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THE PRIOR ART
The task of finding acceptable replacements for the widely used halocarbon
aerosol propellants is not an easy one. Over the years, most compounds
capable of generating the necessary pressures under packing conditions
have been tried, and the industry has settled for reasons of performance,
safety and cost on a relatively limited number of gaseous liquefiable
hydrocarbons, chlorofluorocarbons and a few other common non-toxic gases
such as nitrous oxide and carbon dioxide.
Until recently, chlorofluorocarbons such as propellant 11
(trichloromonofluoromethane) and propellant 114
(dichlorotetrafluoroethane), to name a few, appeared ideally suited for
aerosol propulsion in terms of stability, chemical inertness,
compatibility with aerosol package ingredients, lack of toxicity and
pressure-generating capacity. While they still benefit from this excellent
combination of physical and chemical properties within the aerosol pack
area, their continued use is being increasingly challenged because of
their alleged deleterious effect on the layer of ozone in the upper
atmosphere of the planet. In these circumstances, the search for
acceptable substitutes has become imperative. Propellant systems must be
located that possess essentially the same assortment of properties as the
chlorofluorocarbons but are free of the ozone-destroying chlorine.
In this respect, a review of the art for chlorine-free, stable compounds
capable of generating the necessary pressures did not prove very fruitful.
For instance, a few patents exists which teach the use of dimethylether as
aerosol propellant (U.S. Pat. No. 1,800,156). The extreme flammability of
this compound, however, accounts for its lack of favor over the years even
though attempts have been made to circumvent part of its disadvantages by
spraying it together with an aqueous aerosol phase (U.S. Pat. No.
3,207,386). As to the possibility of altering this undesirable facet of
what might otherwise be an acceptable propellant, by fluorination for
instance, the art would only lead the skilled practitioner to negative
conclusions about said possibilities. In terms of chemical stability, to
begin with, it is known that halogenation of the alpha-carbon of methyl
ethers causes instability in the molecule. Thus, compounds such as
CHF.sub.2.O.CH.sub.3 decompose either on standing or on distillation,
CH.sub.2 F.O.CHF.sub.2 decomposes in glass, while other fluorinated methyl
ethers are unstable under hydrolytic conditions such as may be found in
aerosol preparations. The fluorinated methyl ethers did not therefore
appear very promising on that account.
More importantly from the point of view of ecology, safety and health with
which the present invention is concerned, it must be realized that
whatever limited knowledge was available on the physiological properties
of fluorinated ethers was certainly not conducive to the selection of such
compounds for use as propellants in aerosol packaging, especially of
personal products such as toiletries and medicinals. Note the words of
Larsen in this respect [Fluorine Chemistry Rev., Vol. 3 (1969), page 20]
when he states that "as a class, fluorinated ethers show the widest
spectrum of unpredictable biological response, with some being extremely
potent convulsants while others are excellent anesthetics." Obviously,
neither of these properties has any appeal for uses such as those
presently contemplated. A striking illustration of what can be expected
from fluorinated ethers in general is afforded by the fact that
bis(2,2,2-trifluoroethyl) ether, a compound very closely related
chemically to that of the present invention, can evoke seizures in rats at
concentrations as low as 30 parts per million (weight/volume). It is
interesting to note also that this particular diethyl ether finds use as a
therapeutic convulsant in mental therapy [Goodman & Gilman, The
Pharmaceutical Basis of Therapeutics, 4th edition, pages 355-6, The
MacMillan Co. (1970)]. There is no need to list here any later published
data in support in Larsen's views on fluorinated alkyl ethers. Let us just
say that the recent developments in the fields of anesthesia and mental
therapy generally confirm these views.
As to the aerosol field, the most recent pertinent art reveals that two new
azeotropic mixtures composed of pentafluorodimethyl ether and dimethyl
ether can be used, inter alia, as propellants (U.S. Pat. No. 3,922,228).
The impact of this specific disclosure on the newly discovered utility of
the two ethers with which the present application is concerned shall be
discussed later in conjunction with the disclosure of the biological
behavior of the components of said azeotropic mixtures. More recently the
patent art (see U.S. Pat. No. 3,996,153) teaches that gaseous carbon
dioxide can be dissolved in certain solvents to provide a propellant
system. However, from data in the patent, such a solvent-gaseous carbon
dioxide system appears to leave a significant quantity of the pack in the
aerosol container when the gas pressure has fallen to about 75% of the
starting pressure. This then is the field in which the present inventors
prospected in order to find the substitutes for the chlorofluorocarbon
propellants that are eagerly sought by industry and government agencies
such as EPA (Chem. Eng. News, Concentrates, Jan. 12, 1976).
SUMMARY OF THE INVENTION
It has now been discovered that a superior aerosol propellant system is a
combination of liquefied bis(difluoromethyl) ether and gaseous carbon
dioxide wherein the gaseous propellant is from about 0.5 to about 4.0
weight percent based on weight of the bis(difluoromethyl) ether. These
compounds do not contain any chlorine and will not therefore contribute to
the destruction of atomspheric ozone that is said to take place when
conventional chloride-containing propellant gases accumulate in the upper
atomsphere. Furthermore, the bis(difluoromethyl) ether has been found to
be stable and non-toxic, unlike other known fluorinated methyl ethers.
DETAILED DESCRIPTION
The ether compound used in the present invention is a symmetrical dimethyl
ether on which at least two of the hydrogen atoms on each carbon have been
replaced by fluorine atoms. Bis(difluoromethyl) ether has been found to
possess the correct combination of physical, chemical and biological
properties which allows its use in aerosol packaging. It is stable on
storage, resistant to alkaline hydrolysis and is not flammable, even in
direct contact with a torch. The boiling point for bis(difluoromethyl)
ether is -2.degree. C. which corresponds to a vapor pressure of 20 psig
under standard conditions of temperature and pressure.
Perfluorodimethyl ether has a boiling point of -55.degree. C. and a vapor
pressure, under standard conditions of temperature and pressure, of 210
psig. Therefore there is no need to use a gaseous propellant with the
perfluorodimethyl ether described and claimed in parent application, now
U.S. Pat. No. 4,041,148.
The combination of the liquefied propellant, bis(difluoromethyl) ether and
the gaseous propellant, carbon dioxide, yields unexpectedly superior
aerosol patterns and results in the complete discharge of the contents
from the aerosol package as the data in the examples herein will
demonstrate. Other known propellants, i.e., trichlorofluoromethane (Freon
11), methylene chloride when combined with gaseous carbon dioxide do not
provide satisfactory aerosol patterns nor is there a complete discharge of
the contents of the aerosol package.
In preparing an aerosol package, the desired pressure is achieved by mixing
bis(difluoromethyl) ether and carbon dioxide with other liquids involved
in the aerosol preparation and this in whatever proportions indicated by
the conditions at hand. The propellant system of this invention may also
be used together with other conventional gaseous aerosol propellants in
order to achieve various purposes such as changes in compatibility with
specific aerosol preparation ingredients, cost, rate of delivery and the
like. Among usable propellants of that class are conventional gases such
as nitrous oxide, non-halogenated hydrocarbons as well as
fluorohydrocarbons, preferably -- in view of the principal object of the
present invention, those that do not contain any chlorine atoms. As to the
liquid carrier for the product to be dispensed, which does affect the
ultimate vapor pressure of the pack, it is selected from conventional
materials including ethyl alcohol in a weight ratio up to 50:50 with
bis(difluoromethyl) ether, perchloroethylene, trichloroethylene, acetone,
amyl acetate, water and the like. Dimethyl ether up to about 50% by weight
may be included in the propellant system without detracting from the
benefit of using the bis(difluoromethyl) ether-carbon dioxide combination.
In addition to the properties already described for the ether-carbon
dioxide propellant system of this invention, it must be noted that at the
concentrations likely to be created when aerosol products with which they
are packed are dispensed, no deleterious physiological effects will take
place. The compounds are not toxic and do not cause convulsions. Only a
mild anesthetic activity results when mice are exposed to
bis(difluoromethyl) ether for a two hour period. The active species, the
tetrafluoro compound, compares favorably in fact with plain dimethyl ether
in that it has a greater safety margin than the latter, as indicated by
the standard anesthetic index (A.I.) value for each compound, said values
being >3 and 1.3, respectively.
In view of the known chemical instability of ethers in which hydrogen atoms
on the alpha-carbon have been replaced by fluorine atoms -- an instability
which yields toxic products such as hydrogen fluoride for example, and
also in view of the number of known fluorinated dialkyl ethers which cause
convulsions when administered to mammals in small concentration, the
ethers of this invention were tested for biological activity. The
conventional tests that were carried out yielded the following data:
BIOLOGICAL TESTING OF FLUORINATED DIMETHYL ETHERS
Bis(difluoromethyl) ether. Mice were exposed to various concentrations
vapors of the ether in a chamber equipped with a bed of soda lime to
absorb carbon dioxide. The procedure used is standard for evaluation of
inhalation anesthetic and is similar to that of Robbins [Pharmacology and
Experimental Therapeutics 86, 197 (1946)]. Ten mice were exposed to each
concentration tested for a period of two hours. It was thus determined
that bis(difluoromethyl) ether is anesthetic but not toxic at
concentrations of up to slightly more than 20% by volume and that the
recovery time of mice anesthetized with the material is about 2 minutes.
No deaths were observed during and after exposure at those levels. The
anesthetic index of the tetrafluoromethyl ether was determined to be >3
which compares favorably, from the safety point of view, with that of
dimethyl ether, 1.3. The safety of the fluorinated ether was further
determined by exposing rats to a 5% concentration during 3 hours a day for
5 days, with no signs of convulsions nor deaths being noted.
Perfluorodimethyl ether. This compound was tested by exposing 6 mice a
concentration of vapors as high as 75% by volume for a period of 60
minutes. No recognizable biological effect was noted during and after
exposure. This is quite different from the behavior of the
hexafluorodiethyl ether discussed in the prior section which causes
convulsions in rats at 30 ppm.
Pentafluorodimethyl ether. This compound was tested, again by exposing six
mice to various vapor concentrations for a period of 60 minutes. All mice
died either within 75 minutes of exposure or by the next morning when
concentrations of 50, 25 and 12.5% were used. No discernable effects were
noted at 6 and 9% vapor concentrations. Upon autopsy, it appeared that the
mice died of pulomonary edema. Stable concentrations of the ether during
the test and the results of gas chromatography monitoring of the vapors
substantially ruled out the presence of both initial impurities and later
breakdown or metabolic products of the ether.
The picture that emerges from these tests and from the fluorinated alkyl
ether prior art discussed earlier is that two ethers one of which is used
in this invention are surprisingly different from most such alkyl ethers,
and especially from the pentafluorodimethyl ether that has been said to
have some utility, not by itself, but as a member of an azeotropic mixture
with dimethyl ether (U.S. Pat. No. 3,922,228).
However, as the data shows, that pentafluoro compound is not suited for use
in aerosolized personal products, such as toiletries and medicines, which
must come in intimate contact with the user in order to be effective.
The following examples are provided to illustrate various non-limiting
embodiments of the invention. Unless otherwise noted, all proportions used
are on a weight basis. Also in each preparation the propellant, the ethyl
alcohol and the aerosol can are cooled to -25.degree. C. to facilitate the
loading operation.
EXAMPLE 1
Aerosol containers were loaded with carbon dioxide and (1)
octafluorocyclobutane, (2) bis(difluoromethyl) ether, (3)
trichlorofluoromethane (CFCl.sub.3, Freon 11), (4) methylene chloride and
(5) 1,2dichloro,1,1,2,2 tetrafluoroethane (C.sub.2 Cl.sub.2 F.sub.4 Freon
114) respectively. The propellants were combined with approximately an
equal weight of denatured ethanol and the aerosol dispersion and spray
patterns examined. Ethanol was used as the pack material in order to
evaluate the aerosol patterns produced by various liquefied-carbon dioxide
combinations.
______________________________________
Liquid Wt. of Liquid
Wt. of Wt. of Aerosol
Propellant
Propellant,gms
CO.sub.2,gms
Ethanol,gms
Pattern
______________________________________
C.sub.4 F.sub.8
39.9 0.9 39.9 Good
(CF.sub.2 H).sub.2 O
32.3 1.0 31.7 Good
CFCl.sub.3
35 0.8 35.7 Poor
CH.sub.2 Cl.sub.2
31.3 0.9 31.9 Poor
CF.sub.2 ClCF.sub.2 Cl
25.8 0.6 25.8 Fair
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From this it is seen that commonly used liquefied propellants
CFCl.sub.3,CF.sub.2 ClCF.sub.2 Cl and CH.sub.2 Cl.sub.2 when combined with
gaseous carbon dioxide does not provide acceptable aerosol patterns.
Lesser known liquefied propellant octafluorocyclobutane when combined with
carbon dioxide does provide an acceptable spray pattern showing the
unpredictable behavior of liquefied propellants when combined with carbon
dioxide.
EXAMPLE 2
An aerosol container was loaded with 25 grams of ethanol and pressurized
with gaseous carbon dioxide to a pressure of 50 psig. The spraying
characteristics were extremely poor. The discharge of the ethanol was
essentially a pressure discharge with very little break up of the ethanol
stream. An acceptable aerosol spraying pattern was not obtained.
EXAMPLE 3
Bis(difluoromethyl) ether, 23.1 g, was added to denatured ethanol, 26.7 g.
The resulting mixture has a vapor pressure of 5 psig. Despite this low
pressure value, an aerosol system activited by this mixture formed a good
aerosol spray. By adding a small quantity of gaseous carbon dioxide, i.e.,
less than 0.5 g. to the bis(difluoromethyl) ether liquefied propellant a
low pressure formulation having an enhanced aerosol pattern and complete
pack discharge characteristics may be manufactured.
This particular type of low pressure formulation is singularly suitable for
pressurizing glass-contained aerosol systems such as are preferred for
esthetic reasons for dispensing perfumes, colognes and other toiletries.
EXAMPLE 4
A mixture consisting of 50.43% dimethyl ether and 49.57%
bis(difluoromethyl) ether was found to have a vapor pressure of 40 psig.
When this mixture 46 g was placed in an aerosol can with denatured
ethanol, 45 g, giving a 1:1 mix, a fine aerosol spray could be produced.
Mixtures of this type are particularly suitable as propellants for inhaled
aerosols. These are metered and of small capacity, so that the
flammability and abuse potential of dimethyl ether are limited. The
technique, on the other hand, renders available on the virtues of dimethyl
ether, namely its benign action on the heart, a vapor pressure
sufficiently high (62 psi at room temperatures) to permit blending with
bis(difluoromethyl) ether, and, because of solvent capacity, a probably
high compatibility with drugs.
By substituting gaseous carbon dioxide for a portion or all of the dimethyl
ether in this example all concern for the flammability and abuse potential
are essentially eliminated.
EXAMPLE 5
Aerosol containers were loaded with carbon dioxide and (1)
trichlorofluoromethane (CFCl.sub.3, Freon 11), (2) methylene chloride, (3)
bis(difluoromethyl) ether (CHF.sub.2 OCHF.sub.2), and (4)
octafluorocyclobutane (C.sub.4 F.sub.8) along with ethanol as in Example 1
above. The initial pressure and weight of the contents in each container
was noted. The contents of each container was then discharged through an
aerosol valve and the remaining pressure and/or the contents remaining in
each container were recorded at various stages until the container
pressure was 0 or until all the contents were discharged, whichever
occurred first. The results are tabulated below. The aerosol patterns for
octafluorocyclobutane and bis(difluoromethyl) ether were good, while poor
aerosol patterns were observed with trichlorofluoromethane and methylene
chloride.
__________________________________________________________________________
Pressure
in Wt. of Contents
Total Wt.
% of Contents
Propellant
Container
Remaining
Discharged
Dis-
System psig g.m gm. charged
__________________________________________________________________________
CFCl.sub.3 /CO.sub.2
41 55.7 0 0
36 49.9 5.8 10.4
with Ethanol
30 42.7 13.0 23.3
26 36.0 19.7 35.4
20 27.7 28.0 50.3
16 20.5 35.2 63.2
10 9.3 46.4 83.3
6 2.8 52.9 94.8
0 1.3 54.2 97.3
CH.sub.2 Cl.sub.2 /CO.sub.2
41 50.2 0 0
36 46.2 4.0 8.0
with Ethanol
30 40.7 9.5 18.9
26 34.7 15.5 30.9
20 27.6 22.6 45.0
16 20.8 28.9 57.6
10 11.5 38.2 76.1
6 5.2 44.5 88.6
0 0.9 48.8 97.2
CHF.sub.2 OCHF.sub.2 CO.sub.2
43 53.3 0 0
40 48.9 4.4 8.3
with Ethanol
36 42.9 10.4 19.5
30 32.1 21.2 39.8
26 22.7 30.6 57.4
20 13.2 40.1 75.2
14 0 53.3 100.0
C.sub.4 F.sub.8 /CO.sub.2
54 49.4
0 0
50 37.1 12.3 24.9
with Ethanol
44 12.9 36.5 73.9
40 8.3 41.1 83.2
35 4.1 45.3 91.7
30 2.3 47.1 95.3
25 0 49.4 100.0
CFCl.sub.3 /CO.sub.2
26 54.3 0 0
20 49.6 4.7 8.6
with Ethanol
16 41.8 12.5 23.0
12 32.0 22.3 41.1
8 21.3 33.0 60.8
4 16.3 38 70.0
0 6.0 48.3 89.0
CH.sub.2 Cl.sub.2 /CO.sub.2
29 53.2 0 0
22 43.3 9.9 18.6
with Ethanol
18 38.9 14.3 26.9
15 34.4 18.8 35.3
10 28.3 24.9 46.8
6 21.2 32.0 60.2
0 15.2 38.0 71.4
C.sub.4 F.sub.8 /CO.sub.2
45 53.8 0 0
with Ethanol
40 39.2 14.6 27.1
36 31.2 22.6 42.0
30 22.3 31.5 58.6
25 11.3 41.9 77.9
20 3.8 50.0 92.9
12 0 53.8 100.0
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The data in this example teaches incomplete discharge of contents using the
well known liquefied propellants Freon 11 and methylene chloride in
combination with carbon dioxide. Complete discharge of contents is
obtained using a propellant system comprising carbon dioxide and
bis(difluoromethyl) ether. The value of this discovery from a customer
acceptance standpoint is clear.
EXAMPLE 6
A 3% by weight solution of sorbitan trioleate was made in
bis(difluoromethyl) ether. There appeared to be no miscibility problems.
Sorbitan trioleate is commonly used as a vehicle for pharmaceutical
aerosols such as, for instance isoproterenol sulfate.
By adding a very small quantity of gaseous carbon dioxide, i.e., about 0.5
to 2.0 weight percent based on total pack, a pharmaceutical aerosol
allowing complete discharge of aerosol container contents is prepared.
It will be evident to the man skilled in the art that the aerosol
pressurizing system disclosed here can be employed with a large number of
conventionally aerosol packaged materials such as toiletries, household
and personal hygienic products, pharmaceuticals and medicines, and
generally any other type of product generally packed with the
chlorofluoroalkanes of the art, especially when the mode of use of such
product involves a toxicity potential for living species. Furthermore, it
shall be found in many instances that in terms of compatibility with both
organic and inorganic materials, the bis(difluoromethyl) ether-carbon
dioxide propellants system of the present invention are superior to the
oxygen-free molecules of the chlorofluoroalkanes.
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Description |
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