10 528 951 methods of purifying cannabin

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Flockhart et ai.(10) Pub. No.: US 2005/0266108 Al(43) Pub. Date: Dec. 1, 2005

(54) METHODS OF PURIFYING CANNABINOIDSFROM PLANT MATERIAL

(86) PCT No.: PCT/GB03/04078

(75) Inventors: Ian Flockhart, Hull (GB); GaryWilliam Wheatley, Salisbury (GB); SuDring, Hull (GB); Leslie Archer, Hull(GB)

(30) Foreign Application Priority DataSep. 23, 2002 (GB) 0222077.0

Publication ClassificationCorrespondence Address:WOLF GREENFIELD & SACKS, PCFEDERAL RESERVE PLAZA600 ATLANTIC AVENUEBOSTON, MA 02210-2211 (US)

(51) Int. CI? C07D 311/80; A61K 35/78(52) U.S. CI. 424/774; 549/390

(57) ABSTRACT

(21) Appl. No.:(22) PCT Filed:

10/528,951The invention relates to methods of preparing cannabinoidsin substantially pure form starting from plant material. Alsodescribed are substantially pure preparations of variouscannabinoids and cannabinoid acids, and also extractsenriched in cannabinoids and cannabinoid acids.

(73) Assignee: Gw Pharma Limited, Salisbury (GB)

Sep.23,2003


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Patent Application Publication Dec. 1, 2005 Sheet 1 of 21

Figure 1:US 2005/0266108Al

TLC profile of G1 chemovar starting materialand purified THCA

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TLC profile of G5 chemovar starting materialand purified CBOA

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Figure 10: TLC profiles of BOS starting material and purlfled d9 THeV

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Figure 13:US 2005/0266108Al

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Patent Application Publication Dec. 1, 2005 Sheet 18 of 21 US 2005/0266108AlFigure 18: TLC profiles of GSOchemovar startfng material

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99% 1 ' l 9 THC by area nor-malization.[0375] Chromatographic purity superior to commercial lyavailable 1 ' l 9 THC Sigma standard[0376] CBD non detected i.e. 99% by area normaliza-tion.[0394] CBD non detected i.e.


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US 2005/0266108 A1

[0402] Pass a solut ion of the result ing concentrated extractthrough a column packed with Sephadex LH20 and elutingwith 2:1 chloroform/dichloromethane.

[0403] Collect CBG rich fractions and remove solvent byrotary evaporation.

[0404] Re-dissolve crude CBG enriched fractions IIImethanol and remove insoluble residue by fil tration.

[0405] Remove solvent from filtrate by rotary evaporation.

[0406] Re-dissolve crude CBG enriched fractions in pen-tane and remove insoluble residue by fi ltration.

[0407] Remove solvent from filtrate by rotary evaporation.

[0408] i) Highly enriched CBG extract or ii) CBG solution

[0409] Flash chromatography[0410] For i) above:[0411] Yield:[0412] 100 g of G41 chemovar yields approx 300 mg ofCBG enriched fraction.[0413] Characteristics:[0414] Orange/yellow semi-solid.[0415] Identification by GC retention index relative toTHC & CBD standards [ref: Brenneisen, R. & EI Sohly, M.A., "Chromatographic & spectroscopic Profiles of Cannabisof Different Origins: Part I," Journal of Forensic Sciences,JFSCA, vol. 33, No.6, pp. 1385-1404, 1988].[0416] Chromatographic purity >92% by area normaliza-tion with reference to FIG. 14.[0417] CBD non-detected i.e.


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US 2005/0266108 A1

[0446] Chromatographic purity >85% by area normaliza-tion with reference to FIG. 19.[0447] CBD 1.0%[0448] THC 0.3%[0449] CBN 0.1%[0450] For ii) above:[0451] Characteristics:[0452] Clear colourless solution[0453] Chromatographic purity=99.6% CBC by area nor-malisation with reference to FIG. 20[0454] CBD 0.12%[0455] CBN 0.09%1.A method of obtaining a substantially pure cannabinoidor cannabinoid acid or a product enriched in a given can-

nabinoid or cannabinoid acid from a plant material, com-prising:i) obtaining an extract containing a cannabinoid or can-nabinoid acid from a plant material;ii) subject ing the extract of step (i) to a chromatographicstep to produce a partia lly purified extract;iii) dissolving the partially purified extract in a firstsolvent, removing any insoluble material therefrom andremoving the solvent; and

iv) dissolving the product obtained in step iii) in a secondsolvent , removing any insoluble material therefrom,and removing the solvent to obtain the substantiallypure cannabinoid or cannabinoid acid or the productenriched in a given cannabinoid or cannabinoid acid,wherein the first and second solvents are different , andwherein one of the first or second solvents is a solventwhich is substantially more polar than the cannabinoidlcannabinoid acid which it is desired to purify, and theother solvent is a solvent which is substantially lesspolar than the cannabinoid/cannabinoid acid which it isdesired to purify.2. A method according to claim 1 wherein one of the

solvents is an alcohol.3. A method according to claim 2 wherein one of the

solvents is methanol.4. A method according to claim 1 wherein one of thesolvents is a straight or branched chain C5-C12 alkane.5. A method according to claim 4 wherein one of thesolvents is pentane.6. A method according to claim 5 wherein one of thesolvents is pentane and the other solvent is methanol.7. A method according to claim 1 wherein the extract

containing a cannabinoid or cannabinoid acid obtained instep (i) is prepared by a process comprising solvent extrac-tion of the plant material .8. A method according to claim 7 wherein step (i) com-prises dissolving the plant material in an extraction solvent,

removing any insoluble material from the resultant solutionand removing the solvent to form an extract containing acannabinoid or cannabinoid acid.9. A method according to claim 7 wherein the extractionsolvent is a non-polar solvent, ethanol, methanol or carbon

dioxide.

Dec. 1,200517

10. A method according to claim 9 wherein the non-polarsolvent comprises a straight or branched chain C5-C12alkane.11. A method according to claim 10wherein the non-polar

solvent is hexane.12. A method according to claim 7, wherein the extractionsolvent is acidified.13. A method according to claim 12 wherein the extrac-

tion solvent is an acidified non-polar solvent.14. A method according to claim 13 wherein the extrac-tion solvent is an acidified straight or branched chainC5-C12 alkane.15. A method according to claim 14 wherein the extrac-tion solvent is 0.1% v/v acetic acid in hexane.16. A method according to claim 1, which includes a

further step, prior to step (i), of decarboxylating the plantmaterial.17. A method according to claim 1 wherein the extract

containing a cannabinoid or cannabinoid acid obtained instep (i) comprises a botanical drug substance derived fromthe plant material.18. A method according to claim 17 wherein the botanicaldrug substance is prepared by a process comprising solvent

extraction of the plant material.19. A method according to claim 18 wherein the botanicaldrug substance is prepared by extraction with carbon diox-

ide.20. A method according to claim 19 wherein the botanical

drug substance is prepared by a process comprising extrac-tion with carbon dioxide (C02), followed by a secondaryextraction step to remove a proportion of the non-targetmaterials.21. A method according to claim 20 wherein the second-

ary extraction step is ethanolic precipitation.22. A method according to claim 20 wherein the processfor preparing the botanical drug substance further includes acharcoal clean-up step.23. A method according to claim 22 wherein the botanical

drug substance is prepared by a process comprising:i) optional decarboxylation of the plant material,i i) extract ion with liquid CO2, to produce a crude botani-cal drug substance,iii) precipitation with C1-C5 alcohol to reduce the pro-portion of non-target materials,iv) removal of the precipitate,v) treatment with activated charcoal , andvi) evaporation to remove C1-C5 alcohol and water,thereby producing a final botanical drug substance.

24. A method according to claim 1 wherein the chromato-graphic step comprises column chromatography.25. A method according to claim 1 wherein the chromato-

graphic step is based on molecular sizing and polarity.26. A method according to claim 25 wherein the chro-matographic step is carried out using a Sephadex LH-20

matrix.27. A method according to claim 26 wherein the chro-matographic step is carried out using a 2: 1 mixture of

chloroform/dichloromethane as solvent.


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US 2005/0266108 A1

28-39. (canceled)40. A method according to claim 1 which comprises afurther step v) of:v) loading the substantially pure cannabinoid or cannab-inoid acid or the product enriched in a given cannab-inoid or cannabinoid acid onto a Chromabond Flash BT12M silica cartr idge column, eluting with hexane:ethylacetate (98:2) at a flow rate of approximately 5 ml/min.

41-91. (canceled)92. A method of producing 1 ' l 9 THCAcrystals comprising:i) preparing an extract of the cannabis plant material with0.1% v/v acetic acid in hexane,ii) filtering the resultant extract and removing solventfrom the filtrate by rotary evaporation to form anextract enriched in 1 ' l 9 THCA,iii) passing a solution of the resulting 1 ' l 9 tetrahydrocan-nabinolic acid ( 1 ' l 9 THCA) enriched extract through acolumn packed with Sephadex-LlIXl"?", eluting with2: 1 chloroform/dichloromethane,

iv) collecting 1 ' l 9 THCA rich fractions eluted from thecolumn and removing solvent by rotary evaporation,

v) re-dissolving the crude 1 ' l 9 THCA obtained in step iv)in methanol, removing insoluble residue by fil trationand removing solvent from the filtrate by rotary evapo-ration, and

vi) re-dissolving the product of step v) in pentane, remov-ing insoluble residue by filtration and removing solventfrom the fil trate by rotary evaporation to produce said1 ' l 9 THCA crystals.

93. A substantially pure preparat ion of 1 ' l 9 tetrahydrocan-nabinolic acid ( 1 ' l 9 THCA) obtained by the method of claim92, having a chromatographic purity of greater than 95%,more preferably greater than 96%, more preferably greaterthan 97% or most preferably greater than 98% by areanormalisat ion of an HPLC profile.94. A method of producing cannabidiolic acid (CBDA)crystals from plant material comprising:i) preparing an extract of cannabis plant material with0.1% v/v acetic acid in hexane,

ii) filtering the resultant extract and removing solventfrom the filtrate by rotary evaporation to form anextract enriched in CBDA,

iii) passing a solution of the resulting CBDA enrichedextract through a column packed with a matrix ofhydroxypropylated cross-linked dextrans, eluting with2: 1 chloroform/dichloromethane,iv) collecting CBDA rich fractions eluted from the col-umn and removing solvent by rotary evaporation,

v) re-dissolving the crude CBDA obtained in step iv) inmethanol, removing insoluble residue by filtration andremoving solvent from the fi ltrate by rotary evapora-tion, and

vi) re-dissolving the product of step v) in pentane, remov-ing insoluble residue by filtration and removing solventfrom the fil trate by rotary evaporation to produce saidCBDA crystals.

95. A substantially pure preparation of cannabidiolic acid(CBDA) crystals obtained by the method of claim 94, having

Dec. 1,200518

a chromatographic purity of greater than 90%, more pref-erably greater than 92% or most preferably greater than 94%by area normalisation of an HPLC profile.96. A method of producing a semi-solid preparation of 1 ' l 9

tetrahydrocannabinolic acid ( 1 ' l 9 THC) comprising:i) obtaining an ethanolic solution of a botanical drugsubstance from decarboxylated cannabis plant material,ii) passing the solution obtained in step i) through acolumn of activated charcoal, and collecting the eluate,i ii) remove solvent from the eluate by rotary evaporationto give a 1 ' l 9 THC enriched fraction,iv) passing a solution of the resulting 1 ' l 9 THC enrichedextract through a column packed with Sephadex LH20,eluting with 2:1 chloroform/dichloromethane,

v) collecting 1 ' l 9 THC rich fractions and removing solventby rotary evaporation,

vi) re-dissolving the crude 1 ' l 9 THC prepared in step v) inmethanol, removing insoluble residue by filtration andremoving solvent from the filt rate by rotary evapora-tion, and

vii) re-dissolving the crude 1 ' l 9 THC prepared in step vi) inpentane, removing insoluble residue by filt rat ion andremoving solvent from the filtrate by rotary evaporationto give a semi-solid preparation of 1 ' l 9 THe.

97. A substantial ly pure preparation of 1 ' l 9 tetrahydrocan-nabinol ( 1 ' l 9 THC) obtained by the method of claim 96,having a chromatographic purity of >99% by area normali-sation of an HPLC profile .98. A method for producing 1 ' l 9 tetrahydrocannabinol ( 1 ' l 9

THCY) crystals comprising:i) obtaining an ethanolic solution of a botanical drugsubstance from cannabis plant material,ii) passing the solution obtained in step i) through acolumn of activated charcoal, and collecting the eluate,i ii) remove solvent from the eluate by rotary evaporationto give a 1 ' l 9 THCY enriched fraction,iv) passing a solut ion of the result ing 1 ' l 9 THCY enrichedextract through a column packed with Sephadex LH20,eluting with 2:1 chloroform/dichloromethane,

v) collecting 1 ' l 9 THCY rich fractions and removing sol-vent by rotary evaporation,vi) re-dissolving the crude 1 ' l 9 THCY prepared in step v)in methanol, removing insoluble residue by fi ltrationand removing solvent from the filt rate by rotary evapo-ration, and

vii) re-dissolving the crude 1 ' l 9 THCY prepared in step vi)in pentane, removing insoluble residue by filtration andremoving solvent from the filtrate by rotary evaporationto give said crystals of 1 ' l 9 THCY.

99. A substantial ly pure preparation of 1 ' l 9 tetrahydrocan-nabivarin ( 1 ' l 9 THCY) obtained by the method of claim 98,having a chromatographic purity of greater than 95%, morepreferably greater than 96%, more preferably greater than97%, more preferably greater than 98%, and most preferablygreater than 99% by area normalisat ion of an HPLC profile.


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US 2005/0266108 A1

100. A method for producing a highly enriched cannabig-erol (CBG) extract or substantially pure CBG from cannabisplant material comprising:i) decarboxylating the cannabis plant material,ii) preparing an extract of the decarboxylated cannabisplant material with hexane,

iii) filtering the resultant extract and removing solventfrom the filtrate by rotary evaporation to form anextract enriched in CBG,

iv) passing a solution of the resulting CBG enrichedextract through a column packed with Sephadex-LH20TM, eluting with 2:1 chloroform/dichloromethane,v) collecting CBG rich fractions eluted from the columnand removing solvent by rotary evaporation,

vi) re-dissolving the crude CBG obtained in step v) inmethanol, removing insoluble residue by filtration andremoving solvent from the fi ltrate by rotary evapora-tion, and

vii) re-dissolving the product of step vi) in pentane,removing insoluble residue by filtration and removingsolvent from the filtrate by rotary evaporation to pro-duce a highly enriched CBG extract or substantiallypure cannabigerol.

101. A product enriched in cannabigerol (CBG) obtainedby the method of claim 100, having a chromatographicpurity of greater than 90%, preferably greater than 92% byarea normalisation of an HPLC profile.

Dec. 1,200519

102. A method of producing a highly enriched cannab-ichromeme (CBC) extract from cannabis plant materialcomprising:i) decarboxylating the cannabis plant material,ii) preparing an extract of the decarboxylated cannabisplant material with hexane,

iii) filtering the resultant extract and removing solventfrom the filtrate by rotary evaporation to form anextract enriched in CBC,

iv) passing a solution of the resulting CBC enrichedextract through a column packed with Sephadex-LH20TM, eluting with 2:1 chloroform/dichloromethane,

v) collecting CBC rich fractions eluted from the columnand removing solvent by rotary evaporation,vi) re-dissolving the crude CBC obtained in step v) inmethanol, removing insoluble residue by filtration andremoving solvent from the filt rate by rotary evapora-tion, andvii) re-dissolving the product of step vi) in pentane,removing insoluble residue by filtration and removingsolvent from the filtrate by rotary evaporation to pro-duce a highly enriched CBC extract.

103. A product enriched in cannabichromene (CBC)obtained by the method of claim 102, having a chromato-graphic puri ty of greater than 80%, more preferably greaterthan 85% by area normalisation of an HPLC profile.

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10 528 951 methods of purifying cannabin

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