CN105388242A - 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 - Google Patents

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 Download PDF

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CN105388242A
CN105388242A CN201510767228.8A CN201510767228A CN105388242A CN 105388242 A CN105388242 A CN 105388242A CN 201510767228 A CN201510767228 A CN 201510767228A CN 105388242 A CN105388242 A CN 105388242A
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detection method
methyl
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method according
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CN201510767228.8A
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萧伟
仲艳
李家春
陈保来
王志霞
刘利
黄文哲
王振中
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江苏康缘药业股份有限公司
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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02Column chromatography
    • G01N30/88Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86

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

The raw detection method for residual solvent in Buddhist nun's bulk drug of two p-toluenesulfonic acid edge

Technical field

The present invention relates to technical field of analytical chemistry, particularly relate to the raw detection method for residual solvent in Buddhist nun's bulk drug of two p-toluenesulfonic acid edge.

Background technology

(N-(3-chloro-4-(3-fluorinated benzyloxy) phenyl)-6-(3-(4-methyl-4-Oxy-1-nitrogen-4-phospha cyclohexane-1-base) the third-1-alkynyl) quinazoline-4-amine, two 4-toluenesulfonate), having another name called two p-toluenesulfonic acid edge raw for Buddhist nun, is the new quinazoline derivant comprising phosphorus replacement of the I receptor kinases inhibitor developed in recent years.Can be used for treating relevant disease abnormal to protein kinase activity in mammal, as cancer or inflammation.

Two p-toluenesulfonic acid edge are raw replaces Buddhist nun as a kind of medicine newly developed, in order to ensure the security of its quality and medication, in the process of producing and use, all need to carry out determination and analysis to the active constituent content in bulk drug, related substance contamination, residual solvent, microorganism situation.

Residual solvent in medicine refers to and to use in bulk drug, auxiliary material and preparation are produced, but in technological process, fail the organic volatile compound removed completely.Organic solvent is essential and very crucial material in drug synthetic reaction, but when the residual solvent level contained by medicine is higher than safety value, to human body or environmental danger, therefore will more and more receive the concern of people to the control of residual solvent.

Two p-toluenesulfonic acid edge are raw has used organic solvent methyl alcohol, ethanol, isopropyl alcohol and N in the synthesis technique of Buddhist nun, dinethylformamide, these organic solvents can adopt gas chromatography to detect, but not yet have the report about the raw detection method for residual solvent in Buddhist nun of two p-toluenesulfonic acid edge at present.Therefore, should detection limit be developed, quantitative limit is low; Sensitivity, specificity are strong; The raw assay method for residual solvent in Buddhist nun's bulk drug of two p-toluenesulfonic acid edge that precision, accuracy are high.

Summary of the invention

In view of this, to be to provide detection limit, quantitative limit low for the technical problem to be solved in the present invention; Precision, the raw detection method for residual solvent in Buddhist nun's bulk drug of the two p-toluenesulfonic acid edge that accuracy, stability are high.

The raw detection method for residual solvent in Buddhist nun's bulk drug of two p-toluenesulfonic acid edge provided by the invention, dissolves two p-toluenesulfonic acid edge with DMSO raw for Buddhist nun's bulk drug, headspace sampling, gas chromatographic detection residual solvent levels; The column temperature of gas chromatography is: 35 DEG C ~ 50 DEG C keep 5min, 20 DEG C/min to be warming up to 220 DEG C ± 10 DEG C, keep 5min ~ 9min.

Two p-toluenesulfonic acid edge provided by the invention are raw to be undertaken by vapor-phase chromatography for the detection method of related substance in Buddhist nun's bulk drug.Utilizing gas chromatography (GC) to carry out quantitatively detecting to small molecule solvent is detection method conventional at present, faced by need to carry out quantitative test to two p-toluenesulfonic acid edge are raw for residual solvent in Buddhist nun's bulk drug time, adopt gas chromatography to be one mode fast and effectively.But, in prior art, how report does not adopt GC quantitatively to detect for the residual solvent in Buddhist nun two p-toluenesulfonic acid edge are raw, and need to carry out the method many-sided qualifications such as precision, accuracy, durability when adopting GC to detect a kind of new material, specific standards is:

Precision mainly with repeatability embody, preparation need testing solution, adopt method replication 6 provided by the invention this, the RSD of measurement result is not more than 10% explanation and has good reappearance;

Accuracy paper examines average recovery, the recovery is by adding the recovery gained recorded relative to 80%, 100%, 120% 3 each solvent of variable concentrations of standard solution in the test sample of fixed amount.Add the solvent of known quantity, the ratio (recovery) in working sample between the measurement result of each solvent and theoretical value, express with percent %, require that the recovery is between 80%-120%, namely provable the method has good accuracy.

Main consideration stability of solution: need testing solution is stable in 24h, and require that the subtle change of testing conditions is little to the determination influences of main peak content, degree of separation, theoretical cam curve all meet the requirements.

Linear and scope: regression coefficient r: >=0.99.

In order to good Detection results can be reached, need to consider the impact of each parameter on Detection results.

Column temperature is an important operating parameter, directly affects separation efficiency and analysis speed.Improving column temperature can make mass transferring in gas phase speed accelerate, and is conducive to reducing plate height, improves post effect.But increase column temperature and aggravate longitudinal diffusion again simultaneously, thus cause post to imitate decline.In addition, in order to improve separation, improve selectivity, often wish that column temperature is lower, this increases analysis time again.Therefore, column temperature is selected will to take into account the factor of several respects.Rule is: under making the component of the most difficult separation have separation prerequisite as well as possible, take suitably low column temperature, but is suitable for retention time, and peak shape is not trailed for degree.The selection of concrete operations condition should be determined according to actual conditions.

In an embodiment of the present invention, the column temperature of gas chromatography is: 40 DEG C keep 5min, and 20 DEG C/min is warming up to 220 DEG C, keep 7min.

In an embodiment of the present invention, the detector temperature of gas chromatography is 280 DEG C; Injector temperature is 220 DEG C.

In an embodiment of the present invention, dissolve two p-toluenesulfonic acid edge lifes with DMSO and replace Buddhist nun's bulk drug to concentration for 0.1g/mL.

In gas chromatography, various gas, the purity as carrier gas, combustion gas, combustion-supporting gas etc. directly can affect chromatographic sensitivity, stability, the even life-span of chromatographic column, and the flow velocity of carrier gas is one of major reason determining chromatographic resolution.When flow velocity is low, the diffusion ratio of sample is comparatively serious, and post effect is lower; When flow velocity is too high, the resistance to mass tranfer item of sample is comparatively large, and post effect is also lower.

In an embodiment of the present invention, the carrier gas of gas chromatography is nitrogen.

In an embodiment of the present invention, the flow rate of carrier gas of gas chromatography is 2.3mL/min ~ 2.7mL/min.

In an embodiment of the present invention, the flow rate of carrier gas of gas chromatography is 2.5mL/min.

In an embodiment of the present invention, the split ratio of gas chromatography is 1:1.

In an embodiment of the present invention, the air velocity of gas chromatography is 0.8mL/min.

In an embodiment of the present invention, the chromatographic column of gas chromatography is HP-5Agilent18095J-023; Chromatographic column specification is 30m*530 μm * 0.88 μm.

In an embodiment of the present invention, the detecting device of gas chromatography is FID.

In an embodiment of the present invention, the equilibrium temperature of headspace sampling is 90 DEG C ~ 110 DEG C; Equilibration time is 20min ~ 40min.

In an embodiment of the present invention, the equilibrium temperature of headspace sampling is 100 DEG C; Equilibration time is 30min.

In an embodiment of the present invention, the quantity tube temperature of headspace sampling is 110 DEG C; Transmission line temperature is 125 DEG C.

In an embodiment of the present invention, the pressing time of headspace sampling is 0.5min; The quantity tube filling time is 0.2min; Quantity tube equilibration time is 0.1min.

Peak height and sample size linear, if looked into maximum permission sample size, linear relationship can be destroyed.

In an embodiment of the present invention, the sample injection time of headspace sampling is 1min; Sample size is 1.0mL.

In an embodiment of the present invention, the acquisition of residual solvent levels adopts external standard method.

In certain embodiments, the residual quantity of solvent

In formula, Wr is the sample weighting amount of reference substance; Ai is the peak area of each residual solvent in the solution of test sample; Ni is test sample extension rate; Wi is the sample weighting amount of test sample; The mean value of the peak area of each residual solvent in Ar reference substance solution; Nr: the extension rate of reference substance.

The raw detection method for residual solvent in Buddhist nun's bulk drug of two p-toluenesulfonic acid edge provided by the invention, dissolves two p-toluenesulfonic acid edge with DMSO raw for Buddhist nun's bulk drug, headspace sampling, gas chromatographic detection residual solvent levels; The column temperature of gas chromatography is: 35 DEG C ~ 50 DEG C keep 5min, 20 DEG C/min to be warming up to 220 DEG C ± 10 DEG C, keep 5min ~ 9min.Detection method empirical tests provided by the invention is limited to 0.3ppm to detecting of methyl alcohol, is quantitatively limited to 1.6ppm; Detecting of ethanol is limited to 0.5ppm, is quantitatively limited to 2.5ppm; Detecting of isopropyl alcohol is limited to 0.5ppm, is quantitatively limited to 2.6ppm; Detecting of DMG is limited to 8.5ppm, 19.1ppm.Repeat 6 times and detect same sample RSD≤2%, illustrate that there is good precision; Average recovery 97.4% ~ 103.1%, illustrates to have good accuracy.

Accompanying drawing explanation

The method that the invention provides of showing Fig. 1 detects the raw typical curve for residual methanol in Buddhist nun's bulk drug of two p-toluenesulfonic acid edge;

The method that the invention provides of showing Fig. 2 detects the raw typical curve for residual ethanol in Buddhist nun's bulk drug of two p-toluenesulfonic acid edge;

The method that the invention provides of showing Fig. 3 detects the raw typical curve for residual isopropanol in Buddhist nun's bulk drug of two p-toluenesulfonic acid edge;

The method that the invention provides of showing Fig. 4 detects the raw typical curve for DMF residual in Buddhist nun's bulk drug of two p-toluenesulfonic acid edge.

Embodiment

The invention provides the raw detection method for residual solvent in Buddhist nun's bulk drug of two p-toluenesulfonic acid edge, those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can change methods and applications herein or suitably changes and combination not departing from content of the present invention, spirit and scope, realizes and applies the technology of the present invention.

The instrument that the present invention adopts is all common commercially available product, all can buy in market.

Wherein, the raw preparation method for Buddhist nun's bulk drug of two p-toluenesulfonic acid edge is:

301g3-chloro-4-(3-fluoro-benzyloxy)-aniline and 3.28g4-chloro-6-iodo-quinazoline are dissolved in 50mL isopropyl alcohol, by reaction mixture refluxed 12 hours, by filtering mobile phone solid product, with 10mL cold isopropanol and 20mL washed with diethylether, dry and obtain 3.8g [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-base)-amine hydrochlorate;

In parr oscillator under 60psi by 1-benzyl-4-methyl isophthalic acid, the methanol solution (50mL) of 4-azepine phosphine-4-oxide (5g) and 3mol/LHCl (10mL) carry palladium (10% with carbon, 1.0g) hydrogenation 24 hours together, potpourri is through diatomite filtration, under reduced pressure remove all solvents to obtain white crystalline solid 4-methyl isophthalic acid, 4-azepine phosphine-4-oxide hydrochloride, it uses without the need to being further purified;

To Cs 2cO 3(1.3g, 4.0mmol), acetone (5.0mL) and 4-methyl isophthalic acid, add propargyl chloride (150mg, 2.0mmol) in the potpourri of 4-azepine phosphine-4-oxide hydrochloride (0.338mg, 2.0mmol).Stirring the mixture at 50 DEG C and spend the night, filter and concentrate, obtaining light tan solid: 4-methyl isophthalic acid-(Propargyl)-Isosorbide-5-Nitrae-azepine phosphine, 4-oxide, carrying out next step without the need to being further purified;

At N 2by amine, 4-methyl isophthalic acid-(Propargyl)-1 under atmosphere, 4-azepine phosphine, 4-oxide (205mg, 1.2mmol), iodine, [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-base)-amine hydrochlorate (505mg, 1.0mmol), PdCl 2(PPh 3) 2(35mg, 5%mol), Et 3the potpourri heated overnight of N (1.0mL) and CuI (64mg, 20%mol) in 10mLDMF.Concentrated and by the rapid column chromatography (5%MeOH on silica gel, in DCM) purifying, obtain the expectation product as brown ceramic powder, i.e. N-(3-chloro-4-(3-fluorinated benzyloxy) phenyl)-6-(3-(4-methyl isophthalic acid, 4-azepine phosphine-1-base) the third-1-alkynyl) quinazoline-4-amine.LCMSESI(+)m/z:550(M+1)。

1HNMR(CD 3OD300MHz)δ7.96(d,J=2.4Hz,1H),7.83(dd,J1=3.6Hz,J2=8.1Hz,1H),7.71(d,J=8.4Hz,1H),7.60(dd,J1=2.7Hz,J2=9.3Hz,1H),7.39(td,J1=0.7Hz,J2=7.5Hz,1H),7.29(d,J=7.5Hz,1H),7.24(d,J=9.9Hz,1H),7.13(d,J=9.0Hz,1H),7.05(td,J1=1.8Hz,J2=8.1Hz,1H),5.21(s,2H),3.73(s,2H),3.35(s,1H),3.20(m,2H),3.00(m,2H),2.00(m,4H),1.62(d,J=13.2Hz,3H)。

By N-(3-chloro-4-(3-fluorinated benzyloxy) phenyl)-6-(3-(the 4-methyl isophthalic acid obtained, 4-azepine phosphine-1-base) the third-1-alkynyl) quinazoline-4-amine (i.e. edge raw for Buddhist nun) and p-toluenesulfonic acid be dissolved in solvent (isopropyl alcohol: water=10:1), wherein, the raw mol ratio for Buddhist nun and p-toluenesulfonic acid of edge is 1:2.Heating reflux reaction is crystallisation by cooling after 10 hours, obtains two p-toluenesulfonic acid edge raw for Buddhist nun's bulk drug, as sample with methyl alcohol making beating 1h suction filtration.

Below in conjunction with embodiment, set forth the present invention further:

Embodiment 1

Investigate the system suitability of the method that the invention provides:

Continuous sample introduction 6 standard solution.By each solvent peak area in replication 6 standard solution, and calculate the relative standard deviation RSD of 6 peak areas, investigate the size of its RSD numerical value to judge system suitability, concrete grammar is:

1, instrument

Gas chromatograph model: Agilent6890A

Head-space sampler model: Agilent7694E

2, chromatographic condition: as table 1, headspace sampling condition is as table 2:

Table 1 chromatographic condition

Table 2 head-space sampler parameter

Equilibrium temperature (DEG C) 100 Quantity tube temperature (DEG C) 110 Transmission line temperature (DEG C) 125 Ml headspace bottle jolting mode / Ml headspace bottle equilibration time (min) 30 Pressing time (min) 0.5 The quantity tube filling time (min) 0.2 Quantity tube equilibration time (min) 0.1 Sample injection time (min) 1.0 Sample size (mL) 1.0

The preparation of 3 solution

Blank solution: accurately pipette 10ml DMSO (DMSO) in the headspace sampling bottle of 20ml.

The preparation of contrast stock solution: precision takes the volumetric flask that methyl alcohol, ethanol, isopropyl alcohol, DMF are placed in 100ml in right amount, dissolves and is settled to scale, shaking up, to obtain final product with DMSO.

The preparation of contrast solution: the standard reserving solution that precision pipettes 1ml is placed in the ml headspace bottle of 20ml, quantitatively adds 9mLDMSO, shakes up, to obtain final product.

The preparation of need testing solution: take 1g bis-p-toluenesulfonic acid edge raw for Buddhist nun's bulk drug, after accurately weighed, precision measures and adds DMSO10ml, is placed in the headspace sampling bottle of 20ml.

System flexibility requires: repeat into 6 pin standard solution, and in the chromatogram of gained, require RSD≤10% of peak area measured by sample introduction 6 times, the peak-to-peak degree of separation of each solvent is as many as 1.5.

Computing formula:

The residual quantity of solvent

In formula, Wr is the sample weighting amount of reference substance; Ai is the peak area of each residual solvent in the solution of test sample; Ni is test sample extension rate; Wi is the sample weighting amount of test sample; The mean value of the peak area of each residual solvent in Ar reference substance solution; Nr: the extension rate of reference substance.

6 times testing result is as shown in table 3:

Table 3 system flexibility testing result

Loading sequence Methyl alcohol Ethanol Isopropyl alcohol DMF Weigh quality (mg) 300.73 497.35 495.36 85.32 Concentration of standard solution (μ g/ml) 300.73 497.35 495.36 85.32 Peak area 1 120.4 261.6 310.4 3.8 Peak area 2 125.6 274.3 323.1 3.8 Peak area 3 123.2 266.6 315.8 3.4 Peak area 4 125.6 272.2 322.1 3.7 Peak area 5 120.0 264.1 314.1 3.5 Peak area 6 123.4 267.6 318.2 3.5 Average peak area 123.1 267.7 317.3 3.6 RSD% 2.0 1.8 1.5 4.6

Conclusion: that repeats the RSD of the peak area that sample introduction records for 6 times is all less than 10%, meets the requirement of system suitability.

Embodiment 2

Specificity selectivity is investigated and is mainly investigated the discriminating at peak and the selectivity at peak, requires: only the location solution of blank solution and all solvents determines all potential impurity respectively, and main peak and the peak-to-peak degree of separation of adjacent chromatogram must not be less than 1.5 to it.

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

Table 4 residual solvent location measured in solution result

Residual solvent The quantity of solvent (μ L) added Retention time Methyl alcohol location solution 20 3.677 Ethanol location solution 20 4.196 Isopropyl alcohol 20 4.724 DMF location solution 20 9.757

Table 5 mixed standard solution measurement result

Residual solvent The quantity of solvent (μ g/ml) added Retention time Degree of separation Methyl alcohol 300.73 3.701 Ethanol 497.35 4.231 10.01 Isopropyl alcohol 495.36 4.769 8.54 DMF 85.32 9.804 75.93

Conclusion: test shows, the sample that the method records, result is good, and degree of separation is all greater than 1.5.

Embodiment 3

The mixing reference substance solution of compounding methanol 63.09 μ g/ml, ethanol 100.49 μ g/ml, isopropyl alcohol 102.39 μ g/ml and DMF solution 19.05 μ g/ml.Respectively by above-mentioned solution dilution extremely appropriate concentration, get 10mL sample introduction in 20mL ml headspace bottle respectively.For the residual solvent that these are known, quantitative limit is determined by the calculating of signal to noise ratio (S/N ratio).The stock solution of known residual solvent is diluted to finite concentration, and the response signal measured and the response signal of blank space compare, the true and reliable least concentration that can be detected calculated.Instrument, chromatographic condition, solution are identical with embodiment 1, and testing result is as shown in table 6:

Table 6: quantitative limit test result

Test solution Concentration (μ g/ml) Signal to noise ratio (S/N ratio) Peak area Methyl alcohol 0.3 3.4 0.8950 Ethanol 0.5 2.8 0.3982 Isopropyl alcohol 0.5 3.5 0.7033 DMF 8.5 2.9 0.3415

Result shows, method provided by the invention has lower detectability, illustrates that sensitivity is higher.

Embodiment 4

For each solvent, in the scope of the 25%-200% of concentration of standard solution, get 5 concentration point (25%, 50%, 100%, 150%, 200% of standard solution) linearly studied.The compound method of concrete solution is see the preparation of standard solution.Linear relationship is mapped to the concentration of need testing solution with response signal, carries out linear regression by least square method, and calculate linear regression coeffficient, the numerical range of linearly dependent coefficient R is 0.999-1.000.Instrument, chromatographic condition, solution are identical with embodiment 1, and testing result is as shown in table 7 ~ 10, and typical curve as shown in figures 1-4.

The linear result of table 7 methyl alcohol

Sample concentration (μ g/ml) Peak area 1 Peak area 2 Average peak area 30.073 16.4 14.5 15.4 75.183 34.7 37.1 35.9 150.366 76.1 74.4 75.2 300.730 156.5 149.1 152.8 451.098 222.5 223.9 223.2 601.464 301.0 300.2 300.6

Result shows, methyl alcohol is in the concentration range of 30.1-601.5 μ g/ml, and regression coefficient R is 0.9999, linearly, meets proof scheme requirement.

The linear result of table 8 ethanol

Sample concentration (μ g/ml) Peak area 1 Peak area 2 Average peak area 49.735 35.3 30.7 33.0 124.339 75.8 81.2 78.5 248.68 165.8 163.6 164.7 497.35 342.4 325.6 334.0 746.031 486.3 487.5 486.9 994.708 657.8 654.5 656.2

Result shows, in the concentration range that concentration of alcohol is 49.7-994.7 μ g/ml, regression coefficient R=0.9999, linearly, meets proof scheme requirement.

The linear result of table 9 isopropyl alcohol

Sample concentration (μ g/ml) Peak area 1 Peak area 2 Average peak area 49.54 43.1 38.1 40.7 123.84 91.6 97.5 94.5 247.68 195.8 193.4 194.6 495.37 400.8 382.8 391.8 743.05 570.0 571.4 570.7 990.74 770.3 766.9 768.6

Result shows, in the concentration range that isopropyl alcohol concentration is 43.1-770.3 μ g/ml, regression coefficient, R=0.9999, linearly, meets proof scheme requirement.

Table 10N, the linear result of dinethylformamide (DMF)

Sample concentration (μ g/ml) Peak area 1 Peak area 2 Average peak area 21.33 0.9 1.0 1.0 42.66 2.3 2.2 2.2 85.32 4.8 4.6 4.7 127.98 7.1 6.9 7.0 170.64 9.3 9.1 9.2

Result shows, in the concentration range that DMF concentration is 21.3-170.64 μ g/ml, regression coefficient R=0.9993, linearly, meets proof scheme requirement.

Embodiment 5

By the standard solution prepared, measure 6 times, the RSD of the result of mensuration is not more than 10%.Instrument, chromatographic condition, solution are identical with embodiment 1, and result is as shown in table 11:

Table 11 the invention provides the repeatability checking of method

Note: "-" be not for detect.

Conclusion: above-mentioned replica test result display, the RSD of methyl alcohol, isopropyl alcohol, ethanol, DMF is all less than 2%, and the detection two p-toluenesulfonic acid edge of prompting this method is raw good for damping system precision.

Embodiment 6

Sample thief is about 1.0g respectively, accurately weighed, takes 9 parts, put in the ml headspace bottle of 20ml, then precision measures each three parts of reference substance storage liquid 0.8ml, 1.0ml, 1.2ml, adds respectively in ml headspace bottle, add dimethyl sulfoxide and be diluted to 10ml, ultrasonic dissolution is as supplying trial target solution.Accurate measuring reference substance storage liquid 1ml puts 20ml ml headspace bottle, adds dimethyl sulfoxide and is diluted to 10ml, shake up, in contrast product solution.Precision measures head space 1ml, inject gas chromatograph, and calculate content and the recovery of each solvent to be measured by external standard method, instrument, chromatographic condition, solution are identical with embodiment 1, the results are shown in Table 12.

Table 12 two p-toluenesulfonic acid edge is raw checks (average recovery test) for Buddhist nun's salt residual solvent

Note: "-" be not for detect.

Conclusion: above-mentioned recovery test result display, the average recovery of methyl alcohol, isopropyl alcohol, ethanol, DMF is all between 85.0% ~ 120.0%, and RSD is all less than 5%, and the accuracy of prompting this method is better.

Embodiment 7

Standard solution is added in KU004 need testing solution, investigate the stability of solution of 8 hours, namely according to the peak area of the solution of placement 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h recorded compared with the peak area of 0h solution, investigate the RSD% of the peak area in its 8h.Instrument, chromatographic condition, solution are identical with embodiment 1, and experimental result is as shown in table 13:

Table 13 stability of solution the result

Time Methyl alcohol Ethanol Isopropyl alcohol DMF 0 199.5 386.4 505.4 7.5 1 202.0 384.8 499.8 7.8 3 202.9 390.1 509.3 7.5 4 202.0 392.8 509.8 7.4 5 206.2 395.7 512.5 7.7 6 207.3 403.0 523.6 7.7 8 209.3 405.3 525.1 7.8 On average 204.2 394.0 512.2 7.6 RSD 1.7% 2.0% 1.8% 2.1%

Conclusion: show that two p-toluenesulfonic acid edge are raw good at 8h internal stability for four kinds of residual solvents in Buddhist nun's need testing solution.

Embodiment 8

Adopt instrument, chromatographic condition and need testing solution that embodiment 1 provides, adjustment flow rate of carrier gas, investigates the durability of the method that the invention provides.Result is as shown in table 14:

The test result of the different flow rate of carrier gas impact of table 14

Conclusion: the subtle change (2.3ml/min ~ 2.7ml/min) of flow rate of carrier gas, to the retention time of each residual solvent, peak area, tailing factor and theoretical cam curve, the equal no significant difference of degree of separation.Namely the subtle change of flow rate of carrier gas can not affect the detection of each residual solvent.

Embodiment 9

Adopt instrument, chromatographic condition and need testing solution that embodiment 1 provides, adjustment column temperature, investigates the durability of the method that the invention provides.Result is as shown in Table 15:

The test result of the different column temperature impact of table 15

Conclusion: the subtle change (35 DEG C ~ 50 DEG C) of column temperature, to the retention time of each residual solvent, peak area, tailing factor and theoretical cam curve, the equal no significant difference of degree of separation.Namely the subtle change of column temperature can not affect the detection of each residual solvent.

Embodiment 10

Adopt instrument, chromatographic condition and need testing solution that embodiment 1 provides, adjustment head space equilibration time, investigates the durability of the method that the invention provides.Result is shown in table 16:

The test result of the different head space equilibration time impact of table 16

Conclusion: the change (20min ~ 40min) of less head space equilibration time, to the retention time of each residual solvent, peak area, tailing factor and theoretical cam curve, the equal no significant difference of degree of separation.Namely the subtle change of head space equilibration time can not affect the detection of each residual solvent.

Embodiment 11

Adopt instrument, chromatographic condition and need testing solution that embodiment 1 provides, adjustment head space equilibrium temperature, investigates the durability of the method that the invention provides.Result is shown in table 16:

The test result of the different head space equilibrium temperature impact of table 17

Conclusion: the change (90 DEG C ~ 110 DEG C) of less head space equilibrium temperature, to the retention time of each residual solvent, peak area, tailing factor and theoretical cam curve, the equal no significant difference of degree of separation.Namely the subtle change of head space equilibrium temperature can not affect the detection of each residual solvent.

Below be only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.

Claims (10)

1. the raw detection method for residual solvent in Buddhist nun's bulk drug of two p-toluenesulfonic acid edge, is characterized in that, dissolves two p-toluenesulfonic acid edge raw for Buddhist nun's bulk drug, headspace sampling, gas chromatographic detection residual solvent levels with DMSO;
The column temperature of described gas chromatography is: 35 DEG C ~ 50 DEG C keep 5min, 20 DEG C/min to be warming up to 220 DEG C ± 10 DEG C, keep 5min ~ 9min.
2. detection method according to claim 1, is characterized in that, the column temperature of described gas chromatography is: 40 DEG C keep 5min, and 20 DEG C/min is warming up to 220 DEG C, keep 7min.
3. detection method according to claim 1, is characterized in that, the detector temperature of described gas chromatography is 280 DEG C; Injector temperature is 220 DEG C.
4. detection method according to claim 1, is characterized in that, the carrier gas of described gas chromatography is nitrogen.
5. detection method according to claim 1, is characterized in that, the flow rate of carrier gas of described gas chromatography is 2.3mL/min ~ 2.7mL/min.
6. detection method according to claim 1, is characterized in that, the split ratio of described gas chromatography is 1:1.
7. detection method according to claim 1, is characterized in that, the equilibrium temperature of described headspace sampling is 90 DEG C ~ 110 DEG C; Equilibration time is 20min ~ 40min.
8. detection method according to claim 1, is characterized in that, the quantity tube temperature of described headspace sampling is 110 DEG C; Transmission line temperature is 125 DEG C.
9. detection method according to claim 1, is characterized in that, the pressing time of described headspace sampling is 0.5min; The quantity tube filling time is 0.2min; Quantity tube equilibration time is 0.1min.
10. detection method according to claim 1, is characterized in that, the acquisition of described residual solvent levels adopts external standard method.
CN201510767228.8A 2015-11-11 2015-11-11 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 CN105388242A (en)

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