-up of reaction sequence

Synthesis of Oxcarbazepine (Trileptal ) • Chemical route via a dianion intermediate

Reference:

P. Fuenfschilling, W. Zaugg, U. Beutler, D. Kaufmann, O. Lohse, J.-P. Mutz, U. Onken, J.-L. Reber, D. Shenton, Organic Process Research & Development (2005), 9(3), 272-277

Technical challenges

• Two strongly exothermic reactions

• Selectivity favours low temperatures (-30 °C) and short residence times


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NO

NH

OO

Na+

N

OO

Li+

Na+

N

OOH

O O

O O

Cl

N

O NH2

O

11

NaOH

12

5

n-butyllithium

2. HCl / water

Oxcarbazepine


Traditional technical concept: 2 semi-batch additions

• Add n-butyllithium into solution of 11 to produce 12

• Add methyl chloroformate reagent to solution of 12

• Quench into HCl / water

• Yield 78-80%, due to side reactions of 12

Considerations for scale-up

• Control of low internal temperature for two consecutive reactions

• Fast transformation to 5 desirable, since intermediate 12 is quite unstable


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N H

OO

N a+

N

OO

L i+

N a+

N

OOH

O O

O O

C l

1 1 1 2

n - b u t y l l i t h i u m

- 2 1 5 k J / m o l

2 . H C l / w a t e r

- 2 2 6 k J / m o l

5


Innovative technical concept: Continuous process

• Tested in 2 coupled continuous stirred tank reactors at 50 ml scale

• 90-95% yield under optimised conditions

• Optimal residence time for second reaction: 4 min (based on kinetic rate constants for carbamoylation reaction and degradation reaction of the dianion intermediate 12)

• Scale-up options: External cooling (up to 100L) or microstructured reactors

• Microreactors not feasible (blocking of channels by precipitated Li salts)


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Reactor 1

50 mL

- 30 °C

Reactor 2

50 mL

- 40 °C Quench reactor

1 L

5 °C

BuLi / cyclohexane 11 / THF

methyl chloroformate / THF

Reaction

volume h v

Heat removal

capacity

Heat duty

@4min

Feasible

addition time

L kW/(m3 K) kW kW min

0.05 20.5 0.04 0.04 4

100 4.5 6 92 59

4000 0.7 29 915 126

Example 3 Drying of a sensitive intermediate

Drying of pharmaceutical intermediates

• Manufacture in multi-step chemical synthesis

• Crystallization and isolation of intermediates: Need to remove the solvent, usually by vacuum drying

• Scale-up of drying is non-trivial for sensitive pharmaceutical intermediates

Drying

• Small-scale drying (0.1-1 kg): Large-scale drying (10-1000 kg):

Tray dryer Dynamic dryer (paddle, double-cone)

Static operation Dynamic operation

Heat transfer straightforward Heat transfer requires agitation

< 24 hours Up to 3 days


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Traditional drying process in a paddle dryer

• Initial state: 50% wet filter cake (mixture of 2 solvents)

• End of drying condition: < 0.2% level for each solvent

• Drying strategy: Step-wise increase of jacket temperature and agitation with decreasing residual solvent content (sampling, headspace GC)


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Controlled drying without sampling

• Near infra-red spectroscopy (NIR) models for both solvents (Process Analytical Technologies, PAT)

• Levels of solvent 1 and 2 are monitored

• Changes of temperature / agitation based on measured solvent levels

• Drying time: 36 24 hours (Productivity x 1.5)


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\\PHGBGR-SP327440\B150_D461MU10/OUT.CV

3.0012

rpm

\\PHGBGR-SP327440\B150_D461PT10/OUT.CV

-3.4723

mbara


1.9373

mbara


0.86703

mbara

\\PHGBGR-SP327440\B150_D461QT10/OUT.CV

0.48193

%

\\PHGBGR-SP327440\B150_D461QT11/OUT.CV

9.9589E-02

%

Agitator Pressure Dryer Pressure Fine Pressure Fine NIR Ethyle Acetate NIR Cyclohexane

18:00 16:00 14:00 12:00 10:00 6:00 4:00 2:00 0:00 22:00 20:00

23/08/2015 19:28:13.2D461

0

0.5

1

1.5

2

2.5

3

3.5

-200

1200

0

600

-200

1200

0

30

0

2.5

22/08/2015 23:06:00

6.7538E-02

-13.070

2.7244

-2.2514

26.178

2.1823

23/08/2015 09:39:44.51801

0.20547

-7.6200

1.8777

5.1183E-02

10.805

0.4591

23/08/2015 13:24:00

1.2028

-5.5822

1.8227

-3.1592

4.2819

0.23227

23/08/2015 15:39:00

3.0057

-5.1028

1.4324

-3.3749

1.7434

0.12796

Level of solvent 1

Level of solvent 2

Summary

Metrics for process intensity

• Consumption of materials: PMI [kg/kg]

• Equipment utilization: Space-time-yield [kg/(m3 h)]

Factors that typically trigger process intensification in industry

• Demand increase

• Pressure on manufacturing costs

Typical strategies for process intensification in Pharma

• Simplification, shortcuts

• Adapt technical concepts from other industries

• Apply innovative technology if adequate and if justified by economics


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Acknowledgements

Contributors

Ulrich Beutler

Jens Burgbacher

Christian Fleury

Fabrice Gallou

Lukas Padeste

Glenn Thomson

Jacques Wiss


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