CN110646520A - Method for separating and/or detecting impurities in atorvastatin calcium - Google Patents
Method for separating and/or detecting impurities in atorvastatin calcium Download PDFInfo
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- CN110646520A CN110646520A CN201810672838.3A CN201810672838A CN110646520A CN 110646520 A CN110646520 A CN 110646520A CN 201810672838 A CN201810672838 A CN 201810672838A CN 110646520 A CN110646520 A CN 110646520A
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- atorvastatin calcium
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- impurities
- enantiomer
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- 229960001770 atorvastatin calcium Drugs 0.000 title claims abstract description 109
- 238000000034 method Methods 0.000 title claims abstract description 37
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- 150000007524 organic acids Chemical class 0.000 claims abstract description 11
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- 235000019253 formic acid Nutrition 0.000 claims description 6
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- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
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- 230000026030 halogenation Effects 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims description 2
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 abstract description 36
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 5
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 5
- 229960005370 atorvastatin Drugs 0.000 description 5
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
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- 102100029077 3-hydroxy-3-methylglutaryl-coenzyme A reductase Human genes 0.000 description 4
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- 230000003287 optical effect Effects 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
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- QQNUXMVDRCYXGJ-UHFFFAOYSA-N acetic acid;n,n-diethylethanamine;ethanol Chemical compound CCO.CC(O)=O.CCN(CC)CC QQNUXMVDRCYXGJ-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
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- 150000001298 alcohols Chemical class 0.000 description 1
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- 229910052791 calcium Inorganic materials 0.000 description 1
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- 229940088679 drug related substance Drugs 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- GOFLNFPIFZZLIP-UHFFFAOYSA-N ethanol;2,2,2-trifluoroacetic acid Chemical compound CCO.OC(=O)C(F)(F)F GOFLNFPIFZZLIP-UHFFFAOYSA-N 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N30/14—Preparation by elimination of some components
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for separating and/or detecting impurities in atorvastatin calcium, wherein the impurities are atorvastatin calcium enantiomer and/or atorvastatin calcium lactone (impurity H), the method adopts high performance liquid chromatography for separation or detection, and the mobile phase of the high performance liquid chromatography is n-hexane-C1‑C6The monohydric alcohol-organic acid-organic base of (A), the n-hexane-C1‑C6The volume ratio of the monohydric alcohol to the organic acid to the organic base is 85-98: 2-15: 0.05-0.5, and the method can effectively separate atorvastatin calcium, an atorvastatin calcium enantiomer and atorvastatin calcium lactone; meanwhile, the method can be used for detecting the atorvastatin calcium enantiomer and the atorvastatin calcium lactone, and can effectively improve the medicine quality and safety of the atorvastatin calcium.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a method for separating or detecting an atorvastatin calcium enantiomer and atorvastatin calcium lactone (impurity H).
Background
Atorvastatin calcium is a third generation statin lipid regulating drug, is a selective and competitive inhibitor of HMG-CoA reductase, reduces cholesterol and lipoprotein levels in plasma by inhibiting the synthesis of HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) and cholesterol in the liver, and enhances the uptake and metabolism of LDL by increasing hepatic LDL receptors on the cell surface.
Atorvastatin calcium is a blood fat reducing drug widely applied in clinic, and can inhibit the synthesis of low-density lipoprotein and cholesterol in vivo by inhibiting HMG-CoA reductase so as to achieve the purpose of reducing blood fat. Atorvastatin calcium has two chiral centers in its molecular structure and thus two pairs of optical isomers. Impurities in pharmaceutically active ingredients, particularly optical isomer impurities, often affect the quality and safety of the drug, and therefore, must be controlled and studied. The optical isomer of atorvastatin can be used for quality research and is a control reference which is used in the production of atorvastatin calcium in daily life. In quality control, only enantiomers of atorvastatin calcium and diastereomers in either form generally need to be synthesized.
Atorvastatin calcium easily contains atorvastatin lactone (impurity H), the medicine contains the impurities, adverse effects are easily brought to the quality and safety of the medicine, adverse reactions are possibly caused, the detection and identification capacity of the impurities is improved, the quality control level is improved, and the safety of the product is effectively guaranteed. Several methods for measuring atorvastatin calcium related substances have been reported in the prior art, such as a method for detecting atorvastatin calcium related substances in an atorvastatin calcium capsule in a patent 201110197172.9, a method for measuring the dissolution rate of an atorvastatin calcium preparation in a patent 201310239929.5, a method for measuring atorvastatin calcium related substances in a patent 200910087797.2 by using a high performance liquid chromatography, and a method for measuring the impurity E in atorvastatin calcium in a patent 201510178001. X. In the prior art, no method for separating and detecting the enantiomer of atorvastatin calcium and the impurity H in atorvastatin calcium is involved, and the method comprises the following steps of: USP40Atorvastatin Calcium (P2898) and Atorvastatin import registration standard (JX20120157) are separated by adopting high performance liquid chromatography, and mobile phases are n-hexane-absolute ethyl alcohol-acidic compounds which are mixed according to a certain proportion to prepare the Atorvastatin Calcium, according to the method in the standard, impurities H and enantiomer in Atorvastatin Calcium cannot be effectively separated, and the accuracy of a detection result cannot be guaranteed.
Disclosure of Invention
Problems to be solved by the invention
The object of the present invention is to provide a method which allows an efficient separation and/or detection of the atorvastatin calcium enantiomer and atorvastatin calcium lactone (impurity H).
Means for solving the problems
The invention provides a method for separating and/or detecting impurities in an atorvastatin calcium tablet, wherein the impurities are atorvastatin calcium enantiomer and/or atorvastatin calcium lactone, the method adopts high performance liquid chromatography for separation or detection, and the method is characterized in that: the mobile phase of the high performance liquid chromatography is n-hexane-C1-C6The volume ratio of the n-hexane-alcohol-organic acid-organic base is 85-98: 2-15: 0.05-0.5.
Further, said C1-C6The monohydric alcohol is one or more of methanol, ethanol and propanol.
Further, the organic acid is C1-C6Carboxylic acids or halogeno-C1-C6The carboxylic acid, preferably formic acid, acetic acid, propionic acid or haloacetic acid or propylAnd (3) one or more of acids, wherein the halogenation is fluoro, chloro or bromo, and more preferably, the organic acid is one of formic acid or acetic acid or a mixture thereof.
Further, the organic base has a structure shown in formula I:
wherein R is1、R2And R3Each independently selected from hydrogen or chain alkyl with 1-12 carbon atoms, and R1、R2And R3At least one other than hydrogen, preferably R1、R2And R3Each independently selected from hydrogen or C1-3 chain alkyl group, and R1、R2And R3At least two are not hydrogen, more preferably diethylamine or triethylamine.
Further, the volume ratio of the n-hexane to the organic alcohol to the organic acid to the organic base is 90-95: 4-12: 0.1-0.3, preferably 90-95: 5-10: 0.1-0.2.
Further, the atorvastatin calcium exists in the form of a bulk drug, a solid preparation, a semi-solid preparation or a liquid preparation. Preferably, the solid preparation comprises tablets, capsules, suppositories, granules, films, pastes or pills, the semisolid preparation comprises gels and ointments, and the liquid preparation comprises injections, mixtures and solutions.
Further, the chromatographic conditions are as follows: the chromatographic column is a polysaccharide derivative chiral chromatographic column, the detection wavelength is 240-250nm, preferably 244nm, the chromatographic column temperature is 30-40 ℃, preferably 35 ℃, and the flow rate is 0.5-2ml/min, preferably 1 ml/min.
Further, the atorvastatin calcium is prepared into a solution to be treated, and the preparation method comprises the following steps: adding atorvastatin calcium into an organic solvent, adding the organic solvent to a constant volume, and filtering to obtain a solution to be treated.
Further, the organic solvent is C1-C6Of monohydric alcohol with n-hexaneThe preferred substance is a mixed solvent of methanol-ethanol-n-hexane with the volume ratio of 1:1-2:1-3, and the concentration of the atorvastatin calcium after adding the solvent to a constant volume is 0.5-2 mg/ml.
ADVANTAGEOUS EFFECTS OF INVENTION
According to the invention, a polysaccharide derivative chiral chromatographic column is adopted, under the chromatographic condition of the invention, effective separation of atorvastatin calcium, an atorvastatin calcium enantiomer and an atorvastatin calcium impurity H can be realized, and a good separation effect is achieved; meanwhile, the method can be used for detecting the atorvastatin calcium enantiomer and the impurity H, and can effectively improve the medicine quality and safety of the atorvastatin calcium.
Drawings
Figure 1 is a chromatogram of atorvastatin calcium impurity H;
figure 2 is a chromatogram of an enantiomer of atorvastatin calcium;
FIG. 3 is a chromatogram of a suitability solution for the system of example 1;
FIG. 4 is a chromatogram of a blank excipient solution of atorvastatin calcium of example 2;
FIG. 5 is a chromatogram of a test solution of atorvastatin calcium of example 2;
FIG. 6 is a chromatogram of a solution suitable for use in the system of example 2;
FIG. 7 is a chromatogram of a solution suitable for use in the system of example 3;
FIG. 8 is a chromatogram of a solution suitable for use in the system of example 4;
FIG. 9 is a chromatogram of a solution suitable for use in the system of example 5;
FIG. 10 is a chromatogram of a solution suitable for use in the system of example 6;
FIG. 11 is a chromatogram of a suitability solution for the system of example 7;
FIG. 12 is a chromatogram of a solution suitable for use in the system of example 8;
FIG. 13 is a chromatogram of a suitability solution for the system of example 9.
Detailed Description
First, the present invention provides a method for separating and/or detecting impurities in atorvastatin calcium tabletsThe method is used for separating or detecting atorvastatin calcium enantiomer and/or atorvastatin calcium lactone by adopting high performance liquid chromatography, and is characterized in that: the mobile phase of the high performance liquid chromatography is n-hexane-C1-C6The monohydric alcohol-organic acid-organic base of (A), the n-hexane-C1-C6The volume ratio of the monohydric alcohol to the organic acid to the organic base is 85-98: 2-15: 0.05-0.5.
In the context of the present invention, the term "atorvastatin calcium" has the formula C66H68CaF2N4O10The English name is Atorvastatin Calcium, and the CAS number is 134523-03-8.
In the context of the present invention, the term "separation and/or detection method" includes separation methods, detection methods and separation and detection methods.
In the context of the present invention, the term "atorvastatin calcium lactone" is the impurity H in atorvastatin calcium, an impurity of atorvastatin calcium degradation.
In the context of the present invention, the term "mobile phase" refers to the material that moves forward during chromatography, carrying the component to be measured.
In the context of the present invention, the term "C1-C6By monohydric alcohol "is meant a monohydric alcohol having from 1 to 6 carbon atoms, preferably methanol, ethanol or propanol, said C1-C6The monohydric alcohol(s) may be a single alcohol or a mixture of a plurality of different organic alcohols, either aqueous or anhydrous, preferably anhydrous.
In a preferred embodiment, the organic acid is one or more of formic acid, acetic acid, propionic acid or halogenated acetic acid or propionic acid, the halogen is fluoro, chloro or bromo, preferably, the organic acid is one or more of formic acid or acetic acid or a mixture thereof.
In a preferred embodiment, the atorvastatin calcium is present as a drug substance, a solid formulation, a semi-solid formulation or a liquid formulation. Preferably, the solid preparation comprises tablets, capsules, suppositories, granules, films, pastes or pills, the semisolid preparation comprises gels and ointments, and the liquid preparation comprises injections, mixtures and solutions.
In a preferred embodiment, the organic base is
The organic base has a structure shown in a formula I:
wherein R is1、R2And R3Each independently selected from hydrogen or chain alkyl with 1-12 carbon atoms, and R1、R2And R3At least one other than hydrogen, preferably R1、R2And R3Each independently selected from hydrogen or C1-3 chain alkyl group, and R1、R2And R3At least two are not hydrogen, more preferably diethylamine or triethylamine.
In a preferred embodiment, the volume ratio of the n-hexane-organic alcohol-organic acid-organic base is 90-95: 4-12: 0.1-0.3, preferably 90-95: 5-10: 0.1-0.2.
In a preferred embodiment, the chromatographic conditions are: the chromatographic column is polysaccharide derivative chiral chromatographic column with detection wavelength of 244nm, chromatographic column temperature of 30-40 deg.C, preferably 35 deg.C, and flow rate of 0.5-2ml/min, preferably 1 ml/min.
In the context of the present invention, the term "polysaccharide derivative chiral chromatography column" is a liquid chromatography column capable of separating chiral compounds, which uses polysaccharide and its derivatives AS a support, and mainly includes celluloses and starches, wherein the fibers include Chiralcel OD and Chiralcel OJ, and the starches include Chiralpak AD and Chiralpak AS.
In a preferred embodiment, the atorvastatin calcium is formulated into a solution to be treated by: adding atorvastatin calcium into an organic solvent, adding the organic solvent to a constant volume, and filtering to obtain a solution to be treated.
In a more preferred embodiment, the organic solvent is a mixed solvent of methanol-ethanol-n-hexane, preferably a mixed solvent of methanol-ethanol-n-hexane with a volume ratio of 1:1-2:1-3, and the concentration of atorvastatin calcium after adding the solvent to a constant volume is 0.5-2mg/ml, preferably 1 mg/ml.
The invention also provides a high performance liquid chromatography detection method of the atorvastatin calcium enantiomer in the atorvastatin calcium tablet, which comprises the following chromatographic conditions:
a chromatographic column: polysaccharide derivative chiral chromatographic column
Mobile phase: n-hexane-methanol-absolute ethanol-acetic acid-triethylamine (95: 1.5: 3.5: 0.1: 0.1);
detection wavelength: 244 nm;
column temperature: 35 deg.C
Flow rate: 1.0ml/min
Preparation of test sample solution
(1) Preparation of test solution
Adding the fine powder of the atorvastatin calcium tablet after being ground into fine powder which accounts for 50% of the total volume of a sample solution to be tested, fully shaking to dissolve atorvastatin, adding a solvent to a constant volume to enable the concentration of atorvastatin calcium to be 1mg/mL, and filtering, wherein the solvent is methanol-absolute ethanol-n-hexane (1: 3);
(2) preparation of self-control solution
Precisely measuring the sample solution, diluting with solvent 500 times, and filtering, wherein the solvent is methanol-anhydrous ethanol-n-hexane (1: 3);
(3) preparation of blank solution
Taking methanol-absolute ethyl alcohol-n-hexane (1: 3) for later use;
and (3) detection: and (3) respectively injecting 20 mu l of blank solvent, system applicability solution and sample solution to be tested into a liquid chromatograph, measuring according to the chromatographic conditions, and recording a chromatogram to finish the measurement of chiral isomers.
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
Example 1
Detection apparatus and chromatographic conditions
A detection instrument: high performance liquid chromatograph
Chromatographic conditions are as follows: the chromatographic column is a polysaccharide derivative chiral chromatographic column, the temperature of the chromatographic column is 35 ℃, an ultraviolet detector is adopted, and the detection wavelength is set to be 244 nm; the flow rate of the mobile phase is 1 ml/min; eluting with n-hexane-anhydrous ethanol-trifluoroacetic acid at volume ratio of 850: 150: 1 as mobile phase.
Preparing an atorvastatin calcium impurity H positioning solution: weighing a proper amount of atorvastatin calcium impurity H, adding a solvent to dissolve and dilute the atorvastatin calcium impurity H to scale so that the concentration of the atorvastatin calcium impurity H is 0.002mg/mL, and filtering the atorvastatin calcium impurity H, wherein the solvent is methanol-absolute ethyl alcohol-n-hexane with the volume ratio of 1: 3;
preparing an atorvastatin calcium enantiomer positioning solution: weighing a proper amount of atorvastatin calcium enantiomer, adding a solvent to dissolve and dilute the atorvastatin calcium enantiomer to scale, so that the concentration of the atorvastatin calcium enantiomer is 0.002mg/mL, and filtering the atorvastatin calcium enantiomer, wherein the solvent is methanol-absolute ethyl alcohol-n-hexane with the volume ratio of 1: 3;
preparation of system suitability solution: adding an atorvastatin calcium reference substance, an atorvastatin calcium enantiomer reference substance and an atorvastatin calcium impurity H reference substance which are in a mass ratio of 500:1:1 into a solvent which accounts for 50% of the total volume of the system applicability test solution, fully shaking to dissolve the atorvastatin calcium enantiomer reference substance and the atorvastatin calcium impurity H reference substance, adding the solvent to dilute the solvent to a scale to ensure that the concentration of atorvastatin calcium is 1.0mg/mL, the concentration of atorvastatin calcium enantiomer is 0.002mg/mL and the concentration of atorvastatin calcium impurity H is 0.002mg/mL, and filtering, wherein the solvent is methanol-absolute ethanol-n-hexane in a volume ratio of 1: 3;
the determination method comprises the following steps: measuring 20 mul of atorvastatin calcium impurity H positioning solution, atorvastatin calcium enantiomer positioning solution and system applicability solution, injecting into a liquid chromatograph, recording a chromatogram, and completing measurement; the chromatograms obtained are shown in FIGS. 1 to 3.
The results show that: the retention time of the atorvastatin calcium enantiomer is basically consistent with that of the impurity H of the atorvastatin calcium, a peak is formed by overlapping in the system applicability, the impurity H interferes with enantiomer detection, and the reference method has serious defects.
TABLE 1
Example 2
Detection apparatus and chromatographic conditions
A detection instrument: high performance liquid chromatograph
Chromatographic conditions are as follows: the chromatographic column is a polysaccharide derivative chiral chromatographic column, the temperature of the chromatographic column is 35 ℃, an ultraviolet detector is adopted, and the detection wavelength is set to be 244 nm; the flow rate of the mobile phase is 1 ml/min; the volume ratio is 95: 2: 3: 0.2: and (3) eluting with 0.2 of n-hexane-methanol-absolute ethyl alcohol-formic acid-diethylamine at equal intervals.
Blank adjuvant solution: adding atorvastatin calcium blank auxiliary materials into a solvent which accounts for 50% of the total volume of the sample solution to be tested, fully shaking to dissolve atorvastatin, adding the solvent to a constant volume to enable the concentration of the blank auxiliary materials to be equal to 1mg/mL of atorvastatin calcium, and filtering, wherein the solvent is methanol-absolute ethyl alcohol-n-hexane with the volume ratio of 1: 3.
Test solution: adding atorvastatin calcium into a solvent which accounts for 50% of the total volume of the sample solution to be tested, fully shaking to dissolve atorvastatin, adding the solvent to a constant volume to enable the concentration of atorvastatin calcium to be 1mg/mL, and filtering, wherein the solvent is methanol-absolute ethyl alcohol-n-hexane with the volume ratio of 1: 3.
Preparation of system suitability solution: adding an atorvastatin calcium reference substance, an atorvastatin calcium enantiomer reference substance and an atorvastatin calcium impurity H reference substance which are in a mass ratio of 500:1:1 into a solvent which accounts for 50% of the total volume of the system applicability test solution, fully shaking to dissolve the atorvastatin calcium enantiomer reference substance and the atorvastatin calcium impurity H reference substance, adding the solvent to dilute the solvent to a scale to ensure that the concentration of atorvastatin calcium is 1.0mg/mL, the concentration of atorvastatin calcium enantiomer is 0.002mg/mL and the concentration of atorvastatin calcium impurity H is 0.002mg/mL, and filtering, wherein the solvent is methanol-absolute ethanol-n-hexane in a volume ratio of 1: 3;
the determination method comprises the following steps: measuring blank auxiliary materials, the test sample solution and the system applicability solution by 20 mul respectively, injecting into a liquid chromatograph, recording a chromatogram, and finishing the measurement; the chromatograms obtained are shown in FIGS. 4-6.
The results show that: the atorvastatin calcium enantiomer, the atorvastatin calcium impurity H and the atorvastatin calcium sequentially flow out, the separation degree is good, blank auxiliary materials and other impurities do not interfere with enantiomer detection, the fact that the atorvastatin calcium impurity H is contained in the solution can be accurately seen from the chromatogram of the test solution, and the result is accurate.
Example 3
Detection apparatus and chromatographic conditions
A detection instrument: high performance liquid chromatograph
Chromatographic conditions are as follows: the chromatographic column is a polysaccharide derivative chiral chromatographic column, the temperature of the chromatographic column is 35 ℃, an ultraviolet detector is adopted, and the detection wavelength is set to be 244 nm; the flow rate of the mobile phase is 1 ml/min; the volume ratio is 95: 2: 3: 0.1: 0.1 n-hexane-methanol-absolute ethanol: trifluoroacetic acid: triethylamine was eluted isocratically as mobile phase.
The system suitability solution in this example was prepared as in example 1.
Injecting 20 mu l of system applicability solution into a liquid chromatograph, measuring according to the chromatographic conditions, recording a chromatogram, and finishing measurement; the resulting chromatogram is shown in FIG. 7.
The results show that: the atorvastatin calcium enantiomer, the atorvastatin calcium impurity H and the atorvastatin calcium sequentially flow out, the separation degree is good, the atorvastatin calcium enantiomer has slightly poor peak type, other impurities do not interfere enantiomer detection, and the result is accurate.
Example 4
Detection apparatus and chromatographic conditions
A detection instrument: high performance liquid chromatograph
Chromatographic conditions are as follows: the chromatographic column is a polysaccharide derivative chiral chromatographic column, the temperature of the chromatographic column is 35 ℃, an ultraviolet detector is adopted, and the detection wavelength is set to be 244 nm; the flow rate of the mobile phase is 1 ml/min; the volume ratio is 95: 2: 3: 0.1: and (3) eluting with 0.1 of n-hexane-methanol-absolute ethyl alcohol-acetic acid-triethylamine in an isocratic manner by using a mobile phase.
The system suitability solution in this example was prepared as in example 1.
Injecting 20 mu l of system applicability solution into a liquid chromatograph, measuring according to the chromatographic conditions, recording a chromatogram, and finishing measurement; the resulting chromatogram is shown in FIG. 8.
The results show that the separation degree of the atorvastatin calcium enantiomer, the atorvastatin calcium impurity H and the atorvastatin calcium is good, baseline separation is achieved, other impurities do not interfere with enantiomer detection, and the results are accurate.
Example 5
Detection apparatus and chromatographic conditions
A detection instrument: high performance liquid chromatograph
Chromatographic conditions are as follows: the chromatographic column is a polysaccharide derivative chiral chromatographic column, the temperature of the chromatographic column is 35 ℃, an ultraviolet detector is adopted, and the detection wavelength is set to be 244 nm; the flow rate of the mobile phase is 1 ml/min; and (3) mixing the components in a volume ratio of 96: 1.5: 2.5: 0.1: and (3) eluting with 0.1 of n-hexane-methanol-absolute ethyl alcohol-acetic acid-triethylamine in an isocratic manner by using a mobile phase.
The system suitability solution in this example was prepared as in example 1.
Injecting 20 mu l of system applicability solution into a liquid chromatograph, measuring according to the chromatographic conditions, recording a chromatogram, and finishing measurement; the resulting chromatogram is shown in FIG. 9.
The results show that the separation degree of the atorvastatin calcium enantiomer, the atorvastatin calcium impurity H and the atorvastatin calcium is good, baseline separation is achieved, other impurities do not interfere with enantiomer detection, and the results are accurate.
Example 6
Detection apparatus and chromatographic conditions
A detection instrument: high performance liquid chromatograph
Chromatographic conditions are as follows: the chromatographic column is a polysaccharide derivative chiral chromatographic column, the temperature of the chromatographic column is 35 ℃, an ultraviolet detector is adopted, and the detection wavelength is set to be 244 nm; the flow rate of the mobile phase is 1 ml/min; the volume ratio is 95: 5: 0.1: and (3) eluting with 0.1 of n-hexane-absolute ethyl alcohol-acetic acid-triethylamine in an isocratic manner by using a mobile phase.
The system suitability solution in this example was prepared as in example 1.
Injecting 20 mu l of system applicability solution into a liquid chromatograph, measuring according to the chromatographic conditions, recording a chromatogram, and finishing measurement; the resulting chromatogram is shown in FIG. 10.
The results show that the separation degree of the atorvastatin calcium enantiomer, the atorvastatin calcium impurity H and the atorvastatin calcium is good, baseline separation is achieved, other impurities do not interfere with enantiomer detection, and the results are accurate.
Example 7
Detection apparatus and chromatographic conditions
A detection instrument: high performance liquid chromatograph
Chromatographic conditions are as follows: the chromatographic column is a polysaccharide derivative chiral chromatographic column, the temperature of the chromatographic column is 35 ℃, an ultraviolet detector is adopted, and the detection wavelength is set to be 244 nm; the flow rate of the mobile phase is 1 ml/min; the volume ratio is 95: 2.5: 2.5: 0.1: and (3) eluting with 0.1 of n-hexane-methanol-absolute ethyl alcohol-acetic acid-triethylamine in an isocratic manner by using a mobile phase.
The system suitability solution in this example was prepared as in example 1.
Injecting 20 mu l of system applicability solution into a liquid chromatograph, measuring according to the chromatographic conditions, recording a chromatogram, and finishing measurement; the resulting chromatogram is shown in FIG. 11.
The results show that: the results show that the separation degree of the atorvastatin calcium enantiomer, the atorvastatin calcium impurity H and the atorvastatin calcium is good, baseline separation is achieved, other impurities do not interfere with enantiomer detection, and the results are accurate.
Example 8
Detection apparatus and chromatographic conditions
A detection instrument: high performance liquid chromatograph
Chromatographic conditions are as follows: the chromatographic column is a polysaccharide derivative chiral chromatographic column, the temperature of the chromatographic column is 35 ℃, an ultraviolet detector is adopted, and the detection wavelength is set to be 244 nm; the flow rate of the mobile phase is 1 ml/min; the volume ratio is 90: 1.5: 3.5: 5: 0.1: and (3) eluting with 0.1 of n-hexane-methanol-absolute ethyl alcohol-isopropanol-acetic acid-triethylamine as a mobile phase at equal intervals.
The system suitability solution in this example was prepared as in example 1.
Injecting 20 mu l of system applicability solution into a liquid chromatograph, measuring according to the chromatographic conditions, recording a chromatogram, and finishing measurement; the resulting chromatogram is shown in FIG. 12.
The results show that: the results show that the separation degree of the atorvastatin calcium enantiomer and the atorvastatin calcium is good, baseline separation is achieved, other impurities do not interfere with enantiomer detection, and the results are accurate.
Example 9
Detection apparatus and chromatographic conditions
A detection instrument: high performance liquid chromatograph
Chromatographic conditions are as follows: the chromatographic column is a polysaccharide derivative chiral chromatographic column, the temperature of the chromatographic column is 35 ℃, an ultraviolet detector is adopted, and the detection wavelength is set to be 244 nm; the flow rate of the mobile phase is 1 ml/min; the volume ratio is 95: 1.5: 3.5: 0.1: and (3) eluting with 0.1 of n-hexane-methanol-absolute ethyl alcohol-isopropanol-acetic acid-triethylamine as a mobile phase at equal intervals.
Preparation of system suitability solution: adding an atorvastatin calcium reference substance, an atorvastatin calcium enantiomer reference substance and an atorvastatin calcium impurity H reference substance which are in a mass ratio of 500:1 into a solvent which accounts for 50% of the total volume of the system applicability test solution, fully shaking to dissolve the atorvastatin calcium enantiomer reference substance and the atorvastatin calcium impurity H reference substance, adding the solvent to dilute the solvent to a scale to ensure that the concentration of atorvastatin calcium is 1.0mg/mL, the concentration of atorvastatin calcium enantiomer is 0.002mg/mL and the concentration of atorvastatin calcium impurity H is 0.01mg/mL, and filtering, wherein the solvent is a methanol-absolute ethanol-n-hexane solution with a volume ratio of 1: 3;
injecting 20 mu l of system applicability solution into a liquid chromatograph, measuring according to the chromatographic conditions, recording a chromatogram, and finishing measurement; the resulting chromatogram is shown in FIG. 13.
The results show that: the results show that the separation degree of the atorvastatin calcium enantiomer, the atorvastatin calcium impurity H and the atorvastatin calcium is good, baseline separation is achieved, other impurities do not interfere with enantiomer detection, and the results are accurate.
TABLE 2
From the results of examples 2 to 9, it can be seen that, by using the polysaccharide derivative chiral chromatographic column, under the chromatographic conditions of the mobile phase selected in the present invention, effective separation of atorvastatin calcium enantiomer, atorvastatin calcium impurity H and atorvastatin calcium can be achieved, the retention time and the peak position of each component are significantly different, and the technical scheme of the present invention is an effective method for detecting atorvastatin calcium enantiomer.
Claims (10)
1. A method for separating and/or detecting impurities in atorvastatin calcium, wherein the impurities are atorvastatin calcium enantiomers and/or atorvastatin calcium lactone, and the method comprises the following steps: comprises the step of separating or detecting by adopting a high performance liquid chromatography, wherein the high performance liquid chromatography adopts n-hexane-C with the volume ratio of a mobile phase of 85-98: 2-15: 0.05-0.51-C6The monohydric alcohol-organic acid-organic base solution of (a).
2. The method for separating and/or detecting impurities in atorvastatin calcium of claim 1, wherein: said C is1-C6The monohydric alcohol is selected from one or more of methanol, ethanol and propanol.
3. The method for separating and/or detecting impurities in atorvastatin calcium of claim 1 or 2, wherein: the organic acid is selected from C1-C6Carboxylic acids or halogeno-C1-C6A carboxylic acid.
4. The method for separating and/or detecting impurities in atorvastatin calcium of claim 1 or 2, wherein: the organic acid is selected from one or more of formic acid, acetic acid, propionic acid or halogenated acetic acid or propionic acid, the halogenation is fluoro, chloro or bromo, and preferably, the organic acid is one or more of formic acid or acetic acid.
5. The method for separating and/or detecting impurities in atorvastatin calcium of claim 1, wherein: the organic base has a structure shown in a formula I:
wherein R is1、R2And R3Each independently selected from hydrogen or chain alkyl with 1-12 carbon atoms, and R1、R2And R3At least one is not hydrogen, preferably diethylamine or triethylamine.
6. The method for separating and/or detecting impurities in atorvastatin calcium of claim 1, wherein: the volume ratio of the n-hexane to the organic alcohol to the organic acid to the organic base is 90-95: 4-12: 0.1-0.3.
7. The method for separating and/or detecting impurities in atorvastatin calcium of claim 1, wherein: the atorvastatin calcium exists in the form of a bulk drug, a solid preparation, a semi-solid preparation or a liquid preparation.
8. The method for separating and/or detecting impurities in atorvastatin calcium of claim 1, wherein: the high performance liquid chromatography adopts polysaccharide derivative chiral chromatographic columns.
9. The method of claim 8, wherein the method comprises the steps of: the high performance liquid chromatography adopts the following chromatographic conditions: the detection wavelength is 240-250nm, preferably 244nm, the temperature of the chromatographic column is 30-40 ℃, preferably 35 ℃, and the flow rate is 0.5-2ml/min, preferably 1 ml/min.
10. The method for separating and/or detecting impurities in atorvastatin calcium of claim 1, wherein: before the step of separating and/or detecting by adopting high performance liquid chromatography, adding the atorvastatin calcium into an organic solvent to prepare a solution to be treated.
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