CN112946154A - HPLC detection method for statins starting material and enantiomers thereof - Google Patents
HPLC detection method for statins starting material and enantiomers thereof Download PDFInfo
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- CN112946154A CN112946154A CN202110160510.5A CN202110160510A CN112946154A CN 112946154 A CN112946154 A CN 112946154A CN 202110160510 A CN202110160510 A CN 202110160510A CN 112946154 A CN112946154 A CN 112946154A
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
Abstract
The invention relates to the technical field of drug detection, and particularly discloses an HPLC (high performance liquid chromatography) detection method for statins starting materials and enantiomers thereof. The chromatographic conditions of the HPLC detection method of the statins starting material and the enantiomers thereof are as follows: a chromatographic column: a chiral chromatographic column using cellulose-tri (4-methyl benzoate) coated silica gel as a filler; mobile phase: sodium acetate buffer and acetonitrile in a volume ratio of 65-70: 32; column temperature: 28-32 ℃; detection wavelength: 240-244 nm; and (3) an elution mode: isocratic elution. The HPLC detection method for the statins starting material and the enantiomers thereof can meet the requirement of accurately detecting the enantiomers of the statins starting material, has high precision, accuracy and sensitivity and good reproducibility and stability, and can be used for quality control and comprehensive evaluation of the statins starting material.
Description
Technical Field
The invention relates to the technical field of drug detection, in particular to an HPLC (high performance liquid chromatography) detection method for statins starting materials and enantiomers thereof.
Background
The chinese name for the statin starting material is: (4R-cis) -6-carboxaldehyde-2, 2-dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester, having the english name: tert-butyl (4R-cis) -6-formaldehydel-2,2-dimethyl-1,3-dioxane-4-acetate, the molecular formula is as follows: c13H22O5The structural formula is as follows:
the enantiomer of (4R-cis) -6-carboxaldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate was: (4S-cis) -6-aldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate, the structural formula of which is as follows:
because the existence of (4S-cis) -6-aldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate can influence the detection of the content of the statins starting materials, no method for effectively separating and detecting the enantiomers of the statins starting materials exists at present, and the existing method for detecting the enantiomers of the statins starting materials has more factors needing to be controlled, complicated operation steps, lower detection efficiency and unsatisfactory accuracy and sensitivity. Therefore, there is an urgent need for a method for rapidly and accurately separating and detecting enantiomers of statin starting materials.
Disclosure of Invention
Aiming at the problems existing in the existing detection of statins starting materials, the invention provides an HPLC detection method of statins starting materials and enantiomers thereof, which can quickly and accurately separate and detect the statins starting materials and the enantiomers thereof.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
a method for HPLC detection of a statin starting material and its enantiomers, said statin starting material being: (4R-cis) -6-carboxaldehyde-2, 2-dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester, the enantiomer of which is: (4S-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate;
the test solution in the HPLC detection method is as follows: carrying out derivatization reaction on a sample to be tested and salicylhydrazine to obtain a reaction product;
the chromatographic conditions of the HPLC detection method of the statins starting material and the enantiomers thereof are as follows:
test solution: performing derivatization reaction on a sample to be tested and salicylhydrazine to obtain a reaction product serving as the test sample solution;
a chromatographic column: a chiral chromatographic column using cellulose-tri (4-methyl benzoate) coated silica gel as a filler;
mobile phase: sodium acetate buffer solution and acetonitrile with the volume ratio of 65-70:32, wherein the concentration of sodium acetate in the sodium acetate buffer solution is 0.148-0.153mg/mL, and the pH value is 4.5-5.5;
detection wavelength: 240-244 nm;
and (3) an elution mode: isocratic elution.
Compared with the prior art, the HPLC detection method for the statins starting materials and the enantiomers thereof can be used for quickly and accurately separating and detecting the statins starting materials and the enantiomers thereof. After the salicyloyl hydrazine is selected as a derivatization reagent to perform derivatization reaction with a statins starting material to be detected, high performance liquid chromatography detection is performed by combining specific chromatographic conditions, so that the high separation of the statins starting material and enantiomers thereof can be realized, each impurity peak has no interference to a main peak, and each chromatographic peak can be completely separated. Therefore, the detection method provided by the invention can meet the requirement of quickly detecting the enantiomers of the statins starting materials, has high precision, accuracy and sensitivity and good reproducibility and stability, can be used for quality control and comprehensive evaluation of the statins starting materials, and provides reliable guarantee for improving and controlling the quality of the statins starting materials.
Preferably, the mobile phase is sodium acetate buffer and acetonitrile in a volume ratio of 68: 32.
The preferable mobile phase can better separate chromatographic peaks, is beneficial to detecting the statins starting material enantiomer, and can effectively improve the peak shape and improve the accuracy and precision of the detection result.
Preferably, the pH of the mobile phase is 5.
Preferably, the column temperature in the HPLC detection method is 28-32 ℃.
Preferably, the detection wavelength is 242 nm.
Preferably, the flow rate in the HPLC detection method is 0.4-0.6 mL/min.
The above-described preferable chromatographic conditions can further improve the degree of separation between the respective detection peaks in the chromatogram.
Preferably, the sample injection volume in the HPLC detection method is 8-12 μ L.
Preferably, the preparation method of the test solution comprises the following steps: dissolving a sample to be tested into a solution containing 0.8-1.2mg of the sample to be tested in each 1ml of the sample to be tested by adding a solvent, uniformly mixing the solution containing the sample to be tested and a derivatization reagent according to the volume ratio of 1:0.8-1.2, heating in a water bath at 55-65 ℃ for 25-35min, and cooling to obtain the sample solution.
Preferably, the solvent is obtained by mixing water and acetonitrile according to the volume ratio of 1: 0.8-1.2.
Preferably, the derivatization reagent is a reagent obtained by adding salicylhydrazine to the solvent to obtain the concentration of the salicylhydrazine of 0.8-1.2 mg/mL.
Drawings
FIG. 1 is an HPLC detection chromatogram of an empty derivatization solution in example 1 of the present invention;
fig. 2 is an HPLC detection chromatogram of the test solution in example 1 of the present invention, in which peak 1: a statin starting material;
FIG. 3 is an HPLC detection chromatogram of an enantiomer-localized solution in example 1 of the present invention, in which peak 2: enantiomers of the statin starting material;
fig. 4 is a chromatogram obtained by superimposing an HPLC detection chromatogram of a test sample solution and an HPLC detection chromatogram of an enantiomer in example 1 of the present invention, in which peak 1: statin starting material, peak 2: statins starting material enantiomers.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
1. Instrument and condition chromatography column: a chiral chromatographic column using cellulose-tri (4-methyl benzoate) coated silica gel as a filler; specification: 150mm × 4.6mm,5 μm;
mobile phase: sodium acetate buffer and acetonitrile in a volume ratio of 68: 32; wherein the pH value of the sodium acetate buffer solution is 0.151mg/mL sodium acetate water solution, and glacial acetic acid is added to adjust the pH value to 5.0;
column temperature: 30 ℃;
detection wavelength: 242 nm;
sample introduction volume: 10 mu L of the solution;
flow rate: 0.5 mL/min;
and (3) an elution mode: isocratic elution;
solvent: water and acetonitrile are uniformly mixed according to the volume ratio of 1:1 to obtain the product;
derivatization reagent: adding salicyloyl hydrazine into a solvent to obtain a reagent with the concentration of the salicyloyl hydrazine being 1 mg/mL;
test solution: taking a sample to be tested of statins starting materials, adding a solvent to carry out ultrasonic dissolution to prepare a solution containing 0.8-1.2mg of the sample to be tested in each 1ml, then uniformly mixing the solution and a derivatization reagent according to the volume ratio of 1:0.8-1.2, heating in a water bath at 60 ℃ for 30min, taking out, and cooling with running water to obtain a test solution;
control solution: taking a proper amount of a test solution, adding the test solution into a solvent to be diluted into a solution containing 1 mu g of a sample to be detected in each 1ml of the solution, and obtaining a control solution;
blank derivatization solution: uniformly mixing a solvent and a derivatization reagent according to the volume ratio of 1:1 to obtain a blank derivatization solution;
enantiomeric positioning solution: taking the statins starting material enantiomer, adding solvent to dilute into solution containing 10 mug enantiomer per 1ml, then evenly mixing the solution containing the enantiomer and derivatization reagent according to the volume ratio of 1:1, heating in water bath at 60 ℃ for 30min, taking out, and cooling with running water to obtain the enantiomer positioning solution.
2. Detection method
Respectively and precisely measuring 10 mu L of each of the test solution, the reference solution, the enantiomer positioning solution and the blank derivatization solution, injecting the solution into a liquid chromatograph, recording a chromatogram, and calculating the content of the enantiomer of the statins starting material according to an area normalization method.
3. Methodology validation
3.1 specificity
The test method comprises the following steps: taking blank derivatization solution, test solution and enantiomer positioning solution, injecting sample for detection according to the detection conditions, and recording chromatogram.
The experimental results are as follows: a chromatogram obtained by recording a blank derivatization solution after being injected into a liquid chromatograph is shown in fig. 1, a chromatogram obtained by recording a test solution after being injected into the liquid chromatograph is shown in fig. 2, a chromatogram obtained by recording an enantiomer positioning solution after being injected into the liquid chromatograph is shown in fig. 3, and chromatograms obtained by superposing the test solution and the enantiomer positioning solution are shown in fig. 4. Therefore, the blank derivatization solution has no chromatographic peak at the peak position of the statins starting material and the enantiomers thereof, and does not interfere with the detection of the enantiomers. Combining fig. 2, fig. 3 and fig. 4, it can be seen that the separation degree of the statin starting material and its enantiomer meets the requirement, and the specificity of the method is good.
3.2, quantitation Limit and detection Limit
The test method comprises the following steps: precisely weighing enantiomers, diluting the enantiomers into different concentrations by using a solvent, preparing enantiomer test solutions with different concentrations by using the derivatization reagent according to the derivatization method, detecting according to the detection method and chromatographic conditions, and recording a chromatogram. The peak height is 10 times of the baseline noise and is the quantitative limit; the peak height was 3 times the baseline noise and was the limit of detection.
(2) The experimental results are as follows: the detection results of the detection limit and the quantification limit are shown in Table 1.
TABLE 1 detection and quantitation limits
The results of the quantitative limit reproducibility tests are shown in table 2.
TABLE 2 repeatability test results for limit of quantitation 6
| 1 | 2 | 3 | 4 | 5 | 6 | Average peak area | RSD/％ | |
| Enantiomers | 3246 | 3409 | 3576 | 3455 | 3306 | 3455 | 3407.8 | 3.45 |
As can be seen from Table 2, the RSD of 6 peak areas of repeated enantiomeric determinations of the statins starting materials is 3.45%, indicating that the detection method has good repeatability of limit of quantitation.
3.3, linearity
The test method comprises the following steps: precisely weighing enantiomers, diluting the enantiomers into different concentrations by using a solvent, preparing enantiomer test solutions with different concentrations by using the derivatization reagent according to the derivatization method, detecting according to the detection method and chromatographic conditions, recording a chromatogram, and obtaining a detection result shown in table 3.
TABLE 3 Linear results
And (4) test conclusion: the linear relationship between the enantiomer concentration of the statins starting material in the range of 0.205 mu g/ml to 2.050 mu g/ml is good, which indicates that the linear relationship is good by the detection method provided by the embodiment.
3.4 recovery rate
The test method comprises the following steps: the enantiomers are precisely weighed, diluted into different concentrations by using a solvent, and prepared into enantiomer test solutions with different concentrations by using the derivatization reagent according to the derivatization method, and simultaneously, the detection is carried out according to the detection method and the chromatographic conditions provided in the embodiment.
The experimental results are as follows: the recovery results are shown in table 4.
TABLE 4 recovery
And (4) test conclusion: as can be seen from Table 1, the recovery rate of the enantiomers of the statins starting material is between 90.39% and 94.97%, and the RSD is 1.91%, which indicates that the method provided by the scheme has good accuracy.
3.5 reproducibility
The test method comprises the following steps: precisely weighing 6 parts of statins starting material to be tested, preparing a test solution according to the preparation method in the embodiment, and respectively detecting according to the detection method and the chromatographic conditions in the embodiment.
(2) The experimental results are as follows: the results of the measurements of 6 test solutions are shown in Table 5.
TABLE 5 duplicate test results
And (4) test conclusion: no enantiomer is detected in 6 test sample solutions, which shows that the method provided by the scheme has good repeatability.
3.6 precision of the apparatus
The test method comprises the following steps: accurately weighing a proper amount of enantiomer, preparing an enantiomer positioning solution according to the preparation method of the scheme, and continuously sampling for 6 times according to the detection method and the chromatographic conditions of the scheme for detection.
The experimental results are as follows: the results of 6 injections are shown in Table 6.
TABLE 6 test results
| 1 | 2 | 3 | 4 | 5 | 6 | Mean value of | RSD％ | |
| Peak area | 48759 | 48521 | 48691 | 48434 | 49098 | 48838 | 48723.5 | 0.49 |
And (4) test conclusion: the sample introduction is carried out for 6 times continuously, and the RSD of the peak area is less than 1 percent, which shows that the detection method provided by the embodiment has good instrument precision.
3.7 solution stability
The test method comprises the following steps: an appropriate amount of the sample is precisely weighed, the sample solution is prepared according to the preparation method of the embodiment, and the detection is carried out according to the detection method and the chromatographic conditions provided by the embodiment at 0h, 2h, 12h, 18h and 22h respectively.
The experimental results are as follows: the solution stability results are shown in table 7.
TABLE 7 stability of the solutions
| Time of standing | 0h | 2h | 12h | 18h | 22h |
| Enantiomers | Not detected out | Not detected out | Not detected out | Not detected out | Not detected out |
And (4) test conclusion: when the test solution is placed at room temperature for 22 hours, no enantiomer is detected, which indicates that the test solution has good stability.
Example 2
1. Instrument and condition chromatography column: a chiral chromatographic column using cellulose-tri (4-methyl benzoate) coated silica gel as a filler; specification: 150mm × 4.6mm,5 μm;
mobile phase: sodium acetate buffer and acetonitrile in a volume ratio of 65: 32; wherein the pH value of the sodium acetate buffer solution is 0.148mg/mL sodium acetate water solution, and glacial acetic acid is added to adjust the pH value to 4.5;
column temperature: 28 ℃;
detection wavelength: 240 nm;
sample introduction volume: 8 mu L of the solution;
flow rate: 0.4 mL/min;
and (3) an elution mode: isocratic elution;
solvent: water and acetonitrile are uniformly mixed according to the volume ratio of 1:0.8 to obtain the compound;
derivatization reagent: adding salicyloyl hydrazine into a solvent to obtain a reagent with the concentration of the salicyloyl hydrazine being 0.8 mg/mL;
test solution: taking a sample to be tested of a statins starting material, adding a solvent to carry out ultrasonic dissolution to prepare a solution containing 0.8mg of the sample to be tested in each 1ml, uniformly mixing the solution and a derivatization reagent according to the volume ratio of 1:0.8, heating in a water bath at 55 ℃ for 25min, taking out, and cooling with running water to obtain a test solution;
control solution: taking a proper amount of a test solution, adding the test solution into a solvent to be diluted into a solution containing 0.8 mu g of a sample to be detected in each 1ml of the solution, and obtaining a control solution;
blank derivatization solution: uniformly mixing a solvent and a derivatization reagent according to the volume ratio of 1:0.8 to obtain a blank derivatization solution;
enantiomeric positioning solution: taking the statins starting material enantiomer, adding solvent to dilute into solution containing 8 mug enantiomer in each 1ml, then evenly mixing the solution containing the enantiomer and derivatization reagent according to the volume ratio of 1:0.8, heating in water bath at 60 ℃ for 30min, taking out and cooling with running water to obtain the enantiomer positioning solution.
2. Detection method
Respectively and precisely measuring 8 mu L of each of the test solution, the reference solution, the enantiomer positioning solution and the blank derivatization solution, injecting the solution into a liquid chromatograph, recording a chromatogram, and calculating the content of the enantiomer of the statins starting material according to an area normalization method. Wherein, the peak shape and the separation degree of the chromatogram obtained by recording the test solution are basically equivalent to those in the example 1.
Example 3
1. Instrument and condition chromatography column: a chiral chromatographic column using cellulose-tri (4-methyl benzoate) coated silica gel as a filler; specification: 150mm × 4.6mm,5 μm;
mobile phase: sodium acetate buffer and acetonitrile in a volume ratio of 70: 32; wherein the sodium acetate buffer solution is 0.153mg/mL sodium acetate water solution, and glacial acetic acid is added to adjust the pH value to 5.5;
column temperature: at 32 ℃;
detection wavelength: 244 nm;
sample introduction volume: 12 mu L of the solution;
flow rate: 0.6 mL/min;
and (3) an elution mode: isocratic elution;
solvent: water and acetonitrile are uniformly mixed according to the volume ratio of 1:1.2 to obtain the compound;
derivatization reagent: adding salicyloyl hydrazine into a solvent to obtain a reagent with the concentration of the salicyloyl hydrazine being 1.2 mg/mL;
test solution: taking a sample to be tested of a statins starting material, adding a solvent to carry out ultrasonic dissolution to prepare a solution containing 1.2mg of the sample to be tested in 1ml, uniformly mixing the solution and a derivatization reagent according to the volume ratio of 1:1.2, heating in a water bath at 65 ℃ for 35min, taking out, and cooling with running water to obtain a test solution;
control solution: taking a proper amount of a test solution, adding the test solution into a solvent to be diluted into a solution containing 1.2 mu g of a sample to be detected in each 1ml of the solution, and obtaining a control solution;
blank derivatization solution: uniformly mixing a solvent and a derivatization reagent according to the volume ratio of 1:1.2 to obtain a blank derivatization solution;
enantiomeric positioning solution: taking the statins starting material enantiomer, adding solvent to dilute into solution containing 1.2 mu g enantiomer per 1ml, then evenly mixing the solution containing the enantiomer and the derivatization reagent according to the volume ratio of 1:1.2, heating in water bath at 65 ℃ for 35min, taking out, and cooling with running water to obtain the enantiomer positioning solution.
2. Detection method
Respectively and precisely measuring 12 mu L of each of the test solution, the reference solution, the enantiomer positioning solution and the blank derivatization solution, injecting the solution into a liquid chromatograph, recording a chromatogram, and calculating the content of the enantiomer of the statins starting material according to an area normalization method. Wherein, the peak shape and the separation degree of the chromatogram obtained by recording the test solution are basically equivalent to those in the example 1.
Comparative example 1
The chromatographic column in example 1 is replaced by a chromatographic column with amylose-tri [3, 5-xylyl carbamate ] as a filler, other instruments, detection conditions and detection methods are the same as those in example 1, the main component and the enantiomer of the statins starting material in the chromatogram obtained from the final test solution cannot be effectively separated, and the sensitivity of enantiomer detection is low.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. An HPLC detection method for statins starting materials and enantiomers thereof is characterized in that: the statins starting materials are: (4R-cis) -6-carboxaldehyde-2, 2-dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester, the enantiomer of which is: (4S-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate;
the test solution in the HPLC detection method is as follows: carrying out derivatization reaction on a sample to be tested and salicylhydrazine to obtain a reaction product;
the chromatographic conditions of the HPLC detection method of the statins starting material and the enantiomers thereof are as follows:
a chromatographic column: a chiral chromatographic column using cellulose-tri (4-methyl benzoate) coated silica gel as a filler;
mobile phase: sodium acetate buffer solution and acetonitrile with the volume ratio of 65-70:32, wherein the concentration of sodium acetate in the sodium acetate buffer solution is 0.148-0.153mg/mL, and the pH value is 4.5-5.5;
detection wavelength: 240-244 nm;
and (3) an elution mode: isocratic elution.
2. The HPLC method for detecting statins starting material and its enantiomers as claimed in claim 1, wherein: the mobile phase is the sodium acetate buffer solution and the acetonitrile in a volume ratio of 68: 32.
3. The HPLC method for detecting statins starting material and its enantiomers as claimed in claim 1, wherein: the pH of the mobile phase was 5.
4. The HPLC method for detecting statins starting material and its enantiomers as claimed in claim 1, wherein: the column temperature in the HPLC detection method is 28-32 ℃.
5. The HPLC method for detecting statins starting material and its enantiomers as claimed in claim 1, wherein: the detection wavelength is 242 nm.
6. The HPLC method for detecting statins starting material and its enantiomers as claimed in claim 1, wherein: the flow rate in the HPLC detection method is 0.4-0.6 mL/min.
7. The HPLC method for detecting statins starting material and its enantiomers as claimed in claim 1, wherein: the sample injection volume in the HPLC detection method is 8-12 mu L.
8. The HPLC method for detecting statins starting material and its enantiomers as claimed in claim 1, wherein: the preparation method of the test solution comprises the following steps: dissolving a sample to be tested into a solution containing 0.8-1.2mg of the sample to be tested in each 1ml of the sample to be tested by adding a solvent, uniformly mixing the solution containing the sample to be tested and a derivatization reagent according to the volume ratio of 1:0.8-1.2, heating in a water bath at the temperature of 55-65 ℃ for 25-35min, and cooling to obtain the sample solution.
9. The HPLC method for detecting statins starting material and its enantiomers as claimed in claim 8, wherein: the solvent is obtained by mixing water and acetonitrile according to the volume ratio of 1: 0.8-1.2.
10. The HPLC method for detecting statins starting material and its enantiomers as claimed in claim 8, wherein: the derivatization reagent is a reagent obtained by adding salicyloyl hydrazine into the solvent, wherein the concentration of the salicyloyl hydrazine is 0.8-1.2 mg/mL.
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