CN100371709C - Method for separating and determining pitavastatin and its optical isomer by means of liquid chromatography - Google Patents
Method for separating and determining pitavastatin and its optical isomer by means of liquid chromatography Download PDFInfo
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- CN100371709C CN100371709C CNB2005100574331A CN200510057433A CN100371709C CN 100371709 C CN100371709 C CN 100371709C CN B2005100574331 A CNB2005100574331 A CN B2005100574331A CN 200510057433 A CN200510057433 A CN 200510057433A CN 100371709 C CN100371709 C CN 100371709C
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- pitavastatin calcium
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- 230000003287 optical effect Effects 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000004811 liquid chromatography Methods 0.000 title claims description 5
- 229960002797 pitavastatin Drugs 0.000 title description 4
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 title description 4
- RHGYHLPFVJEAOC-FFNUKLMVSA-L pitavastatin calcium Chemical compound [Ca+2].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1.[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 RHGYHLPFVJEAOC-FFNUKLMVSA-L 0.000 claims abstract description 50
- 229960003296 pitavastatin calcium Drugs 0.000 claims abstract description 49
- 238000000926 separation method Methods 0.000 claims abstract description 8
- 238000001514 detection method Methods 0.000 claims abstract description 5
- 239000007788 liquid Substances 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 7
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 239000012488 sample solution Substances 0.000 claims description 4
- 229920000856 Amylose Polymers 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000000523 sample Substances 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 4
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 14
- 239000007791 liquid phase Substances 0.000 description 11
- 239000012071 phase Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 159000000007 calcium salts Chemical class 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000003908 quality control method Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- SBTVLCPCSXMWIQ-UHFFFAOYSA-N (3,5-dimethylphenyl) carbamate Chemical compound CC1=CC(C)=CC(OC(N)=O)=C1 SBTVLCPCSXMWIQ-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
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Abstract
The present invention belongs to the field of analytical chemistry, which relates to the separation detection of pitavastatin calcium and optical isomers (impurities) thereof. In the present invention, high performance liquid chromatography or high performance liquid chromatography-mass spectrography is used to separate and detect the optical isomers of the pitavastatin calcium under a certain chromatographic condition. The method can rapidly and accurately separate and detect the pitavastatin calcium and optical isomer impurities containing pitavastatin calcium preparations.
Description
Technical field
The invention belongs to the analytical chemistry field, be specifically related to method with liquid chromatography for separating and determining Pitavastatin Calcium and optical isomer thereof.
Background technology
Pitavastatin Calcium is a kind of lipid-lowering medicine, and by Japanese firm's exploitation listing, molecular formula is C
50H
46C
aF
2N
2O
8, its chemistry is by name: two-[(3R, 5S, 6E)-and 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoic acid] calcium salt, promptly Pitavastatin Calcium is an effective component.Contain 2 asymmetric carbon atoms in the Pitavastatin Calcium molecule, in chemosynthesis, can generate four kinds of optical isomers that spatial configuration is different simultaneously.Except that Pitavastatin Calcium, other three optical isomers are listed in the impurity of Pitavastatin Calcium; The chemical name of the optical isomer impurity of Pitavastatin Calcium is respectively: two-[(3S, 5R, 6E)-and 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoic acid] calcium salt (the present invention abbreviates P1 as), two-[(3R, 5R, 6E)-and 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoic acid] calcium salt (the present invention abbreviates P2 as) and two-[(3S, 5S, 6E)-and 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoic acid] calcium salt (the present invention abbreviates P3 as).
Three kinds of optical isomers for Pitavastatin Calcium are impurity, need to carry out quality control in producing the Pitavastatin Calcium process.The separation of optical isomer that contains the compound of a plurality of asymmetric carbon atoms is the difficult point of chiral drug quality control always, therefore, realizes that the separation determination of Pitavastatin Calcium and other three kinds of optical isomers has realistic meaning aspect the Pitavastatin Calcium quality control.
According to document (Mikio etc., Bioorgananic ﹠amp; Medicinal Chemistry Letters 9 (1999) 2977～2982) report, (150mm * 4.6mm) chiral chromatographic column is a separating column, with 0.02mol/L K with ULTRON ES-OVM
2HPO
4-acetonitrile-methyl alcohol (100: 5: 10) is a moving phase, the optical isomer that can separate Pitavastatin Calcium, we have carried out demonstration test with Pitavastatin Calcium raceme (containing four kinds of Pitavastatin Calcium optical isomers), the result shows that this method can not effectively be separated four kinds of Pitavastatin Calcium optical isomers.Through repetition test, moving phase is adjusted into 0.01mol/L K
2HPO
4(5%H
3PO
4Transfer pH to 6.0)-acetonitrile-isopropyl alcohol (100: 30: 4), also can only be separated into 2 chromatographic peaks (each peak comprises a pair of enantiomorph).Therefore, (150mm * 4.6mm) result of chiral chromatographic column mensuration is insecure, thereby can't carry out reliable and effective quality control to Pitavastatin Calcium with ULTRON ES-OVM.
Find through repetition test, (250mm * 4.6mm) is a separating column with the CHIRALPAK-AD chiral chromatographic column, with normal hexane: ethanol (containing 1.0% trifluoroacetic acid)=92: 8 is moving phase, three optical isomers of Pitavastatin Calcium and other effectively can be separated, thereby can accurately control the quality of Pitavastatin Calcium.Method of the present invention can be simply, separate, detect Pitavastatin Calcium and other three optical isomer impurity quickly and accurately.
Summary of the invention
The object of the present invention is to provide a kind of efficient liquid-phase chromatography method, thereby realize separating and mensuration of Pitavastatin Calcium and its optical isomer impurity (P1, P2, P3) with chiral chromatographic column separation determination Pitavastatin or its calcium salt and optical isomer impurity thereof.
The said method of the present invention with liquid chromatography for separating and determining Pitavastatin or its calcium salt and optical isomer (impurity) thereof, be with three (3, the 5-3,5-dimethylphenyl)-carbamate amylose [Amylose tris (3,5-dimethylphenylcarbamate)] be the chiral chromatographic column of filler, with normal hexane-low-alcohol solution is moving phase, wherein comprises organic acid in the low-alcohol solution.Here said liquid phase chromatography comprises high performance liquid chromatography or high performance liquid chromatography-mass spectroscopy coupling.
Above-mentioned said chiral chromatographic column is selected from the chromatographic column that the trade mark is CHIRALPAK AD and CHIRALPAK AD-H.
Lower alcohol of the present invention is selected from following compound: methyl alcohol, ethanol, propyl alcohol, isopropyl alcohol are preferably ethanol or isopropyl alcohol.
Method of the present invention, the volume ratio of its moving phase normal hexane-low-alcohol solution are 96: 4～88: 12.
The organic acid that comprises in the above-mentioned said low-alcohol solution is selected from formic acid, acetate and trifluoroacetic acid, and the percent by volume that organic acid concentration (V/V) accounts for low-alcohol solution is 0.1～5%.
Method of separating and assaying of the present invention, can realize by the following method:
1) get Pitavastatin Calcium or to contain the formulation samples of Pitavastatin Calcium an amount of, spent glycol dimethyl ether or contain the organic solvent dissolution sample of glycol dimethyl ether, and be mixed with the sample solution that every 1ml contains Pitavastatin Calcium 0.2～10mg;
2) flow velocity that moving phase is set is 0.5～1.5ml/min, and the flow velocity of moving phase is preferably 1ml/min, and the detection wavelength is 235～260nm, and the optimum detection wavelength is 245nm, and chromatographic column post oven temperature, degree is 20～50 ℃; Post oven temperature, degree the best is 40 ℃
3) get 1) sample solution 2～40 μ l, inject high performance liquid chromatograph, finish the separation determination of Pitavastatin Calcium and optical isomer.
Wherein:
High performance liquid chromatograph: Agilent 1100 type high performance liquid chromatographs
Chromatographic column: the CHIRALPAK-AD chiral chromatographic column (250mm * 4.6mm)
Column temperature: 40 ℃
Moving phase: normal hexane: ethanol (containing 1.0% trifluoroacetic acid)=92: 8
Flow: 1ml/min
Detect wavelength: 245nm
Sampling volume: 10 μ l
The present invention adopts the CHIRALPAK-AD chiral chromatographic column, effectively the optical isomer of separation determination Pitavastatin Calcium; Select the glycol dimethyl ether sample dissolution for use, guaranteed the stability of solution; Selecting sampling volume for use is 10 μ l, and column temperature is 40 ℃, has improved the symmetry of chromatographic peak.The invention solves the separation determination Pitavastatin Calcium and contain the mensuration problem of the optical isomer of Pitavastatin calcium preparation, thereby guaranteed the quality controllable of Pitavastatin Calcium and preparation thereof.
Description of drawings
The high-efficient liquid phase chromatogram of Fig. 1 blank solvent
The high-efficient liquid phase chromatogram of Fig. 2 Pitavastatin Calcium raceme
The high-efficient liquid phase chromatogram of Fig. 3 Pitavastatin Calcium
The high-efficient liquid phase chromatogram of Fig. 4 auxiliary material blank
The high-efficient liquid phase chromatogram of Fig. 5 pitavastatin calcium tablet
Embodiment:
Embodiment 1
Instrument and condition
U.S. Agilent 1100 type highly effective liquid phase chromatographic system and workstations; Auto injection; (250mm * 4.6mm) is a separating column with the CHIRALPAK-AD chiral chromatographic column; Ultraviolet detection wavelength: 245nm; Moving phase: normal hexane-ethanolic solution (containing 1.0% trifluoroacetic acid) (92: 8) is a moving phase; 40 ℃ of column temperatures.Sampling volume is 10 μ l.
Experimental procedure
Get the about 25mg of Pitavastatin Calcium raceme, put in the 50ml measuring bottle, add the glycol dimethyl ether dissolving and be diluted to scale, shake up, as need testing solution.
Get blank reagent solution and need testing solution respectively, carry out efficient liquid phase chromatographic analysis by above-mentioned condition, the record chromatogram the results are shown in Figure 1, Fig. 2.
17.222 minutes chromatographic peak of retention time is the chromatographic peak of Pitavastatin Calcium among Fig. 2; 13.610 minute chromatographic peak be the Pitavastatin Calcium enantiomorph; 14.749 minute and two chromatographic peaks of 20.311 minutes two other optical isomer that is Pitavastatin Calcium, they are enantiomorph each other.
Embodiment 2
Get the about 25mg of Pitavastatin Calcium, put in the 50ml measuring bottle, add the glycol dimethyl ether dissolving and be diluted to scale, shake up, as need testing solution.
Get need testing solution, carry out efficient liquid phase chromatographic analysis according to the condition of embodiment 1, the record chromatogram the results are shown in Figure 3.
Fig. 3 proves that the optical purity of Pitavastatin Calcium reaches the bulk drug requirement, and this law can be used for the quality monitoring of Pitavastatin Calcium.
Embodiment 3
It is an amount of to get pitavastatin calcium tablet, is equivalent to Pitavastatin Calcium 25mg approximately, puts in the 50ml measuring bottle, and it is an amount of to add glycol dimethyl ether, and jolting makes dissolving, and the spent glycol dimethyl ether is diluted to scale, shakes up, and filters, and filtrate is as need testing solution.Get need testing solution, carry out efficient liquid phase chromatographic analysis according to the condition of embodiment 1, and carry out the auxiliary material blank test, the results are shown in Figure 4, Fig. 5 with method.
Fig. 4 proves that the auxiliary material blank is interference measurement not, and Fig. 5 shows that this law can be used to contain the quality monitoring of Pitavastatin calcium preparation.
Claims (9)
- One kind with liquid chromatography for separating and determining Pitavastatin calcium salt or/and the method for its optical isomer, it is characterized in that: with three (3, the 5-3,5-dimethylphenyl)-the carbamate amylose is the chiral chromatographic column of filler, with normal hexane-low-alcohol solution is moving phase, wherein comprise a kind of organic acid that is selected from formic acid, acetate and the trifluoroacetic acid in the low-alcohol solution, its concentration (V/V) is 0.1～5%, and normal hexane-low-alcohol solution volume ratio is 96: 4～88: 12.
- 2. method of separating and assaying according to claim 1, chiral chromatographic column are selected from the chromatographic column that the trade mark is CHIRALPAK AD and CHIRALPAKAD-H.
- 3. method of separating and assaying according to claim 1, said lower alcohol are selected from a kind of in the following compound: methyl alcohol, ethanol, propyl alcohol and isopropyl alcohol.
- 4. method of separating and assaying according to claim 3, said lower alcohol are ethanol or isopropyl alcohol.
- 5. method of separating and assaying according to claim 1, said normal hexane-low-alcohol solution volume ratio is 92: 8.
- 6. method of separating and assaying according to claim 1 is characterized in that: said method comprises following steps:1) get Pitavastatin Calcium or to contain the formulation samples of Pitavastatin Calcium an amount of, spent glycol dimethyl ether or contain the organic solvent dissolution sample of glycol dimethyl ether, and be mixed with the sample solution that every 1ml contains Pitavastatin Calcium 0.2～10mg;2) flow velocity that moving phase is set is 0.5～1.5ml/min, and the detection wavelength is 235～260nm, and chromatographic column post oven temperature, degree is 20～50 ℃;3) get 1) sample solution 2～40 μ l, inject high performance liquid chromatograph, finish the separation determination of Pitavastatin Calcium and optical isomer.
- 7. method of separating and assaying according to claim 6, step 2) flow velocity of said moving phase is 1ml/min.
- 8. method of separating and assaying according to claim 6, step 2) said chromatographic column post oven temperature, degree is 40 ℃.
- 9. method of separating and assaying according to claim 6, step 2) said detection wavelength is 245nm.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2005100574331A CN100371709C (en) | 2005-12-12 | 2005-12-12 | Method for separating and determining pitavastatin and its optical isomer by means of liquid chromatography |
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| CNB2005100574331A CN100371709C (en) | 2005-12-12 | 2005-12-12 | Method for separating and determining pitavastatin and its optical isomer by means of liquid chromatography |
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| CN1790012A CN1790012A (en) | 2006-06-21 |
| CN100371709C true CN100371709C (en) | 2008-02-27 |
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| CN102285917B (en) * | 2011-09-20 | 2013-12-11 | 海南美大制药有限公司 | Pitavastatin calcium compound and preparation method thereof |
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| CN107144648B (en) * | 2017-04-26 | 2019-11-22 | 苏州海科医药技术有限公司 | Detect the liquid chromatography-tandem mass spectrometry method of Pitavastatin in human plasma |
| CN109580791A (en) * | 2017-09-28 | 2019-04-05 | 安徽省庆云医药股份有限公司 | A kind of method of HPLC method measurement Pitavastatin calcium content |
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| CN113092597B (en) * | 2019-12-23 | 2022-05-31 | 徐州万邦金桥制药有限公司 | Analysis method of pitavastatin calcium intermediate related substances |
| CN111505150A (en) * | 2020-04-30 | 2020-08-07 | 山东齐都药业有限公司 | Method for detecting potential mutation-causing impurities in pitavastatin calcium tablets |
| CN112782333B (en) * | 2020-12-25 | 2022-07-12 | 石家庄四药有限公司 | HPLC detection method for pitavastatin isopropyl tert-butyl ester diastereoisomer |
| CN114397378A (en) * | 2021-12-15 | 2022-04-26 | 安徽万邦医药科技股份有限公司 | Method for determining pitavastatin concentration in blood plasma by liquid chromatography-mass spectrometry |
| CN115166104B (en) * | 2022-09-08 | 2022-12-20 | 康瑞鑫(天津)药物研究院有限公司 | Method for separating pitavastatin calcium starting material and impurities thereof and application |
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