CN103926359A - Method for measuring residual solvent in bulk drug mifepristone - Google Patents
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Abstract
The invention discloses a method for measuring residual solvent in bulk drug mifepristone, which is characterized in that a gas chromatograph method is established, the chromatogram of measured standard substance solutions of tetrahydrofuran, ethanol, isopropyl ether, ethyl acetate, dichloromethane, pyridine, acetonitrile and benzene can be compared with chromatogram of a bulk drug mifepristone tested object solution, and then calculated to complete the detection method of the residual solvent in the bulk drug mifepristone. The measuring method has the advantages of rapid and simple operation, high sensitivity, good repeatability and accurate result, solvents of residual tetrahydrofuran, ethanol, isopropyl ether, ethyl acetate, dichloromethane, pyridine, acetonitrile and benzene in the bulk drug mifepristone can be detected in a quantification mode, the method provides a good reference for controlling the residue of an organic solvent in a bulk drug mifepristone production technology, ensures the quality of the mifepristone bulk drug, increases the security of clinical medication, and provides a method basis for increasing the quality standard of the mifepristone bulk drug.
Description
Technical field
The present invention relates to a kind of assay method of steroidal antiprogestin bulk drug residual solvent, be specifically related to the assay method of residual solvent in bulk drug mifepristone.
Background technology
Mifepristone is the kind that Chinese Pharmacopoeia version in 2005 is recorded, and is the medicine of a kind of anti-early pregnancy of developing in recent years, has termination of early pregnancy, anti-implantation, induction menstruation and promotes uterotonic effect.This medicine needs to use the organic solvents such as ethanol, tetrahydrofuran, isopropyl ether, ethyl acetate, acetonitrile, benzene, methylene chloride and pyridine in preparation technology, benzene belongs to a class flux, because methylene chloride, acetonitrile, tetrahydrofuran, pyridine belong to Equations of The Second Kind solvent, toxicity is larger, should limit use, and ethanol, ethyl acetate belong to the 3rd kind solvent, use at drug's GMP or the restriction of other quality requirementss, therefore be necessary that the content to them is effectively controlled in quality standard.
Tetrahydrofuran, alcohol, isopropyl ether, ethyl acetate, methylene chloride, acetonitrile, benzene all belong to organic solvent, skin, respiratory mucosa, eye conjunctiva etc. are had to certain spread effect, contact high concentration can cause toxic encephalopathy, has dizziness, headache, the disturbance of consciousness and even stupor in various degree.
Wherein, benzene is a kind of colourless, liquid with special aromatic odor, can dissolve each other with alcohol, ether, acetone and phenixin, is slightly soluble in water, is IARC first kind carcinogenic substance, often Contact benzene, and skin can be because of degreasing desiccation, furfur, some appearance allergic eczemas; The long-term benzene that sucks can cause dirt aplastic anemia again.Tetrahydrofuran has to stimulate and anesthetic action; After suction, cause that the upper respiratory tract stimulates, feels sick, dizzy, headache and central nervous system suppress; Can cause liver, renal damage; Liquid or high concentration steam are irritant to eye.
Ethanol belongs to micro-virus kind, but anesthetic action is larger than methyl alcohol, its main effects be to central nervous system produce suppress due to.In the time that ethanol intake increases, its central nervous system inhibiting effect strengthens, and first acts on cerebral cortex, then affects subcortical center, can cause oblongata vasomotor center and respiratory center paralysis.Isopropyl ether route of entry: suck, eat, absorb through skin; Its health hazard: steam or mist are irritant to eyes, mucous membrane, skin and the upper respiratory tract; After contact, can cause nausea, have a headache, vomiting and anesthetic action; Skin contact repeatedly, can cause contact dermatitis.
Ethyl acetate has spread effect to eye, nose, throat; High concentration sucks can cause slow and progressive anesthetic action; Continue a large amount of suction, can cause respiratory paralysis; There is sensitization, because nervus vasculairs obstacle causes the hyperemia of gum road and mucosal inflammation; Can cause eczema-like dermatitis.Methylene chloride has anesthetic action, mainly damages nervous centralis and respiratory system; Its toxicity: per os belongs to moderate toxicity; Its acute toxicity: open-assembly time increases, and has slight hepatatrophy, steatosis and cellular infiltration.
Pyridine health hazard: have intense stimulus; Can anaesthetize central nervous system; Eye and the upper respiratory tract are had to spread effect; After high concentration sucks, the lighter has glad or sensation of asphyxia, then occurs depression, myasthenia, vomiting; The severe one loss of consciousness, gatism, tonic spasm, blood pressure drops; Wrongly taking can be lethal.Chronic Effect: eat for a long time and occur dizziness, headache, insomnia, instability of gait and digestive tract function disorder; Can there is hepatorenal damage.Can cause dermatitis.
The morbidity of acetonitrile acute poisoning is slow compared with hydrogen cyanide, can have latent period a few hours.Cardinal symptom be weak, unable, complexion is greyish white, nauseating, vomiting, stomachache, diarrhoea, uncomfortable in chest, pectoralgia; Severe patient is breathed and circulation system disorder, breathe shallow, slow and irregular, blood pressure drops, pulse is thin and slow, temperature decline, paroxysmal is twitched, stupor.Can there be frequent micturition, albuminuria etc.
If dissolvent residual in medicine is not carried out to limit test, will make medicine have great potential safety hazard.
Summary of the invention
The object of the present invention is to provide the assay method of residual solvent in a kind of bulk drug mifepristone, set up an air chromatography analysis method to may detecting by residual organic solvent in bulk drug mifepristone, operation is simple fast, highly sensitive, reproducible, result is accurate, and can quantitatively detect the residual tetrahydrofuran of possibility in bulk drug mifepristone, ethanol, isopropyl ether, ethyl acetate, methylene chloride, pyridine, acetonitrile, the organic solvents such as benzene, provide good reference for controlling organic solvent residual in bulk drug mifepristone production technology, ensure the quality of mifepristone bulk drug, thereby improve the security of clinical application, for the quality standard that improves mifepristone bulk drug provides method foundation.
To achieve these goals, the present invention adopts following technical scheme:
An assay method for residual solvent in bulk drug mifepristone, comprises the following steps:
(1) select control substance of plant drug: select tetrahydrofuran, ethanol, isopropyl ether, ethyl acetate, methylene chloride, pyridine, acetonitrile and benzene material in contrast; The purity grade of above-mentioned control substance of plant drug is analyzes pure AR;
(2) prepare need testing solution: accurately take mifepristone test sample, be placed in headspace sampling bottle, add dimethyl sulfoxide (DMSO), ultrasonic dissolution, shake up afterwards as need testing solution, in wherein said mifepristone need testing solution, the concentration of mifepristone is preferably 0.2g/ml;
(3) preparation standard product solution: accurately take respectively reference substance ethanol, tetrahydrofuran, isopropyl ether, ethyl acetate, methylene chloride, pyridine, acetonitrile and be dissolved in the volumetric flask with dimethyl sulfoxide (DMSO), and be diluted to scale with dimethyl sulfoxide (DMSO), shake up to obtain the first mixed solution; Accurately take reference substance benzene and be placed in the volumetric flask with dimethyl sulfoxide (DMSO), and be diluted to scale with dimethyl sulfoxide (DMSO), shake up to obtain the second solution;
A certain amount of the first mixed solution and the second solution are placed in to a volumetric flask, add dimethyl sulfoxide (DMSO) and be diluted to scale, after shaking up, obtain standard solution, this standard solution solution in contrast;
Wherein, in described standard solution, the concentration of each reference substance is preferably: ethanol 200 μ g/mL; Tetrahydrofuran 144 μ g/mL; Isopropyl ether 200 μ g/mL; Ethyl acetate 400 μ g/mL; Methylene chloride 120 μ g/mL, pyridine 40 μ g/mL, acetonitrile 82 μ g/mL, benzene 0.4 μ g/mL;
(4) adopt headspace gas chromatography sample introduction standard solution spininess and need testing solution spininess respectively, obtain respectively the chromatogram of standard solution and the chromatogram of need testing solution, the peak area of each residual solvent respective peaks in peak area by each reference substance respective peaks in standard solution chromatogram and need testing solution chromatogram, adopt following formula to calculate the content that obtains each residual solvent in bulk drug mifepristone, i.e. the content of tetrahydrofuran, ethanol, isopropyl ether, ethyl acetate, methylene chloride, pyridine, acetonitrile and benzene in mifepristone:
In formula: the peak area of each residual solvent in As-need testing solution;
The dilution volume of V-mifepristone test sample, Unit/mL; It is the dilution volume of step (2);
The concentration of corresponding residual solvent in C-standard solution, the mg/mL of unit;
W
sample-sample weighing, the mg of unit;
the average peak area of corresponding residual solvent in-standard solution.
Wherein, adopt headspace gas chromatography to measure relative standard deviation RSD≤10% that requires each solvent peak peak area; Degree of separation >=1.5 between adjacent solvent.
Preferably, front first sample introduction blank solution 1 pin of sample introduction standard solution spininess and need testing solution spininess is as blank; Sample introduction standard solution spininess is 6 pins, and sample introduction need testing solution spininess is 2 pins.
Preferably, while adopting the content of each residual solvent in Headspace Gas Chromatography bulk drug mifepristone, its condition determination is:
(30m × 0.53mm × 3 μ is m) as analysis chromatographic column, and detecting device is fid detector to adopt AgilentDB-624 fused-silica capillary column;
Chromatographic resolution parameter: carrier gas: nitrogen; Flow rate of carrier gas: 3.0mL/min; Split ratio: 10:1;
Detector temperature: 250 DEG C; Injector temperature: 200 DEG C;
Column temperature: initial temperature is 45 DEG C, keeps 10min, with the heating rate to 150 DEG C of 15 DEG C/min, keeps 3min;
Head space detected parameters: heating cabinet: 105 DEG C; Quantitatively ring: 115 DEG C; Transmission line: 125 DEG C;
Gas phase GC cycling time: 25min; Sample injection time: 1min;
Sample equilibration time: 20min; Pressure balance time: 0.2min.
The present invention is many because bulk drug mifepristone sample relates to residual solvent kind, boiling point is wider, for adapting to the detection of residual solvent in bulk drug mifepristone, need to select proper testing conditions, adopted initial column temperature, heating rate are adjusted, through the optimization to above-mentioned other each controlled conditions, 45 DEG C of final definite column temperature initial temperatures, keep 10min, with the heating rate to 150 DEG C of 15 DEG C/min, keep 3min.Head space detected parameters: heating cabinet: 105 DEG C of quantitative rings: 115 DEG C, transmission line: 125 DEG C, GC cycling time: 25min, sample injection time: 1min, sample equilibration time: 20min, pressure balance time: 0.2min.
The assay method of residual solvent in bulk drug mifepristone of the present invention, RSD≤10% of each solvent peak area in its system flexibility contrast liquid; Degree of separation >=1.5 between adjacent solvent; Specificity is following 3 points: 1. blank does not have other impurity peaks, if had, must not disturb detected solvent; 2. the solvent of all checkings is answered separated from one another and is separated degree of separation >=1.5 with related solvent; 3. the residual solvent of all the unknowns should separate with all residual solvents that are verified.RSD≤10% of its precision, repeated each solvent peak area.
The assay method of residual solvent in bulk drug mifepristone of the present invention, by setting up head space gas chromatography method, the chromatogram of the standard solution chromatogram of the tetrahydrofuran of mensuration, ethanol, isopropyl ether, ethyl acetate, methylene chloride, pyridine, acetonitrile and benzene and bulk drug mifepristone need testing solution is compared, calculated, complete the detection method of residual solvent in bulk drug mifepristone.This assay method operation is simple fast, highly sensitive, reproducible, result is accurate, and can quantitatively detect residual tetrahydrofuran, ethanol, isopropyl ether, ethyl acetate, methylene chloride, pyridine, acetonitrile and the benzene equal solvent of possibility in bulk drug mifepristone, provide good reference for controlling organic solvent residual in bulk drug mifepristone production technology, ensure the quality of mifepristone bulk drug, thereby improve the security of clinical application, for the quality standard that improves mifepristone bulk drug provides method foundation.
Brief description of the drawings
Fig. 1-1st, blank solution chromatogram.
Fig. 1-2 is the headspace gas chromatography figure of the 1st pin standard solution.
Fig. 1-3 are empty gas chromatograms of item of the 2nd pin standard solution.
Fig. 1-4 are headspace gas chromatography figure of the 3rd pin standard solution.
Fig. 1-5 are headspace gas chromatography figure of the 4th pin standard solution.
Fig. 1-6 are headspace gas chromatography figure of the 5th pin standard solution.
Fig. 1-7 are headspace gas chromatography figure of the 6th pin standard solution.
Fig. 2-1st, the headspace gas chromatography figure of 1# bulk drug mifepristone need testing solution the 1st pin.
Fig. 2-2nd, the empty gas chromatogram of item of 1# bulk drug mifepristone need testing solution the 2nd pin.
Fig. 2-3rd, 2# bulk drug mifepristone need testing solution the 1st pin headspace gas chromatography figure.
Fig. 2-4th, 2# bulk drug mifepristone need testing solution the 2nd pin headspace gas chromatography figure.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that following examples are only for the present invention is described but not for limiting protection scope of the present invention.
The mensuration of residual solvent in embodiment 1 bulk drug mifepristone
(1) analytical approach: head space gas chromatography method.
Chromatographic system:
Chromatographic column: AgilentDB-624 fused-silica capillary column (30m × 0.53mm × 3 μ m), fid detector.
Chromatographic parameter:
Chromatographic resolution parameter: carrier gas: nitrogen; Flow rate of carrier gas: 3.0mL/min; Split ratio: 10:1;
Detector temperature: 250 DEG C; Injector temperature: 200 DEG C;
Column temperature: 45 DEG C of initial temperatures, keep 10min, with the heating rate to 150 DEG C of 15 DEG C/min, keep 3min.
Head space detected parameters: heating cabinet: 105 DEG C; Quantitatively ring: 115 DEG C; Transmission line: 125 DEG C;
GC cycling time: 25min; Sample injection time: 1min;
Sample equilibration time: 20min; Pressure balance time: 0.2min.
(2) solution preparation:
1, reference substance solution (being standard solution):
Accurately take ethanol 200mg, tetrahydrofuran 144mg, isopropyl ether 200mg, ethyl acetate 400mg, methylene chloride 120mg, pyridine 40mg, acetonitrile 82mg is dissolved in has in the 100mL of appropriate dimethyl sulfoxide (DMSO) volumetric flask, and be diluted to scale with dimethyl sulfoxide (DMSO), shake up solution 1..
Accurately take the 100mL volumetric flask that benzene 40mg is placed in appropriate dimethyl sulfoxide (DMSO), and be diluted to scale with dimethyl sulfoxide (DMSO), shake up.Accurately measure this solution 1.0mL in 100mL volumetric flask, add dimethyl sulfoxide (DMSO) and be diluted to scale, shake up solution 2..
Pipette solution 1. with solution 2. each 10.0mL in 100mL volumetric flask, add dimethyl sulfoxide (DMSO) and be diluted to scale, shake up, in contrast product solution.Pipetting reference substance solution 5.0mL is placed in 20mL head space bottle and get final product.Wherein in reference substance solution, the concentration of each reference substance is: ethanol 200 μ g/mL; Tetrahydrofuran 144 μ g/mL; Isopropyl ether 200 μ g/mL; Ethyl acetate 400 μ g/mL; Methylene chloride 120 μ g/mL, pyridine 40 μ g/mL, acetonitrile 82 μ g/mL, benzene 0.4 μ g/mL.
2, need testing solution:
Accurately take 1.000g test sample, be placed in the empty sample injection bottle of 20mL item, add 5.0mL dimethyl sulfoxide (DMSO), ultrasonic dissolution, shakes up, as need testing solution.
(3) determination step:
Sample introduction blank solution 1 pin, its chromatogram is as Figure 1-1;
Sample introduction reference substance solution 6 pins, obtain chromatogram, record the peak area (as shown in table 2) of each reference substance respective peaks, require the RSD of each reference substance peak area must not be greater than 10%;
Sample introduction need testing solution 2 pins, record chromatic graph spectrum, the peak area of each residual solvent respective peaks in peak area by each reference substance respective peaks in reference substance solution chromatogram and need testing solution chromatogram, adopt following formula to calculate the content that obtains each residual solvent in bulk drug mifepristone, i.e. the content of tetrahydrofuran, ethanol, isopropyl ether, ethyl acetate, methylene chloride, pyridine, acetonitrile and benzene in mifepristone:
According to the each residual solvent levels of calculated by peak area, computing formula is as follows:
In formula: the peak area of each residual solvent in As-sample solution;
V-mifepristone Sample Dilution volume, Unit/mL;
The concentration of corresponding residual solvent in C-standard solution, the mg/mL of unit;
W
sample-sample weighing, the mg of unit;
the average peak area of corresponding residual solvent in-standard solution.
(4) detection and result:
In contrast solution, the system flexibility weighing of each reference substance component value is as shown in table 1.
Table 1 system flexibility weighing value
Detect sample introduction reference substance solution 6 pins by above-mentioned steps, obtain chromatogram (if 1-2 is to as shown in Fig. 1-7) and record each peak-to-peak area, require RSD must not be greater than 10%, its result is as shown in table 2:
Table 2 system flexibility test result
Note: R'min is the degree of separation between the most difficult separation component (acetonitrile and methylene chloride).
Get respectively 2 batches of bulk drug mifepristone samples (as shown in table 3), carry out By Headspace Gas Chromatography by above-mentioned chromatographic condition after determining, record testing result, as shown in table 2 identical of system flexibility result wherein.
Table 3
| Bulk drug lot number | 30011204001 | 3001120402 |
| 1# | 1.0095g | 0.9993g |
| 2# | 1.0102g | 1.0012g |
Sample introduction need testing solution 2 pins, record chromatic graph spectrum, and when need testing solution is measured by headspace gas chromatography instrument, its chromatographic condition is identical with the chromatographic condition of standard solution, obtains test sample chromatogram, and its chromatogram is as shown in Fig. 2-1 and Fig. 2-2.
The concrete outcome calculating by the content formula of each residual solvent in above-mentioned raw materials medicine mifepristone is as shown in table 4.Relatively the chromatogram of need testing solution and standard solution is known, ethanol and acetonitrile peak area are less than standard solution ethanol and acetonitrile peak area, ethanol and acetonitrile component limit meet statutory standards, and other solvents tetrahydrofurane, isopropyl ether, ethyl acetate, methylene chloride, pyridine, benzene do not detect.
Table 4
(5) detection method of each residual solvent in above-mentioned raw materials medicine mifepristone is carried out to methodology checking: comprise each solvent peak peak area RSD≤10% (RSD as shown in table 2 is 5.57% to the maximum) in system flexibility contrast liquid; Degree of separation >=1.5 (degree of separation >=2.66 between the most difficult separation component acetonitrile and methylene chloride as shown in table 2) between adjacent solvent.
Specificity: 1. blank does not have other impurity peaks, if had, must not disturb detected solvent; 2. the solvent of all checkings is answered separated from one another and is separated degree of separation >=1.5 with related solvent; 3. the residual solvent of all the unknowns should separate with all residual solvents that are verified.
Precision, repeated each solvent peak area RSD≤10%, fiducial interval (95%).
As shown in Table 5, its accuracy, average recovery rate are 80%～120%.
Table 5 accuracy test result
Note: the A in above-mentioned table 5
0for the average peak area of each solvent in need testing solution, A
ufor the peak area of each solvent in accuracy solution.
As shown in Table 5, the recovery of each solvent all meets the requirements, and shows that this detection method accuracy is good.
Detectability and quantitative limit: the low concentration solution that all solvents that need verify are prepared to a signal to noise ratio (S/N ratio) >=10 is measured.By following formula by calculating quantitative limit QL.Detectability is drawn by the relation of quantitative limit.
QL＝10C/(S/N)
Wherein: S/N: the signal to noise ratio (S/N ratio) of >=10 low concentration solution,
C: the concentration that represents above-mentioned low concentration solution.
Detectability (DL): infer and calculate by quantitative limit QL:
(1) concrete process for preparation is as follows: the method according to the reference substance solution under solution preparation item in embodiment 1 (being standard solution) is configured, and wherein in the weighing value of reference substance and reference substance solution, the concentration of each reference substance is as shown in table 6.
(2) sample introduction operation steps: each reference substance solution repeats sample introduction 3 times, and follow procedure records corresponding chromatogram.
(3) test result is as shown in table 6.
The each solvent quantitative limit of table 6 and detectability test result
Note: * represents the ppm concentration with respect to reference substance.
Its testing result: as shown in Table 6, in mixing reference substance solution, the QL of each solvent and DL are much smaller than limit value.
Linear dependence degree is investigated:
Investigate l.o.i quantitative limit to limit 120% between linear case, linearly dependent coefficient R
2answer>=0.99.
Getting respectively at 6 and do linear investigation, is 20%, 40%, 60%, 80% according to above-mentioned aqueous standard method product solution dilute concentration, 100%, 120% μ g/mL.
Get respectively the linear solution 5mi of each concentration, adopt headspace gas chromatography headspace sampling, each replication 3 times, follow procedure records chromatogram, obtains equation of linear regression result as follows:
Ethanol: y=0.5735 ×-0.2467R
2=0.9992;
Acetonitrile: y=0.4536 ×-1.4736R
2=0.9967;
Methylene chloride: y=0.5639 ×+0.0231R
2=0.9993;
Isopropyl ether: y=0.0225 ×+1.0181R
2=0.9990;
Ethyl acetate: y=0.1647 ×+0.1476R
2=0.9994;
Benzene: y=0.798 ×-0.1028R
2=0.9949;
Tetrahydrofuran: y=0.0966 ×-0.0339R
2=0.9995;
Pyridine: y=1.3109 ×-0.7997R
2=0.9960.
Each linearly dependent coefficient R in above-mentioned linear dependence degree
2>=0.99, meet the requirements.
Durability, initial column temperature ± 5 DEG C, flow rate of carrier gas+0.2mL/min, stability of solution meets system flexibility requirement; Each solvent peak area RSD≤10%.
In bulk drug mifepristone of the present invention in the assay method of residual solvent, in bulk drug mifepristone, residual solvent is by above-mentioned experimental verification, its result all, between Acceptable criterion, meets the requirements, and therefore this assay method can detect residual solvent detection in bulk drug mifepristone.
Above-described embodiment is illustrative principle of the present invention and effect thereof only, but not for limiting the present invention.Any person skilled in the art scholar all can, under spirit of the present invention and category, modify or change above-described embodiment.Therefore, such as in affiliated technical field, have and conventionally know that the knowledgeable, not departing from all equivalence modifications that complete under disclosed spirit and technological thought or changing, must be contained by claim of the present invention.
Claims (6)
1. an assay method for residual solvent in bulk drug mifepristone, comprises the steps:
(1) select control substance of plant drug: select tetrahydrofuran, ethanol, isopropyl ether, ethyl acetate, methylene chloride, pyridine, acetonitrile and benzene material in contrast;
(2) prepare need testing solution: accurately take mifepristone test sample, be placed in headspace sampling bottle, add dimethyl sulfoxide (DMSO), ultrasonic dissolution, shakes up rear as need testing solution;
(3) preparation standard product solution: accurately take respectively reference substance tetrahydrofuran, ethanol, isopropyl ether, ethyl acetate, methylene chloride, pyridine, acetonitrile and be dissolved in the volumetric flask with dimethyl sulfoxide (DMSO), and be diluted to scale with dimethyl sulfoxide (DMSO), shake up to obtain the first mixed solution; Accurately take reference substance benzene and be placed in the volumetric flask with dimethyl sulfoxide (DMSO), and be diluted to scale with dimethyl sulfoxide (DMSO), shake up to obtain the second solution;
A certain amount of the first mixed solution and the second solution are placed in to a volumetric flask, add dimethyl sulfoxide (DMSO) and be diluted to scale, after shaking up, obtain standard solution, this standard solution solution in contrast;
(4) adopt headspace gas chromatography sample introduction standard solution spininess and need testing solution spininess respectively, obtain respectively the chromatogram of standard solution and the chromatogram of need testing solution, the peak area of each residual solvent respective peaks in peak area by each reference substance respective peaks in standard solution chromatogram and need testing solution chromatogram, adopt following formula to calculate the content that obtains each residual solvent in bulk drug mifepristone, i.e. the content of tetrahydrofuran, ethanol, isopropyl ether, ethyl acetate, methylene chloride, pyridine, acetonitrile and benzene in mifepristone:
In formula: the peak area of each residual solvent in As-need testing solution;
The dilution volume of V-mifepristone test sample, Unit/mL;
The concentration of corresponding residual solvent in C-standard solution, the mg/mL of unit;
W
sample-sample weighing weight, the mg of unit;
the average peak area of corresponding residual solvent in-standard solution.
2. the assay method of residual solvent in bulk drug mifepristone as claimed in claim 1, is characterized in that, in step (2), in described mifepristone need testing solution, the concentration of mifepristone is 0.2g/ml.
3. the assay method of residual solvent in bulk drug mifepristone as claimed in claim 1, is characterized in that, in step (3), in described standard solution, the concentration of each reference substance is: ethanol 200 μ g/mL; Tetrahydrofuran 144 μ g/mL; Isopropyl ether 200 μ g/mL; Ethyl acetate 400 μ g/mL; Methylene chloride 120 μ g/mL, pyridine 40 μ g/mL, acetonitrile 82 μ g/mL, benzene 0.4 μ g/mL.
4. the assay method of residual solvent in bulk drug mifepristone as claimed in claim 1, is characterized in that, adopts headspace gas chromatography to measure relative standard deviation RSD≤10% that requires each solvent peak peak area; Degree of separation >=1.5 between adjacent solvent.
5. the low-priced assay method that stays solvent in bulk drug mifepristone as claimed in claim 1, is characterized in that, before sample introduction standard solution spininess and need testing solution spininess, first sample introduction blank solution 1 pin is as blank; Sample introduction standard solution spininess is 6 pins, and sample introduction need testing solution spininess is 2 pins.
6. in the bulk drug mifepristone as described in as arbitrary in claim 1-5, the assay method of residual solvent, is characterized in that, while adopting the content of each residual solvent in Headspace Gas Chromatography bulk drug mifepristone, its condition determination is:
Adopt AgilentDB-624 fused-silica capillary column as analysis chromatographic column, detecting device is fid detector;
Chromatographic resolution parameter: carrier gas: nitrogen; Flow rate of carrier gas: 3.0mL/min; Split ratio: 10:1;
Detector temperature: 250 DEG C; Injector temperature: 200 DEG C;
Column temperature: initial temperature is 45 DEG C, keeps 10min, with the heating rate to 150 DEG C of 15 DEG C/min, keeps 3min;
Head space detected parameters: heating cabinet: 105 DEG C; Quantitatively ring: 115 DEG C; Transmission line: 125 DEG C;
Gas phase GC cycling time: 25min; Sample injection time: 1min;
Sample equilibration time: 20min; Pressure balance time: 0.2min.
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