CN107860826A - The method that residual solvent in Ezetimibe bulk drug is determined using headspace gas chromatography - Google Patents
The method that residual solvent in Ezetimibe bulk drug is determined using headspace gas chromatography Download PDFInfo
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- CN107860826A CN107860826A CN201610848142.2A CN201610848142A CN107860826A CN 107860826 A CN107860826 A CN 107860826A CN 201610848142 A CN201610848142 A CN 201610848142A CN 107860826 A CN107860826 A CN 107860826A
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
The invention discloses a kind of method that residual solvent in Ezetimibe bulk drug is determined using headspace gas chromatography, the analysis condition of methods described is：Use capillary chromatographic column of the dimethyl polysiloxane of 6% cyanogen propyl group phenyl 94% for stationary phase；It is nitrogen to distinguish sample introduction reference substance solution spininess and need testing solution, carrier gas using shunt mode, by head-space sampler sample introduction, is detected after carrying out temperature programming；Detector is fid detector.Can be by the methanol in Ezetimibe bulk drug using this method, isopropanol, fluorobenzene, toluene and N, N dimethylformamide carry out separation rapidly and efficiently under same chromatographic condition, effectively control the quality of Ezetimibe bulk drug.The detection method specificity is strong, detection sensitivity is high, precision is high, accuracy is strong, easy to operate, can effective control for product quality.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical field, specifically, is surveyed the present invention relates to one kind using headspace gas chromatography
Determine the method for residual solvent in Ezetimibe bulk drug.
Background technology
The chemical name of Ezetimibe raw material is (4S) -3- [(5S) -5- (4- fluorophenyls) -5- hydroxypentanoyls base] -4- benzene
Base -1,3- oxaza pentane -2- ketone, its structural formula are：
To the last organic solvent system not being completely removed used in pharmaceutical raw material medicine and formulation manufacturing processes
Referred to as residual solvent, its residual quantity can cause necessarily to influence if it exceeds safety value on patient's human body.Pressed in ICH guidelines
The extent of injury is not waited, it is specified that 4 class solvents and limit value.According in Chinese Pharmacopoeia the 4th residual solvent determination method of version in 2015
Defined residual solvent levels requirement and Ezetimibe bulk drug synthesis technique, it is necessary to control Ezetimibe bulk drug in synthesis work
The organic solvent that skill is used eventually：Methanol, isopropanol, the residual quantity of toluene and DMF (DMF), limit difference
For：Methanol is 0.3%, isopropanol 0.5%, toluene 0.089%, DMF 0.088%.
The public information announced according to European chemical balance motion office European Chemicals Agency (ECHA), fluorine
Benzene shows feminine gender in genotoxicity test, by literature search according to the toxicology data and its physicochemical property of fluorobenzene, by fluorobenzene
Limit is set to 0.063%.
At present, the method for determining residual solvent in Ezetimibe bulk drug still has much room for improvement.
The content of the invention
It is contemplated that at least solves one of technical problem in correlation technique to a certain extent.Therefore, the present invention
One purpose is in a kind of method of the residual solvent in measure Ezetimibe bulk drug using headspace gas chromatography is proposed, this method
The residual quantity of methanol in Ezetimibe raw material, isopropanol, fluorobenzene, toluene and N,N-dimethylformamide can be detected simultaneously.
And the high sensitivity of method, the degree of accuracy is high, specificity is strong, favorable reproducibility.
The synthetic route of Ezetimibe bulk drug：
Residual solvent present in this technique has：Methanol, isopropanol, toluene, fluorobenzene and DMF.
According to an embodiment of the invention, the analysis condition of methods described is：
Use capillary chromatographic column of the dimethyl polysiloxane of 6% cyanogen propyl group phenyl -94% for stationary phase；Using divergent die
It is nitrogen that formula, which distinguishes sample introduction reference substance solution spininess and need testing solution, carrier gas, by head-space sampler sample introduction, enters line program liter
Detected after temperature；Detector is fid detector.
Thus, it is according to embodiments of the present invention to utilize residual solvent in headspace gas chromatography measure Ezetimibe bulk drug
Method, detected by way of temperature programming direct injected, it is possible to prevente effectively from interference of the blank peak to target peak, so as to improve
Accuracy in detection, while can be realized using this method and the residual of a variety of organic solvents in Ezetimibe bulk drug is carried out soon
Fast efficient separation and assay, and the detection method specificity is strong, precision is high, accuracy is strong, easy to operate, so as to have
The quality of effect control medicine.
The present invention uses headspace sampling system, suitable for volatile organic solvent.Compared to direct injected system, head space
Sampling system can not only avoid the interference of sample substrate, also to prevent Organic Material Blocking and pollution that higher boiling can not gasify
Injection port.In addition, the present invention uses capillary chromatographic column of the dimethyl polysiloxane of 6% cyanogen propyl group phenyl -94% for stationary phase,
This type chromatographic column aims at volatile residual solvent design, and has good inertia to reactive compound.By methodology
Checking, this type chromatographic column have a good separating effect for residual solvent in Ezetimibe bulk drug, and the degree of accuracy is preferable.
The method that residual solvent in Ezetimibe bulk drug is determined using headspace gas chromatography according to embodiments of the present invention,
There can also be following additional technical feature：
In some embodiments of the invention, the chromatographic column model KB-624.
In some embodiments of the invention, the residual solvent is methanol, isopropanol, fluorobenzene, toluene and N, N- diformazan
Base formamide.
In some embodiments of the invention, reference substance solution and the need testing solution use dimethyl sulfoxide (DMSO) to be molten
Agent.
In some embodiments of the invention, the set-up procedure of reference substance solution is：Take methanol, isopropanol, fluorobenzene, toluene
It is each appropriate with DMF, it is accurately weighed, it is diluted to dimethyl sulfoxide (DMSO) in every 1ml and contains methanol 0.30mg, different
Propyl alcohol 0.50mg, fluorobenzene 0.063mg, toluene 0.089mg and DMF 0.088mg mixed solution, as right
According to product solution；Precision pipettes 5ml and is placed in 20ml ml headspace bottles, and capping compresses, parallel to pipette 6 parts.
In some embodiments of the invention, the set-up procedure of need testing solution is：Ezetimibe raw material 0.5g is taken, it is accurate
It is weighed, put in 20ml ml headspace bottles, after adding 5ml dmso solutions, capping compresses, as need testing solution；It is parallel to prepare 2
Part.
In some embodiments of the invention, blank solution process for preparation is：Precision pipettes 5ml dimethyl sulfoxide (DMSO)s and is placed in
In 20ml ml headspace bottles, capping compresses, as blank solution.
In some embodiments of the invention, sample introduction reference substance solution spininess is distinguished and for trying using headspace gas chromatography
Product solution, it is following by the peak area of each residual solvent respective peaks in reference substance solution and need testing solution chromatogram, use
Formula calculates the content of each residual solvent in Ezetimibe raw material：
In formula：
mn- correspond to methanol, isopropanol, fluorobenzene, toluene, DMF sample weighting amount, mg；
M-test sample sample weighting amount, mg；
AnThe peak area of each solvent of chromatogram of-need testing solution record；
The peak average area of each solvent in the chromatogram of As-reference substance solution record；
5000-volume and unit conversion multiple.
Wherein, it is measured using headspace gas chromatography and requires the relative standard deviation RSD of each solvent peak peak area not
10% must be crossed, the separating degree between adjacent solvent is less than 1.5.
According to some embodiments of the present invention, split ratio 1:1~10:1, preferably 1:1.Thus obtained separating effect
Most preferably.
According to some embodiments of the present invention, flow rate of carrier gas is 0.2~2.0ml/min, preferably 1.0ml/min.Thus
Obtained separating effect is optimal.
According to some embodiments of the present invention, headspace sampling mouth temperature is 180~250 DEG C, preferably 200 DEG C；Heater box
Temperature is 80~120 DEG C, preferably 90 DEG C；Quantitative loop temperature is 90~150 DEG C, preferably 100 DEG C；Transmission line temperature is 100
~150 DEG C, preferably 110 DEG C；Thus, it is possible to improve accuracy in detection.
According to some embodiments of the present invention, the equilibration time of headspace sampling is 20~50min, preferably 30min；Circulation
30~60min of time, preferably 50min.Thus, it is possible to further improve separating degree.
According to some embodiments of the present invention, temperature programming is with 5 after initial temperature is 30~50 DEG C of 5~20min of holding
~20 DEG C/min speed rises to 200~250 DEG C, keeps 5~10min.Preferably, the initial temperature of temperature programming is 40 DEG C of guarantors
Hold and rise to 200 DEG C with 10 DEG C/min speed after 15min, keep 8min.Thus obtained separating effect and Detection results are optimal.
According to some embodiments of the present invention, detector temperature is 200~280 DEG C, preferably 250 DEG C.It is thus, it is possible to anti-
Only the moisture condensation in chromatographic system and impurity attachment residual in a detector, cause to damage, so as to further carry to detector
High detection accuracy.
According to a particular embodiment of the invention, each residual solvent in Ezetimibe raw material is determined using headspace gas chromatography
During content, its condition determination is：Use capillary column conduct of the dimethyl polysiloxane of 6% cyanogen propyl group phenyl 94% for stationary phase
Analysis chromatographic column, detector are fid detector；Chromatographic isolation parameter：Carrier gas：Nitrogen；Flow rate of carrier gas：1.0ml/min；Shunting
Than：1:1；Detector temperature：250℃；Injector temperature：200℃；Column temperature：Initial temperature be 40 DEG C keep 15min after with 10
DEG C/min speed rises to 200 DEG C, keep 8min.Head space detection parameters：Heater box temperature：90℃；Quantitative loop temperature：100℃；
Transmission line temperature：110℃；Head space equilibration time：30min；Circulation time：50min；Sample injection time：0.5min；During pressure balance
Between：0.1min.
The present invention establishes residual solvent methanol, isopropanol, fluorine in Ezetimibe raw material by the preferred of chromatographic condition
The detection method of benzene, toluene and DMF, experiment prove that the method specificity established is good, high sensitivity, line
Sexual intercourse and reproducible, degree of accuracy height, the production for dissolvent residual and follow-up Ezetimibe in control Ezetimibe raw material carry
Good quality assurance is supplied.
The additional aspect and advantage of the present invention will be set forth in part in the description, and will partly become from the following description
Obtain substantially, or recognized by the practice of the present invention.
Brief description of the drawings
Fig. 1 shows according to embodiments of the present invention 1, the headspace gas chromatography figure of system suitability solution detection；
Fig. 2 shows according to embodiments of the present invention 2, the headspace gas chromatography figure of system suitability solution detection；
Fig. 3 shows according to embodiments of the present invention 3, the headspace gas chromatography figure of system suitability solution detection；
Fig. 4 shows according to embodiments of the present invention 4, the headspace gas chromatography figure of system suitability solution detection；
Fig. 5 shows according to embodiments of the present invention 5, the headspace gas chromatography figure of system suitability solution detection；
Fig. 6 shows according to embodiments of the present invention 6, the headspace gas chromatography figure of system suitability solution detection；
Fig. 7 shows according to embodiments of the present invention 7, the headspace gas chromatography figure of system suitability solution detection.
Embodiment
Following examples are provided so that the present invention and embodiments thereof is further illustrated.What is provided in embodiment is specific
Detailed content is only in order at the purpose of illustration, rather than should be construed as the limitation present invention.Unreceipted tool in embodiment
Body technique or condition, carried out according to the technology described by document in the art or condition or according to product description.Institute
With reagent or the unreceipted production firm person of instrument, being can be by the conventional products of acquisition purchased in market.
Embodiment 1
Instrument：Agilent 7890A-7697A headspace gas chromatography instrument, fid detector；
Chromatographic column：KB-624 (30m*0.32mm, 3.0 μm)；
Chromatographic parameter：Carrier gas：Nitrogen；Flow rate of carrier gas：1.0ml/min；Split ratio：1:1；
Detector temperature：250℃；Injector temperature：200℃；
Column temperature：Initial temperature rises to 200 DEG C after keeping 15min for 40 DEG C with 10 DEG C/min speed, keeps 8min.
Head space detection parameters：Heater box temperature：90℃；Quantitative loop temperature：100℃；Transmission line temperature：110℃；
Head space equilibration time：30min；Circulation time：50min；Sample injection time：0.5min；
Pressure balance time：0.1min.
1st, specificity
Blank solution：Dimethyl sulfoxide (DMSO) (DMSO).
Methanol stock solution：Methanol about 750mg is taken, it is accurately weighed, put in 25ml measuring bottles, scale is dissolved to DMSO dilutions,
Shake up, produce；
Isopropanol stock solution：Isopropanol about 1250mg is taken, it is accurately weighed, put in 25ml measuring bottles, be dissolved to DMSO dilutions
Scale, shake up, produce；
Fluorobenzene stock solution：Fluorobenzene about 157.5mg is taken, it is accurately weighed, put in 25ml measuring bottles, quarter is dissolved to DMSO dilutions
Degree, shakes up, produces；
Toluene stock solution：Toluene about 222.5mg is taken, it is accurately weighed, put in 25ml measuring bottles, quarter is dissolved to DMSO dilutions
Degree, shakes up, produces；
DMF stock solutions：DMF about 220mg are taken, it is accurately weighed, put in 25ml measuring bottles, be dissolved to scale with DMSO dilutions, shake
It is even, produce；
System suitability solution：Precision pipettes each positioning solution 1.0ml in the 100ml volumetric flasks equipped with 30ml or so DMSO
In, with diluted to scale, shake up.
Precision pipettes blank solution, each 5ml of system suitability solution, is placed in 20ml ml headspace bottles, and capping compresses, head space note
Enter gas chromatograph, record chromatogram.
As a result show, blank solution is noiseless to each blob detection.Retention time is in system suitability solution (see Fig. 1)
5.710min, 10.866min, 21.719min, 24.887min, 26.899min chromatographic peak are followed successively by methanol, isopropanol, fluorine
The separating degree of the chromatographic peak of benzene, toluene and DMF, wherein isopropanol and methanol is 9.869, fluorobenzene and isopropyl
The separating degree of alcohol is 31.615, and the separating degree of toluene and fluorobenzene is 25.417, the separating degree of DMF and toluene
For 19.137.The peak for diluent DMSO in figure after DMF peaks, it is not necessary to integrate.As a result show, the analysis method it is exclusive
Property is strong.
2nd, test limit and quantitative limit
Precision pipettes methanol stock solution 4ml, isopropanol stock solution 2ml, fluorobenzene stock solution 1.5ml and toluene stock solution
0.5ml is placed in same 100ml measuring bottles, adds diluent to be diluted to after scale shakes up, precision pipettes this mixed solution 1ml and is placed in
In 50ml measuring bottles, as methanol, isopropanol, fluorobenzene, toluene quantitative limit solution.Precision pipettes this quantitative limit solution 5ml and put
In 10ml measuring bottles, add diluent to be diluted to scale, shake up, be methanol, isopropanol, fluorobenzene, the test limit solution of toluene.It is another accurate
The stock solution 0.1ml of DMF is pipetted, is placed in 100ml measuring bottles, adds diluent to be diluted to scale, shake up, i.e.,
Obtain its quantitative limit solution.Precision pipettes this quantitative limit solution 3ml, puts in 10ml measuring bottles, adds diluent to be diluted to scale, shakes up,
Produce the test limit solution of N,N-dimethylformamide.
Measurement result is：The detection of methanol is limited to 12 μ g/mL, is quantitatively limited to 24 μ g/mL；The detection of isopropanol is limited to 10 μ
G/mL, quantitatively it is limited to 20 μ g/mL；The detection of fluorobenzene is limited to 0.9 μ g/mL, is quantitatively limited to 1.9 μ g/mL；The detection of toluene is limited to
0.5 μ g/mL, quantitatively it is limited to 0.9 μ g/mL；DMF detection is limited to 4.5 μ g/mL, is quantitatively limited to 8.8 μ g/mL.
As a result show, the detection sensitivity of the analysis method is high.
3rd, precision test (replica test)
Reference substance solution：Homologous ray applicability solution.
Need testing solution：Precision weighs Ezetimibe bulk drug about 0.5g, puts 20ml ml headspace bottles, adds DMSO to be capped after dissolving
Compress, as need testing solution (parallel to prepare 6 parts).Headspace sampling, the area of each solvent in Ezetimibe bulk drug is determined, outside
Mark method calculates each flux content, the results are shown in Table 1.As it can be seen from table 1 the RSD of repeated measurement result is 4.95%, illustrate this
The repeatability of invention residual solvent detection method is good.
The replica test result of table 1
Remarks：ND represents not detect.
4th, accuracy test
50% sample-adding titer：Precision pipettes each stock solution 0.5mL in added with the 100mL measuring bottles of about 20mL dilutions
In, with diluted to scale, shake up.
100% sample-adding standard liquid：Precision pipettes each stock solution 1.0mL in added with the 100mL amounts of about 20mL dilutions
In bottle, with diluted to scale, shake up.
150% sample-adding standard liquid：Precision pipettes each stock solution 1.5mL in added with the 100mL amounts of about 20mL dilutions
In bottle, with diluted to scale, shake up.
50% sample-adding test liquid 1：Precision weighs SM-1 test samples about 0.5g in 20mL ml headspace bottles, and precision pipettes 50% and added
Sample titer 5mL, fully vibration make dissolving complete, seal；It is parallel to prepare 3 parts.
100% sample-adding test liquid 1：Precision weighs SM-1 test samples about 0.5g in 20mL ml headspace bottles, and precision pipettes 100%
Titer 5mL is loaded, fully vibration makes dissolving complete, seals；It is parallel to prepare 3 parts.
150% sample-adding test liquid 1：Precision weighs SM-1 test samples about 0.5g in 20mL ml headspace bottles, and precision pipettes 150%
Titer 5mL is loaded, fully vibration makes dissolving complete, seals；It is parallel to prepare 3 parts.
The rate of recovery of the degree of accuracy is in the range of 80%~120% it can be seen from the accuracy test result of table 2, and reclaims
The relative deviation of rate is no more than 10.0%, and the degree of accuracy is good.
The accuracy test result of table 2
5th, linear test
Precision pipettes methanol stock solution, isopropanol stock solution, fluorobenzene stock solution, toluene stock solution and N, N- dimethyl formyl
Amine stock solution each 2.0ml, 1.5ml, 1.0ml, 0.5ml, 0.2ml and 0.1ml are respectively put in same 100ml measuring bottles, sub- with dimethyl
Sulfone is diluted to scale, shakes up, and carries out linear regression analysis with peak area and concentration, test result is as shown in table 3, and linear relationship is good
It is good.
The linear test result of table 3
| Title | Concentration range (ug/ml) | Linear equation | Coefficient R |
| Methanol | 24.3~455.5 | Y=23055x-17873 | 0.9995 |
| Isopropanol | 20.1~752.6 | Y=34870x-266599 | 0.9998 |
| Fluorobenzene | 1.9~95.6 | Y=144655x-121376 | 0.9997 |
| Toluene | 0.9~137.3 | Y=137405x-128254 | 0.9998 |
| N,N-dimethylformamide | 9.5~175.5 | Y=2758.5x+29543 | 0.9999 |
Embodiment 2
Instrument：Agilent 7890A-7697A headspace gas chromatography instrument, fid detector；
Chromatographic column：KB-624 (30m*0.32mm, 3.0 μm)；
Chromatographic parameter：Carrier gas：Nitrogen；Flow rate of carrier gas：1.2ml/min；Split ratio：1:1；
Detector temperature：250℃；Injector temperature：200℃；
Column temperature：Initial temperature rises to 200 DEG C after keeping 15min for 40 DEG C with 10 DEG C/min speed, keeps 8min.
Head space detection parameters：Heater box temperature：90℃；Quantitative loop temperature：100℃；Transmission line temperature：110℃；
Head space equilibration time：30min；Circulation time：50min；Sample injection time：0.5min；
Pressure balance time：0.1min.
Test procedure：
Blank solution：Dimethyl sulfoxide (DMSO) (DMSO).
System suitability solution：Precision, which pipettes, respectively positions solution 1.0ml in equipped with 30ml or so DMSO's in embodiment 1
In 100ml volumetric flasks, with diluted to scale, shake up.
Precision pipettes blank solution, each 5ml of system suitability solution, is placed in 20ml ml headspace bottles, and capping compresses, head space note
Enter gas chromatograph, record chromatogram.As a result as table 4, system suitability solution collection of illustrative plates are shown in Fig. 2.As a result methanol, isopropyl are shown
Alcohol, fluorobenzene, toluene and DMF can be kept completely separate, and the residual solvent of Ezetimibe bulk drug can be same
Chromatographic condition is issued to good separation.
The system suitability result of 4 embodiment of table 2
| Title | Retention time (minute) | Separating degree |
| Methanol | 4.880 | -- |
| Isopropanol | 9.249 | 9.151 |
| Fluorobenzene | 20.723 | 34.765 |
| Toluene | 24.053 | 25.022 |
| N,N-dimethylformamide | 26.136 | 19.639 |
Embodiment 3
Instrument：Agilent 7890A-7697A headspace gas chromatography instrument, fid detector；
Chromatographic column：KB-624 (30m*0.32mm, 3.0 μm)；
Chromatographic parameter：Carrier gas：Nitrogen；Flow rate of carrier gas：0.8ml/min；Split ratio：1:1；
Detector temperature：250℃；Injector temperature：200℃；
Column temperature：Initial temperature rises to 200 DEG C after keeping 15min for 40 DEG C with 10 DEG C/min speed, keeps 8min.
Head space detection parameters：Heater box temperature：90℃；Quantitative loop temperature：100℃；Transmission line temperature：110℃；
Head space equilibration time：30min；Circulation time：50min；Sample injection time：0.5min；
Pressure balance time：0.1min.
Test procedure：
Blank solution：Dimethyl sulfoxide (DMSO) (DMSO).
System suitability solution：Precision, which pipettes, respectively positions solution 1.0ml in equipped with 30ml or so DMSO's in embodiment 1
In 100ml volumetric flasks, with diluted to scale, shake up.
Precision pipettes blank solution, each 5ml of system suitability solution, is placed in 20ml ml headspace bottles, and capping compresses, head space note
Enter gas chromatograph, record chromatogram.As a result as table 5, system suitability solution collection of illustrative plates are shown in Fig. 3.As a result methanol, isopropyl are shown
Alcohol, fluorobenzene, toluene and DMF can be kept completely separate, and the residual solvent of Ezetimibe bulk drug can be same
Chromatographic condition is issued to good separation.
The system suitability result of 5 embodiment of table 3
| Title | Retention time (minute) | Separating degree |
| Methanol | 6.879 | -- |
| Isopropanol | 13.150 | 10.740 |
| Fluorobenzene | 22.907 | 26.450 |
| Toluene | 25.929 | 25.527 |
| N,N-dimethylformamide | 27.865 | 18.941 |
Embodiment 4
Instrument：Agilent 7890A-7697A headspace gas chromatography instrument, fid detector；
Chromatographic column：KB-624 (30m*0.32mm, 3.0 μm)；
Chromatographic parameter：Carrier gas：Nitrogen；Flow rate of carrier gas：1.0ml/min；Split ratio：1:1；
Detector temperature：250℃；Injector temperature：200℃；
Column temperature：Initial temperature rises to 200 DEG C after keeping 15min for 40 DEG C with 10 DEG C/min speed, keeps 8min.
Head space detection parameters：Heater box temperature：85℃；Quantitative loop temperature：100℃；Transmission line temperature：110℃；
Head space equilibration time：30min；Circulation time：50min；Sample injection time：0.5min；
Pressure balance time：0.1min.
Test procedure：
Blank solution：Dimethyl sulfoxide (DMSO) (DMSO).
System suitability solution：Precision, which pipettes, respectively positions solution 1.0ml in equipped with 30ml or so DMSO's in embodiment 1
In 100ml volumetric flasks, with diluted to scale, shake up.
Precision pipettes blank solution, each 5ml of system suitability solution, is placed in 20ml ml headspace bottles, and capping compresses, head space note
Enter gas chromatograph, record chromatogram.As a result as table 6, system suitability solution collection of illustrative plates are shown in Fig. 4.As a result methanol, isopropyl are shown
Alcohol, fluorobenzene, toluene and DMF can be kept completely separate, and the residual solvent of Ezetimibe bulk drug can be same
Chromatographic condition is issued to good separation.
The system suitability result of 6 embodiment of table 4
| Title | Retention time (minute) | Separating degree |
| Methanol | 5.694 | -- |
| Isopropanol | 10.839 | 9.713 |
| Fluorobenzene | 21.707 | 31.536 |
| Toluene | 24.876 | 25.558 |
| N,N-dimethylformamide | 26.891 | 19.337 |
Embodiment 5
Instrument：Agilent 7890A-7697A headspace gas chromatography instrument, fid detector；
Chromatographic column：KB-624 (30m*0.32mm, 3.0 μm)；
Chromatographic parameter：Carrier gas：Nitrogen；Flow rate of carrier gas：1.0ml/min；Split ratio：1:1；
Detector temperature：250℃；Injector temperature：200℃；
Column temperature：Initial temperature rises to 200 DEG C after keeping 15min for 40 DEG C with 10 DEG C/min speed, keeps 8min.
Head space detection parameters：Heater box temperature：95℃；Quantitative loop temperature：100℃；Transmission line temperature：110℃；
Head space equilibration time：30min；Circulation time：50min；Sample injection time：0.5min；
Pressure balance time：0.1min.
Test procedure：
Blank solution：Dimethyl sulfoxide (DMSO) (DMSO)
System suitability solution：Precision, which pipettes, respectively positions solution 1.0ml in equipped with 30ml or so DMSO's in embodiment 1
In 100ml volumetric flasks, with diluted to scale, shake up.
Precision pipettes blank solution, each 5ml of system suitability solution, is placed in 20ml ml headspace bottles, and capping compresses, head space note
Enter gas chromatograph, record chromatogram.As a result as table 7, system suitability solution collection of illustrative plates are shown in Fig. 5.As a result methanol, isopropyl are shown
Alcohol, fluorobenzene, toluene and DMF can be kept completely separate, and the residual solvent of Ezetimibe bulk drug can be same
Chromatographic condition is issued to good separation.
The system suitability result of 7 embodiment of table 5
| Title | Retention time (minute) | Separating degree |
| Methanol | 5.688 | -- |
| Isopropanol | 10.826 | 9.889 |
| Fluorobenzene | 21.701 | 31.468 |
| Toluene | 24.872 | 25.198 |
| N,N-dimethylformamide | 26.884 | 19.324 |
Embodiment 6
Instrument：Agilent 7890A-7697A headspace gas chromatography instrument, fid detector；
Chromatographic column：KB-624 (30m*0.32mm, 3.0 μm)；
Chromatographic parameter：Carrier gas：Nitrogen；Flow rate of carrier gas：1.0ml/min；Split ratio：1:1；
Detector temperature：250℃；Injector temperature：200℃；
Column temperature：Initial temperature rises to 200 DEG C after keeping 15min for 40 DEG C with 10 DEG C/min speed, keeps 8min.
Head space detection parameters：Heater box temperature：90℃；Quantitative loop temperature：100℃；Transmission line temperature：110℃；
Head space equilibration time：25min；Circulation time：50min；Sample injection time：0.5min；
Pressure balance time：0.1min.
Test procedure：
Blank solution：Dimethyl sulfoxide (DMSO) (DMSO)
System suitability solution：Precision, which pipettes, respectively positions solution 1.0ml in equipped with 30ml or so DMSO's in embodiment 1
In 100ml volumetric flasks, with diluted to scale, shake up.
Precision pipettes blank solution, each 5ml of system suitability solution, is placed in 20ml ml headspace bottles, and capping compresses, head space note
Enter gas chromatograph, record chromatogram.As a result as table 8, system suitability solution collection of illustrative plates are shown in Fig. 6.As a result methanol, isopropyl are shown
Alcohol, fluorobenzene, toluene and DMF can be kept completely separate, and the residual solvent of Ezetimibe bulk drug can be same
Chromatographic condition is issued to good separation.
The system suitability result of 8 embodiment of table 6
| Title | Retention time (minute) | Separating degree |
| Methanol | 5.701 | -- |
| Isopropanol | 10.843 | 9.662 |
| Fluorobenzene | 21.706 | 31.053 |
| Toluene | 24.876 | 25.404 |
| N,N-dimethylformamide | 26.889 | 19.553 |
Embodiment 7
Instrument：Agilent 7890A-7697A headspace gas chromatography instrument, fid detector；
Chromatographic column：KB-624 (30m*0.32mm, 3.0 μm)；
Chromatographic parameter：Carrier gas：Nitrogen；Flow rate of carrier gas：1.0ml/min；Split ratio：1:1；
Detector temperature：250℃；Injector temperature：200℃；
Column temperature：Initial temperature rises to 200 DEG C after keeping 15min for 40 DEG C with 10 DEG C/min speed, keeps 8min.
Head space detection parameters：Heater box temperature：90℃；Quantitative loop temperature：100℃；Transmission line temperature：110℃；
Head space equilibration time：35min；Circulation time：50min；Sample injection time：0.5min；
Pressure balance time：0.1min.
Test procedure：
Blank solution：Dimethyl sulfoxide (DMSO) (DMSO).
System suitability solution：Precision, which pipettes, respectively positions solution 1.0ml in equipped with 30ml or so DMSO's in embodiment 1
In 100ml volumetric flasks, with diluted to scale, shake up.
Precision pipettes blank solution, each 5ml of system suitability solution, is placed in 20ml ml headspace bottles, and capping compresses, head space note
Enter gas chromatograph, record chromatogram.As a result as table 9, system suitability solution collection of illustrative plates are shown in Fig. 7.As a result methanol, isopropyl are shown
Alcohol, fluorobenzene, toluene and DMF can be kept completely separate, and the residual solvent of Ezetimibe bulk drug can be same
Chromatographic condition is issued to good separation.
The system suitability result of 9 embodiment of table 7
| Title | Retention time (minute) | Separating degree |
| Methanol | 5.704 | -- |
| Isopropanol | 10.854 | 9.672 |
| Fluorobenzene | 21.711 | 30.384 |
| Toluene | 24.879 | 25.328 |
| N,N-dimethylformamide | 26.892 | 19.112 |
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means specific features, structure, material or the spy for combining the embodiment or example description
Point is contained at least one embodiment or example of the present invention.In this manual, to the schematic representation of above-mentioned term not
Identical embodiment or example must be directed to.Moreover, specific features, structure, material or the feature of description can be with office
Combined in an appropriate manner in one or more embodiments or example.In addition, in the case of not conflicting, the skill of this area
Art personnel can be tied the different embodiments or example and the feature of different embodiments or example described in this specification
Close and combine.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example
Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, changed, replacing and modification.
Claims (10)
- A kind of 1. method that residual solvent in Ezetimibe bulk drug is determined using headspace gas chromatography, it is characterised in that described The analysis condition of method is：Use capillary chromatographic column of the dimethyl polysiloxane of 6% cyanogen propyl group phenyl -94% for stationary phase；It is nitrogen to distinguish sample introduction reference substance solution spininess and need testing solution, carrier gas using shunt mode, passes through head-space sampler Sample introduction, detected after carrying out temperature programming；Detector is fid detector.
- 2. according to the method for claim 1, it is characterised in that the chromatographic column model KB-624.
- 3. according to the method for claim 1, it is characterised in that the residual solvent is methanol, isopropanol, fluorobenzene, toluene And N,N-dimethylformamide.
- 4. according to the method for claim 1, it is characterised in that the reference substance solution and the need testing solution use Dimethyl sulfoxide (DMSO) is solvent；Optional, contain methanol 0.30mg, isopropanol 0.50mg, fluorobenzene 0.063mg, first in every 1ml in the reference substance solution Benzene 0.089mg and N,N-dimethylformamide 0.088mg.
- 5. according to the method described in claim 1, it is characterised in that first sample introduction before sample introduction reference substance solution spininess and need testing solution The pin of blank solution 1 is as blank control；Sample introduction reference substance solution is 6 pins, and need testing solution is 2 pins.
- 6. according to the method described in claim 1, it is characterised in that the split ratio is 1:1~10:1, preferably 1:1.
- 7. according to the method described in claim 1, it is characterised in that the flow rate of carrier gas is 0.2~2.0ml/min, is preferably 1.0ml/min。
- 8. according to the method described in claim 1, it is characterised in that the headspace sampling mouth temperature is 180~250 DEG C, is preferably 200℃；Optional, heater box temperature is 80~120 DEG C, preferably 90 DEG C；Optional, quantitative loop temperature is 90~150 DEG C, preferably 100 DEG C；Optional, transmission line temperature is 100~150 DEG C, preferably 110 DEG C；Optional, the equilibration time of the headspace sampling is 20~50min, preferably 30min；Optional, GC circulation times are 30~60min, preferably 50min.
- 9. according to the method described in claim 1, it is characterised in that described program heating keeps 5 for 30~50 DEG C of initial temperature~ 200~250 DEG C are risen to 5~20 DEG C/min speed after 20min, keeps 5~10min；Preferably, the initial temperature of temperature programming is 40 DEG C, 200 DEG C risen to after holding 15min with 10 DEG C/min speed, is kept 8min。
- 10. according to the method described in claim 1, it is characterised in that the detector temperature be 200~280 DEG C, preferably 250 ℃。
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