Structure-Activity Relationships of Propylene Glycol, Glycerin, and - - PowerPoint PPT Presentation

▶
structure activity
SMART_READER_LITE
LIVE PREVIEW

Structure-Activity Relationships of Propylene Glycol, Glycerin, and - - PowerPoint PPT Presentation

Dec 30, 2023 486 likes •788 views

Structure-Activity Relationships of Propylene Glycol, Glycerin, and Select Analogs for Carbonyl Thermal Degradation Products Melvin, M.S.; Ballentine, R.M.; Gardner, W.P.; McKinney, W.J.; Smith, D.C.; Pithawalla, Y.B.; Wagner, K.A. Altria

slide-1
SLIDE 1

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 1

Melvin, M.S.; Ballentine, R.M.; Gardner, W.P.; McKinney, W.J.; Smith, D.C.; Pithawalla, Y.B.; Wagner, K.A.

Structure-Activity Relationships of Propylene Glycol, Glycerin, and Select Analogs for Carbonyl Thermal Degradation Products

slide-2
SLIDE 2

Thermal Degradation of eLiquids

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 2

Heat

Propylene Glycol Glycerin Nicotine Flavor Systems

  • Propylene glycol (PG) and Glycerine (GLY) can thermally

degrade upon heating

  • Formaldehyde, Acetaldehyde, Acrolein1,2,3
slide-3
SLIDE 3

Carbonyls in E-Cigarettes

  • Geiss et al. and Gillman et al. demonstrated that carbonyl

formation increased with temperature1,4

  • US FDA PMTA Draft Guidance for ENDS Products recommends

reporting four carbonyls in e-liquid and aerosol5

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 3

slide-4
SLIDE 4

Objectives and Approach

  • Determine the formation pathways of formaldehyde,

acetaldehyde, acrolein, and crotonaldehyde:

  • 1. Identify source of degradation products using 13C3-labeled PG

and GLY

  • 2. Determine the role of 3-hydroxypropanal (3-HPA) as an

intermediate during the thermal degradation of e-liquids

  • 3. Propose rational mechanisms based on results
  • 4. Determine key reaction centers using rationally selected

derivatives of PG and GLY

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 4

slide-5
SLIDE 5

Microwave Model System

  • Model microwave system used to generate

target carbonyls

  • Previously used to identify diacetyl and acetyl

propionyl formation pathways6

  • Microwave system evaluated for equivalent

yields to e-cigarette

  • Sample = 50% PG : 50% GLY + 2.5 % nicotine (w/w)
  • 140 puffs
  • 55 mL puff volume, 5 sec puff duration, 30 sec puff

period, square wave

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 5

CEM Discovery SP Hybrid

slide-6
SLIDE 6

Analyte Yield Comparison

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 6

140 puffs using 55 ml Puff Volume, 5 sec Puff Duration, 30 sec Puff Period; Square Wave

5 10 15 20 25 30

Formaldehyde Acetaldehyde Acrolien Analyte Amount (µg /g)

Liquid Microwave Aerosol

Crotonaldehyde was not detected

slide-7
SLIDE 7

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 7

Identify Source of Degradation Products Using 13C-labeled PG and GLY

slide-8
SLIDE 8

Carbon-13 Labeled PG and GLY

  • Samples:
  • 50% 13C3-PG : 50% GLY + 2.5% nicotine (w/w)
  • 50% PG : 50% 13C3-GLY + 2.5% nicotine (w/w)

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 8

Microwave Heating* DNPH Derivatization UPLC-UV- MS/MS Isotope Distribution

*500 mg of sample heated to 180 °C and held for 3 min

  • Labeled products directly traceable to labeled precursor
slide-9
SLIDE 9

Product Distribution Using 13C3-PG

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 9

50% 13C3-PG : 50% GLY + 2.5 % Nicotine (w/w)

26.1 4.7 0.7 5 10 15 20 25 30

Concentration (µg / g)

25.1% 93.2% 94.0% 74.9% 6.8% 6.0% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Percentage of Total Analyte

13C-PG GLY

13C 13C 13C

Crotonaldehyde was not detected

slide-10
SLIDE 10

Product Distribution using 13C3-GLY

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 10

50% PG : 50% 13C3-GLY + 2.5 % Nicotine (w/w)

22.7% 87.6% 95.3% 77.3% 12.4% 4.7% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Formaldehyde Acetaldehyde Acrolein Percentage of Total Analyte

PG 13C-GLY

Crotonaldehyde was not detected

13C 13C 13C

slide-11
SLIDE 11

Summary: 13C-Labeling Studies

  • Formaldehyde was predominantly formed from GLY
  • Acetaldehyde and acrolein were predominantly formed

from PG

  • Crotonaldehyde was not detected

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 11

slide-12
SLIDE 12

Determine the Role of 3-hydroxypropanal (3-HPA) as an Intermediate During the Thermal Degradation of e-Liquids

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 12

slide-13
SLIDE 13

3-Hydroxypropanal Background

  • Researchers proposed formaldehyde and acetaldehyde are

produced from the retro-aldol condensation of 3-hydroxypropanal (3-HPA)4,7

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 13

slide-14
SLIDE 14

3-HPA Fortification Studies

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 14

500 mg e-liquid 50% PG : 50% GLY + 2.5 % nicotine (w/w) Fortify samples with 3-HPA at 3 levels (300, 700, 1500 µg) Microwave Heating: 180 °C for 3 min DNPH Derivatization UPLC-UV-MS/MS Analysis

slide-15
SLIDE 15

Results: 3-HPA Fortification (N=3)

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 15

50% PG : 50% GLY + 2.5 % Nicotine (w/w)

100 200 300 400 500 600 Unfortified 350 700 1400

Analyte Amount (µg / g)

3-HPA Fortification (µg) Formaldehyde Acetaldehyde Acrolein Acrolein Yield ~ 30%

slide-16
SLIDE 16

Summary: 3-Hydroxypropanal (3-HPA)

  • Unfortified e-liquids
  • 3-HPA, acrolein, and crotonaldehyde were not detected

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 16

  • E-liquids fortified with 3-HPA
  • Crotonaldehyde was not detected
  • No increase in formaldehyde and acetaldehyde
  • 3-HPA converted to acrolein with ~30 % yield
  • The retro-aldol condensation of 3-HPA appears to be a negligible

pathway for the production of formaldehyde and acetaldehyde under test conditions

slide-17
SLIDE 17

Suggested Formation Pathways in Aerosol

3-HPA was not detected

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 17

  • Formaldehyde from Glycerin
  • Acetaldehyde from Propylene Glycol
  • Acetaldehyde from Propylene Glycol
slide-18
SLIDE 18

Determine Key Reaction Centers Using Rationally Selected Derivatives of PG and GLY

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 18

slide-19
SLIDE 19

Experimental: Evaluation of Derivatives

  • Derivatives:
  • Methoxy derivatives selected to reduce autoxidation efficiency
  • Methyl derivatives selected to reduce dehydration efficiency
  • Samples:
  • 50% PG : 50% GLY-Deriv + 2.5 % nicotine (w/w) -> Formaldehyde
  • 50% PG-Deriv : 50% GLY + 2.5 % nicotine (w/w) -> Acetaldehyde and

Acrolein

  • Control = 50% PG : 50% GLY + 2.5% nicotine (w/w)

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 19

Microwave Heating: 180 °C for 3 min DNPH Derivatization UPLC-UV-MS/MS

slide-20
SLIDE 20

GLY Derivatives: Formaldehyde

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 20

Methoxy Derivatives Methyl Derivatives

slide-21
SLIDE 21

Formaldehyde: GLY Derivatives

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 21

Results support proposed mechanism

10 20 30 40 50

Control D E G F H N O P R Q

Formaldehyde (µg / g)

Control

Methoxy Derivatives Methyl Derivatives

slide-22
SLIDE 22

PG Derivatives: Acetaldehyde and Acrolein

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 22

Methoxy Derivatives Methyl Derivatives

slide-23
SLIDE 23

Acetaldehyde: PG Derivatives

Results do not support proposed mechanism

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 23

10 20 30 40

Control A B C I M J K L

Acetaldehyde (µg / g)

Control

Methoxy Derivatives Methyl Derivatives

slide-24
SLIDE 24

Acrolein: PG Derivatives

Results support proposed mechanism

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 24

0.00 0.10 0.20 0.30 0.40

Control A B C I M J K L

Acrolein (µg / g)

Control

Methoxy Derivatives Methyl Derivatives

slide-25
SLIDE 25

Summary: Methoxy and Methyl Derivatives

  • Formaldehyde: GLY Derivatives
  • Substitution reduced formaldehyde generation
  • Consistent with proposed pathway
  • Acetaldehyde: PG Derivatives
  • Substitution increased acetaldehyde production
  • Not consistent with proposed pathway
  • Under further investigation
  • Acrolein: PG Derivatives
  • Substitution decreased acrolein generation
  • Consistent with proposed mechanism
  • Crotonaldehyde was not detected

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 25

slide-26
SLIDE 26

Conclusions

  • Formaldehyde derived primarily from glycerin
  • Acetaldehyde and acrolein derived primarily from propylene glycol
  • 3-hydroxypropanal pathway has negligible contribution to

formaldehyde and acetaldehyde generation

  • Proposed pathways for formaldehyde and acrolein are consistent with

experimental results

  • Acetaldehyde pathway under further investigation

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 26

slide-27
SLIDE 27

References:

1. Geiss, O., Bianchi, I., and Barrero-Moreno, J. (2016) Correlation of volatile carbonyl yields emitted by e-cigarettes with the temperature of the heating coil and the perceived sensorial quality of the generated vapours. Int J Hyg Environ Health 219, 268-277. 2. Farsalinos, K. E., and Gillman, G. (2017) Carbonyl Emissions in E-cigarette Aerosol: A Systematic Review and Methodological

  • Considerations. Front Physiol 8, 1119.

3. Kosmider, L., Sobczak, A., Fik, M., Knysak, J., Zaciera, M., Kurek, J., and Goniewicz, M. L. (2014) Carbonyl compounds in electronic cigarette vapors: effects of nicotine solvent and battery output voltage. Nicotine Tob Res 16, 1319-1326. 4. Gillman, I. G., Kistler, K. A., Stewart, E. W., and Paolantonio, A. R. (2016) Effect of variable power levels on the yield of total aerosol mass and formation of aldehydes in e-cigarette aerosols. Regul Toxicol Pharmacol 75, 58-65. 5.

  • FDA. (2016). Guidance for industry. Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems. Draft Guidance.

Available at: https://www.fda.gov/downloads/TobaccoProducts/Labeling/RulesRegulationsGuidance/UCM499352.pdf. Accessed 15Feb2018. 6. Melvin, M.S.; Avery, K.C.; Ballentine, R.M.; Gardner, W.P.; McKinney, W.J.; Smith, D.C.; Wagner, K.A. Thermal Degradation Studies of Electronic Cigarette Liquids Part 2: Development of a Model Reaction System Used to Study α-Dicarbonyl Formation. Presented at the 71st Tobacco Science research Conference, 2017, Bonita Spring, Fl. 7. Flora, J. W., Meruva, N., Huang, C. B., Wilkinson, C. T., Ballentine, R., Smith, D. C., Werley, M. S., and McKinney, W. J. (2016) Characterization of potential impurities and degradation products in electronic cigarette formulations and aerosols. Regul Toxicol Pharmacol 74, 1-11.

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 27

slide-28
SLIDE 28

Altria Client Services l Matt Melvin l September 18, 2018 l Final l TSRC 2018 #87 l 28

  • Further data and details:

www.altria.com/ALCS-Science