CN112611817A - HPLC method for separating naftopidil and enantiomer thereof - Google Patents
HPLC method for separating naftopidil and enantiomer thereof Download PDFInfo
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- CN112611817A CN112611817A CN202011465890.5A CN202011465890A CN112611817A CN 112611817 A CN112611817 A CN 112611817A CN 202011465890 A CN202011465890 A CN 202011465890A CN 112611817 A CN112611817 A CN 112611817A
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- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000004128 high performance liquid chromatography Methods 0.000 title claims abstract description 16
- HRRBJVNMSRJFHQ-UHFFFAOYSA-N Naftopidil Chemical compound COC1=CC=CC=C1N1CCN(CC(O)COC=2C3=CC=CC=C3C=CC=2)CC1 HRRBJVNMSRJFHQ-UHFFFAOYSA-N 0.000 title abstract description 17
- 229950005705 naftopidil Drugs 0.000 title abstract description 13
- HRRBJVNMSRJFHQ-HXUWFJFHSA-N (2r)-1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-naphthalen-1-yloxypropan-2-ol Chemical compound COC1=CC=CC=C1N1CCN(C[C@@H](O)COC=2C3=CC=CC=C3C=CC=2)CC1 HRRBJVNMSRJFHQ-HXUWFJFHSA-N 0.000 claims abstract description 26
- HRRBJVNMSRJFHQ-FQEVSTJZSA-N (2s)-1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-naphthalen-1-yloxypropan-2-ol Chemical compound COC1=CC=CC=C1N1CCN(C[C@H](O)COC=2C3=CC=CC=C3C=CC=2)CC1 HRRBJVNMSRJFHQ-FQEVSTJZSA-N 0.000 claims abstract description 22
- 238000000926 separation method Methods 0.000 claims abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 239000000654 additive Substances 0.000 claims description 7
- 230000000996 additive effect Effects 0.000 claims description 7
- 239000003643 water by type Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 4
- IQIOLCJHRZWOLS-XOBRGWDASA-N (2s,3s)-2-[9h-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-methylpentanoic acid Chemical group C1=CC=C2C(COC(=O)N(C)[C@@H]([C@@H](C)CC)C(O)=O)C3=CC=CC=C3C2=C1 IQIOLCJHRZWOLS-XOBRGWDASA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000004458 analytical method Methods 0.000 abstract description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 5
- 229910052799 carbon Inorganic materials 0.000 abstract description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 239000013558 reference substance Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- 239000002904 solvent Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229910052730 francium Inorganic materials 0.000 description 1
- KLMCZVJOEAUDNE-UHFFFAOYSA-N francium atom Chemical compound [Fr] KLMCZVJOEAUDNE-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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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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- 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
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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
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
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- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8877—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample optical isomers
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Abstract
The invention discloses an HPLC method for separating naftopidil and an enantiomer thereof. Naftopidil has a chiral center, and a pair of enantiomers (R) -naftopidil and (S) -naftopidil exist. The active ingredient used in clinic is (R) -naftopidil. In order to control the purity of (R) -naftopidil, it is necessary to establish an analytical method capable of separating (R) -naftopidil from (S) -naftopidil. At present, chiral chromatographic columns are used for separating the two, so that the cost is high. The HPLC method provided by the invention is based on an inexpensive eighteen carbon chromatographic column as a separation means, effectively separates (R) -naftopidil and (S) -naftopidil, has short separation time, and can greatly reduce the separation cost of naftopidil and enantiomers thereof.
Description
Technical Field
The invention belongs to the field of pharmaceutical analysis, and particularly relates to an HPLC (high performance liquid chromatography) method for separating naftopidil and an enantiomer thereof.
Background
Naftopidil (Naftopidil) is chemically named as 1- (2-methoxy) -4- [3- (1-naphthoxy) -2-hydroxypropyl ] -piperazine, is a novel receptor antagonist which is developed and marketed by the francium and the Asahi Kasei Pharma Kasei, is firstly approved in Japan for marketing in 1999 within 6 months, and is used for treating diseases such as prostatic hyperplasia.
Naftopidil has a chiral center and a pair of enantiomers, and the chemical structures of the naftopidil are respectively shown as follows:
the active ingredient used in clinic is (R) -naftopidil. In order to control the purity of (R) -naftopidil, it is necessary to establish an analytical method capable of separating (R) -naftopidil from (S) -naftopidil.
YInXiang Sun et al established a method for measuring naftopidil enantiomer by chiral high performance liquid chromatography, and used a chromatographic column of AD-H chiral column (Development of a chiral HPLC method for the analysis of naftopidil enantiomers. journal of Chinese Pharmaceutical sciences. 2009). The shisol and the like establish a method for directly splitting the naftopidil enantiomer by a Chiralpak AD-RH chiral column, and the adopted chromatographic column is the Chiralpak AD-RH chiral column (the Chiralpak AD-RH chiral column directly splits the naftopidil enantiomer, and the journal of drug analysis, 2009).
The AD-H chiral column and the ChiralpakAD-RH chiral column used in the documents are both chiral chromatographic columns specially used for separating chiral compounds, the manufacturing cost and the selling price are both high, and the service life of the chiral chromatographic column is much shorter than that of a conventional eighteen-carbon chromatographic column.
The invention is especially proposed in order to develop an HPLC method for separating (R) -naftopidil and (S) -naftopidil with low cost.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides an HPLC method for separating naftopidil and an enantiomer thereof.
The purpose of the invention is realized by the following technical scheme:
an HPLC method for separating (R) -naftopidil and (S) -naftopidil at low cost is characterized in that a proper amount of chiral additive is added into a mobile phase, and the chiral additive is Fmoc-N-methyl-L-isoleucine.
Preferably, the mobile phase A is a 5% methanol aqueous solution containing 0.05 mol/LFmoc-N-methyl-L-isoleucine, the mobile phase B is a mixed organic solvent formed by acetonitrile and methanol according to a volume ratio of 4:3, and the A phase and the B phase are eluted at an isocratic rate of 35:65 according to the volume ratio.
Preferably, the separation column is a Waters Xbridge C18 column (4.6 mm. times.150 mm, 5 μm).
Has the advantages that:
the HPLC method provided by the invention is based on an inexpensive eighteen carbon chromatographic column as a separation means, effectively separates (R) -naftopidil and (S) -naftopidil, has short separation time, and can greatly reduce the separation cost of naftopidil and enantiomers thereof.
Drawings
FIG. 1 shows the structural formulas of (R) -naftopidil and (S) -naftopidil.
FIG. 2 is an HPLC chromatogram under the conditions of example 1.
FIG. 3 is an HPLC chromatogram under the conditions of example 2.
Detailed Description
The following examples are intended to illustrate the essential technical content of the present invention, and the scope of the present invention should not be limited by the specific general details described in the following examples.
Example 1:
first, instrument and reagent
1. Instrument for measuring the position of a moving object
Agilent 1260 liquid chromatograph (vacuum degasser, binary pump, autosampler), USA.
A chromatographic column: waters Xbridge C18 column (4.6 mm. times.150 mm, 5 μm).
A Mettler toledo electronic balance (XS 105).
2. Reagent
The purity of the (R) -naftopidil reference substance and the purity of the (S) -naftopidil reference substance are not lower than 99 percent, and the structural formula is shown in figure 1.
The chiral additive Fmoc-N-methyl-L-isoleucine was purchased from Meclin reagent with a purity of 98%.
Acetonitrile and methanol are used as chromatographic purity, and water is used as ultrapure water.
Second, method and results
1. Chromatographic conditions
A chromatographic column: waters Xbridge C18 chromatography column (4.6 mm. times.150 mm, 5 μm);
mobile phase a phase: 5% methanol aqueous solution containing 0.05 mol/LFmoc-N-methyl-L-isoleucine (preparation method: first, methanol and water are mixed uniformly according to volume ratio of 5:95, then chiral additive is added to prepare the required concentration);
mobile phase B phase: a mixed organic solvent formed by acetonitrile and methanol according to the volume ratio of 4: 3;
elution mode and ratio: the phase A and the phase B are eluted at equal degrees according to the volume ratio of 35: 65;
flow rate: 1.0 mL/min;
detection wavelength: 283 nm;
column temperature: 30 ℃;
sample introduction amount: 10 μ L.
2. Solution preparation
Mixing the reference solution: taking a proper amount of mobile phase A and B, mixing the two phases according to the volume ratio of 35:65 to serve as a solvent, and preparing a mixed reference substance solution containing 0.6mg/mL of (R) -naftopidil reference substance and 0.6mg/mL of (S) -naftopidil reference substance.
(R) -naftopidil control solution: taking a proper amount of mobile phase A and B, mixing the two phases according to the volume ratio of 35:65 to be used as a solvent, and preparing a solution containing 0.1mg/mL of (R) -naftopidil reference substance.
(S) -naftopidil control solution: taking a proper amount of mobile phase A and B, mixing the two phases according to the volume ratio of 35:65 to be used as a solvent, and preparing a solution containing 0.1mg/mL of (S) -naftopidil reference substance.
3. Analysis of sample introduction
Respectively and precisely measuring 10 mu L of mixed reference substance solution, (R) -naftopidil reference substance solution and (S) -naftopidil reference substance solution, injecting into a liquid chromatograph, analyzing according to the chromatographic conditions, and recording a chromatogram. The results are shown in fig. 2, under the chromatographic conditions, (R) -naftopidil and (S) -naftopidil can achieve baseline separation.
Example 2: comparative example, mobile phase without addition of chiral additive
Instrument and reagent
1. Instrument for measuring the position of a moving object
Agilent 1260 liquid chromatograph (vacuum degasser, binary pump, autosampler), USA.
A chromatographic column: waters Xbridge C18 column (4.6 mm. times.150 mm, 5 μm).
A Mettler toledo electronic balance (XS 105).
2. Reagent
The purity of the (R) -naftopidil reference substance and the purity of the (S) -naftopidil reference substance are not lower than 99 percent, and the structural formula is shown in figure 1.
Acetonitrile and methanol are used as chromatographic purity, and water is used as ultrapure water.
Second, method and results
1. Chromatographic conditions
A chromatographic column: waters Xbridge C18 chromatography column (4.6 mm. times.150 mm, 5 μm);
mobile phase a phase: 5% methanol water solution (preparation method: methanol and water are uniformly mixed according to the volume ratio of 5: 95);
mobile phase B phase: a mixed organic solvent formed by acetonitrile and methanol according to the volume ratio of 4: 3;
elution mode and ratio: the phase A and the phase B are eluted at equal degrees according to the volume ratio of 35: 65;
flow rate: 1.0 mL/min;
detection wavelength: 283 nm;
column temperature: 30 ℃;
sample introduction amount: 10 μ L.
2. Solution preparation
Mixing the reference solution: taking a proper amount of mobile phase A and B, mixing the two phases according to the volume ratio of 35:65 to serve as a solvent, and preparing a mixed reference substance solution containing 0.6mg/mL of (R) -naftopidil reference substance and 0.6mg/mL of (S) -naftopidil reference substance.
(R) -naftopidil control solution: taking a proper amount of mobile phase A and B, mixing the two phases according to the volume ratio of 35:65 to be used as a solvent, and preparing a solution containing 0.1mg/mL of (R) -naftopidil reference substance.
(S) -naftopidil control solution: taking a proper amount of mobile phase A and B, mixing the two phases according to the volume ratio of 35:65 to be used as a solvent, and preparing a solution containing 0.1mg/mL of (S) -naftopidil reference substance.
3. Analysis of sample introduction
Respectively and precisely measuring 10 mu L of mixed reference substance solution, (R) -naftopidil reference substance solution and (S) -naftopidil reference substance solution, injecting into a liquid chromatograph, analyzing according to the chromatographic conditions, and recording a chromatogram. The results are shown in fig. 3, under the chromatographic conditions, (R) -naftopidil and (S) -naftopidil elute peaks together and cannot be separated effectively.
In conclusion, the method of the invention is based on the cheap eighteen carbon chromatographic columns as the separation means, effectively separates (R) -naftopidil and (S) -naftopidil, has short separation time, and can greatly reduce the separation cost of naftopidil and enantiomers thereof.
The above-described embodiments are intended to embody the essential technical content of the present invention, and the scope of the present invention should not be limited by the specific general details described in the above-described embodiments.
Claims (3)
1. An HPLC method for separating (R) -naftopidil and (S) -naftopidil at low cost, which is characterized in that: and adding a proper amount of chiral additive into the mobile phase, wherein the chiral additive is Fmoc-N-methyl-L-isoleucine.
2. An HPLC method according to claim 1, characterized in that: the mobile phase A is a 5% methanol aqueous solution containing 0.05 mol/LFmoc-N-methyl-L-isoleucine, the mobile phase B is a mixed organic solvent formed by acetonitrile and methanol according to a volume ratio of 4:3, and the A phase and the B phase are eluted at equal degrees according to a volume ratio of 35: 65.
3. An HPLC method according to claim 1, characterized in that: the separation column used was a Waters Xbridge C18 column (4.6 mm. times.150 mm, 5 μm).
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1649855A1 (en) * | 2003-07-16 | 2006-04-26 | Kyowa Hakko Kogyo Co., Ltd. | Medicinal composition |
| CN103018361A (en) * | 2012-12-04 | 2013-04-03 | 宁夏多维药业有限公司 | Method for detecting related substance in naftopidil dispersible tablet |
| CN103293235A (en) * | 2012-12-04 | 2013-09-11 | 宁夏多维药业有限公司 | Content measuring method of Naftopidil dispersible tablets |
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2020
- 2020-12-13 CN CN202011465890.5A patent/CN112611817B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1649855A1 (en) * | 2003-07-16 | 2006-04-26 | Kyowa Hakko Kogyo Co., Ltd. | Medicinal composition |
| US20060148885A1 (en) * | 2003-07-16 | 2006-07-06 | Kyowa Hakko Kogyo Co., Ltd. | Medicinal composition |
| CN103018361A (en) * | 2012-12-04 | 2013-04-03 | 宁夏多维药业有限公司 | Method for detecting related substance in naftopidil dispersible tablet |
| CN103293235A (en) * | 2012-12-04 | 2013-09-11 | 宁夏多维药业有限公司 | Content measuring method of Naftopidil dispersible tablets |
Non-Patent Citations (3)
| Title |
|---|
| XIAWEN LIU 等: "Determination of naftopidil enantiomers in rat plasma using chiral solid phases and pre-column derivatization high-performance liquid chromatography", 《JOURNAL OF CHROMATOGRAPHY B》 * |
| 孙银香 等: "手性高效液相色谱法测定萘哌地尔对映异构体(英文)", 《JOURNAL OF CHINESE PHARMACEUTICAL SCIENCES》 * |
| 肖溶 等: "Chiralpak AD-RH手性柱直接拆分萘哌地尔对映体", 《药物分析杂志》 * |
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