CN112684044A - Method for detecting residual solvent in lapatinib raw material medicine - Google Patents
Method for detecting residual solvent in lapatinib raw material medicine Download PDFInfo
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Abstract
The invention relates to a method for detecting residual solvent in lapatinib bulk drug, which adopts a headspace gas chromatography method and specifically comprises the following steps: utilizing a hydrogen Flame Ionization Detector (FID), detecting 7 organic solvents of ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene and N, N-dimethylformamide by a programmed temperature rise and headspace sample injection mode according to an external standard method. The method is simple to operate, high in sensitivity and good in accuracy, and is suitable for detecting 7 solvent residual solvents in lapatinib bulk drugs.
Description
Technical Field
The invention relates to a method for detecting residual solvents in lapatinib raw material medicines, which adopts headspace gas chromatography to detect the contents of ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene and N, N-dimethylformamide in lapatinib according to an external standard method, and belongs to the field of medicine analysis and detection.
Background
Lapatinib (lapatinib), trade name: tiglisha, developed by Kulansu Schker, UK, is an oral small molecule epidermal growth factor tyrosine kinase inhibitor, is unique in that it can act in multiple ways, rendering breast cancer cells unable to receive growth signals, and is suitable for use in combination with capecitabine in the treatment of Her2(ErbB-2) overexpressed in advanced or metastatic breast cancers that have previously been treated with anthracyclines, paclitaxel, and trastuzumab (herceptin). Currently, in China, lapatinib is mainly used as a first-line treatment drug for trastuzumab-resistant patients.
The method accurately measures the content of 7 residual solvents by using gas chromatography aiming at organic solvents of ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene and N, N-dimethylformamide used in the lapatinib raw material medicine synthesis process.
Disclosure of Invention
The invention aims to establish a method for detecting organic residual solvents in lapatinib bulk drugs, and the method is used for quickly and accurately detecting the residual quantity of 7 organic solvents including ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene and N, N-dimethylformamide in lapatinib by using a gas chromatography. The method has the advantages that: 1. the method is universal, high in practicability and simple to operate; 2. has enough sensitivity and good separation degree, and can effectively control the magazines.
The invention provides a method for detecting residual solvent in lapatinib bulk drug, which comprises the following steps:
(1) taking a proper amount of ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene and N, N-dimethylformamide, precisely weighing, placing into a same 100ml measuring flask, adding a dimethyl sulfoxide solvent, diluting to scale, shaking up, and preparing into mixed reference substance solutions with the concentrations of the ethanol, the acetone, the isopropanol, the dichloromethane, the tetrahydrofuran, the toluene and the N, N-dimethylformamide of 500, 60, 70, 90 and 90ug/ml respectively;
(2) accurately weighing 500mg of lapatinib, placing the lapatinib into a 10ml headspace bottle, adding 5ml of dimethyl sulfoxide, sealing, and shaking up gently to obtain a test solution;
(3) adopting gas chromatography and FID detector, heating, introducing sample via headspace, detecting blank solution, reference solution and sample solution, recording chromatogram, and calculating residual solvent content of ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene and N, N-dimethylformamide by external standard method.
Further, in the detection method, a polysiloxane capillary chromatographic column is adopted, the initial temperature is 20-50 ℃, the injection port temperature is 180-230 ℃, the detection temperature is 200-260 ℃, the carrier gas is inert gas, the flow rate is 1.0-4.0 ml/min, and the split ratio is 5-20: 1.
furthermore, in the detection method of the invention, the chromatographic column is Agilent DB-624(30m × 0.32mm, 1.8 μm); the initial temperature is preferably 30-35 ℃, and the optimal value is 30 ℃; the temperature of the injection port is preferably 200-210 ℃, and the optimal value is 200 ℃; the detection temperature is preferably 200-210 ℃, and the optimal value is 200 ℃; the carrier gas is N2(ii) a The flow rate is preferably 2.0 ml/min-4.0 ml/min, and the optimal value is 3.0 ml/min; the preferable flow dividing ratio is 10-15: 1, the optimal value is 10: 1.
compared with the prior art, the invention has the positive effects that:
1. the gas chromatography condition is suitable for detecting the organic solvent residue of the lapatinib bulk drug, and can quickly and accurately detect the content of 7 residual solvents, namely ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene and N, N-dimethylformamide.
2. The detection method disclosed by the invention is accurate, simple and convenient to operate, good in reproducibility and high in sensitivity, can fully meet the requirement of lapatinib bulk drug organic solvent residue determination, can better control the product quality, and ensures the drug safety.
Drawings
FIG. 1 blank solvent gas chromatogram
FIG. 2 is a gas chromatogram of a mixed system of ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene, and N, N-dimethylformamide
FIG. 3 gas chromatogram of sample solution
Detailed Description
Examples
1. Instrument and reagent
The instrument comprises the following steps: agilent 7890A gas chromatograph, 7697A headspace sample injector, detector FID; an Agilent chromatography workstation;
reagent testing: all the reagents are chromatographically pure; lapatinib (homemade).
2. Chromatographic conditions
A chromatographic column: agilent DB-624(30m × 0.32mm, 1.8 μm);
column temperature: maintaining at 30 deg.C for 6min, increasing to 200 deg.C at 30 deg.C/min, and maintaining for 6 min;
sample inlet temperature: 200 ℃;
detecting the temperature: 200 ℃;
carrier gas: n is a radical of2And the split ratio: 10: 1;
and (3) sample introduction mode: a headspace sampling method;
the balance time is as follows: 30 min;
equilibrium temperature: 80 ℃.
3. Solution preparation
Preparing a mixed reference substance solution: taking a proper amount of ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene and N, N-dimethylformamide, precisely weighing, placing in a 100ml measuring flask, adding a dimethyl sulfoxide solvent, diluting to scale, shaking uniformly, and preparing into mixed reference substance solutions of 500, 60, 70, 90 and 90ug/ml of ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene and N, N-dimethylformamide respectively.
Preparing a test solution: accurately weighing 500mg of lapatinib, placing the lapatinib into a 10ml headspace bottle, adding dimethyl sulfoxide to dilute to a scale, and shaking up to obtain a test solution.
4. Sample assay
Testing applicability of system
Precisely measuring 5ml of each of peak location solution of blank solvent (dimethyl sulfoxide), ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene and N, N-dimethylformamide and mixed reference solution, and injecting sample in headspace.
The blank solvent does not interfere with the organic residual solvent, all components are completely separated, R is more than 1.5, and the retention time and the separation degree of all components are shown in table 1. The original map is shown in FIGS. 1-3.
TABLE 1 measurement results of retention time and resolution of each component
(ii) precision test
The mixed control solution was injected into the headspace continuously for 6 times with RSD within 5%, see table 2.
Table 2 precision test results (n ═ 6)
③ Linear test
Precisely measuring mixed reference stock solutions 0.2 ml, 0.3 ml, 0.5 ml, 1.0 ml, 1.5 ml and 2.0ml, respectively placing in 10ml measuring bottles, adding dimethyl sulfoxide for diluting to scale, and shaking up; precisely measuring 5ml, placing into a 10ml headspace bottle, sealing, and making into a series of linear mixed control solutions with different concentrations. And (3) introducing a sample into a headspace, performing linear regression by taking the peak area of a reference substance as an ordinate and the concentration of a reference substance solution of ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene and N, N-dimethylformamide as an abscissa, and determining results shown in table 3.
TABLE 3 results of the Linear test
Recovery test
Precisely weighing 6 parts of lapatinib 100mg, respectively adding 5ml of ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene and N, N-dimethylformamide mixed reference substance stock solutions, adding dimethyl sulfoxide to dilute to a scale, shaking uniformly to serve as recovery rate sample solutions, respectively taking 5ml of headspace sample injection, recording a chromatogram, and calculating the recovery rate according to the following formula. The recovery rates that could be saved were between 90% and 110% (100% + -10%), and the results are shown in Table 4.
TABLE 4 results of recovery test
Detection line and quantitative limit
Calculating a detection line by using the signal-to-noise ratio S/N ═ 3, calculating a quantitative limit by using the signal-to-noise ratio S/N ═ 10, sequentially and respectively diluting ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene and N, N-dimethylformamide mixed reference substance stock solution, taking 5ml of headspace sample injection, recording a chromatogram, and obtaining the measurement results of the detection line and the quantitative limit in table 5.
TABLE 5 measurement results of each component detection line and quantitative limit
Sample detection
Precisely measuring 5ml of each of a test solution and a reference solution under a '3 solution preparation' phase, introducing a sample in a headspace, recording a chromatogram, wherein the content of methanol is not more than 0.5%, the content of acetone is not more than 0.5%, the content of isopropanol is not more than 0.5%, the content of dichloromethane is not more than 0.06%, the content of tetrahydrofuran is not more than 0.072%, the content of toluene is not more than 0.089%, and the content of N, N-dimethylformamide is not more than 0.088% in terms of peak area according to an external standard method.
The organic residual solvent of the sample was detected as described above, methanol 0.0%, acetone 0.0%, isopropanol 0.0%, dichloromethane 0.0%, tetrahydrofuran 0.0%, toluene 0.0%, and N, N-dimethylformamide 0.0%.
Claims (10)
1. A method for detecting residual solvents in lapatinib is characterized in that a detection method combining a gas chromatography and an external standard method is adopted, and 7 organic residual solvents of ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene and N, N-dimethylformamide are simultaneously detected.
2. The detection method according to claim 1, wherein the chromatographic column used in the detection method is a polysiloxane capillary chromatographic column.
3. The detection method according to claim 1, wherein the detection method employs a programmed temperature rise.
4. The method of claim 1, wherein the detection method is initiated at a temperature of 20 ℃ to 50 ℃.
5. The detection method according to claim 1, wherein the injection port temperature is 180 ℃ to 230 ℃.
6. The method according to claim 1, wherein the detection temperature is 200 to 260 ℃.
7. The detection method according to claim 1, wherein the carrier gas is an inert gas and has a flow rate of 1.0 to 4.0 ml/min.
8. The detection method according to claim 1, wherein the flow split ratio is 5-20: 1.
9. the detection method according to claim 1, wherein headspace sampling is employed.
10. The detection method according to claim 1, wherein the sample detection step of the detection method is as follows:
the method comprises the following steps: preparing a reference substance solution of the residual solvent to be detected;
step two: preparing a test solution;
step three: detecting blank solution, reference solution and sample solution by gas chromatography, recording chromatogram, and calculating residual solvent content of ethanol, acetone, isopropanol, dichloromethane, tetrahydrofuran, toluene and N, N-dimethylformamide by external standard method.
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CN103896926A (en) * | 2012-12-27 | 2014-07-02 | 上海创诺医药集团有限公司 | Poly-crystal-form substance of lapatinib ditosylate solvate as well as preparation method and application thereof |
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Patent Citations (3)
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CN103896926A (en) * | 2012-12-27 | 2014-07-02 | 上海创诺医药集团有限公司 | Poly-crystal-form substance of lapatinib ditosylate solvate as well as preparation method and application thereof |
CN111089911A (en) * | 2018-10-24 | 2020-05-01 | 江苏和成显示科技有限公司 | Method for detecting residual solvent in photoelectric display material |
CN110320293A (en) * | 2019-06-28 | 2019-10-11 | 北京澳合药物研究院有限公司 | A kind of method of residual solvent in measurement phthalide analog compound |
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