CN105301118B - A kind of detection method of mosapride citrate in relation to substance - Google Patents
A kind of detection method of mosapride citrate in relation to substance Download PDFInfo
- Publication number
- CN105301118B CN105301118B CN201410312949.5A CN201410312949A CN105301118B CN 105301118 B CN105301118 B CN 105301118B CN 201410312949 A CN201410312949 A CN 201410312949A CN 105301118 B CN105301118 B CN 105301118B
- Authority
- CN
- China
- Prior art keywords
- substance
- mosapride citrate
- sodium dihydrogen
- relation
- dihydrogen phosphate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Investigating Or Analysing Biological Materials (AREA)
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
Abstract
The present invention provides a kind of detection method of mosapride citrate in relation to substance, this method includes, pass through high performance liquid chromatography, using gradient elution method, related substances in pharmaceutical composition is detected, detection method detection impurity number is most, and separating degree is preferable, and response is high, sensitivity is good.
Description
Technical field
The present invention relates to drug tests, and in particular to a kind of detection method of mosapride citrate in relation to substance.
Background technology
Mosapride citrate (Mosapride Citrate, trade name Gasmotin) is by big Japanese pharmaceutical strain formula
Commercial firm exploitation new WeiDongLi Capsule drug, it is potent selectivity 5-HT4 receptor stimulating agents, be clinically used for treat chronic gastritis,
The alleviation of functional dyspepsia FD, reflux esophagitis and a series of adjoint gastrointestinal symptoms of performing the operation.It is in December, 1998
It is listed for the first time in Japan, Chinese chemical name：4- amino -5- chloro-2-ethoxies-N- { [4- (4- luorobenzyls) -2- morpholinyls] first
Base } benzamide citrate；Molecular formula：C21H25ClFN3O3·C6H8O7·2H2O, molecular weight：650.05 structural formula is：
Mosapride is potent selectivity 5-HT4 receptor stimulating agents, passes through the 5-HT4 receptors of excited myenteric nerve plexus, thorn
Swash the release of nerve endings acetylcholine, so as to enhance gastrointestinal motility, but do not influence gastric acid secretion.Its WeiDongLi Capsule with similar structures
Drug is compared, and side effect greatly reduces, with the dopamine D on nervous centralis original synaptic membrane2, α1, 5-HT1 and 5-HT2 receptors
Without affinity, the Extra Pyramidal Syndrome caused by without these receptor blocks.It is all benzamides WeiDongLi Capsule with it
The Cisapride (cisapride) of drug may occur in which Q-T interval prolongations in high quick patient or cause the torsades de pointes room property heart
It is dynamic to overrun, but the electrophysiological characteristics for causing torsade de pointes that Mosapride is not similar to Cisapride.
Meanwhile selectively acting, on Colon Movement without influence, can be reduced due to the hyperfunction caused abdomen of Colon Movement in upper digestive tract
Bitterly, the side effects such as defecation frequency increase, diarrhea and soft stool, in addition, electrophysiologic study shows it without extension isolated ventricular muscle and Pu
The effect of family name's Fibers Action Potential time-histories, security are more preferable.At present, the drug is declared and produced in domestic existing many enterprises.
The impurity of drug refers to present in drug without therapeutic effect or influences the stability of drug, curative effect or even right
The substance that the health of human body is harmful to, in medicine production process, the main source of impurity includes two aspects：1st, due to original used
Expect to react incomplete and reaction intermediate product, the by-product reacted etc. in impure or raw material reaction process and cause drug
The presence of impurity in raw material；2nd, the solvent due to being reacted in raw material production process, the medicine caused by the residual of catalyst equal solvent
The impurity of object.And the impurity of drug and the relation of drug safety are a complicated relations being affected by many factors, usually
Impurity in drug has a potential bioactivity mostly, some even with drug interaction so as to influence the efficiency of drug and
Security, serious there may be toxic actions.All impurity in drug can all influence the stability of drug to some extent
And security, therefore the research in drug, production, storage and clinical practice etc., it is necessary to the purity of drug is kept, reduces medicine
The impurity of object, so just can guarantee the validity and security of drug, the impurity in drug be influence pharmaceutical purity it is main because
Element has more than the impurity of limitation as contained in drug, it is possible to change physicochemical constant, appearance character generates variation, and influences
The stability of drug；Impurity, which increases, also necessarily makes the content of drug relatively low or active reduction, toxic side effect dramatically increase.Therefore,
The Related substances separation of drug is control pharmaceutical purity, ensures an important indicator of drug quality.
Because the property of different pharmaceutical, the mode of production and process conditions are different, introduce impurity also with the difference of drug and
Difference, since special impurities are varied, so inspection method and testing conditions are also multifarious, currently used related substance
Inspection method has：1. physical analysis method：According to drug and impurity smell, the side such as taste, volatility, color, dissolubility and optical activity
The difference in face detects whether related substance meets Light absorbing impurty regulation using the methods of gray scale inspection, optical activity inspection.2. chemistry
Reaction method：The methods of generally comprising volumetric analysis, gravimetry, colorimetric method and turbidimetry.3. chemical analysis：It is common
There are ultraviolet spectrophotometry, Capillary Zone Electrophoresis (CzE), high performance capillary electrophoresis (HPCE) etc..4. chromatography：Including
Thin layer chromatography method (TLC), liquid chromatography (PLC), high performance liquid chromatography (HPLC), ultra-performance liquid chromatography
(UPLC), gas chromatography (GC) etc..Wherein chromatography is the related analysis method of the most frequently used at present and most effective drug, is had
Have high sensitivity, accuracy it is good, it is simple, easy, rapidly and efficiently the features such as, more and more by pharmacopoeia of each country for controlling drug
Related substance, and TLC is typically only capable to as a kind of semi-quantitative method in chromatography, simultaneously because sensitivity is by operating condition shadow
Sound is larger, so being difficult to meet needs that are quick, accurately analyzing sometimes.And high performance liquid chromatography (HPLC) is used as a kind of comparison
Ripe method has been widely used in the determination of foreign matter of drug because of the features such as its separation efficiency is high, specificity is strong and detection is sensitive
In.
There is certain report for the high-efficiency liquid chromatography method for detecting of mosapride citrate at present, but it is only capable of detecting
Go out partial impurities, there are defects inspecting it is infull the phenomenon that, and partial impurities separating degree is not high, can not realize accurate detection.Therefore
Seeking one kind can efficiently separate and related substance in detection Mosapride as much as possible, for mosapride citrate into
One step quality control has a very important significance.
The content of the invention
In order to solve the above technical problems, the present invention provides, a kind of separating degree is good, the related substance of detection is more, detection efficiency is high
Detection method of the mosapride citrate in relation to substance, it includes following steps：
Mosapride citrate test solution sample introduction is taken, is detected according to liquid phase chromatogram condition, wherein described efficient
Liquid chromatogram measuring condition is：Chromatographic column：Octadecylsilane chemically bonded silica is filler；Mobile phase A is that volume ratio is 75：25
The mixed solution of sodium dihydrogen phosphate/acetonitrile, Mobile phase B are that volume ratio is 20:The mixing of 80 sodium dihydrogen phosphates/acetonitrile
Solution, using gradient elution.
Detection method of the mosapride citrate provided by the present invention in relation to substance, wherein the gradient elution program is：
| T(min) | A (%) | B (%) |
| 0 | 100 | 0 |
| 30 | 100 | 0 |
| 100 | 20 | 80 |
Detection method of the mosapride citrate provided by the present invention in relation to substance, wherein the high performance liquid chromatography measures
In condition, the concentration of sodium dihydrogen phosphate is 0.001-0.1mol/L, is preferably 0.01-0.05mol/L, further preferably
0.01mol/L。
Detection method of the mosapride citrate provided by the present invention in relation to substance, wherein the high performance liquid chromatography measures
In condition, the pH value of sodium dihydrogen phosphate is 2.0-6.0, is preferably 3.5；It is preferred that the pH of sodium dihydrogen phosphate adjusts reagent
For H3PO4；
Detection method of the mosapride citrate provided by the present invention in relation to substance, wherein the high performance liquid chromatography measures
In condition, Detection wavelength is 210~360nm, is preferably 220nm；Column temperature：15-40 DEG C, be preferably 35 DEG C；Flow velocity：0.5-
1.5ml/min is preferably 1ml/min.
Detection method of the mosapride citrate provided by the present invention in relation to substance, wherein the high performance liquid chromatography measures
In condition, triethylamine is also contained in mobile phase A, B, the volumetric concentration of the triethylamine is 0.01%-1%, is preferably 0.1%-
0.3%, further preferably 0.1%.
Detection method of the mosapride citrate provided by the present invention in relation to substance, wherein the preparation of the test solution
Method is to take appropriate mosapride citrate, accurately weighed, and Mobile phase B is added to dissolve and dilutes that every 1ml is made is molten containing about 1mg
Liquid to obtain the final product.
The present invention further provides a kind of detection method of mosapride citrate in relation to substance, and it includes following steps：
(a) preparation of test solution：
Appropriate mosapride citrate is taken, it is accurately weighed, Mobile phase B is added to dissolve and dilutes that every 1ml is made is molten containing about 1mg
Liquid to obtain the final product；(b) chromatographic condition：Chromatographic column is that octadecylsilane chemically bonded silica is filler；Using gradient elution, mobile phase A is
Volume ratio is 75：The mixed solution of 25 sodium dihydrogen phosphate/acetonitrile, Mobile phase B are that volume ratio is 20:80 biphosphate
The mixed solution of sodium solution/acetonitrile, column temperature are 350 DEG C, flow velocity 1ml/min, Detection wavelength 220nm, the gradient elution
Program is：
| T(min) | A (%) | B (%) |
| 0 | 100 | 0 |
| 30 | 100 | 0 |
| 100 | 20 | 80 |
Wherein, three that volumetric concentration is 0.1% are contained in the sodium dihydrogen phosphate in the mobile phase A and Mobile phase B
Ethamine, and with phosphoric acid tune pH value to 3.5.
(c) measure：Test solution injection liquid chromatograph is drawn, according to high effective liquid chromatography for measuring.
Gradient elution program is stated in the present invention is：
During 0-30min, mobile phase A 100%, Mobile phase B 0%；
During 30-100min, mobile phase A is from 100% to 20%, and Mobile phase B is from 0% to 80%.
High performance liquid chromatography detection during the related substance detection of present inventor detailed examination mosapride citrate
Condition, when using sodium dihydrogen phosphate：Acetonitrile volume ratio is 75：25 mixed solution is mobile phase A, and sodium dihydrogen phosphate is molten
Liquid：Acetonitrile volume ratio is 20:80 mixed solution is Mobile phase B, and during the above-mentioned condition of gradient elution of use, sodium dihydrogen phosphate is molten
When liquid concentration is more than 0.1M or less than 0.001M, gradient elution baseline fluctuation is larger, when sodium dihydrogen phosphate is 0.001-
During 0.1M, baseline is more steady, and when sodium dihydrogen phosphate is 0.01-0.03M, baseline is more steady, and peak shape is preferable,
When sodium dihydrogen phosphate concentration is 0.01M, peak shape is excellent, and separating degree is best；The pH value of sodium dihydrogen phosphate is carried out
It investigates and finds, when PH is more than 6.0, peak shape is asymmetric, and when PH is less than 2.0, chromatographic column poor resistance, column effect decline, peak shape
When asymmetric PH is 2.0-6.0, peak shape is preferable, and when PH is 3.5, peak shape is the most symmetrical；When adding in triethylamine into mobile phase
When 0.01%~1%, the phenomenon that detection is trailed can be effectively improved, wherein when triethylamine concentration is 0.1%-0.3%, effect
It is more excellent, when triethylamine concentration is 0.1%, it is best to improve smear effects.By investigating diode array detector, (DAD is detected
Device detects) detection absorbing wavelength of the mosapride citrate in relation to substance, learn that it is equal near 210nm, 274nm and 360nm
There is absorption peak, peak intensity successively decreases, and when Detection wavelength is 210-360nm, background interference is smaller, and the absorption of impurity peaks compared with
Good, wherein background and the interference of other miscellaneous peaks are small when Detection wavelength is 220-274nm, and appearance result is stablized, therefore it is preferred that
220-274nm is Detection wavelength, and as Detection wavelength 220nm, detection result is optimal.
Compared with prior art, there are following excellent for the related substance detecting method of mosapride citrate provided by the present invention
Gesture：
1st, the related substance detecting method separating degree of mosapride citrate provided by the invention is good, and baseline fluctuation is not
Greatly, background interference is small, can accurately detect related substance in test sample；
2nd, the related substance detecting method of mosapride citrate provided by the invention can detect more compared with prior art
More impurity can more effectively control the related substance in test sample.
Description of the drawings
Fig. 1 is high-efficient liquid phase chromatogram in embodiment 1
Fig. 2 is high-efficient liquid phase chromatogram in embodiment 2
Fig. 3 is high-efficient liquid phase chromatogram in embodiment 3
Fig. 4 is high-efficient liquid phase chromatogram in embodiment 4
Fig. 5 is high-efficient liquid phase chromatogram in embodiment 5
Fig. 6 is high-efficient liquid phase chromatogram in embodiment 6
Fig. 7 is high-efficient liquid phase chromatogram in embodiment 7
Fig. 8 is high-efficient liquid phase chromatogram in embodiment 8
Fig. 9 is high-efficient liquid phase chromatogram in embodiment 9
Figure 10 is high-efficient liquid phase chromatogram in embodiment 10
Figure 11 is total particle flux mass spectrogram in embodiment 11
Figure 12 is impurity E mass spectrogram in embodiment 11
Figure 13 is impurity F mass spectrogram in embodiment 11
Specific embodiment
The present invention is described in further detail present disclosure by following embodiment, can not be used to limit this
The protection domain of invention.
In detailed description below, used drug, reagent and instrument are as follows：
Mosapride citrate (self-control, lot number：JMB111002,111001), Mosapride reference substance (source：Self-control,
Lot number MBD131101), citric acid reference substance (impurity A source：Zhong Jian institutes, lot number 100396200301), citron acylating acid is not husky
It must sharp reference substance (impurity B source：TCR, 15-THT-139-2), 452 benzoic acid (impurity C sources：Chongqing Ying Sikai chemical industry is limited
Company), defluorinate Mosapride reference substance (impurity D sources：Self-control, lot number JMBI110506), 452 ethyl benzoate reference substances
(impurity E source：Self-control, 702-462-5-1), 452 isobutyl benzoate reference substance (impurity F sources：Self-control, 702-462-8-
1)；Acetonitrile (chromatographically pure, Fisher, Honeywell), disodium hydrogen phosphate (analyze pure, Chengdu Ke Long Chemical Co., Ltd.s), phosphoric acid
Disodium hydrogen (chromatographic grade, Tianjin Kermel Chemical Reagent Co., Ltd.), (analysis is pure, and Chengdu section dragon chemical industry has for dipotassium hydrogen phosphate
Limit company), triethylamine (analyzes pure, Chengdu Ke Long Chemical Co., Ltd.s), and triethylamine (try by chromatographic grade, close europeanized learn of Tianjin section
Agent Co., Ltd), phosphoric acid (analyzes pure, Chengdu Ke Long Chemical Co., Ltd.s), and (analysis is pure, and Chengdu section dragon chemical industry is limited for citric acid
Company), sodium hydroxide (analyzes pure, Chengdu Ke Long Chemical Co., Ltd.s), methanol (Honeywell), liquid chromatograph (Shimadzu
LC-2010C), diode array detector (Shimadzu SPD-M20A), liquid chromatograph (Agilent1200), chromatographic column
(Waters, Waters sunfire C18,4.6 × 250mm), electronic balance (Sartorius BP211D), pH meter (Mei Te
Le-support benefit instrument (Shanghai) Co., Ltd.)
The detection of the related substance of one mosapride citrate of embodiment
It is prepared by test solution：Appropriate mosapride citrate is taken, it is accurately weighed, with flowing phased soln and quantify dilution system
The solution containing 0.25mg into every 1ml.
High performance liquid chromatography detection condition：Mobile phase：(sodium hydroxide test solution tune pH value is extremely for 0.05mol/L citric acid solns
3.0)-methanol (60:40), flow velocity：1ml/min；Detection wavelength：275nm；Column temperature:35 DEG C, sampling volume is 20 μ l.
Test solution is prepared according to the method described above, carries out high performance liquid chromatography detection, and the results are shown in Figure 1, detection
The impurity number arrived is less, and chromatographic peak response is low, and detection sensitivity is low.
The detection of the related substance of two mosapride citrate of embodiment
It is prepared by test solution：Appropriate mosapride citrate is taken, it is accurately weighed, with flowing phased soln and quantify dilution system
The solution containing 0.5mg into every 1ml.
High performance liquid chromatography detection condition：Mobile phase：0.05mol/L sodium dihydrogen phosphate buffers (triethylamine tune pH value
To 3.0)-acetonitrile (72:28), flow velocity：1ml/min；Detection wavelength：276nm；Column temperature:Room temperature (28 DEG C), sampling volume are 10 μ
l。
Test solution is prepared according to the method described above, carries out high performance liquid chromatography detection, and the results are shown in Figure 2, detection
The impurity number arrived is less, and chromatographic peak response is low, and detection sensitivity is low.
The detection of the related substance of three mosapride citrate of embodiment
It is prepared by test solution：Appropriate mosapride citrate is taken, it is accurately weighed, with flowing phased soln and quantify dilution system
The solution containing 1.0mg into every 1ml.
High performance liquid chromatography detection condition：0.1M sodium dihydrogen phosphates (phosphoric acid adjusts pH=4.0)：Methanol is 75：25,
Flow velocity：1ml/min；Detection wavelength：274nm；Column temperature:35 DEG C, sampling volume is 10 μ l.It is molten that test sample is prepared according to the method described above
Liquid carries out high performance liquid chromatography detection, and the results are shown in Figure 3, testing result impurity peaks inferior separating effect, and peak shape is asymmetric,
And chromatographic peak response is low, detection sensitivity is low.
The detection of the related substance of example IV mosapride citrate
It is prepared by test solution：Appropriate mosapride citrate is taken, it is accurately weighed, with flowing phased soln and quantify dilution system
The solution containing 1.0mg into every 1ml.
High performance liquid chromatography detection condition：0.01M sodium dihydrogen phosphates (pH=3.5)：Acetonitrile is 75：25), flow velocity：
1ml/min；Detection wavelength：274nm；Column temperature:35 DEG C, sampling volume is 10 μ l.Test solution is prepared according to the method described above, into
Row high performance liquid chromatography detection, the results are shown in Figure 4, testing result impurity peaks inferior separating effect, and peak shape is asymmetric, and chromatography
Peak response value is low, and detection sensitivity is low.
The detection of the related substance of five mosapride citrate of embodiment
It is prepared by test solution：Appropriate mosapride citrate is taken, it is accurately weighed, with flowing phased soln and quantify dilution system
The solution containing 1.0mg into every 1ml.
High performance liquid chromatography detection condition：0.01M sodium dihydrogen phosphates (0.1% triethylamine, pH=3.5)：Acetonitrile is
75：25 be mobile phase A, 0.01M sodium dihydrogen phosphates (0.1% triethylamine, pH=3.5)：Acetonitrile is 20：80 be Mobile phase B
Using gradient elution：
| T(min) | A (%) | B (%) |
| 0 | 100 | 0 |
| 30 | 80 | 20 |
| 100 | 50 | 50 |
Flow velocity：1ml/min；Detection wavelength：220nm；Column temperature:35 DEG C, sampling volume is 10 μ l.
Test solution is prepared according to the method described above, carries out high performance liquid chromatography detection, the results are shown in Figure 5, and base is miscellaneous
Mass peak inferior separating effect has hangover, and the impurity number detected is less.
The detection of the related substance of six mosapride citrate of embodiment
It is prepared by test solution：Appropriate mosapride citrate is taken, it is accurately weighed, with flowing phased soln and quantify dilution system
The solution containing 1.0mg into every 1ml.
High performance liquid chromatography detection condition：0.01M sodium dihydrogen phosphates (0.1% triethylamine, pH=3.5)：Acetonitrile is
75：25 be mobile phase A, 0.01M sodium dihydrogen phosphates (0.1% triethylamine, pH=4.0)：Acetonitrile is 20：80 be Mobile phase B
Using gradient elution.
| T(min) | A (%) | B (%) |
| 0 | 100 | 0 |
| 30 | 60 | 40 |
| 70 | 30 | 70 |
Flow velocity：1ml/min；Detection wavelength：274nm；Column temperature:35 DEG C, sampling volume is 10 μ l.
Test solution is prepared according to the method described above, carries out high performance liquid chromatography detection, the results are shown in Figure 6, impurity
Peak response value is low, and sensitivity is low, and the impurity number detected is less.
The detection of the related substance of seven mosapride citrate of embodiment
It is prepared by test solution：Appropriate mosapride citrate is taken, it is accurately weighed, with flowing phased soln and quantify dilution system
The solution containing 1.0mg into every 1ml.
It is prepared by impurity A-F reference substance solutions：Take reference substance A-F appropriate, add Mobile phase B dilution be made every 1ml solution containing about
The solution of impurity 1.0mg.
It is prepared by Mosapride reference substance solution：It takes Mosapride reference substance appropriate, adds Mobile phase B dilution that every 1ml is made molten
Liquid is containing about the solution of Mosapride reference substance 1.0mg.
High performance liquid chromatography detection condition：0.01M sodium dihydrogen phosphates (0.1% triethylamine, pH=3.5)：Acetonitrile is
75：25 be mobile phase A, 0.01M sodium dihydrogen phosphates (0.1% triethylamine, pH=3.5)：Acetonitrile is 20：80 be Mobile phase B
Using gradient elution.
| T(min) | A (%) | B (%) |
| 0 | 100 | 0 |
| 30 | 100 | 0 |
| 100 | 20 | 80 |
Flow velocity：1ml/min；Detection wavelength：220nm；Column temperature:35 DEG C, sampling volume is 10 μ l.
Test sample, reference substance solution are prepared according to the method described above, carry out high performance liquid chromatography detection, the results are shown in Figure 7.
6 impurity (A-F) and Mosapride main peak can be efficiently separated out under the conditions of can be seen that this by the testing result in Fig. 7,
Its separating degree is all higher than 1.5, and peak shape is symmetrical, and response is higher, and detection sensitivity is good, wherein corresponding to retention time by reference substance
As can be seen that A peaks are citric acid, B peaks are citron acylating acid Mosapride, and C peaks are 452 benzoic acid, and D peaks are defluorinate Mo Shabi
Profit, 1 is Mosapride, and E is 452 ethyl benzoates, and F is 452 isobutyl benzoates.
The detection of the related substance of eight mosapride citrate of embodiment
It is prepared by test solution：Appropriate mosapride citrate is taken, it is accurately weighed, with flowing phased soln and quantify dilution system
The solution containing 1.0mg into every 1ml.
High performance liquid chromatography detection condition：0.01M sodium dihydrogen phosphates (0.1% triethylamine, pH=6.0)：Acetonitrile is
75：25 be mobile phase A, 0.01M sodium dihydrogen phosphates (0.1% triethylamine, pH=4.0)：Acetonitrile is 20：80 be Mobile phase B
Using gradient elution.
| T(min) | A (%) | B (%) |
| 0 | 100 | 0 |
| 30 | 100 | 0 |
| 100 | 50 | 50 |
Flow velocity：1ml/min；Detection wavelength：220nm；Column temperature:35 DEG C, sampling volume is 10 μ l.
Test solution is prepared according to the method described above, carries out high performance liquid chromatography detection, the results are shown in Figure 8, the gradient
Entire appearance time hysteresis, detection time extend down, and impurity detection number is few, and chromatographic peak response is low, and detection sensitivity is low.
The detection of the related substance of nine mosapride citrate of embodiment
It is prepared by test solution：Appropriate mosapride citrate is taken, it is accurately weighed, with flowing phased soln and quantify dilution system
The solution containing 1.0mg into every 1ml.
High performance liquid chromatography detection condition：0.05M sodium dihydrogen phosphates (0.3% triethylamine, pH=3.5)：Acetonitrile is
75：25 be mobile phase A, 0.05M sodium dihydrogen phosphates (0.3% triethylamine, pH=3.5)：Acetonitrile is 20：80 be Mobile phase B
Using gradient elution.
| T(min) | A (%) | B (%) |
| 0 | 100 | 0 |
| 30 | 100 | 0 |
| 100 | 20 | 80 |
Flow velocity：1ml/min；Detection wavelength：220nm；Column temperature:35 DEG C, sampling volume is 10 μ l.
Test solution is prepared according to the method described above, carries out high performance liquid chromatography detection, the results are shown in Figure 9, baseline
Though there is certain fluctuation, but still the A-F in mosapride citrate totally 6 impurity and 1 Mosapride master can be efficiently separated out
Peak, and response is higher, sensitivity is good.
The detection of the related substance of ten mosapride citrate of embodiment
It is prepared by test solution：Appropriate mosapride citrate is taken, it is accurately weighed, with flowing phased soln and quantify dilution system
The solution containing 1.0mg into every 1ml.
It is prepared by Mosapride reference substance solution：It takes Mosapride reference substance appropriate, adds Mobile phase B dilution that every 1ml is made molten
Liquid is containing about the solution of Mosapride reference substance 1.0mg.
High performance liquid chromatography detection condition：0.01M sodium dihydrogen phosphates (0.1% triethylamine, pH=3.5)：Acetonitrile is
75：25 be mobile phase A, 0.01M sodium dihydrogen phosphates (0.1% triethylamine, pH=3.5)：Acetonitrile is 20：80 be Mobile phase B
Using gradient elution.
| T(min) | A (%) | B (%) |
| 0 | 100 | 0 |
| 30 | 100 | 0 |
| 100 | 20 | 80 |
Flow velocity：1ml/min；Detection wavelength：220nm；Column temperature:35 DEG C, sampling volume is 10 μ l.
Accurate respectively to measure 6 parts of sample 10ul progress high performance liquid chromatography detections, the results are shown in Figure 10,6 parts of samples in figure
Product appearance time is consistent, and peak area is consistent, shows that this method reappearance is good, and testing result is stablized.
Impurity F, the structural confirmation of G in 11 mosapride citrate of embodiment
Result, which can be seen that detection method in the application, from embodiment 7 can effectively detect A-F totally 6 impurity, wherein
Impurity E, F have not yet to see in detection of the mosapride citrate in relation to substance and report.It is analyzed by LC-MS, further confirmed
Its structure, certification process are as follows：
Test equipment：Agilent Infinity1290 (CA, USA) and Finnigan LTQ Ion Trap Mass
Spectrometer (San Jose, CA, USA) is combined, and software is respectively Agilent Chemstation and Xcalibur.
Mass Spectrometry Conditions：Mass spectrograph flow velocity is 0.2ml/min.Electron spray ionisation, positive ion mode detection, nitrogen is as sheath
Gas, auxiliary gas and purge gass.Spray voltage 3.6kV：Sheath gas is 15arb, and auxiliary gas is 5arb, purge gass 0arb；Capillary
Temperature：275 DEG C, capillary voltage 10V, lens voltage 80V.Full scan mass range：150-400amu.Second order ms are used
Data dependence type collection, highest 1 peak of responsiveness intensity is used for second mass analysis, high-purity helium in full scan collection of illustrative plates
Make collision gas, collision energy 35ev.
The sample separating resulting and reference substance E, F obtained to liquid phase chromatogram condition in embodiment 7 carries out Mass Spectrometer Method respectively,
Obtained total particle flux mass-spectrogram is shown in Figure 11.
1st, the structural identification of impurity E (452 ethyl benzoate)
Data in Figure 10 are analyzed, peak is impurity E during wherein RT=19.76, and mass spectrogram is shown in Figure 12, data analysis
It the results are shown in Table 1.
1 impurity E reference substance mass spectroscopy data of table
| m/z | Relative abundance (%) | Remarks | |
| Reference substance | 244 | 100 | M++ 1 quasi-molecular ions |
| Sample | 244 | 100 | M++ 1 quasi-molecular ions |
The molecular ion peak of sample matches with reference substance compound structure, structure and 452 ethyl benzoate of reference substance
Structure is consistent.
2nd, the structural identification of impurity F (452 isobutyl benzoate)
Data in Figure 10 are analyzed, peak is impurity F during wherein RT=26.27, and mass spectrogram is shown in Figure 13, data analysis
It the results are shown in Table 2.
2 impurity F reference substance mass spectroscopy data of table
| m/z | Relative abundance (%) | Remarks | |
| Reference substance | 272 | 100 | M++ 1 quasi-molecular ions |
| Sample | 272 | 100 | M++ 1 quasi-molecular ions |
The molecular ion peak of sample matches with reference substance compound structure, structure and 452 anhydride of reference substance
Ester structure is consistent.
Claims (12)
1. a kind of detection method of mosapride citrate in relation to substance, it includes following steps：Mosapride citrate is taken to supply
Test sample solution sample introduction, is detected according to liquid phase chromatogram condition, and wherein high-efficient liquid phase chromatogram determining condition is：Chromatographic column：18
Alkyl silane bonded silica gel is filler；Mobile phase A is that volume ratio is 75：The mixed solution of 25 sodium dihydrogen phosphate/acetonitrile,
Mobile phase B is that volume ratio is 20:The mixed solution of 80 sodium dihydrogen phosphate/acetonitrile, sodium dihydrogen phosphate concentration are
0.001-0.1mol/L, the pH value of sodium dihydrogen phosphate are 2.0-6.0, also contain triethylamine in mobile phase A and B, described three
The volumetric concentration of ethamine is 0.01%-1%, and Detection wavelength is 210~360nm, and using gradient elution, gradient elution program is：
2. detection method of the mosapride citrate according to claim 1 in relation to substance, wherein the high-efficient liquid phase color
It composes in determination condition, sodium dihydrogen phosphate concentration is 0.01-0.05mol/L.
3. detection method of the mosapride citrate according to claim 2 in relation to substance, wherein the high-efficient liquid phase color
It composes in determination condition, sodium dihydrogen phosphate concentration is 0.01mol/L.
4. detection method of the mosapride citrate according to claim 1 in relation to substance, wherein the high-efficient liquid phase color
It composes in determination condition, it is H that the pH of the sodium dihydrogen phosphate, which adjusts reagent,3PO4。
5. detection method of the mosapride citrate according to claim 1 in relation to substance, wherein the high-efficient liquid phase color
It composes in determination condition, the pH value of sodium dihydrogen phosphate is 3.5.
6. detection method of the mosapride citrate according to claim 1 in relation to substance, wherein the high-efficient liquid phase color
It composes in determination condition, Detection wavelength 220nm.
7. column temperature is 15-40 DEG C in high-efficient liquid phase chromatogram determining condition according to claim 1；Flow velocity is 0.5-1.5ml/
min。
8. column temperature is 35 DEG C in high-efficient liquid phase chromatogram determining condition according to claim 7；Flow velocity is 1ml/min.
9. detection method of the mosapride citrate according to claim 1 in relation to substance, wherein the high-efficient liquid phase color
It composes in determination condition, the volumetric concentration of the triethylamine is 0.1%-0.3%.
10. detection method of the mosapride citrate according to claim 9 in relation to substance, wherein the high-efficient liquid phase color
It composes in determination condition, the volumetric concentration of the triethylamine is 0.1%.
11. detection method of the mosapride citrate according to claim 1 in relation to substance, wherein the test solution
Preparation method be to take appropriate mosapride citrate, it is accurately weighed, Mobile phase B is added to dissolve and dilute be made every 1ml containing about
The solution of 1mg to obtain the final product.
12. detection method of the mosapride citrate in relation to substance according to any one in claim 1-11, bag
Containing following steps：
(a) preparation of test solution：
Appropriate mosapride citrate is taken, it is accurately weighed, Mobile phase B is added to dissolve and is diluted solution of every 1ml containing about 1mg is made i.e.
；
(b) chromatographic condition：Chromatographic column is that octadecylsilane chemically bonded silica is filler；Using gradient elution, mobile phase A is volume
Than for 75：The mixed solution of 25 sodium dihydrogen phosphate/acetonitrile, Mobile phase B are that volume ratio is 20:80 sodium dihydrogen phosphate is molten
The mixed solution of liquid/acetonitrile, column temperature are 35 DEG C, flow velocity 1ml/min, Detection wavelength 220nm, the gradient elution program
For：
Wherein, in the sodium dihydrogen phosphate in the mobile phase A and Mobile phase B containing volumetric concentration be 0.1% triethylamine,
And with phosphoric acid tune pH value to 3.5；
(c) measure：Test solution injection liquid chromatograph is drawn, according to high effective liquid chromatography for measuring.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410312949.5A CN105301118B (en) | 2014-07-02 | 2014-07-02 | A kind of detection method of mosapride citrate in relation to substance |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410312949.5A CN105301118B (en) | 2014-07-02 | 2014-07-02 | A kind of detection method of mosapride citrate in relation to substance |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105301118A CN105301118A (en) | 2016-02-03 |
| CN105301118B true CN105301118B (en) | 2018-05-25 |
Family
ID=55198626
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410312949.5A Active CN105301118B (en) | 2014-07-02 | 2014-07-02 | A kind of detection method of mosapride citrate in relation to substance |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105301118B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111285820A (en) * | 2018-12-07 | 2020-06-16 | 成都康弘药业集团股份有限公司 | Mosapride citrate related substance and preparation method thereof |
| CN111505154B (en) * | 2020-05-07 | 2022-09-30 | 南京百思福医药科技有限公司 | Detection method for mosapride citrate and five key impurities in preparation thereof |
| CN112209895A (en) * | 2020-10-16 | 2021-01-12 | 深圳市祥根生物科技有限公司 | Preparation method of mosapride citrate impurity |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUP0201980A3 (en) * | 2002-06-13 | 2008-06-30 | Richter Gedeon Nyrt | Process for preparing a benzamide derivative and intermediates thereof |
| WO2011107903A1 (en) * | 2010-03-04 | 2011-09-09 | Ranbaxy Laboratories Limited | Highly pure mosapride citrate dihydrate and processes for its preparation |
-
2014
- 2014-07-02 CN CN201410312949.5A patent/CN105301118B/en active Active
Non-Patent Citations (5)
| Title |
|---|
| /#01#23法测定枸橼酸莫沙必利口崩片的含量;刘阿利 等;《齐鲁药事》;20061231;第25卷(第11期);全文 * |
| Application of LC/MS/MS for the identification of a polar impurity in mosapride, a gastroprokinetic drug;Y. Ravindra Kumar et al.;《Journal of Pharmaceutical and Biomedical Analysis》;20031231;第32卷;摘要，第362页，图1，第365页右栏 * |
| HPLC测定枸橼酸莫沙必利胶囊中的有关物质;陈钢 等;《中国现代应用药学》;20100930;第27卷(第9期);全文 * |
| Stability-indicating HPLC–DAD methods for determination of two binary mixtures：Rabeprazole sodium–mosapride citrate and rabeprazole sodium–itopride hydrochloride;Hamed M. El-Fatatry et al.;《Journal of Pharmaceutical Analysis》;20141231;第4卷(第4期);全文 * |
| 枸橼酸莫沙必利糖浆的制备及质量控制;孙秀芹 等;《药学研究》;20131231;第32卷(第2期);全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105301118A (en) | 2016-02-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Fan et al. | Simultaneous quantification of three major bioactive triterpene acids in the leaves of Diospyros kaki by high-performance liquid chromatography method | |
| Li et al. | Pre-column derivatization and gas chromatographic determination of alkaloids in bulbs of Fritillaria | |
| CN105301118B (en) | A kind of detection method of mosapride citrate in relation to substance | |
| Chen et al. | Elevated levels of oxidative nucleic acid modification markers in urine from gastric cancer patients: quantitative analysis by ultra performance liquid chromatography-tandem mass spectrometry | |
| CN105424822B (en) | The method for detecting (1R, 2S) 2 (3,4 difluorophenyl) cyclopropylamine in ticagrelor | |
| Jeong et al. | A sensitive UPLC–ESI–MS/MS method for the quantification of cinnamic acid in vivo and in vitro: Application to pharmacokinetic and protein binding study in human plasma | |
| CN107315058A (en) | A kind of method of total ginkgoic acid in detection ginkgo biloba succi | |
| CN111239303B (en) | Method for simultaneously determining concentrations of ticagrelor, active metabolites thereof and endogenous adenosine in human plasma by liquid chromatography-mass spectrometry | |
| CN108120791A (en) | A kind of method of three kinds of ochratoxin total amounts in Rapid Simultaneous Determination sample | |
| CN108593790A (en) | Detect serum 24,25 simultaneously（OH）The method of 2D and 25OHD | |
| Lee et al. | Sensitive and specific liquid chromatography–tandem mass spectrometric method for the quantitation of dexmedetomidine in pediatric plasma | |
| Qiu et al. | Pharmacokinetic and excretion study of eight active constituents in rat by LC-MS/MS after oral administration of the Toddalia asiatica extract | |
| CN105891368A (en) | Method for detecting acetyl choline content in peripheral blood mononuclear cells | |
| Schneider et al. | Time resolved analysis of risperidone and 9-hydroxy-risperidone in hair using LC/MS-MS | |
| CN107589197A (en) | HPLC method separation determination Isoxepacs and its method about material | |
| CN112198234B (en) | Method for determining content of four bear gall powder related components in phlegm-heat clearing injection | |
| CN112611813B (en) | Method for testing genotoxic impurities of Sacubitril valsartan sodium starting material | |
| CN112114080B (en) | Method for detecting aripiprazole related substances | |
| Li et al. | Rapid detection of propofol in whole blood using an automated on-line molecularly imprinted pretreatment coupled with optical fibre detection | |
| CN114674945A (en) | Quality detection method for cyclobenzaprine hydrochloride | |
| CN110687238B (en) | Detection method of flumatinib mesylate related substances | |
| CN110873767B (en) | Rapid detection method for dexlansoprazole synthetic intermediate and related substances thereof | |
| CN113030323A (en) | Method for detecting residual solvent in nilotinib bulk drug | |
| Wu et al. | Qualitative and quantitative evaluation of ginkgo terpene lactone raw material by HPLC/Q-TOF MS combined with HPLC-DAD-ELSD | |
| Zhong et al. | Simultaneous HPLC quantification of seven chromones in Aloe barbadensis Miller using a single reference standard |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |