The invention belongs to the technical field of separation of chiral enantiomers, and particularly relates to a method for separating chiral enantiomers by adopting a reversed-phase high performance liquid chromatography, wherein sulfobutyl- β -cyclodextrin aqueous solution is used as an additive and added into an original mobile phase to obtain a required reversed-phase chromatographic mobile phase, the original mobile phase is acetonitrile, the concentration of the sulfobutyl- β -cyclodextrin aqueous solution is 0.04g/ml, the volume ratio of the sulfobutyl- β -cyclodextrin aqueous solution to the sulfobutyl- β -cyclodextrin aqueous solution is 35:65, and the flow rate of the mobile phase is 1.0 ml/ml.
Description Method for separating tiagabine hydrochloride chiral enantiomer by adopting reversed-phase high-performance liquid chromatographyTechnical Field
The invention belongs to the technical field of separation of chiral enantiomers, and particularly relates to a method for separating chiral enantiomers by adopting a reversed-phase high performance liquid chromatography.
Background
Tiagabine Hydrochloride (Tiagabine Hydrochloride) as a novel antiepileptic drug with a novel action mode is an important breakthrough in the treatment of antiepileptic drugs. USP 5, 010, 090 (Andersen k.e. et al,J Med. Chem. 1993,361716-1725.) the synthesis of tiagabine hydrochloride and its use as GABA uptake protein inhibitors were first reported. First marketed in Denmark and France by Novo Nordisk corporation in 1996, now in many countries around the world. It has obvious curative effect on about 30% of epilepsy attack which is difficult to control by the existing medicine. The tiagabine hydrochloride contains a chiral carbon atom, belongs to chiral drugs, has a pair of optical isomers, namely R-type tiagabine and S-type tiagabine, and has a structural formula shown in figure 1, wherein R-type tiagabine is clinically used at present. Different stereoisomers of the drug have different pharmacodynamics, pharmacokinetics and toxicology properties in vivo and show different treatment effects and adverse reactions, and the American national medicine administration stipulates that chiral resolution results must be given to produce optically pure drugs when drugs with asymmetric centers are developed, so that a search for an optically pure drug is needed to ensure the quality and clinical safety of the tiagabine hydrochloride bulk drugThe method is a reliable and effective analysis method for separating and determining the chiral isomer of tiagabine hydrochloride.
The chiral drugs are separated by the HPLC method, most of the chiral drugs are separated by adopting a chiral column with high price, and the chiral mobile phase is less in the adoption of the indirect method, the cyclodextrin is a common chiral resolving agent, the chiral separation mechanism is based on the main-object reaction (such as various hydrophobicity, hydrogen bond reaction and the like) of the enantiomer molecules of the chiral compounds entering a cyclodextrin cavity, and the chiral resolving agent is resolved, the complexation has high stereoselectivity and low price, the prior art adopts β -cyclodextrin as a mobile phase additive, and the chiral molecules are resolved by adopting the high performance liquid chromatography, but β -cyclodextrin is poor in water solubility, so that the chromatographic column is easy to be blocked, and the invention adopts better solubility-cyclodextrin as a chiral butyl- β effective resolving agent and hydrochloric acid to ensure effective separation of chiral enantiomers.
Disclosure of Invention
The invention aims to provide a method for separating chiral enantiomers by adopting a reversed-phase high performance liquid chromatography, aiming at the defects of the prior art, the method can effectively avoid the defect that the traditional β -cyclodextrin is easy to cause chromatographic column blockage, and has the advantages of low cost, more economical and applicable property, wide measurement range and wide application prospect.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for separating tiagabine hydrochloride chiral enantiomer by reversed-phase high performance liquid chromatography comprises adding sulfobutyl- β -cyclodextrin water solution as additive into original mobile phase to obtain required reversed-phase chromatographic mobile phase, and subjecting crude drug tiagabine hydrochloride to reverse phase chromatography by using the mobile phaseCarbene chiral enantiomer (3)R,3âR) -1- [4 ', 4 ' -bis (3 ' ' -methyl-2 ' ' -thienyl) -3 ', 4 ' -dihydroxy-1 ' -butyl]3-Piperidinecarboxylic acid hydrochloride (R tiagabine) and (3)R,3âS) -1- [4 ', 4 ' -bis (3 ' ' -methyl-2 ' ' -thienyl) -3 ', 4 ' -dihydroxy-1 ' -butyl]And (3) -piperidinecarboxylic acid hydrochloride (S-tiagabine) is subjected to reverse phase high performance liquid chromatography separation.
Optionally, the original mobile phase is acetonitrile.
Optionally, the concentration of the sulfobutyl- β -cyclodextrin aqueous solution is 0.04 g/ml-0.05 g/ml.
Optionally, the volume ratio of the original mobile phase to the sulfobutyl- β -cyclodextrin aqueous solution is 30: 70-35: 65.
Optionally, when the tiagabine hydrochloride chiral enantiomer is subjected to reversed-phase high performance liquid chromatography separation, the flow rate of the mobile phase is 1.0 ml/min-1.2 ml/min.
Alternatively, when the reversed-phase high performance liquid chromatography is used for separation, the reversed-phase chromatographic stationary phase is a Thermo Hypercarb chromatographic column.
Optionally, the Thermo Hypercarb column has a column temperature of 40 â to 45 â.
Alternatively, the Thermo Hypercarb column has a size specification of 250mm 4.6 mm 5 μm.
The most preferable technical scheme is as follows:
a method for separating tiagabine hydrochloride chiral enantiomers by adopting reverse-phase high performance liquid chromatography comprises the step of adding sulfobutyl- β -cyclodextrin aqueous solution serving as an additive into an original mobile phase to obtain a required reverse-phase chromatographic mobile phase, wherein the original mobile phase is acetonitrile, the concentration of the sulfobutyl- β -cyclodextrin aqueous solution is 0.04g/ml, the volume ratio of the original mobile phase to the sulfobutyl- β -cyclodextrin aqueous solution is 35:65, the flow rate of the mobile phase is 1.0ml/min when the tiagabine hydrochloride chiral enantiomers are subjected to reverse-phase high performance liquid chromatography separation, the reverse-phase chromatographic stationary phase is a Thermo Hypercarb chromatographic column, the column temperature of the Thermo Hypercarb chromatographic column is 40-45 â, and the size specification of the Thermo Hypercarb chromatographic column is 250 mm-4.6 mm-5 mu m.
Compared with the prior art, the invention has the following advantages:
1) according to the invention, sulfobutyl- β -cyclodextrin is selected as a mobile phase additive, and because sulfobutyl- β -cyclodextrin has high solubility in water, the sulfobutyl- β -cyclodextrin is used as a mobile phase and is not easy to cause chromatographic column blockage, so that the defect that the traditional β -cyclodextrin is easy to cause chromatographic column blockage can be effectively avoided;
2) when the method disclosed by the embodiment of the invention is used for separating the chiral enantiomers, the C18 chromatographic column is used for realizing the high-efficiency separation of the enantiomers, and the operation is simple; compared with the traditional chiral enantiomer resolution method, such as chiral stationary phase high performance liquid chromatography, the method adopts a chiral chromatographic column, and the chiral chromatographic column is a chromatographic column which is specially made by fixing a monomer with optical activity on a polymer and the like, is expensive in price and strong in selectivity, is only suitable for separating one type of substance, and is high in cost and complex in operation; the method disclosed by the invention is low in cost, more economical and applicable, wide in measurement range and wide in application prospect.
Drawings
FIG. 1 is a structural diagram of a chiral isomer of tiagabine hydrochloride;
2-1, 2-2, 2-3 are high performance liquid chromatograms of chiral enantiomers of embodiments of the invention with different chiral mobile phase additives;
3-1, 3-2, 3-3 are high performance liquid chromatograms of chiral enantiomers of embodiments of the present invention with different concentrations of chiral additive (sulfobutyl- β -cyclodextrin);
FIGS. 4-1 and 4-2 are high performance liquid chromatograms of chiral enantiomers of embodiments of the present invention under different mobile phase (acetonitrile and methanol) conditions;
5-1, 5-2, 5-3, 5-4 are high performance liquid chromatograms of chiral enantiomers under different flow phase ratio conditions according to embodiments of the present invention;
FIGS. 6-1 and 6-2 are high performance liquid chromatograms of chiral enantiomers of embodiments of the invention under different column conditions.
Detailed Description
In order that those skilled in the art will better understand the present invention, the following examples are provided to illustrate the present invention in terms of a method for separating chiral enantiomers using reversed phase high performance liquid chromatography.
Example 1
The separation method of the tiagabine hydrochloride chiral enantiomer comprises the following steps:
(1) weighing about 5mg of tiagabine hydrochloride chiral enantiomer sample, and dissolving the sample by using acetonitrile as a solvent;
(2) filtering the sample solution obtained in the step (1) by a 0.22-micron filter membrane, and injecting acetonitrile/0.04 g/ml carboxymethyl- β -cyclodextrin aqueous solution, acetonitrile/0.04 g/ml sulfobutyl- β -cyclodextrin aqueous solution and acetonitrile/0.04 g/ml hydroxypropyl- β -cyclodextrin aqueous solution as mobile phases into a high performance liquid chromatograph for determination;
chromatographic conditions are as follows:
shimadzu LC-2010A HT high performance liquid chromatograph
A chromatographic column: thermo Hypercarb (250 mm 4.6 mm 5 μm)
Reagent acetonitrile (chromatographic grade), carboxymethyl- β -cyclodextrin, sulfobutyl- β -cyclodextrin, hydroxypropyl- β -cyclodextrin and secondary water;
mobile phase: vAcetonitrile:VCarboxymethyl- β -cyclodextrin aqueous solution=35:65ãVAcetonitrile:VSulfobutyl- β -cyclodextrin=35:65ãVAcetonitrile:VHydroxypropyl- β -cyclodextrin=35ï¼65ï¼
Flow rate of mobile phase: 1.0 ml/min;
the amount of chiral enantiomer introduced: 20 mu l of the mixture;
in this example, the tiagabine hydrochloride chiral enantiomer is subjected to liquid phase tests under different chromatographic columns, and the test results are shown in fig. 2-1, fig. 2-2 and fig. 2-3, and the separation parameters are shown in the following table 1.
TABLE 1 separation parameters of tiagabine hydrochloride chiral enantiomers under different chiral mobile phase additive conditions
As can be seen from the data in FIGS. 2-1, 2-2, 2-3 and Table 1, under the same other chromatographic conditions, the influence of different chiral mobile phase additives on the chiral separation of tiagabine hydrochloride is respectively examined, the carboxymethyl- β -cyclodextrin system cannot achieve baseline separation under the conditions, the hydroxypropyl- β -cyclodextrin system can be well separated but has relatively long retention time, and the sulfobutyl- β -cyclodextrin system can be well separated and has moderate separation time, so that the sulfobutyl- β -cyclodextrin is selected as the test chiral mobile phase additive.
Example 2
The separation method of the tiagabine hydrochloride chiral enantiomer comprises the following steps:
(1) weighing about 5mg of tiagabine hydrochloride chiral enantiomer sample, and dissolving the sample by using acetonitrile as a solvent;
(2) filtering the sample solution obtained in the step (1) by a 0.22-micron filter membrane, and injecting acetonitrile/water, acetonitrile/0.02 g/ml sulfobutyl- β -cyclodextrin aqueous solution, acetonitrile/0.03 g/ml sulfobutyl- β -cyclodextrin aqueous solution and acetonitrile/0.04 g/ml sulfobutyl- β -cyclodextrin aqueous solution into a high performance liquid chromatograph for determination by respectively using acetonitrile/water, acetonitrile/0.02 g/ml sulfobutyl- β -cyclodextrin aqueous solution and acetonitrile/0.04 g/ml sulfobutyl- β -cyclodextrin aqueous solution as mobile phases;
chromatographic conditions are as follows:
shimadzu LC-2010A HT high performance liquid chromatograph
A chromatographic column: thermo Hypercarb (250 mm 4.6 mm 5 μm)
Reagent acetonitrile (chromatographic grade), sulfobutyl- β -cyclodextrin and secondary water
Mobile phase acetonitrile sulfobutyl- β -cyclodextrin water solution =35:65
Flow rate of mobile phase: 1.0ml/min
The amount of chiral enantiomer introduced: 20 μ l
In the embodiment of the invention, the high performance liquid chromatogram of the tiagabine hydrochloride chiral enantiomer is obtained by resolving the tiagabine hydrochloride chiral enantiomer under sulfobutyl- β -cyclodextrin with different concentrations, the test results are shown in figure 3-1, figure 3-2 and figure 3-3, and the separation parameters are shown in the following table 2.
TABLE 2 separation parameters of tiagabine hydrochloride chiral enantiomers under different concentrations of chiral mobile phase additive
From the data in FIGS. 3-1, 3-2, 3-3 and Table 2, it can be seen that under the condition of using Thermo Hypercarb (250 mm 4.6 mm 5 μm) column as the reversed phase stationary phase, the relative retention time of the two enantiomers is shortened and the separation degree is increased as the concentration of sulfobutyl- β -cyclodextrin aqueous solution in the mobile phase is increased, while when acetonitrile/0.04 g/ml sulfobutyl- β -cyclodextrin aqueous solution is used as the mobile phase, the two enantiomers can achieve better separation effect, and the addition of cyclodextrin concentration, preferably 0.04g/ml, is not recommended because the increase of cyclodextrin concentration may block the liquid column.
Example 3
The separation method of the tiagabine hydrochloride chiral enantiomer comprises the following steps:
(1) weighing about 5mg of tiagabine hydrochloride chiral enantiomer sample, and dissolving the sample by using acetonitrile as a solvent;
(2) filtering the sample solution obtained in the step (1) by a 0.22-micron filter membrane, and injecting acetonitrile/0.04 g/ml sulfobutyl- β -cyclodextrin aqueous solution and methanol/0.04 g/ml sulfobutyl- β -cyclodextrin aqueous solution into a high performance liquid chromatograph for determination by taking the acetonitrile/0.04 g/ml sulfobutyl- β -cyclodextrin aqueous solution and the methanol/0.04 g/ml sulfobutyl- β -cyclodextrin aqueous solution as mobile phases;
chromatographic conditions are as follows:
shimadzu LC-2010A HT high performance liquid chromatograph
A chromatographic column: thermo Hypercarb (250 mm 4.6 mm 5 μm)
The reagent is acetonitrile (chromatographic grade), methanol (chromatographic grade), sulfobutyl- β -cyclodextrin and secondary water
Mobile phase acetonitrile sulfobutyl- β -cyclodextrin water solution =35:65
Methanol sulfobutyl- β -aqueous cyclodextrin solution =35:65
Flow rate of mobile phase: 1.0ml/min
The amount of chiral enantiomer introduced: 20 μ l
In the embodiment of the invention, the tiagabine hydrochloride chiral enantiomer is subjected to liquid phase test under the condition that the organic mobile phase is acetonitrile and methanol, the test results are shown in figures 4-1 and 4-2, and the separation parameters are shown in table 3.
TABLE 3 separation parameters of tiagabine hydrochloride chiral enantiomers under different mobile phase conditions
As can be seen from the data in FIG. 4-1, FIG. 4-2 and Table 3, when the other chromatographic conditions are the same, the good separation of the chiral enantiomer can be achieved by using acetonitrile/0.04 g/ml sulfobutyl- β -cyclodextrin aqueous solution as the mobile phase, while the chiral enantiomer still remains in the chromatographic column within 40min by using methanol/0.04 g/ml sulfobutyl- β -cyclodextrin aqueous solution as the mobile phase, and the required analysis time is longer.
Example 4
The separation method of the tiagabine hydrochloride chiral enantiomer comprises the following steps:
(1) weighing about 5mg of tiagabine hydrochloride chiral enantiomer sample, and dissolving the sample by using acetonitrile as a solvent;
(2) filtering the sample solution in the step (1) by a 0.22 mu m filter membrane, injecting acetonitrile/0.04 g/ml sulfobutyl- β -cyclodextrin aqueous solution as a mobile phase into a high performance liquid chromatograph for determination, wherein the mobile phase ratio is VAcetonitrile:VSulfobutyl- β -cyclodextrin aqueous solution=45:55ãVAcetonitrile:VSulfobutyl- β -cyclodextrin aqueous solution=40:60ãVAcetonitrile:VSulfobutyl- β -cyclodextrin aqueous solution=35:65ãVAcetonitrile:VSulfobutyl- β -cyclodextrin aqueous solution=30:70ï¼
Chromatographic conditions are as follows:
shimadzu LC-2010A HT high performance liquid chromatograph
A chromatographic column: thermo Hypercarb (250 mm 4.6 mm 5 μm)
Reagent acetonitrile (chromatographic grade), sulfobutyl- β -cyclodextrin and secondary water
Flow rate of mobile phase: 1.0ml/min
The amount of chiral enantiomer introduced: 20 μ l
In the embodiment of the invention, the liquid phase test is carried out on the tiagabine hydrochloride chiral enantiomer under the conditions of different flow phase ratios, the test results are shown in figure 5-1, figure 5-2, figure 5-3 and figure 5-4, and the separation parameters are shown in table 4.
TABLE 4 separation parameters of chiral enantiomers under different flow phase ratio conditions
As can be seen from the data of FIG. 5-1, FIG. 5-2, FIG. 5-3, FIG. 5-4 and Table 4, when the mobile phase ratio V isAcetonitrile:VSulfobutyl- β -cyclodextrin aqueous solutionAt 35:65, with a separation degree of 1.5, the chiral enantiomer can be well resolved with a more appropriate retention time, while the mobile phase ratio V isAcetonitrile:VSulfobutyl- β -cyclodextrin aqueous solutionAt 45:55 and 40:60, the chiral enantiomeric separations were 0.7 and 0.9, respectively, and good separation was not achieved, when the mobile phase ratio V wasAcetonitrile:VSulfobutyl- β -cyclodextrin aqueous solutionAt 30:70 the chiral enantiomer may be well resolved, but the longer retention time results in a longer time for the procedure, and therefore the mobile phase ratio V is preferredAcetonitrile:VSulfobutyl- β -cyclodextrin aqueous solutionIs 35: 65.
Example 5
The separation method of the tiagabine hydrochloride chiral enantiomer comprises the following steps:
(1) weighing about 5mg of tiagabine hydrochloride chiral enantiomer sample, and dissolving the sample by using acetonitrile as a solvent;
(2) filtering the sample solution obtained in the step (1) by a 0.22-micron filter membrane, and injecting acetonitrile/0.04 g/ml sulfobutyl- β -cyclodextrin aqueous solution as a mobile phase into a high performance liquid chromatograph for determination;
chromatographic conditions are as follows:
shimadzu LC-2010A HT high performance liquid chromatograph
A chromatographic column: thermo Hypercarb (250 mm 4.6 mm 5 μm) and phenomenex Gemini C18 (250 mm 4.6 mm 5 μm)
Reagent acetonitrile (chromatographic grade), sulfobutyl- β -cyclodextrin and secondary water
Mobile phase acetonitrile sulfobutyl- β -cyclodextrin water solution =35:65
Flow rate of mobile phase: 1.0ml/min
The amount of chiral enantiomer introduced: 20 μ l
In this example, the tiagabine hydrochloride chiral enantiomer was subjected to liquid phase tests under different chromatographic columns, and the test results are shown in fig. 6-1 and 6-2, and the separation parameters are shown in table 5 below.
Table 5 separation parameters of tiagabine hydrochloride chiral enantiomers under different chromatographic column conditions
As can be seen from the data in fig. 6-1, fig. 6-2 and table 5, under the same other chromatographic conditions, when the resolution of the enantiomers is performed by using a thermo hypercarb chromatographic column, the retention times are 10.8 and 12.8min, respectively, and the degree of separation is 1.5, good resolution of the chiral enantiomers can be achieved, but when the resolution is performed by using a phenomenex Gemini C18 chromatographic column, the separation of the chiral enantiomers cannot be achieved.
The above description is only a preferred embodiment of the present invention, and all equivalent changes and modifications made in accordance with the claims of the present invention should be covered by the present invention.
Claims (4)1. A method for separating tiagabine hydrochloride chiral enantiomer by adopting a reversed-phase high performance liquid chromatography is characterized in that sulfobutyl- β -cyclodextrin aqueous solution is used as an additive and added into an original mobile phase to obtain a required reversed-phase chromatography mobile phase;
the original mobile phase is acetonitrile;
the concentration of the sulfobutyl- β -cyclodextrin aqueous solution is 0.04 g/ml-0.05 g/ml;
the volume ratio of the original mobile phase to the sulfobutyl- β -cyclodextrin aqueous solution is 30: 70-35: 65;
when the reversed-phase high performance liquid chromatography is adopted for separation, the reversed-phase chromatographic stationary phase is a Thermo Hypercarb chromatographic column.
2. The method for separating tiagabine hydrochloride chiral enantiomers according to claim 1 by reverse-phase high performance liquid chromatography, characterized in that: when the tiagabine hydrochloride chiral enantiomer is subjected to reversed-phase high performance liquid chromatography separation, the flow velocity of a mobile phase is 1.0 ml/min-1.2 ml/min.
3. The method for separating tiagabine hydrochloride chiral enantiomers according to claim 1 by reverse-phase high performance liquid chromatography, characterized in that: the column temperature of the Thermo Hypercarb chromatographic column is 40 â to 45 â.
4. The method for separating tiagabine hydrochloride chiral enantiomers according to claim 1 by reverse-phase high performance liquid chromatography, characterized in that: the dimensions of the Thermo Hypercarb column are 250mm by 4.6mm by 5 μm.
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