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Crystallizing the science of CBD purification
- 1. Dr. Markus Roggen President/CSO Crystallizing the science of CBD purification
- 2. Introduction DELIC Labs is a research venture that seeks to add fundamental scientific insight to the field of cannabis and mushroom production. We seek to support the cannabis and mushroom industries by establishing a centralized hub in Vancouver, BC, for collaborative research focused on: • Process Design • Process Optimization • Process Analytics • Formulation Research
- 3. Collaborative Research DELIC Labs collaborates with academic, industry and private groups around the globe. Some highlights of those collaborations are: • University of British Columbia, Vancouver • Loyalist College, Belleville • Via Innovations by Dr. Monica Vialpando • Veridient Science by Dr. Linda Klumpers Fundamental Collaboration
- 4. Research Topics • Chemometrics and data analytics for process control and optimization • Kinetic studies to understand mechanisms • In-process analytics for process control • Computational studies to understand mechanisms • Process development, like crystallization Fundamental Cannabis and Mushroom Chemistry
- 5. 3 Outline - CBD, an introduction - Cannabinoids and contaminants - Solubility in common extraction solvents - Crystallization
- 6. Hemp or Cannabis? Legal and Illegal CBD
- 7. Hemp vs. Cannabis: Genetics • Genetic difference between hemp and drug type cannabis • Hemp and cannabis are not different species, as they can interbreed • No indication about 0.3%wt. THC level, yet! • No genetic base for legal limit of 0.3%wt. THC • No genetic difference between Sativa and Indica
- 8. Hemp vs. Cannabis: Regulations • FDA enforces: • Medical claims • THC levels • Don’t ask the DEA • Levels are arbitrary: • USA: 0.3%wt. THC • South Carolina: 0.5%wt. THC • Switzerland: 1%wt. THC • The 0.3%wt. THC limit is binding for all product forms • Sale of >0.3%wt. THC is illegal, but B2B still happens
- 9. Hemp vs. Cannabis: Economics • Consumer price, CBD: ~$100/g • B2B price, CBD: as low as $0.20/g • Massive overproduction of CBD hemp • Bottleneck in remediation Sources: HempBenchmarks®, a division of New Leaf Data Services, LLC. Copyright © 2019 New Leaf Data Services, LLC. All rights reserved.
- 10. Hemp Plant • >24 compound categories • >700 known compounds • >100 cannabinoids • >400 terpenes Hemp Flower CBDA THCA Other Cannabinoids Terpenes Others
- 12. A few Cannabinoids and Terpenes OH HO OH O CBD THC OH HO CBDA OH O OH O THCA OH O O HO O HU331 OH O CBN Decarboxylation Oxydation OH HO CBDV
- 14. Extraction • The goal is to separate the desired compounds from the cannabis plant matrix • Various Solvent Systems • Supercritical CO2 • Alcohol (mainly EtOH) • Hydrocarbon (mainly Butane)
- 16. Extraction: Solubility Hydrocarbon SFE EtOH H2O Terpenes Neutral Cann Acid Cann polar non-polar
- 17. Extraction: Solvents • Supercritical CO2 • Expensive instrumentation • Slow, complicated • Precise Hemp Flower Hemp Extract >0.3% THC
- 18. Extraction: CO2 Precision • Neutral cannabinoids are more soluble than acid form • THC > THCA • CBD more soluble than THC
- 19. Hemp Extract Extraction: Solvents • Alcohols: EtOH, iPrOH • Very Fast • Scalable, affordable instrumentation • Little control about extract Hemp Flower >0.3% THC
- 20. Extraction: EtOH Precision • EtOH: CBD more soluble than THC • Aliphatic: THC more soluble than CBD doi.org/10.1021/acs.jafc.0c01161
- 21. Extraction: Solvents • Hydrocarbons: butane, propane • Fast • Instrumentation and facility require safety rating • Can extract wet flower Hemp Flower Hemp Extract >0.3% THC
- 24. Crystallization • Formation of solids, with highly organized structure of atoms or molecules. • Influenced by temperature, air pressure, and time of fluid evaporation. • Size and shape of crystals depend on cooling rate.
- 25. R² = 0.9646 R² = 0.9705 50 150 250 350 450 550 650 750 0 4 8 12 16 20 24 28 32 36 40 Concentration (mg/ml) Temperature (°C) Cloud point Clear point • Clear points: temperature at which all material is dissolved • Cloud point: temperatures at which crystals are present • Two important curves: • Metastable Zone Width (MSZW): Control crystallization process with cooling rate for purity, yield, and particle size. CBD, MSZW, Graphs Clear points Cloud point Everything dissolved Everything crashed out MSZW Cooling Rate
- 26. Crystal16 • Benchtop multi-reactor instrument • High through-put crystallization experiments • 16 simultaneous crystallization reactors • Integrated transmissivity sensors • Rapid generation of solubility data and MSZW
- 27. Experimental • Studied n-pentane, n-hexane, n-heptane • Concentration profile: 100 mg/ml to 600 mg/ml Temperature (°C) CBD solubility (mg/ml) n-pentane n-hexane n-heptane 0 0 0 0 5 1.80 0.40 0.02 10 11.7 6.11 0.73 15 34.9 30.2 5.72 20 76.1 93.9 24.6 25 138 226 76.7 30 227 464 193 35 344 852 424 40 - 1442 837 50 - 3475 2603 60 - 7130 6578 70 - - 14,402 80 - - 28,396 90 - - 51,680 Temperature (°C) Isolated CBD crystallization yield (%) n-pentane n-hexane n-heptane 22 2 soluble 60 4 84 83 83 -20 >95 >95 >95
- 28. Crystallization in n-Pentane • Current favorite due its high vapor pressure and low boiling point • <10°C, CBD: higher solubility -> lower crystallization yield • Very narrow MSZW -> nucleation difficult • Low b.p. & max. solubility: more solvent required at scale R² = 0.9462 R² = 0.9603 50 150 250 350 450 550 650 750 0 4 8 12 16 20 24 28 32 36 40 Concentration (mg/ml) Temperature (°C) Cloud Point Clear Point
- 29. R² = 0.9627 R² = 0.9698 50 150 250 350 450 550 650 750 0 4 8 12 16 20 24 28 32 36 40 Concentration (mg/ml) Temperature (°C) Cloud Point Clear Point Crystallization in n-Hexane • b.p. (69°C) ~2x n-pentane • Solubility profile between 5°C - 20°C similar • Solubility dramatically increases >20°C, max. ~12.370 g/ml • MSZW larger -> more control over seed nucleating • n-hexane: neurotoxic, environment hazards
- 30. R² = 0.9646 R² = 0.9705 50 150 250 350 450 550 650 750 0 4 8 12 16 20 24 28 32 36 40 Concentration (mg/ml) Temperature (°C) Cloud point Clear point Crystallization in n-Heptane • Moderate CBD solubilization ability 5°C – 35°C • Highest b.p. at 98.4°C and large solubility (~88 g/mL) • ~50°C is recommended • The MSZW comparable to n-hexane • No known risks to humans or environment
- 31. R² = 0.9696 R² = 0.9545 0 3 6 9 12 15 18 10.0 15.0 20.0 25.0 30.0 35.0 40.0 THC wt % Temperature (°C) Cloud Point Clear Point Crystallization with THC in n-Heptane • Real life example: Various [THC] at CBD ~400 mg/mL • THC does not co-crystallize but acts as ‘good’ solvent by increasing solubility of CBD • THC acts as crystal surface impurity, remove with washing • Low temp’s for same yield • No ‘one-size-fits-all’ recipe
- 32. Conclusion • Three popular hydrocarbon solvents (n-pentane, n-hexane, and n- heptane) were investigated for CBD purification by crystallization. • Similar polarity, but, significant differences in crystallization parameters • n-Pentane: highest vapor pressure, faster drying, large solvent volumes required, narrow MSZW • n-Hexane: Medium b.p., high CBD loading capacity, harm to human & environment • n-Heptane: High b.p., medium CBD loading capacity, best safety profile due to lower vapor pressure • THC acts as a ‘good’ solvent • increases solubility of CBD • reduces crystallization temperatures
- 33. Expertise CSO: Dr. Markus Roggen Dr. Roggen has been actively involved in the cannabis industry for over 5 years in executive positions executive positions overseeing production, R&D and process optimization for multiple producers. Dr. multiple producers. Dr. Roggen is also a trusted advisor and mentor for multiple startups, startup startups, startup accelerators and organizations. DELIC LabsTeam Our team covers a wide range of expertise, including analytical chemistry, process chemistry, engineering physics, data science and statistics. ScientificAdvisor: Prof.GlennSammis Prof. Sammis is a Full Professor in the Chemistry Department at the University of British Columbia. He has built an internationally recognized research group working on the development of novel synthetic methods for the preparation of natural products and pharmaceuticals.
Editor's Notes
- Max. conc. of CBD is ~375 mg/ml as b.p. 36.1˚C