CN103364500B - A method of with liquid chromatography for separating and determining bilastine raw material and its preparation - Google Patents
A method of with liquid chromatography for separating and determining bilastine raw material and its preparation Download PDFInfo
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- CN103364500B CN103364500B CN201310267146.8A CN201310267146A CN103364500B CN 103364500 B CN103364500 B CN 103364500B CN 201310267146 A CN201310267146 A CN 201310267146A CN 103364500 B CN103364500 B CN 103364500B
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Abstract
The invention belongs to analytical chemistry fields, the invention discloses a kind of methods with liquid chromatography for separating and determining bilastine in relation to substance, this method is using octadecylsilane chemically bonded silica as the chromatographic column of filler, using a certain proportion of inorganic salt buffer system-organic phase as mobile phase, bilastine and its content in relation to substance can be quantitative determined, to effectively control the quality of bilastine and the formulation products containing bilastine.The method of the present invention specificity is strong, and accuracy is high, easy to operate.
Description
Technical field
The invention belongs to analytical chemistry fields, and in particular to liquid chromatography for separating and determining bilastine and its related substance
Method.
Background technique
Bilastine is a kind of highly selective histamine H 1 receptor antagonist of no sedation, for treating allergia nose's knot
Film is scorching and nettle rash, this product good security, nothing commonly use sedation and cardiac toxic existing for antihistamine drug.Bilastine
Entitled 2- [4- (2- { 4- [1- (2-Ethoxy-ethyl)-the 1H-benzoimidazol-2-yl]-piperidin-1- of chemistry
Yl }-ethyl)-phenyl] -2-methyl-propionic acid, molecular formula C28H37N3O3.Bilastine structural formula are as follows:
During synthesizing the compound, the intermediate for having several steps important may influence medicine due to removing not exclusively
The purity and quality of object, the related substance in these intermediate, that is, Control of drug quality are main for the synthesis of bilastine
There are six the related substances of control, and wherein there are four intermediates, there are two impurity, is 1 Toluene-4- of intermediate respectively
sulfonic acid 2-{4-[1-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-1-methyl-ethyl]-
Phenyl }-ethyl ester, 2 2-Piperidin-4-yl-1H-benzoimidazole of intermediate, 3 2- [1- of intermediate
(2-{4-[1-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-1-methyl-ethyl]-phenyl}-
Ethyl)-piperidin-4-yl] -1H-benzoimidazole, 4 2- of intermediate { 2- [1- (2- { 4- [1- (4,4-
Dimethyl-4,5-dihydro-oxazol-2-yl)-1-methyl-ethyl]-phenyl}-ethyl)-piperidin-4-
yl]-benzoimidazol-1-yl}-ethanol；1 2- of impurity [4- (2- { 4- [1- (2-Hydroxy-ethyl) -1H-
Benzoimidazol-2-yl]-piperidin-1-yl }-ethyl)-phenyl] it is -2-methyl-propionic acid, miscellaneous
2 2- of matter { 2- [1- (2- { 4- [1- (4,4-Dimethyl-4,5-dihydro-oxazol-2-yl) -1-methyl-ethyl] -
Phenyl }-ethyl)-piperidin-4-yl]-benzoimidazol-1-yl }-ethanol, structural formula is respectively as follows:
1 intermediate of intermediate, 2 intermediate 3
4 impurity 1 of intermediate
Impurity 2
It is whether all to need to carry out in bulk pharmaceutical chemicals or preparation for the related substance introduced in synthesis bilastine
Quality control, it therefore, realizes to bilastine and its in relation to the separation of substance, synthesis and production process in bilastine
Quality controlling party face has important practical significance.
Summary of the invention
The purpose of the present invention is to provide a kind of purity for analyzing bilastine and its method in relation to substance is separated, from
And realize the separation and measurement of the associated substance of bilastine, guarantee the quality control of bilastine and the preparation containing bilastine
System.
Purity of the present invention with liquid chromatography analysis bilastine and its method in relation to substance is separated, is
It uses octadecylsilane chemically bonded silica for the chromatographic column of filler, is flowing with a certain proportion of inorganic salt buffer-organic phase
Phase.
Above-mentioned chromatographic column is selected from Apollo-C using octadecylsilane chemically bonded silica as filler18。
Above-mentioned organic phase is selected from following compound: methanol, acetonitrile, propyl alcohol, isopropanol, preferably methanol or acetonitrile.
Above-mentioned method, mobile phase inorganic salt buffer-organic phase use gradient elution.
In above-mentioned method, inorganic salts are selected from following in described inorganic salt buffer: potassium dihydrogen phosphate, biphosphate
Sodium, ammonium dihydrogen phosphate, sodium perchlorate etc., preferably ammonium dihydrogen phosphate.
Wherein the concentration of contained inorganic salts is 0.01~0.05 mol/L in inorganic salt buffer, and optimal is 0.02mol/L.
Method of separating and assaying of the present invention can be realized in accordance with the following methods:
1) it takes bilastine or formulation samples containing bilastine appropriate, with methanol or mobile phase sample dissolution, is configured to
The sample solution of 0.1~1.5mg containing bilastine.
2) setting flow rate of mobile phase is 0.5~1.5mL/min, and flow rate of mobile phase is preferably 1.0mL/min, Detection wavelength
For 210~250nm, best detection wavelength 215nm, chromatographic column post case temperature is 20~40 DEG C, most preferably 25 DEG C of post case column temperature.
3) 10~50 μ L of sample solution 1) is taken, liquid chromatograph is injected, completes bilastine and the separation in relation to substance
Measurement.Wherein:
The model of high performance liquid chromatograph, has no special requirements, and the chromatograph that the present invention uses is Shimadzu Shimadzu: LC-
20ATvp, SPD-M20Avp
Chromatographic column: C18(Apollo, 250 × 4.6 mm, 5 μm)
Mobile phase: A:0.02mol/L ammonium dihydrogen phosphate buffer (pH5.5)；B: acetonitrile is eluted by with Gradient
| Time (min) | 0 | 5 | 10 | 25 | 55 | 60 | 70 |
| B% | 15 | 20 | 30 | 40 | 70 | 15 | 15 |
Flow velocity: 1.0mL/min
Detection wavelength: 215nm
Column temperature: 25 DEG C
Sampling volume: 10 μ L
The present invention uses C18(Apollo, 250 × 4.6 mm, 5 μm) can efficiently separate bilastine and its related
Substance.The present invention solves the problems, such as bilastine and its separation determination in relation to substance, ensures that bilastine and its system
Agent it is quality controllable.
Detailed description of the invention
The high-efficient liquid phase chromatogram of Fig. 1 blank solvent
Fig. 2 bilastine and its high-efficient liquid phase chromatogram in relation to substance
The high-efficient liquid phase chromatogram of Fig. 3 bilastine raw material
The high-efficient liquid phase chromatogram of Fig. 4 bilastine piece auxiliary material blank
The high-efficient liquid phase chromatogram of Fig. 5 bilastine piece
Specific embodiment:
Following embodiment is not limited to the range of this implementation for further understanding the present invention.
Embodiment 1
Instrument and condition
High performance liquid chromatograph: Shimadzu: LC-20ATvp, SPD-M20Avp；
Chromatographic column: C18(Apollo, 250 × 4.6 mm, 5 μm)；
Mobile phase: A:0.02mol/L ammonium dihydrogen phosphate buffer (pH5.5)；B: acetonitrile is eluted by with Gradient
| Time (min) | 0 | 5 | 10 | 25 | 55 | 60 | 70 |
| B% | 15 | 20 | 30 | 40 | 70 | 15 | 15 |
Flow velocity: 1.0mL/min
Detection wavelength: 215nm
Column temperature: 25 DEG C
Sampling volume: 10 μ L
Experimental procedure
Bilastine and its intermediate about 25mg are taken respectively, is set in 50mL measuring bottle, methanol is added to dissolve and is diluted to scale, are shaken
It is even, it respectively takes and is configured to mixing sample solution in right amount.
Blank reagent solution and mixing sample solution are taken respectively, carry out efficient liquid phase chromatographic analysis, record by above-mentioned condition
Chromatogram, the result is shown in Figure 1, Fig. 2.
The chromatographic peak that retention time is 23.218min in Fig. 2 is the chromatographic peak of bilastine, remaining chromatographic peak is than Lars
The chromatographic peak of each intermediate in spit of fland and impurity, as seen from the figure, bilastine can reach baseline point with wherein mesosome and impurity
From meeting the requirement of Chinese Pharmacopoeia.
Embodiment 2
Instrument and condition
High performance liquid chromatograph: Shimadzu: LC-20ATvp, SPD-M20Avp；
Chromatographic column: C18(Kromasil, 250 × 4.6 mm, 5 μm)；
Mobile phase: A:0.02mol/L ammonium dihydrogen phosphate buffer (pH5.5)；B: acetonitrile is eluted by with Gradient
| Time (min) | 0 | 5 | 25 | 55 | 60 | 70 |
| B% | 15 | 20 | 45 | 70 | 15 | 15 |
Flow velocity: 1.0 mL/min；
Detection wavelength: 215nm；
Column temperature: 25 DEG C；
Sampling volume: 10 μ L.
Experimental procedure
Bilastine raw material about 25mg is taken, is set in 50mL measuring bottle, methanol is added to dissolve and is diluted to scale, is shaken up, as confession
Test sample solution.
Test solution is taken, efficient liquid phase chromatographic analysis is carried out by above-mentioned condition, records chromatogram, as a result see Fig. 3.
The chromatographic peak that retention time is 23.727min in Fig. 3 is the chromatographic peak of bilastine, by figure it can be proved that than drawing
The chemical purity of sting reaches the requirement of bulk pharmaceutical chemicals, and this law can be used for the quality-monitoring of bilastine.
Embodiment 3
Instrument and condition
High performance liquid chromatograph: Shimadzu: LC-20ATvp, SPD-M20Avp；
Chromatographic column: C18(Apollo, 250 × 4.6 mm, 5 μm)；
Mobile phase: A:0.02mol/L ammonium dihydrogen phosphate buffer (pH5.5)；B: acetonitrile is eluted by with Gradient
| Time (min) | 0 | 5 | 10 | 25 | 55 | 60 | 70 |
| B% | 15 | 20 | 30 | 40 | 70 | 15 | 15 |
Flow velocity: 1.0 mL/min；
Detection wavelength: 215nm；
Column temperature: 25 DEG C；
Sampling volume: 10 μ L.
Experimental procedure
It takes bilastine piece appropriate, is approximately equivalent to bilastine 12.5mg, set in 25mL measuring bottle, add methanol ultrasonic treatment molten
Solution, and with methanol dilution to scale, it shakes up, filters, take subsequent filtrate as test solution.
Test solution is taken, carries out efficient liquid phase chromatographic analysis by above-mentioned condition, records chromatogram, and carry out blank with method
Auxiliary material test, is as a result shown in Fig. 4, Fig. 5.
Fig. 4 proves that blank auxiliary does not interfere the measurement of this product, and Fig. 5 proves that this law can be used for the quality of bilastine piece
Monitoring.The chromatographic peak of 23.101min is the chromatographic peak of bilastine.
Show from Fig. 1-Fig. 5: method of the invention can clearly separate bilastine with wherein mesosome body, and can
It is quantitative accurately to carry out detecting, to calculate the content of bilastine, to effectively control the product quality of bilastine.
Claims (4)
1. kind of method of the liquid chromatography for separating and determining bilastine in relation to substance, it is characterised in that: with octadecylsilane key
The chromatographic column that silica gel is filler is closed, using 0.02mol/L ammonium dihydrogen phosphate buffer-acetonitrile of pH5.5 as mobile phase, using gradient
Elution, gradient are
, Detection wavelength 215nm, the related substance title of the bilastine of method separation determination and structural formula are as follows
。
2. method of the liquid chromatography for separating and determining bilastine in relation to substance according to claim 1, the chromatographic column
The chromatographic column for being Apollo and Kromasil selected from brand.
3. the method for the liquid chromatography for separating and determining bilastine in relation to substance, feature exist according to claim 1
In, including the following steps:
1) it takes bilastine or formulation samples containing bilastine appropriate, uses methanol or mobile phase sample dissolution respectively, be configured to
Sample solution of every 1mL containing 0.1~1.5mg of bilastine and its intermediate；
2) setting flow rate of mobile phase is 0.5~1.5mL/min, and chromatographic column post case temperature is 20~40 DEG C；
3) 10~50 μ L of sample solution 1) is taken, liquid chromatograph is injected, bilastine is completed and its separation in relation to substance is surveyed
It is fixed.
4. method of the liquid chromatography for separating and determining bilastine in relation to substance according to claim 3, described in step 2
Flow rate of mobile phase be 1.0mL/min.
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105319288B (en) * | 2014-07-31 | 2019-04-16 | 重庆华邦制药有限公司 | A kind of method of process impurity in separation determination bilastine and its preparation |
| CN104101663B (en) * | 2014-08-01 | 2015-10-14 | 江苏联环药业股份有限公司 | By the method for high effective liquid chromatography for measuring related substances in Ebastine |
| CN104730194B (en) * | 2015-04-17 | 2016-06-08 | 北京科莱博医药开发有限责任公司 | The detection method of bilastine |
| CN109212116B (en) * | 2017-07-04 | 2023-10-03 | 万全万特制药江苏有限公司 | Method for separating and measuring chemical purity of bilastine intermediate by high performance liquid chromatography |
Citations (2)
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|---|---|---|---|---|
| CN101268064A (en) * | 2005-07-29 | 2008-09-17 | 奥米罗实验室有限公司 | Pyrazine derivatives useful as adenosine receptor antagonists |
| WO2012146667A1 (en) * | 2011-04-29 | 2012-11-01 | Almirall, S.A. | Imidazopyridine derivatives as pi3k inhibitors |
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2013
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Patent Citations (2)
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|---|---|---|---|---|
| CN101268064A (en) * | 2005-07-29 | 2008-09-17 | 奥米罗实验室有限公司 | Pyrazine derivatives useful as adenosine receptor antagonists |
| WO2012146667A1 (en) * | 2011-04-29 | 2012-11-01 | Almirall, S.A. | Imidazopyridine derivatives as pi3k inhibitors |
Non-Patent Citations (5)
| Title |
|---|
| Benoît Tyl 等.Lack of Significant Effect of Bilastine administered at Therapeutic and Supratherapeutic doses and Concomitantly With ketoconazole on Ventricularrepolarization:results of a Thorough QT Study (TQTS) With QT-Concentrationan alysis.《Journal of Clinical Pharmacology》.2012,第52卷(第6期),第893-903页. |
| Co-administration of ketoconazole with H1-antagonists ebastine and loratadine in healthy subjects:pharmacokinetic and pharmacodynamic effects;P. Chaikin 等;《British Journal of Clinical Pharmacology》;20050331;第59卷(第3期);第346-354页 |
| Matrix solid-phase dispersion technique for the determination of a new antiallergic drug, bilastine, in rat faeces;L.A. Berrueta 等;《Journal of Chromatography B》;20010825;第760卷(第1期);第185-190页 |
| 比拉斯汀关键中间体的合成;夏万东 等;《河北化工》;20130331;第36卷(第3期);第14-15页 |
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