Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Cannabis Chemistry Industrial Applications of Chemistry & Innovation and Entrepreneurship BONUS lecture

672 views

Published on

Lecture at the chemistry department of Imperial College, London. A brought overview and specific deep dive into the chemical aspects of cannabis production.

Published in: Science
  • Be the first to comment

  • Be the first to like this

Cannabis Chemistry Industrial Applications of Chemistry & Innovation and Entrepreneurship BONUS lecture

  1. 1. www.outco.com 1 Dr. Markus Roggen VP Extraction OutCo, San Diego Cannabis Chemistry Industrial Applications of Chemistry & Innovation and Entrepreneurship BONUS lecture
  2. 2. www.outco.com • My gateway drugs • My descent into drugs • My daily drug use • My other habits • Why you should join in • How to get your fix 2 Abstract
  3. 3. www.outco.com 3 Where do I come from?
  4. 4. www.outco.com • Born in Germany • M/Sci Chemistry, Imperial College London, UK • PhD Organic Chemistry, ETH Zürich, CH • PostDoc PhyOrg Chemistry, TSRI, USA • Laboratory Director, DaVinci Laboratory, CA, USA • VP Extraction, OutCo, CA, USA • Climbing Guide, Europe • Triathlete, USA 4 Where do I come from?
  5. 5. www.outco.com • Germany: Process Optimization • Imperial College: Design of Experiment • ETH Zürich: Tolerance to Pain and Suffering • Scripps Research: Life Perspective • DaVinci Laboratory: Analytical Chemistry • OutCo: Research Platform • Climbing: Teaching, Leadership • Triathlon: Connections 5 Where do I come from?
  6. 6. www.outco.com 6 How did I get into drugs?
  7. 7. www.outco.com 6 How did I get into drugs? Serendipity!
  8. 8. www.outco.com • Four options for chemists: • Academia • Industry • Startup • Traitor • Three ways to get a job: • Be amazing • Be pushy • Know the right people 8 How did I get here?
  9. 9. www.outco.com • Cannabis Industry is in its infancy • Great scarcity of scientists • Potential for large impact and fast rise • More than just science • Sin industries pay better • Prohibition did not work 9 Why drugs?
  10. 10. www.outco.com 10 Cannabis Science
  11. 11. www.outco.com • Biology: Plant shape, strains, cultivation • Biochemistry: Active Molecules, biosynthesis • Organic Chemistry: Synthesis • Medicinal Chemistry: Receptors, synthetic cannabinoids • Analytical Chemistry: Testing • Physical Chemistry: Melting Point, shatter • Food Chemistry: Consumption methods • Chemical Engineering: DoE • Mechanical Engineering: Rosin 11 Cannabis Science
  12. 12. www.outco.com 12 CannaBio
  13. 13. www.outco.com 13 The Cannabis Plant
  14. 14. www.outco.com 14 The Cannabis Plant
  15. 15. www.outco.com Outdoor: •Low facility and operations costs •Only one harvest per year Indoor: •Multiple harvests per year •High facility and operations costs Greenhouse: •Uses sunlight •High facility costs Grow Environment
  16. 16. www.outco.com 0.45 0.55 0.65 0.75 0.85 0.95 0 5 10 15 20 25 30 WaterActivity Day of cure Water Activity 0 2 4 6 8 10 12 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 0 5 10 15 20 25 Day of cure Terpenes Limonene Bisabolol Linalool bCP Myrcene Humulene • Dry to preserve plant • ”Cure” plants to develop flavor and make ”smoke-able” Post Processing
  17. 17. www.outco.com • Trim to maximize aesthetics and smoke-ability of buds • 1.5 lbs/day·person (we produce 180 lbs per month) Post Processing
  18. 18. www.outco.com 18 CannaMolecules
  19. 19. www.outco.com So many molecules we should keep track of 19 What is in the plant >140 Cannabinoids >200 Terpenes ~30 Flavonoids Alcohols, Phenols Aldehydes, Ketones Alkaloids Carbohydrates, Fatty Acids Lactones
  20. 20. www.outco.com 20 What is in the plant Biosynthesis: Eur. J. Biochem. 268, 1596 (2001)
  21. 21. www.outco.com 21 What is in the plant THC • The reason we are all here • Psychoactive Decarboxylation THC Acid (THCA) • Naturally occurring • Not Psychoactive CBN • Not naturally occurring • Low Psychoactivity Oxidation CBD • Non-psychoactive • Assumed beneficial health properties
  22. 22. www.outco.com • Indica vs. Sativa • Strain and Cultivars 22 Cannabis strains
  23. 23. www.outco.com • Let’s think about Chemovars 23 Cannabis strains DOI: 10.1089/can.2016.0017 DOI: 10.1089/can.2016.0040
  24. 24. www.outco.com 24 Cannabis strains
  25. 25. www.outco.com 25 CannMed
  26. 26. www.outco.com 26 What is all the fuss about Anandamide From Sanskrit ”ananda” for Joy, Bliss 2-Arachidonoylglycerol Present in relatively high levels
  27. 27. www.outco.com 27 What is all the fuss about Cell 167, 750, October 20, 2016
  28. 28. www.outco.com • Chronic pain and spasticity: moderate-quality evidence • Nausea and vomiting due to chemotherapy: low-quality • Weight gain in HIV infection: low-quality evidence • Sleep disorders: low-quality evidence • Tourette syndrome: low-quality evidence • 79 trials, 6462 participants from >23000 publications • 4 trials were judged at low risk of bias Medical Effects of Cannabinoids JAMA June 23/30, 2015, 313, Number 24 2456 DOI: 10.17226/24625
  29. 29. www.outco.com • National Institute on Drug Abuse (NIDA) is the only legal producer of Cannabis for use in US research studies Medical Studies on Cannabis DOI: 10.1038/srep46528
  30. 30. www.outco.com • Over 50,000 death/year in USA due to opioids • States with legal cannabis have a 25% lower mortality rate Medical Studies on Cannabis doi: 10.1001/jamainternmed.2014.4005
  31. 31. www.outco.com 31 Synthetic Cannabinoids
  32. 32. www.outco.com • THC: Partial agonist to CB1 & CB2 • CBD: Antagonist for CB1 & CB2 • 2-AG: Full agonist for CB1 32 Terms and Conditions
  33. 33. www.outco.com • Not synthesized cannabinoid, but synthesized for endocannabinoid receptor interaction • John William Hoffman: Full agonist, 5x greater than THC, death reported • Alexandros Makriyannis: 100x greater than THC • Raphael Mechoulam: Initial discovery of endocannabinoids • Pfizer: Synthesized in the 1970s and 1980s • Alan C. Spivey: Solid-Phase Synthesis of Rimonabant Analogs 33 Synthetic Cannabinoids
  34. 34. www.outco.com 34 CannOrganic
  35. 35. www.outco.com 35 Stereodivergent Total Synthesis of THC Angew. Chem. Int. Ed. 2014, 53, 13898 D9 -Tetrahydrocannabinols** on Krautwald, David Sarlah, and D9 -Tetrahydrocannabinols** on Krautwald, David Sarlah, and • Allylic Alcohol and Enal • Two chiral catalysts: • Ir/(P,olefin) complex • Secondary amine • All possible stereoisomers of γ,δ-unsaturated aldehyde product • Ring-closing metathesis Grubbs 2cd • Pinnick oxidation/Methylation • Methylation to 3rd-Alcohol • Deprotection • Aryl etherification
  36. 36. www.outco.com 36 Hemp and CBD Isolate EIHA • Fiber: light weight papers, insulation material and bio composites (Bike parts: Dr. Kunal Masania, IC MechEng) • Shivs: animal bedding and construction • Hemp seeds: hemp seed oil, human food and animal feed • Isolation of CBD • 33,000 ha cultivated in 2016 in Europe • Bulk synthesis of CBD please!
  37. 37. www.outco.com 37 CannAnal
  38. 38. www.outco.com Some quantitative methods: • Taste testing • TLC (Quantitative?) • IR (Quantitative?) • GC-FID (Decarboxylation) • LC-UV/Vis (Overlap) • LC-MS/MS (Expensive) • NMR (still working on it) Problems: • 10 Ref. Standards • No official methods • Little understanding by regulatory body • Little interest by industry • No pesticide guidelines • High solvent limits • Edibles are difficult matrix to prepare Thoughts on Testing US herbal pharmacopoeia: cannabis monography
  39. 39. www.outco.com 39 CannaPhys
  40. 40. www.outco.com 40 What extracts are out there? Kief Dry Sift BHO Glass ShatterCrumble Ethanol CO2 Oil Terp Sauce
  41. 41. www.outco.com 41 Munchies
  42. 42. www.outco.com Inhalation Fast acting, high peak concentrations of cannabinoids Danger of lipoid pneumonia Ingestion Slower, gradual uptake of cannabinoids THC is metabolized to 11-OH-THC in the liver 11-OH-THC is more potent and active than THC Danger of overdosing due to delayed effect Topical Targeted application for localized problems Will not fail drug test Delivery DOI: 10.1089/can.2015.0004 DOI: 10.1089/can.2015.0012
  43. 43. www.outco.com Pick your poison: Buds Oil, Shatter, Glass, Wax (budder, crumble, honeycomb) Sublingual, Cream, Tablet, Drink, Edible Product Variations
  44. 44. www.outco.com 44 What is an Extract?
  45. 45. www.outco.com 45 CannExtract
  46. 46. www.outco.com Extraction Methods Butane (Hydrocarbons) Alcohol
  47. 47. www.outco.com Extraction Methods Butane (Hydrocarbons) Alcohol (Ethanol) Carbon Dioxide (SFE)
  48. 48. www.outco.com • Production Yield • Production Costs • Extract Constitution/Quality • Legal Aspects 48 What is the best Extraction System?
  49. 49. www.outco.com For what: • Yield per Run YpR • Yield per Week YpW • Cannabinoid Conc. CC • Terpene Content TC • Recovery Rec 49 Optimizing your Extraction (SFE) With what: • Temperature T • Pressure P • Time t • Flow Rate FR • Particle Size PS
  50. 50. www.outco.com For what: • Yield per Run YpR • Yield per Week YpW • Cannabinoid Conc. CC • Terpene Content TC • Recovery Rec 50 Optimizing your Extraction Process With what: • Temperature T • Pressure P • Time t • Flow Rate FR • Particle Size PS
  51. 51. www.outco.com For what: • Recovery Rec Optimizing your Extraction Process With what: • Time t 0 100 200 300 400 0 5 10 15 20 25 30 35 40 YieldTHC(g) Time (t) Optimizing Run TimeExperiment t (h) Rec (g) 1 4 53.0 2 8 103 3 18 263 4 34 367 Raw n/a 500 Mass Transfer Diffusion
  52. 52. www.outco.com For what: • Yield per Run YpR • Yield per Week YpW • Cannabinoid Conc. CC • Terpene Content TC • Recovery Rec 52 Optimizing your Extraction Process With what: • Temperature T • Pressure P • Time t • Flow Rate FR • Particle Size PS
  53. 53. www.outco.com For what: • Recovery Rec Optimizing your Extraction Process With what: • Particle Size PS Experiment PS (mm) Rec (g) 1 6 215 2 4 230 3 2 235 4 1 253 210 220 230 240 250 260 0 1 2 3 4 5 6 7 YpR(g) PS (mm) Optimizing Particle Size
  54. 54. www.outco.com Optimizing your Extraction Process 0 0.05 0.1 0.15 0.2 0.25 0.3 0 2 4 6 8 10 12 14 16 18 %Weight Terpene Effect of Milling on Terpene Cocentrations Food Blender 0.5mm 1mm 2mm 4mm 6mm 10mm 1mm (700rpm) 10mm (700rpm) Reference
  55. 55. www.outco.com 55 Design of Experiment to the Rescue • Test multiple factors simultaneously • Few test for whole space response surface • Higher order effects of factors • Fast and efficient
  56. 56. www.outco.com Designing the first DoE 1. Defining the problem • Extracting Cannabis with a 20L, 2000psi SFE 2. Determine the response • Yield THC • Percentage Terpenes 3. Determine the factors • Temperature and Pressure 4. Additional things to keep in mind • Comparison • Replication • Blocking • Orthogonality
  57. 57. www.outco.com Critical Point: 304.25 K & 72.9 atm Factor no. Factors lower level upper level Unit 1 Temperature 34 60 °C 2 Pressure 1100 1900 psi Expt. no. Temp (˚C) Pressure (psi) A 34 1100 B 34 1900 C1 47 1500 C2 47 1500 D 60 1100 E 60 1900 Temperature (˚C) Pressure (psi) Yield THC (g) 34 60 1100 1900 47 1500 0 Executing the DoE Temperature (˚C) Pressure (psi) Yield THC (g) 34 60 1100 1900 47 1500 0 400
  58. 58. www.outco.com y0+ ixi+ iixi 2+ ijxixj i i i j Calculating response surface of DoE A Taylor expansion describes the response surface. Matrix algebra solves the Taylor expansion. Y=bX b=(X’X)-1X’Y a=bX
  59. 59. www.outco.com a= 14.9 xT + 123 xp + 18.4 xTxp 59 Analyzing the DoE, THC Recovery (Super)
  60. 60. www.outco.com a= - 14.9 xT - 11.7 xp + 16.8 xTxp 60 Analyzing the DoE, %Terpene (Super)
  61. 61. www.outco.com 61 Visual Guide to Extracts
  62. 62. www.outco.com SFE, 900.0 – 1900 psi, 5.0 – 60 ˚C, 22h max 62 Compare Sub- and Supercritical Response Sub Super THC Recovery 60% 80% Terpene Fraction 52% at 34% yield 63% at 82% yield
  63. 63. www.outco.com • THC extracts faster than THCA • THC to THCA ratio adjusted by SFE 63 Lessons learned in SFE % Decarboxylation S.M. 7h 22h Exp. B 8.0% 25% 10% Exp. J 14% 25% 14%
  64. 64. www.outco.com • CBD extracts faster than THC • CBD to THC ratio adjusted by SFE 64 Lessons learned in SFE CBD/THC S.M. 7h 22h Exp. A 4.1E-03 1.3E-02 5.0E-03 Exp. J 1.7E-04 1.3E-03 3.1E-03 Bonus: Decarboxylation of CBDA slower than for THCA J. of Supercritical Fluids, 2010, 603
  65. 65. www.outco.com • Enrichment in minor cannabinoids • CBG enrichment by SFE 65 Lessons learned in SFE CBG/total Canna. S.M. 7h 22h Exp. B 2.9% 6.% 2.9% Exp. J 3.0% 13% 4.9% J. of Supercritical Fluids, 2010, 603
  66. 66. www.outco.com Changing terpene profiles in SFE • Sativa: rich in monoterpenes • Indica: rich in sesquiterpenes 66 Lessons learned in SFE Hazekamp, et al.; Cannabis and Cannabinoid Research 2016, 202 7h 22h
  67. 67. www.outco.com 67 CannEngineering
  68. 68. www.outco.com Extraction Methods (Mechanical Manipulation) Kief Tumbling Rosin Press Water Extraction
  69. 69. www.outco.com 69 Other Separation Methods Ice Water Hash • ~80% cannabinoid concentration • ~25% recovery achieved • Little effect on molecular makeup 150 micron 25 micron
  70. 70. www.outco.com Rosin Press • Optimized for yield and quality by DoE • ~72% recovery achieved • Little effect on molecular makeup 70 Other Separation Methods Rosin Yield Rosin Quality
  71. 71. www.outco.com X 71 Other Separation Methods
  72. 72. www.outco.com Further Reading • Roggen, M.; Clear vs. Pure: How Fallacies and Ignorance of Extraction Misrepresent the Cannabis Flower. Cannabis Industry Journal August 3rd, Online Editorial • Cortina, C.; Roggen, M.; Comply! Terpene and Testing Aug./Sept. 2017, 36-41 • Grauerholz, B.; Roggen, M.; Journey Down the Production Pipeline. Terpene and Testing June/July 2017, 35-39 • Roggen, M.; Best Before Dates. Terpene and Testing Online Editorial • Roggen, M.; How to optimize your extraction operation. A case study in supercritical CO2 extraction. Terpene and Testing May/June 2017, 35-40
  73. 73. www.outco.com • Cannabis sativa: The Plant of the Thousand and One Molecules (doi: 10.3389/fpls.2016.00019) • Changes in Cannabis Potency Over the Last 2 Decades (1995–2014): Analysis of Current Data in the United States (doi:10.1016/j.biopsych.2016.01.004) • American Herbal Pharmacopoeia, Cannabis Inflorescence, 2013 Further Reading
  74. 74. www.outco.com QA: Chris Cortina Formulation: Taylor Trah Extraction: Blake Grauerholz Production: Matt Zbiec mroggen@outco.com
  75. 75. www.outco.com 75 Why it’s different than biotech?
  76. 76. www.outco.com • Mature industries have set career paths and hierarchies • All your coworkers are PhDs from the same universities • There is literature about what you have to do • People have no idea what you do, but they admire it 76 Why it’s different than biotech?
  77. 77. www.outco.com • Conversion between THC and CBD is not an oxidation • No testing regulation for CA, yet • Solvent limits are ridiculously high in CO (e.g. butane: 5000ppm, xylenes: 2170ppm) • Indica vs. Sativa • Organic, Artists 77 Thoughts on Cannabis vs. Science
  78. 78. www.outco.com 78 How to get into the cannabis field?
  79. 79. www.outco.com • Better not to know the “right” people • Join an “established” company • Start your own thing • Come from a position of strength • Don’t beg 79 How to get into the cannabis field?
  80. 80. www.outco.com • Most companies are expanding • Bring your outside expertise • Location, location, location! • Company culture is even more important 80 Established cannabis companies
  81. 81. www.outco.com • What is your idea? • For ancillary consider Canopy San Diego • For hands-on research: Talk to me! 81 Start your own
  82. 82. www.outco.com 82 What to look out for?
  83. 83. www.outco.com • Licenses • Legality • Background • What is your / their risk limit? • Company culture • Look past the window-dressing 83 What to look out for?
  84. 84. www.outco.com 84 Why do it?
  85. 85. www.outco.com • Startups are stressful • I had to get fingerprinted for my job • I change clothes and backpack when I travel • No job security in startups • Cannabis is schedule 1, there is Jeff Sessions! • Startups are glorious • I work with illegal drugs! • Startups have great perks • We work in warehouses outside of the city! 85 Don’t!

×