CN105319298A - Method for separating and measuring related substances of lercanidipine hydrochloride midbody through liquid chromatography - Google Patents
Method for separating and measuring related substances of lercanidipine hydrochloride midbody through liquid chromatography Download PDFInfo
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- CN105319298A CN105319298A CN201510650638.4A CN201510650638A CN105319298A CN 105319298 A CN105319298 A CN 105319298A CN 201510650638 A CN201510650638 A CN 201510650638A CN 105319298 A CN105319298 A CN 105319298A
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Abstract
The invention belongs to the field of analytical chemistry, and discloses a method for separating and measuring a lercanidipine hydrochloride midbody 2,6-Dimethy-4-(3-nitro-pheny)-1,4-dihydro-pyridine-3,5-dimethyl ester and related substances thereof through liquid chromatography. According to the method, octyl silane bonded silica gel is adopted as a chromatographic column of filler, a buffer salt solution, namely, an organic phase of a certain proportion is adopted as a mobile phase, the content of the lercanidipine hydrochloride midbody and the related substances thereof can be quantitatively measured, and therefore the quality of the lercanidipine hydrochloride midbody is effectively controlled, and it is guaranteed that the quality of lercanidipine hydrochloride is controllable.. The method is high in specificity, high in accuracy and easy and convenient to operate.
Description
Technical field
The invention belongs to analytical chemistry field, be specifically related to the method for liquid chromatography for separating and determining Lercanidipine hydrochloride intermediate and related substance thereof.
Background technology
Lercanidipine hydrochloride is calcium ion channel blockor, is used for the treatment of ariant angina, unstable angina, chronic stable angina clinically; In addition, it can also share separately or with other depressor, for hypertensive treatment.It is C that Lercanidipine hydrochloride intermediated chemistry is called 2,6-Dimethy-4-(3-nitro-pheny)-Isosorbide-5-Nitrae-dihydro-pyridine-3,5-dimethylester molecular formula
17h
18n
2o
6.Lercanidipine hydrochloride intermediate structure formula is:
In the process of this compound of synthesis, some important intermediate owing to removing not exclusively, may cause the generation of subsidiary reaction, thus affects purity and the quality of medicine.For Lercanidipine hydrochloride intermediate 2,6-Dimethy-4-(3-nitro-pheny)-Isosorbide-5-Nitrae-dihydro-pyridine-3,5-dimethylester, the related substance of major control is 3-Nitrol-benzaldehyde, and structural formula is:
Impurity removal in Lercanidipine hydrochloride intermediate is incomplete, will be incorporated into bulk drug finished product, thus affect purity and the quality of medicine.Therefore, realize separation and the quantitative measurement of Lercanidipine hydrochloride intermediate and related substance thereof, have important practical significance in the production and quality control thereof of Lercanidipine hydrochloride.
Summary of the invention
The object of the present invention is to provide a kind of method analyzing Lercanidipine hydrochloride intermediate related substance, thus realize the separated island form of Lercanidipine hydrochloride intermediate and its related substance, realize the quality control of Lercanidipine hydrochloride.
The method of liquid chromatography analysis Lercanidipine hydrochloride intermediated chemistry purity of the present invention adopts octadecylsilane chemically bonded silica to be the chromatographic column of filler, with a certain proportion of buffer salt solution-organic phase for mobile phase.
Above-mentioned said chromatographic column is filler with octadecylsilane chemically bonded silica, is selected from the chromatographic column of the brands such as Kromasil, Apollo and Alltima.
Above-mentioned said organic phase is selected from following compound: methyl alcohol, acetonitrile, propyl alcohol, isopropyl alcohol, preferred acetonitrile.
Above-mentioned said method, its mobile phase buffer salt solution-organic phase adopts isocratic elution.
In above-mentioned said method, buffer salt solution is selected from phosphate, formates, acetate, perchlorate, preferred perchlorate.
Wherein the concentration of buffer salt solution is 0.01 ~ 0.1mol/L, and preferred concentration is 0.02mol/L.
Method of separating and assaying of the present invention, can realize in accordance with the following methods:
1) get Lercanidipine hydrochloride intermediate sample appropriate, by acetonitrile or mobile phase sample dissolution, be mixed with the sample solution of the hydrochloric Lercanidipine intermediate of every 1mL and related substance 0.1 ~ 1.5mg thereof.
2) arranging flow rate of mobile phase is 0.5 ~ 1.5mL/min, the preferred 1.0mL/min of flow rate of mobile phase, and determined wavelength is 205 ~ 280nm, and best detection wavelength is 210nm, and column oven temperature is 10 ~ 25 DEG C, and column oven temperature the best is 25 DEG C.
3) get 1) sample solution 10 ~ 50 μ L, injection liquid chromatography, completes the separation determination of Lercanidipine hydrochloride intermediate and related substance.Wherein:
The model of high performance liquid chromatograph, has no special requirements, and the chromatograph that the present invention adopts is Shimadzu high performance liquid chromatograph:
LC-20AT，CBM-20A，SIL-20AC，SPD-M20A，CTO-10ASvp
Chromatographic column: C
18(Kromasil, 250 × 4.6mm, 5 μm)
Mobile phase: 0.02mol/L sodium perchlorate buffer solution (pH5.5)-methyl alcohol (55:45)
Flow velocity: 1.0mL/min
Determined wavelength: 210nm
Column temperature: 25 DEG C
Sampling volume: 10 μ L
The present invention adopts C
18(Kromasil, 250 × 4.6mm, 5 μm), can effectively be separated Lercanidipine hydrochloride intermediate and related substance thereof.The invention solves the separation determination problem of Lercanidipine hydrochloride intermediate and related substance thereof, thus ensure that the quality of Lercanidipine hydrochloride intermediate, realize quality controllable (the results are shown in accompanying drawing 1 ~ 6) of Lercanidipine hydrochloride bulk drug.
Accompanying drawing explanation
Lercanidipine hydrochloride intermediate when Fig. 1 is embodiment 1 and related substance HPLC thereof scheme;
Lercanidipine hydrochloride intermediate HPLC when Fig. 2 is embodiment 1 schemes;
When Fig. 3 is embodiment 1, solvent HPLC schemes
Lercanidipine hydrochloride intermediate when Fig. 4 is embodiment 2 and related substance HPLC thereof scheme;
The HPLC figure of Lercanidipine hydrochloride intermediate when Fig. 5 is embodiment 2;
Solvent HPLC when Fig. 6 is embodiment 2 schemes;
Embodiment:
Following examples are used for understanding the present invention further, but are not limited to the scope of this enforcement.
Embodiment 1
Instrument and condition
High performance liquid chromatograph: Shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp;
Chromatographic column: C
18(Kromasil, 250 × 4.6mm, 5 μm);
Mobile phase: 0.02mol/L sodium perchlorate buffer solution (pH5.5)-methyl alcohol (55:45);
Flow velocity: 1.0mL/min
Determined wavelength: 210nm
Column temperature: 25 DEG C
Sampling volume: 10 μ L.
Experimental procedure
Get Lercanidipine hydrochloride intermediate and related substance thereof appropriate, use acetonitrile sample dissolution respectively, be mixed with the sample solution that hydrochloric Lercanidipine intermediate and related substance thereof are about 1.0mg/mL.Get above-mentioned Lercanidipine hydrochloride intermediate and related substance solution thereof appropriate, be mixed with system suitability solution; Efficient liquid phase chromatographic analysis is carried out, record chromatogram by above-mentioned condition.To the results are shown in retention time in accompanying drawing 1 ~ 3, Fig. 1 be the chromatographic peak of 22.956min is Lercanidipine hydrochloride intermediate, and all the other chromatographic peaks are the chromatographic peak of Lercanidipine hydrochloride intermediate related substance, and wherein retention time is the chromatographic peak of 8.927min is related substance; In Fig. 2, retention time is the chromatographic peak of 22.627min is Lercanidipine hydrochloride intermediate;
Blank solvent chromatogram when Fig. 3 is embodiment 1.
Embodiment 2
Instrument and condition
High performance liquid chromatograph: Shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp;
Chromatographic column: C
18(Kromasil, 250 × 4.6mm, 5 μm);
Mobile phase: 0.02mol/L sodium perchlorate buffer solution (pH5.5)-methyl alcohol (57:43);
Flow velocity: 1.0mL/min
Determined wavelength: 210nm
Column temperature: 25 DEG C
Sampling volume: 10 μ L.
Experimental procedure
Get Lercanidipine hydrochloride intermediate and related substance thereof appropriate, use acetonitrile sample dissolution respectively, be mixed with the sample solution that hydrochloric Lercanidipine intermediate and related substance thereof are about 1.0mg/mL.Get above-mentioned Lercanidipine hydrochloride intermediate and related substance solution thereof appropriate, be mixed with system suitability solution; Efficient liquid phase chromatographic analysis is carried out, record chromatogram by above-mentioned condition.To the results are shown in retention time in accompanying drawing 4 ~ 6, Fig. 4 be the chromatographic peak of 30.146min is Lercanidipine hydrochloride intermediate, and all the other chromatographic peaks are the chromatographic peak of Lercanidipine hydrochloride intermediate related substance, and wherein retention time is the chromatographic peak of 10.224 is related substance; In Fig. 5, retention time is the chromatographic peak of 30.124min is Lercanidipine hydrochloride intermediate; Fig. 6 is blank solvent chromatogram.
Stability of solution
Get the test liquid of Lercanidipine hydrochloride intermediate and related substance thereof, adopt the method in embodiment 1, respectively at 0,2,4,6,8,10,12,24 hour sample introduction, investigate the stability of solution when sample amounts measures, from result, this solution is stable in 24 hours.
Durability
Because the above-mentioned chromatographic condition determined is isocratic elution, and determine corresponding flow velocity, column temperature, mobile phase pH and chromatographic column model, 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 its related substance of Lercanidipine hydrochloride intermediate 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; In the durability investigation of chromatographic column, each material retention time and degree of separation are without significant change, and each material chromatographic peak purity and degree of separation all meet the requirements.
Claims (11)
1. a method for liquid chromatography for separating and determining Lercanidipine hydrochloride intermediate related substance, is characterized in that: octadecylsilane chemically bonded silica is the chromatographic column of filler, with a certain proportion of buffer salt solution-organic phase for mobile phase.
2. method of separating and assaying according to claim 1, chromatographic column is selected from the chromatographic column that brand is Kromasil, Apollo and Alltima.
3. method of separating and assaying according to claim 1, said organic phase is selected from the one in following compound: methyl alcohol, acetonitrile, propyl alcohol, isopropyl alcohol.
4. method of separating and assaying according to claim 3, said organic phase is acetonitrile.
5. method of separating and assaying according to claim 1, said buffer salt solution is selected from following buffer salt: phosphate, formates, acetate, perchlorate etc.
6. method of separating and assaying according to claim 5, the concentration optimum of said buffer salt solution is 0.02mol/L.
7. method of separating and assaying according to claim 5, the preferred perchlorate of said buffer salt.
8. method of separating and assaying according to claim 1, is characterized in that, comprises following step:
1). get Lercanidipine hydrochloride intermediate sample appropriate, use acetonitrile sample dissolution respectively, be mixed with the sample solution of the hydrochloric Lercanidipine intermediate of every 1mL and related substance 0.1 ~ 1.5mg thereof;
2). arranging flow rate of mobile phase is 0.5 ~ 1.5mL/min, and determined wavelength is 205 ~ 280nm, and chromatographic column column oven temperature is 10 ~ 40 DEG C;
3). get 1) sample solution 10 ~ 50 μ L, injection liquid chromatography, completes the separation determination of Lercanidipine hydrochloride intermediate and related substance thereof.
9. method for separating and analyzing according to claim 7, the pH value of buffer salt solution preferably 5.5.
10. method for separating and analyzing according to claim 8, step 2) the preferred 1.0mL/min of said flow rate of mobile phase.
11. method for separating and analyzing according to claim 8, step 2) the preferred 210nm of said determined wavelength.
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