Detection method of memantine hydrochloride and related substances thereof

Abstract

The invention belongs to the technical field of pharmaceutical analytical chemistry, and discloses a method for detecting memantine hydrochloride and related substances thereof. Memantine hydrochloride and related substances are detected and analyzed by adopting a gas chromatographic method, and memantine hydrochloride and related substances such as 1, 3-dimethyladamantane, 3, 5-dimethyl-1-adamantanol, 1-chloro-3, 5-dimethyladamantane, 1-bromo-3, 5-dimethyladamantane, 1-formamido-3, 5-dimethyladamantane, 1-chloro-3, 5-dimethyladamantane, 1-chloro-3, 5-dimethyladamantane, 1-chloro-3, 5-dimethyladamantane, 1-chloro-3, 5-dimethyladamantane, 1-chloro-3, 5-dimethyladamantane, 1-chloro-3, 5-dimethyladamantane, 1-chloro-3, 5 the compound is prepared from 1, 5-dimethyladamantane and 1-amino-3-methyladamantane hydrochloride. The memantine hydrochloride and the six related substances thereof are separated by adopting specific gas chromatography analysis conditions, so that the separation and quantitative determination of the memantine hydrochloride and the six related substances thereof can be effectively realized, and the influence of the related substances on the quality of a final memantine hydrochloride product is reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical analytical chemistry, and more particularly to a method for detecting memantine hydrochloride and related substances thereof. Background Art

[0002] Memantine hydrochloride is a voltage-dependent, low-affinity, non-competitive (open channel) N-methyl-D-aspartate (NMDA) receptor antagonist and the first FDA-approved drug for the treatment of moderate to severe Alzheimer's disease. Memantine hydrochloride is available in the form of regular tablets (5 mg, 10 mg, 20 mg), oral solution (2 mg / mL), and sustained-release capsules (7 mg, 14 mg, 21 mg, and 28 mg). Currently, memantine has been marketed in the European Union, the United States, the United Kingdom, Japan, Canada, China, and other countries.

[0003] The chemical name of memantine hydrochloride is 1-amino-3,5-dimethyladamantaneamine hydrochloride, and its molecular formula is C 12 H 21 N·HCl, relative molecular weight is 215.76, white or off-white crystalline powder, soluble in water. Memantine hydrochloride is a tricyclic amine compound, which does not have a conjugated structure and has no ultraviolet absorption. The FDA and existing literature on the determination of related substances of memantine hydrochloride are gas chromatography. However, among the methods currently provided, none of them can simultaneously detect related substances A, related substances B, related substances C, related substances D, related substances E, and related substances F of memantine hydrochloride.

[0004] Related substances are key quality attributes of drugs and may affect the safety and effectiveness of drugs. Therefore, whether the research on related substances is comprehensively and accurately analyzed and controlled is directly related to the quality controllability and safety of drugs. The development of drug quality analysis methods is to develop specific methods for the starting materials, intermediates, and finished products in the drug synthesis process route to analyze and test and perform method validation.

[0005] Therefore, developing a simple and reproducible multi-component drug analysis method is an important means to ensure drug quality and is a technical problem that urgently needs to be solved by existing technologies. Summary of the invention

[0006] In view of this, the present invention provides a method for detecting memantine hydrochloride and its related substances, which adopts specific gas chromatography analysis conditions to separate memantine hydrochloride and six related substances, and can effectively achieve the separation and quantitative determination of memantine hydrochloride and the six related substances, so as to reduce the influence of the related substances on the quality of the final memantine hydrochloride product.

[0007] Furthermore, the specific structure of the related substances is as follows:

[0008]

[0009] Furthermore, the above detection method requires that the relevant substance F be subjected to alkalization treatment and then further extracted with an organic solvent to obtain a free base for sample analysis.

[0010] The improvement of the technical concept of the present invention is: after alkalizing and extracting the related substance F, gas chromatography can be used to detect the content of the related substance F, so as to simultaneously detect the related substance A, related substance B, related substance C, related substance D, related substance E, and related substance F of memantine hydrochloride.

[0011] One of the purposes of the present invention is to provide a method for detecting memantine hydrochloride and its related substances, comprising the following steps:

[0012] (1) Prepare system suitability solution:

[0013] Accurately weigh appropriate amounts of 1,3-dimethyladamantane, 3,5-dimethyl-1-adamantanol, 1-chloro-3,5-dimethyladamantane, 1-bromo-3,5-dimethyladamantane, and 1-formamido-3,5-dimethyladamantane, respectively, add organic solvent, and shake ultrasonically to fully dissolve to serve as systemic applicability stock solution A;

[0014] Wherein, the concentration of each relevant substance in the systemic applicability stock solution A is 0.3-2.0 mg / mL;

[0015] Accurately weigh 1-amino-3-methyladamantane hydrochloride, add sodium hydroxide solution, shake ultrasonically, then add organic solvent, shake ultrasonically, let stand to separate, and take the organic solvent layer as system suitability stock solution B;

[0016] Wherein, the concentration of 1-amino-3-methyladamantane hydrochloride in the system suitability stock solution B is 0.4-0.6 mg / mL;

[0017] Accurately weigh the memantine hydrochloride reference substance, add sodium hydroxide solution, shake ultrasonically, then add organic solvent, shake ultrasonically, let stand to separate, and take the organic solvent layer as system suitability reserve solution C;

[0018] Wherein, the concentration of memantine hydrochloride in the system suitability stock solution C is 10.0-15.0 mg / mL;

[0019] Accurately pipette systemic suitability stock solution A, systemic suitability stock solution B, and systemic suitability stock solution C with a volume ratio of 1:1:8 respectively, place them in the same 10mL volumetric flask, make up to volume with an organic solvent, and shake well to prepare the systemic suitability solution;

[0020] (2) Preparation of test solution:

[0021] Accurately weigh the memantine hydrochloride raw material and place it in a 100 mL volumetric flask, add sodium hydroxide solution, shake ultrasonically, then add organic solvent, shake ultrasonically, finally add water to make up to volume, shake ultrasonically, let stand to separate, and take the organic solvent layer as the test solution;

[0022] Wherein, the concentration of memantine hydrochloride in the test solution is 4.0-6.0 mg / mL;

[0023] (3) Prepare blank solution:

[0024] Take the organic solvent as the blank solution;

[0025] (4) Chromatographic analysis: A capillary column with 5% phenyl-95% methylpolysiloxane as the stationary phase was used, and a hydrogen flame ionization monitor was used for detection. The temperature was programmed to set the monitor temperature to 300°C and the injection port temperature to 280°C. The theoretical plate number was calculated based on the memantine hydrochloride peak. The systemic suitability solution, the test solution, and the blank solution were respectively injected into the gas chromatograph to complete the separation and quantitative determination of memantine hydrochloride and its related substances.

[0026] Furthermore, the concentration of the sodium hydroxide solution is 1-7 mol / L, and the organic solvent is one of toluene, n-hexane, dichloromethane, and ethyl acetate.

[0027] Furthermore, in step (1), the mass volume ratio of the 1-amino-3-methyladamantane hydrochloride to the sodium hydroxide solution is 8:3 to 12:3 mg / mL, and the mass volume ratio of the 1-amino-3-methyladamantane hydrochloride to the organic solvent is 4:1 to 6:1 mg / mL;

[0028] The mass volume ratio of the memantine hydrochloride reference substance to the sodium hydroxide solution is 20:3-30:3 mg / mL, and the mass volume ratio of the memantine hydrochloride reference substance to the organic solvent is 10:1-15:1 mg / mL.

[0029] Furthermore, in step (2), the mass volume ratio of the memantine hydrochloride raw material to the sodium hydroxide solution is 16:1 to 24:1 mg / mL, and the mass volume ratio of the memantine hydrochloride raw material to the organic solvent is 4:1 to 6:1 mg / mL.

[0030] Preferably, the concentration of the sodium hydroxide solution is 1 mol / L, and the organic solvent is n-hexane.

[0031] Further preferably, the volume of the added sodium hydroxide solution is 5 to 30 mL, preferably 15 mL; the volume of the added n-hexane solution is 2 to 20 mL, preferably 10 mL.

[0032] Furthermore, in step (4), the programmed temperature is initially maintained at 50°C for 2 min, then increased to 100°C at a rate of 5°C / min, increased to 110°C at a rate of 1°C / min, maintained for 10 min, and increased to 250°C at a rate of 10°C / min, maintained for 10 min.

[0033] Furthermore, in step (4), the injection volume of the gas chromatograph is 1 to 3 μL, the split ratio is 10:1 to 80:1, and the carrier gas flow rate is 1.2 to 2.5 mL / min.

[0034] Preferably, the injection volume of the gas chromatograph is 3 μL, the split ratio is 20:1, and the carrier gas flow rate is 2.0 mL / min.

[0035] Furthermore, the ultrasonic shaking time is 10 to 15 minutes.

[0036] Preferably, the shaking time for the alkalization treatment by adding sodium hydroxide solution is 15 minutes, and the shaking time for the extraction by adding organic solvent is 10 minutes.

[0037] The second object of the present invention is to provide an application of a method for detecting memantine hydrochloride and its related substances, which is used for detecting related substances in memantine hydrochloride and memantine hydrochloride oral preparations.

[0038] It can be seen from the above technical solution that, compared with the prior art, the beneficial effects achieved by the present invention are:

[0039] The method of the present invention establishes a gas phase analysis method for 6 known related substances in a memantine hydrochloride preparation, the method has strong specificity, high sensitivity, and accurate quantitative determination results; the analysis method is simple and fast, all related substances can be separated well in a short time, the separation between each chromatographic peak is greater than 1.5, the related substances in memantine hydrochloride and its preparation can be fully detected, the drug safety is improved, and the basis for formulating the quality standard of memantine hydrochloride preparation is improved. At the same time, the method of the present invention is easy to implement, the instruments and reagents used are all conventional supplies, the experimental parameters are also conventional parameters, there are no harsh conditions, the cost is low, and the conditions of most laboratories can be met. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0041] Figure 1 is the blank solvent chromatogram;

[0042] Figure 2 is the system suitability solution chromatogram;

[0043] Figure 3 is the chromatogram of the test solution;

[0044] Figure 4 is the system suitability solution chromatogram;

[0045] Figure 5 It is the linear relationship diagram of related substance A;

[0046] Figure 6 It is the linear relationship diagram of related substance B;

[0047] Figure 7 It is the linear relationship diagram of related substance C;

[0048] Figure 8 It is the linear relationship diagram of related substance D;

[0049] Fig. 9 It is the linear relationship diagram of related substance E;

[0050] Fig.10 It is the linear relationship diagram of related substance F. DETAILED DESCRIPTION

[0051] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0052] Embodiment 1:

[0053] Instruments and conditions:

[0054] Chromatograph: Agilent 8890 gas chromatograph;

[0055] Detector: Hydrogen flame ionization detector;

[0056] Chromatographic column: capillary column with 5% phenyl-95% methyl polysiloxane as stationary phase (HP-5, 50m×0.32mm×0.52μm);

[0057] Column temperature: initially 50°C for 2 min, then raised to 100°C at a rate of 5°C / min, raised to 110°C at a rate of 1°C / min for 10 min, and raised to 250°C at a rate of 10°C / min for 10 min;

[0058] Inlet temperature: 280°C;

[0059] Detector temperature: 300°C;

[0060] Carrier gas (nitrogen) flow rate: 2.0 mL / min;

[0061] Split ratio: 20:1;

[0062] Injection volume: 3 μL

[0063] Experimental procedures

[0064] Take appropriate amount of related substance A, B, C, D and E reference substances, weigh accurately, add n-hexane to prepare solutions containing related substance A 0.37 mg / mL, related substance B 0.53 mg / mL, related substance C 1.92 mg / mL, related substance D 0.53 mg / mL, related substance E 0.51 mg / mL as system suitability stock solution A.

[0065] Take an appropriate amount of related substance F, accurately weigh it, put it in a volumetric flask, add 9 mL of 1 mol / L sodium hydroxide solution and 6 mL of n-hexane, shake and mix for 10 minutes, let it stand to separate the layers, and the n-hexane layer is used as the system suitability stock solution B. The concentration of related substance F is 0.51 mg / mL.

[0066] Weigh about 75 mg of memantine hydrochloride reference substance accurately, place it in a 25 mL volumetric flask, and add 1 mol·L -1 9 mL of sodium hydroxide solution and 6 mL of n-hexane were shaken and mixed for 10 min, and allowed to stand to separate into layers. The n-hexane layer was used as the system suitability stock solution C. The concentration of memantine hydrochloride was 12.5 mg / mL.

[0067] Accurately pipette 0.5 mL of system suitability stock solution A, 0.5 mL of B, and 4 mL of C into the same 10 mL volumetric flask, dilute to the mark with n-hexane, and shake well to prepare the system suitability solution.

[0068] Weigh 100 mg of memantine hydrochloride raw material into a 100 mL volumetric flask and add 1 mol·L -1 15 mL of sodium hydroxide solution was ultrasonically shaken for 10 min, then 20 mL of n-hexane was accurately added, and finally water was added to make up to the scale, shaken for 10 min, and allowed to stand to separate, and the n-hexane layer was taken as the test solution.

[0069] Take n-hexane as blank solution.

[0070] Analyze according to the above chromatographic conditions and record the chromatogram. The results are shown in the attached Figures 1 to 3 , Figure 1 is the blank solution chromatogram; Figure 2 This is the system suitability solution chromatogram, and the peaks of memantine hydrochloride and related substances have been marked in the figure; Figure 3 The chromatogram of the test solution.

[0071] Figure 1 to Figure 3 It is shown that the method of the present invention can effectively separate memantine hydrochloride from its related substances, and can accurately perform quantitative detection to calculate the limits of the related substances.

[0072] Embodiment 2:

[0073] Instruments and conditions:

[0074] Chromatograph: Agilent 8890 gas chromatograph;

[0075] Detector: Hydrogen flame ionization detector;

[0076] Chromatographic column: capillary column with 5% phenyl-95% methyl polysiloxane as stationary phase (HP-5, 50m×0.32mm×0.52μm);

[0077] Column temperature: initially 50°C for 2 min, then raised to 100°C at a rate of 5°C / min, raised to 110°C at a rate of 1°C / min for 10 min, and raised to 250°C at a rate of 10°C / min for 10 min;

[0078] Inlet temperature: 280°C;

[0079] Detector temperature: 300°C;

[0080] Carrier gas (nitrogen) flow rate: 1.9 mL / min;

[0081] Split ratio: 20:1;

[0082] Injection volume: 3 μL

[0083] Experimental procedures

[0084] Take the system suitability solution in Example 1 and inject it into the gas chromatograph according to the above chromatographic analysis conditions, and record the chromatogram. The results are shown in the attached Figure 4 In the figure, the retention time 20.549min is related substance A, the retention time 30.501min is related substance F, the retention time 31.616 is memantine hydrochloride, the retention time 33.676 is related substance B, the retention time 35.091 is related substance C, the retention time 38.444 is related substance D, and the retention time 43.972 is related substance E.

[0085] The separation degree between each related substance peak and the main component peak was ≥1.5, and the separation effect was good.

[0086] Example 3: The present invention verifies the following items of the analytical method for memantine hydrochloride and its related substances.

[0087] Instruments and conditions:

[0088] Chromatograph: Agilent 8890 gas chromatograph;

[0089] Detector: Hydrogen flame ionization detector;

[0090] Chromatographic column: capillary column with 5% phenyl-95% methyl polysiloxane as stationary phase (HP-5, 50m×0.32mm×0.52μm);

[0091] Column temperature: initially 50°C for 2 min, then raised to 100°C at a rate of 5°C / min, raised to 110°C at a rate of 1°C / min for 10 min, and raised to 250°C at a rate of 10°C / min for 10 min;

[0092] Inlet temperature: 280°C;

[0093] Detector temperature: 300°C;

[0094] Carrier gas (nitrogen) flow rate: 2.0 mL / min;

[0095] Split ratio: 20:1;

[0096] Injection volume: 3 μL

[0097] 1. Linearity and range

[0098] (1) Sample preparation

[0099] Pipette 0.2, 0.4, 0.6, 0.8, and 1.0 mL of system suitability solution A and system suitability solution B under "Example 1" into a 10 mL volumetric flask, and dilute to the mark with n-hexane.

[0100] (2) Test results

[0101] The test results are attached. Figure 5-10 .

[0102] Depend on Figure 5 It can be seen that the related substance A of memantine hydrochloride is between 0.0074 and 0.0370 mg·mL -1 The linearity is good within the range, the linear regression equation is y=3177.4.6x-1.9922, and the correlation coefficient is R 2 =0.9991.

[0103] Depend on Figure 6 It can be seen that the related substance B of memantine hydrochloride is between 0.0106 and 0.0530 mg·mL -1 The linearity is good within the range, the linear regression equation is y=2949.8x-2.1315, and the correlation coefficient is R 2=0.9990.

[0104] Depend on Figure 7 It can be seen that the related substance C of memantine hydrochloride is between 0.0384 and 0.1920 mg·mL -1 The linearity is good within the range, the linear regression equation is y=2645.2x-7.1406, and the correlation coefficient is R 2 =0.9986.

[0105] Depend on Figure 8 It can be seen that the related substance D of memantine hydrochloride is between 0.0101 and 0.0530 mg·mL -1 The linearity is good within the range, the linear regression equation is y=2110x-0.607, and the correlation coefficient R 2 =0.9986.

[0106] Depend on Fig. 9 It can be seen that the related substance E of memantine hydrochloride is between 0.0102 and 0.0510 mg·mL -1 The linearity is good within the range, the linear regression equation is y=2784.1x-2.1533, and the correlation coefficient is R 2 =0.9990.

[0107] Depend on Fig.10 It can be seen that the related substance F of memantine hydrochloride is between 0.0102 and 0.0510 mg·mL -1 The linearity is good within the range, the linear regression equation is y=2725.7x-0.468, and the correlation coefficient is R 2 =0.9970.

[0108] 2. Accuracy

[0109] (1) Sample preparation

[0110] 0.4, 0.5 and 0.6 mL of system suitability solution A and system suitability solution B under "Example 1" were taken and placed in a 10 mL volumetric flask, and the blank excipient solution of memantine hydrochloride sustained-release capsule preparation was added to dilute to the scale, and 3 portions were prepared in parallel.

[0111] (2) Test results

[0112] Table 1 Memantine hydrochloride related substances accuracy test results

[0113]

[0114]

[0115]

[0116] As shown in Table 1, the recoveries of all relevant substances meet the requirements, and the RSD values ​​are all less than 10%, which is in line with the regulations. The accuracy of this method is good.

[0117] 3. Stability

[0118] (1) Solution preparation

[0119] Pipette 0.5 mL of system suitability solution A and system suitability solution B in "Example 1" into a 10 mL volumetric flask, and dilute to volume with n-hexane. After standing at room temperature for 0, 2, 4, 6, 8, 10, and 12 hours, accurately measure 3 μL and inject it into the gas chromatograph.

[0120] (2) Test results

[0121] Table 2 Solution stability of memantine hydrochloride related substances

[0122]

[0123] It can be seen from Table 2 that the six related substances of memantine hydrochloride are stable in n-hexane within 12 hours.

[0124] 4. Limit of detection and limit of quantification

[0125] (1) Solution preparation

[0126] The system suitability solution A and the system suitability solution B under "Example 1" were taken, continuously diluted with n-hexane and injected into the chromatograph. When the detection signal / baseline noise (S / N) was ≥10, the solution could be used as the quantitative limit solution. When the detection signal / baseline noise (S / N) was ≥3, the solution could be used as the detection limit solution.

[0127] (2) Test results

[0128] Table 3 Detection limit and quantification limit of related substances of memantine hydrochloride

[0129]

[0130] 5. Durability

[0131] Investigate the tolerance of the detection method when there are slight changes in the chromatographic conditions. Investigate the durability of the method for detecting related substances under conditions such as changing the flow rate, column temperature, and detector temperature.

[0132] (1) Solution preparation and parameter setting

[0133] Solution: Same as solution under stability.

[0134] Parameter settings:

[0135] Table 4 Validation of relevant substance analysis methods - Durability parameter range

[0136]

[0137] (2) Test results

[0138] Table 5 Durability-Flow Rate

[0139]

[0140]

[0141] The results in Table 5 show that when the flow rate fluctuates, memantine hydrochloride and its related substances A, B, C, D, E, and F can still be effectively separated, indicating that this method has good durability.

[0142] Table 6 Durability - Initial Column Temperature

[0143]

[0144]

[0145] The results in Table 6 show that when the initial column temperature fluctuates, memantine hydrochloride and its related substances A, B, C, D, E, and F can still be effectively separated, indicating that this method has good durability.

[0146] Table 7 Durability-injection port temperature

[0147]

[0148]

[0149] The results in Table 7 show that when the injection port temperature fluctuates, memantine hydrochloride and its related substances A, B, C, D, E, and F can still be effectively separated, indicating that this method has good durability.

[0150] Table 8 Durability - Detector Temperature

[0151]

[0152]

[0153] The results in Table 8 show that when the detector temperature fluctuates, memantine hydrochloride and its related substances A, B, C, D, E, and F can still be effectively separated, indicating that this method has good durability.

[0154] The various embodiments in this specification are described in a progressive manner, and each embodiment focuses on the differences from other embodiments. The same or similar parts between the various embodiments can be referenced to each other.

Claims

1. A method for detecting memantine hydrochloride and its related substances, characterized in that, Memantine hydrochloride and six related substances of memantine hydrochloride can be separated and quantitatively determined simultaneously, wherein the related substances of memantine hydrochloride are 1,3-dimethyladamantane, 3,5-dimethyl-1-adamantanol, 1-chloro-3,5-dimethyladamantane, 1-bromo-3,5-dimethyladamantane, 1-formamido-3,5-dimethyladamantane and 1-amino-3-methyladamantane hydrochloride.

2. A method for detecting memantine hydrochloride and related substances thereof according to claim 1, characterized in that: The following steps are involved: (1) Prepare system suitability solution: Accurately weigh appropriate amounts of 1,3-dimethyladamantane, 3,5-dimethyl-1-adamantanol, 1-chloro-3,5-dimethyladamantane, 1-bromo-3,5-dimethyladamantane, and 1-formamido-3,5-dimethyladamantane, respectively, add organic solvent, shake ultrasonically, and fully dissolve to form systemic applicability stock solution A, wherein: The concentration of each relevant substance in the systemic applicability stock solution A is 0.3-2.0 mg / mL; Accurately weigh 1-amino-3-methyladamantane hydrochloride, add sodium hydroxide solution, shake ultrasonically, then add organic solvent, shake ultrasonically, let stand and separate, and take the organic solvent layer as system suitability stock solution B, where: The concentration of 1-amino-3-methyladamantane hydrochloride in the system suitability stock solution B is 0.4-0.6 mg / mL; Accurately weigh the memantine hydrochloride reference substance, add sodium hydroxide solution, shake ultrasonically, then add organic solvent, shake ultrasonically, let stand to separate, and take the organic solvent layer as the system suitability reserve solution C, where: The concentration of memantine hydrochloride in the system suitability stock solution C is 10.0-15.0 mg / mL; Accurately pipette systemic suitability stock solution A, systemic suitability stock solution B, and systemic suitability stock solution C with a volume ratio of 1:1:8 respectively, place them in the same 10mL volumetric flask, make up to volume with an organic solvent, and shake well to prepare the systemic suitability solution; (2) Preparation of test solution: Accurately weigh the memantine hydrochloride raw material and place it in a 100 mL volumetric flask, add sodium hydroxide solution, shake ultrasonically, then add organic solvent, shake ultrasonically, finally add water to make up to volume, shake ultrasonically, let stand to separate, and take the organic solvent layer as the test solution, where, The concentration of memantine hydrochloride in the test solution is 4.0-6.0 mg / mL; (3) Prepare blank solution: Take the organic solvent as the blank solution; (4) Chromatographic analysis: A capillary column with 5% phenyl-95% methylpolysiloxane as the stationary phase was used, and a hydrogen flame ionization monitor was used for detection. The temperature was programmed to set the detector temperature to 300°C and the injection port temperature to 280°C. The theoretical plate number was calculated based on the memantine hydrochloride peak. The systemic suitability solution, the test solution, and the blank solution were respectively injected into the gas chromatograph to complete the separation and quantitative determination of memantine hydrochloride and its related substances.

3. A method for detecting memantine hydrochloride and related substances thereof according to claim 2, characterized in that: The concentration of the sodium hydroxide solution is 1-7 mol / L, and the organic solvent is one of toluene, n-hexane, dichloromethane and ethyl acetate.

4. A method for detecting memantine hydrochloride and related substances thereof according to claim 2, characterized in that: In step (1), the mass volume ratio of the 1-amino-3-methyladamantane hydrochloride to the sodium hydroxide solution is 8:3 to 12:3 mg / mL, and the mass volume ratio of the 1-amino-3-methyladamantane hydrochloride to the organic solvent is 4:1 to 6:1 mg / mL; The mass volume ratio of the memantine hydrochloride reference substance to the sodium hydroxide solution is 20:3-30:3 mg / mL, and the mass volume ratio of the memantine hydrochloride reference substance to the organic solvent is 10:1-15:1 mg / mL.

5. A method for detecting memantine hydrochloride and related substances thereof according to claim 2, characterized in that: In step (2), the mass volume ratio of the memantine hydrochloride raw material to the sodium hydroxide solution is 16:1 to 24:1 mg / mL, and the mass volume ratio of the memantine hydrochloride raw material to the organic solvent is 4:1 to 6:1 mg / mL.

6. A method for detecting memantine hydrochloride and related substances thereof according to claim 2, characterized in that: In step (4), the programmed temperature is initially maintained at 50°C for 2 min, then increased to 100°C at a rate of 5°C / min, increased to 110°C at a rate of 1°C / min, maintained for 10 min, and increased to 250°C at a rate of 10°C / min, maintained for 10 min.

7. A method for detecting memantine hydrochloride and related substances thereof according to claim 2, characterized in that: In step (4), the injection volume of the gas chromatograph is 1 to 3 μL, the split ratio is 10:1 to 80:1, and the carrier gas flow rate is 1.2 to 2.5 mL / min.

8. A method for detecting memantine hydrochloride and related substances thereof according to claim 2, characterized in that: The ultrasonic shaking time is 10 to 15 minutes.

9. An application of a method for detecting memantine hydrochloride and related substances thereof, characterized in that: The method according to any one of claims 1 to 8 is used for detecting related substances in memantine hydrochloride and memantine hydrochloride oral preparations.

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