CN110514604A - The measuring method of the anisidine value of Alprostadil freeze-dried liplid emulsions - Google Patents
The measuring method of the anisidine value of Alprostadil freeze-dried liplid emulsions Download PDFInfo
- Publication number
- CN110514604A CN110514604A CN201810485809.6A CN201810485809A CN110514604A CN 110514604 A CN110514604 A CN 110514604A CN 201810485809 A CN201810485809 A CN 201810485809A CN 110514604 A CN110514604 A CN 110514604A
- Authority
- CN
- China
- Prior art keywords
- ether
- emulsion
- dehydrated alcohol
- phase
- measuring method
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000839 emulsion Substances 0.000 title claims abstract description 106
- 238000000034 method Methods 0.000 title claims abstract description 72
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 title claims abstract description 64
- 229960000711 alprostadil Drugs 0.000 title claims abstract description 48
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 title claims abstract description 48
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 title claims abstract description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 130
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000006210 lotion Substances 0.000 claims abstract description 38
- 229960000935 dehydrated alcohol Drugs 0.000 claims abstract description 37
- 238000005259 measurement Methods 0.000 claims abstract description 31
- 238000012360 testing method Methods 0.000 claims abstract description 19
- -1 alkali metal salt Chemical class 0.000 claims abstract description 18
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 15
- 238000005406 washing Methods 0.000 claims abstract description 9
- 238000004945 emulsification Methods 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- MHZZQFJGUZUBCN-UHFFFAOYSA-N propan-2-ol;2,2,4-trimethylpentane Chemical compound CC(C)O.CC(C)CC(C)(C)C MHZZQFJGUZUBCN-UHFFFAOYSA-N 0.000 claims description 24
- 239000012085 test solution Substances 0.000 claims description 24
- 235000002639 sodium chloride Nutrition 0.000 claims description 21
- 239000012046 mixed solvent Substances 0.000 claims description 20
- 238000004108 freeze drying Methods 0.000 claims description 17
- 229960000583 acetic acid Drugs 0.000 claims description 15
- 239000012362 glacial acetic acid Substances 0.000 claims description 15
- 238000000605 extraction Methods 0.000 claims description 14
- 238000002347 injection Methods 0.000 claims description 14
- 239000007924 injection Substances 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 11
- 238000000870 ultraviolet spectroscopy Methods 0.000 claims description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 238000002835 absorbance Methods 0.000 claims description 10
- 238000004064 recycling Methods 0.000 claims description 10
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 238000013461 design Methods 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- 238000012545 processing Methods 0.000 claims description 5
- 238000002390 rotary evaporation Methods 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 4
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 claims description 4
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 4
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 4
- 235000011151 potassium sulphates Nutrition 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- 238000012546 transfer Methods 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 238000005375 photometry Methods 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 235000007686 potassium Nutrition 0.000 claims description 2
- 238000013517 stratification Methods 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 239000000284 extract Substances 0.000 abstract description 3
- 238000007689 inspection Methods 0.000 abstract description 3
- 239000000523 sample Substances 0.000 description 22
- 239000003921 oil Substances 0.000 description 15
- 235000019198 oils Nutrition 0.000 description 15
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 12
- 239000002960 lipid emulsion Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000003549 soybean oil Substances 0.000 description 7
- 235000012424 soybean oil Nutrition 0.000 description 7
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 6
- 229960004134 propofol Drugs 0.000 description 6
- 238000011084 recovery Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000004519 grease Substances 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical group O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/33—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using ultraviolet light
Landscapes
- Physics & Mathematics (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
- Cosmetics (AREA)
Abstract
The present invention relates to a kind of measuring methods of the anisidine value of Alprostadil freeze-dried liplid emulsions comprising following steps: Alprostadil freeze-dried liplid emulsions being carried out emulsion processing, obtain emulsion lotion；Dehydrated alcohol is added in emulsion lotion and alkali metal salt is demulsified；Anhydrous ether is added to be extracted, ether phase is collected, remaining sugar and alkali metal salt, obtain ether phase and water phase then plus in water washing ether phase；It is evaporated ether phase in 40 DEG C or less vacuum rotatings, obtains residue I；Residue I is dissolved with dehydrated alcohol, is then evaporated dehydrated alcohol in 60 DEG C or less vacuum rotatings, obtains residue II as test sample for measuring anisidine value.This method oil mutually extracts complete, accuracy height, can exclude interference of the sugar to measurement, can be effectively controlled product quality, and specificity is strong, reproducible, measurement result is accurate, improves the quality inspection standard of Alprostadil freeze-dried liplid emulsions.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical fields, more particularly to a kind of methoxyl group of Alprostadil freeze-dried liplid emulsions
The measuring method of aniline value.
Background technique
Alprostadil freeze-dried liplid emulsions belong to intravenous lipid emulsion, are to stir Alprostadil, oil for injection
It mixes, mix, obtain oily phase；Water phase is added in freeze drying protectant, oil is added mutually or in water phase according to its dissolubility in emulsifier, two-phase warp
Made of emulsion is made in high pressure homogenization method, then freeze-dried method is lyophilized.
Anisidine value is the Xiang Zhibiao for reflecting peroxide second decomposition product aldehyde in grease, ketone content, these
Decomposition product can destroy the normal physiological function of human cell membrane, lead to the occurrence and development of disease, and anisidine value is excessively high
It is also possible to damage human body liver function.Meanwhile anisidine value is also the key of Fat Emulsion ejection preparation quality control
Index.
During the preparation process, the lubricant component in Alprostadil freeze-dried liplid emulsions, which may be oxidized, resolves into one
Determine the substances such as aldehyde, the ketone of toxicity, causes Hidden Trouble In Clinical Medication Security.It is therefore desirable to the first to Alprostadil freeze-dried liplid emulsions
Oxygroup aniline value is controlled.Referring to " fat emulsion injection (C14-C24) quality standard " (sign of Chinese Pharmacopoeia committee publication
Seek opinion original text) and " Propofol emulsus injection quality standard " (exposure draft) in anisidine value item measuring method pair
Alprostadil freeze-dried liplid emulsions carry out in the continuous mode of anisidine value, and existing greatest problem is effectively to go
Except the interference of the freeze drying protectant sugar in sample causes measurement result unstable to influence the dissolution evenness of sample solution
And inaccuracy.
Therefore, before the assay before the anisidine value of your freeze-drying liplid emulsions of column ground, it is necessary to find a kind of pair of sample
The pre-treating method effectively except sugar is carried out, to improve the effective of Alprostadil freeze-dried liplid emulsions anisidine value measurement
Property.Obviously, it solves the problems, such as to remove the critical issue that sugar is Alprostadil freeze-dried liplid emulsions anisidine value measurement.
The Chinese Pharmacopoeia committee " fat emulsion injection (C14-C24) quality standard " (exposure draft) and " Propofol cream
Shape injection quality standard " measuring method of anisidine value is removed using dehydrated alcohol rotary evaporation in (exposure draft)
It is measured after water, mixed solvent dissolved residue, when this method is measured Alprostadil freeze-dried liplid emulsions, after recycling dehydrated alcohol
Residue in modeling shape, and molten sample solvent cannot be dissolved in, cause sample solution state inhomogenous, this is because the freeze-drying in sample
Caused by the influence of protective agent sugar.
Chinese patent CN103712936A mutually measures the anisidine value of fat emulsion using extraction extract oil, uses
When this method is measured Alprostadil freeze-dried liplid emulsions, test solution produces cotton-shaped after reacting with 4- aminoanisole
Precipitating, causes solution to be determined inhomogenous, has an impact to measurement result, measured value is also bigger than normal.
Therefore, be badly in need of researching and developing at present it is a kind of operate it is feasible, effectively except sugar, quality controllable method is with measuring forefront
The anisidine value of your freeze-drying liplid emulsions.
Summary of the invention
It is an object of the invention to make up the deficiencies in the prior art, a kind of feasible, the effective measurement forefront of operation is provided
The method of the anisidine value of your freeze-drying liplid emulsions, to eliminate the interference as freeze drying protectant sugar, and mutually complete to oil
It is complete to extract, effective control for product quality.
The purpose of the present invention is what is be achieved through the following technical solutions:
A kind of measuring method of the anisidine value of Alprostadil freeze-dried liplid emulsions comprising following steps:
(1) Alprostadil freeze-dried liplid emulsions are subjected to emulsion processing, obtain emulsion lotion, takes emulsion lotion, then exist
Dehydrated alcohol is added in the emulsion lotion taken and alkali metal salt is demulsified；
(2) anhydrous ether is added to be extracted, collects ether phase, then plus in water washing ether phase remaining sugar and alkali are golden
Belong to salt, obtains ether phase and water phase；
(3) it is evaporated ether phase in 40 DEG C or less vacuum rotatings, obtains residue I；
(4) residue I is dissolved with dehydrated alcohol, is then evaporated dehydrated alcohol in 60 DEG C or less vacuum rotatings, obtains residual
Stay object II as test sample, for measuring anisidine value.
Measuring method of the invention is suitable for the Alprostadil freeze-dried liplid emulsions of various formulas, especially suitable for removing it
In include freeze drying protectant sugar interference.In general, may include emulsifier (such as egg yolk lecithin, soybean lecithin in fat emulsion
Rouge etc.), as the sugar (such as sucrose, maltose, lactose, glucose, trehalose) of freeze drying protectant, oil for injection (such as soybean
Oil, medium chain triglyceride, medium chain diglycerides, one ester of medium chain triglyceride, olive oil etc.) etc..Emulsifier in fat emulsion has
Very strong emulsibility, and alkali metal salt (such as potassium chloride, sodium chloride, potassium sulfate, sodium sulphate) is used as good demulsifier, not only
The balance of emulsion can be destroyed, and can be avoided sample in extraction process and emulsify；Since the Alprostadil after emulsion freezes
Dry liplid emulsions belong to O/W type emulsion, and appropriate dehydrated alcohol is added, and can suitably destroy emulsion outer layer water layer, appear oil reservoir, just
Oily phase in extracted by ether emulsion.Due to the low boiling point of ether, and sugar is not dissolved in ether, grease type be dissolved in ether without
Be dissolved in water and water be slightly soluble in the characteristic of ether, using anhydrous ether as extractant, can rapidly remove extractant and
Oily phase and freeze drying protectant can be efficiently separated, and can also avoid bringing new moisture into as far as possible；It is residual in oily phase in extraction process
The a small amount of moisture stayed can be boiled off with dehydrated alcohol dissolution residual substance I back spin and be removed.
Preferably, measuring method of the present invention is further comprising the steps of:
(a) isopropanol-isooctane mixed solvent that residue II volume ratio is 2: 8 is dissolved, it is molten obtains test sample
Liquid I, then using volume ratio be 2: 8 isopropanol-isooctane mixed solvent as blank control, using UV-vis spectroscopy light
Degree method measures absorbance value A at the wavelength of 350nm0；
(b) accurate to measure isopropanol-isooctane mixed solvent that isometric test solution I and volume ratio are 2: 8, point
It is not placed in two tool plug test tubes of first, second, the 4- aminoanisole glacial acetic acid of each 0.25% (g/ml) that same volume is added is molten
Liquid obtains isopropanol-isooctane mixed solution of test solution II and the glacial acetic acid of aminoanisole containing 4-, with volume ratio
For 2: 8 isopropanol-isooctane mixed solvent as blank control, according to UV-VIS spectrophotometry 350nm wavelength
Place measures the absorbance of isopropanol-isooctane mixed solution of test solution II and the glacial acetic acid of aminoanisole containing 4- respectively
Value, is denoted as A1, A2 respectively.
In certain embodiments of the invention, in the step of measuring method (1), the alkali metal salt is selected from chlorination
One of potassium, sodium chloride, potassium sulfate or sodium sulphate are a variety of；Preferably, based on g/ml, the amount (g) of alkali metal salt with take
The ratio between the amount (ml) of emulsion lotion be 2: 100~1000.
In certain embodiments of the invention, in the step of measuring method (2), anhydrous ether and the emulsion taken
The volume ratio of lotion is 3~7: 1, and the volume ratio of water and the emulsion lotion taken is 7~12: 1.
In certain embodiments of the invention, also anhydrous comprising carrying out second in the step of measuring method (2)
Ether extraction, collects ether phase, and remaining sugar and metal salt, obtain ether phase and water phase then plus in water washing ether phase；It is excellent
Then plus water selection of land, the water phase that second of anhydrous ether is obtained by extraction carry out the extraction of third time anhydrous ether, collect ether phase,
Remaining sugar and metal salt in oily phase are washed, ether phase and water phase are obtained；Wherein, the body of anhydrous ether and the emulsion lotion taken
For product than being 1~5: 1, the volume ratio for the emulsion lotion for adding water washing ether phase Shi Shuiyu to take is 3~10: 1.
In certain embodiments of the invention, in the step of measuring method (2), after each anhydrous ether extraction,
Ether phase and water phase stratification time are 20~30min, preferably 30min.
In certain embodiments of the invention, it in the step of measuring method (3), is steamed in 30 DEG C or less vacuum rotatings
Dry diethyl ether；Preferably, vacuum rotating is evaporated the time of ether as 5~10min.
In certain embodiments of the invention, it in the step of measuring method (4), is steamed in 50 DEG C or less vacuum rotatings
Dry dehydrated alcohol；It is preferred that residue I is dissolved with dehydrated alcohol, it then is evaporated dehydrated alcohol in 60 DEG C or less vacuum rotatings, instead
It carries out 3 times again, sufficiently to eliminate moisture；Preferably, vacuum rotating is evaporated the time of dehydrated alcohol as 10~15min.
In a specific embodiment of measuring method of the present invention, Alprostadil freeze-dried lipid of the present invention
The measuring method of the anisidine value of emulsion the following steps are included:
(1) g/ bottles or 10 bottle 5 g/ bottles of μ of 5 bottle of 10 μ of Alprostadil freeze-dried liplid emulsions are taken, 10ml water is added and is dissolved as cream
Liquid obtains emulsion lotion, and emulsion lotion is taken to be placed in separatory funnel；Or take 6 bottles (10 g/ bottles of μ) or 12 bottles of forefront (5 g/ bottles of μ)
Your freeze-drying liplid emulsions of ground are added 12ml water and are dissolved as emulsion form, obtain emulsion lotion, take emulsion lotion 10ml, are subsequently placed in point
In liquid funnel；
(2) 5ml dehydrated alcohol is added in separatory funnel, mixes, adds alkali metal salt 0.02g~0.2g and anhydrous
Ether 30ml~70ml acutely shakes, and collects ether phase, adds water 70ml~120ml and acutely shake；
(3) it stands to complete layering, by upper layer ether oil phase transfer into flask, lower layer's water phase is placed in separatory funnel again
It is extracted twice with anhydrous ether, each anhydrous ether additional amount 10ml~50ml, is acutely shaken, stood to complete layering, merge
Ether phase three times discards water layer；
(4) the ether phase that ether is obtained by extraction three times is collected, is placed in separatory funnel, 30ml~100ml water is then added,
Acutely shaking stands to complete layering, discards water layer to get ether phase；
(5) rotary evaporation in vacuo recycling design processing is mutually carried out to ether under the conditions of being lower than 40 DEG C, obtain residue I；
(6) 20ml dehydrated alcohol dissolution residual substance I is used, dehydrated alcohol phase is obtained, is carried out under the conditions of being lower than 60 DEG C true
Sky rotation is evaporated processing, is repeated 3 times, obtains residue II as test sample；
(7) isopropanol-isooctane mixed solvent that volume ratio is 2: 8 is added in residue II, keeps residue II molten
It solves and is quantitatively transferred in 25ml volumetric flask, isopropanol-isooctane mixed solvent that volume ratio is 2: 8 is added and is diluted to quarter
Degree, shakes up, and is filtered with 0.45 μm of syringe filter, takes filtrate as test solution I；
(8) test solution I is taken, using isopropanol-isooctane mixed solvent that volume is 2: 8 as blank control, is used
UV-VIS spectrophotometry measures absorbance value A0 at the wavelength of 350nm；
(9) the accurate isopropanol-each 5ml of isooctane mixed solvent for measuring test solution I and volume is 2: 8, sets respectively
In two tool plug test tubes of first, second, each accurate 0.25% (g/ml) 4- aminoanisole glacial acetic acid solution 1ml that brand-new is added,
Jump a queue, shake, be protected from light it is accurate place 10 minutes, respectively obtain the different of test solution II and the glacial acetic acid of aminoanisole containing 4-
Propyl alcohol-isooctane mixed solution, using volume ratio be 2: 8 isopropanol-isooctane mixed solvent as blank control, according to purple
Outside-visible spectrophotometry measures absorbance A 1, A2 respectively at the wavelength of 350nm；
(10) anisidine value is calculated as follows:
In formula: V is the amount for the emulsion lotion that step (1) takes, unit ml；C is in the emulsion lotion that step (1) takes
The amount of oil for injection, unit g/ml；
Wherein, the value of C can be obtained by calculation according to the amount of emulsion lotion and the labelled amount of prescription taken；
Numerical value 1.2 is the solution dilution gfactor being added after 4- aminoanisole acetum.
The present invention is demulsified to the freeze-drying liplid emulsions after emulsion using alkali metal salt, then uses anhydrous ether extraction oil
Phase washes remaining sugar and alkali metal salt in oily phase, the moisture in test sample is finally removed with dehydrated alcohol, with ultraviolet spectrometry light
It spends meter method and measures anisidine value, method is feasible, and completely, solution is uniform for extraction, and testing result is accurate, controllable.Through methodology
Verifying, this measuring method specificity is strong, reproducible, and the rate of recovery is high, test solution more stable homogeneous.In continuous mode,
It so that oily phase is kept completely separate with sugar, can also prevent the auxiliary material in removal process from aoxidizing.Test result shows using we
The sample of method measurement, test solution is more uniform, and measurement result is more accurate reasonable, illustrates that this method can really reflect in sample
Anisidine value as a result, can be effectively controlled the quality of product.
The present invention has filled up the blank of the prior art, provides a kind of feasible, stable, accurate first for freeze-drying liplid emulsions
The measuring method of oxygroup aniline value, convenient for the control of liplid emulsions security property figureofmerit is lyophilized.This method oil mutually extract completely,
Accuracy is high, can exclude interference of the sugar to measurement, can be effectively controlled product quality, improves Alprostadil freeze-dried liplid emulsions
Quality inspection standard.
Specific embodiment
Combined with specific embodiments below to the inspection of Alprostadil freeze-dried liplid emulsions anisidine value of the present invention
Survey method is further described, but is not limited to the range of present embodiment.
Embodiment 1
The measurement of Alprostadil freeze-dried liplid emulsions anisidine value
1, instrument, drug and reagent:
220 type ultraviolet-visible spectrophotometer of Thermo company Evolution
Shanghai Ai Lang Instrument Ltd N-1100 type Rotary Evaporators and SB-1100 type water-bath
Alprostadil freeze-dried liplid emulsions: self-control
Preparation method: referring to each component in table 1,1 batch of Alprostadil freeze-dried lipid milk sample product is prepared respectively.By forefront
You are separately added into 10g oil for injection 5mg, 20g emulsifier, and stirring mixes, and obtain oily phase；200g freeze drying protectant is added
In 500ml water for injection, stirring is mixed, and is obtained water phase, is settled to 1000ml after two-phase mixtures, and cream is made through high pressure homogenization method
Agent, then it is freeze-dried, obtain Alprostadil freeze-dried liplid emulsions.
The Alprostadil freeze-dried liplid emulsions adjunct ingredient table of table 1
Dehydrated alcohol used in the present invention, anhydrous ether, isopropanol, isooctane, potassium chloride, sodium chloride, potassium sulfate, sulphur
Sour sodium, 4- aminoanisole and glacial acetic acid are that Sinopharm Chemical Reagent Co., Ltd. provides (analysis is pure)；Water is Shenyang baby
The heartily drinking pure water of Co., Ltd.
2, testing conditions
Detection method: UV-VIS spectrophotometry
Detection wavelength: 350nm.
3, the preparation of solution
(1) preparation of test solution
The preparation of isopropanol-isooctane (volume ratio 2: 8) mixed solvent: taking isopropanol 200ml, isooctane 800ml, mixes
Close, shake up to get.
The preparation of 0.25%4- aminoanisole glacial acetic acid solution: before use, precision weighs the 4- methoxy of 0.025g for measurement
Base aniline into 10ml brown volumetric flask, glacial acetic acid dissolve and be diluted to scale to get.
(2) preparation of test solution
It takes 10 bottles (5 g/ bottles of μ) Alprostadil freeze-dried liplid emulsions that 10ml water is added and is dissolved as emulsion form, obtain emulsion cream
Liquid takes whole emulsion lotions, then sets in separatory funnel；
5ml dehydrated alcohol is added in separatory funnel, mixes, adds sodium chloride 0.1g and anhydrous ether 50ml, it is acute
Strong shaking collects ether phase, adds water 80ml and acutely shake；
It stands to complete layering, by upper layer ether phase transfer into flask, lower layer's water phase is placed in separatory funnel uses nothing again
Water ether is extracted twice, each anhydrous ether additional amount 25ml, is acutely shaken, and is stood to complete layering, is merged ether phase three times,
Discard water layer；
The ether collected three times is mutually placed in separatory funnel, 50ml water is added, acutely shakes, is stood to complete layering
Afterwards, water layer is discarded to get ether phase；
Rotary evaporation in vacuo recycling design processing is mutually carried out to ether under the conditions of 38 DEG C, obtains residue I；
Using 20ml dehydrated alcohol dissolution residual substance I, dehydrated alcohol phase is obtained, vacuum rotating steaming is carried out under the conditions of 55 DEG C
Dry-cure is repeated 3 times, obtains residue II as test sample；
Isopropanol-isooctane (volume ratio 2: 8) is added in residue II to be dissolved residue II and is quantitatively transferred to
In 25ml volumetric flask, it is diluted to scale along with solvent is stated, is shaken up, filtered with 0.45 μm of syringe filter, taking filtrate is to supply
Test sample solution I.
4, aminoanisole values determination method
Test solution I is taken, with isopropanol-isooctane (volume ratio 2: 8) for blank control, using UV-vis spectroscopy
Photometry measures absorbance value A0 at the wavelength of 350nm；
Precision measures test solution I and isopropanol-isooctane (volume ratio 2: 8) each 5ml, is respectively placed in first, second two
In tool plug test tube, each accurate 0.25%4- aminoanisole glacial acetic acid solution that is added (faces with brand-new) 1ml, jumps a queue, shakes, be protected from light
It is accurate to place 10 minutes, respectively obtain isopropanol-isooctane of test solution II and the glacial acetic acid of aminoanisole containing 4-
Mixed solution, with isopropanol-isooctane (volume ratio 2: 8) for blank control, according to UV-VIS spectrophotometry, 350nm's
Absorbance A 1, A2 are measured at wavelength respectively；
Anisidine value is calculated as follows:
In formula: V is the amount for the emulsion lotion that step (1) takes, unit ml；
The amount of oil for injection, unit g/ml in the emulsion lotion that C takes for step (1)；
Numerical value 1.2 is the solution dilution gfactor being added after 4- aminoanisole acetum.
5, repeatability is investigated
6 parts of (first part to the 6th part) test solutions are prepared simultaneously according to above method, measure aminoanisole respectively
Value investigates the repeatability of sample solution measuring method.
6, result
The measurement of the Alprostadil freeze-dried liplid emulsions anisidine value of table 2 and repeatability investigate result
The above result shows that can be very good the interference of removal freeze drying protectant using method of the invention, for measuring
The anisidine value of Alprostadil freeze-dried liplid emulsions, it is as a result stable, it is reproducible.
Embodiment 2-5
The measurement of Alprostadil freeze-dried liplid emulsions anisidine value
Embodiment 2-5 is using emulsion volume and demulsifier type used in embodiment 1, in demulsifier, dehydrated alcohol, head
It is different in washing dosage after secondary extractant anhydrous ether, for the first time amount of water, oil mutually merge, as shown in table 3.Remaining operation step
Suddenly with embodiment 1.
Washing amount after demulsifier, dehydrated alcohol, extractant, amount of water, oil phase merging for the first time for the first time in 3 embodiment 2-5 of table
Use scale
Measurement result: the anisidine value that embodiment 2-5 is measured is respectively 3.21,3.27,3.19 and 3.34.Conclusion:
The dosage of washing amount is in certain use scope after demulsifier, dehydrated alcohol, extractant, amount of water, oil phase merging for the first time for the first time
It inside can be with Accurate Determining anisidine value.
Embodiment 6-9
The measurement of Alprostadil freeze-dried liplid emulsions anisidine value
For operating parameter and step in embodiment 6-9 with embodiment 1, the emulsion volume only taken is different from embodiment 1,
As shown in table 4.
The emulsion volume taken in 4 embodiment 6-9 of table
| Embodiment is used | Embodiment 6 | Embodiment 7 | Embodiment 8 | Embodiment 9 |
| Emulsion volume (ml) | 5 | 8 | 15 | 20 |
| Anisidine value (mean value) | 3.15 | 3.21 | 3.18 | 3.23 |
Using the anisidine value of the Alprostadil freeze-dried lipid emulsion emulsion of method measurement different volumes of the invention.
The result shows that it is in a linear relationship to take different emulsion volume (V) and 1.2 (A1-A2)-A0 calculated values, coefficient R2=
0.990, therefore, in the linear range, anisidine value measurement result, explanation are not influenced using different emulsion volumetric usages
Measuring method of the invention is feasible.
Embodiment 10
The measurement of Alprostadil freeze-dried liplid emulsions anisidine value
For the operating parameter and step of embodiment 10 with embodiment 1, the temperature for only recycling ether is different from embodiment 1.It is real
Apply (18 DEG C) operations under the conditions of lower than 20 DEG C of example 10.
Measurement result: the result of the anisidine value of 6 parts of the 1706012nd batch of samples of parallel determination is respectively as follows: 3.10,
3.12,3.09,3.08,3.11,3.09.Conclusion: recycling anhydrous ether when being lower than 20 DEG C, equally can be with Accurate Determining methoxyl group
Aniline value.
Embodiment 11
The measurement of Alprostadil freeze-dried liplid emulsions anisidine value
The operating parameter and step of embodiment 11 are with embodiment 1, and the temperature and embodiment 1 for only recycling dehydrated alcohol are not
Together, (38 DEG C) operations under the conditions of being lower than 40 DEG C of embodiment 11.
Measurement result: the result of the anisidine value of 6 parts of the 1706012nd batch of samples of parallel determination is respectively as follows: 3.07,
3.10,3.05,3.09,3.12,3.10.Conclusion: recycling dehydrated alcohol when being lower than 40 DEG C, equally can be with Accurate Determining methoxyl group
Aniline value.
Embodiment 12-14
The measurement of Alprostadil freeze-dried liplid emulsions anisidine value
The operating parameter and step of embodiment 12-14 is with embodiment 1, and only demulsifier used is different from embodiment 1, such as
Shown in table 5,
Demulsifier type used in 5 embodiment 12-14 of table
| Embodiment dosage | Embodiment 12 | Embodiment 13 | Embodiment 14 |
| Demulsifier | Potassium chloride | Potassium sulfate | Sodium sulphate |
| Anisidine value (mean value) | 3.22 | 3.17 | 3.13 |
Measurement result: the anisidine value that embodiment 12-14 is measured is respectively 3.22,3.17 and 3.13.The result shows that
It, can be with Accurate Determining anisidine value using different alkali metal salts as demulsifier.
Embodiment 15
The investigation of measuring method accuracy
The sample recovery rate for measuring this method with soybean oil and egg yolk lecithin respectively investigates the accuracy of method, including
Following steps:
(1) Alprostadil freeze-dried liplid emulsions are taken, lotion 10ml after emulsion is taken, operates, survey simultaneously as described in Example 1
The anisidine value of fixed 6 parts of samples, is averaged A1；
(2) 1g soybean oil is taken, is operated as described in Example 1, its anisidine value A2 is measured；
(3) 0.12g phosphatide is taken, is operated as described in Example 1, its anisidine value A3 is measured；
(4) Alprostadil freeze-dried liplid emulsions are taken, lotion 10ml after emulsion is taken, 1g soybean oil test liquid is added, by implementation
The method of example 1 operates, while measuring the anisidine value of 6 parts of samples, is averaged A4；
(5) Alprostadil freeze-dried liplid emulsions are taken, lotion 10ml after emulsion is taken, 0.12g phosphatide test liquid is added, by implementation
The method of example 1 operates, while measuring the anisidine value of 6 parts of samples, is averaged A5；
(6) sample result directly measured by 1 method of embodiment and addition soybean oil or phosphatide sample are measured respectively
As a result compare, calculate as follows:
Soybean oil sample recovery rate=(A4-A1)/A2；
Phosphatide sample recovery rate=(A5-A1)/A3.
It is calculated according to formula, the sample recovery rate for obtaining soybean oil and phosphatide is respectively 95.2% and 96.7%, and RSD is respectively
4.2% and 3.7%.Illustrate that the accuracy of measuring method of the present invention is higher.
Comparative example 1
It is retouched in " the Propofol emulsus injection quality standard " issued using method of the invention and the Chinese Pharmacopoeia committee
The method stated is measured Alprostadil freeze-dried liplid emulsions anisidine value.
The method of the present invention referring to embodiment 1 extraction.
Method (" standard law ") described in " Propofol emulsus injection quality standard " is directly to Alprostadil freeze-dried rouge
Matter emulsion lotion is removed water using dehydrated alcohol rotary evaporation, is measured after mixed solvent dissolved residue.
Remaining is the same as embodiment 1.
Measurement result: 6 are shown in Table.
Table 6 compares Alprostadil freeze-dried liplid emulsions anisidine value measurement result
By the comparison present invention with the measurement result of " Propofol emulsus injection quality standard " the method it is found that same
Product is measured using method of the invention, and sample residue is translucent oily after recycling design, and it is molten to be dissolved completely in mixing
Agent, state clear, measurement result are stablized, and repeatability is good, and accuracy is preferable；And according to " Propofol emulsus injection matter
Amount standard " the method measurement anisidine value result it is significantly higher, sample operation poor reproducibility, sample after recycling design
Residue is in modeling shape and is not exclusively dissolved in solvent, measurement result inaccuracy.Illustrate measuring method of the invention more rationally, can
It goes, is accurate.
Claims (10)
1. a kind of measuring method of the anisidine value of Alprostadil freeze-dried liplid emulsions, which is characterized in that the method packet
Include following steps:
(1) Alprostadil freeze-dried liplid emulsions are subjected to emulsion processing, obtain emulsion lotion, take emulsion lotion, is answered what is taken
Dehydrated alcohol is added in lotion and alkali metal salt is demulsified；
(2) anhydrous ether is added to be extracted, collects ether phase, remaining sugar and alkali metal then plus in water washing ether phase
Salt obtains ether phase and water phase；
(3) it is evaporated ether phase in 40 DEG C or less vacuum rotatings, obtains residue I；
(4) residue I is dissolved with dehydrated alcohol, is then evaporated dehydrated alcohol in 60 DEG C or less vacuum rotatings, is obtained residue II
As test sample, for measuring anisidine value.
2. measuring method as described in claim 1, which is characterized in that the method also includes following steps:
(a) isopropanol-isooctane mixed solvent that residue II volume ratio is 2: 8 is dissolved, obtains test solution I,
Then using volume ratio be 2: 8 isopropanol-isooctane mixed solvent as blank control, using UV-VIS spectrophotometry
Absorbance value A is measured at the wavelength of 350nm0；
(b) accurate to measure isopropanol-isooctane mixed solvent that isometric test solution I and volume ratio are 2: 8, it sets respectively
In two tool plug test tubes of first, second, the 4- aminoanisole glacial acetic acid solution of each 0.25% (g/ml) that same volume is added is obtained
To test solution II and isopropanol-isooctane mixed solution of the glacial acetic acid of aminoanisole containing 4-, with volume ratio for 2: 8
Isopropanol-isooctane mixed solvent as blank control, the wavelength according to UV-VIS spectrophotometry in 350nm is punished
Not Ce Ding test solution II and the glacial acetic acid of aminoanisole containing 4- isopropanol-isooctane mixed solution absorbance value,
It is denoted as A1, A2 respectively.
3. measuring method as claimed in claim 1 or 2, which is characterized in that in step (1), the alkali metal salt is selected from chlorine
Change one of potassium, sodium chloride, potassium sulfate or sodium sulphate or a variety of；Preferably, the amount of the alkali metal salt and the emulsion taken
The ratio between amount of lotion is 2g: 100~1000ml.
4. measuring method as claimed in claim 1 or 2, which is characterized in that in step (2), anhydrous ether is answered with what is taken
The volume ratio of lotion is 3~7: 1, and the volume ratio of water and the emulsion lotion taken is 7~12: 1.
5. measuring method as claimed in claim 1 or 2, which is characterized in that in step (2), carry out second and third time
Anhydrous ether extraction, wherein anhydrous ether and the volume ratio for the emulsion lotion taken are respectively 1~5: 1, add water washing ether phase
The volume ratio for the emulsion lotion that Shi Shuiyu takes is 3~10: 1.
6. measuring method as claimed in claim 5, which is characterized in that in step (2), after each anhydrous ether extraction, second
Ether phase and water phase stratification time are 20~30min, preferably 30min.
7. measuring method as claimed in claim 1 or 2, which is characterized in that in step (3), in 30 DEG C or less vacuum rotatings
It is evaporated ether phase；Preferably, vacuum rotating is evaporated the time of ether as 5~10min.
8. measuring method as claimed in claim 1 or 2, which is characterized in that in step (4), in 50 DEG C or less vacuum rotatings
It is evaporated dehydrated alcohol；It is preferred that residue I is dissolved with dehydrated alcohol, it then is evaporated dehydrated alcohol in 60 DEG C or less vacuum rotatings,
It is repeated 3 times；Preferably, vacuum rotating is evaporated the time of dehydrated alcohol as 10~15min.
9. measuring method as described in claim 1, which is characterized in that the measuring method includes the following steps:
(1) g/ bottles or 10 bottle 5 g/ bottles of μ of 5 bottle of 10 μ of Alprostadil freeze-dried liplid emulsions are taken, 10ml water is added and is dissolved as emulsion form,
Obtain emulsion lotion；Emulsion lotion is taken to be placed in separatory funnel；Or take 6 bottles (10 g/ bottles of μ) or 12 bottles of (5 g/ bottles of μ) Alprostadils
Freeze-drying liplid emulsions are added 12ml water and are dissolved as emulsion form, obtain emulsion lotion, take emulsion lotion 10ml, are subsequently placed in liquid separation leakage
In bucket；
(2) 5ml dehydrated alcohol is added in separatory funnel, mixes, adds alkali metal salt 0.02g~0.2g and anhydrous ether
30ml~70ml acutely shakes, and collects ether phase, adds water 70ml~120ml and acutely shake；
(3) it stands to complete layering, by upper layer ether phase transfer into flask, lower layer's water phase is placed in separatory funnel again with anhydrous
Ether is extracted twice, each anhydrous ether additional amount 10ml~50ml, is acutely shaken, and is stood to complete layering, is merged second three times
Ether phase, discards water layer；
(4) the ether phase that ether is obtained by extraction three times is collected, is placed in separatory funnel, 30ml~100ml water is then added, acutely
Shaking stands to complete layering, discards water layer to get ether phase；
(5) rotary evaporation in vacuo recycling design processing is mutually carried out to ether under the conditions of being lower than 40 DEG C, obtain residue I；
(6) 20ml dehydrated alcohol dissolution residual substance I is used, dehydrated alcohol phase is obtained, vacuum rotation is carried out under the conditions of being lower than 60 DEG C
Turn to be evaporated processing, is repeated 3 times, obtains residue II as test sample；
(7) mixed solvent that volume ratio is 2: 8 isopropanols-isooctane is added in residue II, dissolves residue II and determines
Amount is transferred in 25ml volumetric flask, and isopropanol-isooctane mixed solvent that volume ratio is 2: 8 is added and is diluted to scale, shakes up,
It is filtered with 0.45 μm of syringe filter, takes filtrate as test solution I；
(8) take test solution I, using volume be 2: 8 isopropanol-isooctane mixed solvent as blank control, using it is ultraviolet-
Visible spectrophotometry measures absorbance value A0 at the wavelength of 350nm；
(9) the accurate isopropanol-each 5ml of isooctane mixed solvent for measuring test solution I and volume ratio is 2: 8, is respectively placed in
In two tool plug test tubes of first, second, the 4- aminoanisole glacial acetic acid solution 1ml of each accurate 0.25% (g/ml) that brand-new is added,
Jump a queue, shake, be protected from light it is accurate place 10 minutes, respectively obtain the different of test solution II and the glacial acetic acid of aminoanisole containing 4-
Propyl alcohol-isooctane mixed solution, using volume ratio be 2: 8 isopropanol-isooctane as blank control, according to ultraviolet-visible point
Light photometry measures absorbance A 1, A2 respectively at the wavelength of 350nm；
(10) anisidine value is calculated as follows:
In formula: V is the amount for the emulsion lotion that step (1) takes, unit ml；
The amount of oil for injection, unit g/ml in the emulsion lotion that C takes for step (1).
10. measuring method as claimed in any one of claims 1-9 wherein is frozen in measurement by the Alprostadil of freeze drying protectant of sugar
Purposes in the anisidine value of dry liplid emulsions.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810485809.6A CN110514604B (en) | 2018-05-21 | 2018-05-21 | Method for measuring anisidine value of alprostadil freeze-dried lipid emulsion |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810485809.6A CN110514604B (en) | 2018-05-21 | 2018-05-21 | Method for measuring anisidine value of alprostadil freeze-dried lipid emulsion |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110514604A true CN110514604A (en) | 2019-11-29 |
| CN110514604B CN110514604B (en) | 2022-09-27 |
Family
ID=68621496
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810485809.6A Active CN110514604B (en) | 2018-05-21 | 2018-05-21 | Method for measuring anisidine value of alprostadil freeze-dried lipid emulsion |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110514604B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114002169A (en) * | 2021-09-29 | 2022-02-01 | 江苏天宇检测技术有限公司 | Technical improvement research and development method of extracting agent for determination of phosgene in air |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101158665A (en) * | 2006-12-18 | 2008-04-09 | 重庆药友制药有限责任公司 | Alprostadil emulsions measuring method |
| CN102809503A (en) * | 2012-08-21 | 2012-12-05 | 浙江九旭药业有限公司 | Method for determining anisidine value of lipid emulsion |
| CN103712936A (en) * | 2013-12-09 | 2014-04-09 | 李宏 | Determination method for anisidine value of lipid emulsion |
| CN106546684A (en) * | 2015-09-17 | 2017-03-29 | 蓬莱诺康药业有限公司 | A kind of detection method of Alprostadil freeze-dried liplid emulsions |
| CN106840799A (en) * | 2017-02-27 | 2017-06-13 | 浙江圣兆药物科技股份有限公司 | The assay method of anisidine value in a kind of dried emulsifier |
| CN107543798A (en) * | 2016-06-24 | 2018-01-05 | 华仁药业股份有限公司 | The assay method of anisidine value in a kind of drug-loaded emulsion agent |
| US20180116957A1 (en) * | 2016-10-27 | 2018-05-03 | Tovaristvo Z Obmezhenou Vidpovidalnistu "Nanomedtrast" | Method of producing of pharmacologically active liposomal composition containing cytochrome c, and liposomal composition obtained by this method |
-
2018
- 2018-05-21 CN CN201810485809.6A patent/CN110514604B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101158665A (en) * | 2006-12-18 | 2008-04-09 | 重庆药友制药有限责任公司 | Alprostadil emulsions measuring method |
| CN102809503A (en) * | 2012-08-21 | 2012-12-05 | 浙江九旭药业有限公司 | Method for determining anisidine value of lipid emulsion |
| CN103712936A (en) * | 2013-12-09 | 2014-04-09 | 李宏 | Determination method for anisidine value of lipid emulsion |
| CN106546684A (en) * | 2015-09-17 | 2017-03-29 | 蓬莱诺康药业有限公司 | A kind of detection method of Alprostadil freeze-dried liplid emulsions |
| CN107543798A (en) * | 2016-06-24 | 2018-01-05 | 华仁药业股份有限公司 | The assay method of anisidine value in a kind of drug-loaded emulsion agent |
| US20180116957A1 (en) * | 2016-10-27 | 2018-05-03 | Tovaristvo Z Obmezhenou Vidpovidalnistu "Nanomedtrast" | Method of producing of pharmacologically active liposomal composition containing cytochrome c, and liposomal composition obtained by this method |
| CN106840799A (en) * | 2017-02-27 | 2017-06-13 | 浙江圣兆药物科技股份有限公司 | The assay method of anisidine value in a kind of dried emulsifier |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114002169A (en) * | 2021-09-29 | 2022-02-01 | 江苏天宇检测技术有限公司 | Technical improvement research and development method of extracting agent for determination of phosgene in air |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110514604B (en) | 2022-09-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Akramipour et al. | Speciation of organic/inorganic mercury and total mercury in blood samples using vortex assisted dispersive liquid-liquid microextraction based on the freezing of deep eutectic solvent followed by GFAAS | |
| Cullum | Introduction to surfactant analysis | |
| El-Shahawi et al. | A new method for analysis of sunset yellow in food samples based on cloud point extraction prior to spectrophotometric determination | |
| DE69230318T3 (en) | REAGENT COMPOSITIONS FOR ANALYTICAL TESTS | |
| CN101915760B (en) | Method for detecting cysteine content in real time by colorimetric method | |
| CN107621399A (en) | A kind of method of oligosaccharide in detection breast milk | |
| Hussein et al. | A greenness evaluation and environmental aspects of solidified floating organic drop microextraction for metals: A review | |
| Shi et al. | Effective extraction of fluorescent brightener 52 from foods by in situ formation of hydrophobic deep eutectic solvent | |
| Liang et al. | Supramolecular solvent dispersive liquid–liquid microextraction based on solidification of floating drop and graphite furnace atomic absorption spectrometry for the determination of trace lead in food and water samples | |
| Mohd et al. | Determination of carcinogenic herbicides in milk samples using green non-ionic silicone surfactant of cloud point extraction and spectrophotometry | |
| Jafarvand et al. | Supramolecular-based dispersive liquid–liquid microextraction in high salt concentrations | |
| CN111351872B (en) | HPLC (high performance liquid chromatography) detection method for residual quantity of sincalide in food | |
| Khorshidi et al. | A novel ion pair based surfactant assisted microextraction modified by orthogonal signal correction partial least squares for determination of food dyes | |
| CN110514604A (en) | The measuring method of the anisidine value of Alprostadil freeze-dried liplid emulsions | |
| CN102809503B (en) | Method for determining anisidine value of lipid emulsion | |
| Rageh et al. | A surfactant-based quasi-hydrophobic deep eutectic solvent for dispersive liquid-liquid microextraction of gliflozins from environmental water samples using UHPLC/fluorescence detection | |
| CN108008047A (en) | The detection method of tocopherol content in a kind of edible oil | |
| CN104251897A (en) | Method for simultaneously measuring residue contents of five weedicides with different structures in soil | |
| Burakham et al. | Exploiting sequential injection analysis with lab-at-valve (LAV) approach for on-line liquid–liquid micro-extraction spectrophotometry | |
| Khazaeli et al. | Response surface methodology based on central composite design as a chemometric tool for optimizing dispersive liquid–liquid microextraction for determining ultra-trace amounts of zinc in oil and water samples | |
| CN106706526B (en) | Ion liquid abstraction-ultraviolet-visible spectrophotometry measurement mexiletine hydrochloride method | |
| CN103712936B (en) | The assay method of fat emulsion anisidine value | |
| CN106198811A (en) | Quickly measure water and aquatic products Malachite Green and the test kit of crystal violet and method | |
| Sidwell et al. | The determination of substituted phenylurea herbicides and their impurities in technical and formulated products by use of liquid chromatography | |
| CN106226256A (en) | A kind of surfactant quantitative detecting method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: No.18-1, Nanping East Road, Hunnan New District, Shenyang City, Liaoning Province Applicant after: Yuanda Life Science (Liaoning) Co.,Ltd. Address before: No.18-1, Nanping East Road, Hunnan New District, Shenyang City, Liaoning Province Applicant before: LIAONING GRAND NUOKANG BIOPHARMACEUTICAL Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20220825 Address after: 265600 No. 118 Jinchuang Road, Penglai City, Yantai City, Shandong Province Applicant after: PENGLAI NUOKANG PHARMACEUTICAL Co.,Ltd. Address before: No.18-1, Nanping East Road, Hunnan New District, Shenyang City, Liaoning Province Applicant before: Yuanda Life Science (Liaoning) Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |