CN117030891A

CN117030891A - Method for detecting desflurane or related substances in inhalant preparation thereof

Info

Publication number: CN117030891A
Application number: CN202311034775.6A
Authority: CN
Inventors: 赵翠然; 勾佳; 靳宏娣; 郭永辉; 赵东明; 张博; 王金静; 鲍小茹; 贾宗英
Original assignee: Hebei Yipin Pharmaceutical Co ltd; Hebei Yipin Biomedical Co ltd
Current assignee: Hebei Yipin Pharmaceutical Co ltd; Hebei Yipin Biomedical Co ltd
Priority date: 2023-08-16
Filing date: 2023-08-16
Publication date: 2023-11-10

Abstract

The invention relates to the technical field of medicine analysis, and particularly discloses a detection method of desflurane or related substances in an inhalation preparation thereof. The invention adopts gas chromatography to detect, uses DB-WAXETR (60 m multiplied by 0.32mm multiplied by 1.0 mu m) as chromatographic column, and uses specific temperature programming mode to match with specific sample inlet temperature, detector temperature, split ratio and other gas chromatography conditions, thus realizing the accurate detection of difluoro-chloromethane, trifluoro-ethanol, methylene dichloride, trichloromethane, dichloro-fluoromethane and trichlorofluoromethane in desflurane or the inhalant preparation thereof. The method provided by the invention has the advantages of strong specificity, high sensitivity, good linear relation, good accuracy and durability, and can realize the simultaneous detection of a plurality of potential related substances in the desflurane or the inhalant preparation thereof, make up the blank that the prior art can not effectively detect a plurality of related substances in the desflurane or the inhalant preparation thereof at the same time, and have higher practical value.

Description

Method for detecting desflurane or related substances in inhalant preparation thereof

Technical Field

The invention relates to the technical field of medicine analysis, in particular to a detection method of desflurane or related substances in an inhalation preparation thereof.

Background

Desflurane, english name Desflurane, chemical name 2-difluoromethoxy-1, 2-tetrafluoro-ethane, has the following structural formula. The desflurane is a fluorine-containing inhalation anesthetic marketed in 1992, is a fluorine-containing chlorine compound of isoflurane, has a low boiling point (23 ℃) and a blood gas distribution coefficient of 0.42, is lower than other fluorine-containing inhalation anesthetics, so that the anesthesia induction and recovery are faster, and the anesthesia depth is easy to adjust. The minimum intra-alveolar concentration (MAc) is 5.6% -6%, so that the anesthesia efficacy is lower than that of other fluorine-containing adsorption anesthetics, and therefore, compared with other inhalation anesthetics, the effect on the circulatory system is smaller, the liver and kidney functions are not damaged, and the method is widely applied to modern anesthetics.

The existing technology for synthesizing desflurane mainly comprises the following steps: the isoflurane is used as raw material, antimony salt is used as catalyst, hydrogen fluoride is used as fluorinating agent, and the crude desflurane is obtained through reaction, quenching, washing and dehydration, and the crude desflurane is purified by rectification to obtain the finished product. In the preparation of isoflurane, the starting materials of difluoromethane chloride and trifluoroethanol, wherein, in the 3-class carcinogenic list, the difluoromethane chloride and the trifluoroethanol belong to medium toxic substances, all can remain in isoflurane, and further influence the product quality of desflurane. Meanwhile, the desflurane may also contain impurities such as dichloromethane, trichloromethane, dichlorofluoromethane, trichlorofluoromethane and the like, and the four impurities are also recorded in the current European pharmacopoeia USP.

However, when the detection method of the related substances under the term of desflurane in the current USP standard is adopted for detection, the separation degree of the desflurane and the related substances of the desflurane, namely the dichlorofluoromethane, is low and less than 1.0, and the potential genotoxic impurities, namely the dichlorofluoromethane and trifluoroethanol, cannot be detected. In order to better monitor the quality of desflurane or its inhaled formulation and ensure the clinical medication safety of desflurane or its inhaled formulation products, it is necessary to develop a method for accurately and reliably detecting various related substances in desflurane or its inhaled formulation.

Disclosure of Invention

Aiming at the problem that the prior art can not effectively detect various impurities such as difluoro chloromethane, trifluoroethanol, methylene dichloride, trichloromethane, dichloro fluoromethane, trichlorofluoromethane and the like in desflurane or an inhalation preparation thereof at the same time, the invention provides a detection method of relevant substances in desflurane or an inhalation preparation thereof.

In order to solve the technical problems, the technical scheme provided by the invention is as follows:

a detection method of relevant substances in desflurane or an inhalation preparation thereof, wherein the relevant substances are difluoro-chloromethane, trifluoroethanol, dichloromethane, trichloromethane, dichloro-fluoromethane and trichlorofluoromethane, and the detection is carried out by adopting a gas chromatography method, and the detection method comprises the following steps:

(1) Preparing a test solution and a mixed reference solution:

taking desflurane or an inhalation preparation thereof to prepare a test sample solution;

preparing a mixed reference substance solution from difluoromethane, trifluoroethanol, dichloromethane, trichloromethane, dichlorofluoromethane and trichlorofluoromethane reference substances by using a solvent;

(2) Detecting the mixed reference substance solution and the sample solution, wherein the gas chromatography conditions are as follows:

a detector: a hydrogen flame ionization detector;

chromatographic column: DB-WAXETR,60 m.times.0.32 mm.times.1.0 μm;

column temperature: maintaining at 28-32deg.C for 7-9 min, heating to 90-110deg.C at 8-12deg.C/min, maintaining for 2-6 min, heating to 120-160deg.C at 15-25deg.C/min, and maintaining for 3-5 min;

sample inlet temperature: 170-180 ℃;

detector temperature: 195-205 ℃;

split ratio: 22-24:1.

Compared with the prior art, the detection method of desflurane or related substances in the inhalation preparation adopts a gas chromatography method, uses DB-WAXETR (60 m multiplied by 0.32mm multiplied by 1.0 mu m) as a chromatographic column, and realizes the accurate detection of six related substances of difluoro-chloromethane, trifluoroethanol, dichloromethane, trichloromethane, dichloro-fluoro-methane and trichlorofluoro-methane in the desflurane or the inhalation preparation by matching with gas chromatography conditions such as specific sample inlet temperature, detector temperature, split ratio and the like in a specific temperature programming mode. The method provided by the invention has the advantages of strong specificity, high sensitivity, good linear relation, good accuracy and durability, can realize simultaneous detection of a plurality of potential related substances in the desflurane or the inhaled preparation thereof, is used as a qualitative and quantitative detection means of a plurality of impurities in the desflurane or the inhaled preparation thereof, makes up the blank that the prior art can not effectively detect a plurality of related substances in the desflurane or the inhaled preparation thereof at the same time, is more favorable for truly reflecting the quality of the desflurane or the inhaled preparation thereof, is further favorable for reducing the medication safety risk of desflurane medicines, and has higher practical value.

Further, the column temperature is: maintaining at 30deg.C for 8min, heating to 100deg.C at 10deg.C/min, maintaining for 4min, and heating to 140deg.C at 20deg.C/min, and maintaining for 4min.

The preferred temperature programming mode is matched with a specific chromatographic column, so that the separation degree of the desflurane and the related substances of the desflurane and the dichlorofluoromethane can be improved, and the difluorochloromethane and the trifluoroethanol can be fully detected, thereby realizing the quantitative detection of various related substances in the desflurane or the inhalation preparation thereof.

Further, the sample inlet temperature was 175 ℃.

Further, the detector temperature was 200 ℃.

The preferred sample inlet temperature and detector temperature can improve the separation degree of desflurane and each impurity quality inspection, thereby being beneficial to improving the accuracy and sensitivity of detection.

Further, the split ratio was 23:1.

Further, the carrier gas is nitrogen, and the flow rate is 1.5mL/min-1.9mL/min.

Preferably, the carrier gas flow rate is 1.7mL/min.

Further, the sample injection mode is automatic sample injection, and the sample injection volume is 2 mu L.

Further, the solvent for preparing the mixed reference solution is desflurane.

Further, the concentration of difluoromethane, trifluoroethanol, dichloromethane, chloroform, dichlorofluoromethane and trichlorofluoromethane in the mixed reference solution was 35. Mu.g/g, 12. Mu.g/g, 24. Mu.g/g, 36. Mu.g/g, respectively.

In the present invention, a commercially available methanol solution having a concentration of 994.0. Mu.g/mL was selected as a reference difluoromethane, a commercially available methanol solution having a concentration of 2000. Mu.g/mL was selected as a reference dichlorofluoromethane, a commercially available methanol solution having a concentration of 9991.2. Mu.g/mL was selected as a reference trichlorofluoromethane, a commercially available reference having a purity of 99.5% was selected as dichloromethane, a commercially available reference having a purity of 99.5% was selected as trichloromethane, and a commercially available reference having a purity of 99.507% was selected as trifluoroethanol.

The preferable gas chromatography detection conditions can ensure that the main components and various impurities in the desflurane and the preparation thereof can reach higher separation degree, and can ensure the effective detection of various impurities, thereby achieving the purpose of effectively and accurately controlling the content of relevant substances in the desflurane raw materials and the preparation.

The detection method provided by the invention is suitable for detecting related substances in desflurane raw materials and desflurane preparations for inhalation.

The detection method provided by the invention can realize the effective separation between six impurities (difluoro-chloromethane, trifluoroethanol, dichloromethane, trichloromethane, dichloro-fluoromethane and trichlorofluoromethane) and main components in the desflurane and the preparation thereof, accurately, qualitatively and quantitatively detect the condition of the impurities in the desflurane and the preparation thereof, and the detected impurity types and quantity are higher than those of the existing method, thereby providing technical support for improving and better controlling the quality of the desflurane and the preparation thereof, guaranteeing the clinical safety and effectiveness of the desflurane and the preparation thereof, and having higher practical value.

Drawings

FIG. 1 is a chromatogram of the blank solvent under item 1.1 of example 1;

FIG. 2 is a chromatogram of the difluoromethane chloromethane identification solution under item 1.1 of example 1;

FIG. 3 is a chromatogram of the trifluoroethanol discrimination solution under item 1.1 in example 1;

FIG. 4 is a chromatogram of the dichloromethane identification solution under item 1.1 of example 1;

FIG. 5 is a chromatogram of the chloroform identification solution under item 1.1 of example 1;

FIG. 6 is a chromatogram of the dichlorofluoromethane identification solution under item 1.1 of example 1;

FIG. 7 is a chromatogram of the trichlorofluoromethane identification solution under item 1.1 of example 1;

FIG. 8 is a chromatogram of the mixed control solution under item 1.1 of example 1;

FIG. 9 is a chromatogram of the 1.1 point down-labeled test solution of example 1;

FIG. 10 is a chromatogram of a test solution for dichlorofluoromethane identification using the test method for the USP standard desflurane-related material under item 1.1 of example 1;

FIG. 11 is a chromatogram of a test solution for detection of a labeled sample using the method for detection of a USP standard desflurane-related substance under item 1.1 of example 1;

FIG. 12 is a chromatogram of the labeled test solution of comparative example 1;

FIG. 13 is a chromatogram of the test sample solution labeled in comparative example 2;

FIG. 14 is a chromatogram of the labeled test solution of comparative example 3.

Detailed Description

The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.

Trifluoroethanol, methylene dichloride and chloroform used in the following examples are all commercial chromatographic grade controls, the purity of the methylene dichloride control is 99.5%, the purity of the chloroform control is 99.5%, and the purity of the trifluoroethanol control is 99.507%;

the difluoromethane reference substance was a commercially available methanol solution with a concentration of 994.0. Mu.g/mL, the difluoromethane reference substance was a commercially available methanol solution with a concentration of 2000. Mu.g/mL, and the trichlorofluoromethane reference substance was a commercially available methanol solution with a concentration of 9991.2. Mu.g/mL.

Example 1

And (3) methodological verification:

1.1 specificity

Chromatographic conditions:

instrument: island liquid gas chromatograph GC-2010plus;

chromatographic column: agilent DB-WAXETR,60 m0.32mmx1.0μm;

heating program: maintaining at 30deg.C for 8min, heating to 100deg.C at 10deg.C/min, maintaining for 4min, heating to 140deg.C at 20deg.C/min, and maintaining for 4min;

detector temperature: 200 ℃;

sample inlet temperature: 175 ℃;

carrier gas: nitrogen gas;

flow rate: 1.7mL/min;

split ratio: 23:1;

sample injection volume: 2. Mu.L.

The test steps are as follows:

blank solvent: desflurane;

test solution: desflurane;

difluoro-chloromethane identification solution: 100 mu L of a methanol solution of difluoro-chloromethane with the concentration of 994.0 mu g/mL is precisely weighed and placed in a sample injection small bottle filled with 400 mu L of desflurane, and shaking is carried out uniformly to obtain a difluoro-chloromethane identification solution.

Trifluoroethanol identification solution: 45.12mg of trifluoroethanol reference substance is precisely weighed and placed in a headspace bottle filled with 10mL of desflurane, and the mixture is shaken uniformly to obtain the trifluoroethanol identification solution.

Dichloromethane identification solution: 15.08mg of dichloromethane reference substance is precisely weighed and placed in a headspace bottle filled with 10mL of desflurane, and shaking is carried out uniformly to obtain dichloromethane identification solution.

Chloroform identification solution: 30.04mg of chloroform reference substance is precisely weighed and placed in a headspace bottle filled with 10mL of desflurane, and shaking is carried out uniformly to obtain a chloroform identification solution.

Dichlorofluoromethane identification solution: 100 mu L of a methanol solution of dichlorofluoromethane with the concentration of 2000 mu g/mL is precisely measured and placed in a sample injection small bottle filled with 400 mu L of desflurane, and the mixture is shaken uniformly to obtain a dichlorofluoromethane identification solution.

Trichlorofluoromethane identification solution: 100 mu L of a methanol solution of trichlorofluoromethane with the concentration of 9991.2 mu g/mL is precisely measured and placed in a sample injection small bottle with 400 mu L of desflurane, and the mixture is shaken uniformly to obtain a trichlorofluoromethane identification solution.

Control stock solution: 2.25mL of a methanol solution of difluoromethane with the concentration of 994.0 mug/mL, 0.5mL of a trifluoroethanol identification solution, 0.5mL of a dichloromethane identification solution, 0.5mL of a chloroform identification solution, 0.225mL of a methanol solution of dichlorofluoromethane with the concentration of 2000 mug/mL and 1.125mL of a methanol solution of trichlorofluoromethane with the concentration of 9991.2 mug/mL are respectively taken, precisely weighed and placed in a headspace bottle filled with 5mL of desflurane, and uniformly shaken to obtain a reference stock solution.

Mixing the reference substance solution: taking 1mL of control stock solution, placing the control stock solution in a headspace bottle filled with 4mL of desflurane, and shaking uniformly to obtain a mixed control solution.

Adding a labeled test sample solution: 200 mu L of reference stock solution and 800 mu L of desflurane are taken, precisely weighed, placed in the same sample injection small bottle and shaken uniformly to obtain the solution of the added standard sample. 6 parts were prepared in parallel.

And precisely measuring 2 mu L of each of a blank solvent, a difluoro-chloromethane identification solution, a trifluoroethanol identification solution, a dichloromethane identification solution, a trichloromethane identification solution, a dichloro-fluoromethane identification solution, a trichlorofluoromethane identification solution, a mixed reference substance solution and a standard test substance solution, detecting by adopting the chromatographic conditions, and recording chromatographic peaks.

Wherein, the chromatogram of the blank solvent is shown in figure 1, the chromatogram of the difluoro-chloromethane identification solution is shown in figure 2, the chromatogram of the trifluoroethanol identification solution is shown in figure 3, the chromatogram of the dichloromethane identification solution is shown in figure 4, the chromatogram of the trichloromethane identification solution is shown in figure 5, the chromatogram of the dichloro-chloromethane identification solution is shown in figure 6, the chromatogram of the trichloro-chloromethane identification solution is shown in figure 7, the chromatogram of the mixed reference solution is shown in figure 8, and the chromatogram of the labeled sample solution is shown in figure 9. The peak time results for each identified solution are shown in table 1.

The chromatograms of the dichlorofluoromethane identification solution and the labeled test solution are shown in fig. 10 and 11, respectively, using the current USP standard desflurane-related substance detection method.

TABLE 1 specificity

Name of the name	Retention time (min)
		Desflurane (DEF)	13.496
Difluoro chloromethane	5.248
		Trichlorofluoromethane	5.585
Dichlorofluoromethane	10.067
		Dichloromethane (dichloromethane)	14.137
Trichloromethane	16.480
		Trifluoroethanol	19.499

As can be seen from the table, according to the detection method provided by the scheme, the desflurane and the dichlorofluoromethane can be completely separated, the separation degree of each component is good, and meanwhile, the genotoxic impurities of the difluorochloromethane and the toxic substance trifluoroethanol can be detected, so that the method is good in specificity.

1.2 durability

Taking 2 mu L of each of the prepared blank solvent, the sample solution, the mixed reference solution and the standard sample solution, detecting according to the chromatographic conditions under the specific items and the partial chromatographic conditions, recording the chromatograms, and obtaining the results shown in tables 2-4.

TABLE 2 separation results of desflurane and impurities in the Mixed control solutions under different chromatographic conditions

TABLE 3 ratio of the amounts of impurities detected in the sample solutions to the normal conditions under different chromatographic conditions%

TABLE 4 recovery of impurities from sample solutions under different chromatographic conditions%

The result shows that the method is still suitable for detecting relevant substances in desflurane or an inhalation preparation thereof, wherein the separation degree of each impurity in the mixed reference substance solution is not greatly influenced, and the recovery rate of each impurity in the labeled sample solution is more than 97 percent, which indicates that the method has good durability, and the detection result is not influenced at all by changing the chromatographic conditions within a proper range.

1.3 precision

Taking 2 mu L of each of the prepared sample solution, the mixed reference substance solution and the standard-added sample solution, respectively detecting according to chromatographic conditions under a specific item, recording a chromatogram, calculating RSD of detection amounts of all impurities in 6 parts of parallel sample solutions, and calculating RSD of average recovery rates and recovery rates of all impurities in 6 parts of parallel standard-added sample solutions, wherein the results are shown in tables 5-6.

TABLE 5 test solutions

TABLE 6

The above results show that the detection method provided by the invention is adopted to detect related substances, the test sample is repeatedly detected for 6 times, and all impurities are not detected; repeated detection is carried out for 6 times, the recovery rate of each impurity is 97.4% at minimum, and the RSD (reactive species decomposition) of the recovery rate is 2.0% at maximum, so that the method has good precision.

1.4 recovery rate

50% standard recovery solution: 100 mu L of the prepared reference stock solution is precisely measured, precisely measured and placed in a sample injection small bottle filled with 900 mu L of desflurane, and the sample injection small bottle is uniformly shaken to be used as a 50% recovery rate solution to prepare three parts in parallel.

100% standard recovery rate solution: 200 mu L of the prepared reference stock solution is precisely measured, precisely measured and placed in a sample injection small bottle filled with 800 mu L of desflurane, and the mixture is shaken uniformly to prepare three parts in parallel as a 100% recovery rate solution.

150% standard recovery solution: precisely weighing 300 μl of the prepared reference stock solution, precisely weighing, placing into a sample injection vial containing 700 μl of desflurane, shaking, and preparing in parallel three portions as 150% recovery solution.

The prepared mixed reference solution and each group of the standard recovery solutions were measured precisely at 2. Mu.L, and the detection was carried out using the above chromatographic conditions, and the chromatographic peaks were recorded, and the recovery results are shown in Table 7.

Recovery (%) = (measured-original amount)/addition amount×100%.

TABLE 7 recovery rate test results

The results show that the average recovery rates of difluoro-chloromethane, trifluoroethanol, dichloromethane, trichloromethane, dichloro-fluoromethane and trichlorofluoromethane with different concentration levels are above 96%, and the relative standard deviation of the recovery rates is below 2.0%. The method has good accuracy in measuring the contents of difluoro chloromethane, trifluoroethanol, methylene dichloride, trichloromethane, dichloro fluoromethane and trichlorofluoromethane in desflurane or an inhalation preparation thereof.

1.5 Linear Range

The stock solutions of the above-prepared mixed controls were precisely measured and prepared into linear solutions according to table 8.

Table 8 linear solution formulation

Linearity of	mu.L of control stock solution	Volume of solvent. Mu.L
			20％	40	960
50％	100	900
			75％	150	850
100％	200	800
			125％	250	750
150％	300	700
			200％	400	600

2. Mu.L of each linear solution was precisely measured, and the detection was performed using the above-mentioned chromatographic conditions, and the chromatographic peak was recorded. The standard curve was drawn with the concentration (. Mu.g/g) as the abscissa and the peak area as the ordinate, and the regression equation was calculated, and the results are shown in tables 9 to 14.

TABLE 9 Linear test results of difluoromethane chloride

TABLE 10 results of Linear experiments with trifluoroethanol

/>

TABLE 11 Linear test results with methylene chloride

TABLE 12 results of Linear experiments with chloroform

/>

TABLE 13 Linear test results of dichlorofluoromethane

TABLE 14 Linear test results of trichlorofluoromethane

/>

The detection result shows that the correlation coefficient r of each impurity in the linear range is larger than 0.99; good linearity was confirmed.

1.6 detection limit

Limit of detection: taking the prepared reference substances of all impurities, quantitatively diluting step by using desflurane, detecting according to the chromatographic conditions, recording a chromatogram, obtaining a detection limit according to the signal-to-noise ratio of 3-10, and continuously injecting 6 needles for quantitatively limiting the solution when the S/N is more than or equal to 10; the results are shown in Table 15.

Table 15 detection limits and quantitative limit detection results

The result shows that the detection limit concentration of the difluoro chloromethane by the method is 1.74 mug/g, and the quantitative limit is 3.26 mug/g; the detection limit concentration of trifluoroethanol is 0.39 mug/g, and the quantitative limit is 0.72 mug/g; the detection limit concentration of dichloromethane is 0.55 mug/g, and the quantitative limit is 1.03 mug/g; the detection limit concentration of the chloroform is 1.06 mug/g, and the quantitative limit is 1.98 mug/g; the detection limit concentration of the dichlorofluoromethane is 2.13 mug/g, and the quantitative limit is 3.99 mug/g; the detection limit concentration of trichlorofluoromethane was 11.42. Mu.g/g, and the quantitative limit was 21.40. Mu.g/g. The method has high sensitivity and meets the detection requirement of related substances in the finished product.

Example 2

The present example provides a method for detecting relevant substances in desflurane for inhalation, and chromatographic conditions are as follows:

instrument: island liquid gas chromatograph GC-2010plus;

chromatographic column: agilent DB-WAXETR,60 m0.32mmx1.0μm;

heating program: maintaining at 28deg.C for 9min, then heating to 110deg.C at rate of 12deg.C/min, maintaining for 2min, and heating to 120deg.C at rate of 15deg.C/min, and maintaining for 5min;

detector temperature: 195 deg.c;

sample inlet temperature: 170 ℃;

carrier gas: nitrogen gas;

flow rate: 1.9mL/min;

split ratio: 22:1;

sample injection volume: 2. Mu.L.

Taking the sample solution and the mixed reference substance solution, detecting by sample injection, and recording a chromatogram.

Example 3

instrument: island liquid gas chromatograph GC-2010plus;

chromatographic column: agilent DB-WAXETR,60 m0.32mmx1.0μm;

heating program: maintaining at 32deg.C for 7min, heating to 90deg.C at 8deg.C/min, maintaining for 6min, heating to 160deg.C at 25deg.C/min, and maintaining for 3min;

detector temperature: 205 deg.c;

sample inlet temperature: 180 ℃;

carrier gas: nitrogen gas;

flow rate: 1.5mL/min;

split ratio: 24:1;

sample injection volume: 2. Mu.L.

Examples 2-3 all achieved detection results substantially equivalent to the chromatographic conditions in example 1.

Comparative example 1

The method for detecting the relevant substances in the desflurane for inhalation provided in this comparative example is exactly the same as in example 1, and the difference is only that the degree of temperature rise is different, and the specific temperature programming mode is: the initial column temperature was 30℃for 8min, heated to 120℃at a rate of 30℃per min for 8min, and then heated to 140℃at a rate of 20℃per min for 4min. Sample injection detection is carried out on the labeled sample solution prepared in the embodiment 1, and the result is shown in fig. 12.

From the figure, only desflurane and trichloromethane can be detected in the labeled sample solution, and quantitative detection of other related substances cannot be realized.

Comparative example 2

The method for detecting the relevant substances in the desflurane for inhalation provided in this comparative example is exactly the same as in example 1, and the difference is only that the degree of temperature rise is different, and the specific temperature programming mode is: the initial column temperature was 30deg.C for 8min, and the temperature was raised to 140deg.C at a rate of 10deg.C/min for 6min. Sample injection detection is carried out on the labeled sample solution prepared in the embodiment 1, and the result is shown in fig. 13.

From the figure, it can be seen that only chromatographic peaks of desflurane can be detected in the labeled sample solution, and quantitative detection of other related substances cannot be realized.

Comparative example 3

The method for detecting the relevant substances in the desflurane for inhalation provided in this comparative example was exactly the same as in example 1, except that the column was replaced with Agilent DB-FFAP (30 m. Times.0.32 mm. Times.1.0 μm). Sample injection detection is carried out on the labeled sample solution prepared in the embodiment 1, and the result is shown in fig. 14.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.

Claims

1. A method for detecting relevant substances in desflurane or an inhalation preparation thereof, which is characterized in that the relevant substances are difluoro-chloromethane, trifluoroethanol, methylene dichloride, trichloromethane, dichloro-fluoromethane and trichlorofluoromethane, and the detection is carried out by adopting a gas chromatography method, comprising the following steps:

(1) Preparing a test solution and a mixed reference solution:

a detector: a hydrogen flame ionization detector;

chromatographic column: DB-WAXETR,60 m.times.0.32 mm.times.1.0 μm;

sample inlet temperature: 170-180 ℃;

detector temperature: 195-205 ℃;

split ratio: 22-24:1.

2. The method for detecting desflurane or related substances in an inhaled formulation thereof according to claim 1, wherein the column temperature is: maintaining at 30deg.C for 8min, heating to 100deg.C at 10deg.C/min, maintaining for 4min, and heating to 140deg.C at 20deg.C/min, and maintaining for 4min.

3. The method for detecting desflurane or related substances in an inhaled formulation thereof according to claim 1, wherein the sample inlet temperature is 175 ℃.

4. The method for detecting desflurane or related substances in an inhaled formulation thereof according to claim 1, wherein the detector temperature is 200 ℃.

5. The method for detecting desflurane or a related substance in an inhaled formulation thereof according to claim 1, wherein the split ratio is 23:1.

6. The method for detecting desflurane or a related substance in an inhaled formulation thereof according to claim 1, wherein the carrier gas is nitrogen gas at a flow rate of 1.5mL/min to 1.9mL/min.

7. The method for detecting desflurane or related substances in an inhaled formulation thereof according to claim 5, wherein the carrier gas flow rate is 1.7mL/min.

8. The method for detecting desflurane or related substances in an inhaled formulation thereof according to claim 1, wherein the sample is introduced in an automatic sample manner, and the sample volume is 2 μl.

9. The method for detecting desflurane or a related substance in an inhaled formulation thereof according to claim 1, wherein the solvent in which the mixed reference solution is formulated is desflurane.

10. The method for detecting desflurane or a related substance in an inhaled formulation thereof according to claim 1, wherein the concentration of difluoromethane, trifluoroethanol, dichloromethane, trichloromethane, dichlorofluoromethane and trichlorofluoromethane in the mixed reference solution is 35 μg/g, 12 μg/g, 24 μg/g, 36 μg/g, respectively.