CN106872625B - A kind of method of separation determination Itraconazole optical isomer - Google Patents
A kind of method of separation determination Itraconazole optical isomer Download PDFInfo
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- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 title claims abstract description 102
- 229960004130 itraconazole Drugs 0.000 title claims abstract description 102
- 230000003287 optical effect Effects 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 14
- 238000000926 separation method Methods 0.000 title claims abstract description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000012488 sample solution Substances 0.000 claims abstract description 16
- 229940043237 diethanolamine Drugs 0.000 claims abstract description 15
- 239000007788 liquid Substances 0.000 claims abstract description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000000945 filler Substances 0.000 claims abstract description 13
- 150000004676 glycans Chemical class 0.000 claims abstract description 13
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 13
- 239000005017 polysaccharide Substances 0.000 claims abstract description 13
- 239000000741 silica gel Substances 0.000 claims abstract description 13
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 13
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229940087646 methanolamine Drugs 0.000 claims abstract description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 4
- 238000002347 injection Methods 0.000 claims abstract description 3
- 239000007924 injection Substances 0.000 claims abstract description 3
- 239000012046 mixed solvent Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- -1 methyl tertbutyl Chemical group 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- 239000000523 sample Substances 0.000 claims 1
- 238000001514 detection method Methods 0.000 abstract description 13
- 239000002994 raw material Substances 0.000 abstract description 10
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 238000004811 liquid chromatography Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 230000014759 maintenance of location Effects 0.000 description 40
- 239000012071 phase Substances 0.000 description 14
- 239000007791 liquid phase Substances 0.000 description 10
- 238000011017 operating method Methods 0.000 description 10
- 238000005070 sampling Methods 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 5
- 150000003851 azoles Chemical class 0.000 description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Classifications
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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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
-
- 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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- 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)
- Spectroscopy & Molecular Physics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention discloses a kind of method of separation determination Itraconazole optical isomer, the method is high performance liquid chromatography, comprising the following steps: Itraconazole is dissolved in organic solvent, obtains sample solution；Sample solution injection is taken to use using polysaccharide derivatives bonded silica gel as the chiral column of filler, and using the mixed solvent of methyl tertiary butyl ether(MTBE), methanol and diethanol amine as in the high performance liquid chromatograph of mobile phase；Record chromatogram is simultaneously analyzed.4 optical isomers of Itraconazole can be kept completely separate, separating degree is 1.5 or more by the high efficiency liquid chromatography for separating and determining Itraconazole optical isomer that the present invention uses under chromatographic condition；And quantitative detection can be reached, guarantee the content for the Itraconazole optical isomer produced in safe range and effective range, realizes and the raw material of Itraconazole optical isomer and the quality of preparation are controlled.
Description
Technical field
The present invention relates to a kind of optical isomer measuring method, especially a kind of separation determination Itraconazole optical isomer
Method.
Background technique
Itraconazole is a kind of triazole type broad-spectrum antifungal drug, has antibacterial action to deep fungal and superficial fungi,
Clinic is mainly used in infection caused by deep fungal.This general oral or intravenous of drug, the effect of Itraconazole
Mechanism is as other azole antifungals, the conjunction for the ergosterol that it inhibits cell membrane cytochrome p 450 oxidizing ferment to mediate
At.Its English name is Itraconazole, Chinese chemical name 4- [4- [4- [4- [[cis-2- (2,4- dichlorophenyl) -2-
(1H-1,2,4- triazol-1-yl methyl) -1,3- dioxolanes -4- base] methoxyl group] phenyl] piperazine -1- base] phenyl] -2-
[(1RS) -1- methyl-propyl] -1,2,4- triazole -3- ketone.Itraconazole has 4 optical isomers, respectively Itraconazole 2S,
4R, 2 ' R (isomers A), Itraconazole 2S, 4R, 2 ' S (isomer C), the Itraconazole R of 2R, 4S, 2 ' (isomers B) and Yi Qukang
The azoles S of 2R, 4S, 2 ' (isomers D), molecular formula C35H38Cl2N8O4, molecular weight 705.63, chemical structural formula are as follows:
Since the internal pharmacological activity and pharmacokinetics of optical isomer each in chiral drug usually have biggish difference,
Existing analytical technology is difficult to isolate the optical isomer of Itraconazole, it is also difficult to carry out content monitoring to its optical isomer.
Therefore, the measuring method of Itraconazole optical isomer is very important the quality control of final products.
Summary of the invention
The technology that the purpose of the present invention is be difficult to separate and measure for the optical isomer of Itraconazole in the prior art
Problem provides a kind of method for being precisely separating measurement Itraconazole optical isomer, realizing the control of its quality.
To achieve the above object, the technical solution adopted by the present invention is that:
A kind of method of separation determination Itraconazole optical isomer, the method is high performance liquid chromatography, including with
Lower step: Itraconazole is dissolved in organic solvent, sample solution is obtained；Sample solution injection is taken to use with polysaccharide derivatives
Bonded silica gel is the chiral column of filler, and using the mixed solvent of methyl tertiary butyl ether(MTBE), methanol and diethanol amine as the height of mobile phase
In effect liquid phase chromatogram instrument, records chromatogram and analyzed.
The organic solvent is methylene chloride.
Itraconazole concentration is 0.15mg~3.0mg/ml in gained sample solution.
The volume ratio of methyl tertiary butyl ether(MTBE), methanol and diethanol amine is 75~95:25~5:0~0.1 in the mobile phase.
Further, the volume ratio of methyl tertiary butyl ether(MTBE), methanol and diethanol amine is 92:8:0.1 in the mobile phase.
The flow rate of mobile phase is 0.6~1.8ml/min.The column temperature of the chromatographic column is 30~40 DEG C.
It is detected using UV detector, Detection wavelength is 220nm~230nm.
The utility model has the advantages that the high efficiency liquid chromatography for separating and determining Itraconazole optical isomer that the present invention uses, in chromatography
Under the conditions of, 4 optical isomers of Itraconazole can be kept completely separate, separating degree is 1.5 or more；And it can reach quantitative
Detection；Guarantee that the content for the Itraconazole optical isomer produced in safe range and effective range, is realized to Yi Qu
The quality control of the raw material and preparation of health azoles optical isomer.
Detailed description of the invention
Fig. 1 is blank solvent chromatic graph spectrum；
Fig. 2 Itraconazole 2S, 4R, 2 ' R (isomers A) raw material chromatography space figure；
Fig. 3 is Itraconazole 2S, 4R, 2 ' S (isomer C) raw material chromatography space figure；
Fig. 4 is Itraconazole 2R, 4S, 2 ' R (isomers B) raw material chromatography space figure；
Fig. 5 is Itraconazole 2R, 4S, 2 ' S (isomers D) raw material chromatography space figure；
Fig. 6 is Itraconazole test solution chromatogram；
Fig. 7 is the high-efficient liquid phase chromatogram of embodiment 2；
Fig. 8 is the high-efficient liquid phase chromatogram of embodiment 3；
Fig. 9 is the high-efficient liquid phase chromatogram of embodiment 4；
Figure 10 is the high-efficient liquid phase chromatogram of embodiment 5；
Figure 11 is the high-efficient liquid phase chromatogram of embodiment 6；
Figure 12 is the high-efficient liquid phase chromatogram of embodiment 7；
Figure 13 is the high-efficient liquid phase chromatogram of embodiment 8；
Figure 14 is the high-efficient liquid phase chromatogram of embodiment 9；
Figure 15 is the high-efficient liquid phase chromatogram of embodiment 10.
Specific embodiment
The present invention is explained in detail combined with specific embodiments below.
Following embodiments are carried out according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015).
Instrument: Thermo Ultimate3000 type high performance liquid chromatograph；
Thermo Ultimate3000 UV detector.
Embodiment 1
Chromatographic condition
Chromatographic column: polysaccharide derivatives bonded silica gel (CHIRALPAK IF-3,4.6 × 250mm, 3um) is filler
Mobile phase: methyl tertiary butyl ether(MTBE)-methanol-diethanol amine (80:20:0.1)
Column temperature: 35 DEG C
Flow velocity: 0.7ml/min
Sampling volume: 10ul
Detection wavelength: 225nm
Operating procedure: taking 4 optical isomers of Itraconazole respectively, accurately weighed, adds methylene chloride and dissolves and quantify
The solution in every 1ml containing 0.8mg is made in dilution, as system suitability solution；It takes Itraconazole appropriate, adds methylene chloride
It dissolves and quantifies the solution for diluting and being made in every 1ml containing 0.8mg, as sample solution.System suitability solution is measured respectively
10ul injects liquid chromatograph, records chromatogram, as a result sees Fig. 2-5.It measures test solution 10ul and injects liquid chromatograph, note
Chromatogram is recorded, the separating degree between each chromatographic peak should be greater than 1.5.As a result see Fig. 6.
Fig. 1 is blank solvent map.Fig. 2 is Itraconazole 2S, 4R, 2 ' R (isomers A) raw material chromatography space figure；Fig. 3 is Yi Qu
Health azoles 2S, 4R, 2 ' S (isomer C) raw material chromatography space figure；Fig. 4 is Itraconazole 2R, 4S, 2 ' R (isomers B) raw material chromatography space figure；Figure
5 be the raw material chromatography space figure of Itraconazole 2R, 4S, 2 ' S (isomers D).
The chromatographic peak of retention time 15.742 is Itraconazole 2S, 4R, 2 ' R (isomers A), retention time in Fig. 6
17.017 chromatographic peak is Itraconazole 2S, 4R, 2 ' S (isomer C), and the chromatographic peak of retention time 20.133 is Itraconazole
The R of 2R, 4S, 2 ' (isomers B), the chromatographic peak of retention time 21.767 are Itraconazole 2R, 4S, 2 ' S (isomers D).Thus may be used
See, 4 optical isomers of Itraconazole can be kept completely separate under the above conditions, meet the requirement of Chinese Pharmacopoeia.
Embodiment 2
Chromatographic condition
Chromatographic column: polysaccharide derivatives bonded silica gel (CHIRALPAK IF-3,4.6 × 250mm, 3um) is filler
Mobile phase: methyl tertiary butyl ether(MTBE)-methanol-diethanol amine (75:25:0.1)
Column temperature: 30 DEG C
Flow velocity: 0.6ml/min
Sampling volume: 10ul
Detection wavelength: 220nm
Operating procedure: taking Itraconazole appropriate, and adding methylene chloride to dissolve and quantify to dilute is made in every 1ml containing 0.8mg's
Sample solution measures 10ul and injects liquid chromatograph, records chromatogram, and the separating degree between each chromatographic peak should be greater than 1.5.As a result
See Fig. 7.
The chromatographic peak of retention time 13.225 is Itraconazole 2S, 4R, 2 ' R (isomers A), retention time in Fig. 7
14.117 chromatographic peak is Itraconazole 2S, 4R, 2 ' S (isomer C), and the chromatographic peak of retention time 16.100 is Itraconazole
The chromatographic peak of the R of 2R, 4S, 2 ' (isomers B), retention time 17.233 are Itraconazole 2R, 4S, 2 ' S (isomers D), above-mentioned
Under the conditions of 4 optical isomers of Itraconazole can be kept completely separate, meet the requirement of Chinese Pharmacopoeia.
Embodiment 3
Chromatographic condition
Chromatographic column: polysaccharide derivatives bonded silica gel (CHIRALPAK IF-3,4.6 × 250mm, 3um) is filler
Mobile phase: methyl tertiary butyl ether(MTBE)-methanol-diethanol amine (85:15:0.1)
Column temperature: 40 DEG C
Flow velocity: 0.7ml/min
Sampling volume: 10ul
Detection wavelength: 230nm
Operating procedure: taking Itraconazole appropriate, and adding methylene chloride to dissolve and quantify to dilute is made in every 1ml containing 0.8mg's
Sample solution measures 10ul and injects liquid chromatograph, records chromatogram, and the separating degree between each chromatographic peak should be greater than 1.5.As a result
See Fig. 8.
The chromatographic peak of retention time 15.792 is Itraconazole 2S, 4R, 2 ' R (isomers A), retention time in Fig. 8
17.067 chromatographic peak is Itraconazole 2S, 4R, 2 ' S (isomer C), and the chromatographic peak of retention time 20.100 is Itraconazole
The chromatographic peak of the R of 2R, 4S, 2 ' (isomers B), retention time 21.717 are Itraconazole 2R, 4S, 2 ' S (isomers D), above-mentioned
Under the conditions of 4 optical isomers of Itraconazole can be kept completely separate, meet the requirement of Chinese Pharmacopoeia.
Embodiment 4
Chromatographic condition
Chromatographic column: polysaccharide derivatives bonded silica gel (CHIRALPAK IF-3,4.6 × 250mm, 3um) is filler
Mobile phase: methyl tertiary butyl ether(MTBE)-methanol-diethanol amine (92:8:0.1)
Column temperature: 35 DEG C
Flow velocity: 1.5ml/min
Sampling volume: 10ul
Detection wavelength: 225nm
Operating procedure: taking Itraconazole appropriate, and adding methylene chloride to dissolve and quantify to dilute is made in every 1ml containing 3.0mg's
Sample solution measures 10ul and injects liquid chromatograph, records chromatogram, and the separating degree between each chromatographic peak should be greater than 1.5.As a result
See Fig. 9.
The chromatographic peak of retention time 16.367 is Itraconazole 2S, 4R, 2 ' R (isomers A), retention time in Fig. 9
18.225 chromatographic peak is Itraconazole 2S, 4R, 2 ' S (isomer C), and the chromatographic peak of retention time 26.000 is Itraconazole
The chromatographic peak of the R of 2R, 4S, 2 ' (isomers B), retention time 28.333 are Itraconazole 2R, 4S, 2 ' S (isomers D), above-mentioned
Under the conditions of 4 optical isomers of Itraconazole can be kept completely separate, meet the requirement of Chinese Pharmacopoeia.
Embodiment 5
Chromatographic condition
Chromatographic column: polysaccharide derivatives bonded silica gel (CHIRALPAK IF-3,4.6 × 250mm, 3um) is filler
Mobile phase: methyl tertiary butyl ether(MTBE)-methanol-diethanol amine (90:10:0.1)
Column temperature: 35 DEG C
Flow velocity: 1.5ml/min
Sampling volume: 10ul
Detection wavelength: 225nm
Operating procedure: taking Itraconazole appropriate, and adding methylene chloride to dissolve and quantify to dilute is made in every 1ml containing 3.0mg's
Sample solution measures 10ul and injects liquid chromatograph, records chromatogram, and the separating degree between each chromatographic peak should be greater than 1.5.As a result
See Figure 10.
The chromatographic peak of retention time 12.483 is Itraconazole 2S, 4R, 2 ' R (isomers A), retention time in Figure 10
13.742 chromatographic peak is Itraconazole 2S, 4R, 2 ' S (isomer C), and the chromatographic peak of retention time 18.367 is Itraconazole
The chromatographic peak of the R of 2R, 4S, 2 ' (isomers B), retention time 19.975 are Itraconazole 2R, 4S, 2 ' S (isomers D), above-mentioned
Under the conditions of 4 optical isomers of Itraconazole can be kept completely separate, meet the requirement of Chinese Pharmacopoeia.
Embodiment 6
Chromatographic condition
Chromatographic column: polysaccharide derivatives bonded silica gel (CHIRALPAK IF-3,4.6 × 250mm, 3um) is filler
Mobile phase: methyl tertiary butyl ether(MTBE)-methanol-diethanol amine (91:9:0.1)
Column temperature: 35 DEG C
Flow velocity: 1.5ml/min
Sampling volume: 10ul
Detection wavelength: 225nm
Operating procedure: taking Itraconazole appropriate, and adding methylene chloride to dissolve and quantify to dilute is made in every 1ml containing 3.0mg's
Sample solution measures 10ul and injects liquid chromatograph, records chromatogram, and the separating degree between each chromatographic peak should be greater than 1.5.As a result
See Figure 11.
The chromatographic peak of retention time 13.933 is Itraconazole 2S, 4R, 2 ' R (isomers A), retention time in Figure 11
15.358 chromatographic peak is Itraconazole 2S, 4R, 2 ' S (isomer C), and the chromatographic peak of retention time 20.833 is Itraconazole
The chromatographic peak of the R of 2R, 4S, 2 ' (isomers B), retention time 22.658 are Itraconazole 2R, 4S, 2 ' S (isomers D), above-mentioned
Under the conditions of 4 optical isomers of Itraconazole can be kept completely separate, meet the requirement of Chinese Pharmacopoeia.
Embodiment 7
Chromatographic condition
Chromatographic column: polysaccharide derivatives bonded silica gel (CHIRALPAK IF-3,4.6 × 250mm, 3um) is filler
Mobile phase: methyl tertiary butyl ether(MTBE)-methanol-diethanol amine (93:7:0.1)
Column temperature: 35 DEG C
Flow velocity: 1.5ml/min
Sampling volume: 10ul
Detection wavelength: 225nm
Operating procedure: taking Itraconazole appropriate, and adding methylene chloride to dissolve and quantify to dilute is made in every 1ml containing 3.0mg's
Sample solution measures 10ul and injects liquid chromatograph, records chromatogram, and the separating degree between each chromatographic peak should be greater than 1.5.As a result
See Figure 12.
The chromatographic peak of retention time 20.025 is Itraconazole 2S, 4R, 2 ' R (isomers A), retention time in Figure 12
22.392 chromatographic peak is Itraconazole 2S, 4R, 2 ' S (isomer C), and the chromatographic peak of retention time 33.200 is Itraconazole
The chromatographic peak of the R of 2R, 4S, 2 ' (isomers B), retention time 36.150 are Itraconazole 2R, 4S, 2 ' S (isomers D), above-mentioned
Under the conditions of 4 optical isomers of Itraconazole can be kept completely separate, meet the requirement of Chinese Pharmacopoeia.
Embodiment 8
Chromatographic condition
Chromatographic column: polysaccharide derivatives bonded silica gel (CHIRALPAK IF-3,4.6 × 250mm, 3um) is filler
Mobile phase: methyl tertiary butyl ether(MTBE)-methanol-diethanol amine (94:6:0.1)
Column temperature: 35 DEG C
Flow velocity: 1.5ml/min
Sampling volume: 10ul
Detection wavelength: 225nm
Operating procedure: taking Itraconazole appropriate, and adding methylene chloride to dissolve and quantify to dilute is made in every 1ml containing 3.0mg's
Sample solution measures 10ul and injects liquid chromatograph, records chromatogram, and the separating degree between each chromatographic peak should be greater than 1.5.As a result
See Figure 13.
The chromatographic peak of retention time 23.800 is Itraconazole 2S, 4R, 2 ' R (isomers A), retention time in Figure 13
26.625 chromatographic peak is Itraconazole 2S, 4R, 2 ' S (isomer C), and the chromatographic peak of retention time 40.733 is Itraconazole
The chromatographic peak of the R of 2R, 4S, 2 ' (isomers B), retention time 44.183 are Itraconazole 2R, 4S, 2 ' S (isomers D), above-mentioned
Under the conditions of 4 optical isomers of Itraconazole can be kept completely separate, meet the requirement of Chinese Pharmacopoeia.
Embodiment 9
Chromatographic condition
Chromatographic column: polysaccharide derivatives bonded silica gel (CHIRALPAK IF-3,4.6 × 250mm, 3um) is filler
Mobile phase: methyl tertiary butyl ether(MTBE)-methanol-diethanol amine (92:8:0.1)
Column temperature: 35 DEG C
Flow velocity: 1.8ml/min
Sampling volume: 10ul
Detection wavelength: 225nm
Operating procedure: taking Itraconazole appropriate, and adding methylene chloride to dissolve and quantify to dilute is made in every 1ml containing 3.0mg's
Sample solution measures 10ul and injects liquid chromatograph, records chromatogram, and the separating degree between each chromatographic peak should be greater than 1.5.As a result
See Figure 14.
The chromatographic peak of retention time 13.308 is Itraconazole 2S, 4R, 2 ' R (isomers A), retention time in Figure 14
14.800 chromatographic peak is Itraconazole 2S, 4R, 2 ' S (isomer C), and the chromatographic peak of retention time 21.000 is Itraconazole
The chromatographic peak of the R of 2R, 4S, 2 ' (isomers B), retention time 22.875 are Itraconazole 2R, 4S, 2 ' S (isomers D), above-mentioned
Under the conditions of 4 optical isomers of Itraconazole can be kept completely separate, meet the requirement of Chinese Pharmacopoeia.
Embodiment 10
Chromatographic condition
Chromatographic column: polysaccharide derivatives bonded silica gel (CHIRALPAK IF-3,4.6 × 250mm, 3um) is filler
Mobile phase: methyl tertiary butyl ether(MTBE)-methanol (92:8)
Column temperature: 35 DEG C
Flow velocity: 1.5ml/min
Sampling volume: 10ul
Detection wavelength: 225nm
Operating procedure: taking Itraconazole appropriate, and adding methylene chloride to dissolve and quantify to dilute is made in every 1ml containing 3.0mg's
Sample solution measures 10ul and injects liquid chromatograph, records chromatogram, and the separating degree between each chromatographic peak should be greater than 1.5.As a result
See Figure 15.
The chromatographic peak of retention time 17.482 is Itraconazole 2S, 4R, 2 ' R (isomers A), retention time in Figure 15
28.597 chromatographic peak is Itraconazole 2S, 4R, 2 ' S (isomer C), and the chromatographic peak of retention time 19.703 is Itraconazole
The chromatographic peak of the R of 2R, 4S, 2 ' (isomers B), retention time 31.413 are Itraconazole 2R, 4S, 2 ' S (isomers D), above-mentioned
Under the conditions of 4 optical isomers of Itraconazole can be kept completely separate, meet the requirement of Chinese Pharmacopoeia.
Claims (1)
1. a kind of method of separation determination Itraconazole optical isomer, which is characterized in that the method is high performance liquid chromatography
Method, comprising the following steps: take Itraconazole, adding methylene chloride, it is molten to dissolve and quantify the sample that dilution is made in every 1ml containing 3.0mg
Liquid；The injection of 10ul sample solution is taken to use using polysaccharide derivatives bonded silica gel as the chiral column of filler, and with methyl tertbutyl
The mixed solvent of ether, methanol and diethanol amine is in the high performance liquid chromatograph of mobile phase；Record chromatogram is simultaneously analyzed；
The volume ratio of methyl tertiary butyl ether(MTBE), methanol and diethanol amine is 92:8:0.1 in the mobile phase；
The flow rate of mobile phase is 1.8ml/min；
The column temperature of the chromatographic column is 35 DEG C；
It is detected using UV detector, wavelength 225nm；
The Itraconazole optical isomer includes Itraconazole 2S, 4R, 2 ' R, Itraconazole 2S, 4R, 2 ' S, Itraconazole 2R,
4S, 2 ' R and Itraconazole 2R, 4S, 2 ' S.
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| US9095589B2 (en) * | 2007-04-05 | 2015-08-04 | Johns Hopkins University | Chirally pure isomers of itraconazole for use as angiogenesis inhibitors |
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| CN104788437A (en) * | 2015-04-14 | 2015-07-22 | 扬州艾迪生物科技有限公司 | Method for chiral resolution of itraconazole |
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