Thermal Degradation Studies of Electronic Cigarette Liquids Part 2: Development of a Model Reaction System Used to Study α-dicarbonyl Formation

Transcription

1 Thermal Degradation Studies of Electronic Cigarette Liquids Part 2: Development of a Model Reaction System Used to Study α-dicarbonyl Formation Melvin, M.S.; Avery, K.C.; Ballentine, R.M.; Gardner, W.P.; McKinney, W.J.; Smith, D.C.; Wagner, K.A. Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 1

2 Diacetyl (µg/g) Diacetyl Formation During Aerosol 2.0 Generation Liquid Aerosol A B C D E F G H Product Diacetyl levels elevated in aerosol relative to e-liquid suggesting diacetyl formation during aerosol generation Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST11 2

3 Observed Diacetyl Formation in Aerosol Glycerin Propylene Glycol??? Diacetyl Nicotine Attributed to thermal degradation processes Provide more detailed information on reaction pathway Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 3

4 Diacetyl Formation: Approach Develop equivalent model reactor - Equivalent = generate similar product yields as aerosol process Identify precursor compounds - 13 C-labeled propylene glycol and glycerin Propose reaction pathway Confirm proposed pathway - Identify key intermediates - Verify with synthetic organic chemistry Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 4

5 Microwave Optimization Reference formulation: - 50:50 propylene glycol:glycerin containing 2.5% nicotine and 15% water (on a weight basis) Sample size: mg of sample Screened range of times and temperatures - Fixed power of 200W - 1 to 15 minutes - 80 C to 220 C in 20 C increments Analyze samples using o-phenylenediamine method CEM Discovery SP Hybrid Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 5

6 Diacetyl (ng/g (ng/g of e-liquid) e-liquid) Reaction Screening Studies (N=3) Diacetyl Diacetyl Yield Yield at Varying at Indicated Temperatures Temperatures 3 Min Over Reaction Time Time 160 C 180 C Temperature Time (minutes) ( C) Diacetyl generation increased linearly with time Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 6

7 Diacetyl (ng/g of e-liquid) Reaction Screening Studies (N=3) Diacetyl Yield at Varying Temperatures at 3 Min Reaction Time Temperature ( C) Diacetyl generation increased linearly with time Yields increased with temperature Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 7

8 Microwave System Compared to Aerosol Microwave: - Standard conditions = 3 minutes at 180 C using 200 W power Aerosol collection: - Reference formulation (900 mg) - MarkTen XL cartridge - 50 puffs - 55 ml Puff Volume, 5 sec Puff Duration, 30 sec Puff Interval, Square Wave Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 8

9 Analyte Yield (ng/g) Microwave System Compared to Aerosol (55 ml Puff Volume, 5 sec Puff Duration, 30 sec Puff Interval, Square Wave, 50 puffs) Liquid Microwave Aerosol Glyoxal MethylGlyoxal Diacetyl Acetyl Propionyl Equivalent results for diacetyl and acetyl propionyl Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 9

10 Analyte Yield (ng/g) Microwave System Compared to Aerosol (55 ml Puff Volume, 5 sec Puff Duration, 30 sec Puff Interval, Square Wave, 50 puffs) Liquid Microwave Aerosol Glyoxal MethylGlyoxal Diacetyl Acetyl Propionyl Equivalent results for diacetyl and acetyl propionyl Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 10

11 Analyte Yield (ng/g) Microwave System Compared to Aerosol (55 ml Puff Volume, 5 sec Puff Duration, 30 sec Puff Interval, Square Wave, 50 puffs) Liquid Microwave Aerosol Glyoxal MethylGlyoxal Diacetyl Acetyl Propionyl Equivalent results for diacetyl and acetyl propionyl Elevated levels of glyoxal and methylglyoxal observed in aerosol relative to microwave system Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 11

12 Isotope Labeling Studies Microwave conditions mg of sample reacted for 3 minutes at 180 C Test e-liquids - 50:50 propylene glycol: 13 C 3 -glycerin + 2.5% nicotine Method for determining % enrichment - Created single-ion recording MS method for all possible isotopes - Obtained relative isotopic abundances - Percentage of 13 C incorporation was then determined Natural isotope contribution and mass bias corrections applied according Paine et.al. 1 1) Paine, J. B., et al. (2007), J. Anal. Appl. Pyrolysis 80(2): Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 12

13 Percent of Total Diacetyl Yield Diacetyl Isotopic Distribution C = 0 13C = 1 13C = 3 13C = 4 Number of 13 C Atoms Incorporated into Diacetyl Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 13

14 Isotope Labeling Analysis No 13 C labeled diacetyl: - Diacetyl can be generated from PG alone One 13 C labeled diacetyl: - Predominate pathway; GLY contributes one carbon-13 unit Three 13 C labeled diacetyl: - Minor pathway; GLY contributes three carbon-13 units Four 13 C labeled diacetyl: - GLY contributes four carbon-13 units to diacetyl formation Yield similar to diacetyl formation from propylene glycol alone Summary: Diacetyl formed from one carbon and three carbon precursors both of which can originate from both PG and GLY Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 14

15 Proposed Pathway: Acetol Formation Formation of acetol (hydroxyacetone) from propylene glycol or glycerin - Acetol yields similar to formaldehyde yields Acetol isomerization - Key step in proposed pathway Observed by NMR 2 2) Jensen, R. P., et al. (2017). Sci Rep 7: Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 15

16 Proposed Pathway: Acetol to Diacetyl Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 16

17 Verify with Synthetic Organic Chemistry Fortify reference solution with acetol and formaldehyde Perform aldol condensation using propylene glycol as reaction solvent Evaluate acid and base catalyzed aldol condensations Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 17

18 Diacetyl (ng/g of e-liquid) Acetol Effect on Diacetyl Yield 500 mg of reference formulation 3 minutes at 180 C Amount of Added Acetol (ng) Diacetyl yield increases with increasing acetol concentration Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 18

19 Diacetyl (ng/g of e-liquid) Formaldehyde Effect on Diacetyl Yield 500 mg of reference formulation 3 minutes at 180 C Amount of Added Formaldehyde (ng) Added Formaldehyde showed little effect Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 19

20 Diacetyl (ng/g e-liquid) Diacetyl (ng/g e-liquid) Diacetyl Yields from Aldol Reactions 500mg of propylene glycol µm Acetol µm Formaldehyde 3 minutes at 180 C Base Catalyzed: Nicotine Amount Added Nicotine (ng) Acid Catalyzed: Acetic Acid Aldol reaction replicated in microwave model system - Base catalysis not as efficient as acid catalysis Amount Added Acetic Acid (µl) Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 20

21 Conclusions a-dicarbonyl compounds are formed during the generation of aerosol for the device types tested Rapid heating via microwave technology can prove a useful tool as a model system for studying the formation of these compounds This tool was applied to the determination of pathways for diacetyl formation Diacetyl appears to be formed through the aldol condensation between acetol and formaldehyde Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 21

22 Acknowledgements George Karles, Yezdi Pithawalla, and Pete Lipowicz Thutrang Nguyen, Kathy Jerome, and Ha Nguyen CEM Corporation Altria Client Services Regulatory Sciences Matt S. Melvin October 9, CORESTA - ST12 22

23 Backup 23