CN113607843A - Method for detecting residual solvent in sirolimus raw material medicine - Google Patents
Method for detecting residual solvent in sirolimus raw material medicine Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 45
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 229960002930 sirolimus Drugs 0.000 title claims abstract description 42
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 title claims abstract description 42
- 239000013557 residual solvent Substances 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 27
- 239000002994 raw material Substances 0.000 title claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 99
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 82
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 75
- 239000000243 solution Substances 0.000 claims abstract description 42
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000000523 sample Substances 0.000 claims abstract description 30
- 229940079593 drug Drugs 0.000 claims abstract description 29
- 238000001514 detection method Methods 0.000 claims abstract description 25
- 238000002347 injection Methods 0.000 claims abstract description 18
- 239000007924 injection Substances 0.000 claims abstract description 18
- 239000012085 test solution Substances 0.000 claims abstract description 10
- 238000010812 external standard method Methods 0.000 claims abstract description 7
- 239000012490 blank solution Substances 0.000 claims abstract description 6
- 238000004817 gas chromatography Methods 0.000 claims abstract description 6
- 239000012088 reference solution Substances 0.000 claims abstract description 6
- 239000012488 sample solution Substances 0.000 claims abstract description 4
- 238000005070 sampling Methods 0.000 claims abstract description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 45
- 238000012360 testing method Methods 0.000 claims description 25
- 239000011550 stock solution Substances 0.000 claims description 20
- 239000007789 gas Substances 0.000 claims description 19
- 239000012159 carrier gas Substances 0.000 claims description 9
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- 238000005259 measurement Methods 0.000 description 17
- 239000002904 solvent Substances 0.000 description 10
- 238000000926 separation method Methods 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 8
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 5
- WDCDAAMJNUHOIY-UHFFFAOYSA-N ethyl acetate;2-propan-2-yloxypropane Chemical compound CCOC(C)=O.CC(C)OC(C)C WDCDAAMJNUHOIY-UHFFFAOYSA-N 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241000187391 Streptomyces hygroscopicus Species 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010200 validation analysis Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
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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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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
- G01N2030/047—Standards external
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N2030/065—Preparation using different phases to separate parts of sample
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Abstract
The invention relates to a method for detecting residual solvent in sirolimus bulk drug, belonging to the technical field of drug analysis and detection, which adopts a gas chromatography external standard method to simultaneously detect ethanol, ether, isopropyl ether and ethyl acetate in sirolimus bulk drug, and comprises the following detection steps: (1) preparing a mixed control solution; (2) preparing a test solution; (3) and (3) determination: and (3) respectively injecting the blank solution, the mixed reference solution and the sample solution into a gas chromatograph by headspace sampling, and calculating the contents of ethanol, diethyl ether, isopropyl ether and ethyl acetate in sirolimus by peak area according to an external standard method. The method simultaneously detects the ethanol, the diethyl ether, the isopropyl ether and the ethyl acetate in the sirolimus bulk drug by using gas chromatography-headspace sample injection, is simple, convenient and sensitive, has strong specificity and accurate and reliable detection result, meets the detection requirement of the residual solvent, is suitable for the conventional detection of the residual solvent in the sirolimus bulk drug, and simultaneously provides reference and basis for the formulation of the residual solvent detection item in the quality standard.
Description
Technical Field
The invention relates to a method for detecting residual solvent in sirolimus raw material medicine, belonging to the technical field of medicine analysis and detection.
Background
Sirolimus (Sirolimus), molecular formula: c51H79NO13Relative molecular mass: 914.2, a macrolide compound extracted from fermentation broth of Streptomyces hygroscopicus FC904(Streptomyces hygroscopicus FC904), which is lipophilic, slightly soluble in water, hardly soluble in ether, but soluble in ethanol, and is clinically used as a potent immunosuppressant for the treatment of rejection reaction in organ transplantation and autoimmune diseases.
Sirolimus is mainly produced by a microbial fermentation process or a semi-synthesis method, the product has complex impurities, the crude sirolimus product is crystallized and purified by using an organic solvent in the production process, if the process parameters are not strictly controlled, the residual organic solvent in the finished product is high, when the residual solvent level in the medicine is higher than a safety value, the medicine can cause harm to human bodies or the environment,
the organic solvents used in the sirolimus bulk drug production process comprise ethanol, diethyl ether, isopropyl ether and ethyl acetate, wherein the ethanol, the diethyl ether and the ethyl acetate are three types of solvents, the isopropyl ether is four types of solvents, the 4 types of solvents possibly remaining in the sirolimus are necessary to be controlled according to the ICH (International coordination and rationale Commission) guidelines of the technical requirements of human medicines and the control requirements of Chinese pharmacopoeia on the residual solvents in the medicines, but no residual solvent check items exist in the existing quality standard, and meanwhile, because the polarities of the ethanol and the diethyl ether are similar, the detection of the ethanol, the diethyl ether, the isopropyl ether and the ethyl acetate in the sirolimus bulk drug cannot be completed in the same chromatographic system according to the method included in the current general guidelines of Chinese pharmacopoeia, and the product quality cannot be rapidly and comprehensively controlled.
Disclosure of Invention
The invention aims to provide a method for detecting residual solvent in sirolimus bulk drug, which simultaneously detects ethanol, ether, isopropyl ether and ethyl acetate in the sirolimus bulk drug by using a gas chromatography, and has the advantages of simplicity, sensitivity, strong specificity and accurate and reliable detection result.
In order to achieve the purpose, the invention adopts the technical scheme that:
a method for detecting residual solvent in sirolimus raw material medicine adopts a gas chromatography external standard method to simultaneously detect ethanol, ether, isopropyl ether and ethyl acetate in sirolimus raw material medicine, and the detection steps comprise:
(1) preparing a mixed control solution with the mass concentration of 5mg/ml of ethanol, ether, isopropyl ether and ethyl acetate;
(2) preparing a test solution: accurately weighing sirolimus raw material medicine of a test sample, and dissolving the sirolimus raw material medicine in dimethyl sulfoxide to prepare a test sample solution with the mass concentration of 0.1 g/ml;
(3) and (3) determination: and respectively injecting the blank solution, the mixed reference solution and the test solution into a gas chromatograph in a headspace sample injection mode, recording a chromatogram, and calculating the contents of ethanol, diethyl ether, isopropyl ether and ethyl acetate in the sirolimus bulk drug by peak area according to an external standard method.
The technical scheme of the invention is further improved as follows: the chromatographic conditions of the gas chromatography are as follows: the chromatographic column is Agilent DB-624; column temperature: the initial column temperature was 30 ℃, held for 6min, heated to 100 ℃ at a rate of 5 ℃ per minute for 5 min, heated to 200 ℃ at a rate of 20 ℃ per minute for 5 min; sample inlet temperature: 200-240 ℃; detector temperature: 230-270 ℃; carrier gas: n is a radical of2The flow rate is 3.0-5.0 ml/min; the split ratio is as follows: 10: 1; and (3) sample introduction mode: a headspace sampling method is adopted, the equilibrium temperature is 70 ℃, and the equilibrium time is 30 min;
the technical scheme of the invention is further improved as follows: the specification of the chromatographic column is 60m multiplied by 0.53mm and 3.0 mu m.
The technical scheme of the invention is further improved as follows: the injection port temperature is 220 ℃.
The technical scheme of the invention is further improved as follows: the detector temperature was 250 ℃.
The technical scheme of the invention is further improved as follows: the flow rate of the carrier gas was 4.0 ml/min.
The technical scheme of the invention is further improved as follows: the preparation steps of the mixed control solution in the step (1) are as follows: respectively adding dimethyl sulfoxide into ethanol, diethyl ether, ethyl acetate and isopropyl ether to prepare single reference substance stock solutions with mass concentration of 50 mg/ml; and precisely measuring all stock solutions, mixing, diluting with dimethyl sulfoxide, and preparing into mixed control solution with ethanol, diethyl ether, ethyl acetate and isopropyl ether mass concentration of 5 mg/ml.
Due to the adoption of the technical scheme, the invention has the following technical effects:
the method simultaneously detects the residual ethanol, ether, isopropyl ether and ethyl acetate in the sirolimus bulk drug by gas chromatography-headspace sample injection, is simple, convenient and sensitive, has strong specificity and accurate and reliable detection result, meets the detection requirement of the residual solvent, is suitable for the conventional detection of the residual solvent in the sirolimus bulk drug, and simultaneously provides reference and basis for the formulation of the residual solvent detection item in the quality standard.
The detection method disclosed by the invention is short in detection time, the obtained peaks are symmetrical in shape, the peak width meets the requirement, the separation degree of each residual solvent is good, the detection result is accurate and reliable, and the detection requirement of the residual solvent is met.
The method can detect the organic solvent residue possibly existing in sirolimus, so that the product quality is comprehensively controlled to meet the requirement of medication safety, the quality of the raw material medicine is effectively improved, and the clinical medication risk is reduced.
Drawings
FIG. 1 is a gas chromatogram of a blank solution according to the invention;
FIG. 2 is a gas chromatogram of a mixed control solution according to the invention;
FIG. 3 is a gas chromatogram of a test solution according to the present invention;
wherein, 1, ethanol, 2, diethyl ether, 3, ethyl acetate, 4, isopropyl ether, 0 and dimethyl sulfoxide.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. Experimental procedures without specifying specific conditions in the following examples were carried out according to conventional methods and conditions.
Examples
1. Instrument and reagent
The instrument comprises the following steps: agilent 7890B gas chromatograph; 7697A headspace sampler; a hydrogen Flame Ionization Detector (FID); an Agilent Open LBACDS Chem Station Edition workstation; a pure water hydrogen generator; SGK-2LB Low noise air Pump.
Reagent testing: the ethanol, the ether, the ethyl acetate and the isopropyl ether are analytically pure; dimethyl sulfoxide (DMSO) was chromatographically pure.
And (3) testing the sample: sirolimus raw material medicine, batch number: s190401, S200901 and S200902.
2. Chromatographic conditions
A chromatographic column: agilent DB-624, 60m × 0.53mm, 3.0 μm;
column temperature: the initial column temperature was 30 ℃, held for 6min, heated to 100 ℃ at a rate of 5 ℃ per minute for 5 min, heated to 200 ℃ at a rate of 20 ℃ per minute for 5 min;
sample inlet temperature: 220 ℃;
detector temperature: 250 ℃;
carrier gas: n2, flow rate 4.0 ml/min;
the split ratio is as follows: 10: 1;
and (3) sample introduction mode: and (3) adopting a headspace sampling method, keeping the balance temperature at 70 ℃ and keeping the balance time for 30 min.
3. Solution preparation
Blank solution: precisely measuring 5mL of DMSO, placing the DMSO in a headspace sample injection bottle, and sealing;
ethanol control stock solution: accurately weighing 2.5108g of ethanol, placing the ethanol in a 50mL measuring flask, diluting the ethanol to a scale with DMSO, and shaking up;
ether control stock solution: accurately weighing 2.5089g of ether, placing the ether in a 50mL measuring flask, diluting the ether to a scale with DMSO, and shaking up;
isopropyl ether control stock: accurately weighing 2.5078g of isopropyl ether, placing the isopropyl ether in a 50mL measuring flask, diluting the isopropyl ether to a scale with DMSO, and shaking up;
ethyl acetate control stock: accurately weighing 2.5119g of ethyl acetate, placing the ethyl acetate in a 50mL measuring flask, diluting the ethyl acetate to a scale with DMSO, and shaking up;
mix control stock solution: precisely measuring 5mL of the stock solution, placing into a 50mL measuring flask, diluting with DMSO to scale, and shaking to obtain mixed control stock containing 5mg/mL of ethanol, diethyl ether, ethyl acetate and isopropyl ether;
mixing the control solution: precisely measuring 5mL of mixed control stock solution, placing in a 50mL measuring flask, adding DMSO to dilute to scale, shaking to obtain control solution, precisely measuring 5mL, placing in a headspace sample injection flask, and sealing;
test solution: precisely weighing 0.5g of a test sample (sirolimus bulk drug), placing the test sample in a headspace bottle, precisely adding 5mL of DMSO (dimethyl sulfoxide), dissolving, and sealing to obtain the sirolimus pharmaceutical composition.
4. Sample assay
And (4) respectively injecting the blank solution, the mixed reference solution and the test solution into a gas chromatograph, and recording the chromatogram. The results are shown in the attached figures 1-3, and under the chromatographic conditions, the peak emergence sequence is as follows: the peak of each component can reach baseline separation, and the separation degree is more than 1.5; the solvent has no interference to the sample determination, and other impurity peaks and main peaks are well separated.
5. Calculation of results
According to an external standard method, calculating by peak area, and the formula is as follows:
in the formula: a. thex-peak areas of corresponding solvent peaks in the test sample solution; a. ther-peak areas of corresponding solvent peaks in the mixed control solution; cr-mixing the concentrations (mg/mL) of the corresponding solvents of the control solutions; cxOf solutions of the test substancesConcentration (mg/mL).
The sirolimus raw material medicine contains not less than 0.5 percent of ethanol, not more than 0.5 percent of diethyl ether, not more than 0.5 percent of isopropyl ether and not more than 0.5 percent of ethyl acetate.
The results of the three test sample batches are shown in the following table:
sample measurement results (%)
| Batch number | S190401 | S200901 | S200902 | Standard provisions | Percent of pass |
| Ethanol | 0.05 | 0.08 | 0.09 | ≤0.5 | 100.0 |
| Ether (A) | 0.02 | 0.03 | 0.02 | ≤0.5 | 100.0 |
| Isopropyl ether | 0.01 | 0.02 | 0.02 | / | / |
| Ethyl acetate | 0.10 | 0.21 | 0.35 | ≤0.5 | 100.0 |
6. Methodology validation
(1) Detection limit and quantification limit
And taking each contrast stock solution, diluting the contrast stock solution step by step, injecting the diluted contrast stock solution into a gas chromatograph, and recording a chromatogram until the signal-to-noise ratio s/n is about 10, namely the corresponding quantitative limit of the contrast solution, which is shown in the following table 1.
And taking each contrast stock solution, diluting the contrast stock solution step by step, injecting the diluted contrast stock solution into a gas chromatograph, and recording a chromatogram until the signal-to-noise ratio s/n is about 3, namely the detection limit of the corresponding contrast solution, which is shown in the following table 1.
TABLE 14 quantitative and detection limits for residual solvents
| Item | Ethanol | Ether (A) | Isopropyl ether | Ethyl acetate |
| Limit of quantification | 15.065μg/mL | 1.505μg/mL | 1.505μg/mL | 5.027μg/mL |
| Detection limit | 5.022μg/mL | 0.502μg/mL | 0.502μg/mL | 1.624μg/mL |
(2) Linearity and range
Preparing an ethanol linear solution: accurately sucking 0.1, 1, 5, 10, 20, 50mL of ethanol control stock solution, placing in 100mL measuring flask respectively, adding DMSO to dilute to scale, shaking, and making into series ethanol control solution.
And (5) carrying out sample injection measurement according to the chromatographic conditions, and recording the peak area.
Preparing an ether linear solution: accurately sucking ether control stock solutions 0.01, 1, 5, 10, 20, 50mL, respectively placing in 100mL measuring bottles, adding DMSO to dilute to scale, shaking up, and making into series ether control solutions.
And (5) carrying out sample injection measurement according to the chromatographic conditions, and recording the peak area.
Preparation of isopropyl ether linear solution: accurately sucking 0.01mL, 1mL, 5mL, 10mL, 20mL and 50mL of isopropyl ether control stock solution, respectively placing in a 100mL measuring flask, adding DMSO for dilution to scale, shaking up, and making into series of isopropyl ether control solutions. And (5) carrying out sample injection measurement according to the chromatographic conditions, and recording the peak area.
Preparation of ethyl acetate linear solution: accurately sucking 0.1, 1, 5, 10, 20 and 50mL of ethyl acetate control stock solution, respectively placing in a 100mL measuring flask, adding DMSO to dilute to scale, shaking up, and making into a series of ethyl acetate control solutions. And (5) carrying out sample injection measurement according to the chromatographic conditions, and recording the peak area.
The peak area was plotted on the ordinate and the solution concentration was plotted on the abscissa, and linear regression was performed, and the measurement results are shown in Table 2.
TABLE 2 results of the Linear test
(3) Accuracy test
Standard addition solution: precisely measuring 2.5mL, 5.0mL and 7.5mL of mixed control stock solution, placing in a 50mL measuring flask, adding DMSO to dilute to scale, and shaking to obtain standard addition solution (1), standard addition solution (2) and standard addition solution (3);
test solution: precisely weighing 0.5g of the product, 9 parts in total, dividing into 3 groups, placing into a headspace bottle, respectively adding 5.0mL of the standard addition liquid (1) into the 1 st group, dissolving, shaking uniformly, and sealing; respectively adding 5.0mL of the standard addition solution (2) into the component 2, dissolving, shaking uniformly and sealing; 5.0mL of the above standard addition solution (3) was added to group 3, and the mixture was dissolved, shaken and sealed. And (4) respectively injecting the solutions into a gas chromatograph, and recording a chromatogram.
The ratio of the measured amount to the added amount was the recovery rate, and the results are shown in Table 3 below: the average recovery rate of the 4 residual solvents is 99.84-102.88% (n-9), and all meet the recovery rate limit requirement specified in the validation guidelines of the drug quality standard analytical methods.
TABLE 3 results of recovery test
(4) Precision test
And (3) sample injection precision test: and (5) injecting the mixed control solution into a gas chromatograph, and recording a chromatogram. Sample introduction is repeated for 6 times, RSD is calculated, and the precision of the instrument is inspected. The measurement results are shown in Table 4, the RSD is within 5 percent, and the injection precision is good.
TABLE 4 sample introduction precision test measurement results
| Components | Ethanol | Ether (A) | Isopropyl ether | Ethyl acetate |
| Retention time RSD | 0.09％ | 0.19％ | 0.05％ | 0.04％ |
| Peak area RSD | 0.15％ | 0.03％ | 0.08％ | 0.25％ |
And (3) repeatability test: preparing 6 parts of mixed reference solution and 6 parts of test solution, respectively injecting into a gas chromatograph, and recording the chromatogram. The repeatability of the method was examined. The measurement results are shown in Table 5, the RSD is within 5 percent, and the method has good repeatability.
TABLE 5 repeatability test results
| Components | Ethanol | Ether (A) | Isopropyl ether | Ethyl acetate |
| Content RSD (%) | 0.0 | 0.0 | 0.0 | 0.0 |
Intermediate precision test: different experimenters operate according to the reference substance solution and the test substance solution to prepare 6 parts of mixed reference substance solution and 6 parts of test substance solution. Injecting into a gas chromatograph, and recording the chromatogram. The results are shown in Table 6, the RSD is within 5%, and the method has good reproducibility.
TABLE 6 measurement results of intermediate precision test
| Components | Ethanol | Ether (A) | Isopropyl ether | Ethyl acetate |
| Content RSD (%) | 0.0 | 0.0 | 0.0 | 0.0 |
(5) Stability test
Preparing mixed reference solution, standing at room temperature for 0, 1, 2, 3, 4, 5, and 6 hr, injecting the above solutions into gas chromatograph, and recording chromatogram. The measurement results are shown in Table 7, and it is understood from the test results that: the mixed control solution was stable for 6 hours at room temperature.
TABLE 7 measurement results of intermediate precision test
| Components | Ethanol | Ether (A) | Isopropyl ether | Ethyl acetate |
| RSD(％) | 0.18 | 0.41 | 0.18 | 0.18 |
(6) Method tolerance
1) Flow rate of carrier gas
Injecting the mixed control solution into a gas chromatograph, inspecting the chromatographic retention behavior of 4 organic solvents under the conditions of carrier gas flow rate of 3mL/min, 4mL/min and 5mL/min, taking the separation degree and theoretical plate number of each component as evaluation indexes, and obtaining the measurement results shown in Table 8: baseline separation was achieved with 4 solvents, ethanol, diethyl ether, isopropyl ether and ethyl acetate at the flow rate of the carrier gas under investigation.
TABLE 8 measurement results of different carrier gas flow rates
2) Temperature at sample inlet
Injecting the mixed control solution into a gas chromatograph, inspecting the chromatographic retention behavior of 4 organic solvents at the injection port temperature of 200 ℃, 220 ℃ and 240 ℃, and taking the separation degree and the theoretical plate number of each component as evaluation indexes, wherein the measurement results are shown in table 9: the baseline separation can be achieved by 4 solvents, namely ethanol, ethyl ether, isopropyl ether and ethyl acetate, at the investigated injection port temperature.
TABLE 9 measurement results of temperatures at different injection ports
3) Temperature of detector
Injecting the mixed control solution into a gas chromatograph, observing the chromatographic retention behavior of five organic solvents under the conditions of 230 ℃, 250 ℃ and 270 ℃ of a detector, taking the separation degree and the theoretical plate number of each component as evaluation indexes, and obtaining the measurement results shown in table 10: baseline separation was achieved with 4 solvents, ethanol, diethyl ether, isopropyl ether and ethyl acetate, at the detector temperatures examined.
TABLE 10 results of temperature measurements of various detectors
In summary, the method for simultaneously determining the content of the 4 organic solvents in the sirolimus bulk drug by gas chromatography-headspace sample injection is established, is simple, accurate and high in sensitivity, meets the detection requirement of the residual solvent, is suitable for daily detection of the residual solvent in the sirolimus bulk drug, provides reference and basis for revising the residual solvent examination item in the quality standard of the product, effectively improves the quality of the bulk drug, and reduces the clinical medication risk.
Claims (7)
1. A method for detecting residual solvent in sirolimus raw material medicine is characterized in that: simultaneously detecting ethanol, diethyl ether, isopropyl ether and ethyl acetate in sirolimus bulk drug by adopting a gas chromatography external standard method, wherein the detection steps comprise:
(1) preparing a mixed control solution with the mass concentration of 5mg/ml of ethanol, ether, isopropyl ether and ethyl acetate;
(2) preparing a test solution: accurately weighing sirolimus raw material medicine of a test sample, and dissolving the sirolimus raw material medicine in dimethyl sulfoxide to prepare a test sample solution with the mass concentration of 0.1 g/ml;
(3) and (3) determination: and respectively injecting the blank solution, the mixed reference solution and the test solution into a gas chromatograph in a headspace sample injection mode, recording a chromatogram, and calculating the contents of ethanol, diethyl ether, isopropyl ether and ethyl acetate in the sirolimus bulk drug by peak area according to an external standard method.
2. The method for detecting residual solvent in sirolimus bulk drug according to claim 1, wherein: the chromatographic conditions of the gas chromatography are as follows: the chromatographic column is Agilent DB-624; column temperature: the initial temperature is 30 ℃, the temperature is kept for 6min, the temperature is increased to 100 ℃ at the rate of 5 ℃ per minute and is kept for 5 min, and then the temperature is increased to 200 ℃ at the rate of 20 ℃ per minute and is kept for 5 min; sample inlet temperature: 200-240 ℃; detector temperature: 230-270 ℃; carrier gas: n is a radical of2The flow rate is 3.0-5.0 ml/min; the split ratio is as follows: 10: 1; and (3) sample introduction mode: and (3) adopting a headspace sampling method, keeping the balance temperature at 70 ℃ and keeping the balance time for 30 min.
3. The method for detecting residual solvent in sirolimus bulk drug according to claim 2, characterized in that: the specification of the chromatographic column is 60m multiplied by 0.53mm and 3.0 mu m.
4. The method for detecting residual solvent in sirolimus bulk drug according to claim 2, characterized in that: the injection port temperature is 220 ℃.
5. The method for detecting residual solvent in sirolimus bulk drug according to claim 2, characterized in that: the detector temperature was 250 ℃.
6. The method for detecting residual solvent in sirolimus bulk drug according to claim 2, characterized in that: the flow rate of the carrier gas was 4.0 ml/min.
7. The method for detecting residual solvent in sirolimus bulk drug according to claim 1, wherein: the preparation steps of the mixed control solution in the step (1) are as follows: respectively adding dimethyl sulfoxide into ethanol, diethyl ether, ethyl acetate and isopropyl ether to prepare single reference substance stock solutions with mass concentration of 50 mg/ml; and precisely measuring all stock solutions, mixing, diluting with dimethyl sulfoxide, and preparing into mixed control solution with ethanol, diethyl ether, ethyl acetate and isopropyl ether mass concentration of 5 mg/ml.
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