15.1.2013, Nairobi, 1

Semi-synthetic artemisinin project progress report

Dirk Pohlmann

project management MPIKG and CEO ArtemiFlow GmbH

15.1.2013, Nairobi, 2

SINGLET OXYGEN GENERATION

Photochemical generation via photosensitizers

green reagent, high atom economy

S0

S1

T1

photosensitizer

3O2

1O2

oxygen

hn 1260 nm

http://spie.org/x16290.xml l=660 nm l=560 nm

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SCALE-UP OF PHOTOCHEMICAL REACTIONS

Light intensity diminishes rapidly with path depth

e = 50000 M-1 cm-1

𝐴 = 𝜀 ∙ 𝑐 ∙ 𝑑

www.uv-consulting.de/deutsch/produkte/produktuebersicht.html

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SCALE-UP OF PHOTOCHEMICAL REACTIONS

Decreasing path length: high irradiation intensity

Continuous removal of product: prevention of side reactions

Batch Falling film Channel

L A

M P

l

I/I0

L A

M P

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BENEFITS OF FLOW CHEMISTRY

Small tubing: high irradiation intensity

Excellent control over reaction parameters (time, temperature,

mixing, pressure etc.)

High surface / volume ratio – control exothermic reactions

Lower operating volumes – safety and reagent consumption

In-line analysis

Ready scale-up by number-up

Easy automation

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BIPHASIC REACTIONS

High gas-liquid interfacial area: enhanced rate of mass transfer

Extended pressure increases oxygen solubility

Gases: • Hydrogen • Fluorine • Carbon dioxide • Carbon monoxide • Singlet oxygen • Triplet oxygen • Ozone

www.imm-mainz.de

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BIPHASIC REACTIONS

Flow pattern change with gas/liquid flow rate:

Specific interfacial area in batch : 100 m2m-3 to 2000 m2m-3

Plug flow

Slug flow Liquid phase Gas phase

Thin film of liquid Annular flow

Specific interfacial area

(a)

18700 m2m-3

23500 m2m-3

3500 m2m-3

Ehrfeld, W.; Hessel, V.; Löwe, H. Microreactors: New Technology for Modern Chemistry, Wiley-VCH, 2000

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BIPHASIC REACTIONS

Chen, L., Tian, Y. S., Karayiannis, T. G. Int. J. Heat Mass Transfer, 2006, 49, 4220-4230

increasing gas flow rate 1.1 mm tube

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SEMI-SYNTHESIS

Singlet oxygen reacts with dihydroartemisinic acid, further reactions

mediated by acid

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INITIAL REACTOR

2 Pumps required: delivery of substrate solution, addition of acid

450 W medium pressure mercury lamp for photochemical step

Artemisinin yield: 40%, productivity: 200 g/d

High energy consumption and low yield Lèvesque, F., Seeberger, P.H. Angew. Chem. Int. Ed., 2012, 51, 1706 –1709

Lèvesque, F., Seeberger, P.H. Org. Lett., 2011, 13, 5008 –5011

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INITIAL REACTOR

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ENERGY REQUIREMENTS

Mercury lamp 450 W + chiller: 1700 W

200 g/d artemisinin: 200 kWh per kg artemisinin!

improvement in energy efficiency required

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NEW GENERATION PHOTOREACTOR

Improved setup:

LED lamp matches spectrum of photosensitizer

High energy efficiency

Less energy required for cooling

small footprint

1to per year for industry version

Artemisinin yield up to 65%

Larger reactor possible

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NEW GENERATION PHOTOREACTOR

Photoreactor:

cheap FEP-tubing wrapped around glass/PC plate

7.5 mL volume

high transmission of light

chemically resistant

can be immersed in cooling liquid for thermosetting

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CONTINUOUS ONE-POT PROCESS

Simple setup, small footprint of system

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YIELD

Yield of 65% can be achieved, simplifying purification

NMR of crude: • mainly artemisinin • main side products

known:

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PURIFICATION

Recrystallization yields artemisinin of high purity

No impurities detected by NMR and HPLC with MS/ELSD detector

Minor impurity peaks with UV detection (210 nm)

HPLC - UV detection NMR

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CONTINUOUS PURIFICATION

Continuous purification benefical

single continuous process yielding pure product

Evaluation of two processes:

continuous crystallization

Simulated Moving Bed (SMB) chromatography

http://www.nitechsolutions.co.uk/

Juza, M., Mazzotti, M., Morbidelli, M., Trends Biotechnol. 2000, 18, 108–118

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STARTING MATERIAL

Dihydroartemisinic acid present in plant

Unused „waste“ compound from extraction process

Mother liquor remaining from artemisinin extraction: ~ 8% DHAA (results provided by AnalytiCon) Basic extract: 42% DHAA, can be converted to artemisinin without purification

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COMPANY

ArtemiFlow GmbH, founded in November 2012 Personnel: 3 Prof. Peter Seeberger CSO: Dr. Daniel Kopetzki (Junior Scientist of the Year, Brandenburg 2012) CEO: Dirk Pohlmann Milestones for ArtemiFlow GmbH: funding defined business plan written (waiting for more lab data) clients identified Development company for industry prototype indentified cost estimates known

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DHAA

Artesunate Artemether

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PLANTS

Which plants do we need?

First answers:

no turbos?

young plants up to 3 months

fresh dried

cheap seeds? Or new seeds=combined ART and DHAA content?

max combination of Artimisinin +DHAA after 3 months

3 harvests per year = breaking the pork cycle