Method for detecting nitrite ions in dilsulfon hydrochloride sustained release tablet

Abstract

The invention relates to a method for detecting nitrite ions in a dilsulfon hydrochloride # imgabs0 # sustained release tablet, which comprises the following steps: leaching dilsulfon hydrochloride # imgabs1 # sustained release tablet powder to be detected by using an organic solvent, and then mixing with deionized water for extraction; after standing and clarifying, dropwise adding a silver nitrate test solution, and carrying out centrifugal separation to obtain precipitates, insoluble substances and supernate; washing the precipitates and insoluble substances with deionized water for multiple times, and centrifugally collecting washing liquid; combining the rinsing solution with the supernate, filtering with a water-based filter membrane to remove impurities, and fixing the volume to obtain a test solution; preparing reference substance solutions of a series of concentration gradients of nitrite ions; and detecting by using ion chromatography, and calculating the content of nitrite ions in the diltim hydrochloride # imgabs2 # sustained release tablet to be detected by using an external standard method. According to the method, the to-be-detected sample is fully extracted and then subjected to ion chromatography detection, the trace nitrite ions in the diltim hydrochloride # imgabs3 # sustained release tablet can be effectively detected, the accuracy is high, and the specificity is high.

Description

Technical Field

[0001] The present invention relates to a method for detecting nitrite ions in diltiazem hydrochloride sustained-release tablets, belonging to the technical field of drug detection. Background Art

[0002] In recent years, due to the possible risk of nitrosamine carcinogenic impurities in some pharmaceutical preparations containing secondary and tertiary amine chemical structures, regulatory agencies such as the FDA and EMA have formulated a series of industry guidelines and regulatory measures to strengthen the control and management of nitrosamine impurities. According to existing research data, there is a direct relationship between trace nitrite that may be contained in the drug prescription and the formation of nitrosamine impurities. Therefore, controlling trace (ppm level) nitrite in drugs has become an urgent task at present, and reasonable and effective detection methods need to be developed to monitor its content, so as to reduce the risk of nitrosamine impurities and improve the safety of drugs.

[0003] Diltiazem As a calcium antagonist, it is mainly used clinically as a vascular protectant for the treatment of hypertension and angina pectoris of coronary heart disease. Diltiazem The drug parent is a benzothiazepine compound, which contains a tertiary amine group in its chemical structure. Therefore, there is a risk of nitrosamine carcinogenic impurities, and it is necessary to control the content of trace (ppm level) nitrite impurities in the drug.

[0004] Currently, the commonly used detection methods for nitrite mainly include electrode method, spectrophotometry, chromatography, etc. The electrode method and ultraviolet spectrophotometry are generally only applicable to the determination of constant nitrite, and have poor specificity; the high-performance liquid chromatography method has high requirements for samples, is easily affected by impurities, and is also greatly affected by pH value and temperature. In addition, if the sample matrix is relatively complex, it will greatly increase the difficulty of detection, resulting in low detection sensitivity and poor reproducibility.

[0005] Although there are currently some ion chromatography methods for detecting nitrite, they are mainly applied to water, single known excipients or other simple matrices, and there is less research on the detection of nitrite ions in pharmaceutical preparations. There is no literature report on the detection of nitrite in diltiazem sustained-release tablets. This is mainly because the components contained in the drug prescription are complex, so the requirements for sample pretreatment are high, and when there are a large number of other inorganic anions in the sample, the detection difficulty of trace (ppm level) nitrite will also increase; especially for diltiazem sustained-release tablets, the sample matrix is relatively complex and the determination and separation difficulty is large.

[0006] Therefore, it is urgent to develop a method that can effectively solve the interference caused by the complex sample matrix in the preparation, so as to effectively detect diltiazem hydrochloride​ Detection method for nitrite ions in sustained-release tablets.

[0007] Upon retrieval, it is found that the invention patent application with the application number 20121029301.9 and the application publication number CN102798681A discloses a method for determining nitrate and nitrite ions in cigarette tipping paper; the invention patent application with the application number 201310574027.7 and the application publication number CN103675118A discloses a detection method for simultaneous determination of nitrite, nitrate and polyphosphate in aquatic products; the invention patent application with the application number 202110533682.2 and the application publication number CN113295818A discloses a detection method for nitrite and nitrate in high-concentration sodium chloride solution; although the above technical solutions all use ion chromatography to determine the content of nitrite and nitrate, none of them are for detecting diltiazem sustained-release tablets, and the sample matrix of diltiazem sustained-release tablets is relatively complex, so the above technical solutions cannot actually be used to detect nitrite ions in diltiazem Summary of the Invention

[0008] The main object of the present invention is to overcome the problems existing in the prior art and provide a detection method for nitrite ions in diltiazem sustained-release tablets. After fully extracting the sample to be tested and then performing ion chromatography detection, it can effectively detect trace nitrite ions in diltiazem sustained-release tablets, with high accuracy and strong specificity.

[0009] The technical solution for the present invention to solve its technical problems is as follows:

[0010] A detection method for nitrite ions in diltiazem sustained-release tablets, comprising the following steps:

[0011] First step: Take a predetermined number of diltiazem sustained-release tablets to be tested, grind them into powder, and weigh an appropriate amount of powder into a container.

[0012] Second step: Add an organic solvent to the container for extraction, then add deionized water and mix and shake for extraction, and then let it stand until the supernatant is clear.

[0013] Third step: Prepare silver nitrate test solution; drop the silver nitrate test solution on the supernatant liquid obtained in the second step until no white precipitate appears; use a centrifuge to centrifuge and separate to obtain the precipitate and insoluble matter, as well as the supernatant liquid.

[0014] Step 4: Wash the precipitate and insoluble matter obtained in Step 3 with deionized water multiple times. After each washing, centrifuge to collect the washing liquid, and combine the washing liquid with the supernatant obtained in Step 3.

[0015] Step 5: Filter the combined liquid obtained in Step 4 through an aqueous filter membrane to remove impurities, collect the filtrate, place it in a preset volumetric flask, and make up the volume with deionized water to obtain a test solution for ion chromatography analysis.

[0016] Step 6: Weigh an appropriate amount of nitrite standard, use deionized water as a solvent, and obtain a series of concentration gradient reference solutions through volume preparation and stepwise dilution.

[0017] Step 7: Perform ion chromatography detection on the test solution obtained in Step 5 and each reference solution obtained in Step 6. The detection data includes the chromatographic peak area of nitrite ions; draw a standard curve based on the detection data of each reference solution, combine the detection data of the test solution, and use the external standard method to calculate the content of nitrite ions in the to-be-detected diltiazem hydrochloride sustained-release tablets.

[0018] The inventor team found through research and analysis that the main potential determination interferents in the matrix of diltiazem hydrochloride sustained-release tablets include chloride ions, sulfate ions, sulfite ions, and nitrate ions. Among them, the main source of chloride ions is diltiazem hydrochloride bulk drug, and its content in the pharmaceutical preparation is about 5%, so its content is more than 10,000 times that of nitrite content; sulfate ions and sulfite ions come from a small amount of antioxidant sodium metabisulfite in the preparation, and the content is between dozens to hundreds of times that of nitrite content; while nitrate ions generally appear simultaneously with nitrite, and the content difference is not significant without additional addition.

[0019] The inventor team developed the above method through in-depth practice research. After fully extracting the to-be-detected diltiazem hydrochloride sustained-release tablet sample and then performing ion chromatography detection, it can effectively reduce the interference of matrix components in diltiazem hydrochloride sustained-release tablets on nitrite detection, especially the interference of high-concentration chloride ions, sulfate ions, sulfite ions, and nitrate ions in the matrix components, and can effectively separate these interfering components from nitrite, thereby improving the accuracy and specificity of detection. This method has the advantages of simple sample pretreatment, easy operation, low pollution, less interference of the to-be-detected components by other components in the sample, high sensitivity, and good repeatability.

[0020] The further improved technical solution of the present invention is as follows:

[0021] Preferably, in Step 1, the predetermined quantity is not less than 10 tablets, and the container is a volumetric flask.

[0022] By adopting the above preferred solutions, the specific technical features of the first step can be further optimized.

[0023] Preferably, in the second step, the weight of the powder taken in the first step: the volume of the organic solvent = 5 ± 1 g: 2 ± 0.5 mL; the organic solvent is ethanol, methanol or acetonitrile; the volume of the organic solvent: the volume of deionized water = 2 ± 0.5: 10 ± 2.

[0024] More preferably, in the second step, extraction is carried out at room temperature; the extraction time is at least 1 hour; the oscillation extraction time is at least 20 minutes; the standing time is at least 30 minutes.

[0025] By adopting the above preferred solutions, the specific technical features of the second step can be further optimized.

[0026] Preferably, in the third step, the concentration of the silver nitrate test solution is 0.05 - 0.2 mol / L; the dropping method is slow dropping; the centrifugation speed is 4000 - 5000 revolutions per minute.

[0027] By adopting the above preferred solutions, the specific technical features of the third step can be further optimized.

[0028] Preferably, in the fourth step, the weight of the powder taken in the first step: the volume of deionized water = 5 ± 1 g: 5 - 6 mL; the number of rinsing times is at least 3 times; each time during rinsing, vortex mixing is carried out with a vortex mixer for 30 - 40 seconds; the centrifugation conditions are the same as those in the third step.

[0029] By adopting the above preferred solutions, the specific technical features of the fourth step can be further optimized.

[0030] Preferably, in the fifth step, the pore size of the aqueous filter membrane is 0.22 - 0.45 microns; the aqueous filter membrane is an aqueous nylon filter membrane; the preset volumetric flask is a 25 mL volumetric flask.

[0031] By adopting the above preferred solutions, the specific technical features of the fifth step can be further optimized.

[0032] Preferably, in the sixth step, the range of the series of concentration gradients includes at least the concentration range of 0.05 - 5 mg / L; there are at least three concentration points in the series of concentration gradients; the nitrite ion standard is sodium nitrite NaNO2; the concentration of the reference solution is calculated based on nitrite ions.

[0033] By adopting the above preferred solutions, the specific technical features of the sixth step can be further optimized.

[0034] Preferably, in the seventh step, the ion chromatography detection conditions include:

[0035] Use a Dionex Ion Pac AS11 HC analytical column and a Dionex Ion Pac AG11 HC guard column, with the column temperature ranging from 30°C to 37°C; the eluent used is a potassium hydroxide solution with a concentration of 8 - 12 mmol / L; isocratic elution is adopted, and the eluent flow rate is 1.3 - 1.7 mL / min.

[0036] Preferably, in the seventh step, in the ion chromatography detection conditions, use a Dionex EGC 500 - KOH eluent generator, suppressor, and conductivity detector; the suppressor is AERS 4mm, and the suppression current of the suppressor during detection is 80 mA; the detection cell temperature of the conductivity detector during use is 35°C.

[0037] Adopting the above - preferred scheme can further optimize the specific technical features of the seventh step.

[0038] Compared with the prior art, the method for detecting nitrite ions in the diltiazem hydrochloride sustained - release tablets, after fully extracting the sample to be tested and then performing ion chromatography detection, can effectively reduce the interference of matrix components in the diltiazem hydrochloride sustained - release tablets on nitrite detection, especially the interference of high - concentration chloride ions, sulfate ions, sulfite ions, and nitrate ions in the matrix components, and can effectively separate these interfering components from nitrite, thereby improving the accuracy and specificity of the detection. Brief Description of the Drawings

[0039] Figure 1 It is the ion chromatogram of the mixed standard control solution in Example 1 of the present invention.

[0040] Figure 2 It is the diltiazem hydrochloride to be tested in Example 1 of the present invention Example of the ion chromatogram of the sustained - release tablet sample. Detailed Description of the Invention

[0041] The specific technical solution of the present invention is as follows:

[0042] A method for detecting nitrite ions in diltiazem hydrochloride sustained - release tablets, comprising the following steps:

[0043] First step, take a predetermined number of diltiazem hydrochloride sustained - release tablets to be tested, grind them into powder, and weigh an appropriate amount of the powder into a container.

[0044] Among them, the predetermined number is not less than 10 tablets, and the container is a volumetric flask.

[0045] Step 2: After adding an organic solvent to the container for extraction, add deionized water, mix and shake for extraction, and then let it stand until the supernatant is clear.

[0046] Among them, the weight of the powder taken in the first step: the volume of the organic solvent = 5 ± 1 g: 2 ± 0.5 mL; the organic solvent is ethanol, methanol or acetonitrile; extraction is carried out at room temperature; the extraction time is at least 1 hour; the volume of the organic solvent: the volume of deionized water = 2 ± 0.5: 10 ± 2; the shaking extraction time is at least 20 minutes; the standing time is at least 30 minutes.

[0047] Step 3: Prepare a silver nitrate test solution; take the silver nitrate test solution and drop it on the supernatant surface of the liquid obtained in the second step until no white precipitate appears; use a centrifuge to centrifuge to separate and obtain the precipitate and insoluble matter, as well as the supernatant.

[0048] Among them, the concentration of the silver nitrate test solution is 0.05 - 0.2 mol / L (for example, 0.05 mol / L, 0.1 mol / L, 0.15 mol / L, 0.2 mol / L, etc., but not limited to the above-listed values, and other unlisted values within the above numerical range are equally applicable); the dropping method is slow dropping; the centrifugation speed is 4000 - 5000 revolutions per minute.

[0049] This can remove high-concentration chloride ions, most sulfate ions, and sulfite ions.

[0050] Step 4: Wash the precipitate and insoluble matter obtained in the third step with deionized water multiple times. After each washing, centrifuge to collect the washing liquid, and combine the washing liquid with the supernatant obtained in the third step.

[0051] Among them, the weight of the powder taken in the first step: the volume of deionized water = 5 ± 1 g: 5 - 6 mL; the number of washing times is at least 3 times; each time during washing, use a vortex mixer to fully shake and mix for 30 - 40 seconds; the centrifugation conditions are the same as those in the third step.

[0052] This is conducive to reducing the adsorption of nitrite ions to improve the extraction recovery rate.

[0053] Step 5: Filter and remove impurities from the liquid obtained by combining in the fourth step with an aqueous filter membrane, collect the filtrate, place it in a preset volumetric flask, and make up the volume with deionized water to obtain a test solution for ion chromatography analysis.

[0054] Among them, the pore size of the aqueous filter membrane is 0.22 - 0.45 microns; the aqueous filter membrane is an aqueous nylon filter membrane; the preset volumetric flask is a 25 mL volumetric flask.

[0055] This can further remove impurities from the sample and remove particulate matter to protect the chromatographic column.

[0056] Step 6: Weigh an appropriate amount of nitrite ion standard product, use deionized water as the solvent, and obtain a series of control solutions with gradient concentrations through volume fixation preparation and stepwise dilution.

[0057] Among them, the range of the series of concentration gradients includes at least a concentration range of 0.05 - 5 mg / L; there are at least three concentration points in the series of concentration gradients (the number of concentration points is, for example, three, four, five, etc., and the specific concentration points are, for example, 0.05 mg / L, 0.1 mg / L, 1 mg / L, 2 mg / L, 5 mg / L, etc., but not limited to the values listed above); the nitrite ion standard product uses sodium nitrite NaNO₂; the concentration of the control solution is based on nitrite ions.

[0058] Step 7: Perform ion chromatography detection on the test solution obtained in Step 5 and each control solution obtained in Step 6. The detection data includes the chromatographic peak area of nitrite ions; draw a standard curve based on the detection data of each control solution, and combine with the detection data of the test solution to calculate the nitrite ion content in the to-be-detected diltiazem hydrochloride sustained-release tablets by the external standard method.

[0059] Among them, the ion chromatography detection conditions include:

[0060] Use a Dionex Ion Pac AS11 HC analytical column and a Dionex Ion Pac AG11 HC guard column, and the column temperature is 30℃ - 37℃.

[0061] The eluent used is potassium hydroxide solution; the concentration of the potassium hydroxide solution is 8 - 12 mmol / L, such as 8 mmol / L, 9 mmol / L, 10 mmol / L, 11 mmol / L, 12 mmol / L, etc., but not limited to the values listed above, and other unlisted values within the above value range are equally applicable.

[0062] Use isocratic elution, and the eluent flow rate is 1.3 - 1.7 mL / min, such as 1.3 mL / min, 1.4 mL / min, 1.5 mL / min, 1.6 mL / min, 1.7 mL / min, etc., but not limited to the values listed above, and other unlisted values within the above value range are equally applicable.

[0063] Specifically, use a Dionex EGC 500 - KOH eluent generator, suppressor, and conductivity detector; the suppressor is AERS 4mm, and the suppression current of the suppressor is 80 mA during the detection process; the detection cell temperature of the conductivity detector is 35℃ during use, and qualitative analysis is based on the retention time and quantitative analysis is based on the external standard method.

[0064] The present invention will be further described in detail below with reference to the accompanying drawings and in conjunction with embodiments. However, the present invention is not limited to the given examples. For the experimental operations involved in the following content, if the specific experimental conditions are not indicated, they are carried out under conventional conditions or according to the conditions recommended by the manufacturer. For the experimental materials and reagents involved in the following content, unless otherwise specified, they are all commercially available products.

[0065] Example 1

[0066] In this example, the specific steps for detecting nitrite in diltiazem hydrochloride sustained-release tablets are as follows: The specific steps for detecting nitrite in diltiazem hydrochloride sustained-release tablets are as follows:

[0067] S1. Take no less than 10 diltiazem hydrochloride sustained-release tablets to be tested, grind them into powder, weigh about 5 g of the sample, and place it in a 25 mL volumetric flask. S1. Take no less than 10 diltiazem hydrochloride sustained-release tablets to be tested, grind them into powder, weigh about 5 g of the sample, and place it in a 25 mL volumetric flask.

[0068] S2. Add 2 mL of organic solvent ethanol to the volumetric flask, extract for 1 hour; add 10 mL of deionized water and mix, shake and extract for 20 minutes, and let it stand for 30 minutes to clarify the supernatant.

[0069] S3. Prepare 50 mL of silver nitrate test solution with a concentration of 0.1 mol / L. Take 5 mL of the silver nitrate test solution and slowly drip it onto the supernatant liquid obtained in S2 until no white precipitate appears; use a centrifuge to centrifuge at 4000 revolutions per minute to separate the precipitate and insoluble matter, as well as the supernatant.

[0070] S4. Rinse the precipitate and insoluble matter obtained in S3 with a total of about 5 mL of deionized water in 3 portions, shake well with a vortex mixer for 30 seconds each time and centrifuge to collect the rinsing liquid (the centrifugation conditions are the same as those in S3), and combine the rinsing liquid with the supernatant obtained in S3.

[0071] S5. Filter and remove impurities from the liquid obtained by combining in S4 with a 0.22 μm aqueous nylon filter membrane, collect the filtrate (optionally discard the first 1 mL and collect the subsequent filtrate), place it in a 25 mL volumetric flask, and then make up the volume with deionized water to obtain a test solution for ion chromatography analysis.

[0072] S6. Accurately weigh the nitrite ion reference standard, use deionized water as the solvent, and prepare reference solutions with concentrations of 0.05 mg / L, 0.1 mg / L, 1 mg / L, 2 mg / L, and 5 mg / L (the concentration is based on nitrite ion).

[0073] Note: The nitrite ion reference standard used in this example is: sodium nitrite, NaNO2, analytical pure, and the concentration is based on nitrite ion.

[0074] S7. Inject the reference solutions and the test solution into an ion chromatograph for detection respectively to obtain the detection data of each solution (including the chromatographic peak area of nitrite ions); draw a standard curve based on the detection data of each reference solution, and combine with the detection data of the test solution to calculate the content of nitrite ions in the diltiazem hydrochloride sustained-release tablets to be tested by the external standard method. Content of nitrite ions in the sustained-release tablets.

[0075] In S7, the ion chromatography detection conditions are as follows:

[0076] Use a Dionex Ion Pac AS11 HC (4×250 mm) analytical column and a Dionex Ion Pac AG11HC (4×50 mm) guard column, and the column temperature is 30 °C.

[0077] Use a Dionex EGC 500-KOH eluent generator, a suppressor and a conductivity detector; among them, the Dionex EGC 500-KOH eluent generator uses an isocratic elution method, the concentration of KOH is 10 mmol / L, and its flow rate is 1.5 mL / min; the suppressor is AERS (4 mm), and the suppression current during detection is 80 mA; the detection cell temperature of the conductivity detector during use is 35 °C, qualitative by retention time, and quantitative by the external standard method. The ion chromatogram example of the diltiazem hydrochloride sustained-release tablet sample is as shown. Figure 2 as shown.

[0078] Inject a mixed standard control solution containing 5 mg / L chloride standard (sodium chloride, NaCl, analytical grade, concentration based on chloride ions), 10 mg / L nitrite standard (sodium nitrite, NaNO2, analytical grade, concentration based on nitrite ions), 15 mg / L nitrate standard (sodium nitrate, NaNO3, analytical grade, concentration based on nitrate ions), 20 mg / L sulfite standard (sodium sulfite, Na2SO3, analytical grade, concentration based on sulfite ions), and 20 mg / L sulfate standard (sodium sulfate, Na2SO4, analytical grade, concentration based on sulfate ions) into an ion chromatograph for analysis according to the above ion chromatography analysis conditions. The obtained chromatogram is as Figure 1 shown, and the ions corresponding to each chromatographic peak are shown in Table 1 below.

[0079] Table 1. Ions corresponding to each chromatographic peak

[0080] Chromatographic peak # Name Concentration (mg / L) 1 Chloride 5 2 Nitrite 10 3 Nitrate 15 4 Sulfite 20 5 Sulfate 20

[0081] The above results indicate that the ion chromatography analysis conditions adopted in this embodiment can achieve good separation of the chromatographic peaks of each ion in Table 1, thus effectively eliminating the matrix interference of the diltiazem hydrochloride sustained-release tablets.

[0082] (1) The following examples are adopted in this embodiment to verify the influence of using different organic solvents in S2.

[0083] Example 1: The organic solvent in S2 remains ethanol.

[0084] Example 2: It is basically the same as Example 1, except that the organic solvent in S2 is changed to methanol.

[0085] Example 3: It is basically the same as Example 1, except that the organic solvent in S2 is changed to acetonitrile.

[0086] Examples 1 to 3 are detected, and the results are shown in Table 2 below.

[0087] Table 2. Detection results of Examples 1 to 3

[0088]

[0089] The above results indicate that using methanol, ethanol, or acetonitrile as the organic solvent in S2 has almost no influence on the sample determination. Considering the reagent cost and toxicity and safety aspects, ethanol can be preferably used as the extraction solvent in S2.

[0090] (2) The following examples are adopted in this embodiment to verify the influence of using different concentrations of silver nitrate test solution in S3.

[0091] Example 4: Exactly add nitrite ions equivalent to 5.0 ppm to the sample by the standard addition method, and change the concentration of the silver nitrate test solution in S3 to 0.05 mol / L.

[0092] Example 5: It is basically the same as Example 4, except that the concentration of the silver nitrate test solution in S3 is changed to 0.1 mol / L.

[0093] Example 6: It is basically the same as Example 4, except that the concentration of the silver nitrate test solution in S3 is changed to 0.2 mol / L.

[0094] Examples 4 to 6 are detected and the recovery rate of nitrite is calculated. The results are shown in Table 3 below.

[0095] Table 3. Detection results of Examples 4 to 6

[0096]

[0097] The above results indicate that adjusting the concentration of silver nitrate test solution in S3 within the range of 0.05 - 0.2 mol / L has basically no effect on the test results.

[0098] (III) The following examples are adopted in this embodiment to verify the influence of different precipitation rinsing times in S4.

[0099] Example 7: Accurately add nitrite ions equivalent to 5.0 ppm to the sample by the standard addition method, and change the precipitation rinsing times in S4 to 2 times.

[0100] Example 8: It is basically the same as Example 7, except that the precipitation rinsing times in S4 are changed to 3 times.

[0101] Example 9: It is basically the same as Example 7, except that the precipitation rinsing times in S4 are changed to 4 times.

[0102] Samples from Example 7 to Example 9 are detected and the recovery rate of nitrite is calculated. The results are shown in Table 4 below.

[0103] Table 4. Detection Results of Example 7 to Example 9

[0104]

[0105] The above results indicate that the precipitation rinsing times in S4 have a great influence on the determination recovery rate, and the precipitation rinsing times should be limited to at least 3 times to ensure the accuracy of the determination.

[0106] (IV) The following examples are adopted in this embodiment to verify the influence of different concentrations of KOH in the ion chromatography analysis conditions of S7.

[0107] Example 10: Change the KOH concentration in the ion chromatography analysis conditions of S7 to 5 mmol / L.

[0108] Example 11: It is basically the same as Example 10, except that the KOH concentration in the ion chromatography analysis conditions of S7 is changed to 8 mmol / L.

[0109] Example 12: It is basically the same as Example 10, except that the KOH concentration in the ion chromatography analysis conditions of S7 is changed to 12 mmol / L.

[0110] Example 13: It is basically the same as Example 10, except that the KOH concentration in the ion chromatography analysis conditions of S7 is changed to 15 mmol / L.

[0111] Samples from Example 10 to Example 13 are detected and the recovery rate of nitrite is calculated. The results are shown in Table 5 below.

[0112] Table 5. Detection Results of Example 10 to Example 13

[0113]

[0114] The above results show that by controlling specific ion chromatography parameters and keeping the key parameter, the KOH concentration, within a certain range, the resolution between interfering components and nitrite can be effectively improved, and the recovery rate of nitrite is not affected. However, when the ion chromatography parameters are adjusted beyond the specific range, problems such as interference in chromatographic peak determination or overly long analysis time will occur, which will have a negative impact on the determination.

[0115] Specifically, in Example 13, chloride ions already interfere with the determination of nitrite, and in Example 10, the retention time of nitrite exceeds 15 minutes, and the entire injection time exceeds 60 minutes, significantly affecting the test efficiency.

[0116] Overall, when the KOH concentration is controlled at 8–12 mmol / L, the determination results are satisfactory.

[0117] (V) The following examples are used in this embodiment to verify the influence of using different flow rates in the ion chromatography analysis conditions of S7.

[0118] Example 14: Change the flow rate in the ion chromatography analysis conditions of S7 to 1.0 mL / min.

[0119] Example 15: It is basically the same as Example 4, except that: change the flow rate in the ion chromatography analysis conditions of S7 to 1.3 mL / min.

[0120] Example 16: It is basically the same as Example 4, except that: change the flow rate in the ion chromatography analysis conditions of S7 to 1.7 mL / min.

[0121] Example 17: It is basically the same as Example 4, except that: change the flow rate in the ion chromatography analysis conditions of S7 to 2.0 mL / min.

[0122] Detect Examples 14 to 17 and calculate the recovery rate of nitrite. The results are shown in Table 6 below.

[0123] Table 6. Detection Results of Examples 14 to 17

[0124]

[0125] The above results show that by controlling specific ion chromatography parameters and keeping the key parameter, the flow rate, within a certain range, the resolution between interfering components and nitrite can be effectively improved, and the recovery rate of nitrite is not affected. However, when the ion chromatography parameters are adjusted beyond the specific range, problems such as interference in chromatographic peak determination or overly long analysis time will occur, which will have a negative impact on the determination.

[0126] Specifically, in Example 17, chloride ions have interfered with the determination of nitrite ions, while in Example 14, the retention time of nitrite ions exceeds 15 minutes, and the entire injection time exceeds 60 minutes, significantly affecting the test efficiency.

[0127] Generally speaking, when the flow rate is controlled at 1.3 - 1.7 mL / min, the determination results are satisfactory.

[0128] (VI) Methodology verification:

[0129] The methodology of the method in Example 1 was verified. The experimental process referred to the methodology verification guiding principles of the Chinese Pharmacopoeia (2020 Edition). The specificity, linearity and range, precision, accuracy, quantitation limit, detection limit, solution stability and method durability of the method in Example 1 were investigated. The investigation results are shown in Table 7 below.

[0130] Table 7. Methodology verification results

[0131]

[0132] The above results indicate that the method in Example 1 has the advantages of good specificity, good precision, high accuracy and strong durability, which is of great significance for the quality control of nitrite ions.

[0133] Based on the above content of the examples, it can be seen that the method for detecting nitrite ions in the diltiazem hydrochloride sustained-release tablets of the present invention can effectively reduce the interference of matrix components in the diltiazem hydrochloride #imgpt38# sustained-release tablets on the detection of nitrite ions by performing ion chromatography detection after sufficient extraction of the sample to be tested, especially the interference of high-concentration chloride ions, sulfate ions, sulfite ions and nitrate ions in the matrix components, and can effectively separate these interfering components from nitrite ions, thereby improving the accuracy and specificity of the detection.

[0134] The method of the present invention has the advantages of simple sample pretreatment, easy operation, low pollution, less interference of the component to be measured by other components in the sample, high sensitivity and good repeatability.

[0135] The applicant declares that the present invention uses the above examples to illustrate the technical solutions of the present invention, but the present invention is not limited to the above examples, that is, it does not mean that the present invention must rely on the above examples to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of each step of the method of the present invention, addition of auxiliary steps, selection of specific methods, etc. all fall within the protection scope and disclosure scope of the present invention.

[0136] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0137] In addition, it should be noted that, in the various specific technical features described in the above specific embodiments, they can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not separately describe various possible combination methods.

Claims

1. A method for detecting nitrite ions in diltiazem hydrochloride sustained-release tablets, characterized in that It includes the following steps: Step 1: Take a predetermined amount of diltiazem hydrochloride sustained-release tablets to be tested, grind them into powder, and weigh an appropriate amount of the powder into a container; ​ In the second step, after adding an organic solvent to the container for extraction, deionized water is added, mixed and shaken for extraction, and then left to stand until the supernatant is clarified; In the third step, prepare a silver nitrate test solution; take the silver nitrate test solution and drop it on the supernatant surface of the liquid obtained in the second step until no white precipitate appears; Use a centrifuge to centrifuge, and separate to obtain the precipitate and insoluble matter, as well as the supernatant; In the fourth step, wash the precipitate and insoluble matter obtained in the third step with deionized water multiple times. After each washing, centrifuge to collect the washing liquid, and combine the washing liquid with the supernatant obtained in the third step; In the fifth step, filter the liquid obtained by combining in the fourth step with a hydrophilic filter membrane to remove impurities, collect the filtrate, place it in a preset volumetric flask, and make up the volume with deionized water to obtain a test solution for ion chromatography analysis; In the sixth step, weigh an appropriate amount of nitrite ion standard product, use deionized water as a solvent, and obtain a series of concentration gradient reference solutions through volume preparation and stepwise dilution; Step 7: Perform ion chromatography on the test sample solution obtained in Step 5 and each reference solution obtained in Step 6. The detection data includes the chromatographic peak area of nitrite ions. Draw a standard curve based on the detection data of each reference solution, and combine it with the detection data of the test sample solution. Calculate the content of nitrite ions in the diltiazem hydrochloride sustained-release tablets to be tested by the external standard method. ​ 2. A method for detecting nitrite ions in the diltiazem hydrochloride sustained-release tablets according to claim 1, characterized in that, In the first step, the predetermined quantity is not less than 10 tablets, and the container is a volumetric flask. ​ 3. The detection method of nitrite ions in the sustained-release tablets of diltiazem hydrochloride according to claim 1, characterized in that, in the second step, the weight of the powder taken in the first step: the volume of the organic solvent = 5 ± 1 g: 2 ± 0.5 mL; the organic solvent is ethanol, methanol or acetonitrile; the volume of the organic solvent: the volume of deionized water = 2 ± 0.5: 10 ± 2. ​ 4. A method for detecting nitrite ions in the diltiazem hydrochloride sustained-release tablets according to claim 3, characterized in that, In the second step, extract at room temperature; the extraction time is at least 1 hour; the shaking extraction time is at least 20 minutes; the standing time is at least 30 minutes. ​ 5. A method for detecting nitrite ions in the sustained-release tablets of diltiazem hydrochloride according to claim 1, characterized in that, In the third step, the concentration of the silver nitrate test solution is 0.05 - 0.2 mol / L; the dropping method is slow dropping; the centrifugation speed is 4000 - 5000 revolutions per minute. ​ 6. The detection method of nitrite ion in the diltiazem hydrochloride sustained-release tablets according to claim 1, characterized in that, in the fourth step, the weight of the powder taken in the first step: the volume of deionized water = 5 ± 1 g: 5-6 mL; the number of rinsing times is at least 3 times; each time of rinsing, it is fully shaken and mixed by a vortex mixer for 30-40 seconds; the centrifugation conditions are the same as those in the third step. ​ 7. The detection method of nitrite ion in the diltiazem hydrochloride sustained release tablets according to claim 1, characterized in that in the fifth step, the pore size of the aqueous filter membrane is 0.22 to 0.45 microns; the aqueous filter membrane is an aqueous nylon filter membrane; the preset volumetric flask is a 25 mL volumetric flask.

8. A method for detecting nitrite ions in the sustained-release tablets of diltiazem hydrochloride according to claim 1, characterized in that, In the sixth step, the range of the series of concentration gradients includes at least a concentration range of 0.05 - 5 mg / L; there are at least three concentration points in the series of concentration gradients; the nitrite ion standard product uses sodium nitrite NaNO₂; the concentration of the reference solution is calculated based on nitrite ions. ​ 9. A method for detecting nitrite ions in the sustained-release tablets of diltiazem hydrochloride according to any one of claims 1 to 8, characterized in that, In the seventh step, the ion chromatography detection conditions include: Use a Dionex Ion Pac AS11 HC analytical column and a Dionex Ion Pac AG11 HC guard column, with the column temperature being 30°C - 37°C; the eluent used is a potassium hydroxide solution, and the concentration of the potassium hydroxide solution is 8 - 12 mmol / L; use isocratic elution, and the eluent flow rate is 1.3 - 1.7 mL / min.

10. A method for detecting nitrite ions in the diltiazem hydrochloride sustained-release tablets according to claim 9, characterized in that, in the seventh step, in the ion chromatography detection conditions, a Dionex EGC 500-KOH eluent generator, a suppressor and a conductivity detector are used; the suppressor is AERS 4mm, and the suppression current of the suppressor is 80 mA during the detection process; the detection cell temperature of the conductivity detector is 35 °C during use. ​

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