CA2437603C - Fluoroether compositions and methods for inhibiting their degradation in the presence of a lewis acid - Google Patents

Abstract

Degradation of a Lewis acid by a quantity of sevoflurane is provided by combining the quantity of sevoflurane with a Lewis acid inhibitor, for example, water, butylated hydroxytoluene, methylparaben, propylparben, propofol and thymol. A method of the invention involves a method for storing a quantity of sevoflurane, the method comprising the steps of providing a container defining an interior space, the container having an interior wall adjacent the interior space defined by the container; providing a quantity of sevoflurane; coating the interior wall of the container with the Lewis acid inhibitor; placing the quantity of sevoflurane in the interior space defined by the container.

Description

FLUOROETHER COMPOSITIONS AND METHODS FOR INHIBITING
TH~IR DEGRADATION IN THE PRESENCE OF A LEWIS ACll~
Technical Field of the Invention 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.
This application is a division of Canadian Application 2,352,597 filed January 23, 1998.
Background c2f the Invention 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-chioro-1,1,2-trifluoroethyl difluoromethyl ether), isoflurane ( 1-chloro-2,2,2-trifluoroethyl difluoromcthyl ether), methoxyflurane (2,2-dichloro-I,l-difluoroethyl methyl ether), and desflurane ((~-)-2-difluoromethyi I?,2,2-tetrafluoroethyl ether).
Although fluoroethers are excellent anesthetic agents, it has been discovered that some fluoroethers experience stability problems. More spe~cally, 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.
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 I:ewis 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.
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, dimethyieneglycol bishexafluoroisopropyl ether and methyleneglycol fluoromethyl hexafluoroisopropyl ether. The hydrofluoric acid proceeds to further attack the glass surface and expose more of the Ixwis acid on the glass surface. This results in further degradation of sevoflurane.
The degradation mechanism of sevoflurane in the presence of a Ixwis acid can be illustrated as follows:
SiFd - ~i-OH
(CF3)2CHOCH2F------_._______-w>(CF3)xCHOCH2OH + -Si-F
Scvoflurane (Surface-Bound Intermediate Lewis Acid) Scvoflurane + Intermediate ---_------____ __> (CF3)2~OCH20CH2OCH(CF3)2 + HF

Sevoflurane + Intermediate --_-_._._________-___> (CF3)2CHOH +
FCH2OCH20CH(CF3y~

(CF3)~CHOCH2F + (CF3)2CHOH -------------> (CF~)2CHOCH~OCH(CF3)2 + HF
Sevoflurane HFIP P i $,6bv. f~o~~ound Name ~ueture HFIP hexafluoroisopropyl alcohol (CF3)2CHOH
P1 methyleneglycol bishexafluoroisopropyl (CF3)2CHOCH20CH(CF3)2 ether P2 dimethyleneglycol bishexafluoroisopropyl (CF3)2CHOCHZOCH~OCH(CF3)2 ether S 1 methyleneglycol fluoromethyl (CF3)2CHOCH~OCH2F
hexafluoroisoproyl ether 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 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.
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.
In accordance with one aspect of the invention, there is provided a method for storing a quantity of sevoflurane, the method comprising the steps of providing a container defining an interior space, said container having an interior wall adjacent said interior space defined by said container; providing a quantity of sevoflurane; coating said interior wall of said container with a Lewis acid inhibitor; placing said quantity of sevoflurane in said interior space defined by said container.
In another aspect of the invention, there is provided a method of preventing degradation by a Lewis acid of sevoflurane comprising the steps of washing or rinsing a container with an amount of Lewis acid inhibitor, said inhibitor being selected from the group consisting of water, butylated hydroxytoluene, methylparaben, propylparaben, propofol, and thymol; filling the container with the sevoflurane; and sealing the container.
In still another aspect of the invention, there is provided a method for preventing degradation by Lewis acids of a quantity of sevoflurane, said method comprising providing a quantity of sevoflurane and contacting said quantity of sevoflurane with an amount of Lewis acid inhibitor, said amount of Lewis acid inhibitor being selected such that said Lewis acid inhibitor is present in an amount 3a of at least 150 parts per million parts of a total of said quantity of sevoflurane and said amount of Lewis acid inhibitor.
Brief Description of the Figures Figure 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 Figure 1 are hexafluoroisopropyl alcohol (HFIP), methyleneglycol bishexafluoroisopropyl ether (P1), dimethyleneglycol bishexafluoroisopropyl ether (P2) and methyleneglycol fluoromethyl hexafluoroisopropyl ether (S1).
Figure 2 depicts a chromatogram showing the degradation of sevoflurane after heating in an autoclave at 119°C for 3 hours.
Figure 3 depicts a chromatogram showing the effects of water on the inhibition of the degradation of sevoflurane after heating in an autoclave at 119°C
for 3 hours.
Figure 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.
Figure 5 shows a bar graph comparing the sevoflurane degradant S 1 in activated type III amber glass bottles from Examples ~ and 6. The graph shows that the degradation of sevoflurane is inhibited by the addition of 400 ppm of water.
Dg~,~l Desr~i~~?n o_ f thr.~~~,v lion 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. , The anesthetic composition of the present invention contains at least one anhydrous fluoroether compound. The term "anhydrous" as used herein means that the fiuoroether compound contains less than about 50 ppm of water. The fluoroether compound used in the composition corresponds to Formula I, below.
R1 Ra R2-C-~'C-F (n In Formula I, each RI; RZ; Rs; R4; and RS can independently be a hydrogen, halogen, an alkyl group having from 1 to 4 carbon atoms (C1 - C~ alkyl), or a substituted alkyl having from 1 to 4 carbon atoms (C~ - C4 substituted allcyl). In the prefcrnd embodiment of Formula I, Rl and R3 are each the substituted alkyl CF3 and Rz, R4 and RS are each a hydrogen.
As used herein, the term "alkyl" refers to a straight or branched chain alkyl group derived from saturated hydracarbons by the removal of one hydrogen atom.
Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like. As used herein, the acrm "substituted alkyl" refers to an alkyl group substituted by one or more gmups such as halogen. amino, metho~ty, difluoromethyl, trifluoromethyl, dichloromethyi, chlorofluoromethyl, etc. As used herein, the term "halogen"
refers to one of the electronegative elements of group VnA of the periodic table, The fluoroether compounds having the Formula l 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 wxic chemicals.
Examples of anhydrous fluorocther compounds of Formula I that can be used in the pzesent invention are sevofiurane; eriflurane, isofiurane, methoxyflurane aitd desflurane. The preferred fluoroether compound for use in the present invention is scvoflurane.
Methods for making the fluoroether compounds having Formula I are well lmown 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 LJ.S. Patent 3,689,571 and U.S.
Patent 2,992,276 .
The composition of the present invention contains a total of from about 9896 w/w to about 100% w/w of a ffuoroether compound having the Formula I. Preferably, the composition contains at least 99.0°k w/w of the fluoroether compound.
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 Lcwis 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-ditncthyl-ethyl)-4-methyiphenol), methylparaben (4-hydroxybanzoic acid methyl ester), pmpylparabcn (4-hydroxybenzoic acid propyl ester), propofol (2,6-diisopropyl phenol) and thymol (5-methyl-2-(1-methylethyl)phenoI).
The composition of the grasent invention contai;is 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 wih be appreciated that the saturation level may be temperature dependent. The saturation level also will depend on the particular fiuoroethcr compound and the particular Lewis acid inhibitor being used in the composition. For cxampie, when the fluoroether compound is sevofiurane 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°.b 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 L.ewis acid inhibitor reacts with the Lewis acid to prevent the unwanted degradative reaction of Lewis acid inhibitor with the composition.
The lewis acid inhibitor preferred for use in the composition of the present irrvention 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 w the composition is believed to be about 0.0150°k w/w to aboue 0.1496 w/w, and is preferably about 0.0400% w/w to about 0.0800°do w/w. For any other l.ewis acid inhibitor, a molar equivalent based upon moles of water should be used.
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 orbita 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.
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 fluoraether 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.
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 l;.ewis acid inhibitor may be added directly to a container already containing the fluoroether compound.
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.

The Lewis acid inhibitor can be added to the composition at any appropriate paint 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 storable size for use in the industry, such as 250 rnL glass bottles. Additionally, small quantities of the composition containing appropriate amounts of the L,ewis 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 scaling the container.
By way of example, but not of limitation, examples of the present invention will now be given.
Exarrno,~t Activaxed Al!,umina g~ a L,ewis Acid Type ITI 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 sevofluranc. However, undex certain conditions (anhydrous, acidic), the glass surface can be attacked or altered, exposing sevoflurane to active Lxwis acid sites such as aluminum oxide.
The effect of water on the degradation of sevoflurane was swdied 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; Z) 100 ppm - spiked;
and 3) 260 ppm water - spiked. Table 1 below shows the experimental matrix.
Table 1 1 2 3 _ r A 50 mg AI203 50 mg A1203 50 mg A12Q3 20 ppm Water 100 ppm Water 260 ppm Water B 20 mg A1203 20 mg A1203 20 mg Al~

20 ppm Water 100 ppm Water 260 ppm Water C IO mg A1203 10 mg A12O~ 10 mg Al2Os 20 ppm Water I00 ppm Water 260 pprn Water It will be appreciated that 20 ppm Water is equivalent to 0.0022% w/w Water.
The samples were placed at 60' C and analyzed by gas chromatography after 22 hours. 1~igure 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 l0 mg of aluminum oxide (Rows B and C).
Eon Dep~tion in Amgrules of Sevoflurane by Heat wi~~,d wi ho t~~e ddition of Water.
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' C for three hours.
The contents of the two ampules were then analyzed by gas chromatography. Figure 2 shows that the sevoflurane in the first ampule degraded. Figure 3 shows that tttc sevofluranc in the second ampule did not degrade as a result of the Lewis acid inhibitor, namely the added water.
v Type I clear glass ampnles 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 arnpule.
The ampules were then scaled. 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' 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 hexafluroisopropanol (HFIP) and total degradants (including methyleneglycol bishexafluaroisopropyl ether, dimcthyleneglycol bishexafluoroisopropyl ether, methyleneglycol fluoromethyl hexafluoro isopropyl ether) were measured by gas chromatography. The results are shown below in Table 2.

Table 2 Total MoisturepH HFIP Total Degradants Sample Calculated (ppm) without HFIP
(ppm) (ppm) Control. Bottle 6.0 6 57 Control, AmpuIe 3:0 7 50 I, RT

Control, Ampule 4.0 6 51 2, RT

Set A (Shaken Overni ht) 1 109 0 1.525 201614 2 206 0 2.456 105518 3 303 0 4.027 12?134 4 595 5.0 7 g2 5 951 5.0 I2 84 Set B (Not Shakenl _ 1 109 0 1.936 195364 2 20b 0 3.390 1708b9 __ _ 0 5.269 101845 4 595 6.0 21 107 5 951 6.0 10 b3 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.
~,~ Ip a 4: Degtadation of Sevoflurane in Amnules Usin~~ Water $pik~j, Ssvofl ~ranP
Studies at b0'C or 40' C
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 wtre placed on a 60°
C stability station for 144 hours or placed on a 40' 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 arc shown below in Table 3.
Table 3 Total MoisturepH HFIP Total Degradants Sample {ppm) {ppm) Water- iked. 60' C.
144 hrs 2 206 3.5 7 48 8 b5 3-1 303 3.5 13 68 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-spliced, 40' C, 200 hrs 6-1 No H20 added 0 232 102435 6-2 No Hz0 added Z.5 24 68 7 109 3.0 40 77 8 206 5.0 7 59 9 303 5.0 6 59 10 595 6.0 6 60 I1 951 6.0 5 60 The results in Table 3 demonstrate that at 4(?' C for 200 hours, water levels higher than 206 ppm inhibit the degradation of sevoflurane. For samples stored at 60' C for I44 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.
Epampl~." 5: Sevo ~Iurane Drgr~atisn in Activated Type lII Amber Glass BottPc 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 degradui sevofluranc 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' C for 18 hours.
Hexafluoroisopropyl alcohol {H1ZP) and dimethyleneglycol ether (P2) were measured. The results are shown in Tables 4 and 5 below.
Table 4 Results at Time Zero Degradation products (ppm) Bottle NumberHFIP P2 Totai 1 124 <10 185 2 84 <10 I23 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 Table 5 Results at 50' C, 18 Hours Degradation Products (ppm) Bottle NumberHFIP P2 Total 3 1160 4b62 104'T4 S 90? bb87 11774 7 1152 2371 ~ 6695 8 1i99 2925 7386 9 15b0 4183 10325 10 ~ 1455 2255 6667 The results in Tables 4 and 5 show that the glass surfaces in these bottles were "activated"
by degraded sevoflurane. "Acavated" glass surfaces thus seared as initiators for the degradation of fresh sevoflurane.
Example Cz: ~~ygsnal Studies of Sev 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, $) and the Study Sevo Group (containing Bottles 1, 4, 6, 9, 10).
All ten bottles were re-rinsed several rimes 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 Gmup bottles, 100 mL of sevoflurane containing about 400 ppm of water (spiked) was added to each bottle.
Gas chromatography for ail samples was performed at time zero and after heating at 50' C for 18 hours. Hexafluoroisopmpyl alcohol (HFIP), dimethyleneglycol bishexafluoroisopropyl ether (P2) and total degradants were measured. The results arc shown below in Table 6.
Table 6 Results at the Zero Hour and Eighteen Hours Degradation ~ Products (ppm) mrw~rn l , ~ P2 To~l _ 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 6352 5 I1 688 <10 244.6 <50 5485 7 a10 894 <10 1171 <50 4124 8 <14 824 <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 The resulu in Table 6 show that at zero hoot, no significant degradation of scvoflurane 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 (dimethylcneglycol bishexafluoroisopropyl ether) and S 1 (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 surfacts were still somewhat active.
Figure 4 shows a graphic comparison of the degradant dimethyleneglycol bishexafiuoroisopropyl ether (P2) from the data in Tables 5 and 6. Figure 5 shows a graphic comparison of the degradant methyieneglycol fluoromethyi hexafluomisopropyl ether (S 1) as it appears in Examples 5 and 6. Both Figure 4 and Figure 5 demonstrate that the degradation of sevoflurane is inhibited by the addition of water at 400 ppm.
Example 7:
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 rtplaccd by 100 mL of sevoflurane containing 400 (spiked) ppm of water. Gas chromatography analysis for all samples was performed after heating at 50' C for 18 hours, 36 hours, and 178 hours.
Bishexafluoroisopropyl ether (P2) and fatal degradants were measured. The results are shown below in Table 7.
Table 7 Degradation Products (pprn) ~~

HFIP ~ P2 Total Degradants Time 36 hour 178 hour36 hour178 hour3b hour178 hour Study Group (400 ppm water) 1 <10 16 <I0 <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 ' <5O <50 ~

The results in Table 7 demonstrate that the degradation of sevoflurane was greatly inhibited by treaxing the activated glass surface with water saturated-sevoflurane prior to heating.

Claims (6)

CLAIMS:

1. A method for storing a quantity of sevoflurane in an anesthetic composition, the method comprising the steps of:
providing a container defining an interior space, said container having an interior wall adjacent said interior space defined by said container;
providing a quantity of sevoflurane;
coating said interior wall of said container with a Lewis acid inhibitor;
placing said quantity of sevoflurane in said interior space defined by said container.

2. The method for storing a quantity of sevoflurane in accordance with claim 1, wherein said Lewis acid inhibitor is selected from the group consisting of water, butylated hydroxytoluene, methylparaben, propylparaben, propofol, and thymol.

3. The method for storing a quantity of sevoflurane in accordance with claim 1, wherein said Lewis acid inhibitor is water.

4. The method for storing a quantity of sevoflurane in accordance with claim 1, wherein said Lewis acid inhibitor is water saturated sevoflurane.

5. The method for storing a quantity of sevoflurane in accordance with claim 2 or 3, wherein the step of coating said interior wall of said container is accomplished by placing said container in a humidity chamber for a sufficient time to allow said Lewis acid inhibitor to accumulate in said container in an amount effective to inhibit degradation by a Lewis acid of said quantity of sevoflurane.

6. The method for storing a quantity of sevoflurane in accordance with claim 1 or 5, the method further comprising the step of sealing the container following the placing of said quantity of sevoflurane in said interior space defined by said container.