Tetrafluoroethane (HFC)

1 Nonproprietary Names pressure, or as a gas when exposed to room temperature and

atmospheric pressure. The liquid is practically odorless and
None adopted.
colorless. The gas in high concentrations has a slight etherlike
odor. Tetrafluoroethane is noncorrosive, nonirritating, and
2 Synonyms nonflammable.
Dymel 134a/P; fluorocarbon 134a; Frigen 134a; Genetron
134a; HFA 134a; HFC 134a; Isceon 134a; Klea 134a; 9 Pharmacopeial Specifications
propellant 134a; refrigerant 134a; Solkane 134a; Suva 134a; —
Zephex 134a.

10 Typical Properties
3 Chemical Name and CAS Registry Number
Boiling point: 26.28C
1,1,1,2-Tetrafluoroethane [811-97-2] Critical pressure: 4.11 MPa (40.55 atm)
Critical temperature: 101.08C
4 Empirical Formula and Molecular Weight Density:
1.226 g/cm3 for liquid at 208C;
C2H2F4 102.0 1.207 g/cm3 for liquid at 258C.
Flammability: nonflammable.
5 Structural Formula Freezing point: 1088C
Kauri-butanol value: 8
Solubility: soluble in ethanol (95%), ether, and 1 in 1294 parts
of water at 208C.
Surface tension: 8.6 kN/m
Vapor density (absolute): 4.466 g/cm3 at standard temperature
and pressure.
Vapor density (relative): 3.53 (air = 1)
Vapor pressure:
6 Functional Category 569 kPa at 208C;
662 kPa at 258C.
Aerosol propellant. Viscosity (dynamic):
0.222 mPa s (0.222 cP) for liquid at 208C;
7 Applications in Pharmaceutical Formulation 0.210 mPa s (0.210 cP) for liquid at 258C.
or Technology
Tetrafluoroethane is a hydrofluorocarbon (HFC) or hydro- 11 Stability and Storage Conditions
fluoroalkane (HFA) aerosol propellant (contains hydrogen, Tetrafluoroethane is a nonreactive and stable material. The
fluorine, and carbon) as contrasted to a CFC (chlorine, liquified gas is stable when used as a propellant and should be
fluorine, and carbon). The lack of chlorine in the molecule stored in a metal cylinder in a cool dry place.
and the presence of hydrogen reduces the ozone depletion
activity to practically zero. Hence tetrafluoroethane can be
considered as an alternative to CFCs in the formulation of 12 Incompatibilities
metered-dose inhalers (MDIs).(1–9) It has replaced CFC-12 as a The major incompatibility of tetrafluoroethane is its lack of
refrigerant since it has essentially the same vapor pressure. Its miscibility with water. Since it has a very low Kauri-butanol
very low Kauri-butanol value and solubility parameter indicate value, tetrafluoroethane is considered to be a very poor solvent
that it is not a good solvent for the commonly used surfactants for most drugs used in MDI formulations. It also shows a low
for MDIs. Sorbitan trioleate, sorbitan sesquioleate, oleic acid, solubility for some of the commonly used MDI surfactants.
and soya lecithin show limited solubility in tetrafluoroethane
and the amount of surfactant that actually dissolves may not be
sufficient to keep a drug readily dispersed. 13 Method of Manufacture
When tetrafluoroethane (P-134a) is used for pharmaceutical Tetrafluoroethane can be prepared by several different routes;
aerosols and MDIs, the pharmaceutical grade must be specified. however, the following routes of preparation illustrate the
Industrial grades may not be satisfactory due to their impurity methods used:
profiles. Isomerization/hydrofluorination of 1,1,2-trichloro-1,2,2-
trifluoroethane (CFC-113) to 1,1-dichloro-1,2,2,2-tetrafluoro-
ethane (CFC-114a), followed by hydrodechlorination of the
8 Description
latter.
Tetrafluoroethane is a liquefied gas and exists as a liquid at Hydrofluorination of trichloroethylene, via 1-chloro-1,1,1-
room temperature when contained under its own vapor trifluoroethane (HCFC-133a).
 Tetrafluoroethane (HFC) 7 73

14 Safety Currently, there are no pharmacopeial specifications for

tetrafluoroethane. However, typical specifications are shown in
Tetrafluoroethane is used as a refrigerant and as a non-CFC
Table I.
propellant in various aerosols including pharmaceuticals
(MDIs). Tetrafluoroethane is regarded as nontoxic and non-
irritating when used as directed. No acute or chronic hazard is
present when exposures to the vapor are below the acceptable Table I: Typical product specifications for tetrafluoroethane.
exposure limit (AEL) of 1000 ppm, 8-hour and 12-hour time
weighed average (TWA).(10) In this regard it has the same value Test Value
as the threshold limit value (TLV) for CFC-12. Inhaling a high
concentration of tetrafluoroethane vapors can be harmful and Appearance Clear and colorless
is similar to inhaling vapors of CFC-12. Intentional inhalation High boiling impurities 40.01%
of vapors of tetrafluoroethane can be dangerous and may cause Acidity as HCl 40.1 ppm
death. The same labeling required on CFC aerosols would be Non-volatile residue 45 ppm
required for those containing tetrafluoroethane as a propellant Non-absorbable gases 41.5 %
(except for the EPA requirement). See Chlorofluorocarbons, Water 410 ppm
Section 14. Total unidentified impurities 410 ppm
Assay 599.99 %

15 Handling Precautions
Tetrafluoroethane is usually encountered as a liquefied gas and
appropriate precautions for handling should be taken. Eye
protection, gloves, and protective clothing are recommended.
Tetrafluoroethane should be handled in a well-ventilated
environment. The vapors are heavier than air and do not
support life; therefore, when cleaning large tanks that have
contained the propellant, adequate provisions for oxygen
supply in the tanks must be made in order to protect workers
cleaning the tanks.
Although nonflammable, when heated to decomposition
tetrafluoroethane emits toxic fumes.
In the UK, the long-term exposure limit (8-hour TWA) for
tetrafluoroethane is 4240 mg/m3 (1000 ppm).(11)
16 Regulatory Status
Included in the FDA Inactive Ingredients Guide (aerosol
formulations for inhalation and nasal applications). Included
in nonparenteral medicines licensed in the UK.
17 Related Substances
Difluoroethane; heptafluoropropane.
18 Comments
The use of tetrafluoroethane as a propellant for MDIs has been
the subject of numerous patents throughout the world. These
patents cover the formulation of MDIs and use of specific
surfactants, cosolvents, etc. A US patent claims a self-propelling
aerosol formulation that may be free of CFCs and which
comprises a medicament, 1,1,1,2-tetrafluoroethane, a surface-
active agent, and at least one compound having a higher
polarity than 1,1,1,2-tetrafluoroethane.(12) Another patent has
been issued by the European Patent Office and has 14 claims,
among them a claim that includes tetrafluoroethane, an alcohol
(such as ethanol), surfactant, and medicament.(13) The for-
mulator is referred to the patent literature prior to formulating
a MDI with tetrafluoroethane as the propellant. The formula-
tion of MDI with this non-CFC propellant is complicated since
tetrafluoroethane serves as a replacement for dichlorodifluor-
omethane or dichlorotetrafluoroethane. The use of an HFC as
the propellant also requires a change in manufacturing
procedure, which necessitates a redesign of the filling and
packaging machinery for a MDI.(14)
19 Specific References
1 Strobach DR. Alternative to CFCs. Aerosol Age 1988; 33(7): 32–
33, 42–43.
2 Daly J. Properties and toxicology of CFC alternatives. Aerosol Age
1990; 35(2): 26–27, 40.
3 Dalby RN, Byron PR, Shepherd HR, Papadopoulos E. CFC
propellant substitution: P-134a as a potential replacement for P-12
in MDIs. Pharm Technol 1990; 14(3): 26–33.
4 Kontny MJ, Destefano G, Jagen PD, et al. Issues surrounding MDI
formulation development with non-CFC propellants. J Aerosol
Med 1991; 4(3): 181–187.
5 Anonymous. 3M first with a CFC-free asthma inhaler. Pharm J
1995; 254: 388.
6 Taggart SCO, Custovic A, Richards DH, Woodcock A.
GR106642X: a new, non-ozone depleting propellant for inhalers.
Br Med J 1995; 310: 1639–1640.
7 Elvecrog J. Metered dose inhalers in a CFC-free future. Pharm
Technol Eur 1997; 9(1): 52–55.
8 Tansey IP. Changing to CFC-free inhalers: the technical and clinical
challenges. Pharm J 1997; 259: 896–898.
9 McDonald KJ, Martin GP. Transition to CFC-free metered dose
inhalers: into the new millenium. Int J Pharm 2000; 201: 89–107.
10 DuPont. Technical literature: Dymel 134a/P pharmaceutical grade
HFC-134a propellant, 1996.
11 Health and Safety Executive. EH40/2002: Occupational Exposure
Limits 2002. Sudbury: Health and Safety Executive, 2002.
12 Purewal TS, Greenleaf DJ. Medicinal aerosol formulations. United
States Patent No. 5,605,674; 1997.
13 Purewal TS, Greenleaf DJ. Medicinal aerosol formulations.
European Patent 372777B1; 1993.
14 Tzou T, Pachuta RR, Coy RB, Schultz RK. Drug form selection in
albuterol-containing metered-dose inhaler formulations and its
impact on chemical and physical stability. J Pharm Sci 1997; 86:
1352–1357.
20 General References
Harrison LI, Donnell D, Simmons JL, et al. Twenty-eight day double-
blind safety study of an HFA 134a inhalation aerosol system in
healthy subjects. J Pharm Pharmacol 1996; 48: 596–600.
Hoet P, Graf MLM, Bourdi M, et al. Epidemic of liver disease caused by
hydrochlorofluorocarbons used as ozone-sparing substitutes of
chlorofluorocarbons. Lancet 1997; 350: 556–559.
Sawyer E, Green B, Colton HM. Microorganism survival in non-CFC
propellant P134a and a combination of CFC propellants P11 and
P12. Pharm Technol 2001; 25(3): 90–96.
77 4 Tetrafluoroethane (HFC)

Steed KP, Hooper G, Brickwell J, Newman SP. The oropharyngeal and 21 Authors
lung deposition patterns of a fusafungine MDI spray delivered by
HFA 134a propellant or by CFC 12 propellant. Int J Pharm 1995; CJ Sciarra, JJ Sciarra.
123: 291–293.
Tiwari D, Goldman D, Dixit S, et al. Compatibility evaluation of
metered-dose inhaler valve elastomers with tetrafluoroethane 22 Date of Revision
(P134a), a non-CFC propellant. Drug Dev Ind Pharm 1998; 24:
345–352. 21 August 2005.