U.S. patent application number 09/924573 was filed with the patent office on 2002-02-07 for fluoroether compositions and methods for inhibiting their degradation in the presence of a lewis acid.
Invention is credited to Bieniarz, Christopher, Chang, Steve H., Cromack, Keith R., Huang, Shuyen L., Kawai, Toshikazu, Kobayashi, Manami, Loffredo, David, Raghavan, Rajagopalan, Speicher, Earl R., Stelmach, Honorate A..
Application Number | 20020016373 09/924573 |
Document ID | / |
Family ID | 25148366 |
Filed Date | 2002-02-07 |
United States Patent
Application |
20020016373 |
Kind Code |
A1 |
Bieniarz, Christopher ; et
al. |
February 7, 2002 |
Fluoroether compositions and methods for inhibiting their
degradation in the presence of a lewis acid
Abstract
The present invention relates to an anesthetic composition
containing a fluoroether compound and a physiologically acceptable
Lewis acid inhibitor. This composition exhibits improved stability
and does not readily degrade in the presence of a Lewis acid.
Inventors: |
Bieniarz, Christopher;
(Highland Park, IL) ; Chang, Steve H.; (Gurnee,
IL) ; Cromack, Keith R.; (Lake Bluff, IL) ;
Huang, Shuyen L.; (Riverwoods, IL) ; Kawai,
Toshikazu; (Saitama, JP) ; Kobayashi, Manami;
(Saitama, JP) ; Loffredo, David; (Elmhurst,
IL) ; Raghavan, Rajagopalan; (Grayslake, IL) ;
Speicher, Earl R.; (Buffalo Grove, IL) ; Stelmach,
Honorate A.; (Lake Forest, IL) |
Correspondence
Address: |
Steven F. Weinstock
ABBOTT LABORATORIES
Dept. 377/AP6D-2
100 Abbott Park Road
Abbott Park
IL
60064-6050
US
|
Family ID: |
25148366 |
Appl. No.: |
09/924573 |
Filed: |
August 8, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09924573 |
Aug 8, 2001 |
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09447853 |
Nov 23, 1999 |
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6288127 |
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Current U.S.
Class: |
514/723 ;
514/533; 514/729; 514/731 |
Current CPC
Class: |
A61K 47/12 20130101;
A61K 9/0019 20130101; A61K 47/02 20130101; A61K 31/08 20130101;
A61K 47/10 20130101; A61P 23/00 20180101; Y10S 514/816 20130101;
A61K 47/14 20130101 |
Class at
Publication: |
514/723 ;
514/533; 514/729; 514/731 |
International
Class: |
A61K 031/05; A61K
031/08 |
Claims
What is claimed is:
1. An anesthetic composition comprising a fluoroether compound
having an alpha fluoroether moiety having added thereto an
effective stabilizing amount of a Lewis acid inhibitor.
2. The composition of claim 1 wherein the fluoroether compound is
selected from a group consisting of sevoflurane, enflurane,
isoflurane, methoxyflurane, and desflurane.
3. The composition of claim 1 wherein the Lewis acid inhibitor is
selected from a group consisting of water, butylated
hydroxytoluene, methylparaben, propylparaben, propofol, and
thymol.
4. The composition of claim 1 wherein the fluoroether compound is
sevoflurane and the Lewis acid inhibitor is water.
5. The composition of claim 4 containing at least about 0.04% w/w
to about 0.14% w/w of water.
6. A method of preparing the anesthetic composition of claim 1
comprising the step of adding the Lewis acid inhibitor to the
fluoroether compound.
7. A method of preparing the anesthetic composition of claim 1
comprising the step of adding the fluoroether compound to the Lewis
acid inhibitor.
8. A method of stabilizing a fluoroether compound having an alpha
fluoroether moiety, the method comprising the step of adding to the
fluoroether compound an effective stabilizing amount of a Lewis
acid inhibitor to prevent the degradation of the fluoroether
compound by the Lewis acid.
9. The method of claim 8 wherein the fluoroether compound is
selected from a group consisting of sevoflurane, enflurane,
isoflurane, methoxyflurane, and desflurane.
10. The method of claim 8 wherein the Lewis acid inhibitor is
selected from a group consisting of water, butylated
hydroxytoluene, methylparaben, propylparaben, propofol and
thymol.
11. The method of claim 8 wherein the fluoroether compound is
sevoflurane and the Lewis acid inhibitor is water.
12. The method of claim 11 wherein the amount of water added to the
sevoflurane is from about 0.04% w/w to about 0.14% w/w.
Description
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates generally to stable,
anesthetic fluoroether compositions that do not degrade in the
presence of a Lewis acid. The present invention also relates to a
method of inhibiting the degradation of fluoroethers in the
presence of Lewis acids.
BACKGROUND OF THE INVENTION
[0002] Fluoroether compounds are commonly employed as anesthetic
agents. Examples of fluoroether compounds used as anesthetic agents
include sevoflurane
(fluoromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether),
enflurane ((.+-.-)-2-chloro-1,1,2-trifluoroethyl difluoromethyl
ether), isoflurane (1chloro-2,2,2-trifluoroethyl difluoromethyl
ether), methoxyflurane (2,2-dichloro-1,1-difluoroethyl methyl
ether), and desflurane ((.+-.-)-2-difluoromethyl
1,2,2,2-tetrafluoroethyl ether).
[0003] Although fluoroethers are excellent anesthetic agents, it
has been discovered that some fluoroethers experience stability
problems. More specifically, it has been determined that certain
fluoroethers, in the presence of one or more Lewis acids, degrade
into several products including potentially toxic chemicals such as
hydrofluoric acid. Hydrofluoric acid is toxic by ingestion and
inhalation and is highly corrosive to skin and mucous membranes.
Thereupon, the degradation of fluoroethers to chemicals such
hydrofluoric acid is of great concern to the medical community.
[0004] Degradation of fluoroethers has been found to occur in glass
containers. The degradation of fluoroethers in glass containers is
believed to be activated by trace amounts of Lewis acids present in
the container. The source of the Lewis acids can be aluminum
oxides, which are a natural component of glass. When the glass wall
becomes altered or etched in some manner, the aluminum oxide become
exposed and come into contact with the contents of the container.
The Lewis acids then attack the fluoroether and degrade it.
[0005] For example, when the fluoroether sevoflurane is contacted
with one or more Lewis acids in a glass container under anhydrous
conditions, the Lewis acid initiates the degradation of sevoflurane
to hydrofluoric acid and several degradation products. The
degradation products of sevoflurane are hexafluoroisopropyl
alcohol, methyleneglycol bishexafluoroisopropyl ether,
dimethyleneglycol bishexafluoroisopropyl ether and methyleneglycol
fluoromethyl hexafluoroisopropyl ether. The hydrofluoric acid
proceeds to further attack the glass surface and expose more of the
Lewis acid on the glass surface. This results in further
degradation of sevoflurane.
[0006] The degradation mechanism of sevoflurane in the presence of
a Lewis acid can be illustrated as follows:
1 1 Sevoflurane + Intermediate .fwdarw.
(CF.sub.3).sub.2CHOCH.sub.2OCH.sub.2OCH(CF.sub.3).sub.2 + HF P2
Sevoflurane + Intermediate .fwdarw. (CF.sub.3).sub.2CHOH +
FCH.sub.2OCH.sub.2OCH(CF.sub.3).sub.2 HFIP S1
(CF.sub.3).sub.2CHOCH.sub.2F + (CF.sub.3).sub.2CHOH .fwdarw.
(CF.sub.3).sub.2CHOCH.sub.2OCH(CF.sub.3).sub.2 + HF Sevoflurane
HFIP P1 Abbv. Compound Name Structure HFIP hexafluoroisopropyl
alcohol (CF.sub.3).sub.2CHOH P1 methyleneglycol
(CF.sub.3).sub.2CHOCH.sub.2OCH(CF.sub.3).sub.2
bishexafluoroisopropyl ether P2 dimethyleneglycol
bishexafluoroisopropyl (CF.sub.3).sub.2CHOCH.sub.2OCH.sub.2OCH(CF-
.sub.3).sub.2 ether S1 methyleneglycol fluoromethyl
(CF.sub.3).sub.2CHOCH.sub.2OCH.sub.2F hexafluoroisopropyl ether
[0007] Therefore, a need exists in the art for a stable anesthetic
composition containing fluoroether compounds that does not degrade
in the presence of a Lewis acid.
SUMMARY OF THE INVENTION
[0008] The present invention involves a stable anesthetic
composition that contains a fluoroether compound having an alpha
fluoroether moiety having added thereto an effective stabilizing
amount of a Lewis acid inhibitor. The preferred fluoroether
compound is sevoflurane and the preferred Lewis acid inhibitor is
water. The composition can be prepared by adding the Lewis acid
inhibitor to the fluoroether compound, by adding the fluoroether
compound to the Lewis acid inhibitor, or by washing a container
with the Lewis acid inhibitor and then adding the fluoroether
compound.
[0009] The present invention also involves a method for stabilizing
a fluoroether compound having an alpha fluoroether moiety. The
method involves adding an effective stabilizing amount of a Lewis
acid inhibitor to the fluoroether compound to prevent the
degradation of the fluoroether compound by a Lewis acid. The
preferred fluoroether compound is sevoflurane and the preferred
Lewis acid inhibitor is water.
BRIEF DESCRIPTION OF THE FIGURES
[0010] FIG. 1 shows a chromatogram demonstrating that in the
presence of the same amount of aluminum oxide (50 mg), the
degradation of sevoflurane decreases with increasing amounts of
water. The identified degradation products of sevoflurane shown in
FIG. 1 are hexafluoroisopropyl alcohol (HFIP), methyleneglycol
bishexafluoroisopropyl ether (P1), dimethyleneglycol
bishexafluoroisopropyl ether (P2) and methyleneglycol fluoromethyl
hexafluoroisopropyl ether (S1).
[0011] FIG. 2 depicts a chromatogram showing the degradation of
sevoflurane after heating in an autoclave at 119.degree. C. for 3
hours.
[0012] FIG. 3 depicts a chromatogram showing the effects of water
on the inhibition of the degradation of sevoflurane after heating
in an autoclave at 119.degree. C. for 3 hours.
[0013] FIG. 4 shows a bar graph comparing the sevoflurane degradant
P2 in activated type III amber glass bottles from Examples 5 and 6.
The graph demonstrates that the degradation of sevoflurane is
inhibited by the addition of 400 ppm of water.
[0014] FIG. 5 shows a bar graph comparing the sevoflurane degradant
S1 in activated type III amber glass bottles from Examples 5 and 6.
The graph shows that the degradation of sevoflurane is inhibited by
the addition of 400 ppm of water.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The present invention provides a stable, anesthetic
composition that does not degrade in the presence of a Lewis acid.
The present invention also relates to methods of preparing said
anesthetic composition.
[0016] The anesthetic composition of the present invention contains
at least one fluoroether compound. The fluoroether compound used in
the composition corresponds to Formula I, below. 2
[0017] In Formula I, each R.sub.1; R.sub.2; R.sub.3; R4; and
R.sub.5 can independently be a hydrogen, halogen, an alkyl group
having from 1 to 4 carbon atoms (C.sub.1-C.sub.4 alkyl), or a
substituted alkyl having from 1 to 4 carbon atoms (C.sub.1-C.sub.4
substituted alkyl). In the preferred embodiment of Formula I,
R.sub.1 and R.sub.3 are each the substituted alkyl CF.sub.3 and
R.sub.2, R4 and R.sub.5 are each a hydrogen.
[0018] As used herein, the term "alkyl" refers to a straight or
branched chain alkyl group derived from saturated hydrocarbons by
the removal of one hydrogen atom. Examples of alkyl groups include
methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, and the like. As used herein, the term "substituted
alkyl" refers to an alkyl group substituted by one or more groups
such as halogen, amino, methoxy, difluoromethyl, trifluoromethyl,
dichloromethyl, chlorofluoromethyl, etc. As used herein, the term
"halogen" refers to one of the electronegative elements of group
VIIA of the periodic table.
[0019] The fluoroether compounds having the Formula I contain the
alpha fluoroether moiety --C--O--C--F--. Lewis acids attack this
moiety which results in the degradation of the fluoroether to
various degradation products and toxic chemicals.
[0020] Examples of fluoroether compounds of Formula I that can be
used in the present invention are sevoflurane, enflurane,
isoflurane, methoxyflurane and desflurane. The preferred
fluoroether compound for use in the present invention is
sevoflurane.
[0021] Methods for making the fluoroether compounds having Formula
I are well known in the art and can be used in preparing the
composition of the present invention. For example, sevoflurane can
be prepared using the methods described in U.S. Pat. No. 3,689,571
and U.S. Pat. No. 2,992,276 herein incorporated by reference.
[0022] The composition of the present invention contains a total of
from about 98% w/w to about 100% w/w of a fluoroether compound
having the Formula I. Preferably, the composition contains at least
99.0% w/w of the fluoroether compound.
[0023] The anesthetic composition of the present invention also
contains a physiologically acceptable Lewis acid inhibitor. As used
herein, "Lewis acid inhibitor" refers to any compound that
interacts with the empty orbital of a Lewis acid thereby blocking
the potential reaction sites of the acid. Any physiologically
acceptable Lewis acid inhibitor can be used in the composition of
the present invention. Examples of Lewis acid inhibitors that can
be used in the present invention include water, butylated
hydroxytoluene (1,6-bis(1,1-dimethyl-ethyl)4-methylphenol),
methylparaben (4-hydroxybenzoic acid methyl ester), propylparaben
(4-hydroxybenzoic acid propyl ester), propofol (2,6-diisopropyl
phenol) and thymol (5-methyl-2-(1-methylethyl)phenol).
[0024] The composition of the present invention contains an
effective stabilizing amount of a Lewis acid inhibitor. It is
believed that the effective stabilizing amount of Lewis acid
inhibitor that can be used in the composition is about 0.0150% w/w
(water equivalent) to about the saturation level of the Lewis acid
inhibitor in the fluoroether compound. As used herein, the term
"saturation level" means the maximum solubility level of the Lewis
acid inhibitor in the fluoroether compound. It will be appreciated
that the saturation level may be temperature dependent The
saturation level also will depend on the particular fluoroether
compound and the particular Lewis acid inhibitor being used in the
composition. For example, when the fluoroether compound is
sevoflurane and the Lewis acid inhibitor is water, the amount of
water employed to stabilize the composition is believed to be from
about 0.0150% w/w to about 0.14% w/w (saturation level). It should
be noted, however, that once the composition is exposed to Lewis
acids, the amount of Lewis acid inhibitor in the composition may
decrease as the Lewis acid inhibitor reacts with the Lewis acid to
prevent the unwanted degradative reaction of Lewis acid inhibitor
with the composition.
[0025] The Lewis acid inhibitor preferred for use in the
composition of the present invention is water. Purified or
distilled water or a combination of both can be used. As stated
earlier, the effective amount of water that can be added to the
composition is believed to be about 0.0150% w/w to about 0.14% w/w,
and is preferably about 0.0400% w/w to about 0.0800% w/w. For any
other Lewis acid inhibitor, a molar equivalent based upon moles of
water should be used.
[0026] When the fluoroether compound is exposed to a Lewis acid,
the physiologically acceptable Lewis acid inhibitor present in the
composition donates electrons to the empty orbital of the Lewis
acid and forms a covalent bond between the inhibitor and the acid.
Thereupon, the Lewis acid is prevented from reacting with the alpha
fluoroether moiety of the fluoroether and degrading the
fluoroether.
[0027] The composition of the present invention can be prepared in
several ways. In one aspect, a container, such as a glass bottle,
is first washed or rinsed with the Lewis acid inhibitor and then
filled with the fluoroether compound. Optionally, the container may
be partially dried after the washing or rinsing. Once the
fluoroether is added to the container, the container is sealed. As
used herein, the term "partially dried" refers to an incomplete
drying process that leaves a residual of a compound on or in the
container being dried. Also as used herein, the term "container"
refers to a receptacle made from glass, plastic, steel or other
material that can be used for holding goods. Examples of containers
include bottles, ampules, test tubes, beakers, etc.
[0028] In another aspect, the Lewis acid inhibitor is added to a
dried container prior to filling the container with the fluoroether
compound. Once the Lewis acid inhibitor has been added, the
fluoroether compound is added to the container. Alternatively, the
Lewis acid inhibitor may be added directly to a container already
containing the fluoroether compound.
[0029] In another aspect, the Lewis acid inhibitor may be added to
a container filled with the fluoroether compound under humid
conditions. For example, water can be added to a container filled
with the fluoroether compound by placing the container in a
humidity chamber for a sufficient amount of time to allow the water
to accumulate in the container.
[0030] The Lewis acid inhibitor can be added to the composition at
any appropriate point in the manufacturing process, e.g., at the
final manufacturing step before filling into shipping containers,
e.g., 500 liter shipping container. Appropriate quantities of the
composition can be dispensed from the container and packaged in
containers of more suitable size for use in the industry, such as
250 mL glass bottles. Additionally, small quantities of the
composition containing appropriate amounts of the Lewis acid
inhibitor can be used to wash or rinse containers to neutralize any
Lewis acids that might be present in the container. Once the Lewis
acids have been neutralized, the container may be emptied and
additional quantities of the fluoroether composition added to the
container prior to sealing the container.
[0031] By way of example, but not of limitation, examples of the
present invention will now be given.
EXAMPLE 1
Activated Alumina as a Lewis Acid
[0032] Type III glass consists mainly of silicon dioxide, calcium
oxide, sodium oxide and aluminum oxide. Aluminum oxide is a known
Lewis acid. The glass matrix is normally inert to sevoflurane.
However, under certain conditions (anhydrous, acidic), the glass
surface can be attacked or altered, exposing sevoflurane to active
Lewis acid sites such as aluminum oxide.
[0033] The effect of water on the degradation of sevoflurane was
studied by adding various amounts of activated alumina to 20 ml of
sevoflurane containing the following three levels of moisture: 1)
20 ppm water--measured water, no additional water added; 2) 100
ppm--spiked; and 3) 260 ppm water--spiked. Table 1 below shows the
experimental matrix.
2 TABLE 1 1 2 3 A 50 mg Al.sub.2O.sub.3 50 mg Al.sub.2O.sub.3 50 mg
Al.sub.2O.sub.3 20 ppm Water 100 ppm Water 260 ppm Water B 20 mg
Al.sub.2O.sub.3 20 mg Al.sub.2O.sub.3 20 mg Al.sub.2O.sub.3 20 ppm
Water 100 ppm Water 260 ppm Water C 10 mg Al.sub.2O.sub.3 10 mg
Al.sub.2O.sub.3 10 mg Al.sub.2O.sub.3 20 ppm Water 100 ppm Water
260 ppm Water
[0034] It will be appreciated that 20 ppm Water is equivalent to
0.0022% w/w Water. The samples were placed at 60.degree. C. and
analyzed by gas chromatography after 22 hours. FIG. 1 shows that in
the presence of the same amount of aluminum oxide (50 mg) that the
degradation of sevoflurane decreases with increasing amounts of
water (Row A from Table 1). A similar trend was observed for 20 mg
and 10 mg of aluminum oxide (Rows B and C).
EXAMPLE 2
Degradation in Ampules of Sevoflurane by Heat with and without the
Addition of Water.
[0035] Approximately 20 mL of sevoflurane was added to a 50 mL Type
I clear ampule and approximately 20 mL of sevoflurane and 1300 ppm
of water was added to a second ampule. Both ampules were
flame-sealed and then autoclaved at 119.degree. C. for three hours.
The contents of the two ampules were then analyzed by gas
chromatography. FIG. 2 shows that the sevoflurane in the first
ampule degraded. FIG. 3 shows that the sevoflurane in the second
ampule did not degrade as a result of the Lewis acid inhibitor,
namely the added water.
EXAMPLE 3
Degradation of Sevoflurane in Ampules Using Water-Spiked Studies
(109 ppm to 951 ppm)
[0036] Type I clear glass ampules were used to study the effect of
various levels of water in inhibiting the degradation of
sevoflurane. Approximately 20 mL of sevoflurane and different
levels of water ranging from about 109 ppm to about 951 ppm were
added to each ampule. The ampules were then sealed. A total of ten
ampules were filled with sevoflurane and varying amounts of water.
Five of the ampules were included in Set A and the other five
ampules were included in Set B. The ampules were then autoclaved at
119.degree. C. for three hours. Samples in Set A were placed on a
mechanical shaker overnight to allow the moisture to coat the glass
surface. Samples in Set B were prepared without equilibrating the
water with the glass surface. Several control samples were also
prepared. Two non-autoclaved ampules (Control Ampule 1 and Control
Ampule 2) and a bottle (Control bottle) were each filled with 20 mL
of sevoflurane. No water was added to any of the control samples.
Also, the controls samples were not shaken overnight The levels of
hexafluoroisopropanol (HFIP) and total degradants (including
methyleneglycol bishexafluoroisopropyl ether, dimethyleneglycol
bishexafluoroisopropyl ether, methyleneglycol fluoromethyl
hexafluoro isopropyl ether) were measured by gas chromatography.
The results are shown below in Table 2.
3TABLE 2 Total Total Moisture Degradants Calculated HFIP without
Sample (ppm) pH (ppm) HFIP (ppm) Control, Bottle 6.0 6 57 Control,
Ampule 1, RT 3.0 7 50 Control, Ampule 2, RT 4.0 6 51 Set A (Shaken
Overnight) 1 109 0 12525 201614 2 206 0 2,456 105518 3 303 0 127134
4 595 5.0 7 82 5 951 5.0 12 84 Set B (Not Shaken) 1 109 0 1,936
195364 2 206 0 3,390 170869 3 303 0 5,269 101845 4 595 6.0 21 107 5
951 6.0 10 63
[0037] The results in Table 2 above demonstrate that for the
ampules in Set A and in Set B, at least 595 ppm of water was
sufficient to inhibit the degradation of sevoflurane. The results
show no significant difference between the ampules that were shaken
overnight and those that were not shaken overnight.
EXAMPLE 4
Degradation of Sevoflurane in Ampules Using Water Spiked
Sevoflurane Studies at 60.degree. C. or 40.degree. C.
[0038] Type I clear glass ampules were employed to study the effect
of various levels of water and temperature in inhibiting the
degradation of sevoflurane. Approximately 20 mL of sevoflurane and
different levels of water ranging from about 109 ppm to about 951
ppm were added to each ampule. The ampules were then flame-sealed.
To accelerate the degradation process, samples from each moisture
level were placed at two heating conditions. Samples were placed on
a 60.degree. C. stability station for 144 hours or placed on a
40.degree. C. stability station for 200 hours. The resulting
sevoflurane in each of the samples was analyzed by gas
chromatography and pH. Hexafluoroisopropyl alcohol (HFIP) and the
total degradants of sevoflurane were measured. The results are
shown below in Table 3.
4TABLE 3 Total Total HFIP Degradants Sample Moisture pH (ppm) (ppm)
Water-spiked, 60.degree. C., 144 hrs 1 109 0 850 474796 2 206 3.5 7
48 8 65 3-1 303 3.5 13 68 16 88 3-2 303 5.0 8 60 4 595 5.5 7 66 5-1
951 5.5 4 52 5-2 951 5.5 5 60 Water-spiked, 40.degree. C., 200 hrs
6-1 No H.sub.2O 0 232 102435 added 6-2 No H.sub.2O 2.5 24 68 added
7 109 3.0 40 77 8 206 5.0 7 59 9 303 5.0 7 59 10 595 6 60 11 951
6.0 5 60
[0039] The results in Table 3 demonstrate that at 40.degree. C. for
200 hours, water levels higher than 206 ppm inhibit degradation of
sevoflurane. For samples stored at 60.degree. C. for 144 hours or
longer, water levels higher than 303 ppm inhibit the degradation of
sevoflurane. This data suggests that as the temperature increases,
the amount of water required to inhibit the degradation of
sevoflurane will increase.
EXAMPLE 5
Sevoflurane Degradation in Activated Type III Amber Glass
Bottles
[0040] Type III amber glass bottles that were used to store
degraded sevoflurane were examined. Those bottles that exhibited a
significant amount of etching inside the bottle were selected. A
total of ten Type III amber glass bottles were selected. The
degraded sevoflurane contained in each of these bottles was drained
and the bottles were rinsed several times with non-degraded fresh
sevoflurane. Approximately 100 mL of non-degraded sevoflurane
containing about 20 ppm water was added to each bottle. Gas
chromatography analysis for all the samples was performed at the
time zero and after heating at 50.degree. C. for 18 hours.
Hexafluoroisopropyl (HFIP) and dimethyleneglycol ether (P2) were
measured. The results are shown in Tables 4 and 5 below.
5TABLE 4 Results at Time Zero Degradation Products (ppm) Bottle
Number HFIP P2 Total 1 124 <10 185 2 84 <10 123 3 77 <10
137 4 56 <10 89 5 144 <10 190 6 63 <10 96 7 58 <10 95 8
60 <10 102 9 51 <10 106 10 65 <10 140
[0041]
6TABLE 5 Results at 50.degree. C., 18 Hours Degradation Products
(ppm) Bottle Number HFIP P2 Total 1 1026 7938 14243 2 912 3013 6428
3 1160 4662 10474 4 908 3117 7381 5 907 6687 11774 6 1128 5448
11313 7 1152 2371 6695 8 1199 2925 7386 9 1560 4183 10325 10 1455
2255 6667
[0042] The results in Tables 4 and 5 show that the glass surfaces
in these bottles were "activated" by degraded sevoflurane.
"Activated" glass surfaces thus served as initiators for the
degradation of fresh sevoflurane.
EXAMPLE 6
Additional Studies of Sevoflurane Degradation In Activated Type III
Amber Glass Bottles
[0043] The extent of the degradation of sevoflurane in each of the
bottles from Example 5 were quantified by gas chromatography. The
ten bottles were divided into two groups, the Control Sevo Group
(containing bottles 2, 3, 5, 7, 8) and the Study Sevo Group
(containing Bottles 1, 4, 6, 9, 10).
[0044] All ten bottles were re-rinsed several times with
non-degraded sevoflurane containing about 20 ppm of water. For the
five Control Sevo Group bottles, 100 mL of sevoflurane containing
about 20 ppm of water was added to each bottle. For the five Study
Group bottles, 100 mL of sevoflurane containing about 400 ppm of
water (spiked) was added to each bottle.
[0045] Gas chromatography for all samples was performed at time
zero and after heating at 50.degree. C. for 18 hours.
Hexafluoroisopropyl alcohol (HFIP), dimethyleneglycol
bishexafluoroisopropyl ether (P2) and total degradants were
measured. The results are shown below in Table 6.
7TABLE 6 Results at the Zero Hour and Eighteen Hours Degradation
Products (ppm) HFIP P2 Total Time 0 hour 18 hour 0 hour 18 hour 0
hour 18 hour Control Group (20 ppm water) 2 <10 777 <10 2291
<50 5995 3 <10 790 <10 2714 <50 6552 5 11 688 <10
2446 <50 5485 7 <10 894 <10 1171 <50 4124 8 <10 824
<10 1950 <50 5139 Study Group (400 ppm water) 1 12 605 <10
<10 <50 669 4 <10 84 <10 <10 <50 98 6 <10 331
<10 <10 <50 357 9 <10 294 <10 <10 <50 315 10
10 528 <10 <10 <50 577
[0046] The results in Table 6 show that at zero hour, no
significant degradation of sevoflurane was observed when compared
to that of the zero-hour results in Table 4. The results in Table 6
show that, in the Study Sevo Group (400 ppm water), the degradation
of sevoflurane was significantly reduced. The amounts of degradants
P2 (dimethyleneglycol bishexafluoroisopropyl ether) and S1
(methyleneglycol fluoromethyl hexafluoroisopropyl ether) were much
less than those in Control Group 1 (20 ppm water). The HFIP
concentration in the Study Sevo Group, however, was quite high and
suggests that the glass surfaces were still somewhat active.
[0047] FIG. 4 shows a graphic comparison of the degradant
dimethyleneglycol bishexafluoroisopropyl ether (P2) from the data
in Tables 5 and 6. FIG. 5 shows a graphic comparison of the
degradant methyleneglycol fluoromethyl hexafluoroisopropyl ether
(S1) as it appears in Examples 5 and 6. Both FIG. 4 and FIG. 5
demonstrate that the degradation of sevoflurane is inhibited by the
addition of water at 400 ppm.
EXAMPLE 7
Additional Studies of Sevoflurane Degradation in Activated Type III
Amber Glass Bottles
[0048] Sevoflurane was decanted from the five bottles of the Study
Sevo Group from Example 6. Each bottle was rinsed thoroughly with
fresh sevoflurane. Approximately 125 mL of water-saturated
sevoflurane was then put into each bottle. The five bottles were
then placed on a mechanical roller for approximately two hours to
allow the water to coat the activated glass surfaces. The
water-saturated sevoflurane was then drained form each bottle and
replaced by 100 mL of sevoflurane containing 400 (spiked) ppm of
water. Gas chromatography analysis for all samples was performed
after heating at 50.degree. C. for 18 hours, 36 hours, and 178
hours. Bishexafluoroisopropyl ether (P2) and total degradants were
measured. The results are shown below in Table 7.
8 TABLE 7 Degradation Products (ppm) HFIP P2 Total 178 178 178 Time
36 hour hour 36 hour hour 36 hour hour Study Group (400 ppm water)
1 <10 16 <10 <10 <50 <50 4 <10 <10 <10
<10 <50 <50 6 <10 28 <10 <10 <50 <50 9
<10 15 <10 <10 <50 <50 10 <10 19 <10 <10
<50 <50
[0049] The results in Table 7 demonstrate that the degradation of
sevoflurane was greatly inhibited by treating the activated glass
surface with water saturated-sevoflurane prior to heating.
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