CN106442807A - Method for detecting posaconazole chiral isomers through high performance liquid chromatography - Google Patents
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Abstract
The invention discloses a method for detecting posaconazole chiral isomers through high performance liquid chromatography. The method has the advantages that chromatographic columns filled with silica-gel-surface covalent bonding polysaccharide derivatives are adopted, double moving phases, namely a moving phase A and a moving phase B, are used for gradient elution, the moving phase A is a binary moving phase, and the moving phase B is a ternary moving phase, so that separation effect is good, and the method is simple, convenient and easy to operate; test results prove that posaconazole and the chiral isomers thereof can be well separated under the chromatographic conditions, and quality of bulk drugs of the posaconazole is controlled better.
Description
Technical field
The invention belongs to pharmaceutical analysiss field, and in particular to a kind of with high performance liquid chromatography detection posaconazole chiral photo-isomerisation
The method of body.
Background technology
Posaconazole (posaconazole) is wide by one kind of research and development company of schering-Plough company of U.S. research and development
Spectrum antifungal drug in triazole class.For the fungal infection caused by refractory disease or other drugs drug resistance.This product compares comparison medicine
Thing fluconazol and itraconazole, can more effectively prevent aggressive aspergillin infection and can reduce the disease of invasive infections with fungi correlation
Dead rate.
Posaconazole contains 4 chiral centres, in addition to posaconazole, also 15 chiral isomers.Presently used medicine
Thing mostly is less than the molecular organic molecule of 50 originals, greatly also has chirality, and their pharmacological action is to pass through
Strict chirality is mated and molecular recognition realization between internal macromolecular.The isomer of the chemicalses containing chiral factor exists
There is significant difference in the pharmacologically active, metabolic process and toxicity in human body.Drug molecule must be with the receptor (thing for reacting
Matter) molecular geometry coupling, can just play due drug effect, as the right hand can only carry right hand set the same.Therefore, often two kinds
It is effective to only have one kind in isomer, and another kind is invalid or even harmful.For example, levocetirizine is to account for antiallergic agent maximum city
The optically active form of the cetirizine of market share, has higher drug effect and higher safety than cetirizine；Receptor blocking agent
The external activity of two enantiomers of Propranolol differs 98 times；L-DOPA is the Parkinsonian medicine for the treatment of, d-isomer
Can build up in vivo will not be by internal enzyme metabolism, consequently, it is possible to working the mischief to the health of human body；And for example the two of Thalidomide
(S)-enantiomer is a kind of strength teratogen with the effect of alleviation gestation reaction to only have (R)-enantiomer in individual enantiomer,
Gestation was taken in the 1st～2 month can cause fetal anomaly.
According to food and medicine Surveillance Authority of the U.S. (FDA) to the technical requirements with chiral centre medicine, need to medicine
The chiral isomer of thing is controlled.Posaconazole has 15 chiral isomers, but does not moor sand with separating and controlling at present
The document report of health azoles chiral isomer.
Content of the invention
Posaconazole has 15 chiral isomers, but may generate in building-up process mainly have 9, its structure is such as
Under：
For ensureing the safety of clinical application, strictly control the limit of invalid or chiral isomer with side effect, with
When make up prior art lack separation detection posaconazole chiral photo-isomerisation body technique deficiency, present inventors have developed one
The method with high performance liquid chromatography separation detection posaconazole chiral isomer is planted, the chiral isomer of posaconazole is carried out
Analysis, so as to ensure Drug safety, quality controllability.
In the course of the study, it was found by the inventors of the present invention that because the chiral isomer of posaconazole and posaconazole
Physicochemical property is similar to, and also is difficult to although with chiral column and conventional mobile phase each composition is preferable under same chromatographic condition
Realize baseline separation.When two impurity peak complete-superposings, the detection of total impurities content can not be affected, but if two impurity
Partial intersection cannot realize baseline separation, then testing result is inaccurate.
Through many experiments and research, the present inventor finally obtains the husky health of one kind high performance liquid chromatography detection pool
The method of azoles chiral isomer, can realize efficiently separating for posaconazole and its 9 chiral isomers, additionally it is possible to Accurate Determining
The content of posaconazole and its limit of chiral isomer, specificity is strong, sensitivity height；The operational approach is simple, with easy,
Quick advantage.Methods described comprises the steps：
1) configuration posaconazole chiral isomer mixed reference substance solution and need testing solution；
2) with high performance liquid chromatography detection need testing solution and chiral isomer mixed reference substance solution, chromatographic condition：Make
It is the chromatographic column of filler in order to Silica Surface covalent bonding polysaccharide derivates；Using dual-flow phase, i.e. mobile phase A and Mobile phase B
Carry out gradient elution, the mobile phase A and B are the mixed solution of C2～C4 halogenated alkane and C1～C4 alcohols, the halo
Referring to, the element for chlorine, bromine and iodine being selected from by least one replaces；
3) according to the chromatogram of need testing solution and the chromatogram of chiral isomer mixed reference substance solution, determine test sample
The limit of chiral isomer in solution.
The detection method of the present invention adopts dual-flow phase, and wherein mobile phase A and B is all at least binary mobile phase, used as excellent
Choosing, it is ternary mobile phase that mobile phase A is binary mobile phase, Mobile phase B.Mobile phase A and B be C2～C4 halogenated alkane and C1～
The mixed solution of C4 alcohols, the alkane includes side chain and linear paraffin, can be a kind of alkane can also be multiple alkane
Mixing, the alcohol can be a kind of alcohol can also be multiple alcohol mixing.The inventive method is adopted with Silica Surface covalent bonding
Polysaccharide derivates are the chromatographic column of filler, and its separating effect meets the requirement of analysis detection, and overcoming prior art cannot be same
One chromatographic condition similarly hereinafter when separate analysis posaconazole 9 chiral isomers a difficult problem.
Preferably, the present invention is used for mobile phase A and C2～C4 halogenated alkane of B is selected from dichloromethane, chloroform
In a kind of or 2 kinds of mixing, preferably dichloromethane.
Preferably, the present invention is used for C1～C4 alcohols of mobile phase A and B selected from methanol, ethanol, propanol and isopropanol
In one or more of combination.It is of the present invention multiple including two or more in the case of no specified otherwise,
The combination of preferably ethanol or ethanol and isopropanol.
In some embodiments of the invention, the mobile phase A is dichloromethane-isopropanol mixed liquor, the Mobile phase B
For isopropanol-dichloromethane-ethanol mixed liquor.
Preferably, the volume ratio of dichloromethane-isopropanol is (2-6) in the mobile phase A：(8-4), the mobile phase
In B, the volume ratio of isopropanol-dichloromethane-ethanol is (5-7)：(4-0.5)：(1-2.5).
Preferably, the volume ratio of dichloromethane-isopropanol is (48～52) in the mobile phase A：(48～52), as
More excellent selection, in mobile phase A, the volume ratio of dichloromethane-isopropanol is 1：1.
Preferably, described Mobile phase B is (55-65) for volume ratio：(40-25)：(5-10) isopropanol-dichloromethane
Alkane-alcohol mixeding liquid, the preferably Mobile phase B are 6 for volume ratio：3：1 isopropanol-dichloromethane-ethanol mixed liquor.
In some embodiments of the invention, step 2) condition of the gradient elution is：
0-8min, the volume ratio shared by mobile phase A phase is：(12%～8%) → 0%, the volume ratio shared by Mobile phase B phase
For：(88%～92%) → 100%；
8-50min, the volume ratio shared by mobile phase A phase is：0%, the volume ratio shared by Mobile phase B phase is：100%；
50-55min, the volume ratio shared by mobile phase A phase is：0% → 100%, the volume ratio shared by Mobile phase B phase is：
100% → 0%；
55-80min, the volume ratio shared by mobile phase A phase is：100%, the volume ratio shared by Mobile phase B phase is：0%.
Preferably, 10～20 μ L of sampling volume detected by high efficiency chromatography liquid phase systems, flow rate of mobile phase is 0.9～
1.1ml/min, the column temperature of chromatographic column is 31～35 DEG C, and theoretical cam curve is calculated by posaconazole chromatographic peak and is not less than 1000.
Preferably, it is 260nm that the detector of high efficiency chromatography liquid phase systems is UV-detector, Detection wavelength.
Preferably, above-mentioned steps 1) single isomery of the chiral isomer mixed reference substance solution containing 2ug described in per 1ml
Body, need testing solution posaconazole containing 2mg sample described in per 1ml.
According to the high-efficient liquid phase chromatogram condition that the present invention is provided, those skilled in the art can select suitable computational methods
The limit of posaconazole content and its chiral isomer is calculated, the computational methods include but is not limited to internal standard method, external standard method.
Some embodiments of the present invention determine the limit of chiral isomer using impurity reference substance external standard method, and concrete grammar is such as
Under：
1) mobile phase is prepared：Mobile phase A and Mobile phase B are prepared respectively, with volume ratio 1:1 dichloromethane-isopropanol is mixed
Compound is mobile phase A, with volume ratio 6:3:1 isopropanol-dichloromethane-ethanol mixture is Mobile phase B；
2) preparation of single isomer control product storing solution：9 chiral isomers of aforementioned posaconazole are taken respectively, accurate
Weighed, plus acetonitrile-isopropanol (75：:25) dissolve, make reference substance storing solution of every 1ml containing about 0.10mg.
3) preparation of isomer mixed reference substance solution：Take step 2) each 0.2ml of single isomer control product storing solution,
Put with isopropanol-dichloromethane-ethanol (6 in 10ml volumetric flask:3:1) dissolve, make reference substance deposit of every 1ml containing about 2ug
Liquid.
4) preparation of need testing solution：Posaconazole is taken, accurately weighed, plus isopropanol-dichloromethane-ethanol (6:3:1)
Dissolving, makes sample solution of every 1ml containing about 2mg.
5) step 4 is taken respectively) need testing solution and step 3) 10 μ L of isomer mixed reference substance solution injection separates
In detecting system, the detection of posaconazole isomer is completed.
Wherein the high-efficient liquid phase chromatogram condition is as follows：
Using the chromatographic column with Silica Surface covalent bonding polysaccharide derivates as filler；Gradient is carried out with mobile phase A, B to wash
De-.Carried out detecting 10 μ L of sampling volume with high efficiency chromatography liquid phase systems；0.9～1.1ml/min of flow velocity；31～35 DEG C of column temperature；Inspection
Survey wavelength is 260nm.
The Gradient program is as follows：
6) according to step 5) chromatographic results that detect, chiral isomer total impurities being calculated using the computational methods of external standard method contains
Amount.
The chromatographic condition that the experiment results proved present invention is selected can preferably separate main constituent and its isomer, method simplicity
Easy, can realize the total miscellaneous limit of 9 isomers is detected under same chromatographic condition, preferably monitor posaconazole crude drug
Quality, while also provide reference for the quality research of preparation.
Description of the drawings
Fig. 1 is the high-efficient liquid phase chromatogram of separating degree solution in the embodiment of the present invention 1.
Fig. 2 is the high-efficient liquid phase chromatogram of separating degree solution in the embodiment of the present invention 2.
Fig. 3 is the high-efficient liquid phase chromatogram of separating degree solution in comparative example of the present invention 3.
Fig. 4 is the high-efficient liquid phase chromatogram of separating degree solution in the embodiment of the present invention 4.
Fig. 5 is the high-efficient liquid phase chromatogram of separating degree solution in the embodiment of the present invention 5.
Fig. 6 is the high-efficient liquid phase chromatogram of sample solution in the embodiment of the present invention 5.
Specific embodiment
Hereinafter with reference to accompanying drawing, the preferred embodiments of the present invention are described in detail.Unreceipted tool in preferred embodiment
The experimental technique of concrete conditions in the establishment of a specific crime, generally according to normal condition, illustrated embodiment be in order to preferably say to present disclosure
Bright, but be not that present disclosure is only limitted to illustrated embodiment.So this area those having ordinary skill in the art is according in foregoing invention
Holding carries out nonessential modifications and adaptations to embodiment, still falls within protection scope of the present invention.
The structure of posaconazole chiral isomer of following examples detection is：
Embodiment 1
Instrument and chromatographic condition:
Shimadzu LC-10AD type high performance liquid chromatograph；Chromatographic column is IC chromatographic column (250mm × 4.6mm × 5 μm)；Chromatograph
33 DEG C of post column temperature；With ethanol mobile phase；Carried out detecting 10 μ L of sampling volume with high efficiency chromatography liquid phase systems；Flow velocity 1.0ml/min；
Using UV-detector；Detection wavelength is 260nm.
Experimental procedure
The preparation of single isomer control product storing solution：9 chiral isomers of posaconazole are taken respectively, accurately weighed,
Plus acetonitrile-isopropanol (75：25) dissolve, make reference substance storing solution of every 1ml containing about 0.10mg.
The preparation of isomer mixed reference substance solution：Take step 1) each 0.2ml of single isomer control product storing solution, puts
Dissolved with ethanol in 10ml volumetric flask, make reference substance storing solution of every 1ml containing about 2ug.
The preparation of need testing solution：Posaconazole is taken, accurately weighed, plus ethanol dissolving, make sample of every 1ml containing about 2mg
Product solution.
Separating degree solution：Take posaconazole, accurately weighed, plus isomer mixed reference substance solution, make every 1ml containing about
The separating degree solution of 2mg posaconazole.
Precision measures blank solvent, need testing solution, isomer mixed reference substance solution, each 10 μ of separating degree solution respectively
L, sample introduction is determined, and is recorded chromatogram, is seen Fig. 1.
Result of the test shows, solvent peak is noiseless to posaconazole and its isomer, the peak of separating degree solution isomer it
Between can not whole baseline separation.
Embodiment 2
Instrument and chromatographic condition:
Shimadzu LC-10AD type high performance liquid chromatograph；Chromatographic column is IC chromatographic column (250mm × 4.6mm × 5 μm)；Chromatograph
33 DEG C of post column temperature；With dichloromethane-isopropanol (1:4) it is mobile phase；Detected with high efficiency chromatography liquid phase systems, sampling volume
10μL；Flow velocity 1.0ml/min；Using UV-detector；Detection wavelength is 260nm.
Remaining operating procedure and condition are all with embodiment 1.
Result of the test shows, sees Fig. 2, and solvent peak is noiseless to posaconazole and its isomer, separating degree solution isomer
Peak between can not whole baseline separation.
Embodiment 3
Instrument and chromatographic condition:
Shimadzu LC-10AD type high performance liquid chromatograph；Chromatographic column is IC chromatographic column (250mm × 4.6mm × 5 μm)；Chromatograph
33 DEG C of post column temperature；With dichloromethane-isopropanol (1:1) it is mobile phase A, with ethanol-isopropanol (1:3) it is Mobile phase B；Carry out ladder
Degree eluting.Detected with highly effective liquid phase chromatographic system, 10 μ L of sampling volume；Flow velocity 1.0ml/min；Using UV-detector；
Detection wavelength is 260nm.
Gradient elution program is as follows：
Remaining operating procedure and condition are all with embodiment 1.
Result of the test shows, solvent peak is noiseless to posaconazole and its isomer, the peak of separating degree solution isomer it
Between can not whole baseline separation, see Fig. 3.
Embodiment 4
Instrument and chromatographic condition:
Shimadzu LC-10AD type high performance liquid chromatograph；Chromatographic column is IC chromatographic column (250mm × 4.6mm × 5 μm)；Chromatograph
35 DEG C of post column temperature；；With dichloromethane-isopropanol (48:52) it is mobile phase A, with isopropanol-dichloromethane-ethanol (6:3:1) it is
Mobile phase B；Carry out gradient elution.Carried out detecting 10 μ L of sampling volume with high efficiency chromatography liquid phase systems；Flow velocity 1.0ml/min；Adopt
Use UV-detector；Detection wavelength is 260nm.
Gradient elution program is as follows：
Experimental procedure
The preparation of single isomer control product storing solution：9 chiral isomers of posaconazole are taken respectively, accurately weighed,
Plus acetonitrile-isopropanol (75：25) dissolve, make reference substance storing solution of every 1ml containing about 0.10mg.
The preparation of isomer mixed reference substance solution：Take step 1) each 0.2ml of single isomer control product storing solution, puts
Isopropanol-dichloromethane-ethanol (6 is used in 10ml volumetric flask:3:1) dissolve, make reference substance storing solution of every 1ml containing about 2ug.
The preparation of need testing solution：Posaconazole is taken, accurately weighed, plus isopropanol-dichloromethane-ethanol (6:3:1) molten
Solution, makes sample solution of every 1ml containing about 2mg.
Separating degree solution：Take posaconazole, accurately weighed, plus isomer mixed reference substance solution, make every 1ml containing about
The separating degree solution of 2mg posaconazole.
Precision measures blank solvent, need testing solution, isomer mixed reference substance solution, each 10 μ of separating degree solution respectively
L, sample introduction is determined, and is recorded chromatogram, is seen Fig. 4.
Result of the test shows, solvent peak is noiseless to posaconazole and its isomer, does not detect that isomer is miscellaneous in sample
Matter, the separating degree between each composition of separating degree solution is all higher than 1.5.
Embodiment 5
Instrument and chromatographic condition:
Shimadzu LC-10AD type high performance liquid chromatograph；Chromatographic column is IC chromatographic column (250mm × 4.6mm × 5 μm)；Chromatograph
31 DEG C of post column temperature；；With dichloromethane-isopropanol (52:48) it is mobile phase A, with isopropanol-dichloromethane-ethanol (6:3:1) it is
Mobile phase B；Carry out gradient elution.Carried out detecting 10 μ L of sampling volume with high efficiency chromatography liquid phase systems；Flow velocity 1.0ml/min；Adopt
Use UV-detector；Detection wavelength is 260nm.
Gradient-structure is as follows：
Remaining operating procedure and condition are all with embodiment 4.
Result of the test shows, solvent peak is noiseless to posaconazole and its isomer, dividing between each composition of separating degree solution
1.5 are all higher than from degree, see Fig. 5, isomer impurities, such as Fig. 6 in sample, are not detected,.
Although embodiments of the present invention are described in detail, it should be understood that, without departing from the present invention's
In the case of spirit and scope, embodiments of the present invention can be made with various changes, replacement and change.
Claims (10)
1. a kind of method of use high performance liquid chromatography detection posaconazole chiral isomer, comprises the steps：
1) configuration posaconazole chiral isomer mixed reference substance solution and need testing solution；
2) with high performance liquid chromatography detection need testing solution and chiral isomer mixed reference substance solution, chromatographic condition：Using with
Silica Surface covalent bonding polysaccharide derivates are the chromatographic column of filler；Carried out using dual-flow phase, i.e. mobile phase A and Mobile phase B
Gradient elution, the mobile phase A and B are the mixed solution of C2～C4 halogenated alkane and C1～C4 alcohols, and the halo is referred to
The element for chlorine, bromine and iodine being selected from by least one replaces；
3) according to the chromatogram of need testing solution and the chromatogram of chiral isomer mixed reference substance solution, determine need testing solution
The limit of middle chiral isomer.
2. the method for use high performance liquid chromatography detection posaconazole chiral isomer according to claim 1, its feature exists
In it is ternary mobile phase that mobile phase A is binary mobile phase, Mobile phase B.
3. the method for use high performance liquid chromatography detection posaconazole chiral isomer according to claim 1, its feature exists
In C2～C4 halogenated alkane is selected from the mixing of any one or two kinds of in dichloromethane, chloroform, preferably dichloro
Methane.
4. the method for use high performance liquid chromatography detection posaconazole chiral isomer according to claim 1, its feature exists
In the alcohols is selected from the combination of one or more in methanol, ethanol, propanol and isopropanol, preferably ethanol or ethanol
Combination with isopropanol.
5. the method for use high performance liquid chromatography detection posaconazole chiral isomer according to claim 1, its feature exists
In it is isopropanol-dichloromethane-ethanol mixing that the mobile phase A is dichloromethane-isopropanol mixed liquor, the Mobile phase B
Liquid.
6. the method for use high performance liquid chromatography detection posaconazole chiral isomer according to claim 5, its feature exists
In in described mobile phase A, the volume ratio of dichloromethane-isopropanol is (2-6)：(8-4), isopropanol-dichloro in the Mobile phase B
The volume ratio of methane-ethanol is (5-7)：(4-0.5)：(1-2.5).
7. the method for use high performance liquid chromatography detection posaconazole chiral isomer according to claim 6, its feature exists
In in described mobile phase A, the volume ratio of dichloromethane-isopropanol is (48～52)：(48～52), dichloro in preferable mobile phase A
The volume ratio of methane-isopropanol is 1：1.
8. the method for use high performance liquid chromatography detection posaconazole chiral isomer according to claim 5, its feature exists
In described Mobile phase B is (55-65) for volume ratio：(40-25)：(5-10) isopropanol-dichloromethane-ethanol mixed liquor, excellent
It is 6 for volume ratio to select the Mobile phase B：3：1 isopropanol-dichloromethane-ethanol mixed liquor.
9. the method for use high performance liquid chromatography detection posaconazole chiral isomer according to claim 1, its feature exists
In：Step 2) condition of the gradient elution is：
0-8min, the volume ratio shared by mobile phase A phase is：(12%～8%) → 0%, the volume ratio shared by Mobile phase B phase is：
(88%～92%) → 100%；
8-50min, the volume ratio shared by mobile phase A phase is：0%, the volume ratio shared by Mobile phase B phase is：100%；
50-55min, the volume ratio shared by mobile phase A phase is：0% → 100%, the volume ratio shared by Mobile phase B phase is：100%
→ 0%；
55-80min, the volume ratio shared by mobile phase A phase is：100%, the volume ratio shared by Mobile phase B phase is：0%.
10. the method for use high performance liquid chromatography detection posaconazole chiral isomer according to claim 1, its feature exists
In：
The structure of the isomer is：
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| CN107957477A (en) * | 2017-12-20 | 2018-04-24 | 郑州泰丰制药有限公司 | A kind of method using non-aqueous titration measure posaconazole content |
| CN108828105A (en) * | 2018-08-29 | 2018-11-16 | 四川百特芳华医药科技有限公司 | A kind of posaconazole method for detecting impurities |
| CN111323493A (en) * | 2018-12-14 | 2020-06-23 | 武汉赛沃医药科技有限公司 | Method for detecting enantiomer of posaconazole starting material |
| CN112903857A (en) * | 2021-01-23 | 2021-06-04 | 河南泰丰生物科技有限公司 | Method for effectively detecting isomer in posaconazole injection |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107957477A (en) * | 2017-12-20 | 2018-04-24 | 郑州泰丰制药有限公司 | A kind of method using non-aqueous titration measure posaconazole content |
| CN107957477B (en) * | 2017-12-20 | 2020-06-19 | 郑州泰丰制药有限公司 | Method for determining content of posaconazole by non-aqueous titration method |
| CN108828105A (en) * | 2018-08-29 | 2018-11-16 | 四川百特芳华医药科技有限公司 | A kind of posaconazole method for detecting impurities |
| CN111323493A (en) * | 2018-12-14 | 2020-06-23 | 武汉赛沃医药科技有限公司 | Method for detecting enantiomer of posaconazole starting material |
| CN112903857A (en) * | 2021-01-23 | 2021-06-04 | 河南泰丰生物科技有限公司 | Method for effectively detecting isomer in posaconazole injection |
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