Method for detecting related substances of diphenhydramine hydrochloride intermediate I

Abstract

The invention relates to the technical field of drug analysis, and provides a method for detecting related substances of a diphenhydramine hydrochloride intermediate I. Gas chromatography is adopted, and the chromatographic conditions are as follows: a chromatographic column is an amine compound analysis gas chromatographic column, the specification is 30m * 0.32 mm, and the initial temperature of a column box is 60 DEG C; the temperature of a sample inlet is 230 DEG C; a detector is a flame ionization detector, and the temperature of the detector is 250 DEG C; the carrier gas is nitrogen, and the split ratio is 20: 1; the sample size is 2 microliters. The method provided by the invention can realize accurate detection and effective separation of the diphenhydramine hydrochloride intermediate I and impurities thereof, and has important meanings for controlling the quality of the diphenhydramine hydrochloride intermediate I, ensuring the safety of diphenhydramine hydrochloride and improving the quality stability of diphenhydramine hydrochloride.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical analysis, and in particular to a method for detecting related substances of a diphenhydramine hydrochloride intermediate I. Background Art

[0002] Diphenhydramine hydrochloride is a first-generation antihistamine that has an antihistamine H1 receptor effect, has a strong inhibitory effect on the central nervous system, and also has an atropine-like effect. It is suitable for allergic diseases of the skin and mucous membranes, such as urticaria, hay fever, allergic rhinitis, etc. It can also be used to prevent motion sickness such as seasickness, carsickness, and airsickness.

[0003] In the prior art, the synthesis process of diphenhydramine hydrochloride mainly uses dimethylethanolamine or benzhydrol as the starting material and is obtained through chemical synthesis, chlorination, condensation, salt formation and other steps.

[0004] Among them, the synthesis process of diphenhydramine hydrochloride intermediate I (2-dimethylaminoethyl chloride hydrochloride) mainly uses dimethylethanolamine as raw material, undergoes chlorination reaction with thionyl chloride, and then is filtered and dried to obtain it.

[0005] According to the reaction mechanism of the above-mentioned 2-dimethylaminochloroethane hydrochloride synthesis process, the possible impurities include: 1) hydrochloride formed from the unreacted starting material dimethylethanolamine; 2) hydrochloride formed from dimethylamine introduced from the starting material; and 3) 2-chloro-N-methylethylamine hydrochloride, a reaction byproduct produced from the starting material dimethylethanolamine.

[0006] 2-Dimethylaminoethyl chloride hydrochloride is an important intermediate in the synthesis of diphenhydramine hydrochloride. Its product quality affects the quality of the final product. However, there are currently no reports on the detection method for related substances of 2-dimethylaminoethyl chloride hydrochloride. Therefore, an effective detection method is urgently needed to monitor its quality. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a method for detecting related substances of diphenhydramine hydrochloride intermediate I. The method can achieve accurate detection and effective separation of diphenhydramine hydrochloride intermediate I (2-dimethylaminoethyl chloride hydrochloride) and its impurities (dimethylethanolamine hydrochloride, dimethylamine hydrochloride, 2-chloro-N-methylethylamine hydrochloride), which is of great significance for controlling the quality of diphenhydramine hydrochloride intermediate I, ensuring the safety of diphenhydramine hydrochloride and improving its quality stability.

[0008] The related substances of the diphenhydramine hydrochloride intermediate I of the present invention mainly refer to the diphenhydramine hydrochloride intermediate I (2-dimethylaminoethyl chloride hydrochloride and its main impurities dimethylamine hydrochloride, dimethylethanolamine hydrochloride, and 2-chloro-N-methylethylamine hydrochloride. The basic information is shown in Table 1.

[0009] Table 1 Structural information of related substances of diphenhydramine hydrochloride intermediate I

[0010] The present invention adopts the following technical solutions to solve the above technical problems: A method for detecting related substances of a diphenhydramine hydrochloride intermediate I, comprising detecting a test solution of the diphenhydramine hydrochloride intermediate I by gas chromatography, wherein the chromatographic conditions include: The chromatographic column is a gas chromatography column for analyzing amine compounds (such as CP-Volamine, size 30m×0.32mm), and the initial column box temperature is 60℃; Inlet temperature 230°C; The detector was a flame ionization detector with a detector temperature of 250°C; The carrier gas was nitrogen with a split ratio of 20:1; Injection volume: 2 μl.

[0011] As one of the preferred embodiments of the present invention, the chromatographic conditions further include using programmed temperature rise: the initial temperature of the column box is 60°C, maintained for 5 minutes; increased to 100°C at a rate of 10°C per minute, maintained for 10 minutes; increased to 240°C at a rate of 20°C per minute, maintained for 2 minutes.

[0012] As one of the preferred embodiments of the present invention, the diphenhydramine hydrochloride intermediate I-related substances refer to 2-dimethylaminochloroethane hydrochloride and its impurities dimethylamine hydrochloride, dimethylethanolamine hydrochloride, and 2-chloro-N-methylethylamine hydrochloride.

[0013] As one of the preferred embodiments of the present invention, the present invention comprises the following specific steps: (1) Solution preparation Diluent preparation: Use organic solvent as diluent; Preparation of system suitability solution: Pre-treat each of dimethylamine hydrochloride, dimethylethanolamine, 2-chloro-N-methylethylamine hydrochloride, and 2-dimethylaminoethyl chloride hydrochloride reference substances with sodium carbonate solution. Dissolve each of these substances in a diluent and quantitatively dilute to prepare a mixed solution containing dimethylamine hydrochloride, dimethylethanolamine, 2-chloro-N-methylethylamine hydrochloride, and 2-dimethylaminoethyl chloride hydrochloride as the system suitability solution. Preparation of test solution: Take a sample of the intermediate I to be tested, add sodium carbonate solution for pretreatment, and then dilute it with a diluent to prepare a solution containing the sample of the intermediate I to be tested, which is used as the test solution; (2) Gas chromatography analysis The gas chromatograph was used for detection. The gas chromatographic conditions were as follows: the chromatographic column was a 30m×0.32mm gas chromatographic column for the analysis of amine compounds; the initial column temperature was 60°C and maintained for 5 minutes; the temperature was increased to 100°C at a rate of 10°C per minute and maintained for 10 minutes; the temperature was increased to 240°C at a rate of 20°C per minute and maintained for 2 minutes; the injection port temperature was 230°C; the detector was a flame ionization detector at a temperature of 250°C; the carrier gas was nitrogen with a split ratio of 20:1; the injection volume was 2 μl; Separately take the system suitability solution and the test solution and inject them into the gas chromatograph, record the chromatogram, and calculate the content of each component according to the external standard method.

[0014] As one of the preferred embodiments of the present invention, in the diluent preparation in step (1), the organic solvent is 95% ethanol, which is used to dilute and prepare the system suitability solution and the test solution.

[0015] As one of the preferred embodiments of the present invention, in the preparation of the system suitability solution in step (1), 2 ml of 0.5 mol / L sodium carbonate solution is added for pretreatment.

[0016] As one of the preferred embodiments of the present invention, in the preparation of the system suitability solution in step (1), a mixed solution containing 50 μg of dimethylamine hydrochloride, 50 μg of dimethylethanolamine, 50 μg of 2-chloro-N-methylethylamine hydrochloride and 10 mg of 2-dimethylaminochloroethane hydrochloride is finally prepared per 1 ml.

[0017] As one of the preferred embodiments of the present invention, in the preparation of the test solution in step (1), 2 ml of 0.5 mol / L sodium carbonate solution is added for pretreatment.

[0018] As one of the preferred embodiments of the present invention, in the preparation of the test solution in step (1), a solution containing 10 mg of the intermediate I to be tested per 1 ml is finally prepared.

[0019] The advantages of the present invention over the prior art are: (1) The present invention can achieve effective separation of diphenhydramine hydrochloride intermediate I and its impurities by selecting appropriate gas chromatography conditions and sample pretreatment conditions (sodium carbonate solution pretreatment), accurately test the impurities and their contents, and has good system applicability and specificity, which helps to control the quality of diphenhydramine hydrochloride intermediate I; (2) The sample pretreatment conditions of the present invention are simple, mild, rapid, and environmentally friendly, and can be used for batch processing of samples. At the same time, the analysis speed is fast, the lower limit of quantification is low, and it has a good linear range and accuracy (the main peak of the test sample and other impurities interfere with each other); (3) The present invention provides a new detection method that can be used to control the risk of impurity residues that may exist in diphenhydramine hydrochloride intermediate I, ensure the safety of the drug, and facilitate the quality control of diphenhydramine hydrochloride.

[0020] In summary, the present invention can achieve accurate detection and effective separation of related substances in diphenhydramine hydrochloride intermediate I, which is of great significance for controlling the quality of diphenhydramine hydrochloride intermediate I, ensuring the safety of diphenhydramine hydrochloride and improving its quality stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is a graph showing the separation test results in Example 2; Figure 2 This is a linear relationship result diagram in Example 2; Figure 3 This is a durability comparison chart in Example 2. DETAILED DESCRIPTION

[0022] The following examples of the present invention are described in detail. The present examples are implemented based on the technical solution of the present invention, and detailed implementation methods and specific operating procedures are given. However, the scope of protection of the present invention is not limited to the following examples. At the same time, the raw materials, reagents, equipment and methods used in the following examples are all conventional raw materials, reagents, equipment and methods in the art unless otherwise specified, and are not described in detail.

[0023] Example 1 A method for detecting related substances of diphenhydramine hydrochloride intermediate I of the present embodiment.

[0024] The diphenhydramine hydrochloride intermediate I related substances refer to 2-dimethylaminochloroethane hydrochloride and its impurities dimethylamine hydrochloride, dimethylethanolamine hydrochloride, and 2-chloro-N-methylethylamine hydrochloride. The detection method is as follows: (1) Solution preparation Diluent: 95% ethanol.

[0025] System suitability solution: Pretreat each of the dimethylamine hydrochloride, dimethylethanolamine, 2-chloro-N-methylethylamine hydrochloride, and 2-dimethylaminoethyl chloride reference substances by adding 2 ml of 0.5 mol / L sodium carbonate solution. Dissolve each solution in a diluent (95% ethanol) and quantitatively dilute to a mixture containing 50 μg of dimethylamine hydrochloride, 50 μg of dimethylethanolamine, 50 μg of 2-chloro-N-methylethylamine hydrochloride, and 10 mg of 2-dimethylaminoethyl chloride per ml. This solution serves as the system suitability solution.

[0026] Preparation of test solution: Take a sample of the intermediate I to be tested, add 2 ml of 0.5 mol / L sodium carbonate solution for pretreatment, and then dilute it with a diluent to make a solution containing 10 mg of the intermediate I to be tested per 1 ml, which is used as the test solution.

[0027] (2) Gas chromatography analysis The results were detected by gas chromatography, and the gas chromatography conditions were as follows: an amine compound analysis gas chromatography column (CP-Volamine, specification 30m×0.32mm) was used; the initial column box temperature was 60°C, maintained for 5 minutes; the temperature was increased to 100°C at a rate of 10°C per minute and maintained for 10 minutes; the temperature was increased to 240°C at a rate of 20°C per minute and maintained for 2 minutes; the injection port temperature was 230°C; the detector was a flame ionization detector, and the detector temperature was 250°C; the carrier gas was nitrogen, with a split ratio of 20:1; the injection volume was 2μl.

[0028] Separately take the system suitability solution and the test solution and inject them into the gas chromatograph, record the chromatogram, and calculate the content of each component according to the external standard method.

[0029] Example 2 This example provides a methodological verification of the method of the present invention.

[0030] The instrument and chromatographic conditions were the same as in Example 1.

[0031] 1. Specificity Investigate the separation between peaks.

[0032] Diluent (blank solvent), system suitability solution, and test solution are the same as in Example 1.

[0033] Dimethylamine hydrochloride calibration solution: Take 10 mg of dimethylamine hydrochloride reference substance, accurately weigh it, place it in a 10 ml volumetric flask, add 2 ml of 0.5 mol / L sodium carbonate solution to dissolve it, then dilute it to the 10 ml mark with 95% ethanol, shake well, and filter to obtain the solution.

[0034] 2-Chloro-N-methylethylamine hydrochloride calibration solution: Take 10 mg of 2-chloro-N-methylethylamine hydrochloride reference substance, accurately weigh it, place it in a 10 ml volumetric flask, add 2 ml of 0.5 mol / L sodium carbonate solution to dissolve it, then dilute it to the 10 ml mark with 95% ethanol, shake well, and filter to obtain the solution.

[0035] Dimethylethanolamine positioning solution: Take dimethylethanolamine reference substance, accurately weigh it, dilute it with 95% ethanol to make a solution containing 1 mg per 1 ml, shake well, and obtain it.

[0036] Intermediate I localization solution: Take 100 mg of 2-dimethylaminoethyl chloride hydrochloride reference substance, accurately weigh it, place it in a 10 ml volumetric flask, add 2 ml of 0.5 mol / L sodium carbonate solution, and then dilute it to the 10 ml mark with 95% ethanol. Shake well and filter to obtain the product.

[0037] Separation test solution: Take appropriate amounts of dimethylamine hydrochloride reference substance, 2-chloro-N-methylethylamine hydrochloride reference substance, dimethylethanolamine reference substance and intermediate I sample (batch number: YF230201-I), add 2 ml of 0.5 mol / L sodium carbonate solution to pretreat each sample, then dissolve them in 95% ethanol and quantitatively dilute them to make a mixed solution containing 50 μg of dimethylamine hydrochloride, 50 μg of 2-chloro-N-methylethylamine hydrochloride, 50 μg of dimethylethanolamine and 10 mg of intermediate I per 1 ml. Shake well and filter to obtain the solution.

[0038] Take 2 μl of each of the blank solvent, test solution, system suitability solution, each positioning solution and resolution test solution and inject them separately, and record the chromatogram. The resolution results are shown in Table 2, and the resolution test chromatogram is shown in Figure 1 shown.

[0039] Table 2 Separation results

[0040] The above results indicate that the blank solvent (ethanol) does not interfere with the analysis of related substances in this product. In the resolution test solution, the order of peak elution for the analytes is dimethylamine hydrochloride, 2-chloro-N-methylethylamine hydrochloride, dimethylethanolamine, and Intermediate I, with the separation ratio for each component exceeding 1.5. In the test solution, the separation ratio for the main peak of Intermediate I and its adjacent peaks is greater than 1.5. This demonstrates that this method provides good resolution between impurity peaks, a high number of theoretical plates, and excellent specificity.

[0041] 2. Limit of Detection and Limit of Quantitation The diluent (blank solvent) was the same as in Example 1.

[0042] Stock solution of dimethylamine hydrochloride reference substance: Take 10 mg of dimethylamine hydrochloride reference substance, accurately weigh it, place it in a 10 ml volumetric flask, add 2 ml of 0.5 mol / L sodium carbonate solution, and then dilute to the scale with 95% ethanol, shake well, and filter to obtain.

[0043] 2-Chloro-N-methylethylamine hydrochloride reference stock solution: Take 10 mg of 2-chloro-N-methylethylamine hydrochloride reference substance, place it in a 10 ml volumetric flask, accurately weigh, add 2 ml of 0.5 mol / L sodium carbonate solution, and then dilute to the scale with 95% ethanol, shake well, and filter to obtain.

[0044] Dimethylethanolamine reference substance stock solution: Take dimethylethanolamine reference substance, accurately weigh it, dilute it with 95% ethanol to make a solution containing 1 mg per 1 ml, shake well, and obtain it.

[0045] Intermediate I reference substance stock solution: Take an appropriate amount of intermediate I reference substance, accurately weigh it, place it in a 10ml volumetric flask, add 2ml of 0.5mol / L sodium carbonate solution, and then dilute it to the scale with 95% ethanol, shake well, and filter to obtain the solution.

[0046] (1) Detection limit Accurately measure the stock solutions of the above-mentioned reference substances, dilute them with ethanol, and prepare the corresponding detection limit solutions when the signal-to-noise ratio is 3:1.

[0047] 2 μl of each detection limit solution was injected and the color pattern was recorded. The results are shown in Table 3.

[0048] Table 3 Detection limit determination results

[0049] From the above results, it can be seen that the detection limits of dimethylamine hydrochloride, 2-chloro-N-methylethylamine hydrochloride and dimethylethanolamine are lower than 30% of the limit set for impurities (0.5%), which meets the requirements.

[0050] (2) Limit of quantification Accurately pipette the stock solution of intermediate I reference substance under the above detection limit, dilute it with ethanol, and prepare the quantification limit solution when the signal-to-noise ratio is 10:1.

[0051] 2 μl of the quantification limit solution of intermediate I was injected six times continuously, and the color pattern was recorded. The results are shown in Table 4.

[0052] Table 4 Quantitation limit determination results

[0053] From the above results, it can be seen that after 6 repeated injections of the quantitative limit solution, the RSD of the peak area of ​​intermediate I was ≤10.0%, which met the precision requirement of the quantitative limit.

[0054] 3. Linear The diluent (blank solvent) was the same as in Example 1.

[0055] Linear solution 1: the quantitative limit solution under the above quantitative limit item.

[0056] Linear solution 2: 50% solution. Accurately weigh 50.41 mg of intermediate I reference substance and place it in a 10 ml volumetric flask. Add 2 ml of 0.5 mol / L sodium carbonate solution and dilute to the mark with 95% ethanol. Shake well and filter to obtain the product.

[0057] Linear solution 3: 80% solution. Accurately weigh 80.10 mg of intermediate I reference substance and place it in a 10 ml volumetric flask. Add 2 ml of 0.5 mol / L sodium carbonate solution and dilute to the mark with 95% ethanol. Shake well and filter to obtain the product.

[0058] Linear solution 4: 100% solution. Accurately weigh 99.84 mg of intermediate I reference substance and place it in a 10 ml volumetric flask. Add 2 ml of 0.5 mol / L sodium carbonate solution and dilute to the mark with 95% ethanol. Shake well and filter to obtain the product.

[0059] Linear solution 5: 150% solution. Take 149.99 mg of intermediate I reference substance, accurately weigh it, place it in a 10 ml volumetric flask, add 2 ml of 0.5 mol / L sodium carbonate solution, and then dilute to the mark with 95% ethanol. Shake well and filter to obtain the product.

[0060] Take the blank solvent and each concentration linear solution and inject them separately, record the chromatogram, the results are shown in Table 5, and the linear relationship diagram is shown in Figure 2 .

[0061] Table 5 Linearity results

[0062] From the above results, it can be seen that intermediate I has a good linear relationship in the concentration range of 0.004 mg / ml~14.86 mg / ml.

[0063] 4. Repeatability The diluent (blank solvent), system suitability solution, and test solution are the same as those in Example 1.

[0064] Take the above blank solvent, system suitability solution and test solution and inject them respectively, record the chromatogram, and the results are shown in Table 6.

[0065] Table 6 Repeatability test results

[0066] From the above results, we can see that after repeated injection of 6 injections of the test solution, the RSD of the impurity content in the intermediate I test sample is less than 10.0%, and the RSD of the purity of intermediate I is less than 10.0%. The method has good repeatability.

[0067] 5. Durability The diluent (blank solvent), system suitability solution, and test solution are the same as those in Example 1.

[0068] Durability solution: Take appropriate amounts of dimethylamine hydrochloride reference substance, 2-chloro-N-methylethylamine hydrochloride reference substance, dimethylethanolamine reference substance and intermediate I sample, add 2 ml of 0.5 mol / L sodium carbonate solution respectively, then dissolve with 95% ethanol and quantitatively dilute to make a mixed solution containing 50 μg of dimethylamine hydrochloride, 50 μg of 2-chloro-N-methylethylamine hydrochloride, 50 μg of dimethylethanolamine and 10 mg of intermediate I per 1 ml. Shake well and filter to obtain the solution.

[0069] Take the blank solvent and durability solution and inject them separately, record the chromatogram, and the parameters of the chromatographic conditions are shown in Table 7. The statistics of the durability solution injection results are shown in Table 8 and Table 9, and the durability results of diphenhydramine hydrochloride intermediate I are shown in Figure 3 .

[0070] Table 7 Chromatographic condition variation parameters

[0071] Table 8 Test results of the effects of different initial column temperatures

[0072] Table 9 Test results of the influence of different column flow rates

[0073] These results demonstrate that adjusting the initial column temperature and column flow rate results in a separation greater than 1.5 between the dimethylamine hydrochloride, 2-chloro-N-methylethylamine hydrochloride, dimethylethanolamine, and Intermediate I peaks and their adjacent peaks. This indicates that changing the initial column oven temperature and column flow rate has no significant effect on the test results, demonstrating the robustness of this method.

[0074] In summary, the detection method provided by the present invention has strong specificity and good durability. Changing chromatographic conditions such as column flow rate and initial column temperature within a small range will not affect the detection of related substances in diphenhydramine hydrochloride intermediate I. The method can accurately detect related substances in diphenhydramine hydrochloride intermediate I, and the separation between impurities and between the main component and the impurities is good. The detection results are accurate and reliable, and the quality standard of diphenhydramine hydrochloride intermediate I can be controlled more scientifically, which is of great significance to improving the quality stability of diphenhydramine hydrochloride.

[0075] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for detecting related substances of diphenhydramine hydrochloride intermediate I, characterized in that: The diphenhydramine hydrochloride intermediate I test solution was tested by gas chromatography, and the chromatographic conditions included: The chromatographic column is a gas chromatography column for analyzing amine compounds, with a specification of 30m×0.32mm and an initial column box temperature of 60°C; Inlet temperature 230°C; The detector was a flame ionization detector with a detector temperature of 250°C; The carrier gas was nitrogen with a split ratio of 20:1; Injection volume: 2 μl.

2. the detection method of diphenhydramine hydrochloride intermediate I related substance according to claim 1, is characterized in that, The chromatographic conditions also include using programmed temperature rise: the initial temperature of the column box is 60°C, maintained for 5 minutes; increased to 100°C at a rate of 10°C per minute, maintained for 10 minutes; increased to 240°C at a rate of 20°C per minute, maintained for 2 minutes.

3. the detection method of diphenhydramine hydrochloride intermediate I related substance according to claim 1, is characterized in that, The diphenhydramine hydrochloride intermediate I related substances refer to 2-dimethylaminochloroethane hydrochloride and its impurities dimethylamine hydrochloride, dimethylethanolamine hydrochloride, and 2-chloro-N-methylethylamine hydrochloride.

4. according to the detection method of the related substance of the arbitrary described diphenhydramine hydrochloride intermediate I of claim 1~3, it is characterized in that, The specific steps include: (1) Solution preparation Diluent preparation: Use organic solvent as diluent; Preparation of system suitability solution: Pre-treat each of dimethylamine hydrochloride, dimethylethanolamine, 2-chloro-N-methylethylamine hydrochloride, and 2-dimethylaminoethyl chloride hydrochloride reference substances with sodium carbonate solution. Dissolve each of these substances in a diluent and quantitatively dilute to prepare a mixed solution containing dimethylamine hydrochloride, dimethylethanolamine, 2-chloro-N-methylethylamine hydrochloride, and 2-dimethylaminoethyl chloride hydrochloride as the system suitability solution. Preparation of test solution: Take a sample of the intermediate I to be tested, add sodium carbonate solution for pretreatment, and then dilute it with a diluent to prepare a solution containing the sample of the intermediate I to be tested, which is used as the test solution; (2) Gas chromatography analysis The gas chromatograph was used for detection. The gas chromatographic conditions were as follows: the chromatographic column was a 30m×0.32mm gas chromatographic column for the analysis of amine compounds; the initial column temperature was 60°C and maintained for 5 minutes; the temperature was increased to 100°C at a rate of 10°C per minute and maintained for 10 minutes; the temperature was increased to 240°C at a rate of 20°C per minute and maintained for 2 minutes; the injection port temperature was 230°C; the detector was a flame ionization detector at a temperature of 250°C; the carrier gas was nitrogen with a split ratio of 20:1; the injection volume was 2 μl; Separately take the system suitability solution and the test solution and inject them into the gas chromatograph, record the chromatogram, and calculate the content of each component according to the external standard method.

5. the detection method of diphenhydramine hydrochloride intermediate I related substance according to claim 4, is characterized in that, In the diluent preparation of step (1), the organic solvent is 95% ethanol, which is used to dilute and prepare the system suitability solution and the test solution.

6. the detection method of diphenhydramine hydrochloride intermediate I related substance according to claim 4, is characterized in that, In the preparation of the system suitability solution in step (1), 2 ml of 0.5 mol / L sodium carbonate solution was added for pretreatment.

7. The method for detecting related substances of diphenhydramine hydrochloride intermediate I according to claim 4, wherein In the preparation of the system suitability solution in step (1), a mixed solution containing 50 μg of dimethylamine hydrochloride, 50 μg of dimethylethanolamine, 50 μg of 2-chloro-N-methylethylamine hydrochloride and 10 mg of 2-dimethylaminochloroethane hydrochloride per 1 ml is finally prepared.

8. The method for detecting related substances of diphenhydramine hydrochloride intermediate I according to claim 4, wherein In the preparation of the test solution in step (1), 2 ml of 0.5 mol / L sodium carbonate solution was added for pretreatment.

9. The method for detecting related substances of diphenhydramine hydrochloride intermediate I according to claim 4, wherein In the preparation of the test solution in step (1), a solution containing 10 mg of the intermediate I to be tested per 1 ml is finally prepared.

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