CN103712936A - Determination method for anisidine value of lipid emulsion - Google Patents
Determination method for anisidine value of lipid emulsion Download PDFInfo
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- CN103712936A CN103712936A CN201310664114.1A CN201310664114A CN103712936A CN 103712936 A CN103712936 A CN 103712936A CN 201310664114 A CN201310664114 A CN 201310664114A CN 103712936 A CN103712936 A CN 103712936A
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- fat emulsion
- injection
- ether
- isooctane
- ethyl acetate
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- 239000002960 lipid emulsion Substances 0.000 title claims abstract description 128
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 238000000034 method Methods 0.000 title claims abstract description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 124
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 111
- 239000000243 solution Substances 0.000 claims abstract description 50
- -1 alkali metal salt Chemical class 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 15
- 238000012360 testing method Methods 0.000 claims description 77
- 229940090044 injection Drugs 0.000 claims description 74
- 238000002347 injection Methods 0.000 claims description 74
- 239000007924 injection Substances 0.000 claims description 74
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 41
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 claims description 41
- 238000003556 assay Methods 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- 238000012545 processing Methods 0.000 claims description 33
- 239000000839 emulsion Substances 0.000 claims description 32
- 235000019198 oils Nutrition 0.000 claims description 27
- 235000002639 sodium chloride Nutrition 0.000 claims description 25
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 16
- 238000002835 absorbance Methods 0.000 claims description 14
- 238000000870 ultraviolet spectroscopy Methods 0.000 claims description 14
- 238000004090 dissolution Methods 0.000 claims description 13
- 239000011780 sodium chloride Substances 0.000 claims description 11
- 229960000583 acetic acid Drugs 0.000 claims description 8
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims description 8
- 229960001690 etomidate Drugs 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 8
- 239000001103 potassium chloride Substances 0.000 claims description 8
- 235000011164 potassium chloride Nutrition 0.000 claims description 8
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 8
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 8
- 235000011151 potassium sulphates Nutrition 0.000 claims description 8
- 229960004134 propofol Drugs 0.000 claims description 8
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 claims description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 8
- 235000011152 sodium sulphate Nutrition 0.000 claims description 8
- FINHMKGKINIASC-UHFFFAOYSA-N Tetramethylpyrazine Chemical compound CC1=NC(C)=C(C)N=C1C FINHMKGKINIASC-UHFFFAOYSA-N 0.000 claims description 6
- 238000013517 stratification Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
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- 229960000623 carbamazepine Drugs 0.000 claims description 3
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 claims description 3
- PBKVEOSEPXMKDN-LZHUFOCISA-N chembl2311030 Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.CS(O)(=O)=O.CS(O)(=O)=O.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)C)C(C)C)=C3C2=CNC3=C1.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)CC)C(C)C)=C3C2=CNC3=C1.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)CC(C)C)C(C)C)=C3C2=CNC3=C1.C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](C(N21)=O)(NC(=O)[C@H]1CN(C)[C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C1)C(C)C)C1=CC=CC=C1 PBKVEOSEPXMKDN-LZHUFOCISA-N 0.000 claims description 3
- 229960001265 ciclosporin Drugs 0.000 claims description 3
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- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 claims description 3
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Landscapes
- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
Abstract
The invention relates to the technical field of determination methods for anisidine value, and discloses a determination method for the anisidine value of lipid emulsion. The determination method comprises the steps of performing extraction treatment on the lipid emulsion by using an alkali metal salt as a demulsifier and diethyl ether as an extracting agent to obtain a diethyl ester phase and a water phase; carrying out vacuum rotary evaporation treatment on the diethyl ester phase at a temperature lower than 40 DEG C to obtain a residue I; dissolving the residue I with ethyl acetate to obtain an ethyl acetate phase; carrying out vacuum rotary evaporation treatment on the ethyl acetate phase at the temperature lower than 40 DEG C to obtain a residue II which is to be used as a sample. In a technical solution provided by the invention, vacuum rotary evaporation is carried out at the temperature lower than 40 DEG C, so that the problems of oxidation and degradation of unsaturated fatty acid esters caused by high temperature can be prevented; and accuracy for measurement of the anisidine value can be increased.
Description
Technical field
The present invention relates to measure the technical field of anisidine value, particularly relate to a kind of assay method of fat emulsion anisidine value.
Background technology
Intravenous lipid emulsion is mainly by oil phase, the oil-in-water emulsion of making through emulsification as soybean oil, median chain triglyceride oil, phosphatide and water.Wherein in oil phase and phospholipid composition, contain unsaturated link, easily oxidation conversion becomes superoxide.Anisidine value is the index that reflection peroxide breakdown becomes aldehyde, letones, and its value is high, may have infringement to human liver function.
The assay method of existing fat emulsion anisidine value is with reference to the < < of Chinese Pharmacopoeia council fat emulsion injection (C14-C24) quality standard > > (exposure draft).There is following shortcoming and defect part in the method.
Oil phase in fat emulsion as soybean oil and phosphatide can not withstand high temperatures, especially phosphatide, if operation may make the unsaturated fatty acid ester oxidation in soybean oil and phosphatide accelerate under hot conditions, cause superoxide to increase, and the method adopts 60 ℃ of water-bath rotary evaporation in vacuo to remove moisture, the too high and rotary evaporation overlong time of temperature may cause superoxide to continue to be degraded to aldehyde, ketone and little molecule aldehyde, through high-temperature vacuum rotary evaporation, may be removed, and causes the inaccurate of measurement result.
Summary of the invention
The invention provides a kind of assay method of fat emulsion anisidine value, in order to improve the accuracy of measurement of fat emulsion anisidine value.
The assay method of fat emulsion anisidine value of the present invention, comprising:
Adopt alkali metal salt as emulsion breaker, and adopt ether, as extractant, fat emulsion is extracted to processing, obtain ether phase and water;
Under lower than 40 ℃ of conditions, ether is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue one;
Adopt acetic acid ethyl dissolution residue one, obtain ethyl acetate phase, under lower than 40 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue two as test sample.
In technical solution of the present invention, under lower than 40 ℃ of conditions, carry out rotary evaporation in vacuo, avoid high temperature to cause the problem of oxidation and the degraded of unsaturated fatty acid ester, improve the accuracy of measuring, and the phosphatide in fat emulsion is zwitterionic surfactant and has stronger emulsifiability, and alkali metal salt, if sodium chloride, potassium chloride, sodium sulphate, potassium sulfate etc. are one of good emulsion breaker, therefore, can avoid the emulsification of sample in leaching process and can shorten extraction time, improving detection efficiency; Adopt ether as extractant, due to extremely low can being removed rapidly of boiling point of ether, therefore can further shorten extraction time; In addition, because ether may be brought a small amount of moisture into, ether cannot be taken a small amount of water out of when removing fast, therefore with revolving after the slightly high acetic acid ethyl dissolution residue one of boiling point to steam, moisture is taken out of again.
Preferably, the assay method of described fat emulsion anisidine value, also comprises:
Test sample is dissolved with isooctane, as need testing solution, using isooctane as blank, adopt UV-VIS spectrophotometry at 350nm wavelength place, to measure the absorbance A of need testing solution
1;
Measure isopyknic need testing solution and isooctane, the glacial acetic acid solution that adds respectively isopyknic 0.25% 4-aminoanisole, obtain respectively test sample mixed liquor and isooctane mixed liquor, take isooctane mixed liquor as blank, adopt UV-VIS spectrophotometry at 350nm wavelength place, to measure the absorbance A of test sample mixed liquor
2.
Concrete, the assay method of described fat emulsion anisidine value, described assay method comprises the steps:
Precision measures fat emulsion 10mL(milliliter) be placed in separating funnel;
In described separating funnel, add ethanol 5mL, mix, then add alkali metal salt 0.05～0.15g and ether 20mL, violent jolting;
Stratification, is transferred to upper oil phase in flask, and lower floor's water is used extracted with diethyl ether twice again, and each ether 10mL, merges oil phase, obtains ether phase;
Under lower than 60 ℃ of conditions, ether is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue one;
Adopt 10mL acetic acid ethyl dissolution residue one, obtain ethyl acetate phase, under lower than 60 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue three;
Adopt 10mL acetic acid ethyl dissolution residue three, obtain ethyl acetate phase, under lower than 60 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue two as test sample;
Test sample is dissolved with isooctane and shift to put in 25mL volumetric flask and with isooctane and be diluted to scale, the solution with anhydrous sodium sulfate dehydration, after filtering is as need testing solution;
Get need testing solution, using isooctane as blank, adopting UV-VIS spectrophotometry to record need testing solution absorbance at 350nm wavelength place is A
1;
Precision measures need testing solution 10mL and puts in brown tool plug test tube, and precision adds the glacial acetic acid solution 2mL of 0.25% 4-aminoanisole, the jolting of jumping a queue, and lucifuge is placed 10 minutes, obtains test sample mixed liquor; Another precision measures isooctane 10mL and replaces need testing solution, with method operation, obtains isooctane mixed liquor, usings isooctane mixed liquor as blank, and the absorbance that adopts UV-VIS spectrophotometry to record test sample mixed liquor at 350nm wavelength place is A
2, by following calculating formula, calculate anisidine value:
In formula: the sampling amount that V is test sample, Unit/mL; B is the labelled amount of oil phase in need testing solution, the g/mL of unit.
Preferably, the assay method to above-mentioned any fat emulsion anisidine value, described alkali metal salt is sodium chloride, potassium chloride, sodium sulphate or potassium sulfate.
Alkali metal salt is as emulsion breaker, can be sodium chloride, potassium chloride, sodium sulphate, potassium sulfate etc., preferably adopt sodium chloride, the present invention does not adopt hydrochloric acid as emulsion breaker, be can change the pH value of water due to hydrochloric acid, thereby make the pH value of water below the isoelectric point of phosphatide, therefore, can cause part phosphatide to extract not out, may affect the accuracy of measurement result.
In the assay method of above-mentioned any fat emulsion anisidine value, under lower than 30 ℃ of conditions, ether is carried out to the processing of vacuum rotating evaporate to dryness mutually; Under lower than 30 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually.
Preferred, in the assay method of above-mentioned fat emulsion anisidine value, under lower than 20 ℃ of conditions, ether is carried out to the processing of vacuum rotating evaporate to dryness mutually; Under lower than 20 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually.
The assay method of above-mentioned fat emulsion anisidine value is applicable to the mensuration of following fat emulsion: nutrition emulsion injection, Java brucea fruit oil emulsion injection, propofol injection, alprostadil injection, elemene injection, Etomidate fatty emulsion parenteral solution, Etomidate medium and long chain fat emulsion injection, Propofol medium and long chain fat emulsion injection, docetaxel fat emulsion injection, ICZ fat emulsion injection, fish oil fat emulsion injection, compound liposoluble vitamins fat emulsion injection, dexamethasone palmitate fat emulsion injection, perfluorocarbon fat emulsion injection, taxol fat emulsion injection, cyclosporin A fat emulsion injection, azithromycin fat emulsion injection, carbamazepine fat emulsion injection, amphotericin B fat emulsion injection, HCPT fat emulsion injection, diazepam fat emulsion injection, curcuma zedoary oil fat injection, ligustrazine fat emulsion injection, dihydroergotoxine methanesulfonate fat emulsion injection or sevoflurane fat emulsion injection.
Embodiment
In order to improve the accuracy of measurement of fat emulsion anisidine value, the embodiment of the present invention provides a kind of assay method of fat emulsion anisidine value, in this technical scheme, adopt alkali metal salt as emulsion breaker, and adopt ether as extractant, the aldehyde in fat emulsion, ketone to be extracted, when vacuum rotating evaporate to dryness, temperature all operates under lower than 40 ℃ of conditions, therefore, avoid high temperature to cause the problem of oxidation and the degraded of unsaturated fatty acid ester, improve the accuracy of measuring.For making the object, technical solutions and advantages of the present invention clearer, by the following examples the present invention is described in further detail.
The embodiment of the present invention provides a kind of assay method of fat emulsion anisidine value, comprising:
Adopt alkali metal salt as emulsion breaker, and adopt ether, as extractant, fat emulsion is extracted to processing, obtain ether phase and water;
Under lower than 40 ℃ of conditions, ether is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue one;
Adopt acetic acid ethyl dissolution residue one, obtain ethyl acetate phase, under lower than 40 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue two as test sample.
In embodiments of the present invention, under lower than 40 ℃ of conditions, carry out rotary evaporation in vacuo, avoid high temperature to cause the problem of oxidation and the degraded of unsaturated fatty acid ester, improve the accuracy of measuring, and the phosphatide in fat emulsion is zwitterionic surfactant and has stronger emulsifiability, and alkali metal salt, if sodium chloride, potassium chloride, sodium sulphate, potassium sulfate etc. are one of good emulsion breaker, therefore, can avoid the emulsification of sample in leaching process and can shorten extraction time, improving detection efficiency; Adopt ether as extractant, because ether has good dissolubility to the phosphatide in fat emulsion and aldehyde, ketone, and the boiling point of ether is extremely low can be removed rapidly, therefore can further shorten extraction time; In addition, because ether may be brought a small amount of moisture into, ether cannot be taken a small amount of water out of when removing fast, therefore with revolving after the slightly high acetic acid ethyl dissolution residue one of boiling point to steam, moisture is taken out of again.
Lower than 40 ℃ of conditions, refer to that solvent can revolve at the temperature steaming lower than 40 ℃ in vacuum rotary evaporator, for example, can be 39 ℃, 38 ℃, 35 ℃, 30 ℃, 25 ℃, 20 ℃, 15 ℃, 12 ℃, 10 ℃, 8 ℃, 5 ℃ or 2 ℃, in order to improve, revolve steaming efficiency, temperature is generally higher than zero degrees celsius.
Preferably, the assay method of described fat emulsion anisidine value, also comprises:
Test sample is dissolved with isooctane, as need testing solution, using isooctane as blank, adopt UV-VIS spectrophotometry at 350nm wavelength place, to measure the absorbance A of need testing solution
1;
Measure isopyknic need testing solution and isooctane, the glacial acetic acid solution that adds respectively isopyknic 0.25% 4-aminoanisole, obtain respectively test sample mixed liquor and isooctane mixed liquor, take isooctane mixed liquor as blank, adopt UV-VIS spectrophotometry at 350nm wavelength place, to measure the absorbance A of test sample mixed liquor
2.
Concrete, the assay method of described fat emulsion anisidine value, described assay method comprises the steps:
Precision measures fat emulsion 10mL and is placed in separating funnel;
In described separating funnel, add ethanol 5mL, mix, then add alkali metal salt 0.05～0.15g and ether 20mL, violent jolting;
Stratification, is transferred to upper oil phase in flask, and lower floor's water is used extracted with diethyl ether twice again, and each ether 10mL, merges oil phase, obtains ether phase;
Under lower than 60 ℃ of conditions, ether is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue one;
Adopt 10mL acetic acid ethyl dissolution residue one, obtain ethyl acetate phase, under lower than 60 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue three;
Adopt 10mL acetic acid ethyl dissolution residue three, obtain ethyl acetate phase, under lower than 60 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue two as test sample;
Test sample is dissolved with isooctane and shift to put in 25mL volumetric flask and with isooctane and be diluted to scale, the solution with anhydrous sodium sulfate dehydration, after filtering is as need testing solution;
Get need testing solution, using isooctane as blank, adopting UV-VIS spectrophotometry to record need testing solution absorbance at 350nm wavelength place is A
1;
Precision measures need testing solution 10mL and puts in brown tool plug test tube, and precision adds the glacial acetic acid solution 2mL of 0.25% 4-aminoanisole, the jolting of jumping a queue, and lucifuge is placed 10 minutes, obtains test sample mixed liquor; Another precision measures isooctane 10mL and replaces need testing solution, with method operation, obtains isooctane mixed liquor, usings isooctane mixed liquor as blank, and the absorbance that adopts UV-VIS spectrophotometry to record test sample mixed liquor at 350nm wavelength place is A
2, by following calculating formula, calculate anisidine value:
In formula: the sampling amount that V is test sample, Unit/mL; B is the labelled amount of oil phase in need testing solution, the g/mL of unit.
Soybean oil and phosphatide in fat emulsion do not dissolve in water, but dissolve in ether, therefore, select ether as extractant, and because fat emulsion is O/W(Oil/Water, oil-in-water) type emulsion, therefore, add appropriate ethanol oil-in-water system can be destroyed, facilitate the extraction of ether to oily matter in fat emulsion.
Preferably, the assay method to above-mentioned any fat emulsion anisidine value, described alkali metal salt is sodium chloride, potassium chloride, sodium sulphate or potassium sulfate.
Alkali metal salt is as emulsion breaker, can be sodium chloride, potassium chloride, sodium sulphate, potassium sulfate etc., preferably adopt sodium chloride, the present invention does not adopt hydrochloric acid as emulsion breaker, be can change the pH value of water due to hydrochloric acid, thereby make the pH value of water below the isoelectric point of phosphatide, therefore, can cause part phosphatide to extract not out, may affect the accuracy of measurement result.
In the assay method of above-mentioned any fat emulsion anisidine value, under lower than 30 ℃ of conditions, ether is carried out to the processing of vacuum rotating evaporate to dryness mutually; Under lower than 30 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually.
Experiment showed, 10 ℃ of the every raisings of temperature of revolving steaming, the degradation rate of compound can improve 2～4 times, and therefore, assay method of the present invention, 40 ℃ of following operations, preferably, below 30 ℃, more preferably below 20 ℃, can guarantee that superoxide is non-degradable.
Preferred, in the assay method of above-mentioned fat emulsion anisidine value, under lower than 20 ℃ of conditions, ether is carried out to the processing of vacuum rotating evaporate to dryness mutually; Under lower than 20 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually.
The assay method of above-mentioned fat emulsion anisidine value is applicable to the mensuration of following fat emulsion: nutrition emulsion injection or main ingredient be the medicine carrying fat emulsion without uv absorption at 350nm wavelength place, and at 350nm wavelength place, the medicine carrying fat emulsion without uv absorption comprises Java brucea fruit oil emulsion injection to described main ingredient, propofol injection, alprostadil injection, elemene injection, Etomidate fatty emulsion parenteral solution, Etomidate medium and long chain fat emulsion injection, Propofol medium and long chain fat emulsion injection, docetaxel fat emulsion injection, ICZ fat emulsion injection, fish oil fat emulsion injection, compound liposoluble vitamins fat emulsion injection, dexamethasone palmitate fat emulsion injection, perfluorocarbon fat emulsion injection, taxol fat emulsion injection, cyclosporin A fat emulsion injection, azithromycin fat emulsion injection, carbamazepine fat emulsion injection, amphotericin B fat emulsion injection, HCPT fat emulsion injection, diazepam fat emulsion injection, curcuma zedoary oil fat injection, ligustrazine fat emulsion injection, dihydroergotoxine methanesulfonate fat emulsion injection or sevoflurane fat emulsion injection.
Below enumerate the assay method that embodiment preferably illustrates fat emulsion anisidine value of the present invention.But the present invention is not limited to following embodiment.
Embodiment 1
The assay method of fat emulsion anisidine value, step is as follows:
Precision measures fat emulsion (Etomidate fatty emulsion parenteral solution) 10mL and is placed in separating funnel;
In described separating funnel, add ethanol 5mL, mix, then add sodium chloride 0.1g and ether 20mL, violent jolting;
Stratification, is transferred to upper oil phase in the flask of 250mL, and lower floor's water is used extracted with diethyl ether twice again, and each ether 10mL, merges oil phase, obtains ether phase;
Under lower than 40 ℃ of conditions, ether is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue one;
Adopt 10mL acetic acid ethyl dissolution residue one, obtain ethyl acetate phase, under lower than 40 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue three;
Adopt 10mL acetic acid ethyl dissolution residue three, obtain ethyl acetate phase, under lower than 40 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue two as test sample;
Test sample is dissolved with isooctane and shift to put in 25mL volumetric flask and with isooctane and be diluted to scale, the solution with anhydrous sodium sulfate dehydration, after filtering is as need testing solution;
Get need testing solution, using isooctane as blank, adopting UV-VIS spectrophotometry to record need testing solution absorbance at 350nm wavelength place is A
1;
Precision measures need testing solution 10mL and puts in brown tool plug test tube, and precision adds the glacial acetic acid solution 2mL of 0.25% 4-aminoanisole, the jolting of jumping a queue, and lucifuge is placed 10 minutes, obtains test sample mixed liquor; Another precision measures isooctane 10mL and replaces need testing solution, with method operation, obtains isooctane mixed liquor, usings isooctane mixed liquor as blank, and the absorbance that adopts UV-VIS spectrophotometry to record test sample mixed liquor at 350nm wavelength place is A
2, by following calculating formula, calculate anisidine value:
In formula: the sampling amount that V is test sample, Unit/mL; B is the labelled amount of oil phase in need testing solution, the g/mL of unit; Coefficient 1.2 is: add the solution dilution factor after the glacial acetic acid solution of 4-aminoanisole.
The result of simultaneously measuring 6 duplicate samples is respectively: 1.16,1.24,1.16,1.07,1.14,1.28.
Embodiment 2～6
Embodiment 2～6 adopts embodiment 1 fat emulsion used, only in initially adding separating funnel, the consumption of fat emulsion, emulsion breaker, extractant and ethanol is different, consumption as shown in table 1, those skilled in the art can steam according to the general knowledge of this area the consumption of agent and do corresponding adjusting to revolving, operation steps is identical with embodiment 1.
In table 1 embodiment 2～6, fat emulsion, emulsion breaker, extractant and ethanol uses scale
| Consumption in embodiment | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 |
| Fat emulsion (mL) | 5 | 8 | 15 | 20 | 25 |
| Sodium chloride (g) | 0.05 | 0.08 | 0.1 | 0.1 | 0.15 |
| Ether (mL) | 10 | 20 | 20 | 20 | 20 |
| Ethanol (mL) | 2 | 2 | 5 | 5 | 5 |
| Anisidine value (mean value) | 1.25 | 1.32 | 1.30 | 1.20 | 1.30 |
Adopt assay method of the present invention to measure the anisidine value of the fat emulsion of different volumes, learn as calculated the volume of the fat emulsion measuring (V) and 1.2A
2-A
1linear, coefficient R
2reach 0.993, therefore, no matter adopt the anisidine value of the fat emulsion that the fat emulsion of how many volumes records identical, illustrate that assay method of the present invention is workable, and reappearance is better.
Embodiment 7
Embodiment 7 is only different from embodiment 1 operating temperature, and all the other are all identical with embodiment 1, and embodiment 7 operates under lower than 20 ℃ of conditions, and the result of simultaneously measuring 6 duplicate samples is respectively: 1.22,1.17,1.19,1.25,1.20,1.15.
Embodiment 8
Embodiment 8 is only different from embodiment 1 fat emulsion used, all the other are all identical with embodiment 1, embodiment 8 fat emulsion used is Propofol medium and long chain fat emulsion injection, and the result of simultaneously measuring 6 duplicate samples is respectively: 2.01,2.15,2.08,1.98,2.04,1.96.
Embodiment 9
Embodiment 9 is that from the difference of embodiment 8 emulsion breaker used is different, and all the other are all identical with embodiment 8, and embodiment 9 emulsion breaker used is sodium sulphate, and the result of simultaneously measuring 6 duplicate samples is respectively: 1.31,1.25,1.19,1.27,1.16,1.22.
Embodiment 10
Embodiment 10 and the difference of embodiment 1 are that fat emulsion used is different with emulsion breaker used, and all the other are all identical with embodiment 1, and embodiment 10 fat emulsion used is nutrition emulsion injection (fat emulsion injection (C
14-C
24)), emulsion breaker is potassium sulfate, the result of simultaneously measuring 6 duplicate samples is respectively: 2.10,1.95,1.87,2.07,2.15,1.94.
Embodiment 11
Embodiment 11 and the difference of embodiment 1 are that fat emulsion used is different with emulsion breaker used, all the other are all identical with embodiment 1, embodiment 11 fat emulsion used is Propofol medium and long chain fat emulsion injection, emulsion breaker is potassium chloride, and the result of simultaneously measuring 6 duplicate samples is respectively: 1.99,2.18,2.06,1.94,2.11,2.02.
Take respectively the accuracy that soybean oil and phosphatide is blank determination assay method of the present invention, comprise the following steps:
Get soybean oil and within 12 minutes, obtain oil phase test liquid in 121 ℃ of heating, get 1g oil phase test liquid and measure its anisidine value A
d;
Get lecithin and be dissolved in isooctane and within 12 minutes, obtain phosphatide phase test liquid in 121 ℃ of heating, get 1mL phosphatide phase test liquid and measure its anisidine value A
p;
Remove the negative sample 10mL of soybean oil, phosphatide, add 1g oil phase test liquid, by the method operation of embodiment 1, measure the anisidine value of 6 duplicate samples the A ' that averages simultaneously
d;
Remove the negative sample 10mL of soybean oil, phosphatide, add 1mL phosphatide phase test liquid, by the method operation of embodiment 1, measure the anisidine value of 6 duplicate samples the A ' that averages simultaneously
p;
The result of respectively method by embodiment 1 being measured with directly get oil phase test liquid or the comparison of phosphatide phase test liquid measurement result, according to following formula calculating:
The recovery that calculates soybean oil and phosphatide is respectively 97.8%, 96.4%, and relative standard deviation (Relative Standard Deviation is called for short RSD) is respectively 3.9%, 3.0%.The accuracy that assay method of the present invention is described is higher.
Comparative example
Precision measures Etomidate fatty emulsion parenteral solution 10mL and is placed in separating funnel, adds the hydrochloric acid 1mL of 2mol/L, and adds ethanol 1mL along bottle wall, ethyl acetate 10mL, violent jolting.Stratification, is transferred to upper solution in 250mL flask, and water layer is extracted with ethyl acetate twice, each 10mL, combined ethyl acetate liquid.With Rotary Evaporators, 40 ℃ of following concentrating, eliminate solvents.Residue adds isooctane and dissolves and shift and put in 25mL measuring bottle, and all the other steps are all identical with embodiment 1.Measure 6 duplicate samples simultaneously.
In comparative example, adopt hydrochloric acid as emulsion breaker, adopt ethyl acetate as extractant, the consumption of all the other medicines used and medicine is according to consumption shown in embodiment 1, and operation steps is identical with embodiment 1.The result of simultaneously measuring 6 duplicate samples is respectively: 1.21,1.16,1.18,1.23,1.12,1.14.
In embodiment 1,6 duplicate samples duration used when extracting operation all completes is respectively 3 minutes, 3 minutes, 3 minutes, 3 minutes, 3 minutes, 3 minutes, and average duration is 3 minutes; And 6 duplicate samples duration used when extracting operation all completes is respectively 10 minutes, 10 minutes, 10 minutes, 10 minutes, 10 minutes, 10 minutes in comparative example, average duration is 10 minutes.
Visible, the relatively shorter and phosphatide of assay method extraction time of the present invention can all be proposed, and has greatly improved the accuracy of determination efficiency and mensuration.Comparative example assay method extraction time used length may be because ethyl acetate can not extract phosphatide completely, and phosphatide is water insoluble, cause separated slower in water and ethyl acetate phase of phosphatide, and adopt ether as extractant, ether can extract phosphatide completely, so the stratification time is shorter.
Reference example
Get fat emulsion sample and add ethanol,aldehyde free and revolve and steam to dry residue and distillate in 60 ℃, toward hydro-oxidation potassium test solution in distillate, in 50～60 ℃ of water-baths, place 24 hours; Separately, get respectively ethanol,aldehyde free and ethanol (in 95% ethanol, all containing a small amount of aldehyde) with method operation, obtain respectively ethanol,aldehyde free liquid and ethanol.
Found that, distillate and ethanol all become yellow, and ethanol,aldehyde free liquid color is constant.Therefore, at 60 ℃, revolve while steaming except also the aldehyde of part being taken out of and caused measurement result untrue when the water in fat emulsion can be taken out of.Therefore, assay method of the present invention operates under lower than 40 ℃ of conditions and even under lower than 20 ℃ of conditions, operates, and the measurement result of having avoided pyroprocessing to cause is inaccurate.
Obviously, those skilled in the art can carry out various changes and modification and not depart from the spirit and scope of the present invention the present invention.Like this, if within of the present invention these are revised and modification belongs to the scope of the claims in the present invention and equivalent technologies thereof, the present invention is also intended to comprise these changes and modification interior.
Claims (7)
1. an assay method for fat emulsion anisidine value, is characterized in that, comprising:
Adopt alkali metal salt as emulsion breaker, and adopt ether, as extractant, fat emulsion is extracted to processing, obtain ether phase and water;
Under lower than 40 ℃ of conditions, ether is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue one;
Adopt acetic acid ethyl dissolution residue one, obtain ethyl acetate phase, under lower than 40 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue two as test sample.
2. the assay method of fat emulsion anisidine value as claimed in claim 1, is characterized in that, also comprises:
Test sample is dissolved with isooctane, as need testing solution, using isooctane as blank, adopt UV-VIS spectrophotometry at 350nm wavelength place, to measure the absorbance A of need testing solution
1;
Measure isopyknic need testing solution and isooctane, the glacial acetic acid solution that adds respectively isopyknic 0.25% 4-aminoanisole, obtain respectively test sample mixed liquor and isooctane mixed liquor, take isooctane mixed liquor as blank, adopt UV-VIS spectrophotometry at 350nm wavelength place, to measure the absorbance A of test sample mixed liquor
2.
3. the assay method of fat emulsion anisidine value as claimed in claim 2, is characterized in that, described assay method comprises the steps:
Precision measures fat emulsion 10mL and is placed in separating funnel;
In described separating funnel, add ethanol 5mL, mix, then add alkali metal salt 0.05～0.15g and ether 20mL, violent jolting;
Stratification, is transferred to upper oil phase in flask, and lower floor's water is used extracted with diethyl ether twice again, and each ether 10mL, merges oil phase, obtains ether phase;
Under lower than 40 ℃ of conditions, ether is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue one;
Adopt 10mL acetic acid ethyl dissolution residue one, obtain ethyl acetate phase, under lower than 40 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue three;
Adopt 10mL acetic acid ethyl dissolution residue three, obtain ethyl acetate phase, under lower than 40 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually, obtain residue two as test sample;
Test sample is dissolved with isooctane and shift to put in 25mL volumetric flask and with isooctane and be diluted to scale, the solution with anhydrous sodium sulfate dehydration, after filtering is as need testing solution;
Get need testing solution, using isooctane as blank, adopting UV-VIS spectrophotometry to record need testing solution absorbance at 350nm wavelength place is A
1;
Precision measures need testing solution 10mL and puts in brown tool plug test tube, and precision adds the glacial acetic acid solution 2mL of 0.25% 4-aminoanisole, the jolting of jumping a queue, and lucifuge is placed 10 minutes, obtains test sample mixed liquor; Another precision measures isooctane 10mL and replaces need testing solution, with method operation, obtains isooctane mixed liquor, usings isooctane mixed liquor as blank, and the absorbance that adopts UV-VIS spectrophotometry to record test sample mixed liquor at 350nm wavelength place is A
2, by following calculating formula, calculate anisidine value:
In formula: the sampling amount that V is test sample, Unit/mL; B is the labelled amount of oil phase in need testing solution, the g/mL of unit.
4. the assay method of the fat emulsion anisidine value as described in claim 1～3 any one, is characterized in that, described alkali metal salt is sodium chloride, potassium chloride, sodium sulphate or potassium sulfate.
5. the assay method of the fat emulsion anisidine value as described in claim 1～3 any one, is characterized in that, under lower than 30 ℃ of conditions, ether is carried out to the processing of vacuum rotating evaporate to dryness mutually; Under lower than 30 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually.
6. the assay method of fat emulsion anisidine value as claimed in claim 5, is characterized in that, under lower than 20 ℃ of conditions, ether is carried out to the processing of vacuum rotating evaporate to dryness mutually; Under lower than 20 ℃ of conditions, ethyl acetate is carried out to the processing of vacuum rotating evaporate to dryness mutually.
7. the assay method of fat emulsion anisidine value as claimed in claim 1, is characterized in that, described fat emulsion is nutrition emulsion injection, Java brucea fruit oil emulsion injection, propofol injection, alprostadil injection, elemene injection, Etomidate fatty emulsion parenteral solution, Etomidate medium and long chain fat emulsion injection, Propofol medium and long chain fat emulsion injection, docetaxel fat emulsion injection, ICZ fat emulsion injection, fish oil fat emulsion injection, compound liposoluble vitamins fat emulsion injection, dexamethasone palmitate fat emulsion injection, perfluorocarbon fat emulsion injection, taxol fat emulsion injection, cyclosporin A fat emulsion injection, azithromycin fat emulsion injection, carbamazepine fat emulsion injection, amphotericin B fat emulsion injection, HCPT fat emulsion injection, diazepam fat emulsion injection, curcuma zedoary oil fat injection, ligustrazine fat emulsion injection, dihydroergotoxine methanesulfonate fat emulsion injection or sevoflurane fat emulsion injection.
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