CN105510512B - A kind of RT-HPLC detection method of doxylamine succinate in relation to substance - Google Patents
A kind of RT-HPLC detection method of doxylamine succinate in relation to substance Download PDFInfo
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Abstract
The present invention relates to Pharmaceutical Analysis technical field, reversed-phase high performance liquid chromatography detection method of more particularly to a kind of doxylamine succinate in relation to substance.The invention discloses a kind of RT HPLC detection method of doxylamine succinate in relation to substance, include the following steps：Allocation Analysis solution；Chromatographic condition；Upper machine measures.The present invention can effectively measure the presence of various related impurities in doxylamine succinate solution, especially realize the separation of doxylamine succinate characteristic peak and related impurities in spectrogram.So that it is guaranteed that product is quality controllable.
Description
Technical field
The present invention relates to Pharmaceutical Analysis technical field, reverse phase of more particularly to a kind of doxylamine succinate in relation to substance is high
Effect liquid phase chromatogram detection method.
Background technology
So-called in Pharmaceutical Analysis " related substance (related substances) " refers to the band in production of raw medicine
The substances such as the starting material, reagent, intermediate, by-product and the isomers that enter, it is also possible to which preparation is being produced, stores and transported
The special impurities such as the catabolite, polymer or the crystal transfer that are generated in journey.The synthetic route of type and drug in relation to substance
Closely related with preparation process, drug may all cause its related in the change of any one of synthesis and production process factor
The type of substance is different, thus related substance to detect and control process relative complex.Detection in relation to substance is control drug
The important indicator of quality.
Doxylamine succinate category ethyl alcohol class antihistamine drug has antihistamine effect, cholinolytic effect and significant town
Quiet soporific function, it is suitable for a variety of anaphylaxis dermatosis, hay fever, allergic rhinitis, asthmatic bronchitis etc.；Due to it
Sleepiness can be generated by inhibiting central nervous system, therefore also be used as short-term treatment of the hypnotic for insomnia.
In October, 1978, the doxylamine succinate 25mg tablets of FDA approval CHATTEM companies listed, and were used to help mitigate to fall asleep and be stranded
It is difficult.Become OTC (non-prescribed medicine) within 1979.The approval of in September, 1996,2004 Nian8Yue LNK companies are as imitation medicine official listing.
The OTC antihistamine drugs that doxylamine succinate is slept as auxiliary treatment, clinical safety is effective, general reaction rate is high, resistance to
It is good by property.
Doxylamine succinate structural formula is：
The related substance of doxylamine succinate is impurity A, B, C, D, E；It is as shown in the table：
Table 1
Mobile phase in USP35 in doxylamine succinate piece assay：Include 340mg potassium dihydrogen phosphates, 150mg tri-
Acetic acid hydrochloride, 150mg lauryl sodium sulfate, 63mL water are settled to 100mL with acetonitrile；Succinic acid is more under the conditions of obtaining this
The quick main peak hangover of hila is serious, as shown in Figure 1：In USP35 doxylamine succinate gas phase detection method for impurity E in high temperature
Under the conditions of degrade, do not apply to；And sample consumption is big, extraction operation is cumbersome (needs 0.65g samples every time, need to use hydroxide
Sodium alkali tune, dichloromethane extraction, vacuum distillation solvent and etc.), and impurity content is easily influenced by extraction operation.Therefore, if
Can be detected by RT-HPLC methods and it is firm go out solution in impurity A, B, C, D, E presence, for the matter of doxylamine succinate
Amount control has major and immediate significance.
Invention content
In order to solve the problems, such as that the prior art can not detach doxylamine succinate and characteristic peak in relation to substance, this hair
It is bright that a kind of RT-HPLC detection method of the doxylamine succinate in relation to substance is provided, include the following steps：
A) Allocation Analysis solution
With 0.01~0.5mol/L hydrochloric acid solutions or mobile phase sample dissolution, analytical solution is made；
B) chromatographic condition
Chromatographic column is reversed-phase column, and the mixed liquor with inorganic salt solution-organic phase is mobile phase, and the inorganic salt solution is by ten
Dialkyl sulfonates or lauryl sodium sulfate, phosphate, triethylamine hydrochloride solution are formulated, and the organic phase is first
The mixed solution of alcohol, acetonitrile or methanol and acetonitrile；Isocratic desorption method is taken, flow velocity is 0.8~1.2ml per minute, detects wave
A length of 220~300nm, column temperature are 30~45 DEG C；
C machine measures on)
Take step A) made of analytical solution 10-30 μ l injection high performance liquid chromatograph in, carry out chromatography, record color
Spectrogram.
In some embodiments, the reverse-phase chromatographic column is C18 or C8 silane group silica gel chromatographic columns, preferably C8 silane key
Close silica gel chromatographic column；
In some instances, the specification of the reverse-phase chromatographic column is as follows：Column length is between 100mm to 300mm, chromatography column internal diameter
Between 1mm to 10mm, grain size is between 1 μm to 10 μm.Preferably ZORBAX-SB C8 (Agilent C8 250mm × 4.6mm, 5 μ
m)。
In some embodiments, the phosphate is sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, phosphoric acid hydrogen
Dipotassium or potassium dihydrogen phosphate.Preferably potassium dihydrogen phosphate.
In some embodiments, a concentration of 2.5~3.5g/L of the phosphate solution, dodecyl sodium sulfate or dodecane
A concentration of 1.0~1.5g/L of base metabisulfite solution, 1.0~2.0g/L of concentration of triethylamine hydrochloride solution.
In some embodiments, the mobile phase is inorganic salt solution-organic phase, the inorganic salt solution and organic phase
Volume ratio is 75:25~60:40, preferably 65:35.The organic phase is the mixed solution of methanol and acetonitrile, acetonitrile and methanol
Volume ratio be 28:7~32:3, preferably 30:5.
In some embodiments, the reverse-phase chromatographic column is C8 silane group silica gel chromatographic columns, with potassium dihydrogen phosphate 3.4g/
L, triethylamine hydrochloride 1.5g/L, dodecyl sodium sulfate 1.5g/L are the inorganic salt solution of mobile phase, inorganic salts in mobile phase
The ratio of solution-organic phase is 65:35, the organic phase be acetonitrile-methanol solution, ratio 5:30.
The present invention can effectively measure various in doxylamine succinate solution, the presence and separation of relative substance, separation
Degree reaches more than 2, and tailing factor 2.5 is hereinafter, (impurity B and impurity D cannot divide completely for the liquid phase process of doxylamine in USP35
Open), compared to USP35 gas phase process, sample pre-treatments are simple, and amount of samples is few, and above-mentioned improvement can further ensure that product
It is quality controllable.
Description of the drawings
To doxylamine succinate and impurity A, B, C, D, E separation chromatography figure under Fig. 1, USP35 chromatographic condition；
The chromatogram of Fig. 2,1 mobile phase condition of embodiment；
The chromatogram of Fig. 3,2 mobile phase condition of embodiment；
The chromatogram of Fig. 4,3 mobile phase condition of embodiment.
Specific embodiment
Below in conjunction with specific embodiment, the present invention is further explained.These embodiments are merely to illustrate the present invention and do not have to
In limiting the scope of the invention.Test method without specific conditions in the following example usually according to normal condition or is pressed
According to the condition proposed by manufacturer.Unless otherwise defined, all professional and scientific terms used in text and this neighborhood are ripe
It is identical to practice meaning known to personnel.In addition, any method similar or impartial to described content and material all can be applied to
In the method for the present invention.Preferred approach described herein is for illustrative purposes only with material.Embodiment one
(1) instrument and chromatographic condition
High performance liquid chromatograph：Agilent1260 highly effective liquid phase chromatographic systems and work station；
Chromatographic column：Agilent C8250mm × 4.6mm, 5 μm；
Prepare mobile phase：Potassium dihydrogen phosphate 3.4g, triethylamine hydrochloride 1.5g are taken, dodecyl sodium sulfate 1.5g adds water
650ml, stirring make fully to dissolve, and add acetonitrile 300ml, add methanol 50ml, and stirring clarifies solution, filters, and take filtrate as flowing
Phase；Flow velocity is 1.0ml per minute, and Detection wavelength 262nm, column temperature is 40 DEG C.
(2) experimental procedure
Doxylamine succinate, impurity A (starting material introducing), impurity B (intermediate impurities), impurity C (piptonychias are taken respectively
Base impurity), impurity D (starting material), impurity E (single oxidation impurities) in right amount, put in 10ml measuring bottles, add 0.1M HCl dissolve and it is dilute
It releases to scale, shakes up, as test solution.Another precision pipettes doxylamine succinate test solution 1ml, puts 100ml amounts
Bottle adds 0.1M HCl dilutions that 1% own control solution is made.
Above-mentioned 20 μ l of analytical solution are taken, inject liquid chromatograph, chromatogram are recorded, until 2 times of principal component peak retention time.
As a result see attached drawing 2, it can be seen that doxylamine succinate main peak and other impurity peaks are kept completely separate under this condition.
Embodiment two
(1) instrument and chromatographic condition
High performance liquid chromatograph：Agilent1260 highly effective liquid phase chromatographic systems and work station；
Chromatographic column：Agilent C8250mm × 4.6mm, 5 μm；
Prepare mobile phase：Potassium dihydrogen phosphate 3.4g, triethylamine hydrochloride 1.5g, dodecyl sodium sulfate 1.5g add water
700ml, stirring make fully to dissolve, and add acetonitrile 295ml, add methanol 55ml, and stirring clarifies solution, filters, and take filtrate as flowing
Phase；Flow velocity is 1.0ml per minute, and Detection wavelength 262nm, column temperature is 40 DEG C.
(2) experimental procedure
Doxylamine succinate, impurity A (starting material introducing), impurity B (intermediate impurities), impurity C (piptonychias are taken respectively
Base impurity), impurity D (starting material), impurity E (single oxidation impurities) in right amount, put in 10ml measuring bottles, add 0.1M HCl dissolve and it is dilute
It releases to scale, shakes up, as test solution.Another precision pipettes doxylamine succinate test solution 1ml, puts 100ml amounts
Bottle adds 0.1M HCl dilutions that 1% own control solution is made.
Above-mentioned 20 μ l of analytical solution are taken, inject liquid chromatograph, chromatogram are recorded, until 2 times of principal component peak retention time.
As a result see attached drawing 3, it can be seen that doxylamine succinate main peak and other impurity peaks are kept completely separate under this condition.
Embodiment three
(1) instrument and chromatographic condition
High performance liquid chromatograph：Agilent1260 highly effective liquid phase chromatographic systems and work station；
Chromatographic column：Agilent C8250mm × 4.6mm, 5 μm；
With potassium dihydrogen phosphate making 3.4g, triethylamine hydrochloride 1.5g, dodecyl sodium sulfate 1.5g, add water 600ml, stir
Make fully to dissolve, add acetonitrile 305ml, add methanol 45ml, stirring clarifies solution, filters, and it is mobile phase to take filtrate；Flow velocity is every
Minute 1.0ml, Detection wavelength 262nm, column temperature are 40 DEG C.
(2) experimental procedure
Doxylamine succinate, impurity A (starting material introducing), impurity B (intermediate impurities), impurity C (piptonychias are taken respectively
Base impurity), impurity D (starting material), impurity E (single oxidation impurities) in right amount, put in 10ml measuring bottles, add 0.1M HCl dissolve and it is dilute
It releases to scale, shakes up, as test solution.Another precision pipettes doxylamine succinate test solution 1ml, puts 100ml amounts
Bottle adds 0.1M HCl dilutions that 1% own control solution is made.
Above-mentioned 20 μ l of analytical solution are taken, inject liquid chromatograph, chromatogram are recorded, until 2 times of principal component peak retention time.
As a result see attached drawing 4, it can be seen that doxylamine succinate main peak and other impurity peaks are kept completely separate under this condition.
Claims (9)
1. a kind of HPLC detection method of doxylamine succinate in relation to substance, includes the following steps：
A）Prepare analytical solution
With 0.01 ~ 0.5mol/L hydrochloric acid solutions or mobile phase sample dissolution, analytical solution is made；
B）Chromatographic condition
Chromatographic column is reverse-phase chromatographic column, and the mixed liquor with inorganic salt solution-organic phase is mobile phase, and the inorganic salt solution is by ten
Dialkyl sulfonates or lauryl sodium sulfate, phosphate, triethylamine hydrochloride solution are formulated, and the organic phase is first
The mixed solution of alcohol and acetonitrile；Take isocratic desorption method, flow velocity is 0.8 ~ 1.2ml per minute, Detection wavelength 220-300nm,
Column temperature is 30 ~ 45 DEG C, and the organic phase methanol and acetonitrile mixed solution ratio are 7:28~3:32, the inorganic salt solution is with having
The volume ratio of machine phase is 75:25~60:40；
C）Upper machine measures
Take step A）In manufactured 10 ~ 30 μ l of analytical solution injections high performance liquid chromatograph, chromatography is carried out, records chromatography
Figure；
The related substance is：The chemical structural formula of impurity A is, impurity B chemical structural formula be, impurity C chemical structural formula be, impurity D chemical structural formula be, it is miscellaneous
The chemical structural formula of matter E is。
2. HPLC detection methods as described in claim 1, which is characterized in that the reverse-phase chromatographic column is C18 or C8 silane keys
Close silica gel chromatographic column.
3. HPLC detection methods as claimed in claim 2, which is characterized in that the reverse-phase chromatographic column is C8 silane group silica gel
Chromatographic column.
4. HPLC detection methods as claimed in claim 2, which is characterized in that the specification of the reverse-phase chromatographic column is：Column length is situated between
In 100mm to 300mm, chromatography column internal diameter is between 1mm to 10mm, and grain size is between 1 μm to 10 μm.
5. HPLC detection methods as described in claim 1, which is characterized in that the phosphate for sodium phosphate, disodium hydrogen phosphate,
One of sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate or potassium dihydrogen phosphate.
6. HPLC detection methods as claimed in claim 5, which is characterized in that the phosphate is potassium dihydrogen phosphate.
7. HPLC detection methods as described in claim 1, which is characterized in that the dodecyl sodium sulfate or dodecyl sulphur
A concentration of 1.0 ~ 1.5g/L of acid sodium solution, a concentration of 2.5 ~ 3.5g/L of phosphate solution, triethylamine hydrochloride 1.0 ~
2.0g/L。
8. HPLC detection methods as described in claim 1, which is characterized in that the step B）It is C8 for the reverse-phase chromatographic column
Silane group silica gel chromatographic column, mobile phase are with potassium dihydrogen phosphate 3.4g/L, triethylamine hydrochloride 1.5g/L, dodecyl sodium sulfonate
Sodium 1.5g/L is inorganic salt solution, and the ratio of mobile phase inorganic salt solution-methanol-acetonitrile is 65：5：30, isocratic elution is carried out,
Flow velocity is 1.0mL/min；Column temperature is 40 DEG C, Detection wavelength 262nm.
9. HPLC detection methods as described in claim 1, which is characterized in that the sample is doxylamine succinate.
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| CN106083699B (en) * | 2016-06-01 | 2019-02-19 | 合肥创新医药技术有限公司 | A kind of preparation method of doxylamine impurity G |
| CN106896167B (en) * | 2017-01-23 | 2019-09-17 | 合肥创新医药技术有限公司 | Analysis method in relation to substance in a kind of doxylamine succinate |
| CN109400577B (en) * | 2019-01-07 | 2021-01-19 | 石药集团中奇制药技术（石家庄）有限公司 | Rivaroxaban related compound and preparation method and application thereof |
| CN115078556B (en) * | 2021-03-11 | 2023-10-24 | 远大生命科学(武汉)有限公司 | Method for simultaneously measuring content of doxylamine and pyridoxine |
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| US6340695B1 (en) * | 2000-12-20 | 2002-01-22 | Duchesnay Inc. | Rapid onset formulation |
| CN104122360A (en) * | 2014-08-04 | 2014-10-29 | 人福普克药业（武汉）有限公司 | Method for analyzing night cold flu cough allergy capsule by utilizing HPLC (High Performance Liquid Chromatography) |
| CN105001149A (en) * | 2015-07-22 | 2015-10-28 | 南京济群医药科技有限公司 | Method for preparing 2-pyridinemethanol-alpha-methyl-alpha-phenyl serving as intermediate of doxylamine succinate |
| CN105237467A (en) * | 2015-09-23 | 2016-01-13 | 南京济群医药科技有限公司 | Preparation method of doxylamine succinate |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6340695B1 (en) * | 2000-12-20 | 2002-01-22 | Duchesnay Inc. | Rapid onset formulation |
| CN104122360A (en) * | 2014-08-04 | 2014-10-29 | 人福普克药业（武汉）有限公司 | Method for analyzing night cold flu cough allergy capsule by utilizing HPLC (High Performance Liquid Chromatography) |
| CN105001149A (en) * | 2015-07-22 | 2015-10-28 | 南京济群医药科技有限公司 | Method for preparing 2-pyridinemethanol-alpha-methyl-alpha-phenyl serving as intermediate of doxylamine succinate |
| CN105237467A (en) * | 2015-09-23 | 2016-01-13 | 南京济群医药科技有限公司 | Preparation method of doxylamine succinate |
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Address after: Longmian road Jiangning District of Nanjing City, Jiangsu province 211112 No. 568 Nanjing life science and Technology Innovation Park, building 9, floor 5 Applicant after: Nanjing Ji medicine Polytron Technologies Inc Address before: Longmian road Jiangning District of Nanjing City, Jiangsu province 211112 No. 568 Nanjing life science and Technology Innovation Park, building 1, floor 5 Applicant before: NANJING JIQUN PHARMACEUTICAL SCIENCE AND TECHNOLOGY CO.,LIMITED |
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Inventor after: Huo Liru Inventor after: Zhang Hui Inventor after: Lu Xiang Inventor after: Zhou Jie Inventor after: Zhang Yuanyuan Inventor after: Zhao Qing Inventor after: Li Zhan Inventor after: Yu Qiuyang Inventor before: Huo Liru Inventor before: Zhang Hui Inventor before: Lu Xiang Inventor before: Zhou Jie Inventor before: Zhang Yuanyuan Inventor before: Zhao Qing Inventor before: Li Zhan |
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