CN107860826B - Method for measuring residual solvent in ezetimibe bulk drug by using headspace gas chromatography - Google Patents
Method for measuring residual solvent in ezetimibe bulk drug by using headspace gas chromatography Download PDFInfo
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Abstract
The invention discloses a method for measuring residual solvent in an ezetimibe raw material medicine by utilizing headspace gas chromatography, which comprises the following analysis conditions: adopting a capillary chromatographic column taking 6 percent of cyanopropylphenyl-94 percent of dimethyl polysiloxane as a stationary phase; respectively injecting a reference substance solution with multiple needles and a test substance solution in a split-flow mode, injecting a carrier gas which is nitrogen gas by a headspace injector, and detecting after carrying out temperature programming; the detector is a FID detector. By adopting the method, methanol, isopropanol, fluorobenzene, methylbenzene and N, N-dimethylformamide in the ezetimibe bulk drug can be quickly and efficiently separated under the same chromatographic condition, and the quality of the ezetimibe bulk drug can be effectively controlled. The detection method has the advantages of strong specificity, high detection sensitivity, high precision, strong accuracy and convenient operation, and can effectively control the product quality.
Description
Technical Field
The invention belongs to the technical field of drug analysis, and particularly relates to a method for determining a residual solvent in an ezetimibe raw material drug by utilizing headspace gas chromatography.
Background
The chemical name of the ezetimibe raw material is (4S) -3- [ (5S) -5- (4-fluorophenyl) -5-hydroxypentanoyl ] -4-phenyl-1, 3-oxazepan-2-one, and the structural formula is as follows:
the organic solvent which is used in the production process of the pharmaceutical raw material medicament and the preparation and is not completely removed at last is called residual solvent, and if the residual amount exceeds a safe value, the residual amount can cause certain influence on the human body of a patient. The ICH guidelines specify 4 classes of solvents and limits, depending on the degree of harm. According to the requirement of the content of the residual solvent specified in the fourth method for measuring the residual solvent in the pharmacopoeia 2015 edition of China and the synthesis process of the ezetimibe raw material medicine, the organic solvent used by the ezetimibe raw material medicine in the final synthesis process must be controlled: the residual amounts of methanol, isopropanol, toluene and N, N-Dimethylformamide (DMF), respectively, are: 0.3% methanol, 0.5% isopropanol, 0.089% toluene, 0.088% N, N-dimethylformamide.
According to published information published by European chemical industries Agency (ECHA), fluorobenzene is negative in genotoxicity test, and the limit of fluorobenzene is limited to 0.063% by literature search based on toxicological data and physicochemical properties of fluorobenzene.
At present, the method for determining the residual solvent in the ezetimibe bulk drug still needs to be improved.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, an object of the present invention is to provide a method for measuring residual solvents in an ezetimibe raw material by using headspace gas chromatography, wherein the method can simultaneously detect the residual amounts of methanol, isopropanol, fluorobenzene, toluene and N, N-dimethylformamide in the ezetimibe raw material. And the method has high sensitivity, high accuracy, strong specificity and good reproducibility.
The synthetic route of the ezetimibe raw material medicine is as follows:
residual solvents present in the process are: methanol, isopropanol, toluene, fluorobenzene and DMF.
According to an embodiment of the invention, the analysis conditions of the method are:
adopting a capillary chromatographic column taking 6 percent of cyanopropylphenyl-94 percent of dimethyl polysiloxane as a stationary phase; respectively injecting a reference substance solution with multiple needles and a test substance solution in a split-flow mode, injecting a carrier gas which is nitrogen gas by a headspace injector, and detecting after carrying out temperature programming; the detector is a FID detector.
Therefore, according to the method for measuring the residual solvent in the ezetimibe bulk drug by using the headspace gas chromatography, disclosed by the embodiment of the invention, the interference of a blank peak on a target peak can be effectively avoided by detecting in a direct sample injection mode of temperature programming, so that the detection accuracy is improved, meanwhile, the method can be used for quickly and efficiently separating and measuring the residual of various organic solvents in the ezetimibe bulk drug, and the detection method is strong in specificity, high in precision, strong in accuracy and convenient to operate, so that the quality of a drug is effectively controlled.
The invention adopts a headspace sampling system and is suitable for volatile organic solvents. Compared with a direct sample introduction system, the headspace sample introduction system can not only avoid the interference of a sample matrix, but also prevent organic matters with high boiling points which can not be gasified from blocking and polluting a sample introduction port. In addition, the invention adopts a capillary chromatographic column taking 6 percent of cyanopropyl phenyl-94 percent of dimethyl polysiloxane as a fixed phase, and the chromatographic column is specially designed for volatile residual solvent and has good inertia to active compounds. Proved by methodology, the chromatographic column has good separation effect and good accuracy on residual solvent in the ezetimibe bulk drug.
The method for determining the residual solvent in the ezetimibe bulk drug by using headspace gas chromatography according to the embodiment of the invention can also have the following additional technical characteristics:
in some embodiments of the invention, the column model is KB-624.
In some embodiments of the invention, the residual solvent is methanol, isopropanol, fluorobenzene, toluene, and N, N-dimethylformamide.
In some embodiments of the present invention, both the control solution and the test solution employ dimethylsulfoxide as a solvent.
In some embodiments of the invention, the control solution is prepared by: taking a proper amount of methanol, isopropanol, fluorobenzene, methylbenzene and N, N-dimethylformamide respectively, precisely weighing, and diluting with dimethyl sulfoxide to obtain a mixed solution containing 0.30mg of methanol, 0.50mg of isopropanol, 0.063mg of fluorobenzene, 0.089mg of methylbenzene and 0.088mg of N, N-dimethylformamide in each 1ml as a reference solution; precisely transferring 5ml of the mixture into a 20ml headspace bottle, capping and compacting the bottle, and parallelly transferring 6 parts of the mixture.
In some embodiments of the present invention, the preparation process of the test solution is: taking 0.5g of ezetimibe raw material, precisely weighing, placing in a 20ml headspace bottle, adding 5ml of dimethyl sulfoxide for dissolving, capping and compacting to obtain a test solution; 2 parts are prepared in parallel.
In some embodiments of the invention, the blank solution formulation process is: precisely transferring 5ml of dimethyl sulfoxide, placing the dimethyl sulfoxide into a 20ml headspace bottle, covering and compacting the bottle to obtain a blank solution.
In some embodiments of the present invention, a headspace gas chromatography is used to sample a reference solution and a test solution respectively, and the content of each residual solvent in the ezetimibe raw material is calculated by using the following formula according to the peak area of the corresponding peak of each residual solvent in the chromatograms of the reference solution and the test solution:
in the formula:
mnweighing corresponding methanol, isopropanol, fluorobenzene, methylbenzene and N, N-dimethylformamide to obtain mg;
m is the sample weighing and mg of the sample;
Anpeak areas of each solvent of the chromatogram recorded by the test solution;
as-average area of peaks of each solvent in chromatogram recorded for reference solution;
5000-volume and unit conversion times.
Wherein, the relative standard deviation RSD of the peak area of each solvent is required to be not more than 10 percent when the detection is carried out by adopting the headspace gas chromatography, and the separation degree between adjacent solvents is lower than 1.5.
According to some embodiments of the invention, the split ratio is 1:1 to 10:1, preferably 1: 1. The separation effect obtained thereby is optimal.
According to some embodiments of the invention, the carrier gas flow rate is 0.2-2.0 ml/min, preferably 1.0 ml/min. The separation effect obtained thereby is optimal.
According to some embodiments of the invention, the headspace inlet temperature is 180-250 ℃, preferably 200 ℃; the temperature of the heating box is 80-120 ℃, and preferably 90 ℃; the quantitative ring temperature is 90-150 ℃, and preferably 100 ℃; the temperature of the transmission line is 100-150 ℃, and preferably 110 ℃; thereby, the detection accuracy can be improved.
According to some embodiments of the invention, the equilibration time for headspace sampling is 20-50 min, preferably 30 min; the circulation time is 30-60 min, preferably 50 min. This can further improve the degree of separation.
According to some embodiments of the present invention, the temperature programming is performed by maintaining the temperature at 30-50 ℃ for 5-20 min, and then raising the temperature to 200-250 ℃ at a speed of 5-20 ℃/min for 5-10 min. Preferably, the temperature programming is initiated at 40 ℃ for 15min and then increased to 200 ℃ at a rate of 10 ℃/min for 8 min. The separation and detection effects obtained thereby are optimal.
According to some embodiments of the invention, the detector temperature is 200-280 ℃, preferably 250 ℃. Therefore, the water vapor condensation and impurity attachment in the chromatographic system can be prevented from remaining in the detector to damage the detector, so that the detection accuracy is further improved.
According to the specific embodiment of the invention, when the content of each residual solvent in the ezetimibe raw material is measured by adopting headspace gas chromatography, the measurement conditions are as follows: a capillary column taking 6% cyanopropyl phenyl and 94% dimethyl polysiloxane as a stationary phase is used as a chromatographic column for analysis, and a detector is an FID detector; chromatographic separation parameters: carrier gas: nitrogen gas; flow rate of carrier gas: 1.0 ml/min; the split ratio is as follows: 1: 1; detector temperature: 250 ℃; sample inlet temperature: 200 ℃; column temperature: the initial temperature is 40 deg.C, maintained for 15min, then raised to 200 deg.C at a speed of 10 deg.C/min, and maintained for 8 min. Headspace detection parameters: heating box temperature: 90 ℃; quantitative ring temperature: 100 ℃; transmission line temperature: 110 ℃; headspace equilibrium time: 30 min; cycle time: 50 min; sample introduction time: 0.5 min; pressure balance time: 0.1 min.
The invention establishes the detection method of residual solvents of methanol, isopropanol, fluorobenzene, methylbenzene and N, N-dimethylformamide in the ezetimibe raw material by optimizing the chromatographic conditions, and experiments prove that the established method has good specificity, high sensitivity, good linear relation and repeatability and high accuracy, and provides good quality assurance for controlling the solvent residue in the ezetimibe raw material and the subsequent production of ezetimibe.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
FIG. 1 shows a headspace gas chromatogram for detection of a system suitability solution according to example 1 of the present invention;
FIG. 2 shows a headspace gas chromatogram for system suitability solution detection according to example 2 of the present invention;
FIG. 3 shows a headspace gas chromatogram for system suitability solution detection according to example 3 of the present invention;
FIG. 4 shows a headspace gas chromatogram for system suitability solution detection according to example 4 of the present invention;
FIG. 5 shows a headspace gas chromatogram for system suitability solution detection according to example 5 of the present invention;
FIG. 6 shows a headspace gas chromatogram for system suitability solution detection according to example 6 of the present invention;
FIG. 7 shows a headspace gas chromatogram for system suitability solution detection according to example 7 of the present invention.
Detailed Description
The following examples are provided to further illustrate the invention and its embodiments. The specific details given in the examples are for illustrative purposes only and should not be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1
The instrument comprises the following steps: agilent 7890A-7697A headspace gas chromatograph, FID detector;
a chromatographic column: KB-624(30m × 0.32mm, 3.0 μm);
chromatographic parameters: carrier gas: nitrogen gas; flow rate of carrier gas: 1.0 ml/min; the split ratio is as follows: 1: 1;
detector temperature: 250 ℃; sample inlet temperature: 200 ℃;
column temperature: the initial temperature is 40 deg.C, maintained for 15min, then raised to 200 deg.C at a speed of 10 deg.C/min, and maintained for 8 min.
Headspace detection parameters: heating box temperature: 90 ℃; quantitative ring temperature: 100 ℃; transmission line temperature: 110 ℃;
headspace equilibrium time: 30 min; cycle time: 50 min; sample introduction time: 0.5 min;
pressure balance time: 0.1 min.
1. Specificity
Blank solution: dimethyl sulfoxide (DMSO).
Methanol stock solution: taking about 750mg of methanol, precisely weighing, placing in a 25ml measuring flask, diluting and dissolving to a scale with DMSO, and shaking up to obtain the final product;
isopropyl alcohol stock solution: accurately weighing about 1250mg of isopropanol, placing the isopropanol into a 25ml measuring flask, diluting and dissolving the isopropanol to a scale by DMSO, and shaking up to obtain the isopropanol-containing measuring flask;
fluorobenzene stock solution: precisely weighing about 157.5mg of fluorobenzene, placing the fluorobenzene into a 25ml measuring flask, diluting and dissolving the fluorobenzene to a scale by DMSO, and shaking up to obtain the fluorobenzene;
toluene stock solution: taking about 222.5mg of toluene, precisely weighing, placing in a 25ml measuring flask, diluting and dissolving to a scale with DMSO, and shaking up to obtain the product;
DMF stock solution: taking about 220mg of DMF, precisely weighing, placing in a 25ml measuring flask, diluting and dissolving to a scale with DMSO, and shaking up to obtain the final product;
system applicability solution: precisely transferring 1.0ml of each positioning solution into a 100ml volumetric flask containing about 30ml of DMSO, diluting the solution to a scale with a diluent, and shaking up.
Precisely transferring 5ml of each of the blank solution and the system applicability solution, placing the blank solution and the system applicability solution into a 20ml headspace bottle, capping and compressing, injecting the headspace into a gas chromatograph, and recording the chromatogram.
The results show that the blank solution does not interfere with the detection of each peak. The chromatographic peaks of 5.710min, 10.866min, 21.719min, 24.887min and 26.899min in the system suitability solution (see fig. 1) are the chromatographic peaks of methanol, isopropanol, fluorobenzene, toluene and N, N-dimethylformamide in sequence, wherein the separation degree of the isopropanol from the methanol is 9.869, the separation degree of the fluorobenzene from the isopropanol is 31.615, the separation degree of the toluene from the fluorobenzene is 25.417, and the separation degree of the N, N-dimethylformamide and the toluene is 19.137. The DMF peak is followed by the peak of diluent DMSO, without integration. The result shows that the specificity of the analysis method is strong.
2. Detection limit and quantification limit
Precisely transferring 4ml of methanol stock solution, 2ml of isopropanol stock solution, 1.5ml of fluorobenzene stock solution and 0.5ml of methylbenzene stock solution into the same 100ml measuring flask, adding a diluent to dilute to scale, shaking uniformly, and precisely transferring 1ml of the mixed solution into a 50ml measuring flask to be used as a quantitative limiting solution of methanol, isopropanol, fluorobenzene and methylbenzene. Precisely transferring 5ml of the quantitative limiting solution into a 10ml measuring flask, adding a diluent to dilute to a scale, and shaking up to obtain the detection limiting solution of methanol, isopropanol, fluorobenzene and toluene. And precisely transferring 0.1ml of stock solution of the N, N-dimethylformamide, putting the stock solution into a 100ml measuring flask, adding a diluent to dilute to a scale, and shaking up to obtain the quantitative limiting solution. Precisely transferring 3ml of the quantitative limiting solution, putting the quantitative limiting solution into a 10ml measuring flask, adding a diluent to dilute the quantitative limiting solution to a scale, and shaking up to obtain the detection limiting solution of the N, N-dimethylformamide.
The measurement results are as follows: the detection limit of the methanol is 12 mug/mL, and the quantification limit is 24 mug/mL; the detection limit of the isopropanol is 10 mug/mL, and the quantification limit is 20 mug/mL; the detection limit of fluorobenzene is 0.9 mug/mL, and the quantification limit is 1.9 mug/mL; the detection limit of toluene is 0.5 mug/mL, and the quantification limit is 0.9 mug/mL; the detection limit of DMF was 4.5. mu.g/mL, and the quantitation limit was 8.8. mu.g/mL.
The result shows that the analysis method has high detection sensitivity.
3. Precision test (repeatability test)
Control solution: the same applies to the solution.
Test solution: precisely weighing about 0.5g of ezetimibe raw material medicine, placing the ezetimibe raw material medicine into a 20ml headspace bottle, adding DMSO to dissolve the ezetimibe raw material medicine, covering the bottle and compacting the bottle to obtain a test solution (6 parts are prepared in parallel). And (3) introducing a sample in a headspace, measuring the area of each solvent in the ezetimibe bulk drug, and calculating the content of each solvent by an external standard method, wherein the result is shown in table 1. As can be seen from Table 1, the RSD of the reproducibility measurement result was 4.95%, indicating that the reproducibility of the residual solvent detection method of the present invention was good.
TABLE 1 results of the repeatability tests
Remarking: ND means not detected.
4. Accuracy test
50% sample addition standard solution: 0.5mL of each stock solution was precisely transferred to a 100mL measuring flask to which about 20mL of the diluent had been added, diluted to the scale with the diluent, and shaken well.
100% loading standard solution: precisely transfer 1.0mL of each stock solution into a 100mL measuring flask containing about 20mL of the diluent, dilute the stock solution to the scale with the diluent, and shake the stock solution.
150% loading standard solution: precisely transfer 1.5mL of each stock solution into a 100mL measuring flask containing about 20mL of the diluent, dilute the stock solution to the scale with the diluent, and shake the stock solution.
50% sample addition test solution 1: precisely weighing about 0.5g of SM-1 sample in a 20mL headspace bottle, precisely transferring 5mL of 50% sample-adding standard solution, fully oscillating to completely dissolve, and capping and sealing; 3 parts are prepared in parallel.
100% sample addition test solution 1: precisely weighing about 0.5g of SM-1 sample in a 20mL headspace bottle, precisely transferring 5mL of 100% sample-adding standard solution, fully oscillating to completely dissolve, and capping and sealing; 3 parts are prepared in parallel.
150% sample addition test solution 1: precisely weighing about 0.5g of SM-1 sample in a 20mL headspace bottle, precisely transferring 5mL of 150% sample-adding standard solution, fully oscillating to completely dissolve, and capping and sealing; 3 parts are prepared in parallel.
As can be seen from the accuracy test results in Table 2, the recovery rate of the accuracy is within the range of 80% -120%, the relative deviation of the recovery rate is not more than 10.0%, and the accuracy is good.
TABLE 2 accuracy test results
5. Linear test
Precisely transferring the methanol stock solution, the isopropanol stock solution, the fluorobenzene stock solution, the toluene stock solution and the N, N-dimethylformamide stock solution respectively 2.0ml, 1.5ml, 1.0ml, 0.5ml, 0.2ml and 0.1ml into the same 100ml measuring flask, diluting to a scale with dimethyl sulfoxide, shaking uniformly, carrying out linear regression analysis by peak area and concentration, wherein the test results are shown in Table 3 and have good linear relation.
TABLE 3 results of the Linear test
| Name (R) | Concentration Range (ug/ml) | Linear equation of equations | Coefficient of correlation R |
| Methanol | 24.3～455.5 | y＝23055x-17873 | 0.9995 |
| Isopropanol (I-propanol) | 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 |
Example 2
The instrument comprises the following steps: agilent 7890A-7697A headspace gas chromatograph, FID detector;
a chromatographic column: KB-624(30m × 0.32mm, 3.0 μm);
chromatographic parameters: carrier gas: nitrogen gas; flow rate of carrier gas: 1.2 ml/min; the split ratio is as follows: 1: 1;
detector temperature: 250 ℃; sample inlet temperature: 200 ℃;
column temperature: the initial temperature is 40 deg.C, maintained for 15min, then raised to 200 deg.C at a speed of 10 deg.C/min, and maintained for 8 min.
Headspace detection parameters: heating box temperature: 90 ℃; quantitative ring temperature: 100 ℃; transmission line temperature: 110 ℃;
headspace equilibrium time: 30 min; cycle time: 50 min; sample introduction time: 0.5 min;
pressure balance time: 0.1 min.
The test steps are as follows:
blank solution: dimethyl sulfoxide (DMSO).
System applicability solution: precisely remove 1.0ml of each of the spotting solutions of example 1 into a 100ml volumetric flask containing about 30ml of DMSO, dilute to the mark with the diluent, and shake up.
Precisely transferring 5ml of each of the blank solution and the system applicability solution, placing the blank solution and the system applicability solution into a 20ml headspace bottle, capping and compressing, injecting the headspace into a gas chromatograph, and recording the chromatogram. The results are shown in Table 4, and the system suitability solution profile is shown in FIG. 2. The results show that methanol, isopropanol, fluorobenzene, toluene and N, N-dimethylformamide can be completely separated, and the residual solvent of the ezetimibe bulk drug can be well separated under the same chromatographic condition.
Table 4 example 2 system applicability test results
| Name (R) | Retention time (minutes) | Degree of separation |
| Methanol | 4.880 | -- |
| Isopropanol (I-propanol) | 9.249 | 9.151 |
| Fluorobenzene | 20.723 | 34.765 |
| Toluene | 24.053 | 25.022 |
| N, N-dimethylformamide | 26.136 | 19.639 |
Example 3
The instrument comprises the following steps: agilent 7890A-7697A headspace gas chromatograph, FID detector;
a chromatographic column: KB-624(30m × 0.32mm, 3.0 μm);
chromatographic parameters: carrier gas: nitrogen gas; flow rate of carrier gas: 0.8 ml/min; the split ratio is as follows: 1: 1;
detector temperature: 250 ℃; sample inlet temperature: 200 ℃;
column temperature: the initial temperature is 40 deg.C, maintained for 15min, then raised to 200 deg.C at a speed of 10 deg.C/min, and maintained for 8 min.
Headspace detection parameters: heating box temperature: 90 ℃; quantitative ring temperature: 100 ℃; transmission line temperature: 110 ℃;
headspace equilibrium time: 30 min; cycle time: 50 min; sample introduction time: 0.5 min;
pressure balance time: 0.1 min.
The test steps are as follows:
blank solution: dimethyl sulfoxide (DMSO).
System applicability solution: precisely remove 1.0ml of each of the spotting solutions of example 1 into a 100ml volumetric flask containing about 30ml of DMSO, dilute to the mark with the diluent, and shake up.
Precisely transferring 5ml of each of the blank solution and the system applicability solution, placing the blank solution and the system applicability solution into a 20ml headspace bottle, capping and compressing, injecting the headspace into a gas chromatograph, and recording the chromatogram. The results are shown in Table 5, and the system suitability solution profile is shown in FIG. 3. The results show that methanol, isopropanol, fluorobenzene, toluene and N, N-dimethylformamide can be completely separated, and the residual solvent of the ezetimibe bulk drug can be well separated under the same chromatographic condition.
Table 5 example 3 system applicability test results
| Name (R) | Retention time (minutes) | Degree of separation |
| Methanol | 6.879 | -- |
| Isopropanol (I-propanol) | 13.150 | 10.740 |
| Fluorobenzene | 22.907 | 26.450 |
| Toluene | 25.929 | 25.527 |
| N, N-dimethylformamide | 27.865 | 18.941 |
Example 4
The instrument comprises the following steps: agilent 7890A-7697A headspace gas chromatograph, FID detector;
a chromatographic column: KB-624(30m × 0.32mm, 3.0 μm);
chromatographic parameters: carrier gas: nitrogen gas; flow rate of carrier gas: 1.0 ml/min; the split ratio is as follows: 1: 1;
detector temperature: 250 ℃; sample inlet temperature: 200 ℃;
column temperature: the initial temperature is 40 deg.C, maintained for 15min, then raised to 200 deg.C at a speed of 10 deg.C/min, and maintained for 8 min.
Headspace detection parameters: heating box temperature: 85 ℃; quantitative ring temperature: 100 ℃; transmission line temperature: 110 ℃;
headspace equilibrium time: 30 min; cycle time: 50 min; sample introduction time: 0.5 min;
pressure balance time: 0.1 min.
The test steps are as follows:
blank solution: dimethyl sulfoxide (DMSO).
System applicability solution: precisely remove 1.0ml of each of the spotting solutions of example 1 into a 100ml volumetric flask containing about 30ml of DMSO, dilute to the mark with the diluent, and shake up.
Precisely transferring 5ml of each of the blank solution and the system applicability solution, placing the blank solution and the system applicability solution into a 20ml headspace bottle, capping and compressing, injecting the headspace into a gas chromatograph, and recording the chromatogram. The results are shown in Table 6, and the system suitability solution profile is shown in FIG. 4. The results show that methanol, isopropanol, fluorobenzene, toluene and N, N-dimethylformamide can be completely separated, and the residual solvent of the ezetimibe bulk drug can be well separated under the same chromatographic condition.
Table 6 example 4 system applicability test results
| Name (R) | Retention time (minutes) | Degree of separation |
| Methanol | 5.694 | -- |
| Isopropanol (I-propanol) | 10.839 | 9.713 |
| Fluorobenzene | 21.707 | 31.536 |
| Toluene | 24.876 | 25.558 |
| N, N-dimethylformamide | 26.891 | 19.337 |
Example 5
The instrument comprises the following steps: agilent 7890A-7697A headspace gas chromatograph, FID detector;
a chromatographic column: KB-624(30m × 0.32mm, 3.0 μm);
chromatographic parameters: carrier gas: nitrogen gas; flow rate of carrier gas: 1.0 ml/min; the split ratio is as follows: 1: 1;
detector temperature: 250 ℃; sample inlet temperature: 200 ℃;
column temperature: the initial temperature is 40 deg.C, maintained for 15min, then raised to 200 deg.C at a speed of 10 deg.C/min, and maintained for 8 min.
Headspace detection parameters: heating box temperature: 95 ℃; quantitative ring temperature: 100 ℃; transmission line temperature: 110 ℃;
headspace equilibrium time: 30 min; cycle time: 50 min; sample introduction time: 0.5 min;
pressure balance time: 0.1 min.
The test steps are as follows:
blank solution: dimethyl sulfoxide (DMSO)
System applicability solution: precisely remove 1.0ml of each of the spotting solutions of example 1 into a 100ml volumetric flask containing about 30ml of DMSO, dilute to the mark with the diluent, and shake up.
Precisely transferring 5ml of each of the blank solution and the system applicability solution, placing the blank solution and the system applicability solution into a 20ml headspace bottle, capping and compressing, injecting the headspace into a gas chromatograph, and recording the chromatogram. The results are shown in Table 7, and a map of the system suitability solution is shown in FIG. 5. The results show that methanol, isopropanol, fluorobenzene, toluene and N, N-dimethylformamide can be completely separated, and the residual solvent of the ezetimibe bulk drug can be well separated under the same chromatographic condition.
Table 7 example 5 results of the system suitability test
| Name (R) | Retention time (minutes) | Degree of separation |
| Methanol | 5.688 | -- |
| Isopropanol (I-propanol) | 10.826 | 9.889 |
| Fluorobenzene | 21.701 | 31.468 |
| Toluene | 24.872 | 25.198 |
| N, N-dimethylformamide | 26.884 | 19.324 |
Example 6
The instrument comprises the following steps: agilent 7890A-7697A headspace gas chromatograph, FID detector;
a chromatographic column: KB-624(30m × 0.32mm, 3.0 μm);
chromatographic parameters: carrier gas: nitrogen gas; flow rate of carrier gas: 1.0 ml/min; the split ratio is as follows: 1: 1;
detector temperature: 250 ℃; sample inlet temperature: 200 ℃;
column temperature: the initial temperature is 40 deg.C, maintained for 15min, then raised to 200 deg.C at a speed of 10 deg.C/min, and maintained for 8 min.
Headspace detection parameters: heating box temperature: 90 ℃; quantitative ring temperature: 100 ℃; transmission line temperature: 110 ℃;
headspace equilibrium time: 25 min; cycle time: 50 min; sample introduction time: 0.5 min;
pressure balance time: 0.1 min.
The test steps are as follows:
blank solution: dimethyl sulfoxide (DMSO)
System applicability solution: precisely remove 1.0ml of each of the spotting solutions of example 1 into a 100ml volumetric flask containing about 30ml of DMSO, dilute to the mark with the diluent, and shake up.
Precisely transferring 5ml of each of the blank solution and the system applicability solution, placing the blank solution and the system applicability solution into a 20ml headspace bottle, capping and compressing, injecting the headspace into a gas chromatograph, and recording the chromatogram. The results are shown in Table 8, and a map of the system suitability solution is shown in FIG. 6. The results show that methanol, isopropanol, fluorobenzene, toluene and N, N-dimethylformamide can be completely separated, and the residual solvent of the ezetimibe bulk drug can be well separated under the same chromatographic condition.
Table 8 example 6 results of the system suitability test
| Name (R) | Retention time (minutes) | Degree of separation |
| Methanol | 5.701 | -- |
| Isopropanol (I-propanol) | 10.843 | 9.662 |
| Fluorobenzene | 21.706 | 31.053 |
| Toluene | 24.876 | 25.404 |
| N, N-dimethylformamide | 26.889 | 19.553 |
Example 7
The instrument comprises the following steps: agilent 7890A-7697A headspace gas chromatograph, FID detector;
a chromatographic column: KB-624(30m × 0.32mm, 3.0 μm);
chromatographic parameters: carrier gas: nitrogen gas; flow rate of carrier gas: 1.0 ml/min; the split ratio is as follows: 1: 1;
detector temperature: 250 ℃; sample inlet temperature: 200 ℃;
column temperature: the initial temperature is 40 deg.C, maintained for 15min, then raised to 200 deg.C at a speed of 10 deg.C/min, and maintained for 8 min.
Headspace detection parameters: heating box temperature: 90 ℃; quantitative ring temperature: 100 ℃; transmission line temperature: 110 ℃;
headspace equilibrium time: 35 min; cycle time: 50 min; sample introduction time: 0.5 min;
pressure balance time: 0.1 min.
The test steps are as follows:
blank solution: dimethyl sulfoxide (DMSO).
System applicability solution: precisely remove 1.0ml of each of the spotting solutions of example 1 into a 100ml volumetric flask containing about 30ml of DMSO, dilute to the mark with the diluent, and shake up.
Precisely transferring 5ml of each of the blank solution and the system applicability solution, placing the blank solution and the system applicability solution into a 20ml headspace bottle, capping and compressing, injecting the headspace into a gas chromatograph, and recording the chromatogram. The results are shown in Table 9, and a map of the system suitability solution is shown in FIG. 7. The results show that methanol, isopropanol, fluorobenzene, toluene and N, N-dimethylformamide can be completely separated, and the residual solvent of the ezetimibe bulk drug can be well separated under the same chromatographic condition.
Table 9 example 7 results of the system suitability test
| Name (R) | Retention time (minutes) | Degree of separation |
| Methanol | 5.704 | -- |
| Isopropanol (I-propanol) | 10.854 | 9.672 |
| Fluorobenzene | 21.711 | 30.384 |
| Toluene | 24.879 | 25.328 |
| N, N-dimethylformamide | 26.892 | 19.112 |
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (6)
1. A method for measuring residual solvent in an ezetimibe bulk drug by utilizing headspace gas chromatography is characterized in that the analysis conditions of the method are as follows: adopting a capillary chromatographic column taking 6 percent of cyanopropylphenyl-94 percent of dimethyl polysiloxane as a stationary phase; respectively injecting a reference substance solution with multiple needles and a test substance solution in a split-flow mode, injecting a carrier gas which is nitrogen gas by a headspace injector, and detecting after carrying out temperature programming; the detector is an FID detector;
the type of the chromatographic column is KB-624;
the residual solvent is methanol, isopropanol, fluorobenzene, toluene and N, N-dimethylformamide;
the flow rate of the carrier gas is 0.2-2.0 ml/min;
the temperature of a headspace sample inlet is 200 ℃; the temperature of the heating box is 90 ℃; the quantitative ring temperature is 100 ℃; the temperature of the transmission line is 110 ℃; the balance time of the headspace sample injection is 30 min; GC cycle time was 50 min;
the initial temperature of the programmed temperature rise is 40 ℃, the temperature is kept for 15min, then the temperature is raised to 200 ℃ at the speed of 10 ℃/min, and the temperature is kept for 8 min;
the temperature of the detector is 250 ℃;
and the reference substance solution and the test substance solution both adopt dimethyl sulfoxide as a solvent.
2. The method of claim 1, wherein the control solution comprises 0.30mg of methanol, 0.50mg of isopropanol, 0.063mg of fluorobenzene, 0.089mg of toluene, and 0.088mg of N, N-dimethylformamide per 1 ml.
3. The method of claim 1, wherein a plurality of pins of the reference solution and a pin of a blank solution 1 are used as blank controls before the sample solution is injected; the sample injection reference solution is 6 needles, and the sample solution is 2 needles.
4. The method of claim 1, wherein the split ratio is 1:1 to 10: 1.
5. The method of claim 4, wherein the split ratio is 1: 1.
6. The method of claim 1, wherein the carrier gas flow rate is 1.0 ml/min.
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| CN110208428A (en) * | 2019-07-08 | 2019-09-06 | 苏州天马药业有限公司 | The gas phase detection method of a variety of residual solvents in a kind of bisulfate clopidogrel bulk pharmaceutical chemicals |
| CN111289676B (en) * | 2020-01-20 | 2022-08-16 | 南京林业大学 | Method for detecting residual tert-butylamine in terbutaline sulfate bulk drug |
| CN113376290B (en) * | 2021-06-23 | 2024-01-19 | 东北制药集团股份有限公司 | Vitamin D detection by gas chromatography 2 Method for residual organic solvent in water |
| CN114152691B (en) * | 2021-11-26 | 2024-01-02 | 黄河三角洲京博化工研究院有限公司 | Method for analyzing cyclopentane and extracting agent content by gas chromatography |
| CN114740113B (en) * | 2022-04-12 | 2023-10-20 | 四川汇宇制药股份有限公司 | Separation and detection method for residual solvent and/or related substances in polyacrylic acid |
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