Detection method of residual solvents in (N-(3-chloro-4-(3-fluorobenzyloxy)phenyl-6-(3-(4-methyl-4-oxo-1-nitrogen-4-phosphorus hetero yclohexane-1-yl)propyl-1-alkynyl)quinazoline-4-amine, bis 4-methyl benzenesulfonate bulk drug

A kind of technology of toluenesulfonic acid generation and detection method, which is applied in the field of analytical chemistry

Inactive Publication Date: 2016-03-09
JIANGSU KANION PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Used organic solvent methanol, ethanol, isopropanol and N,N-dimethylformamide in the synthetic technique of di-p-toluenesulfonic acid ersentinib, these organic solvents can be detect

Method used

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  • Detection method of residual solvents in (N-(3-chloro-4-(3-fluorobenzyloxy)phenyl-6-(3-(4-methyl-4-oxo-1-nitrogen-4-phosphorus hetero yclohexane-1-yl)propyl-1-alkynyl)quinazoline-4-amine, bis 4-methyl benzenesulfonate bulk drug
  • Detection method of residual solvents in (N-(3-chloro-4-(3-fluorobenzyloxy)phenyl-6-(3-(4-methyl-4-oxo-1-nitrogen-4-phosphorus hetero yclohexane-1-yl)propyl-1-alkynyl)quinazoline-4-amine, bis 4-methyl benzenesulfonate bulk drug
  • Detection method of residual solvents in (N-(3-chloro-4-(3-fluorobenzyloxy)phenyl-6-(3-(4-methyl-4-oxo-1-nitrogen-4-phosphorus hetero yclohexane-1-yl)propyl-1-alkynyl)quinazoline-4-amine, bis 4-methyl benzenesulfonate bulk drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Investigate the system applicability of the method provided by the present invention:

[0052] Continuous injection of 6 standard solutions. By repeatedly measuring the peak area of ​​each solvent in the standard solution 6 times, and calculating the relative standard deviation RSD of the 6 peak areas, the RSD value is examined to judge the applicability of the system. The specific method is:

[0053] 1. Instrument

[0054] Gas chromatograph model: Agilent6890A

[0055] Headspace sampler model: Agilent7694E

[0056] 2. Chromatographic conditions: as shown in Table 1, headspace sampling conditions as shown in Table 2:

[0057] Table 1 Chromatographic conditions

[0058]

[0059] Table 2 headspace sampler parameters

[0060] Equilibrium temperature (℃)

[0061] 3 Preparation of solution

[0062] Blank solution: Accurately pipette 10ml of dimethyl sulfoxide (DMSO) into a 20ml headspace vial.

[0063] Preparation of the control stock solution: Accurately...

Embodiment 2

[0075] The specificity and selectivity investigation is mainly to investigate the identification and selectivity of peaks, and its requirements: only the blank solution and the positioning solution of all solvents are used to determine all potential impurities, and the separation between the main peak and adjacent chromatographic peaks must not less than 1.5.

[0076] Instrument, chromatographic condition, solution are identical with embodiment 1, and experimental result is as shown in table 4~5:

[0077] Table 4 Residual Solvent Positioning Solution Determination Results

[0078] remaining solvent

[0079] Table 5 mixed standard solution measurement results

[0080] remaining solvent

[0081] Conclusion: The test shows that the samples measured by this method have good results, and the resolution is greater than 1.5.

Embodiment 3

[0083] Prepare a mixed reference solution of methanol 63.09 μg / ml, ethanol 100.49 μg / ml, isopropanol 102.39 μg / ml and DMF solution 19.05 μg / ml. Dilute the above solutions to appropriate concentrations, respectively, take 10mL and inject them into 20mL headspace vials. For these known residual solvents, the limit of quantitation was determined by calculation of the signal-to-noise ratio. Dilute the stock solution of the known residual solvent to a certain concentration, compare the measured response signal with the response signal in the blank, and calculate the true and reliable minimum concentration that can be detected. Instrument, chromatographic condition, solution are identical with embodiment 1, and detection result is as shown in table 6:

[0084] Table 6: Quantitation limit test results

[0085] test solution

[0086] The results show that the method provided by the invention has a lower detection limit, indicating higher sensitivity.

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Abstract

The invention relates to the technical field of analysis chemistry, and in particular relates to a detection method of residual solvents in a (N-(3-chloro-4-(3-fluorobenzyloxy)phenyl-6-(3-(4-methyl-4-oxo-1-nitrogen-4-phosphorus hetero yclohexane-1-yl)propyl-1-alkynyl)quinazoline-4-amine, bis 4-methyl benzenesulfonate bulk drug. According to the method, the (N-(3-chloro-4-(3-fluorobenzyloxy)phenyl-6-(3-(4-methyl-4-oxo-1-nitrogen-4-phosphorus hetero yclohexane-1-yl)propyl-1-alkynyl)quinazoline-4-amine, bis 4-methyl benzenesulfonate bulk drug is dissolved by DMSO, and then is injected in headspace, and the contents of four residual solvents, namely methyl alcohol, ethanol, isopropyl alcohol and N,N-dimethylformamide are detected by gas chromatography; and the column temperature of the gas chromatography is maintained for 5min at 35-50 DEG C, and then raised to 220+/-10 DEG C at the speed of 20 DEG C/min and maintained for 5-9min. According to the detection method, by verification, methyl alcohol has a detection limit of 0.3ppm and a quantification limit of 1.6ppm, ethanol has a detection limit of 0.5ppm and a quantification limit of 2.5ppm, isopropyl alcohol has a detection limit of 0.5ppm and a quantification limit of 2.6ppm, and DMG has a detection limit of 8.5ppm and a quantification limit of 19.1ppm. After the same sample is repeatedly detected for six times, the RSD is less than or equal to 2%, and the added sample recovery rate is 97.4%-103.1%, which indicates that the accuracy and precision are good.

Description

technical field [0001] The invention relates to the technical field of analytical chemistry, in particular to a method for detecting residual solvents in the crude drug of ersentinib di-p-toluenesulfonate. Background technique [0002] (N-(3-Chloro-4-(3-fluorobenzyloxy)phenyl)-6-(3-(4-methyl-4-oxyl-1-nitrogen-4-phosphorinyl Alkyl-1-yl)prop-1-ynyl)quinazolin-4-amine, bis-4-methylbenzenesulfonate), also known as di-p-toluenesulfonic acid, was developed in recent years Novel quinazoline derivatives containing phosphorus substitutions that are inhibitors of type I receptor protein kinases. It can be used to treat diseases associated with abnormal protein kinase activity in mammals, such as cancer or inflammation. [0003] As a newly developed drug, in order to ensure its quality and drug safety, it is necessary to check the content of active ingredients and types of related substances in the raw material drug during production and use. and content, residual solvents, and micr...

Claims

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Application Information

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IPC IPC(8): G01N30/88
CPCG01N30/88
Inventor 萧伟仲艳李家春陈保来王志霞刘利黄文哲王振中
Owner JIANGSU KANION PHARMA CO LTD
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