Analysis of Extractable Compounds
from a Pressurized Metered-Dose
Inhaler (pMDI) Using GC/MSD
Systems
Application Note
Pharmaceuticals
Authors
Abstract
Diana M. Wong and Roger L. Firor
A pressurized metered-dose inhaler (pMDI) is an inhalation device developed for the
Agilent Technologies, Inc.
direct delivery of active pharmaceutical ingredient (API) to the respiratory tract for
Wilmington, DE, USA
the treatment of respiratory conditions. Rubber and plastic components in the pMDI
David Weil
Agilent Technologies, Inc.
Schaumburg, IL, USA
are potential sources of extractables by the API/propellant. Therefore, volatile and
semivolatile extractable compounds were investigated in these components using
two 5977 GC/MSD systems. This application note focuses on identifying extractables in the pMDI using the complementation of headspace GC/MS and MMI
GC/MS.
Industry guidelines and working groups provide the basis for
the analysis of extractables/leachables testing in drug
delivery and medical devices. The Product Quality Research
Institute (PQRI) is a leading working group established to
develop regulatory guidance for extractables/leachables
analysis. PQRI is recognized by the FDA and has released a
recommendation document that includes safety thresholds for
orally inhaled and nasal drug products (OINDP). Several other
guidelines and assessments on extractable and leachable
testing exist, including chapters from USP<661>, USP<1663>,
USP<1664>, USP<1665>, and regulations from international
organizations EP 3.2.2.1 and EP 3.2.8. The intent of this application note is not to provide safety impact or toxicological
information. Recent articles by Dennis Jenke [3], PQRI working group [4,5], and the Extractable Leachable Safety
Information Exchange (ELSIE) group address these issues [6].
Introduction
A regulatory expectation for drug manufacturers is to perform
a safety risk assessment for the presence of potential leachable and extractable compounds in medical devices that may
occur during the manufacturing process. Extractables are
chemical compounds that can be extracted from a pharmaceutical packaging component using high temperatures to
obtain a leachable profile at the worst case scenario or solvent extraction to mimic similar properties of the drug product. Leachables are chemical compounds from the packaging
material that have leached into the drug product. Leachables
are often a subset of extractables and new compounds may
form due to the packaging-drug interaction. Compound
migration involves correlating extractables to leachables.
Extractables determine potential compound migration, while
leachables determine actual compound migration. If leachables are identified, it is necessary to consult with the United
States Food and Drug Administration (FDA) and toxicological
safety guidelines for the acceptable amount. Sources of
leachable/extractable compounds include plastic and elastomeric components, inks and adhesives from labeling, residual impurities from manufacturing, and degradation products
from processing, storage, and sterilization [1,2].
Table 1.
A pressurized metered-dose inhaler (pMDI) is a pharmaceutical construct in the high risk category (Table 1). Inhalation
aerosols/solutions have the highest degree of concern based
on the route of administration [7]. The pMDI administers a
precise amount of medication directly to the lungs in the form
of a short burst of aerosolized drug suspension self-administered through inhalation for treating asthma and respiratory
diseases [8].
Risk Associated with Various Pack Types
Degree of concern
associated with route
of administration
Likelihood of interaction between packaging component and dosage form
High
Medium
Low
Highest
Inhalation aerosols and solution
Injections and injectable suspensions
Sterile powders
Injection powders
Inhalation powders
High
Ophthalmic solutions and suspensions
Transdermal ointments and patches
Nasal aerosols and sprays
Low
Topical solutions and suspensions
Topical and lingual aerosols
Oral solutions and suspensions
Topical powders
Oral powders
Oral tablets
Oral hard capsules
Oral soft gelatin capsules
Adapted from Guidance for Industry; Container Closure Systems for Packaging Human Drug and Biologics, US Department of
Health and Human Services, Food and Drug Administration, Rockville, MD, May 1999.
2
Elastomeric, plastic, and metal components of the pMDI are
capable of leaching compounds into the API formulation due
to the close contact. Components that have the highest likelihood of interaction with the API/propellant include: canister
(metal), retaining cup (plastic), two gaskets (rubber), metering
valve (plastic), o-ring (rubber), valve stem (plastic), spring
(metal), and actuator nozzle (plastic) (Figure 1A). The API
formulation is stored in the canister where the retaining cup
fills with the precise dosage under gravity. When the canister
is pressed, the metering valve delivers an accurate dose of
medication through the stem to the actuator nozzle. The
rubber components (gaskets and o-ring) are placed snugly
around the stem to prevent leakage of API formulation when
the valve is in the closed position. The mouthpiece directs the
API formulation (Figure 1B).
A
Canister (metal)
Drug/propellant
liquid mixture
Actuator
Retaining cup (plastic)
Gaskets (rubber)
Metering valve (plastic)
O-ring (rubber)
Stem (plastic)
Actuator nozzle (plastic)
Metering chamber
High velocity spray
Mouthpiece
B
When canister is
pressed, channel
opens between
metering chamber
and atmosphere
Elastomeric components in the pMDI are considered the
major source of extractables. Rubber seals can swell because
of solubility with the propellant. Heptafluoroalkane (HFA) propellants have been identified as suitable alternatives to the traditional chlorofluorocarbon (CFC) propellants that have been
implicated in stratospheric ozone depletion. HPA propellant is
not soluble with surfactants that are necessary to create an
API formulation. Thus, surfactant and ethanol (cosolvent) are
commonly used in conjunction to increase solubility. However,
ethanol causes swelling of elastomers, increases extractives
of gasket material, and affects the amount of lubrication
between the stem and gaskets. Efforts are in progress to
reformulate HFA propellant and to create valves that exhibit
low levels of extractables/leachables.
Droplets form at nozzle:
2-phase gas-liquid air-blast
Propellants boils
in expansion
chamber
Ligament
produced
from shearing
force
Figure 1.
Evaporation and cooling
Design of a pressurized metered dosed inhaler (A) and operation
of the metering valve (B).
Experimental Methods
This application note focuses on identifying volatile and
semivolatile extractable compounds in an expired pMDI
device using two GC/MS systems. Two types of analysis were
used: headspace sampling and large volume liquid injection.
Plastic and rubber components were investigated using
aggressive extraction conditions, which were intended for
quantitative determination of chemical additives rather than
simulation of a drug product leachable profile. Compounds in
pMDI components were extracted using different solvents
and using high-temperatures.
Materials and instrumentation
The pMDI used in the investigation was expired for
six months and was manufactured by a leading pharmaceutical company. The canister contained fluticasone propionate in
HFA-134a propellant. Extractables analysis of pMDI components were investigated at high temperatures using the
Agilent 7697A Headspace Sampler and an Agilent 7890 Series
GC coupled with an Agilent 5977A MSD (Headspace GC/MS).
Dichloromethane (DCM) (650463), hexane (34859), and
ethanol (459844) were solvents used for extraction and were
purchased from Sigma-Aldrich. Solvent extracts were
analyzed using the Agilent 7693A Automatic Liquid Sampler
(ALS) and a 7890 Series GC coupled with a 5977A MSD. The
ALS was equipped with a multimode inlet (MMI) operated in
solvent vent mode for large volume liquid injection
(MMI GC/MS).
3
Sample preparation
Table 2.
Extractables analysis using MMI GC/MS
Rubber and plastic pMDI components (1-cm2 pieces) were
placed in separate vials for analysis. Components were rinsed
with water to minimize any residue from the API formulation.
Ethanol, DCM, and hexane were solvents used to extract
elastomeric components. DCM and hexane were solvents
used to extract plastic components. Elastomeric seals
(80–90 mg) were extracted with 3.0 mL of solvent. The stem
(100–120 mg) was extracted with 2 mL of solvent. The retaining cup (230–270 mg) was extracted with 3 mL of solvent. The
metering valve (270–280 mg) was extracted with 5 mL of solvent. The actuator nozzle (140–170 mg) was extracted with
5 mL of solvent. Components were extracted with solvent in a
12-mL amber glass vial, sonicated for 5 hours, and allowed to
sit at room temperature for 1–2 days. The organic layer was
transferred to a glass insert placed inside an amber autosampler vial for GC/MS analysis. Ten microliters of extract were
injected using the MMI operated in solvent vent mode. The
solvent elimination wizard was used to develop parameters
specific to the analysis of DCM, hexane, and ethanol extracts.
Similar GC and MSD parameters were used for all extract
analyses (Table 2).
GC and MSD Instrument Parameters for Analysis of DCM Extract
Using MMI GC/MS
Gas chromatograph
Agilent 7890 Series GC
Injection port
Multimode Inlet (MMI), CO2 cooling
Mode
Solvent vent
Inlet program*
–5 °C (0.7 minutes) to 325 °C (5 minutes) at
600 °C/min
Liner
2-mm id, dimpled, ultra inert (p/n 5190-2297)
Inlet vent
100 mL/min (5 psi) until 0.7 minutes
Carrier gas
Helium
Purge flow to split vent 60 mL/min at 3.15 minutes
Extractables analysis using headspace GC/MS
Oven program
50 °C (3 minutes) to 350 °C (5 minutes) at 6 °C/min
Columns
Agilent J&W-5msUI, 30 m × 250 µm, 0.25 µm
(p/n 19091S-433UI)
MSD
Agilent 5977A MSD
Transfer line
280 °C
MS source
300 °C
MS Quad
175 °C
Tune
atune.u
Scan
29 to 700 amu, 2.2 scans/sec
Threshold
150
Gain factor
1.0
Software
Agilent MassHunter B.07.00
*Initial temperature and initial hold time differs depending on solvent extract.
Components (1-cm2 pieces) of pMDI were analyzed in separate 10-mL headspace vials. The components consisted of
seals (90 mg), retaining cup (440 mg), valve stem (230 mg),
metering valve (410 mg), and actuator nozzle (320 mg).
Headspace vials were purged with nitrogen, sealed with a
high-performance PTFE crimp cap, and investigated at headspace equilibration temperature of 250 °C. Table 3 lists the
system parameters.
4
Table 3.
Compound identification
Instrument Parameters Using Headspace GC/MS
Headspace
Agilent 7697A Headspace Sampler
Vial pressurization gas
Helium
Loop size
1.0 mL
Vial standby flow
50 mL/min
Transfer line
0.53 mm id, deactivated fused silica
HS oven temperature
250 °C
HS loop temperature
250 °C
HS transfer line temperature
270 °C
Vial equilibration time
25 minutes, level 2 shake
GC run time
80 minutes
Vials
10 mL, PTFE/silicone septum
Vial fill mode
Flow to pressure
Vial fill pressure
15 psi
Loop fill mode
Custom
Loop ramp rate
20 psi/min
Loop final pressure
1.5 psi
Loop equilibration time
0.05 minutes
Carrier control mode
GC carrier control
Extraction mode
Single
Vent after extraction
ON
Post injection purge
100 mL/min for 1 minutes
Gas chromatograph
Agilent 7890 Series GC
Injection port
Split/Splitless
Liner
0.75-mm ultra-inert, straight, tapered
(p/n 5190-4048)
Inlet temperature
280 °C
Inlet flow
Constant flow, 1.3 mL/min
Split ratio
30:1
Carrier gas
Helium
Oven program
35 °C (2 minutes)
to 320 °C (3 minutes) at 8 °C/min
Columns
Agilent J&W-5ms UI, 30 m × 0.25 mm, 0.5 µm
(p/n 19091S-133UI)
MSD
Agilent 5977A MSD
Transfer line
280 °C
MS Source
280 °C
MS Quad
180 °C
Tune
atune.u
Scan
15 to 700 amu, 2.5 scans/sec
Threshold
0
Gain Factor
1.0
Software
Agilent MassHunter B.07.01
Chemical compounds were characterized using MSD
Chemstation Data Analysis F.01.01, AMDIS 2.72, and
Agilent MassHunter Unknowns Analysis B.07.00. Mass spectra of all compounds were matched with the NIST14 Library
2.2. Compounds with a match score ¡80 were considered
and the top match was selected for investigation.
Results and Discussion
Elastomeric (rubber) seals
Volatiles and semivolatiles investigation of rubber seals using
headspace GC/MS showed peaks attributed to (Figure 2A):
•
•
•
•
•
Softening agent (1,3-dioxolane)
Antioxidant in lubricant (1-naphthalenol)
Releasing agents (palmitic acid)
Rubber composition (octadecanamide, octadecanenitrile)
Molding material (cyclohexasiloxane, dodecamethyl-)
Semivolatiles testing of solvent extracts of rubber seals using
MMI GC/MS showed an extractable profile consisting of
(Figure 2B):
Ethanol extract
• Curing agents in silicone rubber system (Dynasil A)
• Residual solvents (acetophenone)
• Surface active agents (myristic acid)
• Ingredients in rubber products (oleic acid)
• Lubricants (stearic acid)
• Slip agents (oleimide)
• Sealants (13-docosenamide)
• Stabilizers (tris(2,4-di-tert-butylphenyl)phosphate)
DCM extract
• Thermodegradation products (nonanal)
• Antioxidants (2,4-di-tert-butylphenol)
• Monomers (dodecyl acrylate)
Hexane extract
• Wax from the vulcanization of rubber (docosane)
• Antioxidant (Irganox 1076)
5
Counts
Counts
×106
Peak ID
16. 2-Pentene, 2,4,4-trimethyl3.6 A
1. 2-Propanol, 2-methyl17. 2-Ethyl-1-hexanol, trifluoroacetate
25
2. Acetic acid
18. Disulfide, bis(1,1,3,3-tetramethylbutyl)
3.4 TIC of rubber seal (250 °C)
3. 1,3-Dioxolane
19. Cyclohexasiloxane, dodecamethylBackground
3.2
4. Benzene
20. 2,4-Di-tert-butylphenol
Rubber seal
3.0
5. Propanoic acid
21. 1-Naphthalenol
2.8
6. 1-Pentene, 2,4,4-trimethyl22. Phthalate, cyclobutyl propyl
29
7. Pyrrole
23. Myristic acid
2.6
8. 2-Pentanone, 4,4-dimethyl24. Pentadecanenitrile
2.4
9. Propanenitrile, 2-hydroxy25. Palmitic acid
2.2
10. 1,3,5-Trioxepane
26. Octadecanenitrile
2.0
11. 2-Cyclopenten-1-one
27. trans-13-Octadecenoic acid
12. 4-Pentenenitrile, 2-methylene1.8
28. cis-Vaccenic acid
15
13. Benzonitrile
29. Stearic acid
1.6
14. Heptane, 2,2,6,6-tetramethyl30. Octadecanamide
1.4
4-methylene31. Tetracosamethyl-cyclododecasiloxane
1.2
15. 3-Heptene, 2,2,4,6,6-pentamethyl32. Cyclodecasiloxane, eicosamethyl18
1.0
1
28
0.8
27
0.6
24
26
14 17
0.4 3 6
9
20
16
23
0.2 2 4 5 7 8 10
12 13
32
31
21
30
19
22
11
0
3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59
Acquisition time (min)
×107
1.9
Peak ID
B
28 17. 1-Octadecanol
1.8
1. Hexanal, 2,2-dimethylTIC
of
rubber
seal
(ethanol
extract)
18. cis-13-Octadecenoic acid
1.7
2. 2,5-Hexanedione
19. Oleic acid
Background
1.6
3. Dynasil A
20. Stearic acid
Rubber seal
4. Cyclohexanone, 3,3,5-trimethyl1.5
21. Octadecanoic acid, ethyl ester
5. 2,5-Hexanediol, 2,5-dimethyl1.4
22. 1,8-Diazacyclotetradecane-2,7-dione
6. Acetophenone
1.3
23. Behenic alcohol
7. Ethyl benzoate
1.2
24. Oleimide
8. 1-Dodecanol
20
25. Antioxidant BKF
1.1
9. 2,4-Di-tert-butylphenol
26. Di(oct-3-yl) phthalate
1.0
10. Ethyl 4-ethoxybenzoate
27. 13-Docosenamide, (Z)11. Diethyl phthalate
0.9
28. tris(2,4-di-tert-butylphenyl)
16
12. 1-Tetradecanol
0.8
phosphate
13. Phenol, 4-(1,1,3,3-tetramethylbutyl)0.7
29. Fluticasone propionate
14. Myristic acid
19
0.6
15. Dodecyl acrylate
15
0.5
16. Palmitic acid
18
0.4
29
21
0.3
5
22 24
14
6
0.2 2 3
23 25 26
27
8 9 11 12 13
4
7
0.1 1
17
10
0
7
9
11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49
Acquisition time (min)
Figure 2.
Extractables analysis of a rubber seal using headspace equilibrium temperature of 250 °C (A) and ethanol extraction by MMI GC/MS (B).
6
Semivolatiles testing of solvent extracts of retaining cup using
MMI GC/MS showed an extractable profile consisting of
(Figure 3B):
Retaining cup
Volatiles and semivolatiles investigation of retaining cup
using headspace GC/MS showed peaks attributed to
(Figure 3A):
•
•
•
DCM extract
• Antioxidant (2,4-di-tert-butylphenol)
• Plasticizers (Kodaflex TXIB)
• Lubricants (1-hexadecanol)
• Stabilizer (Metilox)
Flavor/fragrance (2,3-butanedione)
Softening agent (1,3-dioxolane)
Thermoplastic composition
(eicosamethyl cyclodecasiloxane)
Hexane extract
• Catalyst (ethyl 4-ethoxybenzoate)
• Phthalate plasticizers (diethyl phthalate)
• Monomer (dodecyl acrylate)
×106
6.0
A
TIC of retaining cup (250 °C)
Background
Retaining cup
5.6
5.2
Peak ID
1. Methylal
2. 2,3-Butanedione
3. 1,3-Dioxolane
4. 1,3-Dioxolane, 2-methyl5. 1,3,5-Trioxane
6. Ethanol, 2-(vinyloxy)7. 1,2-Ethanediol, monoformate
8. 1,3,5-Trioxepane
9. 1,2-Ethanediol, diformate
10. 1,3,5-Trioxane
11. 3-Heptene, 2,2,4,6,6-pentamethyl12. 5-Methyl-2,4-diisopropylphenol
13. Octane, 1,1'-oxybis14. Cyclodecasiloxane, eicosamethyl-
7
4.8
4.4
4.0
Counts
3.6
3.2
2.8
2.4
1
2.0
2
1.6
1.2
4
3
8
5
6
0.8
9
10
0.4
12
11
13
14
0
3
5
7
9
11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59
Acquisition time (min)
×106
B
5.2
TIC of retaining cup (DCM extract)
Background
Retaining cup
4.8
4.4
4.0
3.6
Counts
3.2
8
Peak ID
1. 2,4-Di-tert-butylphenol
2. Kodaflex TXIB
3. 1-Hexadecanol
4. Phenol, 4-(1,1,3,3-tetramethylbutyl)5. 1,2-Benzenediol, o-(4-methoxybenzoyl)-o'-(2,2,3,3,4,4,4-heptafluorobutyryl)6. Dodecyl acrylate
7. 7,9-Di-tert-butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-dione
8. Metilox
2.8
7
2.4
2.0
1.6
6
1.2
0.8
0.4
1
0
2
4
3
5
18.8 19.2 19.6 20.0 20.4 20.8 21.2 21.6 22.0 22.4 22.8 23.2 23.6 24.0 24.4 24.8 25.2 25.6 26.0 26.4 26.8 27.2 27.6 28.0 28.4 28.8
Acquisition time (min)
Figure 3.
Extractables analysis of a retaining cup using headspace equilibrium temperature of 250 °C (A) and
DCM extraction by MMI GC/MS (B).
7
Semivolatiles testing of solvent extracts of the plastic
metering valve using MMI GC/MS showed an extractable
profile consisting of (Figure 4B):
Metering valve
Volatiles and semivolatiles investigation of plastic metering
valve using headspace GC/MS showed peaks attributed to
the compounds listed below (Figure 4A). Octadecanitrile was
also observed in headspace GC/MS analysis of elastomeric
seal at a similar retention time (Figure 2A), indicating
potential compound migration.
•
•
•
•
•
•
•
•
•
•
Hexane extract
• Plasticizer (Kodaflex TXIB)
• Thermoplastic decomposition (eicosamethyl cyclodecasiloxane)
• Antioxidants (Antioxidant BKF)
• Stabilizers (tris(2,4-di-tert-butylphenyl)phosphate)
Solvents (pyridine)
Processing aids (butyrolactone)
Catalysts (propylbenzene)
Monomers (succinimide)
Odor agents (2-pentylcyclopentanone)
Antioxidant for lubricants (1-naphthalenol)
Releasing agents (palmitic acid)
Lubricants (stearic acid)
Plasticizers (diisooctyl phthalate)
Rubber component (octadecanenitrile)
×106 A
2.6
TIC of metering valve (250 °C)
Background
Metering valve
9
2.4
DCM extract
• Plasticizers (Kodaflex TXIB)
• Catalyst (ethyl 4-ethoxybenzoate)
• Polymer byproducts (styrene-acrylonitrile trimer)
• Lubricant (13-docosenamide)
2.2
2.0
Counts
1.8
5
1.6
1.4
1.2
23
1.0
0.8
31
0.6
0.4 1
7
2
6
0.2 34
8
10
12
11 14
13 15
16
17
22
21
20
24 25
18 19
28
26
30
29
27
32
Peak ID
1. Butanal
2. 2-Pentenal, (E)3. 1-Butanol
4. 2H-Pyran, 3,4-dihydro5. Pentanal
6. Propanoic acid
7. Pyridine
8. Pentanenitrile
9. Cyclopentanone
10. Cyclopentanone, 2-methyl11. Pentanoic acid
12. 2-Butenal, 2-ethenyl13. Butyrolactone
14. Benzene, propyl15. Benzaldehyde
16. Pentanamide
17. 2H-Pyran-2-one, tetrahydro18. Succinimide
19. 2-Piperidinone
20. 2-Pentylcyclopentanone
21. Caprolactam
22. Benzenebutanal
23. [1,1'-Bicyclopentyl]-2-one
24. Benzenebutanol
25. Cyclopropylphenylmethane
26. 1-Naphthalenol
27. 3-Octadecene, (E)28. Palmitic acid
29. Octadecanenitrile
30. Methyl stearate
31. Stearic acid
32. 1,8-Diazacyclotetradecane-2,7-dione
33. Diisooctyl phthalate
33
0
3
5
7
9
11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55
Acquisition time (min)
×106 B
1.1 TIC of metering valve (hexane extract)
Background
7
1.0
Metering valve
0.9
0.8
Counts
0.7
0.6
0.5
0.4
16
0.3
0.2
0.1
0
12
3
4
910
5
6 8
12
11
13 14
Peak ID
1. Kodaflex TXIB
2. Hexadecane
3. 1-Tetradecanol
4. Cyclononasiloxane, octadecamethyl5. Octadecane
6. Isobutyl 4-octyl phthalate
7. Dodecyl acrylate
8. Phenanthrene, 1-methyl9. Cyclodecasiloxane, eicosamethyl10. Butyl 4-methylpent-2-yl phthalate
11. Phenanthrene, 2,5-dimethyl12. Cyclodecasiloxane, eicosamethyl13. Tetracosamethyl-cyclododecasiloxane
14. bis(2-ethylhexyl) fumarate
15. Antioxidant BKF
16. tris(2,4-di-tert-butylphenyl) phosphate
15
22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
Acquisition time (min)
Figure 4.
Extractables analysis of a metering valve using headspace equilibrium temperature of 250 °C (A) and hexane extraction by MMI GC/MS (B).
8
Valve stem
DCM extract
• Odor agents (nonanal)
• Resins (dimethyl adipate)
• Adhesives (2,4,7,9-Tetramethyl-5-decyn-4,7-diol)
• Lubricants (1-dodecanol)
• Antioxidants (2,4-di-tert-butylphenol)
• Plasticizers (Kodaflex TXIB)
• Photoinitiators (Irgacure 184)
• Comonomer/intermediate (dodecyl acrylate)
• Antioxidant in polypropylene
(7,9-di-tert-butyl-1oxaspiro(4,5)deca-6,9-diene-2,8-dione)
• Plasticizer (Irganox 1076)
Volatiles and semivolatiles testing of valve stem using
headspace GC/MS showed an extractable profile consisting
of (Figure 5A):
•
•
•
•
•
•
Preservatives (formic acid)
Softening polymer (1,3-dioxolane)
The manufacture of polyols (hydroxyacetone)
Catalysts (ethyl 4-ethoxybenzoate)
Thermoplastic compositions (eicosamethyl cyclodecasiloxane)
Resins (hexadecamethyl cyclooctasiloxane)
Semivolatiles investigation of solvent extracts in valve stem
using MMI GC/MS showed peaks attributed to (Figure 5B):
Hexane extract
• Odor agents (nonanal)
• Molding material (dodecamethyl cyclohexasiloxane)
• Phthalate plasticizer (hept-4-yl isobutyl phthalate)
×106
6.8 1 3 A
TIC of stem (250 °C)
6.4
Background
6.0
Stem
5.6
5.2
4.8
6
4.4
4.0
3.6
3.2
2.8
2.4
2.0 2
1.6
5
10
1.2
8
0.8
9
7
4
13
0.4
14
11 12
0
3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57
Acquisition time (min)
×106
Counts
Peak ID
1. Formic acid
2. 1,3-Dioxolane
3. 1,3-Dioxolane, 2-methyl4. Hydroxyacetone
5. 1,3,5-Trioxane
6. 1,2-Ethanediol, monoformate
7. 1,3,5-Trioxepane
8. 1,2-Ethanediol, diformate
9. 1,3-Propanediol
10. 1,3,5-Trioxane
11. 5-Methyl-2,4-diisopropylphenol
12. Ethyl 4-ethoxybenzoate
13. Cyclooctasiloxane, hexadecamethyl14. Cyclodecasiloxane, eicosamethyl-
B
5.6
5.2
4.8
Peak ID
1. Nonanal
2. Dimethyl glutarate
3. Dimethyl adipate
4. Nonanoic acid
5. Glycerol 1,2-diacetate
6. 2,4,7,9-Tetramethyl-5-decyn-4,7-diol
7. p-Diacetylbenzene
8. 2,6-Di-tert-butyl-p-benzoquinone
9. 1-Dodecanol
10. 2,4-Di-tert-butylphenol
11. Ethyl 4-ethoxybenzoate
12. Kodaflex TXIB
13. Irgacure 184
14. 3,5-di-tert-Butyl-4-hydroxybenzaldehyde
15. Dodecyl acrylate
16. 7,9-Di-tert-butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-dione
17. Irganox 1076
17
TIC of stem (DCM extract)
Background
Stem
4.4
4.0
Counts
3.6
3.2
16
2.8
2.4
2.0
8
1.6
15
1.2
11
0.8
5
0.4
0
11
Figure 5.
12
7
3 4
2
1
13
14
15
6
16
17
18
9
10
19
20
21
23
Acquisition time (min)
12
13
24
25
14
26
27
28
29
30
Extractables analysis of the valve stem using headspace equilibrium temperature of 250 °C (A) and DCM extraction by MMI GC/MS (B).
9
Semivolatiles testing of solvent extract in plastic nozzle using
MMI GC/MS showed peaks attributed to (Figure 6B):
Actuator nozzle
Volatiles and semivolatiles analysis of plastic nozzle using
headspace GC/MS showed peaks attributed to the
compounds listed below (Figure 6A). Dye additive could be
attributed to the colorant in the actuator.
•
•
•
•
•
•
•
•
•
•
•
DCM extract
• Odor agents (2,7-dimethyl-1-octanol)
• Antioxidants (butylated hydroxytoluene, Irgafos 168, 4,4'-ethylenebis(2,6-di-tert-butylphenol))
• Catalysts (ethyl 4-ethoxybenzoate)
• Releasing agents (palmitic acid)
• Stabilizers (tris(2,4-di-tert-butylphenyl) phosphate)
Monomers (acetic acid)
Manufacture of dyes (hydroxyacetone)
Paint/coating (2-pentanone)
Solvents for polymers (methyl isobutyl ketone)
Fragrances (4-methyl-4-penten-2-one)
UV stabilizer (2,4-di-tert-butylphenol)
Catalysts (ethyl 4-ethoxybenzoate)
Releasing agents (palmitic acid)
Lubricants (stearic acid)
Antioxidants (Irgafos 168)
Stabilizers (tris(2,4-di-tert-butylphenyl) phosphate)
Hexane extract
• Lubricants (phytane)
• Antioxidants (butylated hydroxytoluene)
• Catalysts (ethyl 4-ethoxybenzoate)
• Monomers (dodecyl acrylate)
• Thermal conversion of plastics (heneicosane)
• Wax (hentriacontane)
• Antioxidants (Irgafos 168)
• Stabilizers (tris(2,4-di-tert-butylphenyl) phosphate)
×10 7 A
1.0 TIC of actuator nozzle (250 °C)
Background
Nozzle
0.9
Peak ID
1. 1-Pentene, 2-methyl2. Acetic acid
3. Hydroxyacetone
4. 2-Pentanone
5. 2,4-Dimethylfuran
6. Methyl isobutyl ketone
7. 4-Penten-2-one, 4-methyl8. Heptane, 4-methyl9. Acetylacetone
10. 3-Penten-2-one, 4-methyl11. Heptane, 2,4-dimethyl12. 2,4-Dimethyl-1-heptene
13. Octane, 4-methyl14. 2,5-Hexanedione
15. 2-Heptanone, 4-methyl16. 2-Heptanone, 4,6-dimethyl-
11
0.8
0.7
Counts
0.6
17
0.5
12
20
15
0.4
18
13
4
23
21
0.3 1
3 6
9
2 5 8
10
7
0.2
0.1
22 24
19
16
25
26
14
27 28
29
30
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
Dodecane
Octane, 3,5-dimethylUndecane
Dodecane, 2,6,11-trimethylDecane, 3,6-dimethylHeptadecane, 2,6,10,15-tetramethyl2,4-Di-tert-butylphenol
Ethyl 4-ethoxybenzoate
Heptadecane
Hexadecane, 2,6,11,15-tetramethylEicosane, 2-methylPalmitic acid
Stearic acid
Irgafos 168
tris(2,4-Di-tert-butylphenyl) phosphate
31
0
3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 65 67
Acquisition time (min)
×10
2.6
7
B
TIC of actuator nozzle (DCM extract)
Background
Nozzle
2.4
2.2
17
2.0
1.8
Counts
1.6
1.4
1.2
18
1.0
7
0.8
8
10
13
0.6
15
24
0.4 1
3 5
0.2
14
9 11
6
16
12
Peak ID
1. Heptane, 2,4-dimethyl2. Dodecane
3. 1-Octanol, 2,7-dimethyl4. Octane, 2,3,6,7-tetramethyl5. Undecane, 4-methyl6. 2-Bromo dodecane
7. Dodecane, 2,6,11-trimethyl8. Pentadecane
9. Butylated hydroxytoluene
10. Ethyl 4-ethoxybenzoate
11. Pentadecane, 2-methyl12. Tremetone
13. Hexadecane, 2,6,11,15-tetramethyl14. Pentacosane
15. Palmitic acid
16. 4,4'-Ethylenebis(2,6-di-tert-butylphenol)
17. Irgafos 168
18. tris(2,4-Di-tert-butylphenyl) phosphate
0
5
Figure 6.
7
9
11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49
Acquisition time (min)
Extractables analysis of an actuator nozzle using headspace equilibrium temperature of 250 °C (A) and DCM extraction by MMI GC/MS (B).
10
Volatile and semivolatile extractable compounds identified in
pMDI components included monomers, polymers, adhesives,
lubricants, surfactants, odor agents, paint additives, coating
additives, plasticizers, resins, intermediates, antioxidants,
UV-stabilizers, stabilizers, flavor and fragrance byproducts,
colorants, regulators, processing aids, thermoplastic compositions, adhesives, wax from vulcanization of rubber,
preservatives, photoinitiators, rubber ingredients, curing
agents, finishing agents, dyes, and residual solvents. Table 4
contains a list of all extractables identified in pMDI.
Most extractables were identified only by solvent extraction
or only by high-temperature headspace sampling. For
instance, oleimide is a slip agent/lubricant that was identified
by ethanol extraction. Irganox 1076 is an antioxidant that was
characterized using hexane extraction. 3-chlorophenyloctyl
terephthalate is used in the production of polyester that was
identified by DCM extraction. 2-pentanone is a painting/coating additive that was characterized using high-temperature
headspace sampling. Table 3 lists the extraction technique
and pMDI component used to identify the particular
extractable.
Table 4. Extractables identified in pMDI device
Compounda
Extraction
(component)b
[1,1'-Bicyclopentyl]-2-one
HS(V)
Originc
1,2-Benzenediol, o-(4-methoxybenzoyl)-o'-(2,2,3,3,4,4,4-heptafluorobutyryl)- D(C)
1,2-Ethanediol, diformate
HS(C);HS(S)
1,2-Ethanediol, monoformate
HS(C);HS(S)
1,3,5-Trioxane
HS(C);HS(S)
1,3,5-Trioxepane
HS(R);HS(C);HS(S)
1,3-Dioxolane
HS(R);HS(C);HS(S)
1,3-Dioxolane, 2-methyl-
HS(C);HS(S)
Softening polymer (PA and PVC)
1,3-Propanediol
HS(S)
Polyester polymer
1,8-Diazacyclotetradecane-2,7-dione
E(R); D,HS(V)
Ingredient in polymer
13-Docosenamide, (Z)-
E(R),D(V)
Adhesives, sealant, lubricants
1-Butanol
HS(V)
Manufacture of polymers, pyroxylin, plastics
1-Dodecanol
D(S), E(R)
Surfactants, lubrication, polymers
1-Hexadecanol
D(C), H(R)
Lubrication, odor agent, paint and coating additive,
plasticizer
1-Naphthalenol
HS(R,V)
Intermediate for antioxidants in lubricants
1-n-Hexyladamantane
H(R)
1-Octadecanol
E(R)
Lubricants, resins
Odor agent
1-Octanol, 2,7-dimethyl-
D(N)
1-Pentene, 2,4,4-trimethyl-
HS(R)
1-Pentene, 2-methyl-
HS(N)
1-Phenoxypropan-2-ol
H(S)
1-Tetradecanol
E(R),H(C);H(V);H(S)
2,2,4-Trimethyl-1,3-pentanediol diisobutyrate
D(C);D,H(V);D(S)
Plasticizer
2,3-Butanedione
HS(C)
Flavor
2,4,7,9-Tetramethyl-5-decyn-4,7-diol
D(S)
Adhesives, surfactants
2,4-Dimethyl-1-heptene
HS(N)
2,4-Dimethylfuran
HS(N)
2,4-Di-tert-butylphenol
D(C,S); HS(N); E,H,D,HS(R)
2,5-Cyclohexadiene-1,4-dione, 2,6-bis(1,1-dimethylethyl)-;
2,6-di-tert-butyl-p-benzoquinone
D(S)
11
UV stabilizer, potential migrant
Compounda
Extraction
(component)b
2,5-Hexanediol, 2,5-dimethyl-
E,D(R)
Originc
Intermediate
2,5-Hexanedione
E(R);HS(N)
Deodorizing agent
2-[1-(4-Cyano-1,2,3,4-tetrahydronaphthyl)]propanenitrile;
styrene-acrylonitrile trimer
D(V)
Byproduct in acrylonitrile styrene plastics
2-Bromo dodecane
D(N)
2-Butenal, 2-ethenyl-
HS(V)
2-Butenedioic acid (E)-, bis(2-ethylhexyl) ester; bis(2-ethylhexyl)fumarate
H(V)
2-Cyclopenten-1-one
HS(R)
2-Ethyl-1-hexanol, trifluoroacetate
HS(R)
2-Heptanone, 4,6-dimethyl-
HS(N)
2-Heptanone, 4-methyl-
HS(N)
2H-Pyran, 3,4-dihydro-
HS(V)
2H-Pyran-2-one, tetrahydro-; d-valerolactone
HS(V)
Intermediate (copolymer) in polyester
2-Pentanone
HS(N)
Paint and coating additives
2-Pentanone, 4,4-dimethyl-
HS(R)
2-Pentenal, (E)-
HS(V)
Flavor and fragrance agent
2-Pentene, 2,4,4-trimethyl-
HS(R)
2-Pentylcyclopentanone
HS(V)
Odor agent
2-Piperidinone
HS(V)
Intermediate (copolymer)
2-Propanol, 2-methyl-
HS(R)
2-Propanone, 1-hydroxy-; hydroxyacetone
HS(S);HS(N)
3,5-di-tert-Butyl-4-hydroxybenzaldehyde
D(C,S)
3-[1-(4-Cyano-1,2,3,4-tetrahydronaphthyl)]propanenitrile
D(V)
3-Heptene, 2,2,4,6,6-pentamethyl-
HS(C); H,D,HS(R)
Manufacture of polyols, acrolein, dyes
3-Octadecene, (E)-
HS(V)
3-Penten-2-one, 4-methyl-
HS(N)
Flavor and fragrance
4,4'-Ethylenebis(2,6-di-tert-butylphenol)
D(N)
Stabilizer and antioxidant for polyolefins
4-Penten-2-one, 4-methyl-
HS(N)
Flavor and fragrance
4-Pentenenitrile, 2-methylene-
HS(R)
5-Methyl-2,4-diisopropylphenol
HS(C,S)
7,9-Di-tert-butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-dione
D(C,S)
Antioxidant in polypropylene
9-Octadecenamide, (Z)-; oleimide
E(R)
Slip agent, lubricant, corrosion inhibitor;
potential to leach
Acetic acid
HS(R,N)
Production of vinyl acetate monomer
Solvent for plastic and resins
Acetophenone
E(R)
Acetylacetone
HS(N)
Behenic alcohol
E,H(R)
Lubricant
Benzaldehyde
HS(V)
Precursor to plastic additives
Benzene
HS(R)
Benzene, propyl-
HS(V)
Benzenebutanal
HS(V)
Benzenebutanol
HS(V)
Benzenepropanoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-, methyl ester; D(C);D(S); H(R)
Irganox 1076
12
Catalyst for olefin polymerization
Polymer stabilizer
Compounda
Benzoic acid, 4-ethoxy-, ethyl ester; ethyl 4-ethoxybenzoate
Extraction
(component)b
Originc
E(R);H(C);D(V);D,HS(S);
D,H,HS(N)
Catalyst for olefin polymerization
Benzoic acid, ethyl ester; ethyl benzoate
E(R)
Fragrance
Benzonitrile
HS(R)
Butanal
HS(V)
Intermediate
Butylated hydroxytoluene (BHT)
D,H(N)
Antioxidant
Butyrolactone
HS(V)
Colorant; intermediates, process regulators,
processing aid, solvents
Caprolactam
HS(V)
Precursor to nylon 6, a widely used synthetic polymer
cis-13-Octadecenoic acid
E,H,D(R)
Lubrication in plastics and coatings
cis-Vaccenic acid
HS(R)
Cyclodecasiloxane, eicosamethyl-
HS(R);HS(C);H(V);HS(S)
Thermoplastic
Cycloheptasiloxane, tetradecamethyl-
H(S)
Resin
Cyclohexanone, 3,3,5-trimethyl-
E(R)
Monomer for polycarbonate; polymerization initiator,
coating, paint, gloss and surface finish
Cyclohexasiloxane, dodecamethyl-
HS(R);H(S)
Intermediate, solvent, molding material
Polymer synthesis
Cyclononasiloxane, octadecamethyl-
H(C);H(V);H(S)
Cyclooctane, 1,4-dimethyl-, trans-
H(N)
Cyclooctasiloxane, hexadecamethyl-
H,HS(S)
Thermoplastic, resin
Cyclopentanone
HS(V)
Fragrance
Cyclopentanone, 2-cyclopentylidene-
D(V)
Cyclopentanone, 2-methyl-
HS(V)
Cyclopropylphenylmethane
HS(V)
Decane, 3,6-dimethyl-
HS(N)
Dibutyl phthalate
H(C)
Potentially toxic plasticizer
Diethyl phthalate
E,H(R);H(C)
Potentially toxic plasticizer
Diisooctyl phthalate
HS(V)
Potentially toxic plasticizer
Disulfide, bis(1,1,3,3-tetramethylbutyl)
HS(R)
Docosane
H(R)
Dodecane
D,H,HS(N)
Dodecane, 2,6,11-trimethyl-
D,H,HS(N)
Dodecyl acrylate
E,D(R);D,H(C);H(V);D,H(S);
H(N)
Eicosane, 2-methyl-
HS(N)
Ethanol, 2-(vinyloxy)-
HS(C)
Ethanone, 1,1'-(1,4-phenylene)bis-; p-diacetylbenzene
D(S)
Fluticasone propionate
E(R);D(V)
Wax in vulcanization of rubber
Intermediate, comonomer
Corticosteroid used to treat asthma
Formic acid
HS(S)
Preservative and antibacterial agent
Glycerol 1,2-diacetate
D(S)
Thermal conversion of plastics
Heneicosane
H(N)
Hentriacontane
H(N)
Heptadecane
HS(N)
Heptadecane, 2,6,10,15-tetramethyl-
HS(N)
Heptane, 2,2,6,6-tetramethyl-4-methylene-
HS(R)
Heptane, 2,4-dimethyl-
D,H,HS(N)
13
Wax
Compounda
Extraction
(component)b
Heptane, 4-methyl-
HS(N)
Originc
Hexadecane
H(V)
Pyrolysis of plastic
Hexadecane, 2,6,10,14-tetramethyl-; phytane
H(N)
Plasticizers, lubricant
Hexadecane, 2,6,11,15-tetramethyl-
D,HS(N)
Hexadecanoic acid; palmitic acid
E,H,D,HS(R);HS(V);
D,HS(N)
Hexanal, 2,2-dimethyl-
E(R)
Hexanedioic acid, dimethyl ester; dimethyl adipate
D(S)
Hexestrol
D(R)
Isophthalic acid, 3,5-difluorophenyl octyl ester;
3,5-difluorophenyl isophthalate
D(R)
Isophthalic acid, ethyl tridec-2-ynyl ester; ethyl tridec-2-ynyl isophthalate
D(R)
Methanone, (1-hydroxycyclohexyl)phenyl-; Irgacure 184
D(S)
Releasing agent, plasticizer
Photoinitiator
Methyl isobutyl ketone
HS(N)
Solvent for lacquers, polymers and resin
Methyl stearate
HS(V)
Lubricant and surfactants
Methylal
HS(C)
Blowing agent in PU foam system
Nonanal
D(R);D,H(S)
Causes off-taste/odor due to thermo degradation of
polyolefins containers, antioxidants are usually added
to counter
Nonanoic acid
D(S)
Plasticizers; lubricants, paints and coating, plastic and
rubber products
Octadecanamide
HS(R)
Additives in rubber
Octadecane
H(V)
Plasticizer in PVC
Octadecanenitrile
HS(R);HS(V)
Rubber composition
Octadecanoic acid, 2-propenyl ester; allyl stearate
H(R)
Lubricant
Octadecanoic acid, ethyl ester; ethyl stearate
E(R)
Fragrance, plasticizer, lubricant
Octadecanoic acid; stearic acid
E,H,D,HS(R);HS(V);HS(N)
Lubricant, softening, and release agents; soften PVC;
potential to migrate
Octane, 1,1'-oxybis-
HS(C)
Octane, 2,3,6,7-tetramethyl-
D(N)
Octane, 3,5-dimethyl-
HS(N)
Octane, 4-methyl-
H,HS(N)
Oleic acid
E(R)
Plasticizer; ingredient in rubber
Pentacosane
D,H(N)
Plasticizer
Pentadecane
D(N)
Aliphatic hydrocarbon plasticizer with potential
to migrate
Pentadecane, 2-methyl-
D(N)
Pentadecanenitrile
HS(R)
Pentanal
HS(V)
Odor agent
Pentanamide
HS(V)
PA-6 additives (potential migration)
Pentanedioic acid, (2,4-di-t-butylphenyl) mono-ester
H(C)
Pentanedioic acid, dimethyl ester; dimethyl glutarate
D(S)
Pentanenitrile
HS(V)
Pentanoic acid; valeric acid
HS(V)
Phenanthrene, 1-methyl-
H(V)
Phenanthrene, 2,5-dimethyl-
H(V)
14
Resin, viscosity
Lubricant
Compounda
Extraction
(component)b
Originc
Phenol, 2,2'-methylenebis[6-(1,1-dimethylethyl)-4-methyl-; Antioxidant BKF
E,D(R);H(V)
Antioxidant in rubber and plastic
Phenol, 2,4-bis(1,1-dimethylethyl)-, phosphite (3:1); Irgafos 168
D,H,HS(N)
Antioxidant, potential migration
Phenol, 4-(1,1,3,3-tetramethylbutyl)-
E,H,D(R);D(C)
Phthalic acid, butyl 4-methylpent-2-yl ester; butyl 4-methylpent-2-yl phthalate H(V)
Phthalate plasticizer; potentially toxic
Phthalic acid, di(oct-3-yl) ester; di(oct-3-yl) phthalate
E(R)
Phthalate plasticizer; potentially toxic
Phthalic acid, hept-4-yl isobutyl ester; hept-4-yl isobutyl phthalate
H(S)
Phthalate plasticizer; potentially toxic
Phthalic acid, isobutyl 4-octyl ester; isobutyl 4-octyl phthalate
H(V)
Phthalate plasticizer; potentially toxic
Propanenitrile, 2-hydroxy-
HS(R)
Propanoic acid
HS(R);HS(V)
Antimicrobial packaging material
Propanoic acid, 2-methyl-, 3-hydroxy-2,2,4-trimethylpentyl ester;
2,4,4-trimethyl-1,3-pentanediol monoisobutyrate (Kodaflex TXIB)
D(V)
Plasticizer
Pyridine
HS(V)
Solvent and reagent
Pyrrole
HS(R)
Monomer
Silane, diethylheptyloxyoctadecyloxy-
D(N)
Succinimide
HS(V)
Monomer
Terephthalic acid, 3-chlorophenyl octyl ester;
3-chlorophenyl octyl terephthalate
D(R)
Monomer
Tetracosamethyl-cyclododecasiloxane
HS(R);H(C);H(V);H(S)
Tetracosane
H(R)
Plastic decomposition; diffusion out of rubber
Tetradecanoic acid; myristic acid
E,D,HS(R)
Adhesives, sealant, finishing agent, lubrication,
surface active agents
Tetraethyl silicate; Dynasil A
E(R)
Curing agent; crosslinker in silicone rubber system
trans-13-Octadecenoic acid
HS(R)
Tremetone
D,H(N)
Toxic compound
tris(2,4-Di-tert-butylphenyl) phosphate
E,H(R);H(V);D,H,HS(N)
Stabilizer for polymers
Undecane
HS(N)
Lubricant
Undecane, 4-methyl-
D(N)
a
Compounds are alphabetized based on name listed in NIST14 library. Common names are indicated in blue.
b
Solvent extraction: ethanol (E), dichloromethane (D), and hexane (H). High-temperature headspace sampling (HS). pMDI components: rubber seal (R), retaining
cup (C), valve stem (S), metering valve (V), and actuator nozzle (N)
c
Origin of compounds are based on literature reference [3].
15
4. D. L. Norwood, et al. Best practices for extractables and
leachables in orally inhaled and nasal drug products: an
overview of the PQRI recommendations. Pharm. Res. 25,
727-739 (2008).
Conclusion
The complementation of headspace GC/MS and MMI GC/MS
provided a broad extractables profile of compounds that can
be extracted from a pMDI. Most of the compounds identified
were specific to high-temperature headspace sampling or
solvent extraction techniques. The MMI in solvent vent mode
allows for the detection of low-level leachable/extractable
compounds by making large volume injection. Headspace
sampling simplifies sample preparation as the pMDI component can be placed directly into the headspace vial for
analysis. MMI GC/MS and headspace GC/MS provide a
nontargeted approach to determine an extractables/leachables profile. GC/Q-TOF and GC/MSMS would be the next
step for targeted compound analysis. This application note is
not intended to do quantitation on the extractable and leachable components. Literature contains references on using
GC/MS and GC/MSMS to quantify the presence of potential
endrocrine disruptors, such as phthalates, extracting from
pMDI devices [9,10].
5. L. Dick. Best Practices of Routine Extractables Testing
[Webinar]. IPAC-RS Materials Webinar (2012, Sept 13).
Retrieved from http://solutions.3m.com/
3MContentRetrievalAPI/BlobServlet?lmd=1352355247000
&locale=en_WW&assetType=MMM_Image&assetId=131
9241566419&blobAttribute=ImageFile
6. L. M. Nagao, et al. The ELSIE Extractables and Leachables
Database. Pharmaceutical Outsources, Journal of
Pharmaceutical & Biopharmaceutical Contract Services
(2011, Nov 01). Retrieved from http://www.pharmoutsourcing.com
7. Guidance for Industry; Container Closure Systems for
Packaging Human Drug and Biologics, US Department of
Health and Human Services, Food and Drug
Administration, Rockville, MD, May 1999.
8. J. H. Wildhaber, et al. “Inhalation therapy in asthma:
Nebulizer or pressurized metered-dose inhaler with
holding chamber? In vivo comparison of lung deposition in
children” J. Pediatr. 135, 28–33 (1999).
References
1. D. J. Ball, et al. Safety Evaluation, Qualification, and Best
Practices Applied to Inhalation Drug Products. In
Leachables and Extractables Handbook, John Wiley &
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