A method for determining the dissolution curve of oxcarbazepine tablets

Abstract

The present application relates to the technical field of compound detection, and discloses a dissolution curve determination method of oxcarbazepine tablets. The method comprises the following steps: (1) preparing a test sample solution: dissolving the oxcarbazepine tablets to be tested in a dissolution medium to obtain the test sample solution; (2) preparing a control sample solution: mixing oxcarbazepine control sample and acetonitrile to dissolve, then mixing with the dissolution medium, filtering III to obtain a subsequent filtrate III, mixing the subsequent filtrate III with an acetonitrile solution to obtain the control sample solution; (3) introducing the test sample solution and the control sample solution into a liquid chromatograph respectively for chromatographic detection, calculating the cumulative dissolution at each time point, and making a curve to obtain the dissolution curve of the oxcarbazepine tablets to be tested. The method provided by the present application can effectively compare the in-vitro dissolution behavior difference between the generic drug and the original research drug of oxcarbazepine tablets, and can save detection cost.

Description

Technical Field

[0001] This invention relates to the field of compound detection technology, and specifically to a method for determining the dissolution curve of oxcarbazepine tablets. Background Technology

[0002] Oxcarbazepine, chemically named 10,11-dihydro-10-oxo-5H-dibenzo[b,f]aza-5-carboxamide, is a hydantoin antiepileptic drug. Its main mechanism of action is to exert its antiepileptic effect by blocking sodium and calcium ion channels in brain nerve cells. Clinically, it is used alone or in combination with other antiepileptic drugs as a first-line drug for treating partial seizures or secondary generalized seizures in adults, and as an adjunct therapy for partial epilepsy in children aged 2-16 years.

[0003] Currently, the main method for differentiating generic and original oxcarbazepine drugs on the market is through in vitro dissolution behavior difference testing, which primarily uses dissolution curve methods.

[0004] The FDA database discloses the dissolution and release test method for oxcarbazepine tablets, which achieves the purpose of analysis. However, its ability to distinguish the differences in in vitro dissolution behavior between generic and original oxcarbazepine tablets is poor.

[0005] Therefore, there is a need for a method for determining the dissolution profile of oxcarbazepine tablets that can more effectively compare the differences in in vitro dissolution behavior between generic and original drugs, thereby predicting in vivo behavior, while also saving testing costs. Summary of the Invention

[0006] The purpose of this invention is to overcome the problem that the existing technology has poor ability to distinguish the differences in in vitro dissolution behavior between generic drugs and original drugs.

[0007] To achieve the above objectives, the present invention provides a method for determining the dissolution profile of oxcarbazepine tablets, the method comprising:

[0008] (1) Preparation of test solution: At 37℃±0.5℃, place oxcarbazepine tablets in a flow cell, turn on the medium flow rate, so that the oxcarbazepine tablets come into contact with the dissolution medium for dissolution, and take the dissolution solution after filtration I at 10-12 time points. After mixing and filtration II, obtain the filtrate II. Then mix the filtrate II with acetonitrile solution to obtain the test solution.

[0009] The volume ratio of the filtrate II to the acetonitrile solution is 1:1.

[0010] (2) Preparation of reference solution: Take 16.5 mg of oxcarbazepine reference standard and mix it with 5 mL of acetonitrile to dissolve it, then mix it with the dissolution medium, filter it through filter III to obtain filtrate III, mix the filtrate III with the acetonitrile solution to obtain the reference solution;

[0011] The amount of the dissolution medium is controlled such that the total volume of the oxcarbazepine reference standard, the acetonitrile, and the dissolution medium is 50 mL.

[0012] The volume ratio of the filtrate II to the acetonitrile solution is 1:1;

[0013] (3) The test solution and the reference solution are introduced into a liquid chromatograph for chromatographic detection, the cumulative dissolution rate at each time point is calculated, and a curve is plotted to obtain the dissolution curve of the oxcarbazepine tablet to be tested.

[0014] Compared with existing technologies, the method provided by this invention can effectively compare the differences in in vitro dissolution behavior between generic drugs and original drugs, while saving detection costs and serving as an important means of predicting in vivo behavior. Attached Figure Description

[0015] Figure 1 This is a cumulative dissolution curve of a preferred embodiment of the present invention;

[0016] Figure 2 This is a cumulative dissolution curve of a preferred embodiment of the present invention;

[0017] Figure 3 This is a cumulative dissolution curve of a preferred embodiment of the present invention. Detailed Implementation

[0018] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0019] As mentioned above, this invention provides a method for determining the dissolution curve of oxcarbazepine tablets, the method comprising:

[0020] (1) Preparation of test solution: At 37℃±0.5℃, place oxcarbazepine tablets in a flow cell, turn on the medium flow rate, so that the oxcarbazepine tablets come into contact with the dissolution medium for dissolution, and take the dissolution solution after filtration I at 10-12 time points. After mixing and filtration II, obtain the filtrate II. Then mix the filtrate II with acetonitrile solution to obtain the test solution.

[0021] The volume ratio of the filtrate II to the acetonitrile solution is 1:1.

[0022] (2) Preparation of reference solution: Take 16.5 mg of oxcarbazepine reference standard and mix it with 5 mL of acetonitrile to dissolve it, then mix it with the dissolution medium, filter it through filter III to obtain filtrate III, mix the filtrate III with the acetonitrile solution to obtain the reference solution;

[0023] The amount of the dissolution medium is controlled such that the total volume of the oxcarbazepine reference standard, the acetonitrile, and the dissolution medium is 50 mL.

[0024] The volume ratio of the filtrate II to the acetonitrile solution is 1:1;

[0025] (3) The test solution and the reference solution are introduced into a liquid chromatograph for chromatographic detection, the cumulative dissolution rate at each time point is calculated, and a curve is plotted to obtain the dissolution curve of the oxcarbazepine tablet to be tested.

[0026] Preferably, in step (1), the dissolution medium is a hydrochloric acid solution with a sodium dodecyl sulfate (SDS) content of 0.3% w / v and a pH of 1.15-1.25, wherein the concentration of hydrochloric acid is 0.765% v / v. The inventors have found that this preferred configuration allows for more efficient dissolution and release of oxcarbazepine tablets, while also saving costs.

[0027] More preferably, in step (1), the dissolution medium is a product obtained by mixing hydrochloric acid, degassed water at 43°C and sodium dodecyl sulfate.

[0028] Preferably, the concentration of the acetonitrile solution is 80% v / v.

[0029] Preferably, filtration I, filtration II, and filtration III are performed using filter membranes, wherein the filter membrane used for filtration I is adhesive-free glass microfiber filter paper GF / D + glass fiber filter paper GF / F, and the filter membranes used for filtration II and filtration III are PTFE needle filters.

[0030] In a preferred embodiment, the average pore size of the adhesive-free glass microfiber filter paper GF / D is 2.7 μm.

[0031] In a preferred embodiment, the average pore size of the glass fiber filter paper GF / F is 0.7 μm.

[0032] In a preferred embodiment, the PTFE needle filter has an average pore size of 0.45 μm. The inventors have found that, under the above three preferred conditions, the dissolution rate of oxcarbazepine tablets can be determined more effectively.

[0033] According to a preferred embodiment, in step (1), the filtrate is filtered at 10 time points, and after being mixed and filtered at 10 time points, the filtrate II is obtained. The 10 time points are 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min, 120 min and 180 min.

[0034] According to a preferred embodiment, in step (1), the flow cell is the flow cell described in the General Rules of Part IV of the 2020 edition of the Chinese Pharmacopoeia, and the average inner diameter of the flow cell is 22.6 mm.

[0035] Preferably, in step (1), the dissolution is performed using an open-loop system with a medium flow rate of 16 mL / min, a sample volume of 50 mL, and a pulse frequency of 120 pulses / min. The inventors have found that this preferred configuration is more conducive to the dissolution of oxcarbazepine tablets.

[0036] In a preferred embodiment, in step (3), the cumulative dissolution rate at each time point is calculated using a formula including the one shown in Equation I:

[0037] Formula I:

[0038]

[0039]

[0040] in,

[0041] X i Indicates dissolution rate;

[0042] Q i Indicates cumulative dissolution rate;

[0043] C s This indicates the concentration of the reference standard, expressed in mg / ml.

[0044] A s Indicates the area of ​​the main peak in the reference solution;

[0045] V represents the medium flow rate, with units of mL / min;

[0046] U represents the labeled amount, in mg;

[0047] T i This represents the time difference between the i-th and (i-1)-th time points, in minutes.

[0048] T i-1 This represents the time difference between the (i-1)th and (i-2)th time points, in minutes.

[0049] A i and A i-1 These represent the main peak areas of the test solution at the i-th and (i-1)-th sampling points, respectively.

[0050] It should be noted that the present invention does not limit other parameters and conditions, and can be carried out using conventional technical means in the field. For example, the relevant content in the General Chapters of Part IV of the 2020 edition of the Chinese Pharmacopoeia can be referred to.

[0051] The present invention will be described in detail below through examples. Unless otherwise specified, the raw materials used are all commercially available products.

[0052] Unless otherwise specified, "room temperature" or "normal temperature" in this invention refers to a temperature of 25±5℃.

[0053] Acetonitrile solution: concentration 80% v / v;

[0054] The oxcarbazepine tablets to be tested were purchased from Hunan Xiangzhong Pharmaceutical Co., Ltd., batch number 0020230101, tablet strength: 0.3g.

[0055] The oxcarbazepine tablets to be tested were prepared according to the method in Example 1 of CN1407894A, and the content of the substances is as follows:

[0056]

[0057]

[0058] Oxcarbazepine reference standard: purchased from Hubei Gedian Renfu Pharmaceutical Co., Ltd., batch number F-NOXC211105M, content 99.6%;

[0059] Oxcarbazepine Reference I: Purchased from Novartis Pharmaceuticals, Beijing, batch number T0443, specification: 0.3g;

[0060] Oxcarbazepine Reference II: Purchased from Novartis Pharmaceuticals, Beijing, batch number T0451, specification: 0.3g;

[0061] Hydrochloric acid: concentration 37wt%;

[0062] Filter membrane:

[0063] Filter membrane I: consists of unbonded glass microfiber filter paper GF / D (average pore size 2.7 μm) + glass fiber filter paper GF / F (average pore size 0.7 μm);

[0064] Filter membrane II: PTFE needle filter (average pore size 0.45μm);

[0065] High performance liquid chromatograph: Shimadzu 2050C 3D;

[0066] Flow cell: average inner diameter is 22.6 mm;

[0067] The conditions for liquid chromatography detection in the following examples include:

[0068] Chromatographic column: Waters Symmetry C18 (4.6mm*150mm*5μm);

[0069] Filler: Octadecylsilane-bonded silica gel;

[0070] Flow rate: 1.5 mL / min;

[0071] Column temperature: 30℃;

[0072] Detection wavelength: 215nm;

[0073] Injection volume: 10 μL;

[0074] Mobile phase: Phosphate buffer-acetonitrile-methanol (volume ratio 62:16:22) was used as the mobile phase (pH 6.0). The steps for preparing the phosphate buffer included: weighing 6.8 g of potassium dihydrogen phosphate, dissolving it in 1000 mL of water, adding 2 mL of triethylamine, adjusting the pH to 6.0 with phosphoric acid, filtering, and obtaining the phosphate buffer.

[0075] Preparation of dissolution medium I:

[0076] Measure 7.65 mL of hydrochloric acid, dilute it to 1 L with degassed water at 43 °C, add sodium dodecyl sulfate (SO4), mix well, and obtain dissolution medium I with a sodium dodecyl sulfate content of 0.3% w / v.

[0077] Preparation of dissolution medium II:

[0078] Measure 7.65 mL of hydrochloric acid, dilute it to 1 L with degassed water at 43 °C, add sodium dodecyl sulfate, mix well, and obtain dissolution medium II with a sodium dodecyl sulfate content of 0.6% w / v.

[0079] Preparation of dissolution medium III:

[0080] Measure 7.65 mL of hydrochloric acid, dilute it to 1 L with degassed water at 43 °C, add an appropriate amount of sodium dodecyl sulfate, mix well, and obtain dissolution medium III with a sodium dodecyl sulfate content of 0.1% w / v.

[0081] In the following examples, the cumulative dissolution rate at each time point is calculated using the formula shown in Equation I:

[0082] Formula I:

[0083]

[0084]

[0085] in,

[0086] X i Indicates dissolution rate;

[0087] Q i Indicates cumulative dissolution rate;

[0088] C s This indicates the concentration of the reference standard, expressed in mg / ml.

[0089] A s Indicates the area of ​​the main peak in the reference solution;

[0090] V represents the medium flow rate, with units of mL / min;

[0091] U represents the labeled amount, in mg;

[0092] T i This represents the time difference between the i-th and (i-1)-th time points, in minutes.

[0093] T i-1 This represents the time difference between the (i-1)th and (i-2)th time points, in minutes.

[0094] A i and A i-1 These represent the main peak areas of the test solution at the i-th and (i-1)-th sampling points, respectively.

[0095] Example 1

[0096] This embodiment illustrates the method for determining the dissolution curve of oxcarbazepine tablets provided by the present invention, referring to the relevant content in the General Chapters, Part IV of the 2020 edition of the Chinese Pharmacopoeia, and following the steps below:

[0097] (1) Preparation of test solution: At 37℃±0.5℃, place oxcarbazepine tablets in a flow cell, turn on the medium flow rate, and let the oxcarbazepine tablets come into contact with the dissolution medium (dissolution medium I) for dissolution. At time points of 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min, 120 min and 180 min respectively, the dissolution solution is collected by filtration I (using filter membrane I), mixed, and filtered by filtration II (using filter membrane II) to obtain filtrate II. Then, 2 mL of the filtrate II is mixed with 2 mL of acetonitrile solution to obtain the test solution.

[0098] The medium flow rate was 16 mL / min, the sample volume was 50 mL, and the pulse frequency was 120 pulses / min.

[0099] (2) Preparation of reference solution: Take 16.5 mg of oxcarbazepine reference standard and mix it with 5 mL of acetonitrile to dissolve it. Then add the dissolution medium (dissolution medium I) to 50 mL and mix well. After filtration III (using filter membrane II), filtrate II is obtained. Mix 2 mL of the filtrate II with 2 mL of acetonitrile solution to obtain the reference solution.

[0100] (3) The test solution and the reference solution were introduced into a liquid chromatograph for chromatographic detection, the cumulative dissolution rate at each time point was calculated, and a curve was plotted to obtain the dissolution curve of the oxcarbazepine tablets to be tested. Figure 1 ;

[0101] The figure shows that the dissolution rates of the self-developed reagent and the reference reagent are basically the same in the first 30 minutes. However, there are significant differences in dissolution behavior starting from 45 minutes. The self-developed reagent dissolves more slowly than the reference reagent, and the dissolution rate reaches about 80% at 180 minutes.

[0102] Example 2

[0103] This embodiment uses a method similar to that of Example 1, except that dissolution medium II is used for dissolution. The final dissolution curve of the oxcarbazepine tablets to be tested is shown in the figure. Figure 2 ;

[0104] As shown in the figure, the dissolution rates of the self-developed reagent and the reference reagent were basically the same in the first 20 minutes. However, there were significant differences in dissolution behavior starting from 30 minutes. The self-developed reagent dissolved more slowly than the reference reagent. The dissolution trend was consistent with that in Example 1. However, under this medium condition, the amount of SDS required was larger, the dissolution time was longer, and the detection cost was higher.

[0105] Example 3

[0106] This embodiment uses a method similar to that of Example 1, except that dissolution medium III is used, and the sampling time points in step (1) are 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min, 120 min, 180 min, 240 min, and 300 min. The final dissolution curve of the oxcarbazepine tablets to be tested is shown in the figure. Figure 3 ;

[0107] As shown in the figure, the dissolution rates of the self-developed reagent and the reference reagent were basically the same in the first 30 minutes. However, there was a significant difference in dissolution behavior starting from 45 minutes. The self-developed reagent dissolved more slowly than the reference reagent. The dissolution trend was consistent with that in Example 1. However, under this medium condition, the time required to reach the dissolution endpoint of 80% was longer, which resulted in a larger consumption of medium and higher detection costs.

[0108] Example A

[0109] The process was carried out in a similar manner to Example 1, except that in step (1), an equal mass of oxcarbazepine reference I was used instead of the oxcarbazepine tablets to be tested for dissolution. The dissolution solution was collected by filtration I (using filter membrane I) at time points of 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min, 120 min and 180 min, respectively. After mixing and filtration II (using filter membrane II), filtrate II was obtained. Then, 2 mL of the filtrate II was mixed with 2 mL of acetonitrile solution to obtain the oxcarbazepine reference solution.

[0110] The oxcarbazepine reference solution is then used in place of the test solution, and the reference solution obtained in step (2) is introduced into the liquid chromatograph for chromatographic detection.

[0111] The final dissolution curve of oxcarbazepine reference I is shown in the figure. Figure 1 The dissolution curve of the oxcarbazepine reference was used to compare with the dissolution curve of the oxcarbazepine tablets to be tested obtained in Example 1.

[0112] Example B

[0113] The process was carried out in a similar manner to Example 2, except that in step (1), an equal mass of oxcarbazepine reference I was used instead of the oxcarbazepine tablets to be tested for the dissolution.

[0114] The final dissolution curve of oxcarbazepine reference I is shown in the figure. Figure 2 The dissolution curve of the oxcarbazepine reference was used to compare with the dissolution curve of the oxcarbazepine tablets to be tested obtained in Example 2.

[0115] Example C

[0116] The process was carried out in a similar manner to Example 3, except that in step (1), an equal mass of oxcarbazepine reference II was used instead of the oxcarbazepine tablets to be tested for the dissolution.

[0117] The final dissolution curve of oxcarbazepine reference II is shown in the figure. Figure 3 The dissolution curve of the oxcarbazepine reference was used to compare with the dissolution curve of the oxcarbazepine tablets to be tested obtained in Example 3.

[0118] The results above show that the method provided by this invention is simple and easy to operate, and can effectively compare the differences in in vitro dissolution behavior between generic and original oxcarbazepine tablets, thereby achieving the purpose of predicting in vivo behavior, while saving detection costs.

[0119] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for determining the dissolution curve of oxcarbazepine tablets, characterized in that, The method includes: (1) Preparation of test solution: At 37℃±0.5℃, place oxcarbazepine tablets in a flow cell, turn on the medium flow rate, and let the oxcarbazepine tablets come into contact with the dissolution medium for dissolution. Take the dissolution solution after filtration I at 10 time points, mix and filter II to obtain filtrate II, and the 10 time points are 5min, 10min, 15min, 20min, 30min, 45min, 60min, 90min, 120min and 180min; then mix the filtrate II with acetonitrile solution to obtain the test solution. The volume ratio of the subsequent filtrate II to the acetonitrile solution is 1:1; the dissolution medium is a hydrochloric acid solution with a sodium dodecyl sulfate content of 0.3% w / v and a pH of 1.15-1.25, wherein the concentration of hydrochloric acid is 0.765% v / v; (2) Preparation of reference solution: Take 16.5 mg of oxcarbazepine reference standard and mix it with 5 mL of acetonitrile to dissolve it, then mix it with the dissolution medium, filter it through filter III to obtain filtrate III, mix the filtrate III with the acetonitrile solution to obtain the reference solution; The amount of the dissolution medium is controlled such that the total volume of the oxcarbazepine reference standard, the acetonitrile, and the dissolution medium is 50 mL. The volume ratio of the filtrate II to the acetonitrile solution is 1:1; (3) The test solution and the reference solution are introduced into the liquid chromatograph for chromatographic detection, the cumulative dissolution rate at each time point is calculated, and a curve is plotted to obtain the dissolution curve of the oxcarbazepine tablet to be tested; The oxcarbazepine tablets were purchased from: Hubei Gedian Renfu Pharmaceutical Co., Ltd., batch number F-NOXC211105M; Beijing Novartis Pharmaceutical Co., Ltd., batch number T0443; and Beijing Novartis Pharmaceutical Co., Ltd., batch number T0451.

2. The method according to claim 1, wherein, In step (1), the concentration of the acetonitrile solution is 80% v / v.

3. The method according to claim 1 or 2, wherein, In step (1), the dissolution medium is a product obtained by mixing hydrochloric acid, degassed water at 43°C and sodium dodecyl sulfate.

4. The method according to claim 1 or 2, wherein, The filters I, II, and III are performed using filter membranes. Specifically, the filter membrane used in filter I is an adhesive-free glass microfiber filter paper GF / D + glass fiber filter paper GF / F, while the filter membranes used in filters II and III are PTFE needle filters.

5. The method according to claim 4, wherein, The adhesive-free glass microfiber filter paper GF / D has an average pore size of 2.7 μm; and / or The average pore size of the glass fiber filter paper GF / F is 0.7 μm.

6. The method according to claim 5, wherein, The average pore size of the PTFE needle filter is 0.45 μm.

7. The method according to claim 1 or 2, wherein, In step (1), the dissolution is carried out in a flow cell with an average inner diameter of 22.6 mm.

8. The method according to claim 1 or 2, wherein, In step (1), the dissolution is carried out using an open-loop system, with a medium flow rate of 16 mL / min, a sample volume of 50 mL, and a pulse frequency of 120 pulses / min.

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