A method for detecting siloxane and phthalate in lacosamide injection

Abstract

The present invention relates to the technical field of drug analysis, and specifically discloses a detection method for siloxanes and phthalates in lacosamide injection. The present invention adopts gas chromatography-mass spectrometry, and gas chromatography adopts a chromatographic column with a stationary phase of 5% phenyl-methylpolysiloxane, with a specific program heating mode and gas chromatography conditions such as a specific injection port temperature and split ratio, in conjunction with specific mass spectrometry conditions, it is achieved that siloxanes and phthalates in lacosamide injection are accurately detected; and the method provided by the present invention has strong specificity, high sensitivity, and good linear relationship, and at the same time, it has good precision and durability, and it is possible to achieve trace detection of siloxanes and phthalates in lacosamide injection, which can be used as the basis for drug quality monitoring of lacosamide injection, and is more conducive to truly reflecting the quality of lacosamide injection, and thus is conducive to reducing the drug safety risk of lacosamide injection.

Description

Technical Field

[0001] The present invention relates to the technical field of drug analysis, and in particular to a method for detecting siloxane and phthalate in lacosamide injection. Background Art

[0002] Lacosamide, chemical name: (R)-2-(acetylamino)-N-benzyl-3-methoxypropionamide, chemical structure is as follows, is a new N-methyl-D-aspartate (NMDA) receptor glycine site binding antagonist, is an anticonvulsant drug with a new dual mechanism of action, used to treat epilepsy and neuropathic pain. Lacosamide has few side effects, is not metabolized by the liver, does not produce clinically significant drug interactions with other anti-epileptic drugs, has a unique mechanism of action, and can be used as a new treatment option for some patients with epileptic seizures.

[0003]

[0004] According to the Technical Guidelines for Compatibility Studies of Plastic Component Systems Used in the Production of Chemical Injections (Trial Implementation), it is necessary to study and analyze the antioxidants, plasticizers (methyl phthalate, diisobutyl phthalate) and silicone rubber oligomer components (such as D3, D4, D5, D6 epoxy silanes) that may be present in the production components.

[0005] The sensitivity of conventional gas chromatography or liquid chromatography detection methods cannot meet the detection requirements of siloxanes and phthalates in lacosamide injection. In order to better monitor the quality of lacosamide injection products and ensure the clinical drug safety of lacosamide injection products, it is necessary to develop an accurate and reliable method for detecting siloxanes and phthalates in lacosamide injection. Summary of the invention

[0006] In view of the problem that siloxanes and phthalates in lacosamide injection cannot be effectively detected in the prior art, the present invention provides a method for detecting siloxanes and phthalates in lacosamide injection.

[0007] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0008] A method for detecting siloxane and phthalate in lacosamide injection, using gas chromatography-mass spectrometry for detection, comprises the following steps:

[0009] (1) Preparation of test solution and mixed reference solution:

[0010] Take lacosamide injection, add halogenated hydrocarbon solvent for extraction, and take the organic phase as the test solution;

[0011] Taking the siloxane and phthalate reference substances, preparing a mixed reference substance solution with a halogenated hydrocarbon solvent;

[0012] (2) Testing the mixed reference solution and the test solution, wherein the gas chromatography conditions are:

[0013] Chromatographic column: The stationary phase is 5% phenyl-methylpolysiloxane;

[0014] Column temperature: 37-43°C for 2-4 min, then increase the temperature to 295-305°C at a rate of 14-16°C / min, maintain for 4-6 min, then increase the temperature to 315-325°C, maintain for 6-8 min;

[0015] Inlet temperature: 295℃-305℃;

[0016] Injection mode: split injection, split ratio is 18-22:1;

[0017] The mass spectrometer adopts an EI ion source and a single ion detection mode, wherein the quantitative ion of the hexamethylcyclotrisiloxane is 207m / z, and the qualitative ion is 191m / z; the quantitative ion of the octamethylcyclotetrasiloxane is 281m / z, and the qualitative ion is 265m / z; the quantitative ion of the decamethylcyclopentasiloxane is 355m / z, and the qualitative ion is 267m / z; the quantitative ion of the dodecamethylcyclohexasiloxane is 429m / z, and the qualitative ion is 341m / z; the quantitative ion of the dibutyl phthalate is 149m / z, and the qualitative ion is 223m / z; the quantitative ion of the diisobutyl phthalate is 149m / z, and the qualitative ion is 223m / z.

[0018] Compared with the prior art, the method for detecting siloxanes and phthalates in lacosamide injection provided by the present invention adopts gas chromatography, a chromatographic column with a stationary phase of 5% phenyl-methylpolysiloxane, a specific programmed temperature rising method and specific gas chromatography conditions such as injection port temperature and split ratio, and specific mass spectrometry conditions, so as to achieve accurate detection of siloxanes and phthalates in lacosamide injection; and the method provided by the present invention has strong specificity, high sensitivity, good linear relationship, and good precision and durability, and can achieve trace detection of siloxanes and phthalates in lacosamide injection, which can be used as the basis for drug quality monitoring of lacosamide injection, making up for the blank that the prior art cannot effectively detect siloxanes and phthalates in lacosamide injection at the same time, and is more conducive to truly reflecting the quality of lacosamide injection, thereby helping to reduce the drug safety risk of lacosamide injection.

[0019] It should be noted that the siloxanes described in the present invention are hexamethylcyclotrisiloxane, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane and dodecamethylcyclohexasiloxane, and the phthalates are dibutyl phthalate and diisobutyl phthalate.

[0020] Preferably, the column temperature is: maintained at 40°C for 3 min, then raised to 300°C at a rate of 15°C / min, maintained for 5 min, then raised to 320°C, maintained for 7 min.

[0021] It should be noted that the temperature was naturally raised to 320°C by the instrument and maintained for 7 minutes.

[0022] Preferably, the injection port temperature is 300°C.

[0023] Preferably, the split ratio is 20:1.

[0024] Preferably, the specification of the chromatographic column is 30 mm*250 μm, and the filler diameter is 0.25 μm.

[0025] Further preferably, the chromatographic column is Agilent HP-5ms, 30 mm*250 μm, 0.25 μm.

[0026] The preferred programmed temperature rising method combined with a specific chromatographic column can make the peak shape of the main component and each impurity good, and is conducive to improving the separation between the main component and each impurity, thereby realizing the qualitative and quantitative analysis of four siloxanes and two phthalates in lacosamide injection.

[0027] Preferably, the carrier gas is helium with a flow rate of 0.95 mL / min-1.05 mL / min.

[0028] Preferably, the injection volume is 1 μL.

[0029] Preferably, the ion source temperature of the mass spectrometer is 250° C., the quadrupole temperature is 150° C., and the ionization energy is 70 eV.

[0030] Under the optimal mass spectrometry analysis conditions, the accuracy of the determination of siloxanes and phthalates in lacosamide can be maximized.

[0031] Preferably, the halogenated hydrocarbon solvent is dichloromethane.

[0032] The preferred solvent can fully extract the main components of lacosamide as well as siloxanes and phthalates, thereby improving the accuracy of detection.

[0033] Furthermore, the method for preparing the test solution comprises the following steps:

[0034] Take 5 mL of lacosamide injection, add 5 mL of halogenated hydrocarbon solvent, shake and extract, and take the organic phase as the test solution.

[0035] It should be noted that, in order to improve the accuracy of detection, halogenated alkane extraction was used 2-3 times.

[0036] Preferably, the concentrations of hexamethylcyclotrisiloxane, octamethylcyclotetrasiloxane, dibutyl phthalate and diisobutyl phthalate in the mixed reference solution are all 2.5 μg / mL, and the concentrations of decamethylcyclopentasiloxane and dodecamethylcyclohexasiloxane are all 10 μg / mL.

[0037] The detection method provided by the present invention can realize the simultaneous and accurate quantitative detection of trace amounts of four siloxane substances and two phthalate substances in lacosamide injection, and through methodological research and verification, it is proved that the method of the present invention has good sensitivity, accuracy and reproducibility, which makes up for the gap that the prior art cannot realize the simultaneous and effective detection of plasticizers and silicone rubber oligomer components in lacosamide injection, thereby providing effective guarantee for improving and better controlling the quality of lacosamide injection drugs, which is beneficial to ensuring the consistency and stability of the quality of lacosamide injection products, thereby helping to improve the clinical safety and effectiveness of lacosamide injection medication, and has high practical value. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The chromatogram of the blank solution under 2.1 in Example 2;

[0039] Figure 2 The chromatogram of the reference solution under 2.1 in Example 2;

[0040] Figure 3 The chromatogram of the test solution under 2.1 in Example 2;

[0041] Figure 4 The chromatogram of the test sample plus reference solution under 2.1 in Example 2;

[0042] Figure 5 It is the chromatogram of the reference substance solution in Comparative Example 1. DETAILED DESCRIPTION

[0043] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0044] Example 1

[0045] 1.1 Solution preparation

[0046] (1) Blank solution: dichloromethane.

[0047] (2) Reference solution: Take appropriate amounts of hexamethylcyclotrisiloxane (D3), octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), dodecamethylcyclohexasiloxane (D6), dibutyl phthalate and diisobutyl phthalate reference substances, accurately weigh them, and use dichloromethane to prepare a solution containing approximately 2.5 μg each of D3, D4, dibutyl phthalate and diisobutyl phthalate, and 10 μg of D5 and D6 per 1 mL, as the reference solution.

[0048] (3) Test solution: Take 5 mL of lacosamide injection and place it in a 50-mL volumetric flask. Add 5 mL of dichloromethane and shake to extract. Extract twice and combine the organic phases to prepare the test solution.

[0049] (4) Test sample plus reference solution: Take appropriate amount of D3, D4, D5, D6, diisobutyl phthalate and dibutyl phthalate reference substances, weigh accurately, and use ethyl acetate to prepare a solution containing about 50 μg of D3, D4, diisobutyl phthalate and dibutyl phthalate, and 200 μg of D5 and D6 per 1 mL as the stock solution. Take 5 mL of lacosamide injection, place it in a 50 mL volumetric flask, add 0.5 mL of the above stock solution, and then add 5 mL of dichloromethane for extraction by shaking. Extract twice, combine the dichloromethane layers, and use them as the test sample plus reference solution.

[0050] 1.2 Detection method of siloxanes and phthalates in lacosamide injection:

[0051] Chromatographic conditions:

[0052] Instrument: Triple quadrupole gas chromatograph;

[0053] Chromatographic column: Agilent HP-5ms, 30mm*250μm, 0.25μm;

[0054] Carrier gas: helium, flow rate 1 mL / min;

[0055] Heating program: 40 °C for 3 min, then heated to 300 °C at a rate of 15 °C / min, maintained for 5 min, then heated to 320 °C, maintained for 7 min;

[0056] Transmission line temperature: 320°C;

[0057] Inlet temperature: 300°C;

[0058] Split ratio: 20:1;

[0059] The injection volume was 1 μL.

[0060] Mass spectrometry conditions:

[0061] EI ion source was used; quadrupole temperature: 150°C; ion source temperature: 250°C; ionization energy: 70 eV; ion detection mode: SIM mode; the detected ion pairs are shown in the table below.

[0062] name Quantitative ion (m / z) Qualifier ion (m / z) D3 (hexamethylcyclotrisiloxane) 207 191 D4(Octadimethylcyclotetrasiloxane) 281 265 D5 (Decamethylcyclopentasiloxane) 355 267 D6 (Dodecamethylcyclohexasiloxane) 429 341 Diisobutyl phthalate 149 223 Dibutyl phthalate 149 223

[0063] Example 2

[0064] Methodological validation:

[0065] 2.1 Exclusivity

[0066] Take 1 μL of each of the blank solution (dichloromethane), reference solution, test solution and test plus reference solution prepared in Example 1, and perform GC-MS detection according to the above conditions, and record the chromatograms. Figure 1-Figure 4 shown.

[0067] The test results showed that the baseline was stable, and the blank solution and lacosamide test sample had no interference with the detection of each impurity, indicating that this method has good specificity and is suitable for the detection of siloxanes and phthalates in lacosamide injection. The retention time of each impurity is shown in Table 1.

[0068] Table 1 Retention time of each impurity

[0069]

[0070] 2.2 Limit of detection and limit of quantification

[0071] Detection limit: Take the reference solution prepared in Example 1, dilute it quantitatively step by step with dichloromethane, perform GC-MS detection, record the chromatogram, and obtain the detection limit at a signal-to-noise ratio of not less than 3:1. The results are shown in Table 2.

[0072] Limit of quantitation: The reference solution prepared in Example 1 was diluted step by step with dichloromethane, and GC-MS was performed. The chromatogram was recorded, and the limit of quantitation was obtained with a signal-to-noise ratio of not less than 10:1. The results are shown in Table 2. Six portions of the limit of quantitation solution were prepared in parallel, GC-MS was performed, chromatograms were recorded, and the precision of the limit of quantitation was observed. The results are shown in Table 3.

[0073] Table 2 Detection limit and quantification limit test results

[0074]

[0075]

[0076] Table 3 Quantitation limit repeatability test results

[0077]

[0078] The results showed that the detection limit of D3 was 0.24μg / mL, which was equivalent to a detectable concentration of 0.49μg / mL in the sample; the detection limit of D4 was 0.25μg / mL, which was equivalent to a detectable concentration of 0.50μg / mL in the sample; the detection limit of D5 was 1.00μg / mL, which was equivalent to a detectable concentration of 2.00μg / mL in the sample; the detection limit of D6 was 0.95μg / mL, which was equivalent to a detectable concentration of 1.90μg / mL in the sample; the detection limit of diisobutyl phthalate was 0.22μg / mL, which was equivalent to a detectable concentration of 0.44μg / mL in the sample; the detection limit of dibutyl phthalate was 0.24μg / mL, which was equivalent to a detectable concentration of 0.49μg / mL in the sample.

[0079] The quantification limit of D3 is 0.49μg / mL, which is equivalent to a concentration of 0.98μg / mL in the sample that can be quantitatively detected; the quantification limit of D4 is 0.50μg / mL, which is equivalent to a concentration of 0.99μg / mL in the sample that can be quantitatively detected; the quantification limit of D5 is 2.00μg / mL, which is equivalent to a concentration of 3.99μg / mL in the sample that can be quantitatively detected; the quantification limit of D6 is 1.90μg / mL, which is equivalent to a concentration of 3.80μg / mL in the sample that can be quantitatively detected; the quantification limit of diisobutyl phthalate is 0.44μg / mL, which is equivalent to a concentration of 0.87μg / mL in the sample that can be quantitatively detected; the quantification limit of dibutyl phthalate is 0.49μg / mL, which is equivalent to a concentration of 0.98μg / mL in the sample that can be quantitatively detected. The quantification limit of 6 needles has good repeatability, which proves that this method has high sensitivity and meets the detection requirements of impurities in lacosamide injection.

[0080] 2.3 Linear range

[0081] Stock solution of reference substance: Take appropriate amount of D3, D4, D5, D6, diisobutyl phthalate and dibutyl phthalate reference substances, weigh accurately, and use dichloromethane to prepare a solution containing approximately 100 μg of D3, D4, diisobutyl phthalate and dibutyl phthalate, and 400 μg of D5 and D6 per 1 mL, as the stock solution of reference substance.

[0082] Linear solution: Accurately measure an appropriate amount of the reference stock solution and dilute it serially with dichloromethane to obtain the linear solution.

[0083] Each linear solution was taken for GC-MS detection and the spectrum was recorded. The standard curve was drawn with the impurity concentration (μg / mL) as the abscissa and the peak area as the ordinate, and the regression equation was calculated. The results are shown in Tables 4 to 9.

[0084] Table 4D3 linear test results

[0085]

[0086] Table 5D4 Linearity test results

[0087]

[0088] Table 6D5 Linearity test results

[0089]

[0090] Table 7D6 Linearity test results

[0091]

[0092] Table 8 Linearity test results of diisobutyl phthalate

[0093]

[0094] Table 9 Linearity test results of dibutyl phthalate

[0095]

[0096] The test results showed that D3 had a good linear relationship in the concentration range of 0.51-5.08μg / mL, and the linear correlation coefficient r was greater than 0.9992; D4 had a good linear relationship in the concentration range of 0.50-5.03μg / mL, and the linear correlation coefficient r was greater than 0.9991; D5 had a good linear relationship in the concentration range of 2.09-20.95μg / mL, and the linear correlation coefficient r was greater than 0.9989; D6 had a good linear relationship in the concentration range of 2.03-20.34μg / mL, and the linear correlation coefficient r was greater than 0.9989; diisobutyl phthalate had a good linear relationship in the concentration range of 0.50-5.03μg / mL, and the linear correlation coefficient r was greater than 0.9990; dibutyl phthalate had a good linear relationship in the concentration range of 0.52-5.24μg / mL, and the linear correlation coefficient r was greater than 0.9984.

[0097] 2.4 Repeatability

[0098] Test solution: Take 5 mL of lacosamide injection, place it in a 50 mL volumetric flask, add 5 mL of dichloromethane and shake for extraction. Extract twice, combine the organic phases as the test solution, and prepare 6 copies in parallel.

[0099] The test solution prepared above was taken for GC-MS detection, and the chromatogram was recorded. The test results are shown in Table 10.

[0100] Table 10 Repeatability test results

[0101]

[0102] The test results show that 6 solutions were prepared from the same batch of samples, and no diisobutyl phthalate and dibutyl phthalate were detected in the test samples D3, D4, D5, and D6, with good reproducibility.

[0103] 2.5 Accuracy

[0104] Take 80%, 100% and 120% of the impurity limit of each impurity as recovery test samples.

[0105] Recovery rate stock solution: Take appropriate amounts of D3, D4, D5, D6, diisobutyl phthalate and dibutyl phthalate, accurately weigh them, and use ethyl acetate to prepare a solution containing approximately 50 μg of D3, D4, diisobutyl phthalate and dibutyl phthalate, and 200 μg of D5 and D6 per 1 mL, as the recovery rate stock solution.

[0106] Low recovery solution: Take 5 mL of lacosamide injection, place it in a 50 mL volumetric flask, add 0.4 mL of recovery stock solution, and then add 5 mL of dichloromethane for shaking extraction. Extract twice, combine the dichloromethane layers as the low recovery solution, and prepare 3 copies in parallel.

[0107] Medium recovery solution: Take 5 mL of lacosamide injection, place it in a 50 mL volumetric flask, add 0.5 mL of recovery stock solution, and then add 5 mL of dichloromethane for shaking extraction. Extract twice, combine the dichloromethane layers as the medium recovery solution, and prepare 3 copies in parallel.

[0108] High recovery solution: Take 5 mL of lacosamide injection, place it in a 50 mL volumetric flask, add 0.6 mL of recovery stock solution, and then add 5 mL of dichloromethane for shaking extraction. Extract twice, combine the dichloromethane layers as the high recovery solution, and prepare 3 copies in parallel.

[0109] The reference solution and each recovery solution were taken for GC-MS detection, and the spectra were recorded. The recovery results are shown in Tables 11 to 16.

[0110] Recovery rate (%) = (measured amount - original amount) / added amount × 100%.

[0111] Table 11D3 recovery test results

[0112]

[0113] Table 12D4 recovery test results

[0114]

[0115]

[0116] Table 13D5 recovery test results

[0117]

[0118] Table 14D6 recovery test results

[0119]

[0120]

[0121] Table 15 Recovery test results of diisobutyl phthalate

[0122]

[0123] Table 16 Recovery test results of dibutyl phthalate

[0124]

[0125]

[0126] The results showed that the recovery rate RDS of each impurity was less than 10%, and the method had good accuracy.

[0127] 2.6 Precision

[0128] Reference solution: Take appropriate amounts of D3, D4, D5, D6, diisobutyl phthalate and dibutyl phthalate, weigh accurately, and use dichloromethane to prepare a solution containing approximately 2.5 μg of D3, D4, diisobutyl phthalate and dibutyl phthalate, and 10 μg of D5 and D6 per 1 mL, as the reference solution.

[0129] The reference solution was taken for GC-MS detection, and the sample was injected and tested 6 times continuously. The spectrum was recorded and the detection results are shown in Table 17.

[0130] Table 17 Precision test results

[0131]

[0132] The results showed that after 6 consecutive tests, the RSD values ​​of the peak areas of various impurities were all less than 10%, indicating that the method had good precision.

[0133] 2.7 Durability

[0134] Reference solution: Take appropriate amounts of D3, D4, D5, D6, diisobutyl phthalate and dibutyl phthalate, weigh accurately, and use dichloromethane to prepare a solution containing approximately 2.5 μg of D3, D4, diisobutyl phthalate and dibutyl phthalate, and 10 μg of D5 and D6 per 1 mL, as the reference solution.

[0135] The reference solution was subjected to GC-MS detection and the chromatogram was recorded. The durability of each impurity was investigated by fine-tuning the chromatographic conditions: initial column temperature 37°C and 43°C, heating rate 16°C / min and 14°C / min, injection port temperature 305°C and 295°C, carrier gas flow rate 0.95mL / min and 1.05mL / min, and the results are shown in Table 18.

[0136] Table 18 Durability test results

[0137]

[0138]

[0139] The results showed that fine-tuning the chromatographic conditions had no effect on the detection of each impurity, and the method had good durability.

[0140] 2.8 Intermediate precision

[0141] Test solution: Take 5 mL of lacosamide injection, place it in a 50 mL volumetric flask, add 5 mL of dichloromethane and shake for extraction. Extract twice, combine the organic phases as the test solution, and prepare 6 copies in parallel.

[0142] Take the test solution prepared above for GC-MS detection and record the chromatogram. The date and operator of this part of the test are different from those of the repeatability test. The test results are shown in Table 19.

[0143] Table 19 Intermediate precision test results

[0144]

[0145] The results showed that diisobutyl phthalate and dibutyl phthalate were not detected in the 6 test solutions, D3, D4, D5, and D6, which was consistent with the repeatability results. The intermediate precision of this method was good.

[0146] 2.9 Stability

[0147] Reference solution: Take appropriate amounts of D3, D4, D5, D6, diisobutyl phthalate and dibutyl phthalate, weigh accurately, and use dichloromethane to prepare a solution containing approximately 2.5 μg of D3, D4, diisobutyl phthalate and dibutyl phthalate, and 10 μg of D5 and D6 per 1 mL, as the reference solution.

[0148] Test solution: Take 5 mL of lacosamide injection, place it in a 50 mL volumetric flask, add 5 mL of dichloromethane and shake to extract, extract twice, and combine the organic phases as the test solution.

[0149] The reference solution and the test solution were placed at room temperature, and GC-MS detection was performed every 0h, 2h, 4h, 6h, and 8h, and the chromatograms were recorded. The test results are shown in Tables 20 and 21.

[0150] Table 20 Results of stability test of each impurity reference solution

[0151]

[0152] Table 21 Test solution stability test results

[0153]

[0154]

[0155] The results showed that after the test solutions were left at room temperature for 8 hours, diisobutyl phthalate and dibutyl phthalate of D3, D4, D5 and D6 were not detected; after the reference solution was left at room temperature for 8 hours, the RSD of the peak area of ​​each impurity was ≤10%, indicating that the above solutions had good stability.

[0156] Example 3 Sample Detection

[0157] According to the detection method of Example 1, the contents of D3, D4, D5, and D6 diisobutyl phthalate and dibutyl phthalate in 4 batches of lacosamide injection samples were detected. The results are shown in Table 22.

[0158] Table 22 Sample test results

[0159]

[0160] The results showed that diisobutyl phthalate D3, D4, D5, and D6 and dibutyl phthalate were not detected in the four batches of lacosamide injection samples, which was in compliance with regulations.

[0161] Comparative Example 1

[0162] This comparative example provides a method for detecting siloxane and phthalate in lacosamide injection. The detection conditions are exactly the same as those in Example 1, except that the solvent dichloromethane used to prepare the test solution and the reference solution is replaced by ethyl acetate. The chromatogram is shown in FIG. Figure 5 shown.

[0163] According to the determination method of the quantitative limit and detection limit in Example 2, the detection ability of this condition was tested, and the results are shown in Table 23.

[0164] Table 23

[0165]

[0166] The results show that compared with ethyl acetate as a solvent, the reference solution prepared with dichloromethane has less baseline interference and higher detection sensitivity.

[0167] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for detecting siloxane and phthalate in lacosamide injection, wherein the siloxane is hexamethylcyclotrisiloxane, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane and dodecamethylcyclohexasiloxane, and the phthalate is dibutyl phthalate and diisobutyl phthalate, characterized in that: The detection is carried out by gas chromatography-mass spectrometry, which includes the following steps: (1) Preparation of test solution and mixed reference solution: Take lacosamide injection, add dichloromethane for extraction, and take the organic phase as the test solution; Taking the siloxane and phthalate reference substances, preparing a mixed reference substance solution with a halogenated hydrocarbon solvent; (2) Testing the mixed reference solution and the test solution, wherein the gas chromatography conditions are: Chromatographic column: Agilent HP-5ms, 30mm*250µm, 0.25µm; Column temperature: 37-43°C for 2-4 min, then increase the temperature to 295-305°C at a rate of 14-16°C / min, maintain for 4-6 min, then increase the temperature to 315-325°C, maintain for 6-8 min; Inlet temperature: 295℃-305℃; Injection mode: split injection, split ratio is 18-22:1; The mass spectrometer adopts EI ion source and single ion detection mode.

2. The method for detecting siloxane and phthalate in lacosamide injection according to claim 1, characterized in that: The quantitative ion of hexamethylcyclotrisiloxane is 207m / z, and the qualitative ion is 191m / z; the quantitative ion of octamethylcyclotetrasiloxane is 281m / z, and the qualitative ion is 265m / z; the quantitative ion of decamethylcyclopentasiloxane is 355m / z, and the qualitative ion is 267m / z; the quantitative ion of dodecamethylcyclohexasiloxane is 429m / z, and the qualitative ion is 341m / z; the quantitative ion of dibutyl phthalate is 149m / z, and the qualitative ion is 223m / z; the quantitative ion of diisobutyl phthalate is 149m / z, and the qualitative ion is 223m / z.

3. The method for detecting siloxane and phthalate in lacosamide injection according to claim 1, characterized in that: The column temperature was: maintained at 40°C for 3 min, then raised to 300°C at a rate of 15°C / min, maintained for 5 min, then raised to 320°C, maintained for 7 min.

4. The method for detecting siloxane and phthalate esters in lacosamide injection according to claim 1, characterized in that: Inlet temperature: 300℃.

5. The method for detecting siloxane and phthalate in lacosamide injection according to claim 1, characterized in that: The split ratio is 20:

1.

6. The method for detecting siloxane and phthalate in lacosamide injection according to claim 1, characterized in that: The carrier gas was helium with a flow rate of 0.95 mL / min-1.05 mL / min.

7. The method for detecting siloxane and phthalate esters in lacosamide injection according to claim 1, characterized in that: The injection volume was 1 μL.

8. The method for detecting siloxane and phthalate esters in lacosamide injection according to claim 1, characterized in that: The ion source temperature of the mass spectrometer is 250° C., the quadrupole temperature is 150° C., and the ionization energy is 70 eV.

9. The method for detecting siloxane and phthalate esters in lacosamide injection according to claim 1, characterized in that: The concentrations of hexamethylcyclotrisiloxane, octamethylcyclotetrasiloxane, dibutyl phthalate and diisobutyl phthalate in the mixed reference solution were all 2.5 μg / mL, and the concentrations of decamethylcyclopentasiloxane and dodecamethylcyclohexasiloxane were all 10 μg / mL.

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