Method for detecting residual solvent in atorvastatin calcium intermediate by headspace gas chromatography

Abstract

The invention relates to the technical field of pharmaceutical analysis, in particular to a method for detecting a residual solvent in an atorvastatin calcium intermediate by headspace gas chromatography, which comprises the following steps: respectively preparing a reference solution and a sample solution, respectively injecting into a headspace gas chromatograph, recording chromatograms, and calculating by peak area according to an external standard method; the residual solvent comprises methanol, ethanol, dichloromethane, benzene and methyl isopropyl ketone. The method for determining the residual solvents in the atorvastatin calcium intermediate M4, provided by the invention, is quick and simple to operate, high in sensitivity, good in repeatability and accurate in result, and can qualitatively or quantitatively detect the contents of the residual solvents including methanol, ethanol, dichloromethane, benzene and methyl isopropyl ketone in the atorvastatin calcium intermediate M4 at the same time; a good reference is provided for controlling organic solvent residues from raw material introduction, intermediate by-products and a production process of the atorvastatin calcium intermediate M4, and the quality of the atorvastatin calcium intermediate M4 is ensured, so that the safety of clinical medication is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical analysis, in particular to a method for detecting residual solvents in an atorvastatin calcium intermediate by using headspace gas chromatography. Background Art

[0002] Residual solvents in pharmaceuticals refer to organic solvents used in the production of raw materials and preparations but not completely removed during the process. Organic solvents are essential and critical substances in drug synthesis reactions. However, when the level of residual solvents in a drug exceeds the safety value, it may not only reduce the stability of the drug and affect its quality, but also cause harm to the human body or the environment. Therefore, the control of residual solvents is receiving more and more attention. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) divides 69 organic solvents commonly used in the production and purification of drugs into four categories according to the degree of harm to the human body and the environment. For Class I, II, and III solvents, the residual amount in the final drug product must be controlled within the limits required by ICH.

[0003] Atorvastatin calcium (ATv-Ca) is a lipid-regulating drug jointly developed and marketed by Warner-Lambert and Pfizer in the United States in 1997. It is clinically used to treat hypercholesterolemia, combat atherosclerosis, lower blood pressure, and treat diabetic nephropathy. It is the best-selling hydroxymethylglutaryl coenzyme (HMG-CoA) reductase inhibitor on the market. Methanol, ethanol, and dichloromethane are solvents used in the synthesis of atorvastatin calcium intermediate M4. Benzene is an impurity introduced from the raw material fluorobenzene. Methyl isopropyl ketone is a byproduct of the amidation process of atorvastatin calcium intermediate M4. Benzene is a Class I solvent, methanol and dichloromethane are Class II solvents, and ethanol is a Class III solvent.

[0004] At present, only Zhai Mengyang has reported a method for analyzing the residual amount of residual solvents in atorvastatin calcium intermediates (Zhai Mengyang, "A method for analyzing the residual amount of residual solvents in atorvastatin calcium intermediates" [Patent] Invention Patent CN201610701518.7 Zhai Mengyang Application Date: 2016-08-23 Publication Date: 2017-02-01). However, this method is for the detection of residual dichloromethane and isopropanol in atorvastatin calcium intermediate M4, and does not report the detection of residual solvents used in the production process of atorvastatin calcium intermediate M4. A method for simultaneously detecting five solvents, namely, methanol, ethanol, impurity benzene introduced from the raw material fluorobenzene, and methyl isopropyl ketone (a by-product of the M4 amidation process). Since gas chromatography analysis for detecting organic residual solvents has specificity and specificity, it is necessary and urgent to establish an analytical method that can simultaneously detect the residual solvents methanol, ethanol, dichloromethane (these three solvents are used in the production process), benzene (introduced from the raw material fluorobenzene) and methyl isopropyl ketone (a by-product of the M4 amidation process) in M4. Summary of the Invention

[0005] The object of the present invention is to provide a gas chromatography method with high accuracy, strong specificity and good reproducibility, which can simultaneously detect multiple residual solvents in atorvastatin calcium intermediate M4 from raw materials to finished products, thereby ensuring the quality of atorvastatin calcium intermediate M4 and improving the safety of clinical use.

[0006] The present invention provides a method for detecting residual solvents in an atorvastatin calcium intermediate by headspace gas chromatography, comprising: preparing a reference solution and a sample solution respectively, injecting them into a headspace gas chromatograph respectively, recording a chromatogram, and calculating the peak area according to an external standard method; the residual solvents include methanol, ethanol, dichloromethane, benzene and methyl isopropyl ketone;

[0007] The chromatographic conditions are as follows:

[0008] Chromatographic column: quartz capillary column, length 30m, column diameter 0.53mm, coating thickness 3.0μm;

[0009] Column temperature: programmed temperature, starting at 40°C, hold for 8-10 min, heating rate of 15°C / min, rising to 190-200°C, hold for 5 min;

[0010] Carrier gas: nitrogen, column flow rate 2-3 ml / min;

[0011] Detector: FID detector, temperature is 235-245℃;

[0012] Inlet temperature: 175-185°C; quantitative loop temperature: 95-105°C; transfer line temperature: 105-115°C; headspace vial equilibrium temperature: 85-95°C, equilibrium time: 25-35 min; injection volume: 1000 μl; split mode.

[0013] Preferably, the inner wall of the quartz capillary chromatographic column is coated with 6% cyanopropylphenyl-94% dimethylpolysiloxane as the stationary phase.

[0014] Preferably, the column temperature is programmed to start at 40°C, maintain for 10 min, increase the temperature at a rate of 15°C / min, increase to 200°C, and maintain for 5 min.

[0015] Preferably, the split ratio in the split mode is 5:1.

[0016] Preferably, the chromatographic column flow rate is 2.6 ml / min.

[0017] Preferably, the temperature of the quantitative loop is 100° C., the temperature of the transfer line is 110° C., the equilibrium temperature of the headspace bottle is 90° C., and the equilibrium time is 30 min.

[0018] Preferably, the FID detector temperature is 240°C and the injection port temperature is 180°C.

[0019] Preferably, the reference substance stock solution is prepared before the reference substance solution is prepared. The preparation process of the reference substance stock solution includes: accurately weighing methanol, ethanol, dichloromethane, and methyl isopropyl ketone into a volumetric flask, diluting to the scale with N, N-dimethylacetamide, and shaking well to prepare a reference substance stock solution A; accurately weighing benzene into a volumetric flask, diluting to the scale with N, N-dimethylacetamide, and shaking well to prepare a reference substance stock solution B; accurately measuring an appropriate amount of the reference substance stock solution B into a volumetric flask, diluting to the scale with N, N-dimethylacetamide, and shaking well to prepare a reference substance stock solution C; accurately measuring an appropriate amount of the reference substance stock solution C into a volumetric flask, diluting to the scale with N, N-dimethylacetamide, and shaking well to prepare a reference substance stock solution D.

[0020] Preferably, the preparation process of the reference solution includes: accurately measuring 10 ml of reference stock solution A and reference stock solution D into a 100 ml volumetric flask, adding N,N-dimethylacetamide to dilute to the scale, shaking well, taking 5 ml and placing it into a 20 ml headspace bottle, sealing, and using it as the reference solution.

[0021] Preferably, the sample solution preparation process includes: taking 0.5 g of sample, accurately weighing, placing in a 20 ml headspace bottle, adding 5 ml of N, N-dimethylacetamide to dissolve, shaking and sealing to obtain the sample solution.

[0022] In the present invention, the atorvastatin calcium intermediate M4 sample contains a variety of residual solvents with a wide range of boiling points. The boiling points of methanol, ethanol, dichloromethane, benzene, and methyl isopropyl ketone are 64.7°C, 78.4°C, 39.8°C, 80.1°C, and 94.2°C, respectively. To facilitate the detection of residual solvents in atorvastatin calcium intermediate M4, it is necessary to select relatively suitable detection conditions. The inventors adjusted the chromatographic column, starting column temperature, heating rate, and other factors. After optimizing various control conditions, they ultimately determined the most suitable chromatographic conditions.

[0023] Beneficial effects of the present invention:

[0024] The method for determining residual solvents in an atorvastatin calcium intermediate M4 provided by the present invention is quick and simple to operate, has high sensitivity, good repeatability, and accurate results, and can qualitatively or quantitatively detect the contents of residual solvents such as methanol, ethanol, dichloromethane, benzene, and methyl isopropyl ketone in the atorvastatin calcium intermediate M4. The method provides a good reference for controlling the residual organic solvents in the atorvastatin calcium intermediate M4 from the introduction of raw materials, intermediate by-products to the production process, thereby ensuring the quality of the atorvastatin calcium intermediate M4, thereby improving the safety of clinical medication, and providing a methodological basis for improving the quality of the atorvastatin calcium intermediate M4. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0026] Figure 1 Chromatogram recorded when conducting a system suitability test using the reference solution as the system suitability test solution;

[0027] Figure 2 The spectrum recorded in the quantitative limit test in Example 1;

[0028] Figure 3 This is a spectrum recorded from the test for determining the residual solvent in the atorvastatin calcium intermediate M4 according to Example 2;

[0029] Figure 4 This is the spectrum recorded in the system suitability test in Comparative Example 1;

[0030] Figure 5 This is the spectrum recorded in the system suitability test in Comparative Example 2. DETAILED DESCRIPTION

[0031] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present application belongs.

[0032] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular also includes the plural. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they indicate the presence of features, steps, operations, devices, components and / or combinations thereof.

[0033] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0034] Example 1:

[0035] Instruments and reagents: SHIMADZU 2010plus gas chromatograph; Denny automatic headspace sampler; M4 (batch number: 201103); all reagents were HPLC grade.

[0036] Chromatographic conditions: Chromatographic column: (6% cyanopropylphenyl) polydimethylsiloxane as the stationary phase, 30m×0.53mm×3.0μm DB-624 capillary column; column temperature: programmed temperature, starting at 40℃, maintained for 10min, increased to 200℃ at 15℃ / min, and maintained for 5min; detector: FID detector, detector temperature: 240℃; injection port temperature: 180℃; headspace bottle equilibrium temperature: 90℃, equilibrium time: 30min; quantitative loop temperature: 100℃; transfer line temperature: 110℃; column flow rate: 2.6ml / min; split ratio: 5:1; carrier gas: nitrogen; injection volume: 1000μl.

[0037] Solution preparation:

[0038] 1. Preparation of reference substance stock solution

[0039] Accurately weigh 0.3 g methanol, 0.5 g ethanol, 0.06 g dichloromethane and 0.5 g methyl isopropyl ketone into a 100 ml volumetric flask and dissolve them. Add DMAC to dilute to the mark and shake well. This is used as reference stock solution A.

[0040] Accurately weigh 0.04 g of benzene and dissolve it in a 50 ml volumetric flask. Add DMAC to dilute to the mark and shake well. This is used as the reference stock solution B.

[0041] Accurately measure 1 ml of reference stock solution B into a 20 ml volumetric flask, add DMAC to dilute to the mark, shake well, and use this as reference stock solution C.

[0042] Accurately measure 1 ml of reference stock solution C into a 20 ml volumetric flask, add DMAC to dilute to the mark, shake well, and use this as reference stock solution D.

[0043] 2. Preparation of reference solution

[0044] Accurately measure 10 ml of reference substance stock solution A and reference substance stock solution D into a 100 ml volumetric flask, add DMAC to dilute to the scale, shake well, take 5 ml and place it into a 20 ml headspace bottle, seal it, and use it as the reference solution.

[0045] 3. Preparation of sample solution

[0046] Take 0.5 g of sample, accurately weigh it, place it in a 20 ml headspace bottle, add 5 ml of DMAC to dissolve it, shake it well and seal it to obtain the sample solution.

[0047] System suitability test:

[0048] Take the reference solution as the system suitability test solution, accurately measure the solution, measure according to the above chromatographic conditions, and record the chromatogram. Figure 1 , methanol, ethanol, dichloromethane, benzene, and methyl isopropyl ketone peaked in sequence, and the blank solvent had no interference. Each component can be well separated, and the resolution is shown in Table 1 below:

[0049] Table 1 Separation of each solvent

[0050] Component name Methanol ethanol dichloromethane benzene Methyl isopropyl ketone Separation - 11.9 19.0 37.7 4.1

[0051] Limit of quantitation test: Take appropriate amounts of methanol, ethanol, dichloromethane, benzene, and methyl isopropyl ketone, accurately weigh them, dilute them with DMAC to prepare solutions of appropriate concentrations, measure them under the above-mentioned chromatographic conditions, record the chromatogram, and calculate the limit of quantitation with an S / N ratio between 8 and 12. The results are shown in Table 2 below:

[0052] Table 2 Limits of quantification of each solvent

[0053]

[0054] Recovery test:

[0055] Accurately measure 1.5 ml, 2.5 ml, 5.0 ml, and 7.5 ml of each reference substance stock solution A and reference substance stock solution D, respectively, into 50 ml volumetric flasks. Dilute to the mark with DMAC, shake well, and set aside. Accurately measure 5 ml of each solution into a 20 ml headspace vial containing 0.5 g of sample, seal, and obtain four concentrations of loading solutions. Prepare three replicates for each concentration. Inject these loading solutions and sample solutions into the headspace, measure according to the above chromatographic conditions, and record the chromatograms. See Tables 3-7 below for details. The results demonstrate good accuracy of this method.

[0056] Table 3 Methanol recovery test results

[0057]

[0058] Table 4 ethanol recovery test results

[0059]

[0060] Table 5 Dichloromethane recovery test results

[0061]

[0062] Table 6 Benzene recovery test results

[0063]

[0064] Table 7 Methyl isopropyl ketone recovery test results

[0065]

[0066] Example 2 Determination of Residual Solvents in Atorvastatin Calcium Intermediate M4

[0067] Chromatographic conditions: Chromatographic column: (6% cyanopropylphenyl) polydimethylsiloxane as the stationary phase, 30m×0.53mm×3.0μm DB-624 capillary column; column temperature: programmed temperature, starting at 40℃, maintained for 10min, increased to 200℃ at 15℃ / min, and maintained for 5min; detector: FID detector, detector temperature: 240℃; injection port temperature: 180℃; headspace bottle equilibrium temperature: 90℃, equilibrium time: 30min; quantitative loop temperature: 100℃; transfer line temperature: 110℃; column flow rate: 2.6ml / min; split ratio: 5:1; carrier gas: nitrogen; injection volume: 1000μl.

[0068] Solution preparation: Prepare the solution according to the method of Example 1.

[0069] Determination: Accurately measure the sample solution of atorvastatin calcium intermediate M4 and the reference solution and inject them into the headspace respectively, and record the chromatogram (see Figure 3 ). The residual solvent determination results are shown in Table 8 below, calculated by peak area using the external standard method:

[0070] Table 8 Sample solvent residue

[0071] Component name Methanol ethanol dichloromethane benzene Methyl isopropyl ketone Content / ppm Not detected 3.6 Not detected Not detected Not detected

[0072] Comparative Example 1

[0073] The chromatographic conditions were referred to the literature “A method for analyzing the residual solvent content in atorvastatin calcium intermediates” by Zhai Mengyang.

[0074] Chromatographic column: 30m×0.32mm×0.25μm DB-FFAP capillary column with nitroterephthalic acid-modified polyethylene glycol as the stationary phase; column temperature: programmed temperature, starting at 35°C for 6 min, then increasing to 150°C at 20°C / min and maintaining for 8.25 min; detector: FID detector, detector temperature: 250°C; inlet temperature: 200°C; headspace vial equilibration temperature: 90°C, equilibration time: 10 min; quantitative loop temperature: 100°C; transfer line temperature: 105°C; column flow rate: 1.5ml / min; split ratio: 30:1; carrier gas: nitrogen; injection volume: 1000μl.

[0075] Solution preparation:

[0076] 1. Preparation of reference substance stock solution

[0077] Accurately weigh 0.6 g methanol, 1.0 g ethanol, 0.12 g dichloromethane, and 1.0 g methyl isopropyl ketone into a 100 ml volumetric flask and dissolve them. Add DMAC to dilute to the mark and shake well. This is used as reference stock solution A.

[0078] Accurately weigh 0.04 g of benzene and dissolve it in a 50 ml volumetric flask. Add DMAC to dilute to the mark and shake well. This is used as the reference stock solution B.

[0079] Accurately measure 1 ml of reference stock solution B into a 20 ml volumetric flask, add DMAC to dilute to the mark, shake well, and use this as reference stock solution C.

[0080] Accurately measure 1 ml of reference stock solution C into a 20 ml volumetric flask, add DMAC to dilute to the mark, shake well, and use this as reference stock solution D.

[0081] 2. Preparation of reference solution

[0082] Accurately measure 10 ml of reference substance stock solution A and reference substance stock solution D into a 100 ml volumetric flask, add DMAC to dilute to the scale, shake well, take 5 ml and place it into a 20 ml headspace bottle, seal it, and use it as the reference solution.

[0083] System suitability test:

[0084] result:

[0085] Take the reference solution as the system suitability test solution, accurately measure the solution, measure according to the above chromatographic conditions, and record the chromatogram. Figure 4 Methanol, ethanol, dichloromethane, and methyl isopropyl ketone peaks appeared in sequence, but no benzene peak was observed. Using these chromatographic conditions, the sensitivity for benzene detection was extremely low, making quantitative determination of benzene impossible. Furthermore, ethanol and dichloromethane were not baseline-separated, making specificity impossible.

[0086] Comparative Example 2

[0087] Other conditions: different chromatographic columns, different temperature programs, and different flow rates.

[0088] Chromatographic conditions: Chromatographic column: 100% dimethylpolysiloxane as the stationary phase, 30m×0.53mm×5.0μm DB-1 capillary column; column temperature: programmed temperature, starting at 50℃ and maintained for 10min, then increased to 240℃ at 20℃ / min and maintained for 5min; detector: FID detector, detector temperature: 250℃; injection port temperature: 250℃; headspace bottle equilibrium temperature: 90℃, equilibrium time: 30min; quantitative loop temperature: 100℃; transfer line temperature: 110℃; column flow rate: 1.5ml / min; split ratio: 5:1; carrier gas: nitrogen; injection volume: 1000μl.

[0089] Solution preparation:

[0090] 1. Preparation of reference substance stock solution

[0091] Accurately weigh 0.45 g methanol, 0.75 g ethanol, 0.09 g dichloromethane, and 0.75 g methyl isopropyl ketone into a 100 ml volumetric flask and dissolve them. Add DMAC to dilute to the mark and shake well. This is used as reference stock solution A.

[0092] Accurately weigh 0.06 g of benzene and dissolve it in a 50 ml volumetric flask. Add DMAC to dilute to the mark and shake well. This is used as the reference stock solution B.

[0093] Accurately measure 1 ml of reference stock solution B into a 20 ml volumetric flask, add DMAC to dilute to the mark, shake well, and use this as reference stock solution C.

[0094] Accurately measure 1 ml of reference stock solution C into a 20 ml volumetric flask, add DMAC to dilute to the mark, shake well, and use this as reference stock solution D.

[0095] 2. Preparation of reference solution

[0096] Accurately measure 10 ml of reference substance stock solution A and reference substance stock solution D into a 100 ml volumetric flask, add DMAC to dilute to the scale, shake well, take 5 ml and place it into a 20 ml headspace bottle, seal it, and use it as the reference solution.

[0097] System suitability test:

[0098] Take the reference solution as the system suitability test solution, accurately measure the solution, measure according to the above chromatographic conditions, and record the chromatogram. Figure 5 Methanol, ethanol, dichloromethane, and methyl isopropyl ketone eluted in sequence, but no benzene peak was observed. Using these chromatographic conditions, the detection sensitivity of benzene was low, making it impossible to quantitatively determine benzene.

[0099] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for detecting residual solvents in atorvastatin calcium intermediates by headspace gas chromatography, characterized in that: include: Prepare reference solution and sample solution respectively, then inject them into headspace gas chromatograph respectively, record chromatogram, and calculate peak area according to external standard method; the residual solvent includes methanol, ethanol, dichloromethane, benzene and methyl isopropyl ketone; The chromatographic conditions are as follows: Chromatographic column: quartz capillary column, length 30m, column diameter 0.53mm, coating thickness 3.0μm; Column temperature: programmed temperature, starting at 40°C, hold for 8-10 min, heating rate of 15°C / min, rising to 190-200°C, hold for 5 min; Carrier gas: nitrogen, column flow rate 2-3 ml / min; Detector: FID detector, temperature is 235-245℃; Inlet temperature: 175-185°C; Quantitative loop temperature: 95-105°C; transfer line temperature: 105-115°C; headspace vial equilibrium temperature: 85-95°C, equilibrium time: 25-35 min; injection volume: 1000 μl; split mode.

2. The method for detecting residual solvents in an atorvastatin calcium intermediate by headspace gas chromatography according to claim 1, characterized in that: The inner wall of the quartz capillary chromatographic column is coated with 6% cyanopropylphenyl-94% dimethylpolysiloxane as a stationary phase.

3. The method for detecting residual solvents in atorvastatin calcium intermediates by headspace gas chromatography according to claim 1, characterized in that: The column temperature was programmed to start at 40°C, maintain for 10 min, increase at a rate of 15°C / min, and then rise to 200°C, maintaining for 5 min.

4. The method for detecting residual solvents in an atorvastatin calcium intermediate by headspace gas chromatography according to claim 1, characterized in that: The split ratio in the split mode is 5:

1.

5. The method for detecting residual solvents in atorvastatin calcium intermediates by headspace gas chromatography according to claim 1, characterized in that: The chromatographic column flow rate is 2.6 ml / min.

6. The method for detecting residual solvents in atorvastatin calcium intermediates by headspace gas chromatography according to claim 1, characterized in that: The temperature of the quantitative loop was 100° C., the temperature of the transfer line was 110° C., the equilibrium temperature of the headspace bottle was 90° C., and the equilibrium time was 30 min.

7. The method for detecting residual solvents in atorvastatin calcium intermediates by headspace gas chromatography according to claim 1, characterized in that: The FID detector temperature was 240°C, and the injection port temperature was 180°C.

8. The method for detecting residual solvents in atorvastatin calcium intermediates by headspace gas chromatography according to claim 1, characterized in that: Before preparing the reference substance solution, a reference substance stock solution is prepared. The preparation process of the reference substance stock solution includes: accurately weighing methanol, ethanol, dichloromethane, and methyl isopropyl ketone, placing them in a volumetric flask, diluting them to the scale with N,N-dimethylacetamide, and shaking them evenly to prepare reference substance stock solution A; accurately weighing benzene, placing them in a volumetric flask, diluting them to the scale with N,N-dimethylacetamide, and shaking them evenly to prepare reference substance stock solution B; accurately measuring an appropriate amount of reference substance stock solution B, placing it in a volumetric flask, diluting them to the scale with N,N-dimethylacetamide, and shaking them evenly to prepare reference substance stock solution C; accurately measuring an appropriate amount of reference substance stock solution C, placing it in a volumetric flask, diluting them to the scale with N,N-dimethylacetamide, and shaking them evenly to prepare reference substance stock solution D.

9. The method for detecting residual solvents in an atorvastatin calcium intermediate by headspace gas chromatography according to claim 8, characterized in that: The preparation process of the reference solution includes: accurately measuring 10 ml of reference stock solution A and reference stock solution D into a 100 ml volumetric flask, adding N,N-dimethylacetamide to dilute to the scale, shaking well, taking 5 ml and placing it into a 20 ml headspace bottle, sealing, and using it as the reference solution.

10. The method for detecting residual solvents in atorvastatin calcium intermediates by headspace gas chromatography according to claim 1, characterized in that: The sample solution preparation process includes: taking 0.5 g of sample, accurately weighing, placing in a 20 ml headspace bottle, adding 5 ml of N, N-dimethylacetamide to dissolve, shaking and sealing to obtain the sample solution.

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