Method for detecting glycidol in iohexol

Abstract

The invention discloses a method for detecting glycidol in iohexol, and relates to the technical field of pharmaceutical analysis. According to the method, the content of glycidol in iohexol is detected by adopting a GC-MS method, and trace residual glycidol in iohexol can be accurately determined by optimizing gas chromatography conditions and mass spectrometry conditions. The detection method provided by the invention has the advantages of high sensitivity, good repeatability and accurate result.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical analysis technology, and more specifically, to a method for detecting glycidol in iohexol. Background Technology

[0002] Iohexol, as a non-ionic X-CT contrast agent, has lower toxicity, permeability, and electrical properties than ionic contrast agents. This characteristic has led to its widespread clinical use in imaging of key areas of the body, such as the brain, chest, and cardiovascular system. The synthesis process of iohexol is as follows: Iohexol hydrolysate (CAS No.: 31127-80-7) undergoes an alkylation reaction with 3-chloro-1,2-propanediol in a sodium methoxide methanol solution under stirring at room temperature to generate the target iohexol compound. Following desalting, resin purification, crystallization, decolorization, and spray drying, the final iohexol product is obtained.

[0003] ; Iohexol, the target compound, was prepared by alkylation of 3-chloro-1,2-propanediol under alkaline conditions. Since 3-chloro-1,2-propanediol undergoes a deHCl cyclization reaction under alkaline conditions to generate glycidol, glycidol is a byproduct in the iohexol synthesis process. The mechanism is as follows: Under alkaline conditions (such as NaOH, sodium methoxide, etc.), the hydroxyl group of 3-chloro-1,2-propanediol is deprotonated to generate an oxygen anion (O⁻). Subsequently, the oxygen anion attacks the neighboring β-carbon atom, while the chlorine atom is removed as a leaving group to form glycidol.

[0004] Chemical equation: ; C3H7ClO2+NaOH→C3H6O2+NaCl+H2O; Glycidol is readily soluble in water and alcohols, and readily undergoes ring-opening under acidic and alkaline conditions. Under acidic conditions, glycidol reacts with HCl to produce 3-chloro-1,2-propanediol. In water or an alkaline environment containing water, the epoxy group of glycidol readily undergoes hydrolysis with sodium hydroxide to produce propylene glycol (1,3-propanediol or glycerol).

[0005] Glycidol is a byproduct of the synthesis of iohexol. On October 27, 2017, the International Agency for Research on Cancer (IARC) of the World Health Organization published a preliminary list of carcinogens, classifying glycidol as a Group 2A carcinogen. Therefore, whether the reactants and intermediates used in the synthesis of iohexol are carcinogenic, and whether these substances remain in the iohexol, is of significant practical importance.

[0006] However, there is currently no reported method for determining glycidol in iohexol, and there is an urgent need to develop a test method with high sensitivity, good repeatability, and high accuracy for the determination of glycidol in iohexol.

[0007] In view of this, the present invention is proposed. Summary of the Invention

[0008] The purpose of this invention is to provide a method for detecting glycidol in iohexol, aiming to provide a highly sensitive, repeatable, and accurate test method for determining the content of glycidol in iohexol.

[0009] This invention is implemented as follows: In a first aspect, the present invention provides a method for detecting glycidol in iohexol, comprising: detecting the content of glycidol in iohexol using GC-MS; Gas chromatography conditions included: using a VF-WAXms column, controlling the injection port temperature at 165℃-175℃, the injection volume at 0.8μL-1.2μL, the flow rate at 0.8mL / min-1.2mL / min, the split ratio at (4.8-5.2):1, and the control mode at constant flow rate; The mass spectrometry ion source parameters in the mass spectrometry conditions include: acquisition type MRM, ion source EI, solvent delay 3.2 min-3.8 min, transfer line temperature 228℃-232℃, quadrupole temperature 148℃-152℃, and ion source temperature 248℃-252℃. The impurity scanning parameters in the mass spectrometry conditions include: parent ion 43.8 m / z - 44.2 m / z, daughter ion 42.8 m / z - 43.2 m / z, residence time 98 ms - 102 ms, and collision energy 9.8 eV - 10.2 eV.

[0010] In an optional implementation, the chromatographic column has dimensions of 30m × 0.25mm × 0.25μm.

[0011] In an optional implementation, the gas chromatography conditions further include using helium as a carrier gas.

[0012] In an optional embodiment, the gas chromatography conditions further include: using a gradient heating method, controlling the initial temperature at 48℃-52℃, and then heating to 235℃-245℃ at a heating rate of 8℃ / min-12℃ / min, and holding for 1.5min-2.5min.

[0013] In an optional embodiment, the quadrupole includes quadrupole 1 and quadrupole 2, with quadrupole 1 having a temperature of 145°C-155°C and quadrupole 2 having a temperature of 145°C-155°C.

[0014] In an optional implementation, it includes: Dilute the glycidol reference standard to obtain the reference standard stock solution; Iohexol raw material and solvent were mixed to obtain the test solution; The glycidol reference stock solution was diluted to prepare glycidol reference stock solutions of different concentrations. The peak area of ​​glycidol in the glycidol reference stock solution was obtained by GC-MS. The peak area of ​​glycidol in the glycidol reference stock solution was fitted with the concentration of the glycidol reference stock solution to obtain the standard curve. The peak area of ​​glycidol in the test solution was obtained by GC-MS, and the content of glycidol in the test solution was calculated by the standard curve method.

[0015] In an optional embodiment, the preparation process of the test solution includes: mixing iohexol raw material and solvent, sonicating for 5 min-20 min, cooling and weighing, replenishing the weight with solvent, centrifuging and taking the supernatant, and filtering.

[0016] In an optional embodiment, the reference standard stock solution is obtained after multiple dilutions.

[0017] In an optional implementation, the concentration range of the glycidol reference standard stock solution is 19 ng / mL to 200 ng / mL.

[0018] In an optional embodiment, the solvent used to prepare the test solution and the solvent used to dilute the glycidol reference standard are both acetonitrile.

[0019] The present invention has the following beneficial effects: It employs GC-MS to detect the content of glycidol in iohexol. By optimizing the gas chromatography and mass spectrometry conditions, trace amounts of residual glycidol in iohexol can be accurately determined. The detection method provided by the present invention has the advantages of high sensitivity, good repeatability, and accurate results. Attached Figure Description

[0020] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0021] Figure 1 This is a test graph for a blank solution; Figure 2 This is a test diagram of the sample solution; Figure 3 This is a test graph for a 100% limit concentration reference solution; Figure 4 The test diagram shows the spiked sample solution at 100% limit concentration. Figure 5 This is a standard curve graph. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0023] After long-term research, the inventors developed a method for accurately determining trace amounts of glycidol residues in iohexol, as detailed below: This invention provides a method for detecting glycidol in iohexol. The method uses GC-MS to detect the glycidol content in iohexol. To achieve better detection results, the inventors optimized the chromatographic and mass spectrometric conditions. [Chromatographic conditions] A VF-WAXms column was used, with dimensions of 30m × 0.25mm × 0.25μm, meaning the column length is 30m, the inner diameter is 0.25mm, and the film thickness is 0.25μm. The VF-WAXms column is a polar stationary phase gas chromatography column, and using this type of column can further improve the accuracy of glycidol detection.

[0024] Helium was used as the carrier gas, with the inlet temperature controlled at 165℃-175℃, the injection volume at 0.8μL-1.2μL, the flow rate at 0.8mL / min-1.2mL / min, and the split ratio at (4.8-5.2):1. The control mode was constant flow. Optimizing the injection conditions and split ratio improved the separation effect and further enhanced the accuracy of the detection.

[0025] Specifically, the injection port temperature can be 165℃, 168℃, 170℃, 173℃, 175℃, etc.; the injection volume can be 0.8μL, 1.0μL, 1.2μL, etc.; the flow rate can be 0.8mL / min, 1.0mL / min, 1.2mL / min, etc.; and the split ratio can be 4.8:1, 5.0:1, 5.2:1, etc.

[0026] In some embodiments, the gas chromatography conditions further include: employing a gradient temperature increase method, controlling the initial temperature at 48℃-52℃, and then increasing the temperature to 235℃-245℃ at a rate of 8℃ / min-12℃ / min, holding for 1.5min-2.5min. Specifically, the initial temperature can be 48℃, 50℃, 52℃, etc.; the heating rate can be 8℃ / min, 10℃ / min, 12℃ / min, etc.; the temperature after heating can be 235℃, 238℃, 240℃, 242℃, 245℃, etc.; and the holding time can be 1.5min, 2.0min, 2.5min, etc. Preferably, the gradient temperature increase method is as shown in Table 1, controlling the initial temperature at 50℃, and then increasing the temperature to 240℃ at a rate of 10℃ / min, holding for 2.0min.

[0027] Table 1 Gradient heating method

[0028] [Mass Spectrometry Conditions] Mass spectrometry conditions include mass spectrometry ion source parameters and impurity scan parameters: The mass spectrometry ion source parameters in the mass spectrometry conditions include: acquisition type MRM, ion source EI, solvent delay 3.2 min-3.8 min (e.g., 3.2 min, 3.5 min, 3.8 min, etc.); transfer line temperature 228℃-232℃ (e.g., 228℃, 230℃, 232℃, etc.); quadrupole temperature 148℃-152℃ (e.g., 148℃, 150℃, 152℃, etc.); ion source temperature 248℃-252℃ (e.g., 248℃, 250℃, 252℃, etc.). The quadrupole includes quadrupole 1 and quadrupole 2. Quadrupole 1 has a temperature of 145℃-155℃, and quadrupole 2 has a temperature of 145℃-155℃. The temperatures of quadrupole 1 and quadrupole 2 can be the same or different, and can be independently set to 148℃, 150℃, 152℃, etc.

[0029] The impurity scanning parameters in the mass spectrometry conditions include: parent ion 43.8 m / z - 44.2 m / z, such as 43.8 m / z, 43.9 m / z, 44.0 m / z, 44.1 m / z, 44.2 m / z, etc.; daughter ion 42.8 m / z - 43.2 m / z, such as 42.8 m / z, 42.9 m / z, 43.0 m / z, 43.1 m / z, 43.2 m / z, etc.; residence time 98 ms - 102 ms, such as 98 ms, 99 ms, 100 ms, 101 ms, 102 ms, etc.; collision energy 9.8 eV - 10.2 eV, such as 9.8 eV, 9.9 eV, 10.0 eV, 10.1 eV, 10.2 eV, etc.

[0030] It should be noted that the inventors achieved the goal of accurately detecting glycidol in iohexol by optimizing chromatographic and mass spectrometric conditions. The above chromatographic and mass spectrometric conditions are a whole scheme, and the parameters are an organic whole that works together.

[0031] [Analysis Steps] S1. Preparation of the test solution Take iohexol raw material and solvent, mix them evenly to obtain the test solution. The type of solvent is not limited, but acetonitrile is preferred.

[0032] In some embodiments, the iohexol raw material is weighed quantitatively and accurately. The raw material is placed in a centrifuge tube and a solvent (such as acetonitrile) is added. The mixture is ultrasonically treated for 5 min to 20 min (e.g., 5 min, 10 min, 15 min, 20 min, etc.). After cooling, the mixture is weighed again and the weight is reduced by adding solvent. After centrifugation, the supernatant is collected and filtered.

[0033] S2. Preparation of reference standard stock solution The glycidol reference standard and solvent are mixed and diluted to obtain the reference standard stock solution. The type of solvent is not limited, but acetonitrile is preferred.

[0034] In some embodiments, the reference standard stock solution is obtained by multiple dilutions, such as three dilutions, to gradually dilute the reference standard stock solution to obtain a concentration that meets the requirements.

[0035] S3. Draw the standard curve Different concentrations of glycidol reference stock solutions were prepared by diluting the stock solution. The peak area of ​​glycidol in the stock solution was obtained by GC-MS, and the peak area was fitted to the concentration of the stock solution to obtain a standard curve.

[0036] In some embodiments, the concentration range of glycidol reference stock solutions of different concentrations is 19 ng / mL to 200 ng / mL. By preparing glycidol reference stock solutions that conform to this concentration range, multiple groups of glycidol reference stock solutions have a certain concentration gradient, which makes the obtained standard curve more ideal and helps to improve the detection accuracy.

[0037] S4, Quantitative Analysis The peak area of ​​glycidol in the test solution was obtained by GC-MS, and the content of glycidol in the test solution was calculated by the standard curve method. The test conditions were the same as those described above for chromatographic and mass spectrometric conditions.

[0038] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0039] Reagents used: Iohexol, purchased from Jiangxi Brothers Pharmaceutical Co., Ltd.; glycidol standard, purchased from MACKLIN; blank solution, acetonitrile, purity greater than 99.9%.

[0040] Example 1 (1) GC-MS detection conditions Chromatographic conditions: VF-WAXms column (30m×0.25mm, 0.25μm); carrier gas: He; injection port temperature: 170℃; flow rate: 1.00mL / min; injection volume: 1 μL; split mode: split; split ratio: 5:1; control mode: constant flow rate; injection volume: 20μl; gradient temperature was performed according to Table 1.

[0041] The parameters of the mass spectrometry ion source are shown in Table 2: Table 2 Mass spectrometry ion source parameters

[0042] Impurity scanning parameters are shown in Table 3: Table 3 Impurity Scanning Parameters

[0043] (2) Preparation of test solution Weigh approximately 0.2 g of iohexol accurately and place it in a 10 mL centrifuge tube. Accurately add 2 mL of acetonitrile, weigh the tube, sonicate for 10 min, cool, weigh again, replenish the lost weight with acetonitrile, shake well, centrifuge, and filter the supernatant through a 0.22 μm filter membrane.

[0044] (3) Reference stock solution Reference stock solution I: Weigh 23.02 mg of glycidol reference standard accurately, place it in a 20 mL volumetric flask, add acetonitrile to dissolve and dilute to the mark, and shake well.

[0045] Reference stock solution II: Accurately transfer 0.1 mL of the reference stock solution into a 10 mL volumetric flask, dilute to the mark with acetonitrile, and shake well to obtain reference stock solution II.

[0046] Reference stock solution III: Accurately transfer 1.9 mL of reference stock solution II into a 10 mL volumetric flask, dilute to the mark with acetonitrile, and shake well to obtain reference stock solution III.

[0047] (4) Standard curve solution Accurately measure appropriate amounts of the reference stock solution III into different volumetric flasks, dilute to the mark with acetonitrile, and shake well to obtain a series of standard curve solutions with different concentrations.

[0048] Table 4 Standard Curve Solutions of Different Concentrations

[0049] Using the standard curve method, the content of glycidol must not exceed 1 ppm.

[0050] Standard curve such as Figure 5 As shown.

[0051] Establishment and validation of a method for the determination of glycidol (a) System suitability solution Use the "100% limit concentration reference solution (STD4 solution)" under the "Standard Curve Solution" section, and perform six consecutive injections for analysis. Use the system suitability solution for analysis, performing six consecutive injections to assess instrument precision. The RSD (n=6) of the target peak area in the six consecutive injections of the system suitability solution should not exceed 10%, and the RSD of the retention time should not exceed 1%. The results of the system suitability solution measurements are shown in Table 5.

[0052] Table 5 System Applicability Results

[0053] The results showed that for six consecutive injections of the system suitability solution, the RSDs (n=6) for the peak area and retention time of glycidol were 0.7% and 0.1%, respectively, indicating that the system suitability met the requirements.

[0054] (b) Linearity and Range The standard curve solution under the "Standard Curve" item was used for measurement. The correlation coefficient r of the linear regression equation should be ≥0.990, and the ratio of the absolute value of the y-axis intercept to the 100% limit concentration response value should not exceed 20%. The results of the linear solution measurement are shown in Tables 6 and 7.

[0055] Table 6 Linear Results

[0056] Table 7 Linearity and Range Results

[0057] The results showed that glycidol in the range of 19.99 ng / mL to 199.93 ng / mL, which is approximately 20% to 200% of the limit concentration, exhibited good linearity between the peak area and concentration, with a correlation coefficient r of 0.9993. The ratio of the absolute value of the y-axis intercept to the response value at 100% limit concentration was 0.6%, and the linearity results met the requirements.

[0058] (c) Accuracy solution Test solution: Prepare two parallel portions according to the same method as under the "Test Solution" section; 50% limit concentration spiked test solution: Weigh approximately 0.2 g of iohexol sample accurately, place it in a 10 mL centrifuge tube, accurately add 0.05 mL of reference stock solution III, then add 1.95 mL of acetonitrile, weigh, sonicate for 10 min, cool, weigh again, replenish the lost weight with acetonitrile, shake well, centrifuge, and filter the supernatant through a 0.22 μm filter membrane. Prepare 3 aliquots using the same method. 100% limit concentration spiked test solution: Weigh approximately 0.2 g of iohexol sample accurately, place it in a 10 mL centrifuge tube, accurately add 0.10 mL of reference stock solution III, then add 1.90 mL of acetonitrile, weigh, sonicate for 10 min, cool, weigh again, replenish the lost weight with acetonitrile, shake well, centrifuge, and filter the supernatant through a 0.22 μm filter membrane. Prepare 3 aliquots using the same method. 150% limit concentration spiked test solution: Weigh approximately 0.2 g of iohexol sample accurately and place it in a 10 mL centrifuge tube. Accurately add 0.15 mL of reference stock solution III, then add 1.85 mL of acetonitrile. Weigh the solution, sonicate for 10 min, cool, and weigh again. Make up the weight loss with acetonitrile, shake well, centrifuge, and filter the supernatant through a 0.22 μm filter membrane. Prepare three aliquots using the same method. Results are detailed in Table 8.

[0059] Table 8 Accuracy Results

[0060] The results showed that the recovery rate of glycidol in the nine spiked test solutions at 50%, 100% and 150% limit concentrations ranged from 82.6% to 92.5%, with an RSD (n=9) of 3.7%, and the accuracy results met the requirements.

[0061] (d) Specific solutions Blank solvent: Take a blank solution.

[0062] Test solution: Take the test solution.

[0063] 100% limit concentration reference solution: Take the "100% limit concentration reference solution (STD4 solution)" from the "Standard Curve" section; 100% limit concentration spiked test solution: Take the "100% limit concentration spiked test solution" under the "Accuracy Solution" section; In the chromatogram of the test solution, the resolution between the target peak and adjacent peaks should be greater than 1.5; the chromatogram of the 100% limit concentration reference solution should show the target peak; in the chromatogram of the 100% limit concentration spiked test solution, the resolution between the target peak and all adjacent peaks greater than LOQ should be greater than 1.5. Specificity test results for each solution are shown below. Figures 1-4 .

[0064] (e) Stable solutions Test solution: Take the solution from the "Test solution" section; 100% limit concentration reference solution: Take the "100% limit concentration reference solution (STD4 solution)" from the "Standard Curve" section; 100% limit concentration spiked test solution: Take the "100% limit concentration spiked test solution" under the "Accuracy Solution" section; The above solutions were incubated at room temperature for different time periods and then injected once for testing.

[0065] The results showed that the target compound was not detected in any of the test solutions after being placed at room temperature for 36.5 h; (2) within 14.5 h, the ratio of the detection concentration of glycidol in the 100% limit concentration reference solution to the initial (0 h) detection concentration was between 89.3% and 103.2%; within 14.5 h, the ratio of the detection concentration of glycidol in the 100% limit concentration spiked test solution to the initial (0 h) detection concentration was between 93.1% and 100.2%; therefore, the test solutions, 100% limit concentration reference solutions, and 100% limit concentration spiked test solutions were stable after being placed at room temperature for at least 14.5 h. The results are detailed in Table 9.

[0066] Table 9 Stability Results

[0067] (f) Precision Repeatability: Take 2 aliquots of the test solution and 6 aliquots of the 100% limit concentration spiked test solution for determination, record the chromatograms, and the recovery rate of the target compound in the 6 aliquots of the 100% limit concentration spiked test solution should be between 75% and 120%, and the RSD of the recovery rate (n=6) should not be greater than 10%. The results of the repeatability test are shown in Table 10.

[0068] Table 10 Repeatability Results

[0069] The results showed that the recovery rate of glycidol in the six 100% limit concentration spiked test solutions ranged from 83.6% to 90.7%, and the RSD of the recovery rate (n=6) was 3.7%, indicating that the method had good repeatability.

[0070] Intermediate precision: Take 2 aliquots of the test solution and 6 aliquots of the 100% limit concentration spiked test solution for determination, record the chromatograms. The recovery rate of the target compound in the 6 aliquots of the 100% limit concentration spiked test solution of experimenter 2 should be between 75% and 120%, and the RSD of the recovery rate (n=6) should not be greater than 10%. The RSD of the recovery rate of the target compound in the 12 aliquots of the 100% limit concentration spiked test solution of the two experimenters should not be greater than 15%. The results of the intermediate precision solution determination are shown in Table 11.

[0071] Table 11 Intermediate Precision Results

[0072] (g) Durable solution Blank solvent: Take a blank solution; System suitability solution: Take the "100% limit concentration reference solution (STD4 solution)" under the "Standard Curve" section; Standard curve solution: Take the standard curve solutions "STD1" to "STD6" under the "Standard Curve" section; Test solution: The solution under the "Test Solution" section; 100% limit concentration spiked test solution: Take the "100% limit concentration spiked test solution" under the "Accuracy Solution" section; The above solutions were sequentially injected and analyzed under different durability conditions.

[0073] The column temperature was varied between 45℃ and 55℃, and the flow rate was varied between 0.9 mL / min and 1.1 mL / min. Robustness solutions were injected and analyzed, chromatograms were recorded, and the recovery rate of the target compound in the 100% limit concentration spiked test solution was calculated. Under each robustness condition, the system suitability met the acceptance criteria; the correlation coefficient of the standard curve was ≥0.990; the detection results of the target compound in the test solution should be consistent with the standard conditions (all values ​​should be less than the limit of quantitation, or, if not less than the limit of quantitation, the rate of change compared with the standard conditions should not exceed 30%); the recovery rate of the target compound in the 100% limit concentration spiked test solution should be between 75% and 120%. Robustness test results are shown in Tables 12 to 14.

[0074] Table 12 System Suitability Results under Durability Conditions - Peak Area

[0075] Table 13 System Suitability Results under Durability Conditions - Retention Time

[0076] Table 14 Linear Results under Durability Conditions

[0077] (h) Detection limit solution Accurately measure 0.05 mL of the reference stock solution III into a 10 mL volumetric flask, dilute to the mark with acetonitrile, and mix well. See Table 15 for details.

[0078] Table 15 Detection Limit Solutions

[0079] Comparative Example 1 The inventors explored a GC-MS detection method using methanol as a blank solution. Adaptability adjustments were made to the test solution, 100% limit concentration reference solution, and detection line solution, with other test conditions similar to Example 1. Results showed that the target peak was not detected in the blank solution chromatogram, indicating no interference with detection; the signal-to-noise ratio of the target peak in the detection limit solution chromatogram was less than 3; the target peak was not detected in the test solution chromatogram, and the resolution between the target peak and adjacent peaks was greater than 1.5; the target peak was displayed in the 100% limit concentration reference solution chromatogram. However, this method allows high-boiling-point API to enter the chromatographic column after multiple injections, causing column blockage; therefore, the pretreatment method needs optimization.

[0080] Comparative Example 2 Based on Comparative Example 1, the inventors attempted to concentrate the solution using an extraction method. The steps for preparing the system suitability solution are as follows: After preparing reference stock solution III using methanol as a blank solution, 0.1 mL of reference stock solution III was taken into a 10 mL volumetric flask, diluted to the mark with water, and three portions were prepared. Each portion was then subjected to vortex extraction with 2 mL of cyclohexane, 2 mL of toluene, and 2 mL of ethyl acetate, respectively. Other test conditions were similar to those in Example 1. The results showed that, based on a limit of 0.026 ppm, the 100% limit concentration reference solution obtained by extraction had a very low response. The ethyl acetate extraction rate was between 1.8% and 18.5%, indicating a very poor extraction effect that could not meet the recovery requirements. Therefore, this method does not meet the requirements.

[0081] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for detecting glycidol in iohexol, characterized in that, include: The content of glycidol in iohexol was determined by GC-MS. Gas chromatography conditions included: using a VF-WAXms column, controlling the injection port temperature at 165℃-175℃, the injection volume at 0.8μL-1.2μL, the flow rate at 0.8mL / min-1.2mL / min, the split ratio at (4.8-5.2):1, and the control mode at constant flow rate; The mass spectrometry ion source parameters in the mass spectrometry conditions include: acquisition type MRM, ion source EI, solvent delay 3.2 min-3.8 min, transfer line temperature 228℃-232℃, quadrupole temperature 148℃-152℃, and ion source temperature 248℃-252℃. The impurity scanning parameters in the mass spectrometry conditions include: parent ion 43.8 m / z - 44.2 m / z, daughter ion 42.8 m / z - 43.2 m / z, residence time 98 ms - 102 ms, and collision energy 9.8 eV - 10.2 eV.

2. The detection method according to claim 1, characterized in that, The chromatographic column has a specification of 30m × 0.25mm × 0.25μm.

3. The detection method according to claim 1, characterized in that, Gas chromatography conditions also include using helium as a carrier gas.

4. The detection method according to claim 1, characterized in that, Gas chromatography conditions also include: using a gradient temperature increase method, controlling the initial temperature at 48℃-52℃, and then increasing the temperature to 235℃-245℃ at a rate of 8℃ / min-12℃ / min, and holding for 1.5min-2.5min.

5. The detection method according to claim 1, characterized in that, The quadrupole includes quadrupole 1 and quadrupole 2. The temperature of quadrupole 1 is 145℃-155℃, and the temperature of quadrupole 2 is 145℃-155℃.

6. The detection method according to claim 1, characterized in that, include: Dilute the glycidol reference standard to obtain the reference standard stock solution; Iohexol raw material and solvent were mixed to obtain the test solution; The reference stock solution was diluted to prepare glycidol reference stock solutions of different concentrations. The peak area of ​​glycidol in the glycidol reference stock solution was obtained by GC-MS. The peak area of ​​glycidol in the glycidol reference stock solution was fitted with the concentration of the glycidol reference stock solution to obtain a standard curve. The peak area of ​​glycidol in the test solution was obtained by GC-MS, and the content of glycidol in the test solution was calculated by the standard curve method.

7. The detection method according to claim 6, characterized in that, The preparation process of the test solution includes: mixing iohexol raw material and solvent, sonicating for 5 min-20 min, cooling and weighing, replenishing the weight with solvent, centrifuging and taking the supernatant, and filtering.

8. The detection method according to claim 6, characterized in that, The reference standard stock solution was obtained after multiple dilutions.

9. The detection method according to claim 8, characterized in that, The concentration range of glycidol reference stock solutions at different concentrations is 19 ng / mL to 200 ng / mL.

10. The detection method according to claim 6, characterized in that, The solvent used to prepare the test solution and the solvent used to dilute the glycidol reference standard are both acetonitrile.

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