CN114113412B - Analysis method of posaconazole impurity related substances - Google Patents
Analysis method of posaconazole impurity related substances Download PDFInfo
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- CN114113412B CN114113412B CN202111539173.7A CN202111539173A CN114113412B CN 114113412 B CN114113412 B CN 114113412B CN 202111539173 A CN202111539173 A CN 202111539173A CN 114113412 B CN114113412 B CN 114113412B
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- 239000012535 impurity Substances 0.000 title claims abstract description 43
- 229960001589 posaconazole Drugs 0.000 title claims abstract description 29
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 title claims abstract description 29
- 239000000126 substance Substances 0.000 title claims abstract description 20
- 238000004458 analytical method Methods 0.000 title claims abstract description 15
- 238000010828 elution Methods 0.000 claims abstract description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000010606 normalization Methods 0.000 claims abstract description 5
- 238000002347 injection Methods 0.000 claims abstract description 3
- 239000007924 injection Substances 0.000 claims abstract description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000003960 organic solvent Substances 0.000 claims abstract description 3
- 238000004007 reversed phase HPLC Methods 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 230000009286 beneficial effect Effects 0.000 abstract description 5
- 238000001514 detection method Methods 0.000 abstract description 5
- 238000011160 research Methods 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000000741 silica gel Substances 0.000 abstract 1
- 229910002027 silica gel Inorganic materials 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 11
- 239000012490 blank solution Substances 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 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 class 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 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000005303 weighing Methods 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
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Investigating Or Analysing Materials By Optical Means (AREA)
Abstract
The invention provides an analysis method of posaconazole impurity related substances, which adopts reversed-phase high performance liquid chromatography with an ultraviolet detector, and adopts a chromatographic column filled with octadecylsilane chemically bonded silica gel, wherein the specification of the chromatographic column is 250mm 4.6mm and 5 mu m; the mobile phase consists of a mobile phase A and a mobile phase B organic solvent, and elution is carried out by adopting a gradient mobile phase according to the volume fraction; the detection wavelength is 255-265 nm, the flow rate is 0.8-1.2 ml/min, the column temperature is 30-40 ℃, the sample injection volume is 8-12 mu l, and the detection analysis is carried out by adopting an area normalization method; wherein, the posaconazole impurity related substances comprise impurity a, impurity b and impurity c. The analysis method of posaconazole impurity related substances can detect 3 posaconazole related substances at the same time, and is beneficial to quality research and control of posaconazole drugs.
Description
Technical Field
The invention relates to the technical field of medicine analysis, in particular to an analysis method of posaconazole impurity related substances.
Background
The Posaconazole (Posaconazole) is a derivative of itraconazole, is an antifungal drug with remarkable effect, and researches show that the product is not cleared by hemodialysis, is suitable for eubacteremia, respiratory inflammation and the like caused by candida and cryptococcus fungi, and has the characteristics of stable metabolism, high bioavailability and the like.
In order to ensure the research and development and production quality of posaconazole, the quality of the raw materials and the preparation thereof needs to be controlled. At present, posaconazole impurities are mostly studied on isomers and degradation impurities, and detection and analysis methods for intermediate impurities are few. The intermediate impurities comprise impurities a, b and c, and the structural formula of the intermediate impurities is shown as follows:
the impurity a is a compound selected from the group consisting of,
the impurity b is contained in the mixture,
impurity c.
Therefore, research on obtaining a method for detecting posaconazole impurity related substances is particularly urgent for pharmaceutical manufacturing enterprises. By referring to the middle and outer literature and the patent, the current detection method for posaconazole impurities is single, which is not beneficial to the control of enterprises on the product quality, so that an analysis method for effectively determining posaconazole impurities is very important.
Disclosure of Invention
The invention aims to disclose an analysis method of posaconazole impurity related substances, which can detect 3 posaconazole related substances at the same time and is beneficial to the quality research and control of posaconazole drugs.
In order to achieve the aim, the invention provides an analysis method of posaconazole impurity related substances, which adopts reversed-phase high performance liquid chromatography with an ultraviolet detector, and adopts a chromatographic column with octadecylsilane chemically bonded silica filler, wherein the specification of the chromatographic column is 250mm 4.6mm and 5 mu m; the mobile phase consists of a mobile phase A and a mobile phase B organic solvent, and elution is carried out by adopting a gradient mobile phase according to the volume fraction; detecting wavelength is 255-265 nm, flow speed is 0.8-1.2 ml/min, column temperature is 30-40 ℃, sample injection volume is 8-12 mu l, and detecting and analyzing by adopting an area normalization method; wherein, the posaconazole impurity related substances comprise impurity a, impurity b and impurity c.
Further, mobile phase A is water or 0.1% phosphoric acid aqueous solution; mobile phase B is selected from acetonitrile, methanol or mixtures thereof.
Further, the diluent is selected from acetonitrile, ethanol, methanol or a mixture thereof with water.
Further, the gradient mobile phase is eluted according to the volume fraction, and is specifically set as follows:
compared with the prior art, the invention has the beneficial effects that: provides an analysis method capable of simultaneously detecting 3 related substances of posaconazole, which is beneficial to the quality research and control of posaconazole drugs.
Drawings
FIG. 1 is a chromatogram of a hollow white solution (acetonitrile) of the present invention;
FIG. 2 is a chromatogram of a system-applicable solution of the present invention;
FIG. 3 is a chromatogram of a test solution according to the present invention.
Detailed Description
The present invention will be described in detail with reference to the following embodiments, but it should be understood that these embodiments are not limiting, and functional, method, or structural equivalents and alternatives thereof by those skilled in the art are within the scope of the present invention.
In the present invention, the term "area normalization method" refers to a method of quantifying a control substance using a pure product of a component to be measured, by comparing the response signals of the control substance and the component to be measured in a sample.
In the present invention, the term "gradient elution" refers to a gradient elution pattern in which the composition and flow rate of a mobile phase are in accordance with the analysis period of a sample component.
In the present invention, the term "theoretical plate number" refers to the column efficiency parameter of a chromatographic column, and the calculation formula is as follows:
theoretical plate number=16× (retention time/peak width) 2 Or (b)
Theoretical plate number=5.54 × (retention time/half-peak width) 2 。
The invention discloses an analysis method of posaconazole impurity related substances, which comprises the following steps of:
the instruments used were: a Shimadzu 20A high performance liquid chromatograph; chromatographic column: phenomenex luna 5u C18 (2) with a specification of 250mm by 4.6mm; mobile phase a was water and mobile phase B was acetonitrile, performed according to a gradient elution table. The flow rate is 1.0ml/min; the column temperature is 35 ℃; the sample volume was 10. Mu.l.
The experimental steps are as follows:
preparing a solution:
blank solution: a diluent (acetonitrile);
system applicability solution: the posaconazole impurity reference substance and other impurities (impurities a, b, c and phenol) are precisely weighed, placed in the same volumetric flask, and dissolved and diluted into a mixed solution containing about 1mg per 1ml by adding a diluent, and used as a system applicability solution.
Preparation of test solution: precisely weighing a proper amount of posaconazole impurity, adding a mobile phase to dissolve and diluting to prepare a solution containing about 1mg per 1ml, and taking the solution as a test sample solution.
And precisely sucking 10 mu l of each of the blank solution, the system applicability solution and the sample solution, and injecting the solution into a high performance liquid chromatograph for measurement to obtain a chromatogram. As particularly shown in fig. 1-3.
FIG. 1 is a chromatogram of a blank solution (acetonitrile). FIG. 2 is a chromatogram of a system applicability solution. FIG. 3 is a chromatogram of a test solution.
According to the chromatogram, calculating related substances of posaconazole impurities by adopting an area normalization method.
The results show that the blank solution does not interfere with other related substances detection. In the system applicability solution, the separation degree of posaconazole impurities and other impurities meets the requirements, the peak shape is good, the peak purity is good, the theoretical plate number is more than 3000, the tailing factor is less than 1.5, and the standard is met.
The above list of detailed descriptions is only specific to practical embodiments of the present invention, and they are not intended to limit the scope of the present invention, and all equivalent embodiments or modifications that do not depart from the spirit of the present invention should be included in the scope of the present invention.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.
Claims (1)
1. The analysis method of posaconazole impurity related substances is characterized by adopting reversed-phase high performance liquid chromatography with an ultraviolet detector, and selecting a chromatographic column with octadecylsilane chemically bonded silica filler, wherein the specification of the chromatographic column is 250mm 4.6mm and 5 mu m; the mobile phase consists of a mobile phase A and a mobile phase B organic solvent, and elution is carried out by adopting a gradient mobile phase according to the volume fraction; detecting wavelength is 255-265 nm, flow speed is 0.8-1.2 ml/min, column temperature is 30-40 ℃, sample injection volume is 8-12 mu l, and detecting and analyzing by adopting an area normalization method; wherein, the posaconazole impurity related substances comprise impurity a, impurity b and impurity c:
the impurity a is a compound selected from the group consisting of,
the impurity b is contained in the mixture,
impurity c;
the mobile phase A is water or 0.1% phosphoric acid aqueous solution; the mobile phase B is selected from acetonitrile, methanol or a mixture thereof;
the gradient mobile phase is eluted according to the volume fraction, and is specifically set as follows:
。
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| CN114113412B true CN114113412B (en) | 2024-04-16 |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105606736A (en) * | 2016-01-27 | 2016-05-25 | 重庆华邦制药有限公司 | Method for separation determination of posaconazole intermediate Z1 and related substances of posaconazole intermediate Z1 |
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2021
- 2021-12-15 CN CN202111539173.7A patent/CN114113412B/en active Active
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