Method for detecting content of impurity chloromethane in dexmedetomidine hydrochloride intermediate

Abstract

The invention relates to a method for detecting the content of impurity chloromethane in a dexmedetomidine hydrochloride intermediate. According to the method, a chromatographic column is GL # imgabs0 # wanda cap 5, and 5%-phenyl-95% dimethyl polysiloxane is adopted as a stationary liquid; the temperature of a sample inlet is 230-250 DEG C; the temperature of a detection port is 240-260 DEG C (the detector is FID); the split ratio is (2-20): 1; the flow velocity is 2-3 ml / min; the initial temperature is 20-50 DEG C, the temperature is maintained for 3 min, and the temperature is increased to 240 DEG C at the heating rate of 45-55 DEG C / min and maintained for 15 min. The separation degree R of impurity chloromethane can be larger than or equal to 1.5, the impurity content RSD of chloromethane is smaller than or equal to 2.0 after a chloromethane sample is continuously injected for five times, the sample injection repeatability is good, the durability of the method is good, and the method can be used for quality control of dexmedetomidine hydrochloride intermediates.

Description

Technical Field

[0001] The invention belongs to the field of drug analysis, and particularly relates to a method for detecting the content of methyl chloride as an impurity in a dexmedetomidine hydrochloride intermediate. Background Art

[0002] Dexmedetomidine hydrochloride is a selective α2-adrenergic receptor agonist jointly developed by Abott (US) and OrionPharma (Finland). It was first launched in the US in March 2000. By selectively binding to α2-adrenergic receptors, it exerts a sedative and hypnotic effect and can reduce a patient's sensitivity to painful stimuli. The drug may also affect cerebral cortical activity, reducing brainwave frequency and thus producing a sedative effect. Its structural formula is as follows:

[0003]

[0004] 4-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole hydrochloride (Intermediate I) is a key intermediate in the synthesis of dexmedetomidine hydrochloride. During its synthesis, methanol and concentrated hydrochloric acid react to produce chloromethane, a toxic halogenated hydrocarbon impurity. ICH M7 states that chloromethane is mutagenic and genotoxic in vitro, and is classified by IARC as Category 3, with a lifetime exposure limit of 1.361 mg / day.

[0005] There is no analytical method for detecting the impurity chloromethane content in the dexmedetomidine hydrochloride intermediate in the literature report at present. In addition, the volatility of chloromethane also brings certain difficulty to analytical method development. In order to ensure the research and development and production quality of follow-up dexmedetomidine hydrochloride bulk drug and preparation, it is necessary to control the quality of dexmedetomidine hydrochloride intermediate (I). Therefore, research and obtain a detection method for the impurity chloromethane content in the dexmedetomidine hydrochloride intermediate (I), which seems particularly urgent for the pharmaceutical companies producing dexmedetomidine hydrochloride. The structural formula of dexmedetomidine hydrochloride intermediate (I) is as follows:

[0006] Summary of the Invention

[0007] To solve the above technical problems, the object of the present invention is to provide a high performance gas chromatography method with high feasibility, simple and convenient operation process, good applicability, and can be widely used to detect the content of impurity methyl chloride in dexmedetomidine hydrochloride intermediate (I).

[0008] The present invention provides a method for detecting the content of methyl chloride impurity in a dexmedetomidine hydrochloride intermediate (I).

[0009]

[0010] The dexmedetomidine hydrochloride intermediate (I) is analyzed by a high-performance gas chromatography analysis method to obtain a chromatogram, and based on the chromatogram, the content of the impurity methyl chloride in the dexmedetomidine hydrochloride intermediate (I) is determined. The chromatographic column of the high-performance gas chromatography analysis method uses 5%-phenyl-95% dimethylpolysiloxane as a stationary liquid; the injection port temperature is 230-250° C.; the detection port temperature is 240-260° C. (the detector is FID); the split ratio is 2-20:1; the flow rate is 2-3 ml / min; and the temperature is programmed, with an initial temperature of 20-50° C., maintained for 3 minutes, and then increased to 240° C. at a heating rate of 45-55° C. / min, and maintained for 15 minutes.

[0011] It is understandable that the applicant has screened out the appropriate injection port temperature, detection port temperature, flow rate and temperature rise program through a lot of creative work, and under specific conditions, can effectively achieve the separation of dexmedetomidine hydrochloride intermediate (I) and methyl chloride impurity peak.

[0012] In some embodiments, the injection port temperature is 235-245°C.

[0013] In some embodiments, the detection port temperature is 245-255°C.

[0014] In some embodiments, the split ratio is 5 to 15:1.

[0015] In some embodiments, the flow rate is 2.3-2.7 ml / min.

[0016] In some embodiments, the initial temperature of the programmed temperature increase is 25-35°C.

[0017] In some embodiments, the heating rate of the programmed temperature is 48-52° C. / min.

[0018] In some embodiments, the chromatographic column is GL wanda cap 5, 30m×0.53mm×1.50μm.

[0019] In some embodiments, the dexmedetomidine hydrochloride intermediate (I) is provided in the form of a test solution, wherein the test solution is a solution of the dexmedetomidine hydrochloride intermediate (I) in N,N-dimethylacetamide, and based on each milliliter of the test solution, the concentration of the dexmedetomidine hydrochloride intermediate (I) is 50 mg / mL.

[0020] In some embodiments, a method for detecting the content of methyl chloride impurity in a dexmedetomidine hydrochloride intermediate (I) is specifically proposed, comprising:

[0021] (1) Chromatographic conditions

[0022] Chromatographic column: 5%-phenyl-95% dimethylpolysiloxane was used as the stationary liquid;

[0023] Detector: FID; injection port temperature: 230-250°C; detection port temperature: 240-260°C;

[0024] Flow rate: 2-3 ml / min; injection volume: 2 μl; split ratio 2-20:1;

[0025] Heating program: initial temperature 20-50°C, maintain for 3 min, increase to 240°C at a heating rate of 45-55°C / min, maintain for 15 min;

[0026] (2) Preparation of blank solution

[0027] Blank solution: N,N-dimethylacetamide;

[0028] (3) Preparation of test solution

[0029] Take 0.5 g of dexmedetomidine hydrochloride intermediate (I), accurately weigh it, place it in a 10 ml volumetric flask, add blank solvent to dissolve it and dilute it to the scale, shake it well, and obtain it;

[0030] (4) Preparation of reference solution

[0031] Reference substance stock solution (0.5 mg / ml): Take 25 mg of chloromethane reference substance, accurately weigh it, place it in a 50 ml volumetric flask, add solvent to dissolve it and quantitatively dilute it to the scale, shake well, and obtain it;

[0032] Reference substance solution (50 μg / ml): Take 1 ml of the above reference substance stock solution, place it in a 10 ml volumetric flask, add solvent to dilute to the scale, and shake well.

[0033] (5) Determination

[0034] Accurately measure 2 μl of blank solution, reference solution and test solution respectively and inject them into gas chromatograph to record the chromatogram.

[0035] In some embodiments, a more specific method for detecting the content of methyl chloride impurity in dexmedetomidine hydrochloride intermediate (I) is proposed, comprising:

[0036] (1) Chromatographic conditions

[0037] Column: GL wanda cap 5, 30m×0.53mm×1.50μm;

[0038] Detector: FID; injection port temperature: 235-245°C; detection port temperature: 245-255°C;

[0039] Flow rate: 2.3-2.7 ml / min; injection volume: 2 μl; split ratio 5-15:1;

[0040] Heating program: initial temperature 25-35°C, maintain for 3 min, increase to 240°C at a heating rate of 48-52°C / min, maintain for 15 min;

[0041] (2) Preparation of blank solution

[0042] Blank solution: N,N-dimethylacetamide;

[0043] (3) Preparation of test solution

[0044] Take 0.5 g of dexmedetomidine hydrochloride intermediate (I), accurately weigh it, place it in a 10 ml volumetric flask, add blank solvent to dissolve it and dilute it to the scale, shake it well, and obtain it;

[0045] (4) Preparation of reference solution

[0046] Reference substance stock solution (0.5 mg / ml): Take 25 mg of chloromethane reference substance, accurately weigh it, place it in a 50 ml volumetric flask, add solvent to dissolve it and quantitatively dilute it to the scale, shake well, and obtain it;

[0047] Reference substance solution (50 μg / ml): Take 1 ml of the above reference substance stock solution, place it in a 10 ml volumetric flask, add solvent to dilute to the scale, and shake well.

[0048] (5) Determination

[0049] Accurately measure 2 μl of blank solution, reference solution and test solution respectively and inject them into gas chromatograph to record the chromatogram.

[0050] Beneficial effects of the present invention:

[0051] Resolution is used to evaluate the degree of separation between the analyte and the substance being separated. It is a key indicator of the separation efficiency of a chromatographic system. It is represented by R, which is equal to the ratio of the difference in retention time between adjacent chromatographic peaks to the average peak width of the two peaks. A larger R indicates better separation between the two adjacent components. Generally speaking, when R is less than 1.0, there is some overlap between the two peaks. When R = 1.0, the resolution can reach 98%, and when R = 1.5, the resolution can reach 99.7%.

[0052] (1) The present invention provides a method for detecting the content of chloromethane, an impurity in a dexmedetomidine hydrochloride intermediate (I). By changing the chromatographic column, replacing the detector, adjusting the injection port temperature and the detection port temperature, optimizing the flow rate, setting a reasonable heating program, etc., the separation degree between the main peak and related impurities is improved, and the separation effect is significant.

[0053] (2) The method provided by the present invention for detecting the content of the impurity chloromethane in the dexmedetomidine hydrochloride intermediate (I) by high performance gas chromatography has completed methodological validation, including tests such as specificity, precision, durability, linearity and accuracy. After these validations, the analytical method provided by the present invention can achieve a separation degree R ≥ 1.5 for the impurity chloromethane, and the RSD of the chloromethane impurity content is ≤ 2.0 after 5 consecutive injections of the chloromethane sample. The injection repeatability is good and the method is durable, and it can be used for quality control of the dexmedetomidine hydrochloride intermediate (I). BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 , Example 2 Method specificity experiment - blank solution.

[0055] Figure 2 , Example 2 Method Specificity Experiment - Methyl Chloride Positioning Solution.

[0056] Figure 3 , Example 2 Method Specificity Experiment - System Suitability Solution.

[0057] Figure 4 , Example 2 Method specificity experiment - test solution. Specific embodiments

[0058] Example 1: Screening of chromatographic conditions

[0059] The chromatographic conditions are determined by screening the chromatographic column, detector, injection port temperature, detection port temperature, flow rate, etc.

[0060] Example 1-a

[0061] Chromatographic column: DB-62430m×0.53mm×3.0μm;

[0062] Detector: ECD; Inlet temperature: 260°C; Detection port temperature: 270°C;

[0063] Flow rate: 8 ml / min; injection volume: 2 μl; split ratio: 10:1;

[0064] Heating program: initial temperature 40 °C, hold for 2 min, increase to 160 °C at a rate of 20 °C / min, hold for 9 min, increase to 240 °C at a rate of 50 °C / min, hold for 20 min;

[0065] Conclusion: The peak shape of chloromethane is poor.

[0066] Example 1-b

[0067] Try changing the heating program based on 1-a

[0068] Chromatographic column: DB-62430m×0.53mm×3.0μm;

[0069] Detector: ECD; Inlet temperature: 260°C; Detection port temperature: 270°C;

[0070] Flow rate: 8 ml / min; injection volume: 2 μl; split ratio: 10:1;

[0071] Heating program: initial temperature 40 °C, maintain for 2 min, increase to 240 °C at a heating rate of 30 °C / min, maintain for 2 min;

[0072] Conclusion: The peak shape of chloromethane is poor.

[0073] Example 1-c

[0074] Try changing the heating program based on 1-b

[0075] Chromatographic column: DB-62430m×0.53mm×3.0μm;

[0076] Detector: ECD; Inlet temperature: 260°C; Detection port temperature: 270°C;

[0077] Flow rate: 8 ml / min; injection volume: 2 μl; split ratio: 10:1;

[0078] Heating program: initial temperature 30 °C, maintain for 3 min, increase to 240 °C at a heating rate of 50 °C / min, maintain for 15 min;

[0079] Conclusion: The peak shape of chloromethane is poor.

[0080] Example 1-d

[0081] Try replacing the column based on 1-c

[0082] Column: GL wanda cap 530m×0.53mm×1.50μm;

[0083] Detector: ECD; Inlet temperature: 260°C; Detection port temperature: 270°C;

[0084] Flow rate: 8 ml / min; injection volume: 2 μl; split ratio: 10:1;

[0085] Heating program: initial temperature 30 °C, maintain for 3 min, increase to 240 °C at a heating rate of 50 °C / min, maintain for 15 min;

[0086] Conclusion: The separation of impurity methyl chloride is poor and the peak shape is poor.

[0087] Example 1-e

[0088] Try replacing the detector on a 1-d basis

[0089] Column: GL wanda cap 530m×0.53mm×1.50μm;

[0090] Detector: FID; Injection port temperature: 260°C; Detection port temperature: 270°C;

[0091] Flow rate: 8 ml / min; injection volume: 2 μl; split ratio: 10:1;

[0092] Heating program: initial temperature 30 °C, maintain for 3 min, increase to 240 °C at a heating rate of 50 °C / min, maintain for 15 min;

[0093] Conclusion: The separation of impurity methyl chloride is poor and the peak shape is poor.

[0094] Example 1-f

[0095] Try changing the flow rate based on 1-e

[0096] Column: GL wanda cap 530m×0.53mm×1.50μm;

[0097] Detector: FID; Injection port temperature: 260°C; Detection port temperature: 270°C;

[0098] Flow rate: 5 ml / min; injection volume: 2 μl; split ratio: 10:1;

[0099] Heating program: initial temperature 30 °C, maintain for 3 min, increase to 240 °C at a heating rate of 50 °C / min, maintain for 15 min;

[0100] Conclusion: The separation of impurity methyl chloride is improved, but the peak shape is poor.

[0101] Example 1-g

[0102] Try changing the flow rate based on 1-f

[0103] Column: GL wanda cap 530m×0.53mm×1.50μm;

[0104] Detector: FID; Injection port temperature: 260°C; Detection port temperature: 270°C;

[0105] Flow rate: 2.5 ml / min; injection volume: 2 μl; split ratio: 10:1;

[0106] Heating program: initial temperature 30 °C, maintain for 3 min, increase to 240 °C at a heating rate of 50 °C / min, maintain for 15 min;

[0107] Conclusion: The separation of impurity methyl chloride has been improved, but the peak shape is still poor.

[0108] Example 1-h

[0109] Try changing the injection port temperature on a 1-g basis

[0110] Column: GL wanda cap 530m×0.53mm×1.50μm;

[0111] Detector: FID; Injection port temperature: 240°C; Detection port temperature: 270°C;

[0112] Flow rate: 2.5 ml / min; injection volume: 2 μl; split ratio: 10:1;

[0113] Heating program: initial temperature 30 °C, maintain for 3 min, increase to 240 °C at a heating rate of 50 °C / min, maintain for 15 min;

[0114] Conclusion: The separation degree of impurity methyl chloride is 1.50, but the peak shape is poor.

[0115] Example 1-i

[0116] Try changing the detection port temperature on a 1-h basis

[0117] Column: GL wanda cap 530m×0.53mm×1.50μm;

[0118] Detector: FID; Injection port temperature: 240°C; Detection port temperature: 250°C;

[0119] Flow rate: 2.5 ml / min; injection volume: 2 μl; split ratio: 10:1;

[0120] Heating program: initial temperature 30 °C, maintain for 3 min, increase to 240 °C at a heating rate of 50 °C / min, maintain for 15 min;

[0121] Conclusion: The separation degree of impurity methyl chloride is 1.60, which is completely separated, with good peak shape and no interference in the blank.

[0122] Example 2: Method specificity test

[0123] (1) Chromatographic conditions are as follows:

[0124] Column: GL wanda cap 530m×0.53mm×1.50μm;

[0125] Detector: FID; Injection port temperature: 240°C; Detection port temperature: 250°C;

[0126] Flow rate: 2.5 ml / min; injection volume: 2 μl; split ratio: 10:1;

[0127] Heating program: initial temperature 30 °C, maintain for 3 min, increase to 240 °C at a heating rate of 50 °C / min, maintain for 15 min;

[0128] (2) Preparation of solution

[0129] Blank solution: N,N-dimethylacetamide;

[0130] Reference substance stock solution (0.5 mg / ml): Take 25 mg of chloromethane reference substance, accurately weigh it, place it in a 50 ml volumetric flask, add solvent to dissolve it and quantitatively dilute it to the scale, shake well, and obtain it;

[0131] Reference substance solution (50 μg / ml): Take 1 ml of the above reference substance stock solution, place it in a 10 ml volumetric flask, add solvent to dilute to the scale, and shake well.

[0132] Test solution: Take 0.5 g of dexmedetomidine hydrochloride intermediate (I), accurately weigh it, place it in a 10 ml volumetric flask, add blank solvent to dissolve and dilute to the scale, shake well, and obtain;

[0133] The reference substance stock solution was used as the chloromethane impurity location solution.

[0134] Table 1 Impurity location and separation test results

[0135]

[0136] Results: Retention time of impurity methyl chloride: 3.622min; resolution: 1.60.

[0137] The method of the invention can achieve complete separation of the dexmedetomidine hydrochloride intermediate (I) and the impurity methyl chloride, and the method has good specificity.

[0138] Example 3: Precision Test

[0139] Chromatographic conditions: same as Example 2

[0140] Solution preparation: same as Example 2

[0141] (1) Injection precision

[0142] The reference solution was injected 5 times in succession and the chromatogram was recorded. The results are as follows:

[0143] Table 2 Injection precision test results

[0144]

[0145] Results: Five chloromethane sample solutions were injected continuously. The RSD of the chloromethane impurity peak retention time was ≤0.1%, and the RSD of the peak area was ≤1.1%. The experimental method has good reproducibility.

[0146] (2) Repeatability

[0147] Take 6 portions of the test solution, inject them continuously, and record the chromatogram. The results are as follows:

[0148] Table 3 Repeatability test results

[0149]

[0150] Results: In the repeatability test, no results were detected in six parallel measurements, indicating good repeatability.

[0151] Example 4: Durability Test

[0152] The tolerance level within which the results were not affected was determined by adjusting the flow rate, injection port temperature, inspection port temperature, split ratio, heating rate, and chromatographic column. The specific adjustments were as follows: flow rate change of ±0.2 mL / min, injection port temperature change of ±5°C, inspection port temperature change of ±5°C, split ratio change of ±5, heating rate change of ±2°C / min, and replacement of the chromatographic columns with GL Sciences HP-5, 30 m × 0.32 mm × 0.25 μm and Thermo TG-5SILMS, 30 m × 0.32 mm × 0.25 μm, respectively. Two test sample solutions were prepared in parallel under each durability condition and injected separately. The results are as follows:

[0153] Table 4 Durability test results

[0154]

[0155]

[0156] Note: (1) Under normal conditions, the data are derived from the mean of the repeatability test data 1 and 2. Chromatographic columns: Agilent WondaCap5, 30m×0.53mm×1.5μm; (2) GL Sciences HP-5, 30m×0.32mm×0.25μm; (3) Thermo TG-5SILMS, 30m×0.32mm×0.25μm.

[0157] Conclusion: When the column flow rate changes by ±0.2 mL / min, the injection port temperature changes by ±5°C, the detection port temperature changes by ±5°C, the split ratio changes by ±5, the heating rate changes by ±2°C / min, and when different chromatographic columns are replaced, the chloroform peak and the adjacent impurity peaks are well separated under each condition, and the measured amount of impurities is consistent with the result under normal conditions. This method has good durability.

[0158] Example 5: Detection limit and quantification limit test

[0159] Chromatographic conditions: same as Example 2

[0160] Solution preparation:

[0161] Detection limit solution: Take the reference substance stock solution of Example 2, dilute it several times with solvent, accurately measure 2 μl and inject it into the gas chromatograph until the main peak height is about 3 times the baseline noise.

[0162] Quantitation limit solution: Take the reference substance stock solution of Example 2, dilute it several times with solvent, accurately measure 2 μl and inject it into the gas chromatograph until the main peak height is about 10 times the baseline noise.

[0163] The quantification limit solution was injected 6 times and the detection limit solution was injected 1 time, and the chromatograms were recorded. The results are shown in Tables 5 and 6.

[0164] Table 5 Detection limit test results

[0165]

[0166] Table 6 Quantitation limit test results

[0167]

[0168] Conclusion: The detection limit of chloromethane is 1.522 μg / ml, equivalent to a test solution concentration of 30.4 ppm. The quantification limit of chloromethane is 5.058 μg / ml, equivalent to a test solution concentration of 101.2 ppm. Six consecutive measurements of the solution at the lowest limit of quantification showed a retention time RSD of 0.11%, less than 1.0%, and a peak area RSD of 2.53%, less than 20.0%. The LOQ concentration is less than 20% of the limit concentration, meeting the requirements.

[0169] Example 6: Linearity and range test

[0170] Chromatographic conditions: same as Example 2

[0171] Solution preparation:

[0172] Accurately weigh an appropriate amount of chloroform reference substance, dissolve it in a solvent, and quantitatively dilute it to prepare solutions with chloroform concentrations of LOQ, 10 μg / ml (20%), 25 μg / ml (50%), 40 μg / ml (80%), 50 μg / ml (100%), and 100 μg / ml (200%).

[0173] Accurately measure 2 μl of each solution at each concentration and inject it into a gas chromatograph. Record the peak area. Construct a standard curve plotting concentration C (μg / ml) against peak area (A). Calculate the correlation coefficient. The results are shown in Table 7 below.

[0174] Table 7 Linearity and range test results

[0175]

[0176] Conclusion: Chloromethane has a good linear relationship in the concentration range of 5.074-101.5μg / ml, the regression equation is y=0.0193x-0.0097, the intercept of the y axis is within 25% of the 100% response value, r=0.9993, and the concentration has a good linear relationship with the peak area.

[0177] Example 7: Accuracy Test

[0178] Chromatographic conditions: same as Example 2

[0179] Background solution: Take approximately 0.5 g of this product, accurately weigh it, and place it in a 10 ml volumetric flask. Add solvent to dissolve and dilute to the mark. Shake well to obtain the solution. Prepare 2 more portions in parallel.

[0180] Test solutions with added impurities at concentration levels of 50%, 100%, and 150%: accurately weigh about 0.5 g of the product and place it in different 10 ml volumetric flasks (prepare 9 portions in parallel), accurately add 0.5 ml, 1 ml, and 1.5 ml of the reference substance stock solution, dissolve with solvent and quantitatively dilute to the scale, shake well, and use as test solutions with added impurities at concentration levels of 50%, 100%, and 150% (prepare 3 portions for each concentration level in parallel).

[0181] Accurately measure 2 μl of each solution and inject it into a gas chromatograph. Record the chromatogram. Calculate the recovery and precision of chloromethane at different concentration levels of 50%, 100%, and 150% using the external standard method based on the peak area. The results are shown in Table 8 below.

[0182] Table 8 Accuracy test results (methyl chloride)

[0183]

[0184] Conclusion: The recovery of chloromethane between 50% and 150% of the limit concentration was 99.1% to 100.6%, with an average of 99.8% and an RSD of 0.5%, indicating good accuracy.

[0185] Obviously, the above embodiments are merely examples for clarification and are not intended to limit the implementation methods. Those skilled in the art will appreciate that other variations or modifications can be made based on the above description. It is not necessary and impossible to enumerate all implementation methods here. Obvious variations or modifications derived therefrom remain within the scope of protection of the present invention.

Claims

1. A method for detecting the content of methyl chloride as an impurity in a dexmedetomidine hydrochloride intermediate (I), characterized in that: The dexmedetomidine hydrochloride intermediate (I) is analyzed by a high-performance gas chromatography analysis method to obtain a chromatogram, and based on the chromatogram, the content of the impurity methyl chloride in the dexmedetomidine hydrochloride intermediate (I) is determined. The chromatographic column of the high-performance gas chromatography analysis method uses 5%-phenyl-95% dimethylpolysiloxane as a stationary liquid; the injection port temperature is 230-250° C.; the detection port temperature is 240-260° C. (the detector is FID); the split ratio is 2-20:1; the flow rate is 2-3 ml / min; and the temperature is programmed, with an initial temperature of 20-50° C., maintained for 3 minutes, and then increased to 240° C. at a heating rate of 45-55° C. / min, and maintained for 15 minutes.

2. The detection method according to claim 1, characterized in that The injection port temperature is 235-245°C.

3. The detection method according to claim 1, wherein The temperature of the detection port is 245-255°C.

4. The detection method according to claim 1, wherein The split ratio is 5 to 15:

1.

5. The detection method according to claim 1, wherein The flow rate is 2.3-2.7 ml / min.

6. The detection method according to claim 1, characterized in that The initial temperature of the programmed temperature increase is 25-35°C.

7. The detection method according to claim 1, characterized in that The heating rate of the programmed temperature is 48-52°C / min.

8. The detection method according to claim 1, wherein The chromatographic column is GL wandacap 5, 30m×0.53mm×1.50μm.

9. The detection method according to claim 1, wherein The dexmedetomidine hydrochloride intermediate (I) is provided in the form of a test solution, wherein the test solution is a dexmedetomidine hydrochloride intermediate (I) N,N-dimethylacetamide solution, and based on each milliliter of the test solution, the concentration of the dexmedetomidine hydrochloride intermediate (I) is 50 mg / mL.

10. The detection method according to claim 1, characterized in that include: (1) Chromatographic conditions Chromatographic column: 5%-phenyl-95% dimethylpolysiloxane was used as the stationary liquid; Detector: FID; injection port temperature: 230-250°C; detection port temperature: 240-260°C; Flow rate: 2-3 ml / min; injection volume: 2 μl; split ratio 2-20:1; Heating program: initial temperature 20-50°C, maintain for 3 min, increase to 240°C at a heating rate of 45-55°C / min, maintain for 15 min; (2) Preparation of blank solution Blank solution: N,N-dimethylacetamide; (3) Preparation of test solution Take 0.5 g of dexmedetomidine hydrochloride intermediate (I), accurately weigh it, place it in a 10 ml volumetric flask, add blank solvent to dissolve it and dilute it to the scale, shake it well, and obtain it; (4) Preparation of reference solution Reference substance stock solution (0.5 mg / ml): Take 25 mg of chloromethane reference substance, accurately weigh it, place it in a 50 ml volumetric flask, add solvent to dissolve it and quantitatively dilute it to the scale, shake well, and obtain it; Reference substance solution (50 μg / ml): Take 1 ml of the above reference substance stock solution, place it in a 10 ml volumetric flask, add solvent to dilute to the scale, and shake well. (5) Determination Accurately measure 2 μl of blank solution, reference solution and test solution respectively and inject them into gas chromatograph to record the chromatogram.

11. The detection method according to claim 10, characterized in that: include: (1) Chromatographic conditions Column: GL wanda cap 5, 30m×0.53mm×1.50μm; Detector: FID; injection port temperature: 235-245°C; detection port temperature: 245-255°C; Flow rate: 2.3-2.7 ml / min; injection volume: 2 μl; split ratio 5-15:1; Heating program: initial temperature 25-35°C, maintain for 3 min, increase to 240°C at a heating rate of 48-52°C / min, maintain for 15 min; (2) Preparation of blank solution Blank solution: N,N-dimethylacetamide; (3) Preparation of test solution Take 0.5 g of dexmedetomidine hydrochloride intermediate (I), accurately weigh it, place it in a 10 ml volumetric flask, add blank solvent to dissolve it and dilute it to the scale, shake it well, and obtain it; (4) Preparation of reference solution Reference substance stock solution (0.5 mg / ml): Take 25 mg of chloromethane reference substance, accurately weigh it, place it in a 50 ml volumetric flask, add solvent to dissolve it and quantitatively dilute it to the scale, shake well, and obtain it; Reference substance solution (50 μg / ml): Take 1 ml of the above reference substance stock solution, place it in a 10 ml volumetric flask, add solvent to dilute to the scale, and shake well. (5) Determination Accurately measure 2 μl of blank solution, reference solution and test solution respectively and inject them into gas chromatograph to record the chromatogram.

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