CN106370740A - Method for analyzing residual quantity of residual solvents in atorvastatin calcium intermediate - Google Patents
Method for analyzing residual quantity of residual solvents in atorvastatin calcium intermediate Download PDFInfo
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- CN106370740A CN106370740A CN201610701518.7A CN201610701518A CN106370740A CN 106370740 A CN106370740 A CN 106370740A CN 201610701518 A CN201610701518 A CN 201610701518A CN 106370740 A CN106370740 A CN 106370740A
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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
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Abstract
The invention discloses a method for analyzing the residual quantity of residual solvents in an atorvastatin calcium intermediate. The method comprises the following steps: 1, preparing a contrast solution; 2, preparing a sample solution; 3, carrying out headspace sample introduction detection; and 4, calculating the residual quantity of every solvent in the sample by using an external standard technology according to peak areas. The method for analyzing the residual quantity of residual solvents in the atorvastatin calcium intermediate, uses a headspace sample introduction gas chromatograph to ensure the accuracy and the reliability of an analysis result, is simple to operate, and can detect the residual quantity of every residual solvent in the atorvastatin calcium intermediate. The method has the advantages of wide application range, simple steps, short time, low analysis cost, high analysis result accuracy, wide linear range, good reappearance and stable analysis conditions, and can be widely applied to online analysis in production.
Description
Technical field
The invention belongs to chemical analysis method field and in particular in a kind of Atorvastatin calcium intermediate residual solvent residual
The analysis method of allowance.
Background technology
At present, cardiovascular medicament Atorvastatin calcium important intermediate main ring m4(chemical name is 4- fluoro-alpha-[2- first
Base -1- oxygen propyl group]-γ-oxo-n, β-diphenyl benzene butyramide) there is two kinds of residual solvent dichloromethane and isopropyl in fine work
Alcohol, need to control it (no more than 100ppm), to improve the quality of final products Atorvastatin calcium.Existing analysis in Ah
The analysis method of atorvastatin calcium important intermediate main ring m4 residual solvent residual quantity has no.
Content of the invention
The technical problem to be solved in the present invention is to fill up Atorvastatin calcium important intermediate main ring m4 residual solvent residual
The analysis method of amount, provides a kind of the accurate, reliable of analysis result, operating process simple Atorvastatin calcium important intermediate
The assay method of main ring m4 residual solvent residual quantity.
The purpose of the present invention to implement by the following technical programs:
In a kind of Atorvastatin calcium intermediate, the analysis method of residual solvent residual quantity, comprises the steps:
1). reference substance solution is prepared
Precision weighs quantitative dichloromethane, isopropanol and puts together 100ml appropriate n respectively, n- dimethylformamide (dmf)
In measuring bottle, plus dmf dissolves and is diluted to scale, shakes up and must compare stock solution.Draw stock solution 5ml in 100ml volumetric flask, plus
Dmf is settled to scale, shakes up as reference substance solution；
2). need testing solution is prepared
Take test sample, accurately weighed, put in 20ml ml headspace bottle, accurate addition 5mldmf, to scale, shakes up, makees need testing solution；
3). Specimen Determination
Precision measures contrast solution 5ml and puts in 20ml headspace sampling bottle, and sealing and need testing solution are in 90 DEG C of insulation shakings
10min.Under above-mentioned chromatographic condition, after baseline stability, take head space vapour 1000 μ l, by above-mentioned condition sample introduction, record chromatogram；
Confirm noiseless between all solvents.
4). calculate
By external standard method with calculated by peak area, it is calculated as follows the residual quantity of each solvent:
In formula: the peak area of residual solvent in a sample-sample solution；
In a mark-reference substance solution, the peak of residual solvent amasss；
The weighing of m mark-reference substance, g；
The content of p- reference substance, in terms of decimal；
The weighing of m sample-sample, g；
5- diluted sample multiple
The extension rate of 2000- reference substance；
In described step 3), described operation condition of chromatogram is as follows:
Further, in described step 3), after the completion of analysis, check spectrogram, integrate each solvent group swarming；After process, record analyses are tied
Really, after analysis, injector is cleaned with trimethylbenzene, is then cleaned with clear water, dries.
Beneficial effects of the present invention:
The analysis method of residual solvent residual quantity in a kind of present invention Atorvastatin calcium intermediate, analysis method is entered using head space
, it is ensured that accurate, the reliability of analysis result, simply, it can be to Atorvastatin calcium intermediate for operating process for sample gas chromatograph
In the residual quantity of various residual solvents be measured.The present invention has that scope of application width, step be simple, analysis method take short,
Analysis cost is low；The advantages of analysis method is stablized to analysis result accuracy height, range of linearity width, favorable reproducibility, analysis condition,
On-line analyses in can be widely applied to produce.
Specific embodiment
Below by way of specific embodiment, technical scheme is described in further detail, but the protection model of the present invention
Enclose and be not limited thereto.
Embodiment 1
The analysis method of residual solvent residual quantity in a kind of Atorvastatin calcium intermediate
1st, set operation condition of chromatogram
Chromatograph carries out necessary regulation after starting, and to reach the typical operation conditions that table 1 gives, or can obtain detached on an equal basis
Other suitable conditions.After instrument stabilizer, you can be measured.
Chromatographic column and typical operation conditions that table 1 is recommended
2nd, reference substance solution and need testing solution prepare (weighing method)
Precision weighs the dichloromethane of 0.05g, isopropanol and puts together 100ml appropriate n, n- dimethylformamide (dmf) respectively
Measuring bottle in, plus dmf dissolves and is diluted to scale, shakes up and must compare stock solution.Draw stock solution 5ml in 100ml volumetric flask,
Plus dmf is settled to scale, shake up as reference substance solution；
Take test sample, accurately weighed 0.50g, puts in 20ml ml headspace bottle, accurate addition 5mldmf, to scale, shakes up, makees test sample
Solution；
3rd, Specimen Determination
Precision measures contrast solution 5ml and puts in 20ml headspace sampling bottle, and sealing and need testing solution are in 90 DEG C of insulation shakings
10min.Under above-mentioned chromatographic condition, after baseline stability, take head space vapour 1000 μ l, by above-mentioned condition sample introduction, record chromatogram；
Confirm noiseless between all solvents.
Check spectrogram after the completion of analysis, integrate each component peak.After process, record analyses result.
After analysis, injector trimethylbenzene cleans and then is cleaned with clear water and dries.
4th, calculate
By external standard method with calculated by peak area, it is calculated as follows the residual quantity of each solvent:
In formula: the peak area of residual solvent in a sample-sample solution；
In a mark-reference substance solution, the peak of residual solvent amasss；
The weighing of m mark-reference substance, g；
The content of p- reference substance, in terms of decimal；
The weighing of m sample-sample, g；
5- diluted sample multiple
The extension rate of 2000- reference substance；
5th, the statement of analysis result
5.1 after the completion of analysis it is stipulated that 4-digit numbers after the value of result should retain arithmetic point, that is, result takes to 0.0001%.
5.2 it is repeated
Same operator use same instrument, under the same operating conditions, with normal and correct operational approach to same
Sample is measured in succession twice.
Result is not more than the 20% of arithmetic mean of instantaneous value in its difference of 0.001%-0.1% concentration range.
Result is the 5% of difference no more than arithmetic mean of instantaneous value in 0.1%-0.2% concentration range.
Result is being the 2% of difference no more than arithmetic mean of instantaneous value more than 0.2% concentration range.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, although with reference to aforementioned reality
Apply example the present invention has been described in detail, for a person skilled in the art, it still can be to aforementioned each enforcement
Technical scheme described in example is modified, or carries out equivalent to wherein some technical characteristics.All essences in the present invention
Within god and principle, any modification, equivalent substitution and improvement made etc., should be included within the scope of the present invention.
Claims (3)
1. in a kind of Atorvastatin calcium intermediate the analysis method of residual solvent residual quantity it is characterised in that including following walking
Rapid:
1). reference substance solution is prepared
Precision weighs quantitative dichloromethane, isopropanol and puts together 100ml appropriate n respectively, n- dimethylformamide (dmf)
In measuring bottle, plus dmf dissolves and is diluted to scale, shakes up and must compare stock solution；Draw stock solution 5ml in 100ml volumetric flask, plus
Dmf is settled to scale, shakes up as reference substance solution；
2). need testing solution is prepared
Take test sample, accurately weighed, put in 20ml ml headspace bottle, accurate addition 5mldmf, to scale, shakes up, makees need testing solution 0；
3). Specimen Determination
Precision measures contrast solution 5ml and puts in 20ml headspace sampling bottle, and sealing and need testing solution are in 90 DEG C of insulation shakings
10min；Under above-mentioned chromatographic condition, after baseline stability, take head space vapour 1000 μ l, by above-mentioned condition sample introduction, record chromatogram；
4). calculate
By external standard method with calculated by peak area, it is calculated as follows the residual quantity of each solvent:
In formula: the peak area of residual solvent in a sample-sample solution；
In a mark-reference substance solution, the peak of residual solvent amasss；
The weighing of m mark-reference substance, g；
The content of p- reference substance, in terms of decimal；
The weighing of m sample-sample, g；
5- diluted sample multiple
The extension rate of 2000- reference substance.
2. in a kind of Atorvastatin calcium intermediate according to claim 1 residual solvent residual quantity analysis method, its
It is characterised by: in described step 3), described operation condition of chromatogram is as follows:
.
3. in a kind of Atorvastatin calcium intermediate according to claim 1 residual solvent residual quantity analysis method, its
It is characterised by: in described step 3), after the completion of analysis, check collection of illustrative plates, integrate each solvent group swarming；After process, record analyses are tied
Really, after analysis, syringe is cleaned with trimethylbenzene, is then cleaned with clear water, dries.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610701518.7A CN106370740A (en) | 2016-08-23 | 2016-08-23 | Method for analyzing residual quantity of residual solvents in atorvastatin calcium intermediate |
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| CN201610701518.7A CN106370740A (en) | 2016-08-23 | 2016-08-23 | Method for analyzing residual quantity of residual solvents in atorvastatin calcium intermediate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108051523A (en) * | 2017-12-29 | 2018-05-18 | 江苏悦兴医药技术有限公司 | A kind of related substance detecting method of the gas-chromatography of principal component |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080220441A1 (en) * | 2001-05-16 | 2008-09-11 | Birnbaum Eva R | Advanced drug development and manufacturing |
| CN105153110A (en) * | 2015-09-23 | 2015-12-16 | 河南师范大学 | Synthesis method for chiral intermediate of atorvastatin calcium |
| CN105732568A (en) * | 2016-03-25 | 2016-07-06 | 河南师范大学 | Synthesis method of atorvastatin calcium chiral intermediate |
-
2016
- 2016-08-23 CN CN201610701518.7A patent/CN106370740A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080220441A1 (en) * | 2001-05-16 | 2008-09-11 | Birnbaum Eva R | Advanced drug development and manufacturing |
| CN105153110A (en) * | 2015-09-23 | 2015-12-16 | 河南师范大学 | Synthesis method for chiral intermediate of atorvastatin calcium |
| CN105732568A (en) * | 2016-03-25 | 2016-07-06 | 河南师范大学 | Synthesis method of atorvastatin calcium chiral intermediate |
Non-Patent Citations (2)
| Title |
|---|
| 汪惟俊: "顶空气相色谱法测定阿托伐他汀钙原料药残留溶剂含量", 《中国化工贸易》 * |
| 田洁等: "顶空毛细管气相色谱法测定阿托伐他汀钙原料药中残留溶剂", 《中国药物评价》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108051523A (en) * | 2017-12-29 | 2018-05-18 | 江苏悦兴医药技术有限公司 | A kind of related substance detecting method of the gas-chromatography of principal component |
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Application publication date: 20170201 |