CN117871704A - Method for detecting related substances of pirenzepine intermediate - Google Patents
Method for detecting related substances of pirenzepine intermediate Download PDFInfo
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- CN117871704A CN117871704A CN202311671057.XA CN202311671057A CN117871704A CN 117871704 A CN117871704 A CN 117871704A CN 202311671057 A CN202311671057 A CN 202311671057A CN 117871704 A CN117871704 A CN 117871704A
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- 239000000126 substance Substances 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 14
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 229960004633 pirenzepine Drugs 0.000 title claims abstract description 9
- 239000012071 phase Substances 0.000 claims abstract description 10
- 238000010828 elution Methods 0.000 claims abstract description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 6
- 239000012074 organic phase Substances 0.000 claims abstract description 6
- 229910017053 inorganic salt Inorganic materials 0.000 claims abstract description 5
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000000741 silica gel Substances 0.000 claims abstract description 3
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000000872 buffer Substances 0.000 claims abstract 2
- 238000001514 detection method Methods 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000012535 impurity Substances 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 239000007853 buffer solution Substances 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- DBSPUDKBNOZFMX-UHFFFAOYSA-N 7-hydroxyquinolin-2(1H)-one Chemical compound C1=CC(=O)NC2=CC(O)=CC=C21 DBSPUDKBNOZFMX-UHFFFAOYSA-N 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 claims 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- 239000000945 filler Substances 0.000 claims 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 239000002245 particle Substances 0.000 claims 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 8
- NHWKTZWOSIVHOL-UHFFFAOYSA-N 5-pyridin-2-yl-1h-pyridin-2-one Chemical compound N1C(=O)C=CC(C=2N=CC=CC=2)=C1 NHWKTZWOSIVHOL-UHFFFAOYSA-N 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 5
- 239000000523 sample Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- BOHDZKSQXXJHBO-YRNVUSSQSA-N chembl3208829 Chemical compound C1=CC=CC2=NC(/C=N/O)=CC=C21 BOHDZKSQXXJHBO-YRNVUSSQSA-N 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- Investigating Or Analysing Biological Materials (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The invention discloses a method for detecting related substances of a pirenzenenaphthalene intermediate, which comprises the steps of separating and detecting by adopting a gradient elution mode through high performance liquid chromatography, wherein a chromatographic column is a silica gel bonded octadecylsilane column, and an inorganic salt buffer solution-organic phase with a certain proportion is taken as a mobile phase. The method for preparing the related substances of the pirenzepine intermediate has the advantages of strong specificity and high precision, can effectively control the quality of medicines and ensures the safety of the medicines.
Description
Technical Field
The invention relates to the technical field of chemical drug analysis, in particular to an analysis method for analyzing and measuring a pirenzepine intermediate and related impurities by using a liquid chromatography.
Background
The pirenzenenaphthalene intermediate is named as 5- (2-pyridyl) -1, 2-dihydropyridin-2-one, the English name is 5-pyridin-2-yl-1H-pyridin-2-one, and the molecular formula is C10H8N2O, and the molecular weight is 172.18.
Pirenzenene is a drug developed by japan sanitation corporation and inhibits the group action of AMPA-type glutamate receptors by non-competition. Pirenzenenide tablet 2012 is marketed in the european union and the united states as a batch for the treatment of local seizures in patients over 12 years old. The drug is the first antiepileptic drug approved by the FDA and provided with the action mechanism.
For intermediate impurities introduced in the process of synthesizing pirenzenenaphthalene, if the intermediate impurities cannot be completely removed, side reactions are caused, the side reactions can lead to the purity and quality of medicines, and the quality and safety of the medicines can be controlled by detecting related substances. Therefore, the separation of the pirenzenenaphthalene and other related impurities is realized, and the method has important practical significance in the aspect of quality control in the synthesis process of the pirenzenenaphthalene.
Disclosure of Invention
The invention provides an analysis method of related substances of a pirenzepine intermediate, so that the purity and the content of the related substances of the pirenzepine intermediate can be rapidly, effectively and accurately monitored, and the quality control of the bulk drug of a final product is realized.
The invention provides an analysis method of related substances of a pirenzenenaphthalene intermediate, which adopts a high performance liquid chromatography, uses a chromatographic column as a silica gel bonding octadecylsilane chemically bonded column, uses an inorganic salt buffer solution with a certain proportion as a mobile phase A and uses an organic phase as a mobile phase B to perform isocratic elution.
The invention provides an analysis method of a substance related to a pirenzepine intermediate, wherein the gradient elution procedure is as follows:
preferably, the inorganic salt buffer solution is phosphate, in particular potassium dihydrogen phosphate, with a concentration of 0.01mol/L.
Preferably, the organic phase is methanol.
Preferably, the chromatographic column is provided as UITIMAte XB-C18 (4.6 mm. Times.250 mm,5 μm).
The separation and measurement method of the invention can be realized according to the following steps:
(1) Taking a proper amount of 5- (2-pyridyl) -1, 2-dihydropyridin-2-one reference substance, dissolving the sample by using a diluent, and preparing a sample solution containing 0.2mg of 5- (2-pyridyl) -1, 2-dihydropyridin-2-one per 1 ml.
(2) The flow rate of the mobile phase is 0.5-1.5 mL/min, the flow rate of the mobile phase is preferably 1.0mL/min, the detection wavelength is 220-240 nm, the optimal detection wavelength is 220nm, the temperature of the column temperature box is 20-40 ℃, and the temperature of the column temperature box is optimally 30 ℃.
Taking 5-20 mu l of the sample solution of the (1), injecting into a liquid chromatograph, and completing the separation and measurement of 5- (2-pyridyl) -1, 2-dihydropyridin-2-one and related substances. Wherein:
high performance liquid chromatograph: agilent 1260 InfinityII;
chromatographic column: uitimate XB-C18 (4.6mm. Times.250 mm,5 μm);
mobile phase a:0.01mol/L potassium dihydrogen phosphate buffer solution
Mobile phase B: methanol;
elution was performed according to the following gradient:
flow rate: 1.0mL/min; column temperature: 30 ℃; detection wavelength: 220nm; sample injection amount: 10 μl.
The invention adopts a Uitimate XB-C18 (250 multiplied by 4.6mm, 5 mu m) chromatographic column, and can effectively separate 5- (2-pyridyl) -1, 2-dihydropyridin-2-one and related substances thereof. The invention solves the problems of separation and determination of 5- (2-pyridyl) -1, 2-dihydropyridin-2-one and related impurities thereof, improves the content and purity of the product, and ensures the quality controllability of the 5- (2-pyridyl) -1, 2-dihydropyridin-2-one.
Drawings
FIG. 1 is a HPLC chart of 5- (2-pyridyl) -1, 2-dihydropyridin-2-one blank solvent for example 1;
FIG. 2 is an HPLC chart of 5- (2-pyridyl) -1, 2-dihydropyridin-2-one intermediate and related impurities for example 1.
The specific embodiment is as follows:
the following examples are provided for further understanding of the invention, but are not limited to the scope of the present application.
Example 1
Instrument and conditions
High performance liquid chromatograph: agilent 1260 InfinityII;
chromatographic column: uitimate XB-C18 (4.6mm. Times.250 mm,5 μm);
mobile phase a:0.01mol/L potassium dihydrogen phosphate buffer solution
Mobile phase B: methanol;
elution was performed according to the following gradient:
flow rate: 1.0mL/min; column temperature: 30 ℃; detection wavelength: 220nm; sample injection amount: 10 μl;
HPLC detection steps of the 7-hydroxy-2-quinolone related substance as the intermediate of pirenzenepamil are as follows:
taking a proper amount of 5- (2-pyridyl) -1, 2-dihydropyridin-2-one and each impurity reference substance thereof, and dissolving a sample by using a diluent to prepare a sample solution containing 0.2mg/mL of 5- (2-pyridyl) -1, 2-dihydropyridin-2-one and each impurity thereof about 5 mug/mL.
And 5 μl of the solution is injected into a liquid chromatograph, and a chromatogram is recorded, wherein the result is shown in figure 2, the chromatographic peak with retention time of 6.479min in figure 2 is 5- (2-pyridyl) -1, 2-dihydropyridin-2-one, and the rest chromatographic peaks are chromatographic peaks of all impurities.
In summary, the invention can separate 5- (2-pyridyl) -1, 2-dihydropyridin-2-one from each impurity, accurately perform quantitative detection, and effectively control the purity and content of the 5- (2-pyridyl) -1, 2-dihydropyridin-2-one, thereby effectively controlling the product quality of the final product, namely the pirapamide.
Claims (10)
1. A method for detecting related substances of a pirenzenepamil intermediate adopts a high performance liquid chromatography, wherein a chromatographic column is a silica gel bonded octadecylsilane column, and aqueous solution and organic phase with a certain proportion are taken as mobile phases for gradient elution.
2. The analytical detection method for substances of interest in a pirenzenene intermediate according to claim 1, wherein the organic phase is selected from one of the following compounds: methanol, acetonitrile.
3. The method for analytical detection of related substances in a pirenzenene intermediate according to claim 1, wherein the inorganic salt buffer solution is selected from one of the following inorganic salts: citrate, phosphate, perchlorate, carbonate.
4. The analytical detection method for substances of interest in a pirenzeneb intermediate according to claim 1, wherein the gradient process is gradient elution:
5. the analytical detection method for substances of interest in a pirenzenene intermediate according to claim 1, wherein the chromatographic column preferably has a length of 254mm, a diameter of 4.6mm and a filler particle size of 5 μm.
6. A method for the analytical detection of substances of interest in a pirenzenenide intermediate according to claims 1 and 3, characterized in that the inorganic salt buffer is dissolved in a column of preferably 254mm length, 4.6mm diameter and 5 μm filler size according to the method for the analytical detection of substances of interest in a pirenzenenide intermediate according to claim 1. The liquid is preferably a phosphate, and its concentration is optimally 0.01mol/L.
7. The analytical detection method for substances of intermediate of pirenzepine according to claims 2 and 4, wherein the organic phase is preferably methanol.
8. The analytical detection method of related substances in a pirenzeneb intermediate according to claim 1, comprising the steps of: (1) setting the flow rate to be 0.5-1.5 ml/min; (2) setting the detection wavelength to 210-240nm; (3) the column temperature of the chromatographic column is 20-40 ℃; (4) the sample injection amount is 5-20 mu l.
9. The analytical detection method for substances of interest in a pirenzepine intermediate according to claim 8, wherein the chromatographic conditions are as follows: (1) the flow rate is preferably 1.0ml/min; (2) the wavelength is preferably 220nm; (3) the column temperature is preferably 30 ℃; (4) the sample injection amount is preferably 10 mu l.
10. The method for analyzing related substances in 7-hydroxy-2-quinolone as intermediates of pirenzenenaphthalene according to claim 1, wherein the related substance impurities are as follows:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311671057.XA CN117871704A (en) | 2023-12-07 | 2023-12-07 | Method for detecting related substances of pirenzepine intermediate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311671057.XA CN117871704A (en) | 2023-12-07 | 2023-12-07 | Method for detecting related substances of pirenzepine intermediate |
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| Publication Number | Publication Date |
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| CN117871704A true CN117871704A (en) | 2024-04-12 |
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| CN202311671057.XA Pending CN117871704A (en) | 2023-12-07 | 2023-12-07 | Method for detecting related substances of pirenzepine intermediate |
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- 2023-12-07 CN CN202311671057.XA patent/CN117871704A/en active Pending
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