A method for detecting impurities in topiramate medicine and its application

Abstract

The present invention provides a method for detecting impurities in a topiramate drug and its application, the detection method comprising the following steps: mixing a sample to be tested with water to obtain a test solution, then performing ion chromatography detection, and calculating the content of impurities in the sample to be tested according to the detection result; the topiramate drug comprises a topiramate bulk drug or a topiramate preparation; the impurities comprise sulfites; and the eluent for the ion chromatography detection comprises an aqueous solution of potassium hydroxide. The detection method provided by the present invention can detect a variety of impurities including sulfites in a topiramate drug, and the detection result is accurate and the detection limit is low.

Description

Technical Field

[0001] The present invention belongs to the field of drug detection, and specifically relates to a method for detecting impurities in a topiramate drug and an application thereof, and in particular to a method for detecting impurities in a topiramate drug with high accuracy and an application thereof. Background Art

[0002] Topiramate is a new anti-epileptic drug that uses aminosulfonates to replace monosaccharides. Impurities such as fructose, topiramate-related substance A, sulfite, sulfate or aminosulfonate may be present in the sample. Currently, the detection of impurities mainly focuses on sulfate or aminosulfonate. The United States Pharmacopoeia provides an ion chromatography method for the determination of sulfate and aminosulfonate, but the mobile phase needs to be manually prepared under the original chromatographic conditions, which has problems such as baseline drift and poor retention time repeatability. In addition, the United States Pharmacopoeia does not provide a detection method for sulfite.

[0003] In addition, the existing technologies (Li Ji, Li Xia, Luo Jing, et al. Determination of aminosulfonates and sulfates in topiramate original drug by ion chromatography [J]. Chinese Journal of Pharmaceutical Industry, 2015, 46(2):3; Su Haiming, Fan Feng. Determination of aminosulfonates and sulfates in topiramate capsules by IC method [J]. Pharmaceutical Research, 2017(8):453-456.) all involve the detection of impurities in topiramate by ion chromatography, but none of them involve the detection of sulfite. Therefore, how to provide an efficient and accurate method for detecting sulfite impurities in topiramate drugs has become an urgent problem to be solved. Summary of the invention

[0004] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a method for detecting impurities in topiramate drugs and its application, and in particular to provide a method for detecting impurities in topiramate drugs with high accuracy and its application. The detection method provided by the present invention can detect a variety of impurities including sulfite in topiramate drugs, and the detection result is accurate and the detection limit is low.

[0005] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0006] In one aspect, the present invention provides a method for detecting impurities in a topiramate drug, the method comprising the following steps:

[0007] The sample to be tested is mixed with water to obtain a test solution, which is then tested by ion chromatography, and the content of impurities in the sample to be tested is calculated based on the test results.

[0008] The topiramate drug includes topiramate bulk drug or topiramate preparation.

[0009] The impurities include sulfites.

[0010] The eluent for the ion chromatography detection includes an aqueous potassium hydroxide solution.

[0011] The above detection method can effectively detect sulfite impurities in topiramate drugs, and the detection result is accurate and the detection limit is low.

[0012] Preferably, the concentration of topiramate in the test solution is 4-10 mg / mL.

[0013] Preferably, the mixing process is further ultrasonicated, and the ultrasonication time is 0.8-1.2 h.

[0014] Preferably, shaking is performed after the ultrasound, and the shaking time is 0.8-1.2 h.

[0015] Wherein, the concentration of topiramate can be 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL or 10 mg / mL, etc., the ultrasonic time can be 0.8 h, 0.9 h, 1 h, 1.1 h or 1.2 h, etc., and the shaking time can be 0.8 h, 0.9 h, 1 h, 1.1 h or 1.2 h, etc., but are not limited to the values ​​listed above, and other values ​​not listed within the above numerical range are also applicable.

[0016] Preferably, the eluent for ion chromatography detection is a potassium hydroxide-sodium carbonate mixed aqueous solution.

[0017] The above-mentioned specific eluent can further improve the detection accuracy and reduce the detection limit by compounding potassium hydroxide and sodium carbonate.

[0018] Preferably, in the mixed aqueous solution, the concentration of potassium hydroxide is 20-30 mM.

[0019] Preferably, the concentration of sodium carbonate is 4-6 mM.

[0020] Among them, the concentration of potassium hydroxide can be 20mM, 21mM, 22mM, 23mM, 24mM, 25mM, 26mM, 27mM, 28mM, 29mM or 30mM, etc., and the concentration of sodium carbonate can be 4mM, 4.5mM, 5mM, 5.5mM or 6mM, etc., but are not limited to the values ​​listed above, and other values ​​not listed within the above numerical range are also applicable.

[0021] Preferably, the flow rate of the eluent is 0.8-1.2 mL / min.

[0022] Preferably, the column temperature of the ion chromatography detection is 25-35°C.

[0023] Among them, the flow rate can be 0.8mL / min, 0.9mL / min, 1mL / min, 1.1mL / min or 1.2mL / min, and the column temperature can be 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C or 35°C, but are not limited to the values ​​listed above, and other values ​​not listed within the above numerical range are also applicable.

[0024] Preferably, the impurities also include sulfate or sulfamate.

[0025] On the other hand, the present invention also provides the use of the above-mentioned detection method in the quality control of topiramate drugs.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] The present invention provides a method for detecting impurities in a topiramate drug, which can effectively detect sulfite impurities in the topiramate drug, with accurate detection results and low detection limits. Meanwhile, by adopting a specific eluent and controlling relevant parameters, the detection accuracy can be further improved and the detection limit can be reduced. DETAILED DESCRIPTION

[0028] In order to further explain the technical means and effects adopted by the present invention, the technical solution of the present invention is further described below in conjunction with the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.

[0029] Example 1

[0030] This embodiment provides a method for detecting impurities in a topiramate drug, and the specific steps are as follows:

[0031] Accurately weigh appropriate amounts of sodium sulfite, sodium sulfate and aminosulfonic acid reference substances, add water to dissolve and dilute to make a mixed solution containing 6 μg of sulfite, sulfate and aminosulfonate per 1 mL. This is the reference substance solution.

[0032] Accurately weigh 600 mg of topiramate raw material, place it in a 100 mL volumetric flask, add water to dissolve and dilute to the scale, shake well to make a solution with a concentration of 6.0 mg / mL, which is the test solution.

[0033] The reference solution and the test solution are respectively injected into the ion chromatograph for detection, and the chromatograph computer system is started to collect data; the content of specific impurities is calculated using the external standard method;

[0034] The instrument settings are as follows:

[0035]

[0036] Three batches of topiramate API were tested, and the test results are as follows:

[0037]

[0038] Example 2

[0039] This embodiment provides a method for detecting impurities in a topiramate drug, and the specific steps are as follows:

[0040] Accurately weigh appropriate amounts of sodium sulfite, sodium sulfate and aminosulfonic acid reference substances, add water to dissolve and dilute to make a mixed solution containing 6 μg of sulfite, sulfate and aminosulfonate per 1 mL. This is the reference substance solution.

[0041] Take the topiramate sustained-release capsule and open the capsule shell, collect the contents and grind into powder, accurately weigh 1660 mg of the powder of the topiramate sustained-release capsule (equivalent to 600 mg of topiramate), put it in a 100 mL volumetric flask, add 60 mL of water, ultrasonicate for 1 hour, shake for 1 hour, cool, dilute with water to the scale, and shake well. After filtering through a 0.22 μm filter membrane, a solution with a concentration of 6.0 mg / mL is prepared, which is the test solution.

[0042] The reference solution and the test solution are respectively injected into the ion chromatograph for detection, and the chromatograph computer system is started to collect data; the content of specific impurities is calculated using the external standard method;

[0043] The instrument settings are as follows:

[0044]

[0045] Three batches of topiramate sustained-release capsules were tested, and the test results are as follows:

[0046]

[0047] Example 3

[0048] This embodiment provides a method for detecting impurities in a topiramate drug. The specific steps are consistent with those in Example 1 except that the concentration of potassium hydroxide in the potassium hydroxide-sodium carbonate mixed aqueous solution is 20 mM and the concentration of sodium carbonate is 6 mM.

[0049] The test results are as follows:

[0050]

[0051] Example 4

[0052] This embodiment provides a method for detecting impurities in a topiramate drug. The specific steps are consistent with those in Example 1 except that the concentration of potassium hydroxide in the potassium hydroxide-sodium carbonate mixed aqueous solution is 30 mM and the concentration of sodium carbonate is 4 mM.

[0053] The test results are as follows:

[0054]

[0055] Example 5

[0056] This embodiment provides a method for detecting impurities in a topiramate drug. The specific steps are consistent with those in Example 1 except that the concentration of potassium hydroxide in the potassium hydroxide-sodium carbonate mixed aqueous solution is 15 mM and the concentration of sodium carbonate is 7 mM.

[0057] The test results are as follows:

[0058]

[0059] Example 6

[0060] This embodiment provides a method for detecting impurities in a topiramate drug. The specific steps are consistent with those in Example 1 except that the concentration of potassium hydroxide in the potassium hydroxide-sodium carbonate mixed aqueous solution is 35 mM and the concentration of sodium carbonate is 3 mM.

[0061] The test results are as follows:

[0062]

[0063] Example 7

[0064] This embodiment provides a method for detecting impurities in a topiramate drug. The specific steps are the same as those in Example 1 except that the potassium hydroxide-sodium carbonate mixed aqueous solution is replaced with a potassium hydroxide aqueous solution (30 mM).

[0065] The test results are as follows:

[0066]

[0067] Comparative Example 1

[0068] This comparative example provides a method for detecting impurities in a topiramate drug. The specific steps are the same as those in Example 1 except that the potassium hydroxide-sodium carbonate mixed aqueous solution is replaced with a sodium carbonate aqueous solution (30 mM).

[0069] The test results are as follows:

[0070]

[0071] Comparative Example 2

[0072] This comparative example provides a method for detecting impurities in a topiramate drug. The specific steps are consistent with those in Example 1 except that the potassium hydroxide-sodium carbonate mixed aqueous solution is replaced by acetone.

[0073] The test results are as follows:

[0074]

[0075]

[0076] Comparative Example 3

[0077] This comparative example provides a method for detecting impurities in a topiramate drug. The specific steps are consistent with those in Example 1 except that the potassium hydroxide-sodium carbonate mixed aqueous solution is replaced with a sodium bicarbonate buffer solution (30 mM).

[0078] The test results are as follows:

[0079]

[0080] The above data show that the detection method provided by the present invention can effectively detect sulfite impurities in topiramate drugs; by comparing Examples 1 and 3-6, it can be found that the present invention can further improve the detection accuracy and reduce the detection limit by controlling the concentration of the solute in the eluent; by comparing Examples 1 and 7 and Comparative Examples 1-3, it can be found that the present invention can further improve the detection accuracy and reduce the detection limit by compounding potassium hydroxide and sodium carbonate compared with a single solute and other eluents.

[0081] Linear:

[0082] Accurately weigh appropriate amounts of sodium sulfite, sodium sulfate and sodium sulfamate reference substances, dissolve in water and dilute to form a mixed solution containing 40 μg of sulfite, sulfate and sulfamate in each 1 mL, which is the linear solution stock solution. Accurately measure 0.3 mL, 1.0 mL, 3.0 mL, 4.0 mL, and 5.0 mL of the linear solution stock solution respectively, place in a 20 mL volumetric bottle, dilute to the scale with water, and make a linear solution. Detect with the chromatographic conditions in Example 1, and start the chromatograph computer system to collect data at the same time. Use concentration as the horizontal coordinate and the peak area of ​​each impurity as the vertical coordinate to make a linear graph, use the least squares method to perform linear regression, calculate the correlation coefficient, the linear equation, and the results are as follows:

[0083]

[0084]

[0085] The above results show that the detection method provided by the present invention has a good linear relationship for the detection of the three impurities.

[0086] Recovery rate:

[0087] Accurately weigh 600 mg of topiramate bulk drug with known impurity concentration, add known concentrations of sodium sulfite, sodium sulfate and aminosulfonic acid reference substance mixed solution (the concentrations of impurities added are 5.9 μg / mL, 6.2 μg / mL and 6.3 μg / mL, respectively), and then test the reference solution and the test solution according to the methods in Examples 1, 7, Comparative Examples 1 and 3, respectively, and calculate the recovery rate. The results are as follows:

[0088]

[0089] The above data show that the detection method provided by the present invention has high accuracy; by comparing Examples 1 and 7 with Comparative Example 1, it can be found that the present invention can further improve the accuracy of detection by using a compound of potassium hydroxide and sodium carbonate compared with a single solute; by comparing Example 1 and Comparative Example 3, it can be found that the present invention significantly improves the accuracy of sulfite detection by using a specific eluent compared with other eluents.

[0090] Precision:

[0091] Accurately weigh 600 mg of topiramate bulk drug with known impurity concentration, add sodium sulfite, sodium sulfate and aminosulfonic acid reference substance mixed solution with known concentration (the concentration of impurities added was 5.9 μg / mL, 6.2 μg / mL and 6.3 μg / mL, respectively), prepare 6 portions in parallel, and then test the reference substance solution and the test solution according to the method in Example 1, calculate the RSD of the recovery rate of each impurity, and the results are as follows:

[0092]

[0093] The above results show that the method provided by the present invention has good precision.

[0094] The applicant declares that the present invention illustrates the detection method and application of impurities in the topiramate drug of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0095] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0096] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A method for detecting impurities in a topiramate drug, characterized in that: The detection method comprises the following steps: The sample to be tested is mixed with water to obtain a test solution, and then an ion chromatography test is performed, and the content of impurities in the sample to be tested is calculated according to the test results; The topiramate drug includes topiramate bulk drug or topiramate preparation; The impurities include sulfites, sulfates, and sulfamates; The eluent for the ion chromatography detection is a potassium hydroxide-sodium carbonate mixed aqueous solution; In the mixed aqueous solution, the concentration of potassium hydroxide is 20-30 mM, and the concentration of sodium carbonate is 4-6 mM; The flow rate of the eluent is 0.8-1.2 mL / min; The column temperature of the ion chromatography detection is 25-35°C.

2. The detection method according to claim 1, characterized in that: The concentration of topiramate in the test solution is 4-10 mg / mL.

3. The detection method according to claim 1 or 2, characterized in that: The mixing process is also ultrasonicated for 0.8-1.2 h.

4. The detection method according to claim 3, characterized in that: The ultrasonic wave is followed by shaking, and the shaking time is 0.8-1.2 h.

5. Use of the detection method according to any one of claims 1 to 4 in the quality control of topiramate drugs.

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