CN105116062A - Method for separation determination of impurity content in rivastigmine tartrate - Google Patents
Method for separation determination of impurity content in rivastigmine tartrate Download PDFInfo
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- CN105116062A CN105116062A CN201510375682.9A CN201510375682A CN105116062A CN 105116062 A CN105116062 A CN 105116062A CN 201510375682 A CN201510375682 A CN 201510375682A CN 105116062 A CN105116062 A CN 105116062A
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- rivastigmine
- ethyl
- hydrogentartrate
- formic acid
- separating
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Abstract
The present invention belongs to the field of analytical chemistry, and discloses a method for separation determination of N-ethyl-N-methyl amino acid in rivastigmine tartrate by using HPLC-ELSD. According to the present invention, a chromatographic column of a hydrophilic interaction liquid chromatography filler (HILIC) is used and a buffer salt solution-organic phase with a certain ratio is adopted as a mobile phase to quantitatively determine the N-ethyl-N-methyl amino acid content in the rivastigmine tartrate so as to effectively control the quality of the rivastigmine tartrate; and the method has characteristics of strong specificity, high accuracy and simple operation.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical field, in particular to a kind of method of quality control of rivastigmine-hydrogentartrate, particularly relate to the detection method of N-ethyl-N-methyl ammonia formic acid content in rivastigmine-hydrogentartrate.
Background technology
Rivastigmine-hydrogentartrate is a kind of carbamic acid class brain selectivity acetylcholinesteraseinhibitors inhibitors, by delaying merit can completely cholinergic neuron to the degraded of release acetylcholine and the conduction of promotion cholinergic nerve, the effect of the position acetylcholines such as Selective long-range DEPT Cerebral cortex and hippocampus, thus effectively treat light, moderate DAT disease.Its chemistry ethyl-methyl ammonia formic acid-3-[1 (1 by name
s)-dimethylaminoethyl] phenyl ester L-TARTARIC ACID salt, molecular formula is C
14h
22n
2o
2c
4h
6o
6.Structural formula is:
N-ethyl-N-methyl carbamyl chloride is the crucial starting material of rivastigmine-hydrogentartrate, and in the process of this compound of synthesis, it is very easily hydrolyzed into N-ethyl-N-methyl ammonia formic acid.And N-ethyl-N-methyl ammonia formic acid not exclusively may be incorporated in bulk drug finished product owing to removing, therefore need to be controlled N-ethyl-N-methyl ammonia formic acid, its structural formula is:
For the N-ethyl-N-methyl ammonia formic acid introduced in synthesis rivastigmine-hydrogentartrate, need to carry out quality control in bulk drug, therefore, realize being separated of rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid, its synthesis and quality control aspect are had important practical significance.
Summary of the invention
The present inventor has groped the N-ethyl-N-methyl ammonia formic acid in a kind of separating heavy rivastigmine by great many of experiments, and measures the method for its chemical purity, ensures the quality controllable of rivastigmine-hydrogentartrate.
The method of a kind of N-ethyl-N-methyl ammonia formic acid content measured in rivastigmine-hydrogentartrate of the present invention is the chromatographic column adopting hydrophilic interaction liquid chromatography stuffing (HILIC), with a certain proportion of buffer salt solution-organic phase for mobile phase;
HILIC water wettability chromatographic column described above, is selected from Merck brand.
Above-mentioned said organic phase is from following compound: methyl alcohol, acetonitrile, preferred acetonitrile.
Above-mentioned said buffer salt can be formates or acetate, preferred ammonium acetate.
Method of separating and assaying of the present invention, can realize in accordance with the following methods:
1) sample getting rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid is appropriate, uses acetonitrile sample dissolution respectively, is mixed with the sample solution that every 1mL contains rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid 0.1 ~ 1.5mg;
2) arranging flow rate of mobile phase is 0.5 ~ 1.5mL/min;
3) mobile phase A is the ammonium acetate solution of 5 ~ 30mmol/L; Mobile phase B is acetonitrile or methyl alcohol;
4) drift tube temperature that evaporative light detecting device uses is 30 ~ 80 DEG C, and yield value is 5 ~ 12;
5) get 1) sample solution 10 ~ 50 μ L injection liquid chromatography, complete the separation determination of rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid.Wherein:
The model of high performance liquid chromatograph, has no special requirements, and the chromatograph brand that the present invention adopts is Shimadzu:
LC-20AT，CBM-20A，SIL-20AC，ELSD-LTⅡ，CTO-10ASvp
Chromatographic column: HILIC(SeQuant
zIC
-HILIC, 250 × 4.6mm, 5 μm)
Mobile phase: 20mmol/L ammonium acetate-acetonitrile (20:80)
Flow velocity: 1.0mL/min
Sampling volume: 10 μ L
ELSD parameter:
Drift tube temperature: 40 DEG C
Nebulizer gas pressure: 350KPa
Gain value: 9.
The present invention adopt HILIC (
250 × 4.6mm, 5 μm) chromatographic column, can effectively separating heavy rivastigmine and N-ethyl-N-methyl ammonia formic acid.The invention solves being separated and assay problem of rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid, thus ensure that quality controllable (the results are shown in accompanying drawing 1-5) of rivastigmine-hydrogentartrate bulk drug
Accompanying drawing explanation
The HPLC of rivastigmine-hydrogentartrate when Fig. 1 is embodiment 1 and N-ethyl-N-methyl ammonia formic acid schemes;
The HPLC figure of rivastigmine-hydrogentartrate when Fig. 2 is embodiment 1;
Solvent HPLC when Fig. 3 is embodiment 2 schemes;
The HPLC of rivastigmine-hydrogentartrate when Fig. 4 is embodiment 2 and N-ethyl-N-methyl ammonia formic acid schemes;
The HPLC figure of rivastigmine-hydrogentartrate when Fig. 5 is embodiment 2;
embodiment:
Following examples are used for understanding the present invention further, but are not limited to the scope of this experiment.
Embodiment 1
Instrument and condition
The model of high performance liquid chromatograph, has no special requirements, and the chromatograph brand that the present invention adopts is Shimadzu:
LC-20AT，CBM-20A，SIL-20AC，ELSD-LTⅡ，CTO-10ASvp
Chromatographic column: HILIC(SeQuant
zIC
-HILIC, 250 × 4.6mm, 5 μm)
Mobile phase: 20mmol/L ammonium acetate-acetonitrile (15:85)
Flow velocity: 1.0mL/min
Sampling volume: 10 μ L
ELSD parameter:
Drift tube temperature: 40 DEG C
Nebulizer gas pressure: 350KPa
Gain value: 9.
Experimental procedure
Get rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid appropriate, use acetonitrile sample dissolution respectively, be mixed with the sample solution being about 0.5mg/mL containing rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid.Liquid-phase chromatographic analysis is carried out, record chromatogram by above-mentioned condition.The chromatographic peak that the results are shown in retention time 39.898min in accompanying drawing 1 ~ 2, Fig. 1 is that rivastigmine-hydrogentartrate is overlapping with the chromatographic peak of N-ethyl-N-methyl ammonia formic acid; In Fig. 2, the chromatographic peak of retention time 39.378min is the chromatographic peak of rivastigmine-hydrogentartrate, and both degree of separation are undesirable.
Embodiment 2
Instrument and condition
The model of high performance liquid chromatograph, has no special requirements, and the chromatograph brand that the present invention adopts is Shimadzu:
LC-20AT，CBM-20A，SIL-20AC，ELSD-LTⅡ，CTO-10ASvp
Chromatographic column: HILIC(SeQuant
zIC
-HILIC, 250 × 4.6mm, 5 μm)
Mobile phase: 20mmol/L ammonium acetate-acetonitrile (25:75)
Flow velocity: 1.0mL/min
Sampling volume: 10 μ L
ELSD parameter:
Drift tube temperature: 40 DEG C
Nebulizer gas pressure: 350KPa
Gain value: 9.
The following items of above-mentioned rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid analytical approach is verified:
1, system suitability
Under the above-mentioned chromatographic condition determined, get rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid is in right amount each, use acetonitrile sample dissolution respectively, be mixed with the sample solution being about 0.5mg/mL containing rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid; Separately get acetonitrile in right amount as blank solvent.Efficient liquid phase chromatographic analysis is carried out, record chromatogram by above-mentioned condition.The results are shown in accompanying drawing 3 ~ 5, Fig. 3 is solvent chromatogram; In Fig. 4, the chromatographic peak of retention time 5.024min is rivastigmine-hydrogentartrate, and the chromatographic peak of 10.700min is N-ethyl-N-methyl ammonia formic acid; The chromatographic peak rivastigmine-hydrogentartrate of retention time 4.971min in Fig. 5, can find out that between rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid, degree of separation meets the requirements under this condition, meanwhile, each material peak purity and single-point threshold value all meet the requirements.
2, specificity
Get rivastigmine-hydrogentartrate sample appropriate, carry out failure test respectively under each harsh conditions, investigate the separation case destroying product and major component peak.
Acid destroys: get this product appropriate (about containing palmitic acid 9-hydroxy-risperidone 5mg), accurately weighed, is placed in 10mL test tube, adds 1mol/L hydrochloric acid 1mL, place 2h, add 1mol/L sodium hydroxide solution and be neutralized to neutrality, add methyl alcohol and dissolve and be diluted to scale, shake up.
Alkali destroys: get this product appropriate (about containing palmitic acid 9-hydroxy-risperidone 5mg), accurately weighed, is placed in 10mL test tube, adds 1mol/L NaOH 1mL, place 2h, add 1mol/L hydrochloric acid solution and be neutralized to neutrality, add methyl alcohol and dissolve and be diluted to scale, shake up.
Oxidative demage: get this product appropriate (about containing palmitic acid 9-hydroxy-risperidone 5mg), accurately weighed, be placed in 10mL test tube, add 30% hydrogen peroxide 1mL, place 2h, add methyl alcohol and dissolve and be diluted to scale, shake up.
High temperature: get this product appropriate (about containing palmitic acid 9-hydroxy-risperidone 5mg), accurately weighed, be placed in 10mL test tube, be placed in 60 DEG C of baking ovens and place 15 days, add methyl alcohol and dissolve and be diluted to scale, shake up.
Illumination destroys: get this product appropriate (about containing palmitic acid 9-hydroxy-risperidone 5mg), accurately weighed, is placed in 10mL test tube, places 15 days at 4500 ± 500LUX, add methyl alcohol and dissolve and be diluted to scale, shake up.
Get the sample under each failure condition, according to the liquid-phase condition sample introduction of related substance, record chromatogram.Result is visible, and the impurity peaks that this product generates under being used for each failure condition all can be separated well with major component peak.The impurity that this product generates under each failure condition is all little, and the impurity peaks of degraded all has larger absorption near determined wavelength 205nm.
3, stability of solution
Get the test liquid of rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid, respectively at 0,2,4,6,10,12,24 hour sample introduction, investigate the stability of solution when sample size measures, from result, this solution is stable in 24 hours.
4, durability
Because the above-mentioned chromatographic condition determined is isocratic elution, and determine corresponding flow velocity, column temperature, mobile phase pH, therefore these conditions are done corresponding fine setting, investigate the durability of chromatographic condition.
Change in flow is within the scope of ± 0.1mL/min, and the peak shape of rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid does not change, but retention time have corresponding reach and after move; Column temperature change is within the scope of ± 5 DEG C, and the peak shape of each material and retention time are all without larger change; The pH change of mobile phase is in ± 0.2 scope, and the peak shape of each material and retention time are also without larger change.
5, quantitative limit and detectability
Get rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid is in right amount each, accurately weighed, add mobile phase and dissolve the test liquid that each sample is made into response respectively, then precision to measure test liquid appropriate, stepwise dilution, sample introduction is investigated.Each material quantitative limit and detectability data as shown in the table:
Claims (10)
1. one kind measures the method for N-ethyl-N-methyl ammonia formic acid in rivastigmine-hydrogentartrate, it is characterized in that: the method adopting HPLC-ELSD coupling, by the chromatographic column of hydrophilic interaction liquid chromatography stuffing (HILIC), with certain proportion buffer salt solution-organic phase for mobile phase.
2. method of separating and assaying according to claim 1, chromatographic column is selected from Merck brand.
3. method of separating and assaying according to claim 1, said organic phase is methyl alcohol or acetonitrile.
4. method of separating and assaying according to claim 1, said buffer salt can be formates or acetate.
5. method of separating and assaying according to claim 4, the preferred ammonium acetate of said buffer salt.
6. method of separating and assaying according to claim 1, the volume ratio of said buffer salt and organic phase is 40:60 ~ 0:100.
7. method of separating and assaying according to claim 6, the optimum volume ratio of said buffer salt and organic phase is 30:70 ~ 10:90.
8. method of separating and assaying according to claim 1, is characterized in that:
1) sample getting rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid thereof is appropriate, uses acetonitrile sample dissolution respectively, is mixed with the sample solution that every 1mL contains rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid 0.1 ~ 1.5mg thereof;
2) arranging flow rate of mobile phase is 0.5 ~ 1.5mL/min;
3) mobile phase A is the ammonium acetate solution of 5 ~ 30mmol/L; Mobile phase B is acetonitrile or methyl alcohol;
4) drift tube temperature that evaporative light detecting device uses is 30 ~ 80 DEG C, and yield value is 5 ~ 12;
5) get 1) sample solution 10 ~ 50 μ L injection liquid chromatography, complete the separation determination of rivastigmine-hydrogentartrate and N-ethyl-N-methyl ammonia formic acid thereof.
9. the method for N-ethyl-N-methyl ammonia formic acid content in mensuration rivastigmine-hydrogentartrate according to claim 8, is characterized in that: mobile phase A is 20mmol/L ammonium acetate solution; Mobile phase B is acetonitrile.
10. the method for N-ethyl-N-methyl ammonia formic acid content in mensuration rivastigmine-hydrogentartrate according to claim 8, it is characterized in that: chromatographic column is ZIC-HILIC, 5 μm, 250 × 4.6mm(I.D.), flow velocity is 1.0mL/min, drift tube temperature is 40 DEG C, and yield value is 9, can detect under room temperature condition.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109507344A (en) * | 2017-09-15 | 2019-03-22 | 万特制药(海南)有限公司 | Rivastigmine intermediate and its method for separating and detecting in relation to substance |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109507344A (en) * | 2017-09-15 | 2019-03-22 | 万特制药(海南)有限公司 | Rivastigmine intermediate and its method for separating and detecting in relation to substance |
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Application publication date: 20151202 |