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.

Introduction

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].

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. 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.

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.

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 patient
presses the canister, 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 into the patient's lungs (Figure 1B).

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
Patient presses
canister, 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).

Sample preparation

Table 2.

Extractables analysis 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)

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
(8090 mg) were extracted with 3.0 mL of solvent. The stem
(100120 mg) was extracted with 2 mL of solvent. The retaining cup (230270 mg) was extracted with 3 mL of solvent. The
metering valve (270280 mg) was extracted with 5 mL of solvent. The actuator nozzle (140170 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 12 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

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 HP-5msUI, 30 m 250 m, 0.25 m

(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.

Table 3.

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 HP-5ms UI, 30 m 0.25 mm, 0.5 m

(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

Gain Factor

1.0

Software

Agilent MassHunter B.07.01

Compound identification
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)

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
32
31
21
30
13
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
7
4
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).

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

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-

4.8
4.4
4.0
Counts

3.6
3.2
2.8
2.4

2.0

1.6
1.2

4
3

8
5
6

0.8

10

0.4

12

11

13

14

0
3

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

5.2

TIC of retaining cup (DCM extract)

Background
Retaining cup

4.8
4.4
4.0
3.6

Counts

3.2

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

1.2
0.8
0.4

4
2

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).

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

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

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

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

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).

Semivolatiles investigation of solvent extracts in valve stem

using MMI GC/MS showed peaks attributed to (Figure 5B):

Valve stem
Volatiles and semivolatiles testing of valve stem using
headspace GC/MS showed an extractable profile consisting
of (Figure 5A):

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)

Preservatives (formic acid)

Softening polymer (1,3-dioxolane)
The manufacture of polyols (hydroxyacetone)
Catalysts (ethyl 4-ethoxybenzoate)
Thermoplastic compositions (eicosamethyl cyclodecasiloxane)
Resins (hexadecamethyl cyclooctasiloxane)

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-

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

0.4
0

11

Figure 5.

12

3 4

13

14

15

6
16

17

18

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).

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

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

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

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.

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 4 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)

1,3-Propanediol

HS(S)

1,8-Diazacyclotetradecane-2,7-dione

E(R); D,HS(V)

Ingredient in polymer

13-Docosenamide, (Z)-

E(R),D(V)

Adhesives, sealant, lubricants

Softening polymer (PA and PVC)

Polyester polymer

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

1-Octanol, 2,7-dimethyl-

D(N)

Odor agent

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)

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)

Originc

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

Acetophenone

E(R)

Solvent for plastic and resins

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

Extraction
(component)b

Originc

Benzoic acid, 4-ethoxy-, ethyl ester; ethyl 4-ethoxybenzoate

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

Cyclononasiloxane, octadecamethyl-

H(C);H(V);H(S)

Polymer synthesis

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)

Wax in vulcanization of rubber

Intermediate, comonomer

Ethanol, 2-(vinyloxy)-

HS(C)

Ethanone, 1,1'-(1,4-phenylene)bis-; p-diacetylbenzene

D(S)

Fluticasone propionate

E(R);D(V)

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

Corticosteroid used to treat asthma

Wax

Compounda

Extraction
(component)b

Heptane, 4-methyl-

HS(N)

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)

Originc

Releasing agent, plasticizer

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)

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)

Compounds are alphabetized based on name listed in NIST14 library. Common names are indicated in blue.

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)

Origin of compounds are based on literature reference [3].

15

Conclusion

References

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/MS/MS 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 [7,8].

1. D. J. Ball, et al. Safety Evaluation, Qualification, and Best

Practices Applied to Inhalation Drug Products. In

Leachables and Extractables Handbook, John Wiley &
Sons (2012).
2. A. Feilden. Update on Undertaking Extractable and
Leachable Testing 1st ed. Smithers-Rapra (2011).
3. D. Jenke, T. Carlson. A Compilation of Safety Impact
Information for Extractables Associated with Materials
Used in Pharmaceutical Packaging, Delivery,
Administration, and Manufacturing Systems PDA J.
Pharm. Sci. Technol. 68, 407-455 (2014).
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).
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. J. Chan, F. Shuang. Rapid, Sensitive, and Robust Detection
of Phthalates in Food Using GC/MS or LC/MS.
Agilent Technologies Application Note, publication number
5990-9510EN (2012).
8. X. Ye, et al. Analysis of 21 phthalate leachables in
metered dose inhalers by gas chromatography tandem
mass spectrometry Anal. Methods, 6,
4083-4089 (2014).

For More Information

These data represent typical results. For more information on
our products and services, visit our Web site at
www.agilent.com/chem.

16

17

www.agilent.com/chem
Agilent shall not be liable for errors contained herein or for incidental or consequential
damages in connection with the furnishing, performance, or use of this material.
Information, descriptions, and specifications in this publication are subject to change
without notice.

Agilent Technologies, Inc., 2015

Printed in the USA
October 9, 2015
5991-6142EN