CN108535398A - A method of Tiagabine Hydrochloride chiral enantiomer is detached using reversed-phased high performace liquid chromatographic - Google Patents
A method of Tiagabine Hydrochloride chiral enantiomer is detached using reversed-phased high performace liquid chromatographic Download PDFInfo
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Abstract
The invention belongs to the separation technology fields of chiral enantiomer, more particularly to a kind of method using reversed-phased high performace liquid chromatographic separating chiral enantiomer, it is added to sulfobutyl-beta cyclodextrin aqueous solution as additive in original mobile phase, obtains required reverse-phase chromatography mobile phase；The original mobile phase is acetonitrile, and a concentration of 0.04g/ml of sulfobutyl-beta cyclodextrin aqueous solution, the volume ratio with sulfobutyl-beta cyclodextrin aqueous solution is 35:65, the flow velocity of mobile phase is 1.0ml/ml.The separation method of the present invention is and of low cost it is possible to prevente effectively from traditional beta cyclodextrin easily causes the defect of chromatographic column blocking, more economical to be applicable in, and measurement range is wide, has wide application prospect.
Description
Technical field
The invention belongs to the separation technology fields of chiral enantiomer, and in particular to a kind of to use reversed-phased high performace liquid chromatographic
The method of separating chiral enantiomer.
Background technology
Tiagabine Hydrochloride（Tiagabine Hydrochloride）, as the Newer antiepileptic of a novel binding mode, it is
One important breakthrough of Antiepileptic Drugs.USP 5, 010, 090（Andersen K. E. et al,J Med. Chem. 1993, 36:1716-1725.）The synthesis of Tiagabine Hydrochloride is reported earliest and its is inhibited as GABA intake albumen
Agent.It was listed first in Denmark and France by Novo Nordisk companies in 1996, in many country's listings in the whole world.For
About 30% existing drug epileptic attack rambunctious, it has notable curative effect.Tiagabine Hydrochloride contains there are one asymmetric carbon atom,
Belong to chiral drug, there are a pair of of optical isomer, R types Tiagabine and S type Tiagabines, structural formula as shown in Figure 1, face at present
R type Tiagabines are used on bed.Different drug stereoisomers pharmacodynamics in vivo, pharmacokinetics and toxicology
Property is different, and shows different therapeutic effect and adverse reaction, and American National Drug Administration regulation, all development have not
The drug of symmetrical centre, it is necessary to provide chiral resolution as a result, making it to produce optical voidness drug, therefore, to ensure hydrochloric acid thiophene
Add the quality of guest's bulk pharmaceutical chemicals and use clinical safety, needs to find a kind of reliably and effectively analysis method separation determination salt
The chiral isomer of sour Tiagabine.
For chiral molecules in addition to optical activity has differences, physical property is identical, and chemical property may be similar, therefore, with routine
High performance liquid chromatography be difficult to realize two kinds of chiral molecules separation.High performance liquid chromatography at present（HPLC）Resolving chiral medicine
Object has indirect method and direct method.Indirect method refers to chiral reagent derivatization method, i.e., drug enantiomer is first anti-with derivatization reagent
Diastereomer should be formed, then carries out chromatographic isolation measurement.Direct rule is split using chiral stationary phase or Chiral Mobile Phase,
HPLC method resolving chiral drugs mostly use greatly expensive chiral column, and use the fewer of Chiral Mobile Phase.Cyclodextrin is
Common chiral resolving agent, chiral separation mechanism are that the enantiomer molecule based on chipal compounds enters cyclodextrin cavity
Host and guest's precursor reactant（Such as various hydrophobicitys, hydrogen bond reaction）And be split, complexing have High level of stereoselectivity selectivity and
And it is cheap, the prior art uses beta-cyclodextrin as Mobile Phase Additives, using the chiral molecule of high performance liquid chromatography
It is split, but beta-cyclodextrin water solubility is poor, be easy to cause the blocking of chromatographic column, therefore, the present invention is preferable using dissolubility
Sulfobutyl ether β _ cyclodextrin as chiral resolving agent, ensure that the economical and effective separation of Tiagabine Hydrochloride chiral enantiomer.
Invention content
In view of the above-mentioned deficiencies in the prior art, it is an object of the present invention to provide a kind of using reversed-phased high performace liquid chromatographic point
Method from chiral enantiomer.This method is it is possible to prevente effectively from traditional beta-cyclodextrin easily causes the defect of chromatographic column blocking, cost
It is cheap, it is more economical to be applicable in, and measurement range is wide, has wide application prospect.
For achieving the above object, the present invention adopts the following technical scheme that：
A method of Tiagabine Hydrochloride chiral enantiomer is detached using reversed-phased high performace liquid chromatographic：By sulphur butyl-β-ring paste
Smart aqueous solution is added to as additive in original mobile phase, obtains required reverse-phase chromatography mobile phase, right using the mobile phase
Bulk pharmaceutical chemicals Tiagabine Hydrochloride chiral enantiomer (3R,3’R) -1- [4 ', 4 '-two (3 ' '-methyl -2 ' '-thienyls) -3 ', 4 ' -
Dihydroxy -1 '-butyl]-nipecotic acid hydrochloride（R Tiagabines）(3R,3’S) -1- [4 ', 4 '-two (3 ' '-methyl -
2 ' '-thienyl) -3 ', 4 '-dihydroxy -1 '-butyl]-nipecotic acid hydrochloride（S Tiagabines）Carry out RP-HPLC
Chromatographic isolation.
Optionally, the original mobile phase is acetonitrile.
Optionally, a concentration of 0.04g/ml ~ 0.05g/ml of the Sulfobutyl ether β _ cyclodextrin aqueous solution.
Optionally, original mobile phase and the volume ratio of Sulfobutyl ether β _ cyclodextrin aqueous solution are 30:70~35:65.
Optionally, when carrying out reversed-phase high performance liquid chromatography separation to Tiagabine Hydrochloride chiral enantiomer, the flow velocity of mobile phase
For 1.0ml/min ~ 1.2ml/min.
Optionally, when being detached using reversed-phased high performace liquid chromatographic, reverse-phase chromatography stationary phase is Thermo Hypercarb
Chromatographic column.
Optionally, the column temperature of Thermo Hypercarb chromatographic columns is 40 DEG C ~ 45 DEG C.
Optionally, the dimensions of Thermo Hypercarb chromatographic columns is 250mm * 4.6mm*5 μm.
Most preferred technical solution is：
A method of Tiagabine Hydrochloride chiral enantiomer is detached using reversed-phased high performace liquid chromatographic：By sulphur butyl-β-ring paste
Smart aqueous solution is added to as additive in original mobile phase, obtains required reverse-phase chromatography mobile phase；Wherein original mobile phase
For acetonitrile, a concentration of 0.04g/ml of Sulfobutyl ether β _ cyclodextrin aqueous solution, original mobile phase and Sulfobutyl ether β _ cyclodextrin are water-soluble
The volume ratio of liquid is 35:65, when carrying out reversed-phase high performance liquid chromatography separation to Tiagabine Hydrochloride chiral enantiomer, the stream of mobile phase
Speed is 1.0ml/min, and reverse-phase chromatography stationary phase is Thermo Hypercarb chromatographic columns, Thermo Hypercarb chromatographic columns
Column temperature is 40 DEG C ~ 45 DEG C, and the dimensions of Thermo Hypercarb chromatographic columns is 250mm * 4.6mm*5 μm.
Compared with prior art, the present invention includes following advantages：
1）The present invention selects Sulfobutyl ether β _ cyclodextrin as Mobile Phase Additives, since Sulfobutyl ether β _ cyclodextrin dissolves in water
It spends larger, therefore chromatographic column blocking is not easily caused as mobile phase, it is possible to prevente effectively from traditional beta-cyclodextrin easily causes color
Compose the defect that column blocks；
2）When the chiral enantiomer of the method according to embodiments of the present invention is detached, it can be realized pair using C18 chromatographic columns
Efficiently separating for body is reflected, it is easy to operate；Relative to traditional enantiomers separation method, such as chiral stationary phase high-efficient liquid phase color
Spectrometry, the method is using chiral chromatographic column, since chiral chromatographic column is to schedule polymer by monomer solid with optical activation
Deng the chromatographic column of a kind of special facture, expensive and selectivity is stronger, is only applicable to the separation of a substance, therefore expend
It is of high cost and complicated for operation；The method of the invention is of low cost, more economical to be applicable in, and measurement range is wide, has and answers extensively
Use foreground.
Description of the drawings
Fig. 1 is the chiral isomer structure chart of Tiagabine Hydrochloride；
Fig. 2-1, Fig. 2-2, Fig. 2-3 are the chiral enantiomers of the embodiment of the present invention under the conditions of different Chiral Mobile Phase Additives
High-efficient liquid phase chromatogram；
Fig. 3-1, Fig. 3-2, Fig. 3-3 are the chiral enantiomers of the embodiment of the present invention in various concentration chiral additives（Sulphur butyl-β-
Cyclodextrin）Under the conditions of high-efficient liquid phase chromatogram；
Fig. 4-1, Fig. 4-2 are the chiral enantiomers of the embodiment of the present invention in different mobile phases（Acetonitrile and methanol）Under the conditions of it is efficient
Liquid chromatogram；
Fig. 5-1, Fig. 5-2, Fig. 5-3, Fig. 5-4 are the chiral enantiomers of the embodiment of the present invention under the conditions of different mobile phase ratios
High-efficient liquid phase chromatogram；
Fig. 6-1, Fig. 6-2 are high-efficient liquid phase chromatogram of the chiral enantiomer of the embodiment of the present invention under the conditions of different chromatographic columns.
Specific implementation mode
To make those skilled in the art be better understood from the present invention, illustrate this hair below by way of multiple specific embodiments
The bright method using reversed-phased high performace liquid chromatographic separating chiral enantiomer.
Embodiment 1
The separation method of Tiagabine Hydrochloride chiral enantiomer：
（1）About 5mg Tiagabine Hydrochloride chiral enantiomer samples are weighed, acetonitrile is used to carry out the dissolving of sample as solvent；
（2）By step (1) described sample solution after 0.22 μm of membrane filtration, respectively with acetonitrile/0.04g/ml carboxymethyls-β-
Cyclodextrin aqueous solution, acetonitrile/0.04g/ml Sulfobutyl ether β _ cyclodextrins aqueous solution, acetonitrile/0.04g/ml hydroxypropyl-β-cyclodextrins
Aqueous solution is mobile phase, and injection high performance liquid chromatograph is measured；
Chromatographic condition：
Shimadzu LC-2010A HT high performance liquid chromatographs
Chromatographic column：Thermo Hypercarb（250mm *4.6mm*5μm）
Reagent：Acetonitrile（Chromatographic grade）, carboxymethyl-beta-cyclodextrin, Sulfobutyl ether β _ cyclodextrin, hydroxypropyl-β-cyclodextrin, secondary water；
Mobile phase：VAcetonitrile:VCarboxymethyl-beta-cyclodextrin aqueous solution=35:65、VAcetonitrile:VSulfobutyl ether β _ cyclodextrin=35:65、VAcetonitrile:VHydroxypropyl-β-cyclodextrin=35：65；
The flow velocity of mobile phase：1.0ml/min；
The sample size of chiral enantiomer：20μl；
Carry out liquid phase test of the present embodiment to Tiagabine Hydrochloride chiral enantiomer under different chromatographic columns, test result such as Fig. 2-
1, shown in Fig. 2-2, Fig. 2-3, separation parameter such as the following table 1.
Separation parameter of the 1 Tiagabine Hydrochloride chiral enantiomer of table under the conditions of different Chiral Mobile Phase Additives
By Fig. 2-1, Fig. 2-2, Fig. 2-3 and 1 data of table it is found that other chromatographic conditions under the same conditions, investigated respectively not
Influence of the same Chiral Mobile Phase Additives to Tiagabine Hydrochloride chiral separation.Carboxymethyl-beta-cyclodextrin system is under this condition
It is unable to reach baseline separation, though hydroxypropyl-β-cyclodextrin system can be detached preferably, retention time is relatively long, sulphur butyl-β-
It can preferably be detached in cyclodextrin system, and disengaging time is moderate, therefore the present invention selects Sulfobutyl ether β _ cyclodextrin as examination
Test Chiral Mobile Phase Additives.
Embodiment 2
The separation method of Tiagabine Hydrochloride chiral enantiomer：
（1）About 5mg Tiagabine Hydrochloride chiral enantiomer samples are weighed, acetonitrile is used to carry out the dissolving of sample as solvent；
（2）By step (1) described sample solution after 0.22 μm of membrane filtration, respectively with acetonitrile/water, acetonitrile/0.02g/ml
Sulfobutyl ether β _ cyclodextrin aqueous solution, acetonitrile/0.03g/ml Sulfobutyl ether β _ cyclodextrins aqueous solution, acetonitrile/0.04g/ml sulphur butyls-
Beta-cyclodextrin aqueous solution is mobile phase, and injection high performance liquid chromatograph is measured；
Chromatographic condition：
Shimadzu LC-2010A HT high performance liquid chromatographs
Chromatographic column：Thermo Hypercarb（250mm *4.6mm*5μm）
Reagent：Acetonitrile（Chromatographic grade）, Sulfobutyl ether β _ cyclodextrin, secondary water
Mobile phase：Acetonitrile:Sulfobutyl ether β _ cyclodextrin aqueous solution=35:65
The flow velocity of mobile phase：1.0ml/min
The sample size of chiral enantiomer：20μl
Efficient liquid of the embodiment of the present invention to the fractionation Tiagabine Hydrochloride chiral enantiomer under various concentration Sulfobutyl ether β _ cyclodextrin
Phase chromatogram, test result is as shown in Fig. 3-1, Fig. 3-2, Fig. 3-3, separation parameter such as the following table 2.
Separation parameter of the 2 Tiagabine Hydrochloride chiral enantiomer of table under the conditions of various concentration Chiral Mobile Phase Additives
By Fig. 3-1, Fig. 3-2, Fig. 3-3 and 2 data of table it is found that with Thermo Hypercarb（250mm *4.6mm*5μm）Color
Column is composed under the conditions of reverse phase stationary phase, to increase with the concentration of mobile phase Sulfobutyl ether β _ cyclodextrin aqueous solution, two kinds of enantiomer phases
Retention time is shortened, separating degree increases, and when using acetonitrile/0.04g/ml Sulfobutyl ether β _ cyclodextrins aqueous solution as mobile phase, two
Kind enantiomer can reach preferable separating effect, and the concentration due to increasing cyclodextrin is possible to that liquid-phase chromatographic column can be blocked, because
This is it is not recommended that increase cyclodextrin concentration, preferably 0.04g/ml.
Embodiment 3
The separation method of Tiagabine Hydrochloride chiral enantiomer：
（1）About 5mg Tiagabine Hydrochloride chiral enantiomer samples are weighed, acetonitrile is used to carry out the dissolving of sample as solvent；
（2）By step（1）The sample solution is after 0.22 μm of membrane filtration, respectively with acetonitrile/0.04g/ml sulphur butyls-β-
Cyclodextrin aqueous solution, methanol/0.04g/ml Sulfobutyl ether β _ cyclodextrin aqueous solutions be mobile phase, injection high performance liquid chromatograph into
Row measures；
Chromatographic condition：
Shimadzu LC-2010A HT high performance liquid chromatographs
Chromatographic column：Thermo Hypercarb（250mm *4.6mm*5μm）
Reagent：Acetonitrile（Chromatographic grade）, methanol（Chromatographic grade）, Sulfobutyl ether β _ cyclodextrin, secondary water
Mobile phase：Acetonitrile:Sulfobutyl ether β _ cyclodextrin aqueous solution=35:65
Methanol：Sulfobutyl ether β _ cyclodextrin aqueous solution=35:65
The flow velocity of mobile phase：1.0ml/min
The sample size of chiral enantiomer：20μl
The embodiment of the present invention to Tiagabine Hydrochloride chiral enantiomer respectively organic phase flow be acetonitrile and methanol under conditions of into
Row liquid phase is tested, and for test result as shown in Fig. 4-1, Fig. 4-2, separation parameter is as shown in table 3.
Separation parameter of the 3 Tiagabine Hydrochloride chiral enantiomer of table under the conditions of different mobile phases
By Fig. 4-1, Fig. 4-2 with 3 data of table it is found that when other identical chromatographic conditions, with acetonitrile/0.04g/ml sulphur butyls-β-ring
Dextrin in aqueous solution, which is mobile phase, can realize the chiral enantiomer good separation；And with methanol/0.04g/ml Sulfobutyl ether β _ cyclodextrins
For mobile phase, the chiral enantiomer remains in 40min in chromatographic column aqueous solution, and required analysis time is longer.
Embodiment 4
The separation method of Tiagabine Hydrochloride chiral enantiomer：
（1）About 5mg Tiagabine Hydrochloride chiral enantiomer samples are weighed, acetonitrile is used to carry out the dissolving of sample as solvent；
（2）By step（1）The sample solution is after 0.22 μm of membrane filtration, respectively with acetonitrile/0.04g/ml sulphur butyls-β-
Cyclodextrin aqueous solution is mobile phase, and injection high performance liquid chromatograph is measured, and mobile phase ratio is respectively：VAcetonitrile:
VSulfobutyl ether β _ cyclodextrin aqueous solution=45:55、VAcetonitrile:VSulfobutyl ether β _ cyclodextrin aqueous solution=40:60、VAcetonitrile:VSulfobutyl ether β _ cyclodextrin aqueous solution=35:65、VAcetonitrile:
VSulfobutyl ether β _ cyclodextrin aqueous solution=30:70；
Chromatographic condition：
Shimadzu LC-2010A HT high performance liquid chromatographs
Chromatographic column：Thermo Hypercarb（250mm *4.6mm*5μm）
Reagent：Acetonitrile（Chromatographic grade）, Sulfobutyl ether β _ cyclodextrin, secondary water
The flow velocity of mobile phase：1.0ml/min
The sample size of chiral enantiomer：20μl
Carry out liquid phase test of the embodiment of the present invention to Tiagabine Hydrochloride chiral enantiomer under the conditions of different mobile phase ratios is surveyed
For test result as shown in Fig. 5-1, Fig. 5-2, Fig. 5-3, Fig. 5-4, separation parameter is as shown in table 4.
The separation parameter of table 4, chiral enantiomer under the conditions of different mobile phase ratios
By Fig. 5-1, Fig. 5-2, Fig. 5-3, Fig. 5-4 and 4 data of table it is found that working as mobile phase ratio VAcetonitrile:VSulfobutyl ether β _ cyclodextrin aqueous solutionIt is 35:
When 65, good fractionation can be obtained in separating degree 1.5, the chiral enantiomer, and has appropriate retention time, and works as mobile phase
Ratio VAcetonitrile:VSulfobutyl ether β _ cyclodextrin aqueous solutionIt is 45:55、40:When 60, which is respectively 0.7 and 0.9, cannot be met
Its good separation, as mobile phase ratio VAcetonitrile:VSulfobutyl ether β _ cyclodextrin aqueous solutionIt is 30:Though the chiral enantiomer can well be torn open when 70
Point, but retention time is longer, causes operation to take longer, it is therefore preferable that mobile phase ratio VAcetonitrile:VSulfobutyl ether β _ cyclodextrin aqueous solutionIt is 35:
65。
Embodiment 5
The separation method of Tiagabine Hydrochloride chiral enantiomer：
（1）About 5mg Tiagabine Hydrochloride chiral enantiomer samples are weighed, acetonitrile is used to carry out the dissolving of sample as solvent；
（2）By step（1）The sample solution is after 0.22 μm of membrane filtration, respectively with acetonitrile/0.04g/ml sulphur butyls-β-
Cyclodextrin aqueous solution is mobile phase, and injection high performance liquid chromatograph is measured；
Chromatographic condition：
Shimadzu LC-2010A HT high performance liquid chromatographs
Chromatographic column：Thermo Hypercarb（250mm *4.6mm*5μm）With phenomenex Gemini C18（250mm *
4.6mm*5μm）
Reagent：Acetonitrile（Chromatographic grade）, Sulfobutyl ether β _ cyclodextrin, secondary water
Mobile phase：Acetonitrile:Sulfobutyl ether β _ cyclodextrin aqueous solution=35:65
The flow velocity of mobile phase：1.0ml/min
The sample size of chiral enantiomer：20μl
Carry out liquid phase test of the present embodiment to Tiagabine Hydrochloride chiral enantiomer under different chromatographic columns, test result such as Fig. 6-
1, shown in Fig. 6-2, separation parameter such as the following table 5.
Separation parameter of the 5 Tiagabine Hydrochloride chiral enantiomer of table under the conditions of different chromatographic columns
By the data of Fig. 6-1, Fig. 6-2 and table 5 as it can be seen that other chromatographic conditions under the same conditions, utilize Thermo
When Hypercarb chromatographic columns carry out the Chiral Separation, retention time is respectively 10.8 and 12.8min, separating degree 1.5,
When the good fractionation of chiral enantiomer can be achieved, and phenomenex Gemini C18 chromatographic columns being utilized to split, it is unable to reach hand
The separation of property enantiomer.
The foregoing is merely presently preferred embodiments of the present invention, all equivalent changes done according to scope of the present invention patent with
Modification should all belong to the covering scope of the present invention.
Claims (8)
1. a kind of method detaching Tiagabine Hydrochloride chiral enantiomer using reversed-phased high performace liquid chromatographic, it is characterised in that：It will
Sulfobutyl ether β _ cyclodextrin aqueous solution is added to as additive in original mobile phase, obtains required reverse-phase chromatography mobile phase.
2. the side according to claim 1 for detaching Tiagabine Hydrochloride chiral enantiomer using reversed-phased high performace liquid chromatographic
Method, it is characterised in that：The original mobile phase is acetonitrile.
3. the side according to claim 1 for detaching Tiagabine Hydrochloride chiral enantiomer using reversed-phased high performace liquid chromatographic
Method, it is characterised in that：A concentration of 0.04g/ml ~ 0.05g/ml of the Sulfobutyl ether β _ cyclodextrin aqueous solution.
4. the side according to claim 1 for detaching Tiagabine Hydrochloride chiral enantiomer using reversed-phased high performace liquid chromatographic
Method, it is characterised in that：Original mobile phase and the volume ratio of Sulfobutyl ether β _ cyclodextrin aqueous solution are 30:70~35:65.
5. the side according to claim 1 for detaching Tiagabine Hydrochloride chiral enantiomer using reversed-phased high performace liquid chromatographic
Method, it is characterised in that：When carrying out reversed-phase high performance liquid chromatography separation to Tiagabine Hydrochloride chiral enantiomer, the flow velocity of mobile phase is
1.0ml/min~1.2ml/min。
6. the side according to claim 1 for detaching Tiagabine Hydrochloride chiral enantiomer using reversed-phased high performace liquid chromatographic
Method, it is characterised in that：When being detached using reversed-phased high performace liquid chromatographic, reverse-phase chromatography stationary phase is Thermo Hypercarb colors
Compose column.
7. the side according to claim 6 for detaching Tiagabine Hydrochloride chiral enantiomer using reversed-phased high performace liquid chromatographic
Method, it is characterised in that：The column temperature of Thermo Hypercarb chromatographic columns is 40 DEG C ~ 45 DEG C.
8. the side according to claim 6 for detaching Tiagabine Hydrochloride chiral enantiomer using reversed-phased high performace liquid chromatographic
Method, it is characterised in that：The dimensions of Thermo Hypercarb chromatographic columns is 250mm * 4.6mm*5 μm.
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