HK1074434B - Fluoroether compositions and methods for inhibiting their degradation in the presence of a lewis acid - Google Patents

Description

Fluoroether compositions and methods for inhibiting degradation thereof in the presence of lewis acids

Technical Field

The present invention relates generally to stable, anesthetic fluoroether compositions which do not degrade in the presence of lewis acids. The present invention also relates to a method of inhibiting the degradation of fluoroethers in the presence of lewis acids.

Background

Fluoroether compounds are commonly used as anesthetic agents. Examples of the fluoroether compounds useful as anesthetic agents include sevoflurane (fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether), enflurane ((±) -2-chloro-1, 1, 2-trifluoroethyl difluoromethyl ether), isoflurane (1-chloro-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.

Although fluoroethers are excellent anesthetics, certain fluoroethers have been found to have stability problems. More specifically, it has been determined that certain fluoroethers degrade in the presence of one or more lewis acids to a number of products, including potentially toxic chemicals such as hydrofluoric acid. Hydrofluoric acid is toxic and highly corrosive to the skin and mucous membranes through ingestion and inhalation. Thus, the degradation of fluoroethers to other chemicals such as hydrofluoric acid is of great concern to those in the medical arts.

Fluoroether degradation was found to occur in glass containers. It is believed that the degradation of the fluoroether in the glass container is activated by the presence of trace amounts of lewis acid in the container. The lewis acid may be derived from alumina, which is a natural constituent of glass. When the glass wall is altered or etched in some way, the alumina is exposed and contacts the contents of the container. The lewis acid then attacks and degrades the fluoroether.

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 degradation of sevoflurane to hydrofluoric acid and some degradation products. The degradation products of sevoflurane are hexafluoroisopropanol, methylene glycol bis hexafluoroisopropyl ether, dimethylene glycol bis hexafluoroisopropyl ether, and methylene glycol fluoromethyl hexafluoroisopropyl ether. The hydrofluoric acid will further attack the glass surface and thus expose more lewis acid on the glass surface. This further degrades the sevoflurane.

The degradation mechanism of sevoflurane in the presence of a lewis acid is illustrated as follows:

sevoflurane (surface bound Lewis acid) intermediates

Sevoflurane + intermediate>(CF₃)₂CHOCH₂OCH₂OCH(CF₃)₂+HF

P2

Sevoflurane + intermediate>(CF₃)₂CHOH+FCH₂OCH₂OCH(CF₃)₂

HFIP SI

(CF₃)₂CHOCH₂F+(CH₂)₂CHOH------>(CF₃)₂CHOCH₂OCH(CF₃)₂+HF

Sevoflurane HFIP P1

Abbreviated compound name structural formula

HFIP hexafluoroisopropanol (CF)₃)₂CHOH

P1 methylene glycol bis hexafluoroisopropyl ether (CF)₃)₂CHOCH₂OCH(CF₃)₂

P2 dimethylene glycol bis hexafluoroisopropyl ether (CF)₃)₂CHOCH₂OCH₂OCH(CF₃)₂

S1 methylene glycol fluoromethyl hexafluoroisopropyl ether (CF)₃)₂CHOCH₂OCH₂F

Therefore, there is a need in the art for stable anesthetic compositions containing fluoroether compounds that do not degrade in the presence of lewis acids.

Summary of The Invention

The invention relates to a method for preventing sevoflurane from being degraded by Lewis acid, which comprises the following steps: providing a container; providing an amount of sevoflurane; washing or rinsing the container with a lewis acid inhibitor; placing the amount of sevoflurane in the container.

The present invention is also directed to another method of preventing the degradation of an amount of sevoflurane by a lewis acid, comprising: adding a stabilizing effective amount of a Lewis acid inhibitor to sevoflurane to prevent degradation of the sevoflurane by Lewis acid, wherein said stabilizing effective amount is 0.0150% w/w (water equivalent) to the saturation level of the Lewis acid inhibitor in the sevoflurane.

Brief Description of Drawings

Figure 1 shows a chromatogram of sevoflurane degradation decreasing with increasing water amount in the presence of the same amount of alumina (50 mg). The identified degradation products of sevoflurane shown in fig. 1 are Hexafluoroisopropanol (HFIP), methylene glycol bis hexafluoroisopropyl ether (PI), dimethylene glycol bis hexafluoroisopropyl ether (P2), and methylene glycol fluoromethyl hexafluoroisopropyl ether (S1).

FIG. 2 depicts a chromatogram of sevoflurane degradation after heating in an autoclave at 119 deg.C for 3 hours.

FIG. 3 depicts a chromatogram of the effect of water on sevoflurane degradation after heating in an autoclave for 3 hours at 119 ℃.

FIG. 4 shows a bar graph comparing sevoflurane degradation product P2 in activated type III amber glass bottles for examples 5 and 6. The figure shows that the addition of 400ppm of water inhibits sevoflurane degradation.

Fig. 5 shows a bar graph comparing sevoflurane degradation product S1 in activated type III amber glass bottles for examples 5 and 6. The figure shows that the addition of 400ppm water inhibits the degradation of sevoflurane.

Detailed Description

The invention provides a method for preventing sevoflurane from being degraded by Lewis acid, which comprises the following steps: providing a container; providing an amount of sevoflurane; washing or rinsing the container with a lewis acid inhibitor; placing the amount of sevoflurane in the container.

The present invention provides a sevoflurane product protected according to the above method which is protected against degradation by lewis acids.

The present invention provides a stable anesthetic composition that does not degrade in the presence of lewis acids.

The anesthetic compositions of the present invention comprise at least one anhydrous fluoroether compound. The term "anhydrous" as used herein means that the fluoroether compound contains less than about 50ppm water. The fluoroether compound used in the composition corresponds to the formula.

In the formula I, R₁、R₂、R₃、R₄And R₅Independently hydrogen, halogen, alkyl (C) having 1 to 4 carbon atoms₁-C₄Alkyl) or substituted alkyl (C) having 1 to 4 carbon atoms₁-C₄Substituted alkyl). In a preferred embodiment of formula I, R₁And R₃Each being a substituted alkyl CF₃And R is₂、R₄And R₅Each is hydrogen.

The term "alkyl" as used herein refers to a straight or branched chain alkyl group derived from a saturated hydrocarbon by removal of one hydrogen atom. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like. The term "substituted alkyl" as used herein refers to an alkyl group substituted with one or more groups such as halogen, amino, methoxy, difluoromethyl, trifluoromethyl, dichloromethyl, chlorofluoromethyl and the like. The term "halogen" as used herein refers to an electronegative element of group VIIA of the periodic Table.

The fluoroether compounds having formula I contain an alpha fluoroether moiety-C-O-C-F-. Lewis acids attack the moiety, causing the fluoroether compound to degrade into various degradation products and toxic chemicals.

Examples of anhydrous fluoroether compounds of formula I that can be used in the present invention are sevoflurane, enflurane, isoflurane, methoxyflurane and desflurane. The preferred fluoroether for use in the present invention is sevoflurane.

Methods for preparing the fluoroether compounds of formula I are well known in the art and may be used in the preparation of the compositions of the present invention. For example, sevoflurane can be prepared using the methods described in U.S. Pat. No. 3689571 and U.S. Pat. No. 2992276, both of which are incorporated herein by reference.

The compositions of the present invention contain a total of about 98% w/w to about 100% w/w of the fluoroether compound of formula I. Preferably, the composition contains at least 99.0% w/w of the fluoroether compound.

The anesthetic compositions of the present invention also contain 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 and thereby blocks the potential reactive site of the acid. Any physiologically acceptable lewis acid inhibitor may be used in the compositions of the present invention. Examples of lewis acid inhibitors that may be used in the present invention include water, butylated hydroxytoluene (1, 6-bis (1, 1-dimethyl-ethyl) -4-methylphenol), methyl hydroxybenzoate (methyl 4-hydroxybenzoate), propyl p-hydroxybenzoate (propyl 4-hydroxybenzoate), propofol (propofol), and thymol (5-methyl-2- (1-methylethyl) phenol).

The compositions of the present invention contain an effective stabilizing amount of a lewis acid inhibitor. It is believed that an effective stabilizing amount of the Lewis acid inhibitor that may be used in the composition is from about 0.0150% w/w (equivalent weight of water) to about the saturation level of the Lewis acid inhibitor in the fluoroether compound. The term "saturation level" as used herein means the maximum solubility level of the lewis acid inhibitor in the fluoroether compound. It will be appreciated that the saturation level is dependent on temperature. The level of saturation will also depend on the particular fluoroether compound and the particular lewis acid inhibitor used in the composition. For example, where the fluoroether compound is sevoflurane and the Lewis acid inhibitor is water, it is believed that the amount of water used to stabilize the composition is 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 the lewis acid, the amount of lewis acid inhibitor in the composition is reduced as the lewis acid inhibitor reacts with the lewis acid to prevent unwanted degradation reactions of the lewis acid inhibitor with the composition.

The preferred lewis acid inhibitor for use in the composition of the present invention is water. Pure or distilled water or a combination thereof may be used. As noted above, it is believed that an effective amount of water may be added to the composition from about 0.0150% w/w to about 0.14% w/w, and preferably from about 0.0400% w/w to about 0.0800% w/w. For any other lewis acid inhibitor, a molar equivalent based on the moles of water should be used.

Upon exposure of the fluoroether compound to a lewis acid, the physiologically acceptable lewis acid inhibitor present in the composition donates electrons to the lewis acid vacancy track and forms a covalent bond between the inhibitor and the acid. Thus, the lewis acid is prevented from reacting with the alpha fluoroether portion of the fluoroether and from degrading the fluoroether.

The compositions of the present invention can be prepared in several ways. In one aspect, a container (e.g., a glass bottle) is first washed or rinsed with a lewis acid inhibitor and then filled with a fluoroether compound. Optionally, after washing or rinsing, the container may be partially dried. Once the fluoroether is added to the container, the container is immediately sealed. The term "partial drying" as used herein refers to a process of incomplete drying, with the compound remaining on or in the container being dried. The term "container" as used herein refers to a container made of glass, plastic, steel, or other material that may be used to hold goods. Examples of containers include bottles, ampoules, test tubes, beakers, and the like.

Alternatively, the lewis acid inhibitor may be added to a dry container prior to filling the container with the fluoroether compound. Once the lewis acid inhibitor is added, the fluoroether compound is added to the vessel. Alternatively, the lewis acid inhibitor may be added directly to a container already containing the fluoroether compound.

In yet another aspect, the lewis acid inhibitor may be added under wet conditions to a container filled with the fluoroether compound. For example, water is added to a container filled with a fluoroether compound by placing the container in a humid room for a sufficient time to allow water to accumulate in the container.

The lewis acid inhibitor may be added to the composition at any suitable point in the manufacturing process, such as at the final manufacturing step prior to filling into a shipping container (e.g., a 500 liter shipping container). An appropriate amount of the composition can be dispensed from the container and packaged in a container of more suitable size for industrial use, e.g., a 250ml glass bottle. In addition, the container may be washed or rinsed with a small amount of a composition containing a suitable amount of a lewis acid inhibitor to neutralize any lewis acid that may be present in the container. Once the lewis acid is neutralized, the vessel is emptied and an additional amount of the fluoroether composition is added to the vessel, which is then sealed.

Examples of the present invention will now be given, which are not intended to limit the present invention.

Example 1: activated alumina as a Lewis acid

Type III glass consists primarily of silica, calcium oxide, sodium oxide, and alumina. Alumina is a known lewis acid. The glass material is generally inert to sevoflurane. However, under certain conditions (anhydrous, acidic), the glass surface may be attacked or otherwise altered to expose sevoflurane to active lewis acid sites such as alumina.

The effect of water on sevoflurane degradation was studied by adding various amounts of activated alumina to 20ml of sevoflurane containing the following three levels of humidity: 1)20ppm water-measured water, no additional water was added; 2)100 ppm-tracing; and 3)260ppm water-tracer. The following table shows the test materials.

TABLE 1

	1	2	3
				A	50mg Al2O320ppm of water	50mg Al2O3100ppm water	50mg Al2O3260ppm water
B	20mg Al2O320ppm of water	20mg Al2O3100ppm water	20mg Al2O3260ppm water
				C	10mg Al2O320ppm of water	10mg Al2O3100ppm water	10mg Al2O3260ppm water

It will be appreciated that 20ppm of water corresponds to 0.0022% w/w water. The sample was placed at 60 ℃ and analyzed by gas chromatography after 22 hours. FIG. 1 shows that sevoflurane degradation decreases with increasing water amount in the presence of the same amount of alumina (50mg) (Table 1, row A). Similar trends were observed with 20mg and 10mg of alumina (rows B and C).

Example 2: heating with or without water to degrade sevoflurane in ampoules

Approximately 20ml of sevoflurane was added to a 50ml clear type I ampoule and approximately 20ml of sevoflurane and 1300ppm of water were added to a second ampoule. Both ampoules were flame sealed and then heated in an autoclave at 119 ℃ for 3 hours. The contents of the two ampoules were then analysed by gas chromatography. Figure 2 shows the degradation of sevoflurane in the first ampoule. Figure 3 shows that sevoflurane in the second ampoule does not degrade due to the lewis acid inhibitor, i.e., water addition.

Example 3: degradation of sevoflurane in ampoules (109ppm-951ppm) was studied using tracer water

Clear glass type I ampoules were used to study the effect of various levels of water on the inhibition of sevoflurane degradation. About 20ml of sevoflurane and varying levels of water ranging from about 109ppm to about 951ppm were added to each ampoule. The ampoule is then sealed. A total of 10 ampoules were filled with sevoflurane and the amount of water was varied. 5 ampoules were included in the a device and the other 5 ampoules were included in the B device. Then, the ampoule was held at 119 ℃ for 3 hours in an autoclave. The sample in device a was placed in a mechanical shaker overnight to allow moisture to coat the glass surface. Samples in set B were prepared without wrapping the glass surface with water, and some control samples were also prepared. Two non-autoclave heated ampoules (control ampoule 1 and control ampoule 2) and bottle (control bottle) were filled with 20ml of sevoflurane, respectively. No water was added to any of the control samples. Also, the control sample was not shaken overnight. Hexafluoroisopropanol (HFIP) and total degradant (including methylene glycol bis hexafluoroisopropyl ether, dimethylene glycol bis hexafluoroisopropyl ether, methylene glycol fluoromethyl hexafluoroisopropyl ether) levels were measured by gas chromatography. The results are shown in table 2 below.

TABLE 2

Sample (I)	Calculated Total humidity (ppm)	pH	HFIP(ppm)	Total degradants (ppm) other than HFIP
					Contrast, bottle		6.0	6	57
Control, ampoule 1, RT		3.0	7	50
					Control, ampoule 2, RT		4.0	6	51
A device (vibrating overnight)
					1	109	0	1.525	201614
2	206	0	2.456	105518
					3	303	0	4.027	127134
4	595	5.0	7	82
					5	951	5.0	12	84
B device (non-oscillation)
					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

The results in Table 2 above show that at least 595ppm of water is sufficient to inhibit sevoflurane degradation for the ampoules in unit A and unit B. The results showed no significant difference between the overnight shaken ampoule and the overnight unstirred ampoule.

Example 4: study of sevoflurane degradation in ampoules at 60 ℃ or 40 ℃ Using Tracer Water sevoflurane

Clear glass type I ampoules were used to study the effect of various levels of water and temperature on the inhibition of sevoflurane degradation. About 20ml of sevoflurane and varying levels of water ranging from about 109ppm to about 951ppm were added to each ampoule. The ampoule is then flame sealed. To facilitate the degradation process, samples at each wetting level were subjected to two heating conditions. The sample was placed at 60 ℃ steady state for 144 hours or at 40 ℃ steady state for 200 hours. Each sample was analyzed for sevoflurane by gas chromatography and pH. The total degradation of hexafluoroisopropyl alcohol (HFIP) and sevoflurane was measured. The results obtained are shown in table 3 below.

TABLE 3

Sample (I)	Total humidity	pH	HFIP(ppm)	Total degradation (ppm)
					Tracing water at 60 deg.C for 144 hr
1	109	0	850	474796
					2	206	3.5	78	4865
3-1	303	3.5	1316	6868
					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
					Tracing water, 40 deg.C, 200 hours
6-1	Without adding water	0	232	102435
					6-2	Without adding water	2.5	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
11	951	6.0	5	60

The results in Table 3 show that water concentrations above 206ppm inhibit sevoflurane degradation at 40 ℃ for 200 hours. Water concentrations above 303ppm inhibited sevoflurane degradation for samples stored at 60 c for 144 hours or more. This data suggests that with an increase in temperature, the amount of water required to inhibit sevoflurane degradation will increase.

Example 5: degradation of sevoflurane in active type III amber glass bottles

The type III amber glass bottles used to store the degraded sevoflurane were examined. Those bottles were selected that showed a significant amount of etching of the inner wall. A total of 10 type III amber glass vials were selected. The degraded sevoflurane contained in each bottle was drained and the bottle was rinsed several times with fresh, undegraded sevoflurane. About 100ml of undegraded sevoflurane containing about 20ppm water was added to each bottle. All samples were analyzed by gas chromatography after heating for 0 hours and at 50 ℃ for 18 hours. Hexafluoroisopropyl alcohol (HFIP) and dimethylene glycol (P2) ether were measured. The results obtained are shown in tables 4 and 5.

TABLE 4

Result of 0 time

	Degradation products (ppm)
				Bottle number	HFIP	P2	Total amount of
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

TABLE 5

Results at 50 ℃ for 18 hours

	Degradation products (ppm)
				Bottle number	HFIP	P2	Total amount of
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

The results in tables 4 and 5 show the "activity" of the degraded sevoflurane on the glass surface in these bottles. The "live" glass surface thus acts as an initiator for the degradation of fresh sevoflurane.

Example 6: additional study of sevoflurane degradation in active type III amber glass bottles

The extent of sevoflurane degradation in each bottle of example 5 was quantified by gas chromatography. The ten flasks were divided into two groups, control Sevo (including flasks 2, 3, 5, 7, 8) and study Sevo (including flasks 1, 4, 6, 9, 10).

All 10 bottles were re-rinsed several times with undegraded sevoflurane containing about 20ppm water. For the 5 control Sevo group bottles, 100ml of sevoflurane containing about 20ppm water was added to each bottle. For the 5 study Sevo group bottles, 100ml of sevoflurane containing about 400ppm water (tracer) was added to each bottle.

All samples were analyzed by gas chromatography at 0 deg.C and after heating at 50 deg.C for 18 hours. Hexafluoroisopropanol (HFIP), dimethylene glycol bis hexafluoroisopropyl ether (P2) and total degradants were measured. The results are shown in table 6 below.

TABLE 6

Results at 0 hours and 18 hours

	Degradation products (ppm)
								HFIP		P2		Total degradants
Time of day	0 hour	18 hours	0 hour	18 hours	0 hour	18 hours
							Control group (20ppm 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
							Research group (400ppm 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 results in table 6 show that no significant degradation of sevoflurane was observed at 0 hours compared to the 0 hour results in table 4. The results in Table 6 show that sevoflurane degradation is significantly reduced in the study Sevo group (400ppm water). The amounts of degradants P2 (dimethylene glycol bis hexafluoroisopropyl ether) and S1 (methylene glycol fluoromethyl hexafluoroisopropyl ether) were significantly lower than the control (20ppm water). However, the HFIP concentration in the Sevo group was very high, suggesting that the glass surface still has some activity.

FIG. 4 shows a comparative graph of the data degradation product dimethylene glycol bis hexafluoroisopropyl ether (P2) in tables 5 and 6. FIG. 5 shows a comparative graph of the degradant methylene glycol fluoromethyl hexafluoroisopropyl ether (S1) shown in examples 5 and 6. Both fig. 4 and fig. 5 show that addition of 400ppm of water inhibits sevoflurane degradation.

Example 7: additional study of sevoflurane degradation in active type III amber glass bottles

Sevoflurane was decanted from the bottles of the 5 study Sevo groups of example 6. Each bottle was rinsed thoroughly with fresh sevoflurane. Approximately 125ml of water-saturated sevoflurane was then added to each bottle. The 5 bottles were placed on a mechanical roller for approximately two hours to allow the water to wrap around the activated bottle surface. The water saturated sevoflurane was decanted from each bottle and replaced with 100ml of sevoflurane containing 400 (ppm of tracer) water. All samples were gas chromatographed after heating at 50 ℃ for 18 hours, 36 hours and 178 hours. Bis hexafluoroisopropyl ether (P2) and total degradants were measured. The results are shown in table 7 below.

TABLE 7

	Degradation products (ppm)
								HFIP		P2		Total degradants
Time of day	36 hours	178 hours	36 hours	178 hours	36 hours	178 hours
							Research group (400ppm 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

The results in Table 7 show that treatment of activated glass surfaces with saturated sevoflurane prior to heating greatly inhibits degradation of sevoflurane.

Claims (12)

1. A method of preventing degradation of sevoflurane by a lewis acid, the method comprising the steps of:

providing a container;

providing an amount of sevoflurane;

washing or rinsing the container with a lewis acid inhibitor;

placing the amount of sevoflurane in the container.

2. The method of claim 1, wherein the Lewis acid inhibitor is selected from the group consisting of water, butylated hydroxytoluene, methyl paraben, propyl paraben, propofol, or thymol.

3. The method of claim 1, wherein the Lewis acid inhibitor is water.

4. The method of claim 1, wherein the Lewis acid inhibitor is water-saturated sevoflurane.

5. The method of claim 1, wherein the container is partially dried between the washing or rinsing and the resting steps.

6. A method of preventing degradation of sevoflurane by a lewis acid, the method comprising: adding a stabilizing effective amount of a Lewis acid inhibitor to sevoflurane to prevent degradation of the sevoflurane by Lewis acid, wherein said stabilizing effective amount is 0.0150% w/w water equivalent to the saturation level of the Lewis acid inhibitor in the sevoflurane.

7. The method of claim 6, wherein the Lewis acid inhibitor is water.

8. The process of claim 6, wherein the Lewis acid inhibitor is butylated hydroxytoluene.

9. The method of claim 6, wherein the Lewis acid inhibitor is methylparaben.

10. The method of claim 6, wherein the Lewis acid inhibitor is propyl paraben.

11. The method of claim 6, wherein the Lewis acid inhibitor is propofol.

12. The method of claim 6, wherein the Lewis acid inhibitor is thymol.