A method for detecting chloroacetyl chloride impurities in vildagliptin raw materials and its application

Abstract

The present invention belongs to the technical field of analytical chemistry, and relates to a method for checking chloroacetyl chloride impurities in vildagliptin raw materials and applications thereof. The present invention specifically adopts gas chromatography to determine the chloroacetyl chloride impurity content in the vildagliptin raw materials, and systematically optimizes the detection method to determine the best detection method of gas chromatography for chloroacetyl chloride impurities in vildagliptin. Compared with other analytical methods, this method has the advantages of strong specificity, high sensitivity, small sample dosage, good repeatability of quantitative limit, etc., and safe, environmentally friendly and harmless reagents used in the test. Therefore, it is very suitable for the detection of chloroacetyl chloride impurities in vildagliptin, which is beneficial to the product quality control of vildagliptin and has good practical application value.

Description

Technical Field

[0001] The invention belongs to the technical field of analytical chemistry, relates to a method for checking chloroacetyl chloride impurities in a vildagliptin raw material and an application thereof, and specifically provides a method for determining the content of chloroacetyl chloride impurities in the vildagliptin raw material by using gas chromatography. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Vildagliptin is a drug for the treatment of type 2 diabetes and is a selective, competitive, and reversible DPP24 inhibitor. Vildagliptin inhibits the activity of the enzyme by binding to DPP24 to form a DPP24 complex, while increasing the concentration of GLP21 and promoting the production of insulin by pancreatic β cells, it reduces the concentration of glucagon, thereby lowering blood sugar. Compared with other hypoglycemic drugs, it has no significant effect on body weight, reduces total cholesterol, has good tolerance, and has a low probability of adverse reactions. Chloroacetyl chloride is used in the synthesis process of vildagliptin. Chloroacetyl chloride has a strong irritating effect on the eyes, skin mucosa, and respiratory tract. Inhalation may cause death due to spasm, edema, inflammation, chemical pneumonia, and pulmonary edema of the larynx and bronchi. Therefore, it is very important to study the chloroacetyl chloride in vildagliptin.

[0004] The existing methods for testing chloroacetyl chloride include: ① Potentiometric titration, which has the advantages of high accuracy and fast speed, but the disadvantages of poor specificity and is not suitable for the testing of trace impurities. ② Liquid chromatography-mass spectrometry (HPLC-MS / MS), which has the advantages of high sensitivity and strong specificity, but the disadvantages of requiring samples to undergo derivatization pretreatment, harsh derivatization conditions, large uncertainty, the reagents used are harmful to the human body and the environment, the instrument is expensive, and the operation is complicated. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a method for checking chloroacetyl chloride impurities in vildagliptin raw materials and its application. The present invention systematically optimizes the detection method to determine the best detection method for chloroacetyl chloride impurities in vildagliptin by gas chromatography, which has the advantages of strong specificity, high sensitivity, small sample dosage, good repeatability of quantitative limit, safe and environmentally friendly reagents used in the test, simple instrument operation, and applicability to most laboratories. Based on the above research results, the present invention is completed.

[0006] Specifically, the technical solution of the present invention is as follows:

[0007] The first aspect of the present invention provides a method for inspecting chloroacetyl chloride impurities in a vildagliptin raw material, the method comprising detecting chloroacetyl chloride impurities in the vildagliptin raw material using a solution direct injection method based on gas chromatography, wherein the solvent used in the solution is anhydrous ethanol, thereby reducing harm to human body and the environment.

[0008] Specifically, the method includes:

[0009] The gas chromatograph detector is a hydrogen flame ionization detector (FID), the detector temperature is 240-260°C, the injection port temperature is 240-260°C, the chromatographic column uses a dimethylpolysiloxane capillary column, the programmed temperature, the initial column temperature: 70-90°C, maintained for 4-6 minutes, increased to 190-210°C at a rate of 5-15°C / min, maintained for 15-20 minutes.

[0010] The present invention systematically optimizes the above detection parameter conditions, and finally obtains a chloroacetyl chloride detection method with the advantages of strong specificity, high sensitivity, small sample dosage, good repeatability of quantitative limit, high accuracy, strong durability, safe and environmentally friendly test reagents, simple instrument operation, and applicability to most laboratories.

[0011] The second aspect of the present invention provides application of the above inspection method in quality control of vildagliptin.

[0012] The application is specifically to determine and evaluate the presence and content of chloroacetyl chloride in the vildagliptin raw material.

[0013] Beneficial effects of one or more of the above technical solutions:

[0014] The above technical scheme provides an analytical method suitable for chloroacetyl chloride impurities in vildagliptin, specifically using gas chromatography to determine the chloroacetyl chloride impurity content in the vildagliptin raw material, and by systematically optimizing the detection method, the best gas chromatography detection method for chloroacetyl chloride impurities in vildagliptin is determined. Compared with other analytical methods, this method has the advantages of strong specificity, high sensitivity, small sample dosage, good repeatability of quantitative limit, safe, environmentally friendly and harmless reagents used in the test, etc. Therefore, it is very suitable for the detection of chloroacetyl chloride impurities in vildagliptin, which is beneficial to the product quality control of vildagliptin and has good practical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0016] Figure 1 It is a typical detection spectrum in the embodiment of the present invention.

[0017] Figure 2 This is a linear curve diagram of vildagliptin chloroacetyl chloride test in the embodiment of the present invention. DETAILED DESCRIPTION

[0018] It should be noted that the following detailed descriptions are illustrative and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0019] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, it will be described in detail below in conjunction with specific embodiments.

[0020] As mentioned above, the existing methods for detecting chloroacetyl chloride include potentiometric titration and liquid chromatography-mass spectrometry, but they still have disadvantages such as poor specificity, low sensitivity, or the sample needs to be pre-treated by derivatization, harsh derivatization conditions, large uncertainty, the reagents used are harmful to the human body and the environment, the instruments are expensive, and the operation is complicated.

[0021] In view of this, the present invention provides a method for inspecting chloroacetyl chloride impurities in a vildagliptin raw material, the method comprising detecting chloroacetyl chloride impurities in the vildagliptin raw material by a solution direct injection method based on gas chromatography, wherein the solvent used in the solution is anhydrous ethanol, thereby reducing harm to human body and the environment.

[0022] In another specific embodiment of the present invention, the method comprises:

[0023] The gas chromatograph detector is a hydrogen flame ionization detector (FID), the detector temperature is 240-260°C (preferably 250°C), the injection port temperature is 240-260°C (preferably 250°C), the chromatographic column adopts a dimethyl polysiloxane capillary chromatographic column, the programmed temperature is, the initial column temperature is 70-90°C (preferably 80°C), maintained for 4-6min (preferably 5min), the temperature is increased to 190-210°C (preferably 200°C) at a speed of 5-15°C / min (preferably 10°C), and maintained for 15-20min (preferably 18min); the present invention screens and optimizes the above chromatographic conditions, and the chromatogram finally obtained has the characteristics of good separation from adjacent peaks, high sensitivity, and the like.

[0024] As shown above, the sample is dissolved and diluted with anhydrous ethanol, and the direct injection method is adopted, with a flow rate of 1.0-3.0 ml per minute (preferably 2.0 ml); the split ratio is 5-15:1 (preferably 10:1).

[0025] The injection volume is 1-5 μl, preferably 2 μl, and the quantification method adopts the external standard method.

[0026] The reference substance used in the test method is an anhydrous ethanol solution of chloroacetyl chloride (standard substance).

[0027] In another specific embodiment of the present invention, the presence and content of chloroacetyl chloride are calculated by peak area using an external standard method; the chloroacetyl chloride content shall not exceed 15 ppm.

[0028] Calculation formula:

[0029]

[0030] As is the peak area of ​​chloroacetyl chloride in the test solution;

[0031] Ar is the peak area of ​​chloroacetyl chloride in the reference solution;

[0032] Ws is the sample weight of the test product, mg;

[0033] Wr is the sample weight of the reference substance, mg.

[0034] More specifically, the chromatographic column is a 6% cyanopropylphenyl-94% dimethylpolysiloxane capillary chromatographic column (DB-624, 0.53 mm×30 m×3 μm).

[0035] The present invention systematically optimizes the above detection parameter conditions, and finally obtains a chloroacetyl chloride detection method with the advantages of strong specificity, high sensitivity, small sample dosage, good repeatability of quantitative limit, high accuracy, strong durability, safe and environmentally friendly test reagents, simple instrument operation, and applicability to most laboratories.

[0036] In another embodiment of the present invention, the application of the above inspection method in the quality control of vildagliptin is provided.

[0037] The application is specifically to determine and evaluate the presence and content of chloroacetyl chloride in the vildagliptin raw material.

[0038] The present invention is further explained by the following examples, but they are not intended to limit the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. All raw materials used in the examples are commercially available unless otherwise specified.

[0039] Example

[0040] Chloroacetyl chloride, as a highly active substance, is easily hydrolyzed or reacts with other reagents, and the solution stability is poor. The injection method used in this test is direct injection of the solvent using anhydrous ethanol to reduce the harm to the human body and the environment.

[0041] Initial conditions: 6% cyanopropylphenyl-94% dimethylpolysiloxane capillary column (DB-624, 0.53 mm × 30 m × 3 μm); starting temperature 80 ° C, maintained for 5 minutes, increased to 200 ° C at 10 ° C per minute, maintained for 23 minutes; flow rate 2.0 ml per minute; detector is hydrogen flame ionization detector (FID), detector temperature 250 ° C, injection port temperature 250 ° C;

[0042] Solution preparation and exploration process:

[0043] Take about 150 mg of chloroacetyl chloride, weigh it accurately, put it in a 100 ml volumetric flask, add solvent to dissolve and dilute to the mark, shake well, accurately measure 5 ml, put it in a 100 ml volumetric flask, add solvent to dilute to the mark, shake well, as the reference stock solution;

[0044] Accurately measure 5 ml of the reference substance stock solution, place it in a 50 ml volumetric flask, add solvent to dilute to the mark, shake well, and use it as reference substance solution 1 (7.5 μg / ml);

[0045] Accurately measure 1 ml of the reference substance stock solution, place it in a 50 ml volumetric flask, add solvent to dilute to the scale, shake well, and use it as reference substance solution 2 (1.5 μg / ml).

[0046] Chromatographic conditions 1) The split ratio was 5:1.

[0047] Accurately measure 5 μl of reference solution 1 (7.5 μg / ml) and reference solution 2 (1.5 μg / ml), respectively, inject them into the gas chromatograph, and record the chromatograms.

[0048] From the chromatogram, we know that the chloroacetyl chloride content of reference solution 1 is 7.7 mv (calculated based on a noise of 0.05, it is 15 times the limit of quantification); the chloroacetyl chloride content of reference solution 2 is 1.45 mv (calculated based on a noise of 0.05, it is 2.9 times the limit of quantification).

[0049] Take about 200 mg of vildagliptin, weigh accurately, add 2 ml of reference solution 1 (7.5 μg / ml) to dissolve, shake well, and prepare mixed solution 1.

[0050] Take about 200 mg of vildagliptin, weigh accurately, add 2 ml of reference solution 2 (1.5 μg / ml) to dissolve, shake well, and prepare mixed solution 2.

[0051] Chromatographic condition 2) Continue to increase the split ratio to increase its response value, and change the split ratio to 2:1.

[0052] Accurately measure 5 μl of reference solution 2 (1.5 μg / ml) and mixed solution 2, respectively, inject them into the gas chromatograph, and record the chromatogram.

[0053] From the chromatogram, we know that the chloroacetyl chloride of reference solution 2 is 2.6mv (calculated based on noise 0.05, which is 5 times the quantification limit). The response value is good. The chloroacetyl chloride of mixed solution 2 is 2mv (calculated based on noise 0.4, which is 0.5 times the quantification limit). The noise is too loud. Increase the column temperature later.

[0054] Chromatographic conditions 3) Column temperature was changed to a starting temperature of 80°C, maintained for 5 min, increased at 10°C per min to 200°C, increased at 10°C per min to 250°C, and maintained for 18 min;

[0055] Accurately measure 5 μl of reference solution 2 (1.5 μg / ml) and mixed solution 2, respectively, inject them into the gas chromatograph, and record the chromatogram.

[0056] From the chromatogram, we know that chloroacetyl chloride is 2.61 mv (calculated based on a noise of 0.05, which is 5.2 times the limit of quantification), with good sensitivity, a pre-recovery rate of 98%, and a good recovery rate.

[0057] At different times, the reference solution 2 (1.5 μg / ml) and mixed solution 2 were injected repeatedly. The chloroacetyl chloride was 1.7 mv (calculated based on noise 0.05, which is 3 times the quantification limit), which was lower than the previous day (reduced by 1 times the quantification limit). This should be caused by the injection volume being too large, so the injection volume was reduced later.

[0058] Accurately measure 2 μl of reference solution 1 (7.5 μg / ml) and mixed solution 1, respectively, inject them into the gas chromatograph, and record the chromatogram.

[0059] From the chromatogram, we know that chloroacetyl chloride is 7.8mv (calculated based on noise of 0.05, it is 15.7 times the quantification limit, and based on the limit concentration, it is 3 times the quantification limit), and it is well separated from adjacent peaks, with good sensitivity and good peak shape. This method is tentatively determined, and the injection volume is 2μl.

[0060] The final chromatography condition solution preparation method was revised as follows:

[0061] Take an appropriate amount of this product, dissolve it in anhydrous ethanol and dilute it to make a solution containing about 0.1g per 1ml as the test solution; take an appropriate amount of chloroacetyl chloride, dissolve it in anhydrous ethanol and dilute it to make a solution containing about 7.5μg per 1ml as the reference solution. Use a 6% cyanopropylphenyl-94% dimethylpolysiloxane capillary column (DB-624, 0.53mm×30m×3μm), start at 80℃, maintain for 5min, heat to 200℃ at 10℃ / min, maintain for 18 minutes; flow rate is 2.0ml per minute; split ratio is 10:1; detector is hydrogen flame ionization detector (FID), detector temperature is 250℃, injection port temperature is 250℃; accurately measure 2μl of the reference solution, inject it into the gas chromatograph, and record the chromatogram. If there is an impurity peak in the chromatogram, calculate the peak area according to the external standard method, and the chloroacetyl chloride content shall not exceed 15ppm.

[0062] Calculation formula:

[0063]

[0064] As is the peak area of ​​chloroacetyl chloride in the test solution;

[0065] Ar is the peak area of ​​chloroacetyl chloride in the reference solution;

[0066] Ws is the sample weight of the test product, mg;

[0067] Wr is the sample weight of the reference substance, mg.

[0068] The methodological study of the above methods is as follows:

[0069] 1. Chromatographic peak positioning and interference test

[0070] Take about 150 mg of chloroacetyl chloride, accurately weigh it, place it in a 100 ml volumetric flask, add solvent to dissolve and dilute to the scale, shake well, accurately measure 5 ml, place it in a 100 ml volumetric flask, add solvent to dilute to the scale, shake well, accurately measure 5 ml, place it in a 50 ml volumetric flask, add solvent to dilute to the scale, shake well, as the reference solution.

[0071] Take about 200 mg of vildagliptin, weigh accurately, add 2 ml of solvent to dissolve, shake well, and use as the test solution.

[0072] Take about 200 mg of vildagliptin, weigh accurately, add 2 ml of reference solution to dissolve, shake well, and prepare a mixed solution.

[0073] Take about 0.75g of methanol, about 1.25g of isopropanol, about 1.25g of methyl tert-butyl ether, about 1.25g of ethyl acetate, about 0.22g of N,N-dimethylformamide, and about 0.2225g of toluene, accurately weigh, place in a 50ml volumetric flask, add solvent to dilute to the scale, shake well, accurately measure 1ml, place in a 50ml volumetric flask, add solvent to dilute to the scale, shake well, as the interference test solution.

[0074] Accurately measure 2 μl of the above solution and solvent, inject them into the gas chromatograph, and record the chromatogram.

[0075] The test results show that the retention time of chloroacetyl chloride is 9.000 minutes; the solvent and interfering solution do not interfere with the detection of chloroacetyl chloride.

[0076] 2. System suitability test

[0077] Take about 150 mg of chloroacetyl chloride, accurately weigh it, place it in a 100 ml volumetric flask, add solvent to dissolve and dilute to the scale, shake well, accurately measure 5 ml, place it in a 100 ml volumetric flask, add solvent to dilute to the scale, shake well, accurately measure 5 ml, place it in a 50 ml volumetric flask, add solvent to dilute to the scale, shake well, take about 200 mg of vildagliptin, accurately weigh it, add 2 ml of the above solution to dissolve, and use it as the system suitability test solution.

[0078] Accurately measure 2 μl of the above solution, inject it into the gas chromatograph, and record the chromatogram. Repeat the operation 5 times.

[0079] The test results are shown in Table 1.

[0080] Table-1 System suitability test results of vildagliptin chloroacetyl chloride test method

[0081]

[0082] 2. Precision test

[0083] Repeatability test

[0084] Take about 150 mg of chloroacetyl chloride, weigh it accurately, put it in a 100 ml volumetric flask, add solvent to dissolve and dilute to the scale, shake well, accurately measure 5 ml, put it in a 100 ml volumetric flask, add solvent to dilute to the scale, shake well, accurately measure 5 ml, put it in a 50 ml volumetric flask, add solvent to dilute to the scale, shake well, as the repeatability test solution.

[0085] Accurately measure 2 μl of the above solution, inject it into the gas chromatograph, and record the chromatogram. Repeat the operation 6 times.

[0086] The test results are shown in Table 2.

[0087] Table 2 Results of repeatability test of vildagliptin chloroacetyl chloride test method

[0088]

[0089]

[0090] The test results show that this method has good applicability for checking chloroacetyl chloride system.

[0091] 3. Durability test

[0092] Take about 150 mg of chloroacetyl chloride, accurately weigh it, put it in a 100 ml volumetric flask, add solvent to dissolve and dilute to scale, shake well, accurately measure 5 ml, put it in a 100 ml volumetric flask, add solvent to dilute to scale, shake well, accurately measure 5 ml, put it in a 50 ml volumetric flask, add solvent to dilute to scale, shake well, as a reference solution. Take about 200 mg of vildagliptin, accurately weigh it, add 2 ml of the above solution to dissolve, as a mixed solution.

[0093] Designed for durability:

[0094] The initial column temperatures were selected as 75°C, 80°C, and 85°C respectively; the flow rates were selected as 1.8ml / min, 2.0ml / min, and 2.2ml / min respectively; the injection port and detector were selected as 240°C, 250°C, and 260°C respectively; 2μl of the reference solution and the mixed solution were accurately measured and injected into the gas chromatograph respectively, and the durability test was carried out by changing the above parameters.

[0095] The test results are shown in Table 3.

[0096] Table 3 Vildagliptin chloroacetyl chloride inspection durability test results

[0097]

[0098]

[0099] The changes in the above chromatographic conditions only slightly affected the retention time and peak area. The experimental results showed that the chromatographic conditions had good durability in determining chloroacetyl chloride.

[0100] 4. Durability test

[0101] Take about 150mg of chloroacetyl chloride, weigh it accurately, place it in a 100ml volumetric flask, add solvent to dissolve and dilute to the scale, shake well, accurately measure 5ml, place it in a 100ml volumetric flask, add solvent to dilute to the scale, shake well, and use it as the reference stock solution. Accurately measure 1ml, 2.5ml, 5ml, and 6ml of the reference stock solution respectively, place it in a 50ml volumetric flask, add solvent to dilute to the scale, shake well, and use them as 20% concentration, 50% concentration, 100% concentration, and 120% linear concentration series solutions respectively. Accurately measure 2μl of the quantitative limit solution and the above solution under the detection limit and quantitative limit items, respectively inject them into the gas chromatograph, and record the chromatogram. Perform linear regression on the peak area with concentration. Calculate the regression equation, correlation coefficient (r), and the ratio of intercept to 100% concentration response value (%) respectively.

[0102] The test results are shown in 4.

[0103] Table 4 Results of linearity test of vildagliptin chloroacetyl chloride

[0104]

[0105]

[0106] The test results show that chloroacetyl chloride has a good linear relationship in the concentration range of 0.489μg / ml to 8.884μg / ml.

[0107] 5. Detection limit and quantification limit test

[0108] Take an appropriate amount of chloroacetyl chloride reference substance, weigh it accurately, add an appropriate amount of solvent to dissolve and dilute it to make a series of concentration solutions. The quantification limit is when S / N (signal-to-noise ratio) ≈ 10, and the detection limit is when S / N (signal-to-noise ratio) ≈ 3.

[0109] The test results are shown in Table 5.

[0110] Table 5 Results of the quantitative limit and detection limit test of vildagliptin chloroacetyl chloride

[0111]

[0112] Take the quantitative limit concentration solution and inject it 6 times continuously, record the chromatogram, and calculate the relative standard deviation of the retention time and peak area of ​​chloroacetyl chloride.

[0113] The test results are shown in Table 6.

[0114] Table 6 Results of repeatability test for limit of quantitation of vildagliptin chloroacetyl chloride

[0115]

[0116] The test results showed that the quantitative limit concentration had good repeatability.

[0117] 6. Solution stability test

[0118] Take about 200 mg of vildagliptin, weigh accurately, and dissolve in 2 ml of solvent as the test solution;

[0119] Take about 150 mg of chloroacetyl chloride, accurately weigh it, place it in a 100 ml volumetric flask, add solvent to dissolve and dilute to the scale, shake well, accurately measure 5 ml, place it in a 100 ml volumetric flask, add solvent to dilute to the scale, shake well, accurately measure 5 ml, place it in a 50 ml volumetric flask, add solvent to dilute to the scale, shake well, as the reference solution.

[0120] Place the test solution and the reference solution at room temperature for 8 hours. Accurately measure 2 μl of the above solutions at 0 hour, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours, inject them into the gas chromatograph, and record the chromatogram.

[0121] The test results are shown in Table 7.

[0122] Table 7 Vildagliptin chloroacetyl chloride solution stability test results

[0123]

[0124] The test results show that chloroacetyl chloride has no change trend in the test solution and the reference solution, and is basically stable within 8 hours at room temperature.

[0125] 7. Accuracy test

[0126] Take about 150mg of chloroacetyl chloride, accurately weigh it, put it in a 100ml volumetric flask, add solvent to dissolve and dilute to the scale, shake well, accurately measure 5ml, put it in a 100ml volumetric flask, add solvent to dilute to the scale, shake well, as the reference substance stock solution, accurately measure 1ml, 2.5ml, 5ml, 6ml of the reference substance stock solution, put it in different 50ml volumetric flasks, add solvent to dilute to the scale, shake well, take about 200mg of the main component respectively, accurately weigh it, add 2ml of the above solution to dissolve, shake well, and use them as the accuracy series solutions of the recovery rate 0.0015% group, 0.00375% group, 0.0075% group, and 0.0090% group. Prepare three copies in the same way. Accurately measure 5ml of reference stock solution, place in a 50ml volumetric flask, dilute to scale with solvent, shake well, accurately measure 3.3ml and place in a 50ml volumetric flask, dilute to scale with solvent, shake well, take about 200mg of the main component, accurately weigh, add 2ml of the above solution to dissolve, shake well, and use them as the accuracy series solution of 0.0005% recovery rate. Prepare three copies in the same way. Accurately measure 2μl, inject into gas chromatograph, and record chromatogram. Take about 150mg of chloroacetyl chloride, accurately weigh, place in a 100ml volumetric flask, dissolve and dilute to scale with solvent, shake well, accurately measure 5ml, place in a 100ml volumetric flask, dilute to scale with solvent, shake well, accurately measure 5ml, place in a 50ml volumetric flask, dilute to scale with solvent, shake well, and use it as the reference solution. Determine in the same way, and calculate the recovery rate by peak area according to the external standard method.

[0127] The test results are shown in Table 8.

[0128] Table 8 Vildagliptin chloroacetyl chloride test accuracy test results

[0129]

[0130]

[0131] The test results show that the recovery rate of chloroacetyl chloride is between 92.62% and 107.27%, which meets the verification requirements (within the range of 85% to 110%), confirming that the method has good accuracy.

[0132] Summary of Method Validation Results

[0133]

[0134]

[0135] In summary, the present invention is a chloroacetyl chloride inspection method with the advantages of strong specificity, high sensitivity, small sample dosage, good repeatability of quantitative limit, high accuracy, strong durability, safe and environmentally friendly reagents used in the test, simple instrument operation, and applicability to most laboratories.

[0136] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for checking chloroacetyl chloride impurities in a vildagliptin raw material, the method comprising detecting chloroacetyl chloride impurities in the vildagliptin raw material by a direct solution injection method based on gas chromatography, wherein the solvent used in the solution is anhydrous ethanol; Take about 200 mg of vildagliptin, weigh accurately, and dissolve in 2 ml of anhydrous ethanol as the test solution; The method comprises: The gas chromatograph detector is a hydrogen flame ionization detector, the detector temperature is 240-260°C, the injection port temperature is 240-260°C, the chromatographic column uses a 6% cyanopropylphenyl-94% dimethylpolysiloxane capillary chromatographic column with a specification of 0.53mm×30m×3μm, programmed temperature, initial column temperature: 70-90°C, maintained for 4-6min, heated to 190-210°C at a rate of 5-15°C / min, and maintained for 15-20min.

2. The inspection method according to claim 1, characterized in that: The detector temperature was 240-260°C, the injection port temperature was 250°C, the chromatographic column used was 6% cyanopropylphenyl-94% dimethylpolysiloxane capillary column DB-624, the initial column temperature was 80°C, maintained for 5 minutes, then increased to 200°C at a rate of 10°C and maintained for 18 minutes.

3. The inspection method according to claim 2, characterized in that: The detector temperature was 250°C.

4. The inspection method according to claim 1, characterized in that: The sample was dissolved and diluted with anhydrous ethanol, and the direct injection method was adopted with a flow rate of 1.0-3.0 ml per minute and a split ratio of 5-15:

1.

5. The inspection method according to claim 4, characterized in that: The flow rate was 2.0 ml per minute; the split ratio was 10:

1.

6. The inspection method according to claim 1, characterized in that: The injection volume was 1-5 μl.

7. The inspection method according to claim 6, characterized in that: The injection volume was 2 μl.

8. The inspection method according to claim 1, characterized in that: The reference substance used in the test method is an absolute ethanol solution of chloroacetyl chloride.

9. The inspection method according to any one of claims 1 to 8, characterized in that: The quantitative method adopts the external standard method; the presence and content of chloroacetyl chloride are calculated by the peak area; the chloroacetyl chloride content shall not exceed 15ppm.

10. Use of the inspection method according to any one of claims 1 to 8 in the quality control of vildagliptin.

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