Sugar-based productsfor

technical & materialapplications?

November 2017

Patent StudyContinuous Chromatography

Trends in Continuous Chromatography in IP

▪A Patent Intelligence study

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BATCH VERSUS CONTINUOUS

INTRODUCTION CONTINUOUS CHROMATOGRAPHY

Separation in time Separation in space

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CONTINUOUS CHROMATOGRAPHY VIA SIMULATED MOVING BED

INTRODUCTION CONTINUOUS CHROMATOGRAPHY

The Tortoise and the Hare revisited

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CONTINUOUS CHROMATOGRAPHY VIA SIMULATED MOVING BED

INTRODUCTION CONTINUOUS CHROMATOGRAPHY 5

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LABSCALE VERSUS INDUSTRIAL CHROMATOGRAPHY

INTRODUCTION CONTINUOUS CHROMATOGRAPHY 6

Labscale chromatography equipment

Industrial chromatography column

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WHY CONTINUOUS CHROMATOGRAPHY?

INTRODUCTION CONTINUOUS CHROMATOGRAPHY 7

➢ When chromatography is required, eg for chiral chromatography, affinity chromatography, size-exclusion chromatography, ion-exchange chromatography

➢ When crystallization is not possible or to much product is wasted in mother liquor

➢ When acid or base purification involves temporary neutralization

➢ When distillation is not possible or costly:

▪ when boiling points are very close e.g. T10°C or

▪ in case of azeotropes

▪ with heat-sensitive compounds

▪ when volatility is very low (obviously) or so high that cryogenic temperature are required

WHY NOT ?❖ Continuous chromatography is essentially capable of binary

separation

❖ Higher complexity and capital cost compared to normal chromatography and other separation processes

❖ Not readily suited for solvent gradients

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PANORAMA OF CONTINUOUS CHROMATOGRAPHY APPLICATIONS

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PATENT SEARCH STRATEGY

PATENT POOL BUILDING CONTINUOUS CHROMATOGRAPHY 9

1,382 patent families

If CN patents not excluded = 1713 patent families

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NORMALIZED PATENT ACTIVITY

PATENT ANALYSIS CONTINUOUS CHROMATOGRAPHY 10

Continuous chromatography, normalized at 1 in 1995

Global patent database, normalized at 1 in 1995

Conclusion: since early 2000’s, the patent activity in continuous chromatography is significantly more dynamic than the global patent database, especially when we exclude chinese patents, although in saw tooth patterns

Excluding Chinese Patents Including Chinese Patents

Global patent database, normalized at 1 in 1995

Continuous chromatography, normalized at 1 in 1995

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COUNTRY ANALYSIS

PATENT ANALYSIS CONTINUOUS CHROMATOGRAPHY 11

Global

European countries only

Conclusion:USA, France, Germany, Japanand South Korea are the top5global players in continuouschromatography IP

Conclusion:France, Germany, Netherlands,Switzerland and UK are thetop5 European players incontinuous chromatography IP

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TOP 20 COMPANIES IN CONTINUOUS CHROMATOGRAPHY

PATENT ANALYSIS CONTINUOUS CHROMATOGRAPHY 12

Top five companies

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OCCURENCE OF SUGAR KEYWORDS OVERTIME

PATENT ANALYSIS CONTINUOUS CHROMATOGRAPHY 13

Sugar keyword 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Total

sugar 1 2 5 2 10 2 4 3 6 8 8 2 1 5 5 2 16 4 4 90

glucose 2 1 3 1 2 2 6 4 3 1 2 7 4 6 44

polysaccharide 1 3 3 3 1 5 2 2 6 1 1 1 1 3 1 34

sucrose 1 2 1 4 1 2 2 5 2 2 4 1 2 29

monosaccharide 4 1 3 4 3 4 2 21

oligosaccharide 2 4 3 3 3 1 4 20

fructose 1 1 2 1 2 1 1 1 2 1 3 4 20

mannose 2 1 1 3 2 5 2 1 17

galactose 3 1 3 1 4 1 13

xylose 1 3 1 1 3 1 2 12

polyol 1 1 2 1 5 1 1 12

glycol 1 1 2 1 2 1 1 9

sorbitol 2 2 1 1 1 1 1 9

cyclodextrin 1 1 1 5 8

mannitol 1 2 1 1 1 1 7

carbohydrate 1 1 2 1 1 1 7

lactose 1 2 1 1 1 6

furfural 1 4 5

maltose 2 1 1 1 5

xylitol 1 2 1 1 5

Conclusion:Glucose, sucrose fructose, mannose and galactose are the top5 sugar cited in patent title, abstract or claims.

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PATENT VALUE ANALYSIS

PATENT ANALYSIS CONTINUOUS CHROMATOGRAPHY 14

Figure based on analysis of 1382 patents

Invention of SMB continuous chromatography, by D. Broughton of UOP, for large-scale separation of n-paraffins

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THROUGH-CITATION CODE DRIFT

PATENT ANALYSIS CONTINUOUS CHROMATOGRAPHY 15

UOP patentParaffin separation

after crude oil distillation

1957

Separation of oil after cracking

1962

Separation of xylene isomers

19621 patent

493 patents 3470 patents

1st generation 2nd generationPatent zero

Fructose/glucose separation

1978

(Belgian) Beer brewing

PRINCIPLE: TRACKING EVOLUTION THROUGH CITATIONS & PATENT CODE CHANGE

Chiral pharmaceutical ingredient

Peptide separation1997

Separation of bread-making enzymes

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CODE DRIFT AFTER 1st GENERATION: FOCUSING ON APPLICATIONS ONLY

PATENT ANALYSIS CONTINUOUS CHROMATOGRAPHY

Code 1950's 1960's 1970's 1980's 1990's 2000's 2010's Total Code description Initial applicationC08G 1 1 Non-polyolefin polymers Purification of PEG/PPG block copolymers

C25B 1 1 Electrolytic or electrophoretic processes for the production of compounds or non- metals Purification of vanillin from lignin electro-oxidation

A23L 3 1 4 Other foods, foodstuffs, or non-alcoholic beverages Preparation of sugar alcohols and omega-3/omega-6 fatsA61Q 3 3 Specific use of cosmetics preparations Purification of fatty cosmetic ingredientsA61K 1 15 7 23 Preparations for medical, dental purposes Purification of active pharmaceutical ingredientsC07K 1 2 3 Peptides Purification of peptidesC08B 2 2 Polysaccharides Polyglucose preparation

D21C 1 1 2 Production of cellulose by removing non-cellulose substances Fractionation and valorization of Kraft cooking liquor

C11D 3 4 Detergent compositions Purification of surfactants

A23D 1 3 4 Edible oils or fats, e.g. margarines, shortenings, cooking oils Purification of edible fats, eg removing cholesterol

C02F 8 6 14 Treatment of water, waste water, sewage, or sludge Recovery of acids from hydrometallurgy processC07D 1 4 19 16 40 Heterocyclic compounds Separation of heterocyclic compoundsC07J 1 1 Steroids SteroidsC10L 2 1 1 4 Fuels not otherwise provided for Liquid fuelC07H 3 5 2 1 11 Sugar derivatives Sugar derivativesC09F 1 3 4 Natural resins Rosin resin purificationC11B 3 6 5 6 13 33 Producing or refining fatty substances Purification of fatsC11C 2 9 3 3 7 24 Fatty acids obtained from fats, oils or waxes Purification of fatsC12P 1 2 6 3 12 Fermentation or enzyme-using processes Separation of fermentation broth

C13B 2 10 10 8 1 31 Production of sucrose Separation of fructose from corn syrup or invert sugar

C13K 12 22 4 2 3 43 Saccharides, other than sucrose Separation of fructose from corn syrup or invert sugar

C07C 3 5 59 43 20 20 150 Acyclic or carbocyclic compounds Separation of xylene isomersC10G 2 2 5 4 9 1 23 Cracking hydrocarbon oils Separation of cracked petroleum oilB01D 2 4 7 49 57 43 21 183 Separation Separation of paraffins

NUMBER OF PATENT PER DECADE THAT CITE THE PIONEER UOP PATENT

16

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CODE DRIFT AFTER 2nd GENERATION: FOCUSING ON APPLICATIONS ONLY

PATENT ANALYSIS CONTINUOUS CHROMATOGRAPHY

Code 1950's 1960's 1970's 1980's 1990's 2000's 2010's Total Code description Initial application

A61K 25 147 113 285Preparations for medical, dental purposes Purification of active pharmaceutical ingredients

A61P 10 96 73 179 Medicinal preparation Medicinal preparation

C07F 5 10 9 24 Organic compounds with heteroatoms Organic compounds with heteroatoms

A61Q 3 12 8 23 Specific use of cosmetics preparations Purification of cosmetic ingredients

A21D 6 17 23Treatment or preservation of flour or dough Separation of enzymes for bakery application

C07D 4 34 121 119 278 Heterocyclic compounds Separation of heterocyclic compounds

A23L 9 38 59 29 135Other foods, foodstuffs, or non-alcoholic beverages

Preparation of sugar alcohols and omega-3/omega-6 fats

C12N 2 20 98 24 144 Microbiotechnologies Microbiotechnologies

A23D 7 27 39 10 83Edible oils or fats, e.g. margarines, shortenings, cooking oils Purification of edible fats

C07K 1 11 30 7 49 Peptides Purification of peptidesC08B 3 11 11 4 29 Polysaccharides Polyglucose preparationC08G 2 8 6 4 20 Non-polyolefin polymers Purification of PEG/PPG block copolymersA23G 1 12 20 1 34 Cocoa products, confectionnary Cocoa products, confectionnary

C11B 7 30 43 41 52 173 Producing or refining fatty substances Purification of fats

C12P 1 10 64 193 41 309Fermentation or enzyme-using processes Separation of fermentation broth

C11C 6 27 31 45 24 133Fatty acids obtained from fats, oils or waxes Purification of fats

C13K 14 63 33 39 18 167 Saccharides, other than sucroseSeparation of fructose from high fructose corn syrup or invert sugar

C13B 3 26 51 71 14 165 Production of sucroseSeparation of fructose from high fructose corn syrup or invert sugar

C07H 3 24 17 44 13 101 Sugar derivatives Sugar derivatives

C02F 3 22 8 46 8 87Treatment of water, waste water, sewage, or sludge Recovery of acids from hydrometallurgy process

C10L 1 2 3 37 6 49 Fuels not otherwise provided for Liquid fuelC11D 1 16 88 109 214 Detergent compositions Purification of surfactantsC07C 6 21 139 249 309 168 892 Acyclic or carbocyclic compounds Separation of xylene isomersC10G 8 5 26 44 54 17 154 Cracking hydrocarbon oils Separation of cracked petroleum oilB01D 2 12 19 154 361 451 152 1151 Separation Separation of paraffins

: New applications that have emerged at the 2nd generation

Number of patent per decade that cite the pioneer UOP patent

17

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NEW CODE CLUSTERS: NEW APPLICATIONS FOR CONTINUOUS CHROMATOGRAPHY SINCE 2011

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CodeNumber of patents

Code Description Continuous Chromatography application

C10L3/101 8 Removal of contaminants from gaseous fuels, eg Liquefied Petroleum Gas (LPG) or Natural Gas Purification of gaseous fuel, eg LPG of natural gas

C10L2290/542 6 Adsorption of impurities during preparation or upgrading of a fuel Purification of fuels

B01D53/96 4 Regeneration, reactivation or recycling of reactants from waste gases Recovering reactants from waste gases

C07C55/10 4 Succinic acid Succinic acid separation/purification

C12M47/10 4 Separation or concentration of fermentation products Separation of fermentation products

C12P7/46 4 Dicarboxylic acids having four or less carbon atoms, e.g. fumaric acid, maleic acid C2-C4 dicarboxylic acids, eg fumaric acid, maleic acid

C12P2203/00 3 Fermentation products obtained from optionally pretreated or hydrolyzed cellulosic or lignocellulosic material as the carbon source Fermentation of cellulosic-based biomass (2nd generation biofuel)

B01D53/40 2 Removing acidic components from waste gases Removing acidic components from waste gases

C07C39/07 2 Alkylated phenols containing only methyl groups, e.g. cresols, xylenols Alkylated phenols containing only methyl groups, e.g. cresols, xylenols

C07C55/02 2 Dicarboxylic acids Dicarboxylic acids

C07C55/14 2 Adipic acid Adipic acid

C07C9/14 2 Aliphatic saturated hydrocarbons with 5-15 C Aliphatic saturated hydrocarbons with 5-15 C

C07C9/15 2 Aliphatic saturated straight-chain hydrocarbons with 5-15 C Aliphatic saturated straight-chain hydrocarbons with 5-15 C

C07G1/00 2 Lignin;Lignin derivatives Lignin;Lignin derivatives

C07K16/00 2 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies

C12P19/24 2 Production of saccharide by the action of an isomerase, e.g. fructose Production of saccharide by the action of an isomerase, e.g. fructose

A23C9/1465 1 Milk preparation by chromatographic separation of protein or lactose fraction Milk preparation by chromatographic separation of protein or lactose

A23J1/205 1 Obtaining protein compositions from whey, e.g. lactalbumin Obtaining protein compositions from whey, e.g. lactalbumin

A23J7/00 1 Phosphatide compositions for foodstuffs, e.g. lecithin Phosphatide compositions for foodstuffs, e.g. lecithin

A23K10/33 1 Molasses as animal feeding-stuffs Molasses as animal feeding-stuffs

A23L1/09 1 recovery of betaine from molasses (Containing carbohydrate syrups) recovery of betaine from molasses

A23L2/78 1 Clarifying of non-alcoholic beverages by ion-exchange Clarifying of non-alcoholic beverages by ion-exchange

A23L27/34 1 Artificial sweetening agents based on sugar alcohols (eg Xylitol) Artificial sweetening agents based on sugar alcohols (e.g. Xylitol)

A23L33/10 1 Modifying nutritive qualities of foods using additives Modifying nutritive qualities of foods using additives

A23L33/40 1 Infant formula (baby milk) Infant formula (baby milk)

A61K31/352 1 Drugs with oxygen-containing heterocycle condensed with carbocyclic rings, e.g. cannabinols, methantheline

Drugs with oxygen-containing heterocycle condensed with carbocyclic

rings, e.g. cannabinols, methantheline

A61K31/353 1 3,4-Dihydrobenzopyrans, e.g. chroman, catechin 3,4-Dihydrobenzopyrans, e.g. chroman, catechin

A61K31/36 1 Compounds containing methylenedioxyphenyl groups, e.g. sesamin Compounds containing methylenedioxyphenyl groups, e.g. sesamin

A61K31/702 1 Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages Oligosaccharides

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NEW CODE CLUSTERS: NEW APPLICATIONS FOR CONTINUOUS CHROMATOGRAPHY SINCE 2011

PATENT ANALYSIS CONTINUOUS CHROMATOGRAPHY 19

Food Industrial Microbiology Pharma Agro-Industry

Petroleum Industry Petrochemical Industry Chemical Process Industry

▪ Milk preparation by

chromatographic separation

of protein or lactose

▪ Infant formula (baby milk)

▪ Obtaining protein

compositions from whey,

e.g. lactalbumine

▪ Phosphatide compositions

for foodstuffs, e.g. lecithin

▪ Molasses as animal feeding-

stuffs

▪ Recovery of betaine from

molasses

▪ Clarifying of non-alcoholic

beverages by ion-exchange

▪ Artificial sweetening agents

based on sugar alcohols (eg

Xylitol)

▪ Modifying nutritive qualities

of foods using additives

▪ Dicarboxylic acids

▪ Succinic acid

separation/purification

▪ Adipic acid

▪ Separation of fermentation

products

▪ Production of saccharide by

the action of an isomerase,

e.g. fructose

▪ C2-C4 dicarboxylic acids,

e.g. fumaric acid, maleic

acid

▪ Drugs with oxygen-

containing heterocycle

condensed with carbocyclic

rings, e.g. cannabinols,

methantheline

▪ 3,4-Dihydrobenzopyrans,

e.g. chroman, catechin

▪ Compounds containing

methylenedioxyphenyl

groups, e.g. sesamin

▪ Oligosaccharides

▪ Immunoglobulins [IGs], e.g.

monoclonal or polyclonal

antibodies

▪ Lignin; Lignin derivatives

▪ Fermentation of cellulosic-

based biomass (2nd

generation biofuel)

▪ Purification of fuels

▪ Purification of gaseous fuel,

e.g. LPG of natural gas

▪ Aliphatic saturated

hydrocarbons with 5-15 C

▪ Aliphatic saturated straight-

chain hydrocarbons with 5-

15 C

▪ Removing acidic components

from waste gases

▪ Recovering reactants from

waste gases

▪ Alkylated phenols containing

only methyl groups, e.g.

cresols, xylenols

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CONTINUOUS CHROMATOGRAPHY FOR THE SUGAR INDUSTRYContinuous Chromatography is a key purification process for the industrial processing of sugar, both in food and material applications

CASE STUDIES CONTINUOUS CHROMATOGRAPHY 20

Overview of industrial sugar-based products from the previous CREAX study about sugar derivatives:

Fermentation of glucose into 1,3-Propanediol Fermentation of glucose

into PHAs

Itaconic acidLevulinic acid

Fermentation of sugar into levulinic acid and itaconic acid

Fermentation of glucose into 3-hydroxypropionic acid

C-glycoside biosynthesis through fermentation Hydrogenation followed by double dehydration

of hexitols for the synthesis of isosorbide

SOURCE:

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DESCRIPTION

A process that uses a reactive chromatography unit (RCU) to improvethe efficiency of equilibrium-limited reactions, such as a process forreacting glycol ether (GE) and carboxylic acid (CA) to form water andglycol ether ester (GEE). The process includes supplying GE and CA tothe RCU, where one of either the CA or the GE is in a stoichiometricdeficit relative to the other reactant.

Other possible equilibrium-limited chemical reactions that producewater as a reaction product are aldol condensations, esterificationreactions, anhydride formation, and amidation reactions.

DOW GLOBAL TECHNOLOGIES LLC, 2014, WO2014179709A2

REACTIVE CHROMATOGRAPHY – GLYCOL ETHER ESTER PRODUCTION

CHEMICAL REACTIONS CHEMICAL COMPOUNDS

▪ 1- methoxy-2-propanol + ethyl acetate

▪ Propylene glycol methyl ether acetate + ethanol

▪ acylation, transamidation, transamination, transesterification

CONTINUOUS CHROMATOGRAPHYCASE STUDIES

SOURCE:

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DESCRIPTION

Müller-Rochow Process is the most common technology for preparingorganosilicon compounds on an industrial scale. The major productsare typically dimethyldichlorosilane and methyltrichlorosilane, otherproducts include trimethylchlorosilane, methyldichlorosilane, anddimethylchlorosilane. Separation of the organohalosilanes is a vitalstep in the process. Typically, fractional distillation is used to separateorganohalosilanes. Due to the problematic close boiling points ofseveral of the products (e.g. dimethyldichlorosilane b.p. 70.1°C,methyltrichlorosilane b.p. 66.1°C), a large number of separation stagesand high reflux ratios are required. Dimethyldichlorosilane is typicallyused for the synthesis of silicone polymers.

Dow Corning, 2015, US2015141688A1

METHYLCHLOROSILANES SEPARATION FOR SILICONE AND SILICON

CHEMICAL REACTIONS

▪ Methylchloride, dimethyldichlorosilane, methyltrichlorosilan, trimethylchlorosilane etc...

CHEMICAL COMPOUNDS

CONTINUOUS CHROMATOGRAPHYCASE STUDIES

SOURCE:

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DESCRIPTION

An improved SMB process incorporating novel regeneration steps forthe separation of ethanol associated oxygenates such as butanediolfrom a dilute mixture of ethanol and associated oxygenates in water inthe presence of organic compounds derived from a biofermentationprocess. Applicant discovered that increasing the number of raffinatestreams alone or in combination with a hot regeneration zone withinthe SMB cycle can significantly reduce the capital and operating costsassociated with the incorporation of the SMB process in a complex forthe production of ethanol and butanediol from biofermentationeffluent.

OROCHEM Technologies, 2014, US8704016B2

▪ Fermentation ethanol + butanediol

PURIFICATION OF ETHANOL AND BUTANEDIOL

CHEMICAL REACTIONS

▪ Ethanol▪ Butanediol▪ Biofermentation

effluent

CHEMICAL COMPOUNDS

CONTINUOUS CHROMATOGRAPHYCASE STUDIES

SOURCE:

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DESCRIPTION

Cellulosic (bio)ethanol is produced by the fermentation of glucose(and other fermentable sugars) obtained though controled hydrolysisof cellulose. The chemical hydrolysis of cellulose generates by-products which are toxic for ferments. They have to be separatedeconomically. It is also preferable to recycle the acid or base usedduring hydrolyisis.The BlueFire Renewable company has licensed a patent from Arkenolabout a SMB process to separate fermentable sugars, highlyconcentrated sulfuric acid and by-products with high purity. BlueFireuses commercially available ion exchange resins.

BlueFire Renewables

Arkenol technology

Arkenol patent, 2000, US6054611A

▪ Hydrolysis of cellulosic substrates with highly concentrated H2SO4

CELLULOSIC ETHANOL PRODUCTION

CHEMICAL REACTIONS

▪ C5-C6 sugars, sulfuric acid and by-products (furfural, levulinic acid, acetic acid, formic acid etc...)

CHEMICAL COMPOUNDS

CONTINUOUS CHROMATOGRAPHYCASE STUDIES

SOURCE:

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DESCRIPTION

Centrifugal partition chromatography (CPC) is a specialchromatographic technique where both stationary and mobile phaseare liquid, and the stationary phase is immobilized by a strongcentrifugal force. CPC requires obviously a biphasic mixture ofsolvents, but no solid stationary phase.

This patent disclose the preparation of a cannabinoid extract fromhemp, designed for medicinal purposes. There are close to 400cannabinoids in cannabis. Tetrahydrocannabinol (THC) and cannabidiol(CBD) are the two that stand out the most. THC is the cannabinoid thatis responsible for giving a high or ‘stoned’ feeling. CBD, on the otherhand, is not psychoactive but is considered to have a wide scope ofpotential for medical applications.

2016, BIONORICA ETHICS GMBH, EP3061510A1

Cannabis info

▪ Tetrahydrocannabinol (THC), cannabidiol (CBD) and many others at low wt%

CPC PARTITION CHROMATOGRAPHY OF CANNABINOIDS

CHEMICAL COMPOUNDS

CONTINUOUS CHROMATOGRAPHYCASE STUDIES

▪ Stationary phase: heptane

▪ Mobile phase: acetonitrile

▪ Interestingly, aqueous two-phase

systems are also used in CPC

separation investigation

PHASES

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CONCLUSION

CONCLUSION CONTINUOUS CHROMATOGRAPHY

▪ Continuous Chromatography was born in the petrochemical industry, and

spread out to many domains, including fuel, gas, food, pharmacy, industrial

microbiology, chemical process industry and agro-industries.

▪ Continuous Chromatography is currently a key separation process for the

food and pharmaceutical industry.

▪ Great opportunity for Continuous Chromatography in the Agro-Industries,

e.g. sugar-derived products, and in the chemical process industry.

▪ Simulated Moving bed is the most common Continuous Chromatography

system, but other sytems like Centrifugation Partitioning Chromatography are

of interest.

“We want to draw your attention to the fact that we drafted the examples within this document with all applicable diligence and care but, given the nature of this complicated matter, it is impossible to guarantee the completeness and exactness of the provided information.”

JEF VANDENBERGHEManaging Partner

+ 32 496 94 51 43 – j@creax.com

Contact information

T + 32 56 23 94 94 - WALLE 113, 8500 KORTRIJK (BELGIUM)

MATHIEU MOTTRIEManaging Partner - CEO

+ 32 475 84 26 39 – m@creax.com

+32 479 96 88 83 – xs@creax.com

XAVIER SAMAIN

SYSTEMATIC INNOVATION

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