Method for detecting residues of 1, 3-dichloro-2-propanol, 2, 3-dichloro-1-propanol and 3-chloro-1, 2-propylene glycol in dihydroxypropyl theophylline

Abstract

The invention belongs to the technical field of chemical component detection, and particularly relates to a method for detecting residues of 1, 3-dichloro-2-propanol, 2, 3-dichloro-1-propanol and 3-chloro-1, 2-propylene glycol in dihydroxypropyl theophylline. The detection method comprises the following steps: (1) adding a solvent into diprophylline for dilution, and uniformly shaking to prepare a test solution; (2) detecting the liquid to be detected by adopting a gas chromatography-tandem mass spectrometry method, and calculating the content of 1, 3-dichloro-2-propanol, the content of 2, 3-dichloro-1-propanol and the content of 3-chloro-1, 2-propylene glycol in the diprophylline according to an external standard method; the solvent is a mixture of formic acid and DMF (Dimethyl Formamide). The method provided by the invention is good in specificity, high in sensitivity, good in repeatability and high in accuracy, and can be used for simultaneously detecting 1, 3-dichloro-2-propanol, 2, 3-dichloro-1-propanol and 3-chloro-1, 2-propylene glycol in the diprophylline.

Description

Technical Field

[0001] This invention belongs to the field of chemical component detection technology, specifically relating to a method for detecting residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline. Background Technology

[0002] Dihydroxypropyltheophylline belongs to the theophylline class of drugs and is mainly used as a smooth muscle relaxant. It dilates the bronchi and coronary arteries and has a diuretic effect. It is stable in gastric juice and its bronchodilatory effect is similar to that of aminophylline, making it particularly suitable for patients with tachycardia. 3-Chloro-1,2-propanediol is a reactant of the intermediate in this drug and is present in trace amounts in dihydroxypropyltheophylline. It may also generate 1,3-dichloro-2-propanol and 2,3-dichloro-1-propanol impurities. These impurities in dihydroxypropyltheophylline are considered genotoxic impurities and have a genotoxic impurity warning structure. According to relevant studies, 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol are considered to have potential genotoxicity and may have adverse effects on human health; therefore, monitoring their content in the drug is necessary.

[0003] There are few reports on the detection of chloropropanol in dihydroxypropyltheophylline in existing technologies. Li Runyan et al. published "Determination of Trace 3-chloro-1,2-propanediol in Dihydroxypropyltheophylline by Solid Phase Extraction-Gas Chromatography-Mass Spectrometry" in the journal Pharmaceutical Analysis. In this technical scheme, the sample is extracted with saturated sodium chloride, separated and purified by Florisil chromatography, concentrated by rotary evaporation, derivatized with trifluoroacetic anhydride, and then detected by gas chromatography-mass spectrometry. However, the derivatization process of this technical scheme is complicated and can only detect 3-chloro-1,2-propanediol.

[0004] There is no existing method for simultaneously detecting the residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxytheophylline. Therefore, there is an urgent need to establish a method that is highly sensitive, specific, and accurate and can simultaneously determine the residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxytheophylline. Summary of the Invention

[0005] The present invention aims to solve one or more technical problems existing in the prior art, and at least provide a beneficial solution. Specifically, the present invention provides a method for detecting residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline. The method provided by the present invention has good specificity, high sensitivity, good repeatability, and high accuracy, and can simultaneously detect 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: A method for detecting residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline, comprising the following steps: (1) Dilute dihydroxypropyltheophylline with solvent, shake well, and prepare a test solution; (2) Gas chromatography-tandem mass spectrometry was used to detect the test solution, and the contents of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline were calculated by external standard method. The solvent is a mixture of formic acid and DMF (N,N-dimethylformamide).

[0007] Furthermore, the dihydroxypropyltheophylline includes dihydroxypropyltheophylline active pharmaceutical ingredient and / or preparation.

[0008] Furthermore, the volume ratio of formic acid to DMF is 0.5-1.5:1000.

[0009] Furthermore, the volume ratio of formic acid to DMF is 1:1000.

[0010] Furthermore, the concentration of dihydroxypropyltheophylline in the test solution is 5 mg / mL.

[0011] Furthermore, the gas chromatographic column uses polyethylene glycol as the stationary phase.

[0012] Furthermore, the column temperature of the gas chromatograph is as follows: the initial temperature is 50-70℃, held for 1-3 minutes, and then increased to 240-260℃ at a heating rate of 5-15℃ / min, held for 3-5 minutes.

[0013] Furthermore, the gas chromatography conditions are as follows: injection port temperature is 230-250℃; column flow rate is 0.5-1.5mL / min; injection volume is 0.8-1.2μL.

[0014] Furthermore, the conditions for the gas chromatography are as follows: Column temperature: The initial temperature is 60℃, held for 2 min, and then increased to 250℃ at a heating rate of 10℃ / min, held for 4 min. Inlet temperature: 240℃; Carrier gas: Helium; Column flow rate: 1.0 mL / min; Injection volume: 1 μL; Split ratio: 5:1.

[0015] Furthermore, the chromatographic column is a DB-WAX, 30m × 0.25mm × 0.15μm.

[0016] Furthermore, the conditions for the mass spectrometry are as follows: Ion source: EI; Ion source temperature: 230℃; Quadrupole temperature: 150℃; Auxiliary heating chamber temperature: 260℃; Solvent delay: 9 min; Dwell time: 100ms; Testing time: 15 min MS acquisition time: 25 min; Scanning mode: SIM: The quantitative ions for 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol were 49 (m / z), 62 (m / z), and 61 (m / z), respectively. The qualitative ions of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol are 81 (m / z), 64 (m / z), and 79 (m / z), respectively.

[0017] Furthermore, step (1) also includes the preparation of the reference solution: 1,3-dichloro-2-propanol reference standard stock solution, 2,3-dichloro-1-propanol reference standard stock solution, and 3-chloro-1,2-propanediol reference standard stock solution are mixed, diluted with solvent, and shaken well to obtain the reference solution.

[0018] Furthermore, the concentrations of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in the reference solution are all 65 ng / mL.

[0019] Furthermore, the concentration of 1,3-dichloro-2-propanol in the 1,3-dichloro-2-propanol reference standard stock solution is 2.0 mg / mL.

[0020] Furthermore, the concentration of 2,3-dichloro-1-propanol in the 2,3-dichloro-1-propanol reference standard stock solution is 2.0 mg / mL.

[0021] Furthermore, the concentration of 3-chloro-1,2-propanediol in the 3-chloro-1,2-propanediol reference standard stock solution is 2.0 mg / mL.

[0022] Compared with the prior art, the present invention has the following beneficial effects: 1. This invention employs gas chromatography-tandem mass spectrometry (GC-MS) to detect 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxytheophylline. A mixture of formic acid and DMF is used as the solvent, eliminating the need for derivatization. By controlling the column type and parameters in GC, and the detector type and acquisition mode in mass spectrometry, simultaneous detection of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxytheophylline can be achieved. This invention plays a crucial role in the formulation and improvement of quality standards for dihydroxytheophylline raw materials and preparations.

[0023] 2. The detection method provided by this invention has good specificity and high sensitivity. The detection limit for 1,3-dichloro-2-propanol is 1.3 ppm and the quantitation limit is 3.9 ppm; the detection limit for 2,3-dichloro-1-propanol is 1.3 ppm and the quantitation limit is 3.8 ppm; and the detection limit for 3-chloro-1,2-propanediol is 1.3 ppm and the quantitation limit is 3.9 ppm.

[0024] 3. The detection methods provided by this invention show good linearity for 1,3-dichloro-2-propanol in the range of 19.5195 ng / mL to 130.1300 ng / mL; for 2,3-dichloro-1-propanol in the range of 19.0115 ng / mL to 126.7436 ng / mL; and for 3-chloro-1,2-propanediol in the range of 19.4163 ng / mL to 129.4419 ng / mL.

[0025] 4. The detection method provided by this invention has high accuracy. The average spiked recoveries of 1,3-dichloro-2-propanol at 50%, 100%, and 150% levels are 93.8%-104.4%, with an RSD of 4.2%. The average spiked recoveries of 2,3-dichloro-1-propanol at 50%, 100%, and 150% levels are 94.1%-98.3%, with an RSD of 1.3%. The average spiked recoveries of 3-chloro-1,2-propanediol at 50%, 100%, and 150% levels are 98.7%-110.7%, with an RSD of 3.1%.

[0026] 5. The detection method provided by the present invention also has the advantages of good repeatability, high intermediate precision, good durability and good solution stability. Attached Figure Description

[0027] Figure 1 This is the mass spectrum of a blank solution; Figure 2 This is the mass spectrum of the reference solution; Figure 3 Mass spectrum of the test sample solution; Figure 4 Mass spectrum of the spiked test solution; Figure 5 Mass spectrum of 1,3-dichloro-2-propanol localization solution; Figure 6 Mass spectrum of 2,3-dichloro-1-propanol localization solution; Figure 7 Mass spectrum of 3-chloro-1,2-propanediol localization solution; Figure 8 Mass spectrum of solution at the detection limit; Figure 9 Mass spectrum of the solution at the limit of quantitation; Figure 10 Linearity graph of 1,3-dichloro-2-propanol; Figure 11 Linearity graph of 2,3-dichloro-1-propanol; Figure 12 Linearity graph of 3-chloro-1,2-propanediol; Figure 13 The mass spectrum of the spiked test solution for Comparative Example 1 at 100% limit; Figure 14 The mass spectrum of the spiked test solution for Comparative Example 2 at 100% limit; Figure 15 The mass spectrum of the spiked test solution for Comparative Example 3 at 100% limit; Figure 16 The mass spectrum of the spiked test solution for Comparative Example 4 at 100% limit; Figure 17 Mass spectrum of the spiked test solution for Comparative Example 5 at 100% limit; Figure 18 Mass spectrum of the spiked test solution for Comparative Example 6 at 100% limit. Detailed Implementation

[0028] 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.

[0029] In the embodiments and comparative examples of this invention: 1,3-Dichloro-2-propanol reference standard source: Maclean's, batch number: C10563059; 2,3-Dichloro-1-propanol reference standard source: Maclean's, batch number: C10801332; 3-Chloro-1,2-Propanediol reference standard source: Maclean's, batch number: C10660315.

[0030] Example 1: A method for detecting residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline: (1) Solvent preparation: Mix 0.5 mL formic acid and 500 mL DMF until homogeneous; Preparation of test solution: Place 50.13 mg of dihydroxypropyltheophylline in a 10 mL volumetric flask, dilute to the mark with solvent, and shake well. (2) Gas chromatography-tandem mass spectrometry was used to detect the test solution, and the contents of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline were calculated using the external standard method. The detection conditions are shown in Table 1 below: Table 1 .

[0031] Dihydroxypropyltheophylline, sourced from Shanghai Wanxiang Pharmaceutical Co., Ltd., consisted of three batches with batch numbers 2407101, 2407102, and 2407103. The test results for these three batches are shown in Table 2 below.

[0032] Table 2 .

[0033] Specificity of Example 2: (1) Preparation of blank solution: Mix 0.5 mL formic acid and 500 mL DMF thoroughly; (2) Preparation of the test solution: Same as in Example 1; (3) Preparation of reference solution: Reference stock solution A: Accurately weigh 10.14 mg of 1,3-dichloro-2-propanol reference standard, place it in a 5 mL volumetric flask, and prepare a 2.0280 mg / mL reference stock solution A with solvent; Reference stock solution B: Accurately weigh 10.05 mg of 2,3-dichloro-1-propanol reference standard, place it in a 5 mL volumetric flask, and prepare a standard stock solution of 1.9499 mg / mL with solvent; Reference stock solution C: Accurately weigh 10.10 mg of 3-chloro-1,2-propanediol reference standard, place it in a 5 mL volumetric flask, and prepare a standard stock solution of approximately 1.9875 mg / mL with solvent; Reference stock solution: Accurately transfer 32.5 μL of reference stock solution A, 32.5 μL of solution B, and 32.5 μL of solution C1 into the same 10 mL volumetric flask, dilute to the mark with solvent, and mix well (1,3-DCP: 6.5910 μg / mL; 2,3-DCP: 6.3372 μg / mL; 3-MCPD: 6.4593 μg / mL). Reference solution: Accurately transfer 100 μL of the reference stock solution into a 10 mL volumetric flask, dilute to the mark with solvent, and shake well (1,3-DCP: 65.9100 ng / mL; 2,3-DCP: 63.3718 ng / mL; 3-MCPD: 64.5930 ng / mL). Spiked test solution: Accurately weigh 50.13 mg of dihydroxypropyltheophylline and place it in a 10 mL volumetric flask. Dissolve it in an appropriate amount of solvent. Accurately transfer 100 μL of the reference stock solution to the same volumetric flask and dilute to the mark with solvent. Shake well (1,3-DCP: 65.9100 ng / mL; 2,3-DCP: 63.3718 ng / mL; 3-MCPD: 64.5930 ng / mL). 1,3-Dichloro-2-propanol positioning solution: Accurately transfer 32.5 μL of the reference stock solution A into a 10 mL volumetric flask, dilute to the mark with solvent, and mix well; accurately transfer 100 μL of the above solution into a 10 mL volumetric flask, dilute to the mark with solvent again, and mix well. 2,3-Dichloro-1-propanol positioning solution: Accurately transfer 32.5 μL of the reference stock solution B into a 10 mL volumetric flask, dilute to the mark with solvent, and mix well; accurately transfer 100 μL of the above solution into a 10 mL volumetric flask, dilute to the mark with solvent again, and mix well. 3-Chloro-1,2-Propanediol positioning solution: Accurately transfer 32.5 μL of the reference stock solution C into a 10 mL volumetric flask, dilute to the mark with solvent, and shake well; accurately transfer 100 μL of the above solution into a 10 mL volumetric flask, dilute to the mark with solvent again, and shake well.

[0034] (4) Blank solution, reference solution, test solution, spiked test solution, 1,3-dichloro-2-propanol positioning solution, 2,3-dichloro-1-propanol positioning solution, and 3-chloro-1,2-propanediol positioning solution were tested according to the method in Example 1. The test results are shown in Table 3; the chromatograms are shown in Table 3. Figure 1-7 As shown.

[0035] Table 3 .

[0036] From Table 3 and Figure 1-7 It can be seen that neither the blank solvent nor the test solution interferes with the determination of the target peak, indicating that the method has good specificity.

[0037] Example 3: Limit of Detection and Limit of Quantification (1) Preparation of limit of detection (LOD) solution: Transfer 10 μL of the reference stock solution into a 10 mL volumetric flask, dilute to the mark with solvent, and shake well (1,3-DCP: 6.5065 ng / mL; 2,3-DCP: 6.3372 ng / mL; 3-MCPD: 6.4721 ng / mL). (2) Prepare the limit of quantity (LOQ) solution: Transfer 30 μL of the reference stock solution into a 10 mL volumetric flask, dilute to the mark with solvent, and shake well (1,3-DCP: 19.5195 ng / mL; 2,3-DCP: 19.0115 ng / mL; 3-MCPD: 19.4163 ng / mL). (3) The limit of detection solution and the limit of quantitation solution were tested according to the method in Example 1. The detection results of the limit of detection solution (3 injections) are shown in Table 4 below, and the chromatograms are as follows. Figure 8 As shown in Table 5, the detection results of the limit of quantitation solution (6 injections) are shown in the chromatogram. Figure 9 As shown.

[0038] Table 4 .

[0039] Table 5 .

[0040] As shown in Tables 4 and 5: the detection limit (LOD) of 1,3-DCP is 6.5065 ng / mL (equivalent to a sample concentration of 1.3 ppm), and the quantitation limit (LOQ) is 19.5195 ng / mL (equivalent to a sample concentration of 3.9 ppm); the LOD of 2,3-DCP is 6.3372 ng / mL (equivalent to a sample concentration of 1.3 ppm), and the LOQ is 19.0115 ng / mL (equivalent to a sample concentration of 3.8 ppm); the LOD of 3-MCPD is 6.4721 ng / mL (equivalent to a sample concentration of 1.3 ppm), and the LOQ is 19.4163 ng / mL (equivalent to a sample concentration of 3.9 ppm). The signal-to-noise ratio (SNR) and peak area RSD both meet the requirements.

[0041] Example 4 Linear Range: Prepare a series of linear test solutions from LOQ to 200% limit concentration (30%, 50%, 100%, 150%, 200%): 30% Linearity Test Solution: Accurately transfer 30 μL of the reference stock solution into a 10 mL volumetric flask, dilute to the mark with solvent, and shake well (1,3-DCP: 19.5195 ng / mL; 2,3-DCP: 19.0115 ng / mL; 3-MCPD: 19.4163 ng / mL). 50% linearity test solution: Accurately transfer 50 μL of the reference stock solution into a 10 mL volumetric flask, dilute to the mark with solvent, and shake well (1,3-DCP: 32.5325 ng / mL; 2,3-DCP: 31.6859 ng / mL; 3-MCPD: 32.3605 ng / mL). 100% linearity test solution: Accurately transfer 100 μL of the reference stock solution into a 10 mL volumetric flask, dilute to the mark with solvent, and shake well (1,3-DCP: 65.0650 ng / mL; 2,3-DCP: 63.3718 ng / mL; 3-MCPD: 64.7209 ng / mL). 150% linearity test solution: Accurately transfer 150 μL of the reference stock solution into a 10 mL volumetric flask, dilute to the mark with solvent, and shake well (1,3-DCP: 97.5975 ng / mL; 2,3-DCP: 95.0577 ng / mL; 3-MCPD: 97.0814 ng / mL). 200% linearity test solution: Accurately transfer 200 μL of the reference stock solution into a 10 mL volumetric flask, dilute to the mark with solvent, and shake well (1,3-DCP: 130.1300 ng / mL; 2,3-DCP: 126.7436 ng / mL; 3-MCPD: 129.4419 ng / mL).

[0042] Following the method in Example 1, each solution was analyzed once, and the equation and regression coefficient (r) were calculated. The results are shown in Table 6 below.

[0043] Table 6 .

[0044] The linear graph of 1,3-dichloro-2-propanol is shown below. Figure 10 As shown; the linear graph of 2,3-dichloro-1-propanol is as follows. Figure 11 As shown; the linear graph of 3-chloro-1,2-propanediol is as follows. Figure 12 As shown.

[0045] As shown in Table 6, 1,3-DCP exhibits good linearity in the range of 19.5195 ng / mL to 130.1300 ng / mL, with an R² of 1.000; 2,3-DCP exhibits good linearity in the range of 19.0115 ng / mL to 126.7436 ng / mL, with an R² of 1.000; and 3-MCPD exhibits good linearity in the range of 19.4163 ng / mL to 129.4419 ng / mL, with an R² of 0.999. All of these results meet the requirements.

[0046] Accuracy of Example 5: Prepare three spiking solutions each at three limit levels: 50%, 100%, and 150%. 50% spiked test solution: Accurately weigh dihydroxypropyltheophylline and place it in a 10 mL volumetric flask. Add an appropriate amount of solvent to dissolve it. Accurately transfer 50 μL of the reference stock solution to the same volumetric flask and dilute to the mark with solvent. Shake well (1,3-DCP: 32.9550 ng / mL; 2,3-DCP: 31.6859 ng / mL; 3-MCPD: 32.2965 ng / mL).

[0047] 100% spiked test solution: Accurately weigh dihydroxypropyltheophylline and place it in a 10 mL volumetric flask. Dissolve it in an appropriate amount of solvent. Accurately transfer 100 μL of the reference stock solution into the same volumetric flask and dilute to the mark with solvent. Shake well (1,3-DCP: 65.9100 ng / mL; 2,3-DCP: 63.3718 ng / mL; 3-MCPD: 64.5930 ng / mL).

[0048] 150% spiked test solution: Accurately weigh dihydroxypropyltheophylline and place it in a 10 mL volumetric flask. Dissolve it in an appropriate amount of solvent. Accurately transfer 150 μL of the reference stock solution into the same volumetric flask and dilute to the mark with solvent. Shake well (1,3-DCP: 98.8650 ng / mL; 2,3-DCP: 95.0577 ng / mL; 3-MCPD: 96.8896 ng / mL).

[0049] The test was performed according to the method in Example 1, and the results are shown in Tables 7-9 below.

[0050] Table 7 .

[0051] Table 8 .

[0052] Table 9 .

[0053] Conclusions: The recoveries of 1,3-DCP at three concentration levels were 93.8%–104.4%, with an RSD of 4.2%; the recoveries of 2,3-DCP at three concentration levels were 94.1%–98.3%, with an RSD of 1.3%; and the recoveries of 3-MCPD at three concentration levels were 98.7%–110.7%, with an RSD of 3.1%. All results met the requirements, indicating good method accuracy.

[0054] Repeatability of Example 6: Prepare 6 spiked sample solutions at 100% limit level: 100% spiked test solution: Accurately weigh dihydroxypropyltheophylline and place it in a 10 mL volumetric flask. Dissolve it in an appropriate amount of solvent. Accurately transfer 100 μL of the reference stock solution into the same volumetric flask and dilute to the mark with solvent. Shake well (1,3-DCP: 65.9100 ng / mL; 2,3-DCP: 63.3718 ng / mL; 3-MCPD: 64.5930 ng / mL).

[0055] The detection was performed according to the method in Example 1, with each solution sample analyzed once. The results are shown in Tables 10-12 below.

[0056] Table 10 .

[0057] Table 11 .

[0058] Table 12 .

[0059] Conclusion: The RSD of 1,3-DCP content in the 6 reproducible solutions was 1.1%, the RSD of 2,3-DCP content was 0.9%, and the RSD of 3-MCPD content was 1.7%, all of which met the requirements, indicating good method reproducibility.

[0060] Example 7 Intermediate Precision: Six spiked sample solutions at 100% limit level were prepared by another researcher at different times and tested according to the method in Example 1. The results are shown in Tables 13-15 below.

[0061] Table 13 .

[0062] Table 14 .

[0063] Table 15 .

[0064] Conclusion: The solutions were re-prepared by different personnel on different dates. The RSD of 1,3-DCP content was 1.7%, the RSD of 2,3-DCP content was 2.6%, and the RSD of 3-MCPD content was 1.7% in the 12 precision samples, all of which met the requirements, indicating that the method has good precision.

[0065] Example 8 Durability: Two 100% limit spiked test solutions were prepared by changing the injection port temperature and column flow rate respectively. Each condition was injected twice, and the test was performed according to the method in Example 1. The results are shown in Tables 16-18 below.

[0066] Table 16 .

[0067] Table 17 .

[0068] Table 18 .

[0069] Conclusion: The system applicability meets the requirements when the injection port temperature and column flow rate are changed. The RSD of 1,3-DCP content in spiked samples measured under different conditions such as changing injection port temperature and column flow rate is 2.1%, 2,3-DCP content is 1.5%, and 3-MCPD content is 4.1%, all less than 10.0%, which meets the requirements and the method has good robustness.

[0070] Example 9 Solution stability: Prepare one portion each of the reference solution and the 100% limit spiked test solution, and examine the shift of the target peak area in the reference and spiked test solutions relative to 0h within 13h. The results are shown in Table 19-21 below.

[0071] Table 19 .

[0072] Table 20 .

[0073] Table 21 .

[0074] Conclusion: After being placed at room temperature for 13 hours, the peak area ratios of the target impurities at each time point relative to 0 h for both the reference solution and the 100% limit spiked test solution were within the range of 80.0% to 120.0%, indicating good solution stability.

[0075] Comparative Example 1: The only difference from Example 1 is that the solvent is DMF; all other aspects are the same. The spectrum of the 100% limit spiked test solution obtained under the above conditions is as follows. Figure 13 As shown, 1,3-dichloro-2-propanol and 2,3-dichloro-1-propanol cannot be separated.

[0076] Comparative Example 2: The only difference from Example 1 is that the solvent is ethyl acetate; all other aspects are the same. The spectrum of the 100% limit spiked test solution obtained under the above conditions is shown below. Figure 14 As shown, there are impurity peaks, and 1,3-dichloro-2-propanol and 2,3-dichloro-1-propanol cannot be separated.

[0077] Comparative Example 3: The only difference from Example 1 is that the solvent is 5 mL formic acid and 1 LDM; all other aspects are the same. The spectrum of the 100% limit spiked test solution obtained under the above conditions is shown below. Figure 15 As shown, 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol and 3-chloro-1,2-propanediol exhibit impurity peaks.

[0078] Comparative Example 4: The only difference from Example 1 is the gas chromatography conditions: the split ratio was adjusted to 3:1, the column temperature program was 80°C for 1 min, then increased to 250°C at a rate of 20°C / min and held for 5 min; all other conditions remained the same. The chromatogram of the 100% limit-spikened test solution obtained under these conditions is shown below. Figure 16 As shown, the baseline is uneven, and the peak shape of 3-chloro-1,2-propanediol is poor.

[0079] Comparative Example 5: The only difference from Example 1 is the gas chromatography conditions: the split ratio was adjusted to 4:1, the column temperature program was 40°C, held for 3 min, then increased to 250°C at 3°C / min, held for 4 min, and all other conditions remained the same. The chromatogram of the 100% limit-spikened test solution obtained under these conditions is shown below. Figure 17 As shown, the baseline is uneven, and the peak shape of 3-chloro-1,2-propanediol is poor.

[0080] Comparative Example 6: Difference from Example 1. The only difference is in the gas chromatography conditions: splitless, column temperature programmed as follows: initial temperature 50°C, increased to 140°C at 20°C / min, increased to 170°C at 5°C / min, increased to 250°C at 20°C / min and held for 3 min; all other conditions are the same. The chromatogram of the 100% limit spiked test solution obtained under the above conditions is shown below. Figure 18 As shown, 1,3-dichloro-2-propanol and 2,3-dichloro-1-propanol were not separated and showed tailing peaks.

[0081] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for detecting residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline, characterized in that, Includes the following steps: (1) Dilute dihydroxypropyltheophylline with solvent, shake well, and prepare a test solution; (2) Gas chromatography-tandem mass spectrometry was used to detect the test solution, and the contents of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline were calculated by external standard method. The solvent is a mixture of formic acid and DMF.

2. The method for detecting residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline according to claim 1, characterized in that, The volume ratio of formic acid to DMF is 0.5-1.5:1000.

3. The method for detecting residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline according to claim 2, characterized in that, The concentration of dihydroxypropyltheophylline in the test solution was 5 mg / mL.

4. The method for detecting residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline according to claim 3, characterized in that, The gas chromatographic column uses polyethylene glycol as the stationary phase.

5. The method for detecting residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline according to claim 4, characterized in that, The column temperature for the gas chromatograph is as follows: the initial temperature is 50-70℃, held for 1-3 minutes, and then increased to 240-260℃ at a rate of 5-15℃ / min, held for 3-5 minutes.

6. The method for detecting residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline according to claim 5, characterized in that, The gas chromatography conditions are as follows: injection port temperature 230-250℃; column flow rate 0.5-1.5mL / min; injection volume 0.8-1.2μL.

7. The method for detecting residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline according to claim 6, characterized in that, The conditions for the gas chromatography are as follows: Column temperature: The initial temperature is 60℃, held for 2 min, and then increased to 250℃ at a heating rate of 10℃ / min, held for 4 min. Inlet temperature: 240℃; Carrier gas: Helium; Column flow rate: 1.0 mL / min; Injection volume: 1 μL; Split ratio: 5:

1.

8. The method for detecting residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline according to claim 7, characterized in that, The chromatographic column was a DB-WAX, 30m × 0.25mm × 0.15μm.

9. The method for detecting residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline according to claim 8, characterized in that, The conditions for the mass spectrometry include: Ion source: EI; Ion source temperature: 230℃; Quadrupole temperature: 150℃; Auxiliary heating chamber temperature: 260℃; Solvent delay: 9 min; Dwell time: 100ms; Testing time: 15 min MS acquisition time: 25 min.

10. The method for detecting residues of 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol in dihydroxypropyltheophylline according to claim 9, characterized in that, The mass spectrometry conditions also include: scanning mode: SIM; quantitative ions for 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol are 49 m / z, 62 m / z, and 61 m / z, respectively; qualitative ions for 1,3-dichloro-2-propanol, 2,3-dichloro-1-propanol, and 3-chloro-1,2-propanediol are 81 m / z, 64 m / z, and 79 m / z, respectively.

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