Separation and determination method for impurities in thiopride hydrochloride

Abstract

The invention provides a method for separating and determining impurities in thiopride hydrochloride, liquid chromatography is adopted for separating and determining, a chromatographic column adopted by the liquid chromatography is a C18 column, a mobile phase comprises a mobile phase A and a mobile phase B, the mobile phase A is 0.02-0.15 Vt% ammonia water, the mobile phase B is methanol, and the detection wavelength is 240 nm. According to the method provided by the invention, the impurities in the thiopride hydrochloride can be effectively separated from the thiopride hydrochloride, and the impurities can also be remarkably distinguished, so that a theoretical basis is provided for quality evaluation of the thiopride hydrochloride, and safe medication of a patient is ensured.

Description

Technical Field

[0001] The present invention relates to the technical field of drug detection, in particular to a method for separating and determining impurities in sulpiride hydrochloride. Background Art

[0002] Tiapride hydrochloride belongs to the benzamide antipsychotic drug, formerly known as tiapride or tiaprol. The chemical name of tiapride hydrochloride is N -[2-(Diethylamino)ethyl]-5-(methylsulfonyl)-2-methoxybenzamide hydrochloride is mainly used clinically to treat Tourette syndrome, chorea, senile psychosis, analgesia, alcoholism, etc. Regarding the determination methods of related substances in sulpiride hydrochloride raw materials and preparations, current domestic and foreign standards, such as the "Chinese Pharmacopoeia 2020 Edition", "European Pharmacopoeia 11.0", "British Pharmacopoeia 2025", "Japanese Pharmacopoeia 18", National Drug Standard WS-10001-(HD-0464)-2002, National Drug Standard WS-10001-(HD-0465)-2002 and enterprise registration standards, disclose specific determination methods.

[0003] Impurity analysis is a critical component of drug quality control. Impurity research provides insights into the quality differences between generic and brand-name drugs, as well as between generic drugs from different manufacturers. This provides a basis for improving production processes, enhancing generic drug quality, and ensuring patient safety.

[0004] Currently, most sulpiride hydrochloride tablets comply with the national drug standard WS-10001-(HD-0465)-2002, which lacks inspection items for related impurities. This results in the risk of uncontrolled impurities in most sulpiride hydrochloride tablets circulating on the market. The related substance methods in the current quality standards for sulpiride hydrochloride raw materials and preparations are complex in mobile phase preparation and require long detection times, failing to meet the requirements for separating the main impurities in the sample. Currently, the impurities in sulpiride hydrochloride primarily originate from impurities, such as impurities F, G, and H, that are inevitably produced during the preparation of raw materials due to impure starting materials. Existing related substance detection methods are unable to significantly separate sulpiride hydrochloride from impurities, or from individual impurities, making it difficult to qualitatively or quantitatively characterize impurities and impacting the quality evaluation of sulpiride hydrochloride raw materials and preparations.

[0005] Therefore, it is of great significance to establish a simple, accurate and efficient method for the determination of related impurities in sulpiride hydrochloride. Summary of the Invention

[0006] The present invention aims to solve one of the technical problems in the prior art at least to a certain extent. To this end, one object of the present invention is to provide a method for separating and determining impurities in sulpride hydrochloride.

[0007] The present invention proposes a method for separating and determining impurities in sulpiride hydrochloride, which adopts liquid chromatography separation and determination, and the chromatographic column used in the liquid chromatography is C 18 The column, the mobile phase includes mobile phase A and mobile phase B, the mobile phase A is 0.02Vt%-0.15Vt% ammonia water, the mobile phase B is methanol, and the detection wavelength is 240nm.

[0008] The inventors found that using C 18 The column, using a certain concentration of ammonia-methanol solution as the mobile phase, can effectively separate impurities in sulpride hydrochloride from sulpride hydrochloride, and can also clearly distinguish between each other, thereby providing a theoretical basis for the quality evaluation of sulpride hydrochloride and ensuring the safe use of the drug for patients. The method provided by the present invention simplifies the detection steps and costs. The detection wavelength is selected at the maximum absorption wavelength of 240 nm for 8 of the 10 impurities in sulpride hydrochloride (the remaining two have a maximum absorption wavelength of 267 nm), which can simultaneously monitor impurities and sulpride. Compared with detection wavelengths of 254 nm and 287 nm, the response of sulpride and most impurities is improved, the sample concentration can be reduced, and the liquid phase system is protected.

[0009] Specifically, the impurities in the sulpiride hydrochloride include at least one of the following compounds: 、 、 、 、 、 、 、 、 、 .

[0010] It should be noted that in the 2020 edition of the Chinese Pharmacopoeia, ammonia water is named "concentrated ammonia solution". Therefore, the above-mentioned ammonia water can also be called concentrated ammonia solution.

[0011] According to the method for determining impurities in sulpiride hydrochloride provided by the present invention, the liquid chromatography adopts gradient elution, specifically as follows: .

[0012] In some embodiments of the present invention, the C 18 The filler of the column is selected from octadecylsilane bonded silica gel.

[0013] In some embodiments of the present invention, the flow rate of the mobile phase is 0.8-1.1 mL / min.

[0014] In some embodiments of the present invention, the C 18 The column temperature was 30-40°C.

[0015] In some embodiments of the present invention, the injection volume of the liquid chromatography is 5-15 μL.

[0016] In some embodiments of the present invention, the preparation process of the test solution includes: taking an appropriate amount of fine powder of the test sample, accurately weighing it, adding 20Vt% methanol solution to dissolve it and quantitatively diluting it to make a solution containing approximately 1 mg of sulfapride per 1 mL, and filtering it.

[0017] In some embodiments of the present invention, the preparation process of the reference solution includes: accurately weighing an appropriate amount of the reference substance, dissolving it in a 20% methanol solution, and quantitatively diluting it to prepare a solution containing approximately 10 μg per 1 mL.

[0018] In some embodiments of the present invention, the liquid chromatography separation and determination can be followed by a mass spectrometry detector for determination.

[0019] The present invention has at least the following beneficial effects: The method provided by the present invention can effectively separate impurities in sulpride hydrochloride from sulpride hydrochloride, and can also clearly distinguish between the impurities, thereby providing a theoretical basis for the quality evaluation of sulpride hydrochloride and ensuring the safe use of the drug for patients. The assay method provided by the present invention is accurate and can meet the requirements for accurate assay when the sample impurity level is not high. The method also has stronger specificity, is simpler, and has higher economic value than existing liquid phase methods. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the technical solutions in the present invention or the prior art, a brief introduction will be given below to the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0021] Figure 1 This is a liquid phase spectrum of tiapride hydrochloride and 10 impurities in Example 1 of the present invention; Figure 2 This is the liquid phase spectrum of the sulpiride hydrochloride reference substance of Example 1 of the present invention; Figure 3 This is the liquid phase spectrum of the impurity A reference substance in Example 1 of the present invention; Figure 4 This is the liquid phase spectrum of the impurity B reference substance in Example 1 of the present invention; Figure 5 This is the liquid phase spectrum of the impurity C reference substance in Example 1 of the present invention; Figure 6 This is the liquid phase spectrum of the impurity D reference substance in Example 1 of the present invention; Figure 7 This is the liquid phase spectrum of the reference substance of impurity E in Example 1 of the present invention; Figure 8 This is the liquid phase spectrum of the impurity F reference substance in Example 1 of the present invention; Figure 9 This is the liquid phase spectrum of the impurity G reference substance in Example 1 of the present invention; Figure 10 This is the liquid phase spectrum of the impurity H reference substance in Example 1 of the present invention; Figure 11 This is the liquid phase spectrum of impurity I positioning in Example 1 of the present invention; Figure 12 This is the liquid phase spectrum of the reference substance of impurity J in Example 1 of the present invention; Figure 13 This is a liquid phase spectrum of the tiapride hydrochloride raw material of Example 2 of the present invention; Figure 14 These are the primary and secondary mass spectra of impurity I of the present invention; Figure 15 This is an analysis diagram of the structure and fragmentation pathway of impurity I of the present invention; Figure 16 This is the primary and secondary mass spectra of the impurity D reference substance of the present invention; Figure 17 This is an analysis diagram of the cracking pathway of impurity D of the present invention; Figure 18 This is a liquid phase spectrum of Tipride Hydrochloride Tablets A of Example 3 of the present invention; Figure 19 This is a liquid phase spectrum of Tipride Hydrochloride Tablets B of Example 4 of the present invention; Figure 20 This is a liquid phase spectrum of Tipride Hydrochloride Tablets C of Example 5 of the present invention; Figure 21 This is the liquid phase spectrum of Tipride Hydrochloride Tablets D of Example 6 of the present invention; Figure 22 This is the liquid phase spectrum of Tiapride Hydrochloride Tablets E of Example 7 of the present invention; Figure 23 This is a liquid phase spectrum of tiapride hydrochloride and 10 impurities in Example 8 of the present invention; Figure 24 This is a liquid phase spectrum of tiapride hydrochloride and 10 impurities in Example 9 of the present invention; Figure 25 This is a liquid phase spectrum of sulpiride hydrochloride and 10 impurities in Comparative Example 1 of the present invention; Figure 26 This is a liquid phase spectrum of sulpiride hydrochloride and 10 impurities in Comparative Example 2 of the present invention; Figure 27 This is a liquid phase spectrum of sulpiride hydrochloride and 10 impurities in Comparative Example 3 of the present invention; Figure 28 This is a liquid phase spectrum of sulpiride hydrochloride and 10 impurities in Comparative Example 4 of the present invention; Figure 29 This is a liquid phase spectrum of sulpiride hydrochloride and 10 impurities in Comparative Example 5 of the present invention. DETAILED DESCRIPTION

[0022] Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without creative work shall fall within the scope of protection of the present invention. The present invention will be described below with reference to specific embodiments. It should be noted that these embodiments are merely illustrative and do not limit the present invention in any way.

[0023] Example 1 This example provides a test of sulpiride hydrochloride and 10 impurities, as follows: Preparation of sulpiride hydrochloride and impurity solutions: Heat sulpiride hydrochloride raw material at 150°C for 48 hours, cool to room temperature, accurately weigh an appropriate amount, dissolve it in 20% by volume methanol solution, accurately add an appropriate amount of each of the following impurity reference solutions, and quantitatively dilute with 20% by volume methanol solution to prepare a solution containing approximately 1 mg of sulpiride and 1 µg of each impurity per mL.

[0024] Preparation of sulpiride hydrochloride reference solution: Accurately weigh an appropriate amount of sulpiride hydrochloride reference solution, dissolve it in 20Vt% methanol solution and quantitatively dilute it to make a solution containing approximately 10µg of sulpiride per 1mL.

[0025] Preparation of Impurity A Reference Solution: Accurately weigh an appropriate amount of Impurity A Reference Solution, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 10µg per 1mL.

[0026] Preparation of Impurity B Reference Solution: Accurately weigh an appropriate amount of Impurity B Reference Solution, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 10µg per 1mL.

[0027] Preparation of Impurity C Reference Solution: Accurately weigh an appropriate amount of Impurity C Reference, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 10µg per 1mL.

[0028] Preparation of impurity D reference solution: Accurately weigh an appropriate amount of impurity D reference, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 10µg of sulfapride per 1mL.

[0029] Preparation of Impurity E Reference Solution: Accurately weigh an appropriate amount of Impurity E Reference, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 10µg per 1mL.

[0030] Preparation of Impurity F Reference Solution: Accurately weigh an appropriate amount of Impurity F Reference, dissolve it in 20% methanol solution and quantitatively dilute it to a solution containing approximately 10 µg per 1 mL.

[0031] Preparation of Impurity G Reference Solution: Accurately weigh an appropriate amount of Impurity G Reference, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 10µg per 1mL.

[0032] Preparation of Impurity H Reference Solution: Accurately weigh an appropriate amount of Impurity H Reference, dissolve it in 20% methanol solution and quantitatively dilute it to a solution containing approximately 10 µg per 1 mL.

[0033] Preparation of impurity I localization solution: Take sulpride hydrochloride raw material, heat it at 150℃ for 48 hours, cool it, carefully weigh an appropriate amount, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 10µg of impurity I per 1mL.

[0034] Preparation of Impurity J Reference Solution: Accurately weigh an appropriate amount of Impurity J Reference, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 10µg per 1mL.

[0035] Chromatographic conditions: Octadecylsilane bonded silica gel was used as filler (Waters Xbridge C 18 , 4.6 mm × 250 mm), with 0.1Vt% ammonia water as mobile phase A and methanol as mobile phase B, gradient elution was performed according to the program; the detection wavelength was 240 nm; the flow rate was 1.0 mL / min; the column temperature was 35°C; the injection volume was 10 μL; Gradient elution was as follows: .

[0036] Liquid phase spectra of sulpiride hydrochloride and 10 impurities Figure 1 As shown. The liquid phase spectrum of the reference substance of sulpride hydrochloride is as shown Figure 2 As shown. The liquid phase spectrum of impurity A reference substance is as follows Figure 3 As shown. The liquid phase spectrum of impurity B reference substance is as follows Figure 4 As shown. The liquid phase spectrum of impurity C reference substance is as follows Figure 5 As shown. The liquid phase spectrum of impurity D reference substance is as follows Figure 6 As shown. The liquid phase spectrum of impurity E reference substance is as follows Figure 7 As shown. The liquid phase spectrum of impurity F reference substance is as follows Figure 8 As shown. The liquid phase spectrum of impurity G reference substance is as follows Figure 9 As shown. The liquid phase spectrum of impurity H reference substance is as follows Figure 10 As shown. The liquid phase spectrum of impurity I is as follows Figure 11 As shown. The liquid phase spectrum of impurity J reference substance is as follows Figure 12 shown.

[0037] from Figure 1-12It can be seen that the present invention can effectively separate sulpiride hydrochloride from 10 impurities of sulpiride hydrochloride.

[0038] Example 2 This embodiment provides a test of sulfuric acid hydrochloride raw material, which is as follows: Preparation of sulpiride hydrochloride test solution: Accurately weigh an appropriate amount of sulpiride hydrochloride raw material, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 1 mg of sulpiride per 1 mL, and filter it.

[0039] The liquid phase spectrum of the Tipride Hydrochloride raw material of Example 2 is as follows: Figure 13 As shown. Figure 13 It can be seen that the present invention can effectively separate the impurities in the sulpiride hydrochloride raw material from the sulpiride hydrochloride, and the impurities can also be significantly distinguished from each other.

[0040] Mass spectrometry analysis of impurity I Since no reference substance for impurity I was available, the liquid chromatography coupled with mass spectrometry detection method of the present invention was used to analyze the primary and secondary mass spectrometry data to infer the structure and fragmentation pathway of impurity I.

[0041] Mass spectrometry conditions: electrospray ionization (ESI), positive ion mode; capillary temperature, 450°C; sheath gas flow rate, 40 arb; auxiliary gas flow rate, 10 arb; auxiliary heater temperature, 400°C; ion source voltage, 4.5 kV; mass range (m / z), 66.7-1000.0.

[0042] In the positive ion mode, the main fragment obtained by the primary full scan mass spectrum of impurity I was m / z 329.16, and its precise molecular weight was the same as that of sulpiride. The main fragments obtained by the secondary mass spectrum were 199.01 and 242.06, which were basically consistent with the secondary mass spectrum characteristic peaks of impurity D, and it was speculated that the methyl group on the benzene ring was detached.

[0043] The liquid chromatography conditions, preparation of the impurity I localization solution, and preparation of the impurity D reference solution were the same as in Example 1.

[0044] The primary and secondary mass spectra of impurity I are as follows Figure 14 shown.

[0045] Analysis of the structure and fragmentation pathway of impurity I Figure 15 shown.

[0046] The primary and secondary mass spectra of impurity D reference substance are as follows Figure 16 shown.

[0047] Analysis of the fragmentation pathway of impurity D Figure 17 shown.

[0048] Example 3 The only difference between Example 3 and Example 2 is that: Example 3: The sulpiride hydrochloride raw material in Example 2 was replaced with sulpiride hydrochloride tablets A.

[0049] The liquid phase spectrum of the hydrochloride sulpiride tablets A of Example 3 is as follows: Figure 18 As shown. Figure 18 It can be seen that the present invention can effectively separate the impurities in the sulpiride hydrochloride tablets A from the sulpiride hydrochloride, and the impurities can also be significantly distinguished from each other.

[0050] Example 4 The only difference between Example 4 and Example 2 is that: Example 4: The sulpiride hydrochloride raw material in Example 2 was replaced with sulpiride hydrochloride tablets B.

[0051] The liquid phase spectrum of the sulpiride hydrochloride tablets B of Example 4 is as follows: Figure 19 As shown. Figure 19 It can be seen that the present invention can effectively separate the impurities in the sulpride hydrochloride tablets B from the sulpride hydrochloride, and the impurities can also be significantly distinguished from each other.

[0052] Example 5 The only difference between Example 5 and Example 2 is that: Example 5: The sulpiride hydrochloride raw material in Example 2 was replaced with sulpiride hydrochloride tablets C.

[0053] The liquid phase spectrum of the Tipride Hydrochloride Tablet C of Example 5 is as follows: Figure 20 As shown. Figure 20 It can be seen that the present invention can effectively separate the impurities in the sulpride hydrochloride tablets C from the sulpride hydrochloride, and the impurities can also be significantly distinguished from each other.

[0054] Example 6 The only difference between Example 6 and Example 2 is that: Example 6: The sulpiride hydrochloride raw material in Example 2 was replaced with sulpiride hydrochloride tablets D.

[0055] The liquid phase spectrum of the sulpiride hydrochloride tablet D of Example 6 is as follows: Figure 21 As shown. Figure 21 It can be seen that the present invention can effectively separate the impurities in the sulpride hydrochloride tablets D from the sulpride hydrochloride, and the impurities can also be significantly distinguished from each other.

[0056] Example 7 The only difference between Example 7 and Example 2 is that: Example 7: The sulpiride hydrochloride raw material in Example 2 was replaced with sulpiride hydrochloride tablets E.

[0057] The liquid phase spectrum of the sulpiride hydrochloride tablets E of Example 7 is as follows: Figure 22 As shown. Figure 22It can be seen that the present invention can effectively separate the impurities in the sulpiride hydrochloride tablets E from the sulpiride hydrochloride, and the impurities can also be significantly distinguished from each other.

[0058] The minimum detection limits of various impurities in the testing method for impurities in sulpiride hydrochloride tablets provided by the present invention are studied.

[0059] The preparation process of the minimum detection limit solution of sulpiride hydrochloride and each impurity is as follows: Preparation of the minimum detection limit solution of sulpiride hydrochloride: Accurately weigh an appropriate amount of sulpiride hydrochloride reference substance, dissolve it in 20Vt% methanol solution and quantitatively dilute it to prepare a solution containing approximately 15ng of sulpiride per 1mL.

[0060] Preparation of the minimum detection limit solution of impurity A: Accurately weigh an appropriate amount of impurity A reference substance, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 16 ng per 1 mL.

[0061] Preparation of the minimum detection limit solution of impurity B: Accurately weigh an appropriate amount of impurity B reference substance, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 15 ng per 1 mL.

[0062] Preparation of the minimum detection limit solution of impurity C: Accurately weigh an appropriate amount of impurity C reference substance, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 26 ng per 1 mL.

[0063] Preparation of the minimum detection limit solution of impurity D: Accurately weigh an appropriate amount of impurity D reference substance, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 25 ng per 1 mL.

[0064] Preparation of the minimum detection limit solution of impurity E: Accurately weigh an appropriate amount of impurity E reference substance, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 15 ng per 1 mL.

[0065] Preparation of the minimum detection limit solution of impurity F: Accurately weigh an appropriate amount of impurity F reference substance, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 15 ng per 1 mL.

[0066] Preparation of the minimum detection limit solution of impurity G: Accurately weigh an appropriate amount of impurity G reference substance, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 15 ng per 1 mL.

[0067] Preparation of the minimum detection limit solution of impurity H: Accurately weigh an appropriate amount of impurity H reference substance, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 31 ng per 1 mL.

[0068] Preparation of the minimum detection limit solution of impurity J: Accurately weigh an appropriate amount of impurity J reference substance, dissolve it in 20% methanol solution and quantitatively dilute it to make a solution containing approximately 29 ng per 1 mL.

[0069] The detection limits of sulpride and its impurities are shown in Table 1.

[0070] Table 1

[0071] As can be seen from Table 1, the method of the present invention has high sensitivity and can detect sulpiride hydrochloride impurities below 1 ng, and can meet the demand for accurate determination when the sample impurities are not high.

[0072] Example 8 The only difference between Example 8 and Example 1 is that the mobile phase A used is 0.02% ammonia water.

[0073] The liquid phase spectrum of sulpiride hydrochloride and 10 impurities in Example 8 is as follows: Figure 23 As shown. Figure 23 It can be seen that the present invention can effectively separate sulpiride hydrochloride from 10 impurities of sulpiride hydrochloride.

[0074] Example 9 The only difference between Example 9 and Example 1 is that the mobile phase A used is 0.15 wt% ammonia water.

[0075] The liquid phase spectrum of sulpiride hydrochloride and 10 impurities in Example 9 is as follows: Figure 24 As shown. Figure 24 It can be seen that the present invention can effectively separate sulpiride hydrochloride from 10 impurities of sulpiride hydrochloride.

[0076] Comparative Example 1 The difference between Comparative Example 1 and Example 1 is only: The chromatographic conditions used were: octadecylsilane bonded silica gel as filler (Welch Ultimate LP-C 18 Column temperature was 4.6 mm × 250 mm. The column was diluted with a buffer solution (6.8 g of potassium dihydrogen phosphate and 0.1 g of sodium octane sulfonate were weighed, dissolved in water, diluted to 1000 mL, shaken, and the pH adjusted to 2.7 with phosphoric acid)-methanol-acetonitrile (80:15:5). The detection wavelength was 240 nm; the flow rate was 1.0 mL / min; the column temperature was 35°C; and the injection volume was 10 μL. This method is the registered standard for related substances in sulpiride hydrochloride tablets.

[0077] The liquid phase spectrum of sulpiride hydrochloride and 10 impurities in Comparative Example 1 is as follows: Figure 25 As shown. Figure 25 It can be seen that this method cannot separate sulpiride hydrochloride and 10 impurities.

[0078] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is only: Chromatographic conditions used: octylsilane bonded silica gel (Phenomenex luna C8, 4.6 mm × 250 mm) as a packing, a solution containing 6.8 g of potassium dihydrogen phosphate and 0.1 g of sodium octane sulfonate (adjusted to pH 2.7 with phosphoric acid) in methanol and acetonitrile (80:15:5) per 1000 mL; detection wavelength at 240 nm; flow rate at 1.5 mL / min; column temperature at 40°C; injection volume of 10 μL. This method conforms to the method for related substances of tiapride hydrochloride raw materials in the 2020 edition of the Chinese Pharmacopoeia.

[0079] The liquid phase spectrum of sulpiride hydrochloride and 10 impurities in Comparative Example 2 is as follows: Figure 26 As shown. Figure 26 It can be seen that this method cannot separate sulpiride hydrochloride and 10 impurities.

[0080] Comparative Example 3 The difference between Comparative Example 3 and Example 1 is only: The chromatographic conditions used were: octadecylsilane bonded silica gel as filler (Waters Xbridge C 18 The column was prepared using a 4.6 mm × 250 mm column with a mixture of water-methanol-triethylamine (500:500:2); a detection wavelength of 287 nm; a flow rate of 1.0 mL / min; a column temperature of 35°C; and an injection volume of 10 μL. This method is the registered standard for related substances in sulpride hydrochloride and sodium chloride injection.

[0081] The liquid phase spectrum of sulpiride hydrochloride and 10 impurities in Comparative Example 3 is as follows: Figure 27 As shown. Figure 27 It can be seen that this method cannot separate sulpiride hydrochloride and 10 impurities.

[0082] Comparative Example 4 The only difference between Comparative Example 4 and Example 1 is that the mobile phase A used is 0.01% ammonia water.

[0083] The liquid phase spectrum of sulpiride hydrochloride and 10 impurities in Comparative Example 4 is as follows: Figure 28 As shown. Figure 28 It can be seen that this method cannot separate sulpiride hydrochloride and 10 impurities.

[0084] Comparative Example 5 The only difference between Comparative Example 5 and Example 1 is that the mobile phase A used is 0.2% aqueous ammonia.

[0085] The liquid phase spectrum of sulpiride hydrochloride and 10 impurities in Comparative Example 5 is as follows: Figure 29 As shown. Figure 29It can be seen that this method cannot separate sulpiride hydrochloride and 10 impurities.

[0086] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A method for separating and determining impurities in sulpride hydrochloride, characterized in that: The liquid chromatography was used for separation and determination. The chromatographic column used in the liquid chromatography was C 18 The column, the mobile phase includes mobile phase A and mobile phase B, the mobile phase A is 0.02Vt%-0.15Vt% ammonia water, the mobile phase B is methanol, and the detection wavelength is 240nm.

2. The method according to claim 1, characterized in that The liquid chromatography adopts gradient elution, which is as follows: 。 3. The method according to claim 1, characterized in that The impurities in the sulpiride hydrochloride include at least one of the following compounds: 、 、 、 、 、 、 、 、 、 。 4. The method according to any one of claims 1 to 3, characterized in that The C 18 The filler of the column is selected from octadecylsilane bonded silica gel.

5. The method according to any one of claims 1 to 3, characterized in that The flow rate of the mobile phase is 0.8-1.1 mL / min.

6. The method according to any one of claims 1 to 3, characterized in that The C 18 The column temperature was 30-40°C.

7. The method according to any one of claims 1 to 3, characterized in that The injection volume of the liquid chromatography was 5-15 μL.

8. The method according to any one of claims 1 to 3, characterized in that The preparation process of the test solution includes: taking an appropriate amount of fine powder of the test sample, accurately weighing it, adding 20Vt% methanol solution to dissolve it and quantitatively diluting it to make a solution containing about 1 mg of sulfapride per 1 mL, and filtering it.

9. The method according to any one of claims 1 to 3, characterized in that: The preparation process of the reference solution includes: accurately weighing an appropriate amount of the reference substance, dissolving it in a 20Vt% methanol solution and quantitatively diluting it to prepare a solution containing approximately 10µg of sulfapride per 1mL.

10. The method according to any one of claims 1 to 3, characterized in that The liquid chromatography separation and determination can be followed by a mass spectrometry detector for determination.

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