structure-activity relationships of propylene glycol, glycerin, and … · 2020. 1. 27. ·...
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Altria Client Services l Matt Melvin l October 23, 2018 l CORESTA 2018 ST05 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
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Thermal Degradation of eLiquids
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Heat Propylene Glycol
Glycerin
Nicotine
Flavor Systems
Propylene glycol (PG) and Glycerine (GLY) can thermally
degrade upon heating
- Formaldehyde, Acetaldehyde, Acrolein1,2,3
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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US FDA PMTA Draft Guidance for ENDS Products recommends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
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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
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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
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CEM Discovery SP Hybrid
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Analyte Yield Comparison
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140 puffs using 55 ml Puff Volume, 5 sec Puff Duration, 30 sec Puff Period; Square Wave
0
5
10
15
20
25
30
Formaldehyde Acetaldehyde Acrolien
An
aly
te A
mo
un
t (µ
g /
g)
Liquid
Microwave
Aerosol
Crotonaldehyde was not detected
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Identify Source of Degradation Products
Using 13C-labeled PG and GLY
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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)
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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
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Product Distribution Using 13C3-PG
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50% 13C3-PG : 50% GLY + 2.5 % Nicotine (w/w)
26.1
4.7
0.7
0
5
10
15
20
25
30C
on
ce
ntr
ati
on
(µ
g / g
)
25.1%
93.2% 94.0%
74.9%
6.8% 6.0%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Pe
rce
nta
ge o
f To
tal A
naly
te 13C-PG
GLY
13C 13C 13C
Crotonaldehyde was not detected
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Product Distribution using 13C3-GLY
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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
Pe
rce
nta
ge
of
To
tal
An
aly
te
PG
13C-GLY
Crotonaldehyde was not detected
13C 13C
13C
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Summary: 13C-Labeling Studies
Formaldehyde was predominantly formed from GLY
Acetaldehyde and acrolein were predominantly formed
from PG
Crotonaldehyde was not detected
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Determine the Role of 3-hydroxypropanal
(3-HPA) as an Intermediate During the
Thermal Degradation of e-Liquids
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3-Hydroxypropanal Background
Researchers proposed formaldehyde and acetaldehyde are
produced from the retro-aldol condensation of
3-hydroxypropanal (3-HPA)4,7
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3-HPA Fortification Studies
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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
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Results: 3-HPA Fortification (N=3)
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50% PG : 50% GLY + 2.5 % Nicotine (w/w)
0
100
200
300
400
500
600
Unfortified 350 700 1400
An
aly
te A
mo
un
t (µ
g /
g)
3-HPA Fortification (µg)
Formaldehyde Acetaldehyde Acrolein
Acrolein Yield ~ 30%
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Summary: 3-Hydroxypropanal (3-HPA)
Unfortified e-liquids - 3-HPA, acrolein, and crotonaldehyde were not detected
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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
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Suggested Formation Pathways in Aerosol 3-HPA was not detected
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Formaldehyde from Glycerin
Acetaldehyde from Propylene Glycol
Acrolein from Propylene Glycol
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Determine Key Reaction Centers
Using Rationally Selected
Derivatives of PG and GLY
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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)
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Microwave Heating:
180 °C for 3 min
DNPH Derivatization
UPLC-UV-MS/MS
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GLY Derivatives: Formaldehyde
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Methoxy Derivatives
Methyl Derivatives
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Formaldehyde: GLY Derivatives
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Results support proposed mechanism
0
10
20
30
40
50
Control D E G F H N O P R Q
Fo
rmald
eh
yd
e (
µg
/ g
)
Control
Methoxy Derivatives
Methyl Derivatives
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PG Derivatives: Acetaldehyde and Acrolein
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Methoxy Derivatives
Methyl Derivatives
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Acetaldehyde: PG Derivatives Results do not support proposed mechanism
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0
10
20
30
40
Control A B C I M J K L
Ac
eta
lde
hyd
e (
µg
/ g
)
Control
Methoxy Derivatives
Methyl Derivatives
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Acrolein: PG Derivatives Results support proposed mechanism
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0.00
0.10
0.20
0.30
0.40
Control A B C I M J K L
Ac
role
in (
µg
/ g
)
Control
Methoxy Derivatives
Methyl Derivatives
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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
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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
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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.
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