CN106872631A - The method for determining organic impurities in 2 chloromethyl 3 methyl 4 (3 methoxypropoxy) pyridine hydrochloride - Google Patents
The method for determining organic impurities in 2 chloromethyl 3 methyl 4 (3 methoxypropoxy) pyridine hydrochloride Download PDFInfo
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Abstract
The invention discloses the method that one kind determines organic impurities in 2 chloromethyl 3 methyl 4 (3 methoxypropoxy) pyridine hydrochloride, the method uses the chromatographic column with octadecylsilane chemically bonded silica as filler, with PDAD or UV-detector as detector, gradient elution is carried out：During 0min ＜ t≤10min, 30min ＜ t≤40min, mobile phase is the first eluent, it is made up of pH5.5~6.5 cushioning liquid and methyl alcohol, volume of buffer solution fraction is 48%~52%, during 10min ＜ t≤30min, mobile phase is the second eluent, it is made up of pH5.5~6.5 cushioning liquid and acetonitrile, volume of buffer solution fraction is 58%~62%, and method of the present invention specificity is strong, sensitivity is high, can rapidly and accurately detect organic impurities in 2 chloromethyl 3 methyl 4 (3 methoxypropoxy) pyridine hydrochloride.
Description
Technical field
The invention belongs to analyze detection field, and in particular to one kind determines the 2- chloromethyl -3- methyl -4- (oxygen of 3- methoxies third
Base) method of organic impurities in pyridine hydrochloride.
Background technology
2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride (referred to as " thunder shellfish chloride "), is a kind of
Pharmaceutical intermediate, mainly for the preparation of proton pump inhibitor bulk drug such as RABEPRAZOLE SODIUM, dextral-rabeprazole sodium, Rabeprazole
The bulk drugs such as magnesium, dextral-rabeprazole-magnesium and related preparations.The synthetic route of thunder shellfish chloride is as follows：
Organic impurities that may be present has the dichloro- accessory substance (impurity produced during hydroxylate chloro in thunder shellfish chloride
A), the 4- hydroxylate of chloro (impurity B), and initiation material nitrogen oxides (impurity C) and intermediate product hydroxylate for remaining
(impurity D).The quality of thunder shellfish chloride directly affects the quality of the bulk drug and preparation with it as key starting material.On thunder
The method for quantitatively determining of organic impurities in shellfish chloride, has no document report, therefore, exploitation one kind can quantitative determine thunder shellfish chlorination
The method of organic impurities, has important practical significance in thing.
The content of the invention
The technical problem to be solved in the present invention is to overcome the deficiencies in the prior art, there is provided it is a kind of quick and precisely, specificity it is strong,
Organic impurities in sensitivity measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride high, simple to operation
Method.
In order to solve the above technical problems, the present invention uses following technical scheme：
One kind determines the method for organic impurities in 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride, institute
Method is stated for HPLC methods, the HPLC methods use the chromatographic column with octadecylsilane chemically bonded silica as filler, used
PDAD or UV-detector, carry out gradient elution in the following manner：
If elution time is t,
During 0min ＜ t≤10min, 30min ＜ t≤40min, mobile phase be the first eluent, first eluent by
PH5.5~6.5 cushioning liquid and methyl alcohol are constituted, and by volume percent, pH5.5~6.5 cushioning liquid is 48%~
52%, remaining is methyl alcohol；
During 10min ＜ t≤30min, mobile phase is the second eluent, and second eluent is buffered molten by pH5.5~6.5
Liquid is constituted with acetonitrile, and by volume percent, pH5.5~6.5 cushioning liquid is 58%~62%, and remaining is acetonitrile.
The method of organic impurities in above-mentioned measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride
In, it is preferred that pH5.5~6.5 cushioning liquid uses pH6.0 cushioning liquid.
The method of organic impurities in above-mentioned measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride
In, it is preferred that during 0min ＜ t≤10min, 30min ＜ t≤40min, the mobile phase is the first eluent, and described first washes
De- liquid is made up of pH6.0 cushioning liquid and methyl alcohol, and by volume percent, the pH6.0 cushioning liquid is 50%, and remaining is first
Alcohol；
During 10min ＜ t≤30min, the mobile phase is the second eluent, and second eluent is buffered molten by pH6.0
Liquid is constituted with acetonitrile, and by volume percent, the pH6.0 cushioning liquid is 60%, and remaining is acetonitrile.
The method of organic impurities in above-mentioned measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride
In, it is preferred that the concentration range of pH5.5~6.5 cushioning liquid is 0.002mo1/L~0.05mol/L；And/or, detection
Wavelength is 254nm~300nm；And/or, the flow velocity of the mobile phase is 0.8mL/min~1.2mL/min；And/or, column temperature is
25 DEG C~40 DEG C.
The method of organic impurities in above-mentioned measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride
In, it is furthermore preferred that the concentration range of pH5.5~6.5 cushioning liquid is 0.005mo1/L~0.015mol/L；And/or, institute
Detection wavelength is stated for 264nm；And/or, the flow velocity of the mobile phase is 1.0mL/min；And/or, column temperature is 30 DEG C.
The method of organic impurities in above-mentioned measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride
In, it is preferred that pH5.5~6.5 cushioning liquid is pH5.5~6.5 PBS.
The method of organic impurities in above-mentioned measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride
In, it is preferred that the chromatographic column is YMC Triart-C18 posts.
The method of organic impurities in above-mentioned measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride
In, it is preferred that the HPLC methods specifically include following steps：
(1) foundation of organic impurities standard curve：Impurity A reference substance, impurity B reference substance, impurity C controls are weighed respectively
Product, impurity D reference substances and 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride reference substance are appropriate, molten with methyl alcohol
Solve and dilute, be configured to a series of mixed reference substance solution of various concentrations, wherein impure A, impurity B, impurity D and 2- chloromethane
The concentration of base -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride in the range of 4 μ g/ml~0.5 μ g/ml, impure C
Concentration in the range of 2 μ g/ml~0.25 μ g/ml, be measured under the chromatographic condition of the HPLC methods, record chromatogram
Figure, is mapped with each component peak area to its concentration, obtains the standard curve of each component；
(2) in testing sample organic impurity content measure：By 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyrrole
Thiamine hydrochloride testing sample methyl alcohol dissolves and dilutes, and the need testing solution that concentration is 1mg/ml is made, using the HPLC side
Method, is measured under the step (1) identical chromatographic condition, records chromatogram, known impurities A~D in need testing solution
Concentration according in the step (1) correspondence impurity standard curve try to achieve, in need testing solution the concentration of unknown impuritie according to
The standard curve of 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride is tried to achieve in the step (1), is recycled
Each impurity concentration obtains the content of each impurity in testing sample divided by the concentration of need testing solution in need testing solution.
The method of organic impurities in above-mentioned measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride
In, the organic impurities includes impurity A, impurity B, impurity C and impurity D：
The impurity A is：The impurity B is：
The impurity C is：The impurity D is：
The method of organic impurities in above-mentioned measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride
In, in the HPLC methods, impurity A, impurity B, impurity C, impurity D and 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyrrole
Thiamine hydrochloride is kept completely separate, and the separating degree between each adjacent peak is all higher than 1.5；Impurity A, impurity B or impurity D are in test sample
Mass percent be 0.05% when, the quantitative limit that signal to noise ratio is not less than 10, i.e. impurity A, impurity B or impurity D reaches
0.05%；When mass percents of the impurity C in test sample is 0.025%, signal to noise ratio is not less than 10, the i.e. quantitative limit of impurity C
Reach 0.025%.
In assay method of the invention, chromatogram peak sequence is impurity C, impurity D, impurity B, thunder shellfish chloride and impurity
A, the separating degree between each adjacent peak is all higher than 1.5.Guarantor identical with known impurities is such as shown in the chromatogram of need testing solution
The chromatographic peak of time is stayed, by external standard method with the content of each impurity of calculated by peak area, impurity C must not cross 0.1%, impurity A, impurity B
0.2% must not be crossed with impurity D；Unknown impuritie is each unknown miscellaneous with calculated by peak area by external standard method by reference substance of thunder shellfish chloride
The content of matter, must not cross 0.2%, and total impurities must not cross 1.0%.
Compared with prior art, the advantage of the invention is that：
The present invention is to organic in 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride (thunder shellfish chloride)
Impurity is analyzed, and the organic impurities in thunder shellfish chloride is rapidly and accurately determined using C18 chromatographic columns, it is ensured that thunder shellfish chlorination
Thing it is quality controllable, bulk drug synthesis and formulation manufacturing processes quality control in terms of it is significant.Not yet examine at present
HPLC method of the rope to organic impurities in measure thunder shellfish chloride.Organic impurities detection side in the thunder shellfish chloride that the present invention is provided
Method, can rapidly and accurately detect organic impurities in thunder shellfish chloride, and the specificity of the method is strong, and sensitivity is high, simple to operation,
Thunder shellfish chloride can be preferably controlled to produce and the quality in application process.
Brief description of the drawings
Fig. 1 is the typical HPLC collection of illustrative plates (wavelength 264nm) of blank solution methyl alcohol in the embodiment of the present invention 1.
Fig. 2 is the typical HPLC collection of illustrative plates (wavelength 264nm) of separating degree testing liquid in the embodiment of the present invention 1.
Fig. 3 is the typical HPLC collection of illustrative plates (wavelength 264nm) of the medium sensitivity solution of the embodiment of the present invention 1.
Fig. 4 is the typical HPLC collection of illustrative plates of mixed reference substance solution I in the embodiment of the present invention 2.
Fig. 5 is the typical HPLC collection of illustrative plates of need testing solution (20160301 batches) in the embodiment of the present invention 2.
Specific embodiment
Below in conjunction with Figure of description and specific preferred embodiment, the invention will be further described, but not therefore and
Limit the scope of the invention.
Material and instrument employed in following examples are commercially available.
The following is organic impurities in present invention measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride
Method and contrast experiment, the method for the present invention be HPLC methods, the particular content and conditional filtering process of the inventive method are such as
Under：
Embodiment 1：Flowing phase composition and the screening of Detection wavelength
1.1 instruments and reagent
Liquid chromatograph：The quarternary low pressure liquid chromatographs of Agilent 1100, equipped with online vacuum degassing machine, diode battle array
Row detector.
Electronic balance：Sartorious BT 25S, d=0.01mg；Sartorious BSA 124S, d=0.1mg.
Impurity A reference substance (purity is 98.97%), impurity B reference substance (purity is 99.59%), impurity C reference substances are (pure
Spend for 99.55%), impurity D reference substances (purity is 99.47%) and 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine
Hydrochloride (hereinafter referred to as thunder shellfish chloride) reference substance (purity is 99.58%) is provided by Hunan such as rainbow pharmaceutical Co. Ltd；Water
It is ultra-pure water, methyl alcohol, acetonitrile are chromatographically pure, and it is pure that remaining reagent is analysis.The structural formula of impurity A~D is as follows：
The preparation of 1.2 solution
PH6.0 PBSs：Anhydrous potassium dihydrogenphosphate 8.06g, three water dipotassium hydrogen phosphate 1.16g are weighed, plus it is suitable
The water dissolves of amount are simultaneously diluted to 5000ml, shake up, and obtain final product.It is phosphoric acid potassium dihydrogen 0.0118mol in every liter of cushioning liquid, phosphorous
Sour hydrogen dipotassium 0.00102mol.
Different pH value PBSs：Take above-mentioned pH6.0 PBSs appropriate, with 0.1mol/L KOH or
Phosphoric acid is adjusted to required pH value.
Separating degree testing liquid：Take impurity A, impurity B, impurity C, impurity D and Lei Bei chloride reference substance each appropriate, it is accurate
It is weighed, dissolved with methyl alcohol and diluted and be made impure C reference substances 1 μ g, impure A, impurity B, impurity D reference substances each 2 in every 1ml
μ g, the mixed solution of the chloride reference substance of shellfish containing thunder 1mg, obtain final product.
Sensitivity solution：Take impurity A, impurity B, impurity C, impurity D and Lei Bei chloride reference substance each appropriate, precision claims
It is fixed, dissolved with methyl alcohol and diluted and be made impure C reference substances 0.25 μ g, impure A, impurity B, impurity D and Lei Bei chlorine in every 1ml
The mixed solution of each 0.5 μ g of compound reference substance, obtains final product.The concentration folding of impurity A, impurity B, impurity C and impurity D in sensitivity solution
The mass percent being counted as in 1mg/ml thunder shellfish chloride test samples is respectively 0.05%, 0.05%, 0.025%, 0.05%.
1.3 chromatographic conditions
Detector：PDAD (DAD detectors)
Chromatographic column：YMC Triart-C18,4.6mm × 250mm, 5 μm；Column temperature：30℃
Flow velocity：1.0mL/min；Sample size：20μl
1.4 flowing phase composition and the screenings of Detection wavelength
By adjusting mobile phase species and composition, a series of experiments is carried out using separating degree testing liquid, as a result find to work as
When individually using the flow visualizing of water-methanol, water-acetonitrile, cushioning liquid-methyl alcohol or cushioning liquid-acetonitrile composition, although taste
A variety of water phase-organic phase proportion of composing are tried, but can not simultaneously meet impurity A, impurity B, impurity C, impurity D and Lei Bei
Chloride is completely separate from one another and with the requirement compared with high detection sensitivity.
Found by lot of experiments, when mobile phase is totally made up of (by body pH5.5~6.5 cushioning liquid, methyl alcohol, acetonitrile
Product percentage meter), and gradient elution is carried out in the following manner：
During 0min ＜ t≤10min, mobile phase be the first eluent, the first eluent by 48%~52% pH5.5~
6.5 cushioning liquid and 52%~48% methyl alcohol are constituted；
During 10min ＜ t≤30min, mobile phase be the second eluent, the second eluent by 58%~62% pH5.5~
6.5 cushioning liquid and 42%~38% acetonitrile are constituted；
During 30min ＜ t≤40min, mobile phase is the first eluent.
Under these conditions, impurity A, impurity B, impurity C, impurity D and Lei Bei chloride can completely separate from one another, each phases
Separating degree between adjacent peak is all higher than 1.5.
It is furthermore preferred that mobile phase is made up of (by volume percent) pH6.0 PBSs, methyl alcohol, acetonitrile, and
Gradient elution is carried out in the following manner：
0min ＜ t≤10min, pH6.0 PBSs are 50%, and methyl alcohol is 50%, and acetonitrile is 0%；10min ＜
T≤30min, pH6.0 PBS are 60%, and methyl alcohol is 0%, and acetonitrile is 40%；30min ＜ t≤40min, pH6.0
PBS is 50%, and methyl alcohol is 50%, and acetonitrile is 0%.With this understanding, each known impurities peak, thunder shellfish chloride
Can be kept completely separate between peak, the separating degree between each adjacent peak is all higher than 2.0.Using DAD detector recording separating degrees
Whole spectrum of each known impurities and thunder shellfish chloride in testing liquid, as a result find impurity A, impurity B, impurity at 264nm
C, impurity D and Lei Bei chloride have stronger absorption, therefore wavelength when being detected to organic impurities in thunder shellfish chloride sample
Preferably 264nm.
When Detection wavelength uses 264nm, mobile phase is made up of pH6.0 PBSs, methyl alcohol, acetonitrile, and carries out
(0min ＜ t≤10min, cushioning liquid is 50% to gradient elution, and methyl alcohol is 50%, and acetonitrile is 0%；10min ＜ t≤30min,
Cushioning liquid is 60%, and methyl alcohol is 0%, and acetonitrile is 40%；30min ＜ t≤40min, cushioning liquid is 50%, and methyl alcohol is
50%, acetonitrile is that when 0%), the typical chromatogram of blank solution (methyl alcohol) is shown in Fig. 1, the typical chromatogram of separating degree testing liquid
See Fig. 2, the typical chromatogram of sensitivity solution is shown in Fig. 3.The details of Fig. 2 and Fig. 3 are shown in Tables 1 and 2 respectively.By Fig. 1~Fig. 3
And 1~table of table 2 provide information understand, blank solution to determine it is noiseless, impurity C, impurity D, impurity B, thunder shellfish chloride and
Impurity A peak degree detached from each other is all higher than 2.0, and the result of table 2 shows when impurity A, impurity B, impurity C and impurity D are in thunder shellfish chlorine
When mass percent in compound test sample is respectively 0.05%, 0.05%, 0.025% and 0.05%, the signal to noise ratio at each peak is equal
10 are not less than, show that the quantitative limit of impurity A, impurity B and impurity D can reach 0.05%, the quantitative limit of impurity C can reach
0.025%.
The HPLC profile informations of the separating degree testing liquid of table 1
| Ingredient names | Retention time | Peak height | Peak area | Separating degree | Tailing factor | Theoretical cam curve |
| Impurity C | 6.164 | 9.379 | 180.669 | --- | 0.81 | 3038 |
| Impurity D | 7.611 | 1.433 | 36.481 | 2.57 | 1.06 | 2005 |
| Impurity B | 9.204 | 4.729 | 100.934 | 2.61 | 0.96 | 4678 |
| Thunder shellfish chloride | 21.239 | 332 | 8293.101 | 20.25 | 1.06 | 17157 |
| Impurity A | 23.657 | 3.035 | 112.933 | 3.07 | 1.32 | 10501 |
The HPLC profile informations of the sensitivity solution of table 2
Test result indicate that, method of the present invention detection sensitivity is high, can realize to 2- chloromethyl -3- methyl -4- (3- first
Oxygen propoxyl group) organic impurities carries out the purpose of effective monitoring in pyridine hydrochloride.
Embodiment 2：The measure of actual sample
2.1 instruments and reagent
Instrument is with embodiment 1, thunder shellfish chloride 3 batches of (lot numbers of test sample：20160301st, 20160302,20160303) by
Hunan such as rainbow pharmaceutical Co. Ltd provides, and other reagents are with embodiment 1.
2.2 chromatographic determination conditions
Detector：PDAD (DAD detectors) Detection wavelength：264nm；
Chromatographic column：YMC Triart-C18,4.6 × 250mm, 5 μm；Column temperature：30℃
Flow velocity：1.0ml/min；Sample size：20μl
With the difference of elution time, mobile phase successively uses the first eluent, the second eluent and the first eluent, always
(by volume percent) is constituted by pH6.0 PBSs, methyl alcohol, acetonitrile on body, ladder is specifically carried out in the following manner
Degree wash-out：During 0min ＜ t≤10min, pH6.0 PBSs are 50%, and methyl alcohol is 50%, and acetonitrile is 0%；10min
During ＜ t≤30min, pH6.0 PBSs are 60%, and methyl alcohol is 0%, and acetonitrile is 40%；30min ＜ t≤40min
When, pH6.0 PBSs are 50%, and methyl alcohol is 50%, and acetonitrile is 0%.
The preparation of 2.3 solution
PH6.0 PBSs：Compound method is with embodiment 1.
Mixed reference substance solution I：Take impurity A, impurity B, impurity C, impurity D and 2- chloromethyl -3- methyl -4- (3- methoxies
Propoxyl group) pyridine hydrochloride (thunder shellfish chloride) reference substance is each appropriate, accurately weighed, and dissolved with methyl alcohol and diluted and be made every 1ml
In impure C about 2 μ g, impure A, impurity B, the mixed solution of each about 4 μ g of impurity D and Lei Bei chloride, obtain final product.
Need testing solution：Take thunder shellfish chloride test sample appropriate, it is accurately weighed, dissolved with methyl alcohol and diluted and be made every 1ml
In the chloride of shellfish containing thunder be about the solution of 1mg, obtain final product.
The foundation of 2.4 organic impurities standard curves
Take mixed reference substance solution I appropriate, use methyl alcohol stepwise dilution, a series of mixing reference substance that various concentrations are obtained is molten
Liquid, then precision pipette the μ l of each mixed reference substance solution 20, be injected separately into chromatograph, record chromatogram.With each impurity concentration X (μ
G/ml it is) abscissa, with each impurity peak area Y as ordinate, carries out linear regression, obtaining impurity C calibration curve equations is：Y
=179.2953X+0.5412 (r=0.9999)；Impurity D calibration curve equations are：Y=19.4881X-1.8909 (R=
0.9915)；Impurity B calibration curve equation is：Y=47.5948X+0.7077 (R=0.9996)；Impurity A calibration curve equation
For：Y=40.9596X-0.1327 (R=0.9994)；The calibration curve equation of thunder shellfish chloride is：Y=16.2918X-
0.3603 (R=0.9907).
As shown in figure 4, being the typical HPLC collection of illustrative plates of mixed reference substance solution I, retention time 6.187 is impurity C, during reservation
Between 7.753 be impurity D, retention time 9.232 be impurity B, retention time 21.594 be thunder shellfish chloride, retention time 23.950
It is impurity A.
The measure of organic impurity content in 2.5 testing samples
Precision measures the μ l of need testing solution 20, injects high performance liquid chromatograph, records chromatogram.The chromatogram of need testing solution
Such as the chromatographic peak of identical with the known impurities retention time of display in figure, in need testing solution the concentration of known impurities A~D according to
The standard curve of 2.4 lower impurity A~D is tried to achieve, and unknown impuritie concentration is according to 2.4 lower thunder shellfish chloride marks in need testing solution
Directrix curve is tried to achieve, and recycles each impurity concentration divided by the concentration of need testing solution, obtains the percentage composition of each impurity in test sample.
3 each batches of testing results of thunder shellfish chloride actual sample of table
※Remarks：The content of each impurity refers both to impurity shared mass percent in test sample in table.
Fig. 5 is the typical HPLC collection of illustrative plates of need testing solution 20160301 batches, and as shown in Figure 5, retention time 7.681min is
Impurity D peaks, retention time 21.233min is thunder Bei Lvhuawufeng.As shown in Table 3, impurity C contains in each batch of thunder shellfish chloride sample
Amount is below 0.1%, and impurity A, impurity B and impurity D are below 0.2%, and unknown impuritie content is less than 0.2%, and total impurities are low
In 1.0%, show that thunder shellfish chloride meets the requirements, this method can be used for the quality testing of thunder shellfish chloride.
From above-described embodiment, detection method of the invention is easy to operate, and specificity is strong, can delicately detect thunder shellfish
Organic impurities in chloride, it is adaptable to which thunder shellfish chloride is prepared and the quality monitoring in application process.
The above, is only presently preferred embodiments of the present invention, and any formal limitation is not made to the present invention.Though
So the present invention is disclosed as above with preferred embodiment, but is not limited to the present invention.It is any to be familiar with those skilled in the art
Member, in the case where Spirit Essence of the invention and technical scheme is not departed from, all using in the methods and techniques of the disclosure above
Appearance makes many possible variations and modification, or the Equivalent embodiments for being revised as equivalent variations to technical solution of the present invention.Therefore,
Every content without departing from technical solution of the present invention, according to technical spirit of the invention to made for any of the above embodiments any simple
Modification, equivalent, equivalence changes and modification, still fall within the range of technical solution of the present invention protection.
Claims (10)
1. the method that one kind determines organic impurities in 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride, it is special
Levy and be, methods described is HPLC methods, the HPLC methods use the color with octadecylsilane chemically bonded silica as filler
Spectrum post, using PDAD or UV-detector, carries out gradient elution in the following manner：
If elution time is t,
During 0min ＜ t≤10min, 30min ＜ t≤40min, mobile phase is the first eluent, and first eluent is by pH5.5
~6.5 cushioning liquid are constituted with methyl alcohol, and by volume percent, pH5.5~6.5 cushioning liquid is 48%~52%, its
Remaining is methyl alcohol；
During 10min ＜ t≤30min, mobile phase be the second eluent, second eluent by pH5.5~6.5 cushioning liquid with
Acetonitrile is constituted, and by volume percent, pH5.5~6.5 cushioning liquid is 58%~62%, and remaining is acetonitrile.
2. organic in measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride according to claim 1
The method of impurity, it is characterised in that pH5.5~6.5 cushioning liquid uses pH6.0 cushioning liquid.
3. organic in measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride according to claim 2
The method of impurity, it is characterised in that during 0min ＜ t≤10min, 30min ＜ t≤40min, the mobile phase is the first wash-out
Liquid, first eluent is made up of pH6.0 cushioning liquid and methyl alcohol, and by volume percent, the pH6.0 cushioning liquid is
50%, remaining is methyl alcohol；
During 10min ＜ t≤30min, the mobile phase be the second eluent, second eluent by pH6.0 cushioning liquid with
Acetonitrile is constituted, and by volume percent, the pH6.0 cushioning liquid is 60%, and remaining is acetonitrile.
4. organic in measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride according to claim 1
The method of impurity, it is characterised in that the concentration range of pH5.5~6.5 cushioning liquid is 0.002mo1/L~0.05mol/
L；And/or, Detection wavelength is 254nm~300nm；And/or, the flow velocity of the mobile phase is 0.8mL/min~1.2mL/min；
And/or, column temperature is 25 DEG C~40 DEG C.
5. organic in measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride according to claim 4
The method of impurity, it is characterised in that the concentration range of pH5.5~6.5 cushioning liquid is 0.005mo1/L~0.015mol/
L；And/or, the Detection wavelength is 264nm；And/or, the flow velocity of the mobile phase is 1.0mL/min；And/or, column temperature is 30
℃。
6. measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine according to any one of Claims 1 to 5
The method of organic impurities in hydrochloride, it is characterised in that pH5.5~6.5 cushioning liquid is slow for pH5.5~6.5 phosphate
Rush solution.
7. measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine according to any one of Claims 1 to 5
The method of organic impurities in hydrochloride, it is characterised in that the chromatographic column is YMC Triart-C18 posts.
8. measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine according to any one of Claims 1 to 5
The method of organic impurities in hydrochloride, it is characterised in that the HPLC methods specifically include following steps：
(1) foundation of organic impurities standard curve：Impurity A reference substance, impurity B reference substance, impurity C reference substances, miscellaneous is weighed respectively
Matter D reference substances and 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride reference substance are appropriate, are dissolved simultaneously with methyl alcohol
Dilution, is configured to a series of mixed reference substance solution of various concentrations, wherein impure A, impurity B, impurity D and 2- chloromethyl-
The concentration of 3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride is in the range of 4 μ g/ml~0.5 μ g/ml, and impure C's is dense
Degree is measured in the range of 2 μ g/ml~0.25 μ g/ml under the chromatographic condition of the HPLC methods, records chromatogram, with
Each component peak area is mapped to its concentration, obtains the standard curve of each component；
(2) in testing sample organic impurity content measure：By 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridiniujm
Hydrochlorate testing sample methyl alcohol dissolves and dilutes, and is made the need testing solution that concentration is 1mg/ml, using the HPLC methods,
It is measured under step (1) the identical chromatographic condition, records chromatogram, the concentration of known impurities A~D in need testing solution
Standard curve according to correspondence impurity in the step (1) is tried to achieve, and the concentration of unknown impuritie is according to the step in need testing solution
Suddenly the standard curve of 2- chloromethyls -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride is tried to achieve in (1), recycles test sample
Each impurity concentration obtains the content of each impurity in testing sample divided by the concentration of need testing solution in solution.
9. measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine according to any one of Claims 1 to 5
The method of organic impurities in hydrochloride, it is characterised in that the organic impurities includes impurity A, impurity B, impurity C and impurity D, institute
Stating impurity A is：The impurity B is：The impurity C is：The impurity
D is：
10. measure 2- chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine according to any one of Claims 1 to 5
The method of organic impurities in hydrochloride, it is characterised in that in the HPLC methods, impurity A, impurity B, impurity C, impurity D and 2-
Chloromethyl -3- methyl -4- (3- methoxypropoxies) pyridine hydrochloride is kept completely separate, and the separating degree between each adjacent peak is all higher than
1.5；When impurity A, the mass percent of impurity B or impurity D in test sample are 0.05%, signal to noise ratio is not less than 10, i.e., miscellaneous
The quantitative limit of matter A, impurity B or impurity D reaches 0.05%；When mass percents of the impurity C in test sample is 0.025%,
Signal to noise ratio is not less than 10, i.e. the quantitative limit of impurity C reaches 0.025%.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114577913A (en) * | 2020-11-30 | 2022-06-03 | 珠海润都制药股份有限公司 | Method for detecting rabeprazole chloride in rabeprazole sodium |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006105649A (en) * | 2004-10-01 | 2006-04-20 | Towa Yakuhin Kk | Novel measuring method for concentration of benzimidazole proton pump inhibitor in blood |
| CN102106829A (en) * | 2009-12-25 | 2011-06-29 | 北京四环科宝制药有限公司 | Sodium rabeprazole freeze-dried powder injection for injection, preparation method thereof and detection method thereof |
| CN102440967A (en) * | 2010-10-15 | 2012-05-09 | 菏泽步长制药有限公司 | Rabeprazole sodium for injection as well as preparation method and detection method thereof |
| CN104020239A (en) * | 2014-05-16 | 2014-09-03 | 南京长澳医药科技有限公司 | Method for separating and determining rebeprazole sodium and impurities thereof through high performance liquid chromatography (HPLC) |
-
2017
- 2017-04-20 CN CN201710261670.2A patent/CN106872631B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006105649A (en) * | 2004-10-01 | 2006-04-20 | Towa Yakuhin Kk | Novel measuring method for concentration of benzimidazole proton pump inhibitor in blood |
| CN102106829A (en) * | 2009-12-25 | 2011-06-29 | 北京四环科宝制药有限公司 | Sodium rabeprazole freeze-dried powder injection for injection, preparation method thereof and detection method thereof |
| CN102440967A (en) * | 2010-10-15 | 2012-05-09 | 菏泽步长制药有限公司 | Rabeprazole sodium for injection as well as preparation method and detection method thereof |
| CN104020239A (en) * | 2014-05-16 | 2014-09-03 | 南京长澳医药科技有限公司 | Method for separating and determining rebeprazole sodium and impurities thereof through high performance liquid chromatography (HPLC) |
Non-Patent Citations (4)
| Title |
|---|
| N. SHEETAL ANAND等: "A practical HPLC approach for the determination of trace level", 《JOURNAL OF CHEMICAL AND PHARMACEUTICAL RESEARCH》 * |
| R. BUCHI REDDY等: "Structural identification and characterization of potential impurities of", 《JOURNAL OF CHEMICAL AND PHARMACEUTICAL RESEARC》 * |
| 丁琛等: "注射用雷贝拉唑钠有关物质的HPLC法优化检测", 《药学与临床研究》 * |
| 谭淑珍等: "HPLC法同时测定雷贝拉唑钠原料药中8个有机杂质的含量", 《长沙理工大学学报（自然科学版）》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114577913A (en) * | 2020-11-30 | 2022-06-03 | 珠海润都制药股份有限公司 | Method for detecting rabeprazole chloride in rabeprazole sodium |
| CN114577913B (en) * | 2020-11-30 | 2023-05-02 | 珠海润都制药股份有限公司 | Method for detecting rabeprazole chloride in sodium rabeprazole |
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