Determination method for dissolution rate of zotipine tablets

Abstract

The invention discloses a method for determining the dissolution rate of an zotipine tablet. The method comprises the following steps: dissolving out the zotipine tablet by taking a hydrochloric acid solution as a dissolution medium; measuring the content of the zotipine in the dissolved solution by adopting an HPLC (High Performance Liquid Chromatography) method; chromatographic conditions of the HPLC method are as follows: a chromatographic column takes octadecylsilane chemically bonded silica as a filler; a mobile phase is ammonium acetate solution-acetonitrile with the volume ratio of (60-40): (40-60) and the pH value of 3.5-5.0. According to the present invention, the solution obtained by dissolving the hydrochloric acid solution with the pH value of 1.2 as the dissolution medium of the zotipine tablet under the specific liquid chromatography condition is adopted as the liquid chromatography test solution, and the zotipine is completely separated in the chromatogram so as to achieve the accurate dissolution rate determination result of the zotipine tablet;

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical analysis, and particularly relates to a method for determining the dissolution of zotepine tablets. Background Art

[0002] Zotepine, also known as benzathiazepine, is a methyltropine antipsychotic drug. It has obvious therapeutic effects on the overall symptoms, positive symptoms and negative symptoms of schizophrenia, and has good safety, low withdrawal risk, no cardiac toxicity, and no increase in prolactin levels. The zotepine tablets reported currently mainly consist of zotepine and excipients, and the excipients include: lactose, corn starch, hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate, etc., and belong to oral preparations.

[0003] The absorption of drugs is the key first step for oral preparations to exert their effects, and the dissolution of drugs is a prerequisite for absorption. Therefore, it is very necessary to detect the dissolution of zotepine tablets. The generic zotepine tablets on the domestic market need to have the same efficacy as the original research drug, and for this reason, consistency evaluation also needs to be carried out through dissolution curve testing. The 2023 edition of the Japanese Medical Drug Quality Information Collection discloses a method for determining the dissolution of zotepine tablets, which determines the dissolution and dissolution curve of zotepine tablets by the UV method. When detecting complex samples by the UV method, substances with the same absorption peak will interfere, and correct detection results cannot be obtained. Compared with UV, the HPLC method has a separation function. After separating the components in the complex sample, quantitative analysis is carried out on the target substance, and the results are more accurate. However, there is currently no research on the method for determining the dissolution of zotepine tablets by the HPLC method. Summary of the Invention

[0004] To solve the above problems, the present invention provides a method for determining the dissolution of zotepine tablets, and the method includes dissolving zotepine tablets with a pH 1.2 hydrochloric acid solution as the dissolution medium; using the HPLC method to determine the content of zotepine in the dissolved solution;

[0005] The chromatographic conditions of the HPLC method are: chromatographic column: filled with octadecylsilane-bonded silica gel; mobile phase: an ammonium acetate solution-acetonitrile with a volume ratio of 60 - 40:40 - 60 and a pH of 3.5 - 5.0.

[0006] Further, the pH value of the hydrochloric acid solution is 1 - 3, preferably a pH value of 1.2.

[0007] Further, the chromatographic conditions also include: flow rate 0.5 - 2.0 mL / min, detection wavelength 240 - 280 nm, injection volume 5 - 25 μL, column temperature 25 - 40 °C.

[0008] Further, the specific steps of the method are:

[0009] 1) Preparation of reference solution: Take zotepine reference substance, dissolve it with acetonitrile solution to obtain the reference solution.

[0010] 2) Preparation of test solution: Take zotepine tablets, dissolve them in hydrochloric acid solution with pH 1.2 as the dissolution medium, filter the dissolution solution, and take the subsequent filtrate as the test solution.

[0011] 3) Detect the reference solution and the test solution by HPLC, and calculate the dissolution of zotepine tablets by the external standard method based on the peak area.

[0012] The chromatographic conditions of the HPLC are as follows: Chromatographic column: Phenomenex Gemini C 18 column, 4.6 mm × 150 mm, 5 μm or a chromatographic column with equivalent efficiency; Mobile phase: ammonium acetate solution - acetonitrile with a volume ratio of 60 - 40:40 - 60 and pH 3.5 - 5.0; Flow rate 1.0 mL / min, detection wavelength 260 nm, injection volume 10 μL, column temperature 35 °C.

[0013] Furthermore, the concentration of the acetonitrile solution in step 1) is 80 - 100%; Each 1 mL of the reference solution contains 0.01 - 0.1 mg of zotepine.

[0014] Furthermore, each zotepine tablet in step 2) is dissolved with 900 mL of hydrochloric acid solution with pH 1.2.

[0015] Furthermore, the dissolution device in step 2) is a paddle method device, with a rotation speed of 50 - 100 revolutions / min and a time of 15 - 60 min.

[0016] Even further, the rotation speed of the paddle method device is 50 revolutions / min and the time is 30 min.

[0017] Furthermore, the filtration in step 2) is carried out using a Cobetter PTFE membrane or a PES membrane.

[0018] Furthermore, the mobile phase in step 3) is ammonium acetate solution - acetonitrile with a volume ratio of 50:50 and pH 3.5 - 5.0.

[0019] Even further, the concentration of the ammonium acetate solution is 0.04 - 0.06 mol / L.

[0020] Even further, the concentration of the ammonium acetate solution in step 3) is 0.05 mol / L.

[0021] The method for determining the dissolution rate of zotepine tablets of the present invention can use the solution obtained by dissolving zotepine tablets in a dissolution medium of pH 1.2 hydrochloric acid solution as the test solution for liquid chromatography through specific liquid chromatography conditions. Zotepine can be completely separated in the chromatogram, making the determination result of the dissolution rate of zotepine tablets accurate, truly reflecting the release characteristics of zotepine tablets, being applicable to evaluating the bioavailability of the active ingredient of zotepine tablets and the uniformity of the preparation, achieving the in vitro consistency evaluation of zotepine tablets, and having a short detection time, high efficiency, strong specificity, and possessing practical popularization and application value.

[0022] Obviously, based on the above content of the present invention, according to the common general knowledge and customary means in the art, without departing from the above basic technical idea of the present invention, various other forms of modifications, substitutions or changes can be made.

[0023] The following is a further detailed description of the above content of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention. Description of the Drawings

[0024] Figure 1 It is the HPLC chromatogram of the test solution for Example 1;

[0025] Figure 2 It is the HPLC chromatogram of the test solution for Example 2;

[0026] Figure 3 It is the HPLC chromatogram of the test solution for Example 3;

[0027] Figure 4 It is the HPLC chromatogram of the test solution for Example 4;

[0028] Figure 5 It is the HPLC chromatogram of the test solution for Example 5;

[0029] Figure 6 It is the HPLC chromatogram of the test solution for Comparative Example 1;

[0030] Figure 7 It is the HPLC chromatogram of the test solution for Comparative Example 2;

[0031] Figure 8 It is the HPLC chromatogram of the test solution for Comparative Example 3;

[0032] Figure 9 It is the HPLC chromatogram of the test solution for Comparative Example 4;

[0033] Figure 10 It is the HPLC chromatogram of the test solution for Comparative Example 5;

[0034] Figure 11 It is the HPLC chromatogram of the blank solvent in the specificity verification;

[0035] Figure 12 It is the HPLC chromatogram of the hydrochloric acid solution with pH 1.2 in the specificity verification;

[0036] Figure 13 It is the HPLC chromatogram of the blank excipient solution in the specificity verification;

[0037] Figure 14 It is the HPLC chromatogram of the reference substance solution in the specificity verification;

[0038] Figure 15 It is the HPLC chromatogram of the test solution in the specificity verification. Specific implementation mode

[0039] The reagents, test drugs, and equipment used in the specific implementation mode of the present invention are all known products and are obtained by purchasing commercially available products.

[0040] In all examples of the present invention, accurately measure the test solution and the reference substance solution, inject them into the liquid chromatograph respectively, and record the chromatogram; calculate the dissolution amount per tablet by the external standard method based on the peak area.

[0041] Calculation formula:

[0042] C 对 =W 对 ×(1 - H)×P / V F 平 =(F1 + F2) / 2

[0043]

[0044] In the formula:

[0045] C 对 is the concentration of the reference substance solution, mg / ml; W 对 is the weighed amount of the reference substance, mg;

[0046] H is the moisture or loss on drying of the reference substance %, and P is the content % of the reference substance;

[0047] V is the dilution volume of the reference substance, ml; A 样 is the peak area of the test solution;

[0048] A 对 is the peak area of the reference substance solution; B is the labeled amount of the test substance, mg;

[0049] V is the volume of the dissolution medium, ml;

[0050] F 平 is the average response factor of the two reference substance solutions;

[0051] T is the dissolution amount of each tablet of the test article calculated based on the labeled amount, that is, the dissolution degree, %.

[0052] The filter membrane for filtration in the present invention is Cobetter PTFE filter membrane.

[0053] All the operations in accordance with the law in the present invention are based on the dissolution and release determination method (the second method in General Principles 0931, Volume IV of Chinese Pharmacopoeia 2020 Edition).

[0054] The acetonitrile in the present invention is analytical pure and undiluted acetonitrile.

[0055] Detection of Zotepine Tablets in Example 1

[0056] (1) Test article solution: Using hydrochloric acid solution with pH 1.2 as the dissolution medium, put 1 zotepine tablet into 900 mL of the dissolution medium for dissolution. Adopt the paddle method, the dissolution rotation speed is 50 rpm, sample at 30 minutes, obtain the dissolution solution, filter the dissolution solution, and take the subsequent filtrate as the test article solution;

[0057] (2) Reference substance solution:

[0058] Take zotepine reference substance, dissolve it with acetonitrile and quantitatively dilute it to prepare a reference substance stock solution with a zotepine concentration of 0.5 mg / mL;

[0059] Precisely measure the reference substance stock solution and quantitatively dilute it with 80% acetonitrile to prepare a reference substance solution with a zotepine concentration of 0.05 mg / mL;

[0060] (3) Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (Phenomenex Gemini C 18 column, 4.6 mm × 150 mm, 5 μm or a chromatographic column with equivalent efficiency); Use ammonium acetate solution with a concentration of 0.05 mg / mL and pH 4.0 (adjusted with glacial acetic acid)-acetonitrile (v:v = 50:50) as the mobile phase, the flow rate is 1.0 mL / min, the column temperature is 35 °C, the detection wavelength is 260 nm, and the injection volume is 10 μL.

[0061] Precisely measure the test article solution and the reference substance solution, inject them into the liquid chromatograph respectively, and record the chromatogram; Calculate the dissolution degree of zotepine tablets by the external standard method based on the peak area.

[0062] Detection of Zotepine Tablets in Example 2

[0063] Same as Example 1, the difference is:

[0064] Mobile phase: Use ammonium acetate solution with a concentration of 0.05 mg / mL and pH 4.0 (adjusted with glacial acetic acid)-acetonitrile (v:v = 60:40) as the mobile phase.

[0065] Detection of Zotepine Tablets in Example 3

[0066] Same as Example 1, except that:

[0067] Mobile phase: An ammonium acetate solution (adjusted with glacial acetic acid) with a pH of 4.0 and a concentration of 0.05 mg / mL - acetonitrile (v:v = 40:60) was used as the mobile phase.

[0068] Detection of Zotepine Tablets in Example 4

[0069] Same as Example 1, except that:

[0070] Mobile phase: An ammonium acetate solution (adjusted with glacial acetic acid) with a pH of 3.5 and a concentration of 0.05 mg / mL - acetonitrile (v:v = 50:50) was used as the mobile phase.

[0071] Detection of Zotepine Tablets in Example 5

[0072] Same as Example 1, except that:

[0073] Mobile phase: An ammonium acetate solution (adjusted with glacial acetic acid) with a pH of 5.0 and a concentration of 0.05 mg / mL - acetonitrile (v:v = 50:50) was used as the mobile phase.

[0074] Detection of Zotepine Tablets in Example 6

[0075] (1) Test solution: Using a hydrochloric acid solution with a pH of 1.2 as the dissolution medium, place 1 zotepine tablet into 900 mL of the dissolution medium for dissolution. The paddle method was used, and the dissolution rotation speed was 50 rpm. Samples were taken at 30 minutes, and the dissolution solution was obtained. The dissolution solution was filtered, and the subsequent filtrate was taken as the test solution;

[0076] (2) Reference solution:

[0077] Take zotepine reference substance, dissolve it with acetonitrile and quantitatively dilute it to prepare a reference stock solution with a zotepine concentration of 0.5 mg / mL;

[0078] Precisely measure the reference stock solution and quantitatively dilute it with 90% acetonitrile to prepare a reference solution with a zotepine concentration of 0.05 mg / mL;

[0079] (3) Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (Phenomenex Gemini C 18 column, 4.6 mm × 150 mm, 5 μm or a chromatographic column with equivalent efficiency); an ammonium acetate solution (adjusted with glacial acetic acid) with a pH of 4.5 and a concentration of 0.04 mg / mL - acetonitrile (v:v = 50:50) was used as the mobile phase, the flow rate was 1.0 mL / min, the column temperature was 35 °C, the detection wavelength was 260 nm, and the injection volume was 10 μL.

[0080] Precisely measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively, then record the chromatogram; calculate the dissolution of zotepine tablets by the external standard method based on the peak area.

[0081] Detection of Zotepine Tablets in Example 7

[0082] (1) Test solution: Using hydrochloric acid solution with pH 1.2 as the dissolution medium, put 1 zotepine tablet into 900 mL of the dissolution medium for dissolution. Adopt the paddle method, with the dissolution rotation speed of 50 rpm. Sampling is carried out after 30 minutes to obtain the dissolution solution. Filter the dissolution solution and take the subsequent filtrate, which is the test solution.

[0083] (2) Reference solution:

[0084] Take zotepine reference substance, dissolve it with acetonitrile and quantitatively dilute it to prepare a reference stock solution with a zotepine concentration of 0.5 mg / mL.

[0085] Precisely measure the reference stock solution and quantitatively dilute it with acetonitrile to prepare a reference solution with a zotepine concentration of 0.05 mg / mL.

[0086] (3) Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (Phenomenex Gemini C 18 column, 4.6 mm × 150 mm, 5 μm or a chromatographic column with equivalent efficiency); use ammonium acetate solution with a pH of 5.0 and a concentration of 0.06 mg / mL (adjusted with glacial acetic acid)-acetonitrile (v:v = 50:50) as the mobile phase, with a flow rate of 1.0 mL / min, a column temperature of 35 °C, a detection wavelength of 260 nm, and an injection volume of 10 μL.

[0087] Precisely measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively, then record the chromatogram; calculate the dissolution of zotepine tablets by the external standard method based on the peak area.

[0088] Detection of Zotepine Tablets in Comparative Example 1

[0089] (1) Test solution: Using hydrochloric acid solution with pH 1.2 as the dissolution medium, put 1 zotepine tablet into 900 mL of the dissolution medium for dissolution. Adopt the paddle method, with the dissolution rotation speed of 50 rpm. Sampling is carried out after 30 minutes to obtain the dissolution solution. Filter the dissolution solution and take the subsequent filtrate, which is the test solution.

[0090] (2) Reference solution:

[0091] Take zotepine reference substance, dissolve it with acetonitrile and quantitatively dilute it to prepare a reference stock solution with a zotepine concentration of 0.5 mg / mL.

[0092] Precisely measure the reference stock solution and quantitatively dilute it with 80% acetonitrile to prepare a reference solution with a zotepine concentration of 0.05 mg / mL.

[0093] (3) Chromatographic conditions: phenomenex C 18 Column (4.6 mm × 250 mm, 5 μm); Mobile phase: 0.05 mol / L ammonium acetate (adjusted to pH 7.0 with triethylamine)-acetonitrile (20:80); Flow rate: 1.0 mL / min; Column temperature: 25 °C; Detection wavelength: 260 nm.

[0094] Precisely measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively, record the chromatogram; Calculate the dissolution of zotepine tablets by the external standard method based on the peak area.

[0095] Detection of zotepine tablets in Comparative Example 2

[0096] (1) Test solution: Using pH 4.0 acetate solution as the dissolution medium, put 1 zotepine tablet into 900 mL of the dissolution medium for dissolution, adopt the paddle method, the dissolution rotation speed is 50 rpm, sample at 30 minutes, obtain the dissolution solution, filter the dissolution solution, and take the subsequent filtrate, which is the test solution;

[0097] (2) Reference solution:

[0098] Take zotepine reference substance, dissolve it with acetonitrile and quantitatively dilute it to prepare a reference stock solution with a zotepine concentration of 0.5 mg / mL;

[0099] Precisely measure the reference stock solution, and quantitatively dilute it with 80% acetonitrile to prepare a reference solution with a zotepine concentration of 0.05 mg / mL;

[0100] (3) Chromatographic conditions: phenomenex C 18 Column (4.6 mm × 250 mm, 5 μm); Mobile phase: 0.05 mol / L ammonium acetate (adjusted to pH 7.0 with triethylamine)-acetonitrile (20:80); Flow rate: 1.0 mL / min; Column temperature: 25 °C; Detection wavelength: 260 nm.

[0101] Precisely measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively, record the chromatogram; Calculate the dissolution of zotepine tablets by the external standard method based on the peak area.

[0102] Detection of zotepine tablets in Comparative Example 3

[0103] (1) Test solution: Using pH 1.2 hydrochloric acid solution as the dissolution medium, put 1 zotepine tablet into 900 mL of the dissolution medium for dissolution, adopt the paddle method, the dissolution rotation speed is 50 rpm, sample at 30 minutes, obtain the dissolution solution, filter the dissolution solution, measure 1 mL of the subsequent filtrate, place it in a 10 mL volumetric flask, dilute it to the scale with 80% acetonitrile, which is the test solution;

[0104] (2) Reference solution:

[0105] Take ziprasidone reference substance, dissolve it in acetonitrile and quantitatively dilute to prepare a reference stock solution with a ziprasidone concentration of 0.5 mg / mL;

[0106] Precisely measure an appropriate amount of the reference stock solution and quantitatively dilute it with 80% acetonitrile to prepare a reference solution with a ziprasidone concentration of 0.05 mg / mL;

[0107] (3) Chromatographic conditions: phenomenex C 18 Column (4.6 mm × 250 mm, 5 μm); Mobile phase: 0.05 mol / L ammonium acetate (adjusted to pH 7.0 with triethylamine) - acetonitrile (20:80); Flow rate: 1.0 mL / min; Column temperature: 25 °C; Detection wavelength: 260 nm.

[0108] Precisely measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram; Calculate the dissolution of ziprasidone tablets by the external standard method based on the peak area.

[0109] Detection of ziprasidone tablets in Comparative Example 4

[0110] (1) Test solution: Using 0.1 mol / L hydrochloric acid solution as the dissolution medium, place 1 ziprasidone tablet into 900 mL of the dissolution medium for dissolution, adopt the paddle method, the dissolution rotation speed is 50 rpm, sample at 30 minutes, obtain the dissolution solution, filter the dissolution solution, and take the subsequent filtrate as the test solution;

[0111] (2) Reference solution:

[0112] Take ziprasidone reference substance, dissolve it in acetonitrile and quantitatively dilute to prepare a reference stock solution with a ziprasidone concentration of 0.5 mg / mL;

[0113] Precisely measure an appropriate amount of the reference stock solution and quantitatively dilute it with 80% acetonitrile to prepare a reference solution with a ziprasidone concentration of 0.05 mg / mL;

[0114] (3) Chromatographic conditions: Using octadecylsilane chemically bonded silica gel as the filler (Phenomenex Gemini C 18 Column, 4.6 mm × 150 mm, 5 μm or a chromatographic column with equivalent efficiency); Using 0.05 mg / mL ammonium acetate solution (adjusted with glacial acetic acid) with a pH of 6.5 - acetonitrile (v:v = 60:40) as the mobile phase, the flow rate is 1.0 mL / min, the column temperature is 35 °C, the detection wavelength is 260 nm, and the injection volume is 10 μL.

[0115] Precisely measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram; Calculate the dissolution of ziprasidone tablets by the external standard method based on the peak area.

[0116] Detection of Zotepine Tablets in Comparative Example 5

[0117] (1) Test solution: Using hydrochloric acid solution with pH 1.2 as the dissolution medium, place 1 zotepine tablet into 900 mL of the dissolution medium for dissolution. The paddle method is adopted, and the dissolution rotation speed is 50 rpm. Sampling is carried out after 30 minutes to obtain the dissolution solution. The dissolution solution is filtered, and the subsequent filtrate is taken as the test solution;

[0118] (2) Reference solution:

[0119] Take zotepine reference substance, dissolve it with acetonitrile and quantitatively dilute it to prepare a reference stock solution with a zotepine concentration of 0.5 mg / mL;

[0120] Precisely measure the reference stock solution and quantitatively dilute it with 80% acetonitrile to prepare a reference solution with a zotepine concentration of 0.05 mg / mL;

[0121] (3) Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (Phenomenex Gemini C 18 column, 4.6 mm × 150 mm, 5 μm or a chromatographic column with equivalent efficiency); use ammonium acetate solution with pH 6.8 and a concentration of 0.05 mg / mL (adjusted with glacial acetic acid)-acetonitrile (v:v = 40:60) as the mobile phase, the flow rate is 1.0 mL / min, the column temperature is 35 °C, the detection wavelength is 260 nm, and the injection volume is 10 μL.

[0122] Precisely measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively, and record the chromatogram; calculate the dissolution rate of zotepine tablets by the external standard method based on the peak area.

[0123] Figures 1 - 5 They are the test and reference substance chromatograms of Examples 1 - 5 respectively. As can be seen from the figure, using the determination method of the present invention, the test and reference substance chromatograms highly coincide, and the active substance zotepine in zotepine tablets can be accurately located, and then the dissolution rate of the active substance in zotepine tablets can be accurately quantified.

[0124] Figure 6 It is the test substance chromatogram of Comparative Example 1. As can be seen from Figure 6 it, by changing the pH and ratio of the mobile phase and the column temperature, the test substance chromatogram will show peak bifurcation, and the difference from the reference peak is too large, so the active substance zotepine in zotepine tablets cannot be accurately qualitatively determined, which in turn affects the quantification and the dissolution rate of zotepine tablets cannot be accurately measured; Figure 7 It is the test substance chromatogram of Comparative Example 2. As can be seen from Figure 7 it, by changing the pH medium, the pH and ratio of the mobile phase, and the column temperature, under this chromatographic condition, the retention time, peak shape and peak position of the test substance are all different from those of the reference substance, and accurate qualitative and quantitative determinations cannot be made, and the dissolution rate of zotepine tablets cannot be accurately measured;Figure 8 The chromatogram of the test sample for Comparative Example 3 shows that Figure 8 by using the method of Comparative Example 3 and diluting the test sample, the resulting peaks become smaller, the method sensitivity becomes worse, and the operation is more complex; Figure 9 The chromatogram of Comparative Example 4 shows that the detection method of Comparative Example 4 has a too long test time and low detection efficiency; Figure 10 The chromatogram of Comparative Example 5 shows that by using this detection method, the peak emergence times of the test sample and the reference substance are inconsistent, and the detection effect is poor.

[0125] The following is the methodological verification of the detection method of Example 1

[0126] 1. System suitability

[0127] Solution preparation:

[0128] Solvent: water - acetonitrile (20:80).

[0129] Reference substance stock solution: Weigh accurately 25 mg of ziprasidone reference substance, place it in a 50 - ml volumetric flask, dissolve it with acetonitrile and dilute to the mark, and shake well.

[0130] Reference substance solution: Accurately measure 2 ml of the reference substance stock solution, place it in a 20 - ml volumetric flask, dilute it to the mark with the solvent, and shake well.

[0131] Determination: Accurately measure the main component reference substance solution, inject it into the liquid chromatograph, and record the chromatogram. Table 1 shows the results of the system suitability test.

[0132] Conclusion: When the reference substance solution is injected continuously for 5 times, the RSD of the ziprasidone peak area is 0.3%, the RSD of the retention time is 0.1%, and the minimum number of theoretical plates is 6291. The system suitability meets the requirements.

[0133] Table 1 Results of the system suitability test

[0134]

[0135] Note: The average value and RSD value of the number of theoretical plates are not used as system suitability evaluation indicators.

[0136] 2. Specificity

[0137] Interference test of solvent, dissolution medium and excipients

[0138] Solvent: water - acetonitrile (20:80).

[0139] Reference substance stock solution: Weigh accurately 25 mg of ziprasidone reference substance, place it in a 50 - ml volumetric flask, dissolve it with acetonitrile and dilute to the mark, and shake well.

[0140] Reference solution: Accurately pipette 2 mL of the reference stock solution into a 20-mL volumetric flask, dilute to the mark with the solvent, and mix well.

[0141] pH 1.2 hydrochloric acid solution: Take 7.65 mL of hydrochloric acid, dilute to 1000 mL with water, and mix well.

[0142] Test solution: Take 1 tablet of zotepine tablets, place it in a 1000-mL dissolution cup, add 900 mL of pH 1.2 hydrochloric acid solution, use the paddle method, the dissolution rotation speed is 50 rpm, operate according to the law, sample at 30 minutes, obtain the dissolution solution, filter the dissolution solution, and take the subsequent filtrate, which is the test solution. Take about 50 mg of blank excipients and prepare the blank excipient solution in the same way.

[0143] Determination: Inject 10 μL of each of the above solutions into the liquid chromatograph in turn, and record the chromatogram ( Figures 11 - 15 ). Table 2 shows the statistical results of the interference and localization tests;

[0144] Table 2 Statistical results of interference and localization tests

[0145] Name Rt (min) Peak area A Result (Resolution) Blank solvent N / A N / A N / A pH 1.2 medium N / A N / A N / A Blank excipient solution N / A N / A N / A Reference solution 3.008 1491624 N / A Test solution 3.032 1567810 N / A

[0146] It can be seen that the blank solvent, pH 1.2 medium, and blank excipients have no interference at the zotepine peak position.

[0147] Note: The blank solvent, pH 1.2 medium, and blank excipient solution have no peaks, and there is no separation degree statement for a single solution; N / A means not applicable.

[0148] 3. Quantification limit

[0149] Solution preparation: Take zotepine reference substance, dissolve it with acetonitrile and quantitatively dilute to prepare a reference stock solution with a zotepine concentration of 0.5 mg / mL; dilute the reference stock solution according to Table 3 below, and the results are shown in Table 3;

[0150] Determination: Inject the above diluted solutions into the liquid chromatograph for determination respectively. The injection concentration when the signal-to-noise ratio (SN) of the test peak is not less than 10 is its quantification limit; inject the quantification limit solution 6 times repeatedly, and calculate the relative standard deviation of the peak area and retention time. Table 4 shows the quantification limit results.

[0151] Table 3 Dilution results of the reference stock solution

[0152] LR - 10% Stock reference solution: 1 ml → 100 ml 0.005 LR - 50% Stock reference solution: 1 ml → 20 ml 0.025 LR - 80% Stock reference solution: 2 ml → 25 ml 0.04 LR - 100% Stock reference solution: 2 ml → 20 ml 0.05 LR - 120% Stock reference solution: 3 ml → 25 ml 0.06 LR - 150% Stock reference solution: 3 ml → 20 ml 0.075

[0153] Table 4 Quantification limit results

[0154]

[0155] Conclusion: The quantitative limit solution was continuously injected 6 times. The signal-to-noise (SN) value of the zotepine peak was between 11 and 18, the relative standard deviation (RSD) of the peak area was 6%, and the RSD of the retention time was 0.2%, all of which met the requirements.

[0156] 4. Accuracy

[0157] Blank excipient solution: Prepared in the same way as for specificity.

[0158] Reference stock solution: Weigh accurately 25 mg of zotepine reference substance, place it in a 5-ml volumetric flask, dissolve it with acetonitrile and dilute to the mark, and shake well.

[0159] Reference solution: Pipette accurately 2 ml of the reference stock solution into a 20-ml volumetric flask, dilute to the mark with the solvent, and shake well;

[0160] Drug substance stock solution: Weigh accurately about 100 mg of zotepine drug substance, place it in a 20-ml volumetric flask, dissolve it with hydrochloric acid solution of pH 1.2 and dilute to the mark, and shake well.

[0161] 10% spiked test solution: Weigh accurately about 60 mg of blank excipient, place it in a 1000-ml dissolution cup, then accurately add 1 ml of the drug substance stock solution, add 900 ml of hydrochloric acid solution of pH 1.2, rotate at 50 revolutions per minute, operate according to the law, take a sample at 30 minutes, take 10 ml of the dissolution solution, filter, and take the subsequent filtrate. (Prepare 3 parallels)

[0162] 100% spiked test solution: Weigh accurately about 60 mg of blank excipient and about 50 mg of zotepine drug substance, place them in a 1000-ml dissolution cup, add 900 ml of hydrochloric acid solution of pH 1.2, rotate at 50 revolutions per minute, operate according to the law, take a sample at 30 minutes, take 10 ml of the dissolution solution, filter, and take the subsequent filtrate. (Prepare 3 parallels)

[0163] 120% spiked test solution: Weigh accurately about 60 mg of blank excipient and about 60 mg of zotepine drug substance, place them in a 1000-ml dissolution cup, add 900 ml of hydrochloric acid solution of pH 1.2, rotate at 50 revolutions per minute, operate according to the law, take a sample at 30 minutes, take 10 ml of the dissolution solution, filter, and take the subsequent filtrate. (Prepare 3 parallels)

[0164] Determination: Inject the above solutions for determination respectively, and calculate the recovery rate and the RSD of the recovery rate. Table 5 shows the results of the accuracy test.

[0165] Calculation formula:

[0166] Table 5 Results of the accuracy test

[0167]

[0168] Conclusion: In the accuracy solutions with concentrations of 10%, 100%, and 150%, the recovery rate of zotepine was between 95.10% and 98.11%, meeting the standard (85% - 110%), indicating high method accuracy; N / A means the background amount is 0.

[0169] 5. Repeatability

[0170] Reference solution: Weigh accurately 25 mg of zotepine reference substance, place it in a 5 - ml volumetric flask, dissolve it with acetonitrile and dilute to the mark, then shake well.

[0171] Test solution: Take 1 tablet of this product, use 900 ml of pH 1.2 solution as the dissolution medium, rotate at 50 revolutions per minute, operate according to the law, sample at 30 minutes, take 10 ml of the dissolution solution, filter, and take the subsequent filtrate.

[0172] Determination: Inject the above solutions for determination respectively, and calculate the dissolution rate and the RSD of the dissolution rate. Table 6 shows the results of the repeatability test.

[0173] Table 6 Results of the repeatability test

[0174]

[0175] Conclusion: In the 6 test solutions, the RSD of the measured dissolution rate of zotepine was 1%, indicating good method repeatability.

[0176] In summary, the present invention provides a method for determining the dissolution rate of zotepine tablets. This detection method is simple, has good system suitability, strong specificity, high accuracy, and strong repeatability. It can accurately determine the dissolution rate of zotepine tablets, effectively evaluate the consistency of the quality between different batches of preparations, confirm the consistency of the drug quality and efficacy, and effectively control the quality of zotepine tablets.

Claims

1. A method for determining the dissolution rate of zotepine tablets, characterized in that: The method includes subjecting zotepine tablets to dissolution using hydrochloric acid solution as the dissolution medium; determining the zotepine content in the dissolved solution by HPLC method; The chromatographic conditions of the HPLC method are as follows: chromatographic column: octadecylsilane chemically bonded silica gel as the filler; mobile phase: ammonium acetate solution - acetonitrile with a volume ratio of 60 - 40:40 - 60 and a pH of 3.5 - 5.

0.

2. The measurement method according to claim 1, wherein The pH value of the hydrochloric acid solution is 1 - 3, preferably 1.

2.

3. The determination method according to claim 1, characterized in that, The chromatographic conditions also include: flow rate 0.5 - 2.0 mL / min, detection wavelength 240 - 280 nm, injection volume 5 - 25 μL, column temperature 25 - 40 °C.

4. The measurement method according to any one of claims 1 to 3, characterized in that, The specific steps of the method are as follows: 1) Preparation of reference solution: Take zotepine reference substance, dissolve it with acetonitrile solution to obtain the reference solution; 2) Preparation of test solution: Take zotepine tablets, dissolve them using hydrochloric acid solution with a pH of 1.2 as the dissolution medium, filter the dissolved solution, and take the subsequent filtrate as the test solution; 3) Detect the reference solution and the test solution by HPLC, and calculate the dissolution of zotepine tablets by the external standard method based on the peak area; The chromatographic conditions of the HPLC are as follows: chromatographic column: Phenomenex Gemini C 18 column, 4.6 mm × 150 mm, 5 μm or a chromatographic column with equivalent efficiency; mobile phase: ammonium acetate solution - acetonitrile with a volume ratio of 60 - 40:40 - 60 and a pH of 3.5 - 5.0; flow rate 1.0 mL / min, detection wavelength 260 nm, injection volume 10 μL, column temperature 35 °C.

5. The measurement method according to claim 4, wherein: The concentration of the acetonitrile solution in step 1) is 80 - 100%; each 1 mL of the reference solution contains 0.01 - 0.1 mg of zotepine.

6. The measurement method according to claim 4, characterized in that: In step 2), each zotepine tablet is dissolved with 900 mL of hydrochloric acid solution with a pH of 1.2; the dissolution device is a paddle method device, with a rotation speed of 50 - 100 revolutions / min and a time of 15 - 60 min.

7. The measurement method according to claim 6, characterized in that: The rotation speed of the paddle method device is 50 revolutions / min and the time is 30 min.

8. The measurement method according to claim 4, characterized in that: The filtration in step 2) is carried out using a PTFE filter membrane or a PES filter membrane.

9. The measurement method according to claim 4, characterized in that: The mobile phase in step 3) is ammonium acetate solution - acetonitrile with a volume ratio of 50:50 and a pH of 3.5 - 5.

0.

10. The measurement method according to claim 9, wherein: The concentration of the ammonium acetate solution is 0.04 - 0.06 mol / L.

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