CN110208434A - A kind of detection method of the l-ornidazole in relation to substance - Google Patents
A kind of detection method of the l-ornidazole in relation to substance Download PDFInfo
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- CN110208434A CN110208434A CN201910616979.8A CN201910616979A CN110208434A CN 110208434 A CN110208434 A CN 110208434A CN 201910616979 A CN201910616979 A CN 201910616979A CN 110208434 A CN110208434 A CN 110208434A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/50—Conditioning of the sorbent material or stationary liquid
- G01N30/52—Physical parameters
- G01N30/54—Temperature
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N2030/062—Preparation extracting sample from raw material
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
A kind of detection method the present invention provides l-ornidazole in relation to substance, the detection method uses high performance liquid chromatography, by using different Detection wavelengths and gradient and isocratic elution are combined, to realize efficiently separating and detecting for l-ornidazole and related substance IMP-1 to IMP-8.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical fields, the analysis more specifically to a kind of l-ornidazole in relation to substance
Method.
Background technique
L-ornidazole, chemical name are as follows: S- (-)-(3- chlorine-2-hydroxyl propyl) -2- 5-nitro imidazole, compound
Structure are as follows:
Nanjing Shenghe Pharmaceutical Co., Ltd discloses one kind in Chinese patent application CN1752749A and passes through high performance liquid chromatography
The method that method detects ornidazole optical antipode, specific as follows: (1) chromatographic condition: chromatographic column uses cellulose esters to fix
The chiral column of phase；Mobile phase is positive hexane-methyl tert butyl ether-isopropanol-glacial acetic acid；Detection wavelength be 280nm~
340nm.(2) organic solvent is used to match sample for the solution of the 0.05~0.5mg/ml of raceme containing Ornidazole.(3) it measures, note
Record chromatogram.
Chengdu Jindian Pharmaceutical Technology Development Co., Ltd. discloses a kind of Austria in Chinese patent application CN102539564A
The detection method and content assaying method of nitre azoles injection impurity, the detection method are used to detect the impurity in ornidazole injection
2- 5-nitro imidazole and 1- (the chloro- acrylic of 3-) -2- 5-nitro imidazole)；HPLC testing conditions: mobile phase is second
Nitrile-water (or methanol-water) volume ratio are as follows: 15-25: 75-85, impurity 2- 5-nitro imidazole and maximum contaminant Detection wavelength
For 305-315nm.
Nanjing Hailing Pharmaceutical Co., Ltd. of Yangtze River Pharmaceutical Group discloses in Chinese patent application CN102565271A
A kind of method of quality control of Ornidazole, using high performance liquid chromatography (chromatographic condition are as follows: chromatographic column: reverse phase C18 column, flowing
Phase: volume ratio is methanol-water-glacial acetic acid of 30:70:0.2, flow velocity 1.0ml/min, Detection wavelength 310nm, column temperature 30
DEG C) detect Ornidazole and 2- 5-nitro imidazole.
Shaanxi synthesizes medicine company limited liability company;A kind of separation point is disclosed in Chinese patent application CN107917979A
The HPLC method for analysing l-ornidazole isomers, using high performance liquid chromatography, using amylose bonded silica gel as filler, water phase
(pH value 2~9.0) and organic phase are combined into mobile phase centainly to match group, and flow velocity is 0.1~1.0ml/min, and column temperature is 0~40
DEG C, sampling volume is 0.1~100 μ l, using gradient or isocratic carries out elution separation.
In order to guarantee the clinical application safety of l-ornidazole medication, this field is still thirsted for can be with complete detection l-ornidazole matter
Amount, especially its detection in relation to substance.
Summary of the invention
The present inventor is largely studied, and a kind of detection method of the l-ornidazole in relation to substance is successfully developed.
A kind of detection method the present invention provides l-ornidazole in relation to substance, the detection method use high performance liquid chromatography
Method, and detected according to following testing conditions and operation:
Testing conditions 1 are as follows:
Chromatographic column 1: using octadecylsilane chemically bonded silica as filler；
Mobile phase 1: using methanol as mobile phase 1A, water is mobile phase 1B；Carry out gradient elution；
Detection wavelength 1:310nm to 320nm；It preferably, is 318nm；
1:25 DEG C -40 DEG C of column temperature, it is therefore preferable to, 30 DEG C；
Flow velocity 1:1.0 ml/min -1.5 ml/min, it is preferable that be 1.2ml/min；
The preparation of reference substance solution 1: take respectively reference substance IMP01, reference substance IMP02, reference substance IMP03, reference substance IMP04,
Reference substance IMP06 is appropriate, the methanol aqueous solution that the volume ratio with methanol and water is 20:80 dissolve and dilute be made every 1ml containing pair
According to product IMP02 0.2 μ g, IMP01 containing reference substance, pair of reference substance IMP03, reference substance IMP04, each 2.5 μ g of reference substance IMP06
According to product solution 1；
The preparation of test solution 1: the l-ornidazole bulk pharmaceutical chemicals containing about l-ornidazole 50mg are taken, sets in 20ml measuring bottle, adds methanol
Dissolve and quantify with methanol aqueous solution that the volume ratio of water is 20:80 and dilutes that every 1ml is made is molten containing about l-ornidazole 2.5mg
Liquid, as test solution 1；
Under testing conditions 1, precision measures test solution 1 and each 40 μ l of reference substance solution 1, is injected separately into liquid chromatograph,
Record chromatogram.
In the embodiment of the application, the detection method further include:
Testing conditions 2 are as follows:
Chromatographic column 2: using octadecylsilane chemically bonded silica as filler；
Mobile phase 2: using the volume ratio of methanol and water for (15 ~ 25): the methanol aqueous solution of (75 ~ 85) is mobile phase 2, it is preferable that
The volume ratio of methanol and water is 22:78；Carry out isocratic elution；
Detection wavelength 2:310nm to 320nm；It preferably, is 310nm；
2:25 DEG C -40 DEG C of column temperature, it is therefore preferable to, 30 DEG C；
Flow velocity 2:0.9 ml/min -1.2 ml/min, it is preferable that be 1.0ml/min；
Testing conditions 3 are as follows:
Chromatographic column 3: using octadecylsilane chemically bonded silica as filler；
Mobile phase 3: using methanol as mobile phase 3A, water is mobile phase 3B；Carry out gradient elution；
Detection wavelength 3:200nm to 220nm；It preferably, is 210nm；
3:25 DEG C -40 DEG C of column temperature, it is therefore preferable to, 30 DEG C；
Flow velocity 3:1.0 ml/min -1.5 ml/min, it is preferable that be 1.2ml/min；
The preparation of reference substance solution 2: taking reference substance IMP05 appropriate, the methanol aqueous solution that the volume ratio with methanol and water is 20:80
It dissolves and dilutes the reference substance solution 2 that every 0.2 μ g of 1ml IMP05 containing reference substance is made；
The preparation of test solution 2: the l-ornidazole bulk pharmaceutical chemicals containing about l-ornidazole 50mg are taken, sets in 20ml measuring bottle, adds methanol
The methanol aqueous solution that volume ratio with water is 20:80, which dissolves and quantifies dilution, is made every 1ml containing about l-ornidazole 2.5mg for examination
Product solution 2；
The preparation of reference substance solution 3: taking reference substance IMP07, reference substance IMP08 reference substance appropriate respectively, with the body of methanol and water
Product is than the methanol aqueous solution for 20:80 and the solution of every 0.2 μ g of 1ml IMP08 containing reference substance, IMP07 containing reference substance is made in dilution
The reference substance solution 3 of 2.5 μ g；
The preparation of test solution 3: the l-ornidazole bulk pharmaceutical chemicals containing about l-ornidazole 50mg are taken, sets in 20ml measuring bottle, adds methanol
Dissolve and quantify with methanol aqueous solution that the volume ratio of water is 20:80 and dilutes that every 1ml is made is molten containing about l-ornidazole 2.5mg
Liquid, as test solution 3；
Under testing conditions 2, precision measures test solution 2 and each 40 μ l of reference substance solution 2, is injected separately into liquid chromatograph,
Record chromatogram；With
Under testing conditions 3, precision measures test solution 3 and each 40 μ l of reference substance solution 3, is injected separately into liquid chromatograph,
Record chromatogram.
In some embodiments, the detection method uses high performance liquid chromatography, and according to following testing conditions and
Operation is detected:
Testing conditions 1 are as follows:
Chromatographic column 1: using octadecylsilane chemically bonded silica as filler；
Mobile phase 1: using methanol as mobile phase 1A, water is mobile phase 1B；Carry out gradient elution；
Detection wavelength 1:310nm to 320nm；It preferably, is 318nm；
1:25 DEG C -40 DEG C of column temperature, it is therefore preferable to, 30 DEG C；
Flow velocity 1:1.0 ml/min -1.5 ml/min, it is preferable that be 1.2ml/min；
Testing conditions 2 are as follows:
Chromatographic column 2: using octadecylsilane chemically bonded silica as filler；
Mobile phase 2: using the volume ratio of methanol and water for (15 ~ 25): the methanol aqueous solution of (75 ~ 85) is mobile phase 2, it is preferable that
The volume ratio of methanol and water is 22:78；Carry out isocratic elution；
Detection wavelength 2:310nm to 320nm；Preferably, it is；
2:25 DEG C -40 DEG C of column temperature, it is therefore preferable to, 30 DEG C；310nm
Flow velocity 2:0.9 ml/min -1.2 ml/min, it is preferable that be 1.0ml/min；
Testing conditions 3 are as follows:
Chromatographic column 3: using octadecylsilane chemically bonded silica as filler；
Mobile phase 3: using methanol as mobile phase 3A, water is mobile phase 3B；Carry out gradient elution；
Detection wavelength 3:200nm to 220nm；It preferably, is 210nm；
3:25 DEG C -40 DEG C of column temperature, it is therefore preferable to, 30 DEG C；
Flow velocity 3:1.0 ml/min -1.5 ml/min, it is preferable that be 1.2ml/min；
The preparation of reference substance solution 1: take respectively reference substance IMP01, reference substance IMP02, reference substance IMP03, reference substance IMP04,
Reference substance IMP06 is appropriate, the methanol aqueous solution that the volume ratio with methanol and water is 20:80 dissolve and dilute be made every 1ml containing pair
According to product IMP02 0.2 μ g, IMP01 containing reference substance, pair of reference substance IMP03, reference substance IMP04, each 2.5 μ g of reference substance IMP06
According to product solution 1；
The preparation of test solution 1: the l-ornidazole bulk pharmaceutical chemicals containing about l-ornidazole 50mg are taken, sets in 20ml measuring bottle, adds methanol
Dissolve and quantify with methanol aqueous solution that the volume ratio of water is 20:80 and dilutes that every 1ml is made is molten containing about l-ornidazole 2.5mg
Liquid, as test solution 1；
The preparation of reference substance solution 2: taking reference substance IMP05 appropriate, the methanol aqueous solution that the volume ratio with methanol and water is 20:80
It dissolves and dilutes the reference substance solution 2 that every 0.2 μ g of 1ml IMP05 containing reference substance is made；
The preparation of test solution 2: the l-ornidazole bulk pharmaceutical chemicals containing about l-ornidazole 50mg are taken, sets in 20ml measuring bottle, adds methanol
The methanol aqueous solution that volume ratio with water is 20:80, which dissolves and quantifies dilution, is made every 1ml containing about l-ornidazole 2.5mg for examination
Product solution 2；
The preparation of reference substance solution 3: taking reference substance IMP07, reference substance IMP08 reference substance appropriate respectively, with the body of methanol and water
Product is than the methanol aqueous solution for 20:80 and the solution of every 0.2 μ g of 1ml IMP08 containing reference substance, IMP07 containing reference substance is made in dilution
The reference substance solution 3 of 2.5 μ g；
The preparation of test solution 3: the l-ornidazole bulk pharmaceutical chemicals containing about l-ornidazole 50mg are taken, sets in 20ml measuring bottle, adds methanol
Dissolve and quantify with methanol aqueous solution that the volume ratio of water is 20:80 and dilutes that every 1ml is made is molten containing about l-ornidazole 2.5mg
Liquid, as test solution 3；
Under testing conditions 1, precision measures test solution 1 and each 40 μ l of reference substance solution 1, is injected separately into liquid chromatograph,
Record chromatogram；With
Under testing conditions 2, precision measures test solution 2 and each 40 μ l of reference substance solution 2, is injected separately into liquid chromatograph,
Record chromatogram；With
Under testing conditions 3, precision measures test solution 3 and each 40 μ l of reference substance solution 3, is injected separately into liquid chromatograph,
Record chromatogram.
In the above-described embodiment, the gradient elution of the mobile phase 1 are as follows:
| t/min | 0 | 20 | 50 | 60 | 70 | 71 | 80 | |
| Mobile phase 1B volume % | 100 | 80 | 80 | 40 | 40 | 100 | 100 |
Alternatively, the gradient elution of the mobile phase 1 are as follows:
| t/min | 0 | 20 | 50 | 60 | 70 | |
| Mobile phase 1B volume % | 100 | 80 | 80 | 40 | 40 |
In the above-described embodiment, the gradient elution of the mobile phase 3 are as follows:
| t/min | 0 | 20 | 50 | 60 | 70 | 71 | 80 | |
| Mobile phase 3B volume % | 100 | 80 | 80 | 40 | 40 | 100 | 100 |
Alternatively, the gradient elution of the mobile phase 3 are as follows:
| t/min | 0 | 20 | 50 | 60 | 70 | |
| Mobile phase 3B volume % | 100 | 80 | 80 | 40 | 40 |
In the above-described embodiment, may also include that
The preparation of system suitability solution 1: precision weighs l-ornidazole, reference substance IMP01, reference substance IMP02, reference substance
IMP03, reference substance IMP04, reference substance IMP06 are appropriate, and the methanol aqueous solution dissolution that the volume ratio with methanol and water is 20:80 is simultaneously
Dilution be made every 1ml containing about l-ornidazole 2.5mg, containing about the system suitability solution 1 of each 2.5 μ g of reference substance.
In the above-described embodiment, may also include that
Precision measures 1.0ml test solution 1 into 100ml measuring bottle, adds the methanol that the volume ratio of methanol and water is 20:80 water-soluble
Liquid is settled to scale, as contrast solution 1.
In the above-described embodiment, may also include that under testing conditions 1, precision measures system suitability solution 1, for examination
Product solution 1, contrast solution 1 and each 40 μ l of reference substance solution 1 are injected separately into liquid chromatograph, record chromatogram.
In the above-described embodiment, may also include that
The preparation of system suitability solution 2: taking l-ornidazole, reference substance IMP05 appropriate respectively, and the volume ratio with methanol and water is
The methanol aqueous solution of 20:80 dissolve and dilute be made every 1ml containing about l-ornidazole 2.5mg, containing about 2.5 μ g's of reference substance IMP05
System suitability solution 2.
In the above-described embodiment, may also include that
Under testing conditions 2, precision measures system suitability solution 2, test solution 2 and each 40 μ l of reference substance solution 2, respectively
Liquid chromatograph is injected, chromatogram is recorded.
In the above-described embodiment, may also include that
The preparation of system suitability solution 3: taking l-ornidazole, reference substance IMP07, reference substance IMP08 appropriate respectively, with methanol with
The volume ratio of water be 20:80 methanol aqueous solution dissolve and dilute be made every 1ml containing about l-ornidazole 2.5mg, containing about each control
The system suitability solution 3 of 2.5 μ g of product IMP07 and reference substance IMP08.
In the above-described embodiment, may also include that
Under testing conditions 3, precision measures system suitability solution 3, test solution 3 and each 40 μ l of reference substance solution 3, respectively
Liquid chromatograph is injected, chromatogram is recorded.
In the above-described embodiment, it in the chromatogram that testing conditions 1 obtain, deducts in 1 chromatogram of test solution
Solvent peak, gradient peak, such as aobvious impurity peaks, reference substance IMP01, reference substance IMP03, reference substance in the chromatogram of test solution 1
IMP04, reference substance IMP06 must not cross 0.10% by external standard method with calculated by peak area, and reference substance IMP02 is by external standard method with peak area
Must not calculate 0.008%, other single impurity peak areas are not greater than 0.1 times of contrast solution principal component peak area
(0.10%), total impurities must not cross 0.20%.
In the above-described embodiment, in the chromatogram of testing conditions 2, the solvent in test solution chromatogram is deducted
Peak, gradient peak, such as aobvious impurity peaks in the chromatogram of test solution 2, reference substance IMP05 is by external standard method with peak area (bimodal peak
Area is total) must not calculate 0.008%.
In the above-described embodiment, in the chromatogram of testing conditions 3, the solvent in 3 chromatogram of test solution is deducted
Peak, gradient peak, such as aobvious impurity peaks in the chromatogram of test solution 3, reference substance IMP07 must not with calculated by peak area by external standard method
0.10% is crossed, reference substance IMP08 must not cross 0.008% by external standard method with calculated by peak area.
In the above-described embodiment, under testing conditions 1, l-ornidazole and phase in the chromatogram of system suitability solution 1
Separating degree should meet regulation between adjacent impurity peaks, each impurity peaks.
In the above-described embodiment, under testing conditions 2, l-ornidazole and phase in the chromatogram of system suitability solution 2
Separating degree should meet regulation between adjacent impurity peaks, each impurity peaks.
In the above-described embodiment, under testing conditions 3, l-ornidazole and phase in the chromatogram of system suitability solution 3
Separating degree should meet regulation between adjacent impurity peaks, each impurity peaks.
In embodiments of the invention, the chemical name and its structure of the reference substance IMP-1 to reference substance IMP-8 be such as
Under:
Reference substance IMP01
2- 5-nitro imidazole；
Reference substance IMP02
1- (2,3- glycidyl) -2- 5-nitro imidazole；
Reference substance IMP03
1- (2,3- dihydroxypropyl) -2- 5-nitro imidazole；
Reference substance IMP04
S- (-) -1- (3- chlorine-2-hydroxyl propyl) -2- methyl-4-nitro iminazole；
Reference substance IMP05
1- (the chloro- acrylic of 3-) -2- 5-nitro imidazole；
Reference substance IMP06
1- acetonyl -2- 5-nitro imidazole；
Reference substance IMP07
N- (the chloro- 2- hydroxypropyl of 3-) -5- methyl-1,2,4- oxadiazole -3- carboxylic acid amides；
Reference substance IMP08
S- (-) -1- (3- chlorine-2-hydroxyl propyl) -2- 5-nitro imidazole nitrogen oxides.
In some embodiments of the present invention, above-mentioned detection method also can be used for inspection of the Ornidazole in relation to substance
It surveys.
For the quality of the good l-ornidazole of strict control, the content in l-ornidazole in relation to substance can be efficiently detected, this
Inventor screens Detection wavelength, Degrading experiment and eluent gradient by many experiments.
1. the present invention screens Detection wavelength, UV scanning has been carried out to IMP01 ~ IMP08 respectively.As a result table
Bright, IMP01, IMP02, IMP03, IMP04, IMP05, IMP06 and l-ornidazole have an absorption maximum near 318nm, IMP07 and
IMP08 has absorption maximum near 210nm, therefore drafts the method that the Detection wavelength in relation to substance is 318nm, IMP07 and IMP08
Detection wavelength is 210nm.
2. the present invention investigates the mobile phase and chromatographic column of testing conditions 1,3,
Condition A: chromatographic column: Penomenex Luna C18(2), 4.6 × 250mm, 5mm；Mobile phase: methanol-water (volume ratio
20:80) existing method (2015 editions two P161 pages of Chinese Pharmacopoeias)；
Condition B: chromatographic column: Ultimate XB-C18,4.6 × 250mm, 5mm；Mobile phase: A phase: methanol；B phase: water；Gradient
Elution program:
| Time min | 0 | 20 | 50 | 60 | 70 |
| B% | 100 | 80 | 80 | 40 | 40 |
Condition C: chromatographic column: Penomenex Luna C18(2), 4.6 × 250mm, 5mm；Mobile phase: A phase: methanol；B phase:
Water；Gradient elution program:
| Time min | 0 | 20 | 50 | 60 | 70 |
| B% | 100 | 80 | 80 | 40 | 40 |
The result shows that condition A can not be separated, and condition B, C, i.e. A phase methanol-B phase water (gradient elution): when each impurity appearance
Between it is suitable, separating degree meets the requirements between main peak and impurity, between impurity peaks, and blank gradient interference is small, and sample detects impurity number
More, which can be used as related substance research method.Therefore, selection selection chromatographic column C18 (4.6 × 250mm, 5mm), with first
Alcohol, water are that mobile phase carries out gradient elution, effectively can detect and separate the related substance of this product.
3. the present invention has carried out the degradation failure test of l-ornidazole, investigated respectively acid, alkali, oxidation, water-bath, illumination,
The conditions such as high temperature, high humidity.The result shows that can effectively detect the degradation that failure test generates under selected chromatographic condition
Product peak, in 97%-100%, the rate of recovery meets the requirements the rate of recovery of degrading.Peak purity is all larger than threshold value 999, meets regulation.
The utility model has the advantages that the method for quality control in l-ornidazole provided by the invention in relation to substance has the advantage that
The present invention is filtered out according to each structural property in relation to material composition and physical and chemical feature in l-ornidazole by many experiments
The analysis conditions such as optimal Detection wavelength, mobile phase screening, Degrading experiment show provided by the invention through many experiments verifying
In relation to the method for quality control of substance in l-ornidazole, can be effectively detected by the way of dual wavelength, gradient elution from existing
Methodical 3 known impurities increase to 8 known impurities, and the stability of method is good, good to the separating degree of each analysis ingredient, can
With sensitive and accurate each compound of quantitative detecting analysis.Therefore, the quality control in l-ornidazole provided by the invention in relation to substance
Method processed can objective, comprehensively and accurately evaluate the quality of the active constituent l-ornidazole of l-ornidazole chloride injection agent, right
It controls the quality of l-ornidazole and guarantees that clinical application is of great significance safely.
Detailed description of the invention
Fig. 1 shows be 1 reference substance IMP01 ultraviolet scanning spectrum figure of embodiment
What Fig. 2A was indicated is the system suitability HPLC figure of 2 medium wavelength 318nm of embodiment
What Fig. 2 B was indicated is the impurity control HPLC figure of 2 medium wavelength 318nm of embodiment
What Fig. 2 C was indicated is the sample HPLC figure of 2 medium wavelength 318nm of embodiment
What Fig. 2 D was indicated is the 100% mark-on sample HPLC figure of 2 medium wavelength 318nm of embodiment
What Fig. 2 E was indicated is the system suitability HPLC figure of 2 medium wavelength 210nm of embodiment
What Fig. 2 F was indicated is the impurity control HPLC figure of 2 medium wavelength 210nm of embodiment
What Fig. 2 G was indicated is the sample HPLC figure of 2 medium wavelength 210nm of embodiment
What Fig. 2 H was indicated is the 100% mark-on sample HPLC figure of 2 medium wavelength 210nm of embodiment
What Fig. 3 A was indicated is the system suitability HPLC figure of 1 medium wavelength 318nm of comparative example
What Fig. 3 B was indicated is the system suitability HPLC figure of 1 medium wavelength 210nm of comparative example
What Fig. 3 C was indicated is the IMP01 HPLC figure of 1 medium wavelength 318nm of comparative example
What Fig. 3 D was indicated is the IMP08 HPLC figure of 1 medium wavelength 210nm of comparative example.
Specific embodiment
Below by specific embodiment to further illustrate the technical scheme of the present invention；It should be appreciated that following implementations
Example is not limiting of its scope.
Embodiment 1
The selection of ultraviolet wavelength
It in embodiments herein, is scanned using uv analyzer Shimadzu UV2450, solvent is 20% methanol-water
Solution, reference substance IMP01 concentration are 10 μ g/ml, and ultraviolet spectrogram is as shown in Figure 1, wherein 1 wavelength is 309.50.
Reference substance IMP01, reference substance IMP02, reference substance IMP03, reference substance IMP04, reference substance IMP05, reference substance
IMP06 and l-ornidazole have absorption maximum near 318nm, and reference substance IMP07 and reference substance IMP08 have most near 210nm
It is big to absorb, therefore draft the method Detection wavelength that the Detection wavelength in relation to substance is 318nm, reference substance IMP07 and reference substance IMP08
For 210nm.
Test result shows that the characteristic ultraviolet absorption of each known impurities and l-ornidazole is shown, IMP01 ~ IMP06 and left Austria
Nitre azoles absorption maximum is within the scope of 309nm ~ 320nm, IMP07 and IMP08 absorption maximum is in 200nm ~ 220nm range internal reference
The testing conditions for examining l-ornidazole in Chinese Pharmacopoeia 2015 editions select 318nm/210nm wavelength as the related material conditions of this product
The Detection wavelength of investigation.
Embodiment 2
Experimental condition:
Chromatographic column: octadecylsilane chemically bonded silica is filler (4.6 × 250mm × 5 μm)
Mobile phase: A phase: methanol B phase: water
Gradient elution is carried out according to the following table.
| t/min | 0 | 20 | 50 | 60 | 70 | 71 | 80 | |
| B% | 100 | 80 | 80 | 40 | 40 | 100 | 100 |
Detection wavelength: 318nm；Flow velocity: 1.2ml/min；
Sampling volume: 40 μ l；Column temperature: 30 DEG C；
Specific test operation:
System suitability: precision weighs l-ornidazole and impurity reference substance IMP01, IMP02, IMP03, IMP04, IMP06
In right amount, dissolved with the methanol aqueous solution that methanol and water volume ratio are 20:80 and dilute be made every 1ml containing about l-ornidazole 2.5mg,
Solution containing about each 2.5 μ g of impurity takes 40 μ l of system suitability solution to inject liquid chromatograph, such as system suitability solution
Fig. 2A, separating degree should meet regulation between l-ornidazole and other impurities peak, each impurity peaks.
Test solution: taking this product appropriate, is dissolved with the methanol aqueous solution that methanol and water volume ratio are 20:80 and dilutes system
At in every lml containing about l-ornidazole (C7H10ClN3O3) 2.5mg solution, as test solution.
Contrast solution: precision measures 1ml test solution, sets in 100ml measuring bottle, is 20:80 with methanol and water volume ratio
Methanol aqueous solution be diluted to scale, as contrast solution.
Impurity contrast solution: taking IMP01, IMP02, IMP03, IMP04, IMP06 reference substance appropriate respectively, with methanol and water
Volume ratio is that the methanol solution of 20:80 dissolve and diluted every 0.2 μ g/ml of 1ml impurity containing IMP02 is made, contain IMP01, IMP03,
The solution of 2.5 μ g of IMP04, IMP06 impurity is as impurity contrast solution.
The preparation of test sample mark-on solution: taking l-ornidazole about 25mg, accurately weighed, sets in 10ml measuring bottle, adds reference substance
The solution of solution 1 dissolves and is diluted to scale, shakes up, as test sample mark-on solution.
Precision measures test solution, contrast solution, test sample mark-on solution and each 40 μ l of impurity contrast solution, infuses respectively
Enter liquid chromatograph, (impurity compares HPLC such as Fig. 2 B, sample HPLC such as Fig. 2 C, 100% test sample mark-on HPLC to record chromatogram
Such as Fig. 2 D), solvent peak, the gradient peak in test solution chromatogram are deducted, such as shows impurity peaks in the chromatogram of test solution,
IMP01, IMP03, IMP04, IMP06 must not cross 0.1%, IMP02 by external standard method in terms of peak area with calculated by peak area by external standard method
Must not calculate 0.008%, other single impurity peak areas are not greater than 0.1 times (0.1%) of contrast solution principal component peak area, miscellaneous
Matter total amount must not cross 0.2%.
Reference substance IMP05
Experimental condition:
Chromatographic column: octadecylsilane chemically bonded silica is the filler (μ of such as Waters sunfire C18,4.6 × 150mm × 3.5
M)
Mobile phase: methanol-water (volume ratio 22:78)
Detection wavelength: 310nm；Flow velocity: 1.0ml/min；Sampling volume: 40 μ l；Column temperature: 30 DEG C；
Specific test operation:
System suitability: precision weighs l-ornidazole and impurity reference substance IMP05 is appropriate, is with methanol and water volume ratio
The methanol aqueous solution of 20:80 dissolves and dilutes the solution work that every 1ml is made containing about l-ornidazole 2.5mg, containing about each 2.5 μ g of impurity
For system suitability solution, 40 μ l of system suitability solution is taken to inject liquid chromatograph, l-ornidazole and other impurities peak,
Separating degree should meet regulation between the peak IMP05 and other impurities peak.
Test solution: taking this product appropriate, is dissolved with the methanol aqueous solution that methanol and water volume ratio are 20:80 and dilutes system
At in every lml containing about l-ornidazole (C7H10ClN3O3) 2.5mg solution, as test solution.
Impurity contrast solution: taking IMP05 reference substance appropriate, is dissolved with the methanol solution that methanol and water volume ratio are 20:80
And the solution that every 0.2 μ g/ml of 1ml impurity containing IMP05 is made is diluted as impurity contrast solution.
Precision measures test solution and each 40 μ l of impurity contrast solution, is injected separately into liquid chromatograph, records chromatogram
To 2 times of principal component peak retention time, solvent peak, the gradient peak in test solution chromatogram, the color of test solution are deducted
Such as aobvious impurity peaks in spectrogram, IMP05 must not calculate 0.008% by external standard method with peak area (bimodal peak area adds up to).
Reference substance IMP07, reference substance IMP08
Chromatographic condition:
Chromatographic column: octadecylsilane chemically bonded silica is filler (4.6 × 250mm × 5 μm)
Mobile phase: A phase: methanol B phase: water
Gradient elution is carried out according to the following table.
| t/min | 0 | 20 | 50 | 60 | 70 | 71 | 80 | |
| B% | 100 | 80 | 80 | 40 | 40 | 100 | 100 |
Detection wavelength: 210nm；Flow velocity: 1.2ml/min；
Sampling volume: 40 μ l；Column temperature: 30 DEG C；
Specific test operation:
System suitability: precision weighs l-ornidazole and impurity reference substance IMP07, appropriate IMP08, with methanol and water volume
Dissolved than the methanol aqueous solution for 20:80 and dilute be made every 1ml containing about l-ornidazole 2.5mg, it is molten containing about each 2.5 μ g of impurity
Liquid takes 40 μ l of system suitability solution to inject liquid chromatograph as system suitability solution, such as Fig. 2 E, l-ornidazole with it is adjacent
Separating degree should meet regulation between impurity peaks, each impurity peaks.
Test solution: taking this product appropriate, is dissolved with the methanol aqueous solution that methanol and water volume ratio are 20:80 and dilutes system
At in every lml containing about l-ornidazole (C7H10ClN3O3) 2.5mg solution, as test solution.
Impurity contrast solution: taking IMP07, IMP08 reference substance appropriate respectively, the first for being 20:80 with methanol and water volume ratio
Alcoholic solution, which is dissolved and diluted, is made every 0.2 μ g/ml of 1ml impurity containing IMP08, and the solution of 2.5 μ g of impurity containing IMP07 is as impurity pair
According to solution.
The preparation of test sample mark-on solution: taking l-ornidazole about 25mg, accurately weighed, sets in 10ml measuring bottle, adds reference substance
The solution of solution 3 dissolves and is diluted to scale, shakes up, as test sample mark-on solution.
Precision measures test solution, test sample mark-on solution and each 40 μ l of impurity contrast solution, is injected separately into liquid phase color
Spectrometer (impurity compares HPLC such as Fig. 2 F, sample HPLC such as Fig. 2 G, 100% test sample mark-on HPLC such as Fig. 2 H), records chromatogram,
Solvent peak, the gradient peak in test solution chromatogram, such as aobvious impurity peaks in the chromatogram of test solution are deducted, IMP07 is pressed
External standard method, which must not cross 0.1%, IMP08 with calculated by peak area, must not cross 0.008% by external standard method with calculated by peak area.
Concrete outcome is shown in Table 1.
Testing result in relation to substance in 1 l-ornidazole of table
By table 1 the experimental results showed that, detection method of the l-ornidazole provided by the invention in relation to substance, each compound and control
Product have good matching degree, have good separating degree, and from of the invention the experimental results showed that, the left side that the present invention prepares
In Ornidazole sample, the percentage composition of IMP01, IMP02 impurity is respectively less than 0.1%, remaining each impurity is not detected, and also indicates that this
The reliability of invention sample.
The method of quality control stability of the left nitre azoles of Austria provided by the invention and reproducible, can be objective, comprehensive, accurate
Evaluation l-ornidazole injection quality, quality to control l-ornidazole sodium chloride injection active constituent and guarantee clinical
The safety of medication is of great significance.
Comparative example 1
Experiment condition:
Mobile phase: methanol-water (volume ratio 20:80)；
Chromatographic column: Penomenex Luna C18(2), 4.6 × 250mm, 5 μm；
Flow velocity: 1.2ml/min；Detection wavelength: 318nm/210nm；
Column temperature: 30 DEG C；Sample volume: 40 μ l；
The system suitability HPLC figure of 318nm such as Fig. 3 A, system suitability the HPLC figure such as Fig. 3 B, conclusion (of pressure testing): main peak of 210nm
L-ornidazole and reference substance IMP01 ~ reference substance IMP08 separating degree meet regulation, but impurity reference substance IMP01 and impurity reference substance
IMP08 separating degree is poor, separating degree 0.809(210nm, such as Fig. 3 C), 0.770(318nm, such as Fig. 3 D), can not efficiently separate.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (11)
1. a kind of detection method of the l-ornidazole bulk pharmaceutical chemicals in relation to substance, which uses high performance liquid chromatography, and presses
It is detected according to following testing conditions and operation:
Testing conditions 1 are as follows:
Chromatographic column 1: using octadecylsilane chemically bonded silica as filler；
Mobile phase 1: using methanol as mobile phase 1A, water is mobile phase 1B；Carry out gradient elution；
Detection wavelength 1:310nm to 320nm；It preferably, is 318nm；
1:25 DEG C -40 DEG C of column temperature, it is therefore preferable to, 30 DEG C；
Flow velocity 1:1.0 ml/min -1.5 ml/min, it is preferable that be 1.2ml/min；
The preparation of reference substance solution 1: take respectively reference substance IMP01, reference substance IMP02, reference substance IMP03, reference substance IMP04,
Reference substance IMP06 is appropriate, is dissolved and is diluted with the methanol aqueous solution that volume ratio is 20:80 every 1ml IMP02 containing reference substance is made
The reference substance solution 1 of 0.2 μ g, IMP01 containing reference substance, reference substance IMP03, reference substance IMP04, each 2.5 μ g of reference substance IMP06；
The preparation of test solution 1: the l-ornidazole bulk pharmaceutical chemicals containing about l-ornidazole 50mg are taken, sets in 20ml measuring bottle, adds volume
It is dissolved than the methanol aqueous solution for 20:80 and quantifies dilution and solution of every 1ml containing about l-ornidazole 2.5mg is made, as examination
Product solution 1；
Under testing conditions 1, precision measures test solution 1 and each 40 μ l of reference substance solution 1, is injected separately into liquid chromatograph,
Record chromatogram.
2. detection method according to claim 1, the detection method further include:
Testing conditions 2 are as follows:
Chromatographic column 2: using octadecylsilane chemically bonded silica as filler；
Mobile phase 2: using the volume ratio of methanol and water for (15 ~ 25): the methanol aqueous solution of (75 ~ 85) is mobile phase 2, it is preferable that
The volume ratio of mobile phase 2A and mobile phase 2B is 22:78；Carry out isocratic elution；
Detection wavelength 2:310nm to 320nm；It preferably, is 310nm；
2:25 DEG C -40 DEG C of column temperature, it is therefore preferable to, 30 DEG C；
Flow velocity 2:0.9 ml/min -1.2 ml/min, it is preferable that be 1.0ml/min；
Testing conditions 3 are as follows:
Chromatographic column 3: using octadecylsilane chemically bonded silica as filler；
Mobile phase 3: using methanol as mobile phase 3A, water is mobile phase 3B；Carry out gradient elution；
Detection wavelength 3:200nm to 220nm；It preferably, is 210nm；
3:25 DEG C -40 DEG C of column temperature, it is therefore preferable to, 30 DEG C；
Flow velocity 3:1.0 ml/min -1.5 ml/min, it is preferable that be 1.2ml/min；
The preparation of reference substance solution 2: taking reference substance IMP05 appropriate, is dissolved and is diluted with the methanol aqueous solution that volume ratio is 20:80
The reference substance solution 2 of every 0.2 μ g of 1ml IMP05 containing reference substance is made；
The preparation of test solution 2: the l-ornidazole bulk pharmaceutical chemicals containing about l-ornidazole 50mg are taken, sets in 20ml measuring bottle, adds volume
The test solution 2 that every 1ml is made containing about l-ornidazole 2.5mg in dilution is dissolved and quantified than the methanol aqueous solution for 20:80；
The preparation of reference substance solution 3: it takes reference substance IMP07, reference substance IMP08 reference substance appropriate respectively, is 20:80 with volume ratio
Methanol aqueous solution and dilution the solution of every 0.2 μ g of 1ml IMP08 containing reference substance, pair of 2.5 μ g of IMP07 containing reference substance is made
According to product solution 3；
The preparation of test solution 3: the l-ornidazole bulk pharmaceutical chemicals containing about l-ornidazole 50mg are taken, sets in 20ml measuring bottle, adds volume
It is dissolved than the methanol aqueous solution for 20:80 and quantifies dilution and solution of every 1ml containing about l-ornidazole 2.5mg is made, as examination
Product solution 3；
Under testing conditions 2, precision measures test solution 2 and each 40 μ l of reference substance solution 2, is injected separately into liquid chromatograph,
Record chromatogram；With
Under testing conditions 3, precision measures test solution 3 and each 40 μ l of reference substance solution 3, is injected separately into liquid chromatograph,
Record chromatogram.
3. detection method according to claim 1 or 2, wherein the gradient elution of the mobile phase 1 are as follows:
Alternatively, the gradient elution of the mobile phase 1 are as follows:
4. detection method according to claim 1 or 2, wherein the gradient elution of the mobile phase 3 are as follows:
Alternatively, the gradient elution of the mobile phase 3 are as follows:
5. detection method according to claim 1 or 2, may also include that
The preparation of system suitability solution 1: precision weighs l-ornidazole, reference substance IMP01, reference substance IMP02, reference substance
IMP03, reference substance IMP04, reference substance IMP06 are appropriate, dissolved with the methanol aqueous solution that volume ratio is 20:80 and dilute be made it is every
1ml containing about l-ornidazole 2.5mg, containing about the system suitability solution 1 of each 2.5 μ g of reference substance.
6. detection method according to claim 1 or 2, may also include that
Precision measures 1.0ml test solution 1 into 100ml measuring bottle, and adding volume ratio is that the methanol aqueous solution of 20:80 is settled to quarter
Degree, as contrast solution 1.
7. detection method according to claim 6 may also include that under testing conditions 1, it is molten that precision measures system suitability
Liquid 1, test solution 1, contrast solution 1 and each 40 μ l of reference substance solution 1 are injected separately into liquid chromatograph, record chromatogram.
8. detection method according to claim 2, may also include that
The preparation of system suitability solution 2: take l-ornidazole, reference substance IMP05 appropriate respectively, the first for being 20:80 with volume ratio
Alcohol solution dissolves and dilutes the system adaptation that every 1ml is made containing about l-ornidazole 2.5mg, containing about 2.5 μ g of reference substance IMP05
Property solution 2.
9. detection method according to claim 8, may also include that
Under testing conditions 2, precision measures system suitability solution 2, test solution 2 and each 40 μ l of reference substance solution 2, respectively
Liquid chromatograph is injected, chromatogram is recorded.
10. detection method according to claim 2, may also include that
The preparation of system suitability solution 3: it takes l-ornidazole, reference substance IMP07, reference substance IMP08 appropriate respectively, uses volume ratio
Methanol aqueous solution for 20:80 dissolve and dilute be made every 1ml containing about l-ornidazole 2.5mg, containing about each reference substance IMP07 and right
According to the system suitability solution 3 of 2.5 μ g of product IMP08.
11. detection method according to claim 10, may also include that
Under testing conditions 3, precision measures system suitability solution 3, test solution 3 and each 40 μ l of reference substance solution 3, respectively
Liquid chromatograph is injected, chromatogram is recorded.
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| CN202010072552.9A CN112209882A (en) | 2019-07-09 | 2020-01-21 | Levoornidazole impurity C and preparation method and application thereof |
| CN202010073602.5A CN112213407B (en) | 2019-07-09 | 2020-01-22 | Detection method of levoornidazole related substances |
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| CN102565271A (en) * | 2012-01-10 | 2012-07-11 | 扬子江药业集团南京海陵药业有限公司 | Quality control method for ornidazole |
| CN107917979A (en) * | 2016-10-11 | 2018-04-17 | 陕西合成药业股份有限公司 | A kind of HPLC methods for separating analysis l-ornidazole isomers |
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