Method for detecting and analyzing dimethyl sulfate in potassium sulfate
Through the specific settings of gas chromatography, the problem of dimethyl sulfate detection in potassium sulfate is solved, the precise detection of this impurity is achieved, and the safety and quality of the drug are improved.
Patent Information
- Application Number
- CN202411805420.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-08
- Publication Date
- 2025-04-22
AI Technical Summary
The prior art has failed to effectively detect the mutagenic impurity dimethyl sulfate present in potassium sulfate, resulting in possible adverse reactions and toxic side effects.
Gas chromatography is used to achieve accurate detection of dimethyl sulfate in potassium sulfate through specific chromatographic columns, temperature control and detector temperature settings.
This method can accurately detect the content of dimethyl sulfate in potassium sulfate, improve the safety of oral concentrated solution of sodium magnesium sulfate, and ensure product quality.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of medical detection, and in particular relates to a detection and analysis method for dimethyl sulfate in potassium sulfate, a raw material of an oral concentrated magnesium sodium potassium sulfate solution. Background Art
[0002] Magnesium sodium potassium sulfate oral concentrated solution is a laxative that can promote intestinal peristalsis, increase the frequency of bowel movements, and thus relieve constipation symptoms. It is a new type of intestinal cleanser with the characteristics of small dosage, good taste, high patient tolerance, good intestinal cleansing effect, and few adverse reactions.
[0003] Potassium sulfate, the main raw material of magnesium sodium potassium sulfate oral concentrated solution, and its potential mutagenic impurity dimethyl sulfate may cause adverse reactions and toxic side effects.
[0004] The potassium sulfate production process uses methanol as a low-grade alcohol solvent, which reacts with sulfuric acid to generate genotoxic dimethyl sulfate. Dimethyl sulfate is considered to be potentially carcinogenic and a highly toxic organic solvent. It has become a key control target for drug regulatory agencies in many countries.
[0005] At present, the reported detection methods for dimethyl sulfate mainly include gas chromatography, gas chromatography-mass spectrometry, liquid chromatography and liquid-mass spectrometry. The detection fields include air, soil, drugs and surfactants, etc. There are no reports on the detection of dimethyl sulfate in potassium sulfate. Summary of the invention
[0006] The purpose of the present invention is to provide an analytical method for dimethyl sulfate in potassium sulfate, which can realize accurate detection of dimethyl sulfate in potassium sulfate, thereby ensuring the quality of potassium sulfate products and improving the safety of magnesium sodium potassium sulfate oral concentrated solution medicines.
[0007] The analytical method for dimethyl sulfate in potassium sulfate of the present invention adopts the following technical scheme: An analytical method for dimethyl sulfate in potassium sulfate, the method adopts gas chromatography, and the chromatographic conditions are as follows: The chromatographic column is a chromatographic column with a non-polar stationary phase; The column temperature was controlled as follows: the starting temperature was 40~60℃, the holding time was 2min~5min, the temperature was increased to 120~140℃ at a rate of 5℃~20℃ / min, and then the temperature was increased to 230~280℃ at a rate of 15℃~25℃ / min, and maintained for 5min~15min; The injection port temperature is 240℃~280℃; The detector temperature is 250℃~350℃.
[0008] The above-mentioned gas chromatography conditions are adopted in the present invention to realize accurate detection of dimethyl sulfate in potassium sulfate.
[0009] More preferably, the column temperature is controlled to start at 50°C, hold for 3 min, increase to 130°C at a rate of 10°C / min, then increase to 250°C at a rate of 20°C / min, and maintain for 10 min.
[0010] Preferably, in the chromatographic conditions, the split ratio is 5:1; and the column flow rate is 1.2 ml / min.
[0011] Preferably, the capillary column of the non-polar stationary phase is DB-200 or other chromatographic columns with equivalent performance, and the detector is a FID detector.
[0012] Preferably, a method for analyzing dimethyl sulfate in potassium sulfate specifically comprises the following steps: S1: Weigh about 1.0g of this product accurately, place it in a 10ml volumetric flask, add water to dissolve and dilute to the scale, shake well, place it in a separatory funnel, add 1ml of solvent, extract, and take the upper layer as the test solution; S2: dissolving the dimethyl sulfate reference substance with a solvent and diluting it to a set concentration to obtain a reference substance solution; S3: Inject the test solution in step S1 and the reference solution in step S2 into the gas chromatograph respectively, perform the test according to the set chromatographic conditions, and record the chromatogram and chromatographic data.
[0013] Preferably, the solvents in step S1 and step S2 are both ethyl acetate.
[0014] Preferably, in step S3, the content of dimethyl sulfate is calculated using an external standard method based on the recorded chromatogram and chromatographic data.
[0015] Beneficial effects of the present invention: 1. The method provided by the present invention can test the content of dimethyl sulfate in potassium sulfate, which has not appeared in the existing test conditions and can fill the technical gap in this field; 2. The method provided by the present invention can accurately detect the content of dimethyl sulfate in potassium sulfate, and further ensure the quality of magnesium sodium potassium sulfate concentrated solution medicine; 3. The analytical method provided by the present invention has good specificity, good repeatability, low detection limit and high accuracy. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] In order to more clearly illustrate the technical solution of the embodiment of the present invention, the following is a brief introduction to the drawings in the implementation description: Figure 1 is the chromatogram of the dimethyl sulfate reference substance in Example 1 of the present invention; Figure 2 is a chromatogram of the test solution in Example 1 of the present invention; Figure 3 is a chromatogram of the spiked test solution in Example 1 of the present invention; Figure 4 is the detection limit solution chromatogram in Example 2 of the present invention; Figure 5 is the chromatogram of the spiked test solution in Experimental Example 5; Figure 6 is the chromatogram of the test solution at an injection port temperature of 255° C. in Experimental Example 4; Figure 7 is the chromatogram of the test solution at an injection port temperature of 265° C. in Experimental Example 4; Figure 8 is the chromatogram of the test solution at a detector temperature of 295° C. in Experimental Example 4; Fig. 9 is the chromatogram of the test solution at a detector temperature of 305° C. in Experimental Example 4; Fig.10 It is the chromatogram of the test solution at a flow rate of 1.0 ml / min in Experimental Example 4. DETAILED DESCRIPTION
[0017] In order to make the technical means, creative features, objectives and effects of the present invention easy to understand, the present invention is further explained in conjunction with specific embodiments below, but the following embodiments are only preferred embodiments of the present invention, not all. Based on the embodiments in the implementation mode, other embodiments obtained by those skilled in the art without creative work are all within the protection scope of the present invention.
[0018] The experimental methods in the following examples are all conventional methods, and the materials and reagents used in the following examples are all commercially available. Potassium sulfate samples were provided by Changchun Lanjiang Pharmaceutical Technology Co., Ltd. Example 1
[0019] Specificity test 1. Solution preparation Diluent (blank solvent): ethyl acetate Dimethyl sulfate reference solution: Accurately weigh 50.32 mg of dimethyl sulfate reference, dissolve it in a diluent, and dilute it to a concentration of about 0.01 mg / ml.
[0020] Test solution: Take 1.006g potassium sulfate, weigh accurately, place in a 10ml volumetric flask, add water to dissolve and dilute to the scale, shake well, place in a separatory funnel, add 1ml ethyl acetate, extract, and take the upper layer (ethyl acetate layer) as the test solution.
[0021] Spiked test solution: Take 1.021g potassium sulfate, weigh accurately, place in a 10ml volumetric flask, add appropriate amount of water and sonicate to dissolve, dilute to the scale with water, shake well, place the above solution in a separatory funnel, add 1ml of dimethyl sulfate reference solution, shake, let stand for 2 minutes, extract, and take the upper layer (ethyl acetate layer) as the mixed solution.
[0022] 2. Gas phase test conditions Chromatographic column: DB-200 (30m×0.32mm×0.5μm); Inlet temperature: 260°C; Detector temperature: 300°C; Column temperature: initial temperature 50°C, maintain for 5 min, increase to 130°C at a rate of 10°C / min, then increase to 220°C at a rate of 20°C / min, maintain for 10 min; injection volume: 1 μl; column flow rate: 1.2 ml / min; separation ratio: 5:1.
[0023] Take the blank solvent, test solution, spiked test solution, and dimethyl sulfate reference solution and inject them into the gas chromatograph respectively, test according to the above gas phase test conditions, and record the chromatogram and data.
[0024] The chromatogram of the measured dimethyl sulfate reference solution is as follows: Figure 1 The chromatogram of the test solution is shown in Figure 2 The chromatogram of the spiked test solution is shown in Figure 3 The specific spectrum data can be seen in Table 1.
[0025] Table 1
[0026] Note: “—” indicates not applicable from Figure 1~2 As can be seen from the data in Table 1, the blank solvent does not interfere with the detection of impurities and the method has good specificity. Example 2
[0027] Detection limit test 1. Solution preparation Diluent (blank solvent): ethyl acetate According to the preparation method in Example 1, a dimethyl sulfate reference solution was prepared.
[0028] Detection limit solution: Take 1 ml of dimethyl sulfate reference solution, place it in a 20 ml volumetric flask, dilute to the mark with diluent, shake well, accurately measure 3 ml, place it in a 10 ml volumetric flask, dilute to the mark with diluent, shake well.
[0029] The gas chromatography conditions in this example are the same as those in Example 1.
[0030] The chromatogram of the detection limit solution is shown in Figure 4 The specific results are shown in Table 2.
[0031] Table 2 Detection limit test results
[0032] According to the standard requirements: calculated by the external standard method, dimethyl sulfate shall not exceed 0.002%.
[0033] From the spectrum Figure 3 From the results in Table 2, it can be seen that the signal-to-noise ratio of the detection limit of dimethyl sulfate meets the requirements and can reach the detection limit required by the standard. Example 3
[0034] Repeatability test Diluent (blank solvent): ethyl acetate According to the preparation method in Example 1, a dimethyl sulfate reference solution was prepared.
[0035] Mixed solution: Test sample spiked solution: Take 1.021g of this product, weigh accurately, place in a 10ml volumetric flask, add appropriate amount of water and ultrasonically dissolve, dilute to scale with water, shake well, place the above solution in a separatory funnel, add 1ml of dimethyl sulfate reference solution, shake, let stand for 2 minutes, extract, and take the upper layer (ethyl acetate layer) as the mixed solution. (Prepare 6 copies in parallel).
[0036] The reference solution and the mixed solution were taken and tested according to the chromatographic conditions in Example 1. The chromatograms were recorded. The results are shown in Table 3.
[0037] Table 3 Repeatability test results
[0038] It can be seen from the data in Table 3 that the RSD value of dimethyl sulfate content is 2.190%, which is less than 10%, meeting the requirements and the method has good repeatability. Example 4
[0039] Durability test Solution preparation: blank solvent and mixed solution are the same as in Example 3.
[0040] Detection: Take blank solvent and mixed solution and test them under different durable chromatographic conditions (chromatographic condition adjustment can be seen in Table 4). The chromatogram is as follows Figures 5 to 10 , the results are shown in Table 5.
[0041] Table 4 Durability test conditions
[0042] Table 5 Durability test results
[0043] Note: “—” indicates not applicable.
[0044] It can be seen from the results in Table 5 that under different durability conditions, the RSD of the detected amount of each impurity in the mixed solution is less than 10%, which meets the standard requirements. When the chromatographic conditions change slightly, it basically does not affect the determination result of the dimethyl sulfate content of this product. The method of the present invention has good durability. Example 5
[0045] 1. Solution preparation Diluent (blank solvent): ethyl acetate Dimethyl sulfate reference solution: Accurately weigh 48.35 mg of dimethyl sulfate reference, dissolve it in a diluent, and dilute it to a concentration of about 0.01 mg / ml.
[0046] Spiked test solution: Take 1.013g potassium sulfate, weigh accurately, place in a 10ml volumetric flask, add appropriate amount of water and sonicate to dissolve, dilute with water to the scale, shake well, place the above solution in a separatory funnel, add 1ml of dimethyl sulfate reference solution, shake, let stand for 2 minutes, extract, and take the upper layer (ethyl acetate layer) as the mixed solution.
[0047] 2. Chromatographic conditions Chromatographic column: HP-5 (30m×0.32mm×0.5μm); Inlet temperature: 260°C; Detector temperature: 300°C; Column temperature: initial temperature 50°C, maintain for 5 min, increase to 130°C at a rate of 10°C / min, then increase to 220°C at a rate of 20°C / min, maintain for 10 min; injection volume: 1 μl; column flow rate: 1.2 ml / min; separation ratio: 5:1.
[0048] The test spectrum of the spiked test solution is as follows: Figure 5 As shown, the content of dimethyl sulfate calculated by the external standard method is 0.0021%, indicating that the quantitative detection of dimethyl sulfate can be achieved.
Claims
1. A method for analyzing dimethyl sulfate in potassium sulfate, characterized in that: The method uses gas chromatography, and the chromatographic conditions are as follows: The chromatographic column is a capillary column with a non-polar stationary phase; The column temperature was controlled as follows: the starting temperature was 40~60℃, the holding time was 2min~5min, the temperature was increased to 120~140℃ at a rate of 5℃~20℃ / min, and then the temperature was increased to 230~280℃ at a rate of 15℃~25℃ / min, and maintained for 5min~15min; The injection port temperature is 240℃~280℃; the detector temperature is 250℃~350℃.
2. The analysis method according to claim 1, characterized in that In the chromatographic conditions, the separation ratio is 4-6:1 and the column flow rate is 1.0-2.0 ml / min.
3. The analysis method according to claim 1, characterized in that The capillary column of the non-polar stationary phase is DB-200 or other chromatographic columns with equivalent performance, and the detector is a FID detector.
4. The analysis method according to any one of claims 1 to 3, characterized in that The analysis method specifically comprises the following steps: S1: Weigh about 1.0g of this product accurately, place it in a 10ml volumetric flask, add water to dissolve and dilute to the scale, shake well, place it in a separatory funnel, add 1ml of solvent, extract, and take the upper layer as the test solution; S2: dissolving the dimethyl sulfate reference substance with a solvent and diluting it to a set concentration to obtain a reference substance solution; S3: Inject the test solution in step S1 and the reference solution in step S2 into the gas chromatograph respectively, perform the test according to the set chromatographic conditions, and record the chromatogram and chromatographic data.
5. The analysis method according to claim 4, characterized in that The solvents in step S1 and step S2 are both ethyl acetate.
6. The analysis method according to claim 4, characterized in that In step S3, the content of dimethyl sulfate is calculated using an external standard method according to the recorded chromatogram and chromatographic data.