CN107894474B - Method for simultaneously detecting hydroxychloroquine side chain and raw materials and intermediates thereof by gas chromatography - Google Patents
Method for simultaneously detecting hydroxychloroquine side chain and raw materials and intermediates thereof by gas chromatography Download PDFInfo
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Abstract
The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for simultaneously detecting hydroxychloroquine side chains and raw materials and intermediates thereof by using a gas chromatography. The method can simultaneously measure the hydroxyl side chain, ethylamine, xylene, ethylamine ethanol, cyclopentanone, ethylamine diethanolamine, aminopentanone and ethanol, and the specificity, linearity, range, precision, detection line and accuracy of the method all meet the requirements of the verification guidance principle of the traditional Chinese medicine quality standard analysis method in the four appendix of the 2015 version in Chinese pharmacopoeia, and aims to provide a technical basis for the detection and monitoring of the synthesis process of the hydroxyl chloroquine side chain.
Description
Technical Field
The invention relates to the technical field of pharmaceutical analysis, in particular to a method for simultaneously detecting hydroxychloroquine side chains and raw materials and intermediates thereof by using a gas chromatography.
Background
Hydroxychloroquine (formula I) with the chemical name of 7-chloro-4- [5- (N-ethyl-N-2-hydroxyethyl-2-pentyl ] aminoquinoline is a 4-aminoquinoline drug which is firstly used for treating plasmodium and is widely used for treating discoid lupus erythematosus and systemic lupus erythematosus and is also a combined preferred drug for treating rheumatoid arthritis.
Hydroxychloroquine is prepared by Fischer synthesis reaction of 4, 7-dichloroquinoline and 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine, wherein 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine (formula II), also named hydroxychloroquine side chain, is a key intermediate for synthesizing hydroxychloroquine. The Chinese patent publication No. CN 104803859A discloses that 7 raw materials and intermediates are involved in a synthetic route of hydroxychloroquine side chain (formula III), namely ethylamine (formula 1), xylene (formula 5), ethylamine ethanol (formula 2), cyclopentanone (formula 4), ethylamine diethanol amine (formula 3) and aminopentanone (formula 6), and the excessive residual quantity of the raw materials and the incompletely reacted intermediates in the reaction can cause low purity of target products and influence the yield of hydroxychloroquine synthesized with 4, 7-dichloroquinoline at the later stage, thereby reducing the quality and clinical efficacy of hydroxychloroquine. Therefore, the quality control is especially necessary in the synthesis process of the hydroxychloroquine side chain.
As can be seen from the structural formula of the hydroxychloroquine side chain, the conjugate effect and obvious ultraviolet absorption do not exist, and the analysis of the hydroxychloroquine side chain is difficult to be carried out by a simple, convenient and cost-saving liquid chromatography. In addition, all raw materials and intermediates of the hydroxychloroquine side chain are liquid, and have the characteristics of small molecular weight and good thermal stability, so that the method is suitable for analyzing by using a gas chromatography. The Gas Chromatography (GC) technology has the characteristics of high efficiency, convenience and accuracy, has become an important research field of instrument analysis, and provides indispensable important analysis basis for subjects such as physics, chemistry and medicine. Gas chromatography is now a well established technology, and its use will continue to be extended and expanded.
Disclosure of Invention
The invention aims to provide a method for simultaneously detecting hydroxychloroquine side chains and 7 raw materials and intermediates involved in the process by using a gas chromatography, which is rapid, convenient, accurate and sensitive.
In the invention, a novel method for simultaneously measuring the hydroxychloroquine side chain and 7 raw materials and intermediates involved in the process is established by utilizing a directly-injected gas chromatography and selecting and optimizing different stationary phases, temperature programming time and sample preparation solvents, and the scientificity, accuracy and feasibility of the analysis method are determined by verification, so that a technical basis is provided for the detection and monitoring of the hydroxychloroquine side chain synthesis process.
In order to achieve the above object of the present invention, the following technical means is adopted.
A method for detecting hydroxychloroquine side chain and its raw materials and intermediates by gas chromatography comprises detecting hydroxychloroquine side chain, ethylamine ethanol, ethylamine diethanolamine, cyclopentanone, xylene, aminopentanone and ethanol simultaneously; the method comprises the following steps:
(1) chromatographic conditions
The chromatographic column is a cross-linked capillary column, and the temperature is raised by adopting a program; the temperature of a sample inlet is 250-310 ℃; the carrier gas is nitrogen; the detector is a hydrogen flame ionization detector FID, and the temperature of the detector is 260-315 ℃; the separation degree of the hydroxychloroquine side chain, the ethylamine ethanol, the ethylamine diethanolamine, the cyclopentanone, the xylene, the aminopentanone and the ethanol is more than 1.5;
(2) preparation of Mixed control solutions
Precisely weighing hydroxychloroquine side chain, ethylamine ethanol, xylene, cyclopentanone, ethylamine diethanolamine, aminopentanone, ethylamine and ethanol, respectively, placing into a measuring flask, and diluting with solvent to obtain mixed reference solution; in each 1mL of mixed reference solution, the side chain of hydroxychloroquine is 0.01-0.09 g, the contents of ethylamine ethanol, xylene, cyclopentanone, ethylamine diethanolamine, aminopentanone and ethanol are respectively 0.001-0.009 g and the content of ethylamine is 0.011-0.019 g;
(3) preparation of test solution
Precisely weighing hydroxychloroquine side chain, adding solvent to dissolve and dilute into a uniform solution containing 0.19-0.30 g of the product per 1mL, and using the uniform solution as a test solution;
(4) measurement of
Precisely measuring the mixed reference substance solution and the test substance solution with the same volume respectively, and injecting into a gas chromatograph for measurement and calculation respectively to obtain the final product.
In the present invention, in step (1), the crosslinked capillary column is selected from any one of DB-1, HP-5 or DB-624 crosslinked capillary columns.
In the invention, in the step (1), the temperature programming initial temperature is 80-120 ℃ and is kept for 1-8 min, and the temperature is raised to 180-240 ℃ at the speed of 12-17 ℃/min and is kept for 3-15 min.
In the invention, in the step (1), the flow rate of nitrogen is 1.5-3.5 mL/min, and the split ratio is 25: 1-35: 1.
In the invention, in the step (2) and the step (3), the solvent is DMF, DMSO or N-methylpyrrolidone.
In the invention, in the step (2), in every 1mL of the mixed reference solution, the hydroxychloroquine side chain is 0.04-0.06 g, the ethylamine ethanol, the xylene, the chloropentanone, the ethylamine diethanolamine, the aminopentanone and the ethanol are independently 0.004-0.006 g, and the ethylamine is 0.014-0.016 g.
In the invention, in the step (3), each 1mL of the homogeneous solution containing 0.22-0.26 g of the product is used as a test solution.
In the invention, in the step (4), the volume of the mixed reference solution and the test solution is 0.6-1 mu L.
Compared with the prior art, the invention has the beneficial effects that:
the invention discloses a general method for simultaneously measuring 7 raw materials and intermediates of hydroxychloroquine side chains, ethanol, ethylamine ethanol, xylene, cyclopentanone, ethylamine diethanolamine, aminopentanone and ethylamine by using a gas chromatography.
Proved by methodology, the specificity, the system adaptability, the linearity, the range, the detection limit, the precision and the accuracy of the method meet the requirement of the quality standard analysis method verification guiding principle of the traditional Chinese medicine in the four appendices of the 2015 edition of Chinese pharmacopoeia.
The method provides a technical basis for the detection and monitoring of the hydroxychloroquine side chain synthesis process.
Drawings
FIG. 1 is a chromatogram of the measurement results of the control solution. 1. Ethylamine, 2 ethylamine ethanol, 3 ethylamine diethanolamine, 4 cyclopentanone, 5 xylene, 6 aminopentanone, 7 ethanol (ethanol), II hydroxychloroquine side chain 8 NMP.
FIG. 2 blank solution assay chromatogram.
Detailed Description
The technical solution of the present invention will be described in detail with reference to the accompanying drawings and embodiments.
Example 1
(1) Chromatographic conditions and System adaptability test the chromatographic column was a DB-624 cross-linked capillary column (30m × 0.53mm. i.d., 3.0 μm); programming the temperature to 100 deg.C for 2min, heating to 200 deg.C at 15 deg.C, and storing for 10 min; the temperature of a sample inlet is 300 ℃; the carrier gas is nitrogen; the detector is a hydrogen Flame Ionization Detector (FID), and the temperature of the detector is 310 ℃; the flow rate is 3.0mL/min, and the split ratio is 30: 1; the separation degree of hydroxychloroquine side chain, ethylamine ethanol, ethylamine diethanolamine, cyclopentanone, xylene, aminopentanone and ethanol is more than 1.5;
(2) preparation of mixed reference solution A suitable amount of ethylamine ethanol, xylene, cyclopentanone, ethylamine diethanolamine, cyclopentanone, ethylamine, and hydroxychloroquine side chains (pure product, lot number: Y023-150101, provided by Shanghai, China, and Western three-dimensional pharmaceutical industries, Ltd.) were precisely weighed, placed in a same flask, dissolved and diluted with N-methylpyrrolidone to prepare a homogeneous solution containing about 0.004g of ethylamine ethanol, xylene, cyclopentanone, ethylamine diethanolamine, and cyclopentanone, 0.016g of ethylamine, and 0.05g of hydroxychloroquine side chains per 1mL of the reference solution.
(3) Preparation of test solution A proper amount of hydroxychloroquine side chain (pure product, lot number: Y023-150101, provided by Shanghai, China and West three-dimensional pharmaceutical Co., Ltd.) is precisely weighed, dissolved and diluted with N-methylpyrrolidone to prepare a uniform solution containing about 0.25g of the product per 1mL as the test solution;
(4) and precisely measuring the mixed reference solution and the sample solution by 1 mu L respectively, and injecting the mixed reference solution and the sample solution into a gas chromatograph for measurement and calculation in a direct sample injection mode to obtain the final product.
Application example: method for simultaneously determining hydroxychloroquine side chain and raw materials and intermediates thereof by gas chromatography
Hydroxychloroquine is a 4-aminoquinoline drug, is clinically and firstly used for treating plasmodium, is widely used for treating discoid lupus erythematosus and systemic lupus erythematosus and is also a combined preferred drug for treating rheumatoid arthritis. In addition, it has also been used in immunosuppression and anti-inflammatory response. The hydroxychloroquine side chain is a key intermediate for synthesizing hydroxychloroquine. 7 raw materials and intermediates are involved in the synthetic hydroxychloroquine side chain route, the purity of a target product is low due to overhigh residual quantity of the raw materials and the intermediates which are not completely reacted in the reaction, and a byproduct, namely cyclopropylmethyl ketone generated in the reaction is difficult to remove in the later reaction for synthesizing hydroxychloroquine by using the hydroxychloroquine side chain and 4, 7-dichloroquinoline, so that the quality and the clinical efficacy of the hydroxychloroquine are reduced. Therefore, the quality control is especially necessary in the synthesis process of the hydroxychloroquine side chain. Through tests and researches, a gas chromatography for simultaneously measuring the content of the hydroxychloroquine side chain, the synthetic raw materials thereof, and the intermediates ethylamine, ethylamine ethanol, ethylamine diethanolamine, cyclopentanone, xylene, aminopentanone and ethanol is established.
Methodology the following was investigated:
(1) specificity and system adaptability
Taking a proper amount of hydroxychloroquine side chain, ethylamine ethanol, ethylamine diethanolamine, cyclopentanone, xylene, aminopentanone and ethanol, dissolving with N-methylpyrrolidone to prepare a solution, carrying out headspace sample injection according to the method, and carrying out measurement, wherein the retention time is 15.869min of hydroxychloroquine side chain, 2.531min of ethylamine, 5.904min of ethylamine ethanol, 11.613min of ethylamine diethanolamine, 7.691min of cyclopentanone, 6.399, 6.497, 6.841min of xylene, 16.646min of aminopentanone and 2.662min of ethanol (shown in figure 1).
(2) Linearity
Taking a proper amount of hydroxychloroquine side chains, and sequentially diluting the hydroxychloroquine side chains with N-methylpyrrolidone to obtain series of standard solutions containing hydroxychloroquine side chains of 1.0600, 3.2580, 7.6986, 19.246, 28.870, 72.174, 96.232 and 120.29mg/mL respectively. And (5) injecting and measuring according to the drawn-up chromatographic conditions, and performing linear regression on the mass concentration (X, mg/mL) of the corresponding solvent by using the peak area (Y). The obtained hydroxychloroquine side chain has a good linear relation within the concentration range of 1.06-120.29 mg/mL, and the regression equation is as follows:
hydroxychloroquine side chain Y-304609X-887401R 2-0.9992
(3) Precision degree
Precisely measuring 2mL of the test solution, and diluting to 5mL with a solvent to obtain a solution containing 100mg of hydroxychloroquine side chain per mL. 6 parts are prepared, injected into a gas chromatograph according to the formulated chromatographic conditions, and the peak area is recorded. The RSD of the relative standard table difference is calculated to be 1.52 percent, which meets the requirements of 'Chinese pharmacopoeia' 2015 edition.
(4) Minimum detection limit
The limit of detection of hydroxychloroquine side chain was calculated as S/N-3 to 0.2379 μ g/mL.
Accuracy of
Taking 2mL of test solution, and diluting to 5mL with solvent to obtain 100mg of hydroxychloroquine side chain-containing solution per mL. 6 parts are prepared, injected into a gas chromatograph according to the chromatographic conditions, and the average content of the 6 parts is calculated to be 99.42 percent by an area normalization method. And precisely weighing 0.60g of hydroxychloroquine side chain, and adding a proper amount of glacial acetic acid for dissolving. 6 portions were prepared, titrated potentiometrically with 0.1% perchloric acid titration solution, and the content was calculated and the average content was calculated to be 98.97%. Taking the hydroxychloroquine side chain stock solution, sequentially diluting with N-methylpyrrolidone to obtain 3 concentration gradients of 80%, 100% and 120%, preparing 3 parts of each concentration, totaling 9 parts, and injecting into a gas chromatograph according to the chromatographic conditions. The average content was calculated to be 99.38% by area normalization. RSD of the three methods is 0.25 percent
The result shows that the product has good accuracy.
Claims (6)
1. A method for simultaneously detecting hydroxychloroquine side chains and raw materials and intermediates thereof by gas chromatography is characterized in that the method simultaneously detects hydroxychloroquine side chains, ethylamine ethanol, ethylamine diethanolamine, cyclopentanone, xylene, aminopentanone and ethanol; the method comprises the following steps:
(1) chromatographic conditions
The chromatographic column is a cross-linked capillary column, and the temperature is raised by adopting a program; the temperature of a sample inlet is 250-310 ℃; the carrier gas is nitrogen; the detector is a hydrogen flame ionization detector FID, and the temperature of the detector is 260-315 ℃; the separation degree of the hydroxychloroquine side chain, the ethylamine ethanol, the ethylamine diethanolamine, the cyclopentanone, the xylene, the aminopentanone and the ethanol is more than 1.5; the cross-linked capillary column is selected from any one of DB-1, HP-5 or DB-624 cross-linked capillary columns; the temperature programming initial temperature is 80-120 ℃, the temperature is kept for 1-8 min, the temperature is increased to 180-240 ℃ at the speed of 12-17 ℃/min, and the temperature is kept for 3-15 min;
(2) preparation of Mixed control solutions
Precisely weighing hydroxychloroquine side chain, ethylamine ethanol, xylene, cyclopentanone, ethylamine diethanolamine, aminopentanone, ethylamine and ethanol, respectively, placing into a measuring flask, and diluting with solvent to obtain mixed reference solution; in each 1mL of mixed reference solution, the side chain of hydroxychloroquine is 0.01-0.09 g, the contents of ethylamine ethanol, xylene, cyclopentanone, ethylamine diethanolamine, aminopentanone and ethanol are respectively 0.001-0.009 g and the content of ethylamine is 0.011-0.019 g;
(3) preparation of test solution
Precisely weighing hydroxychloroquine side chains, adding a solvent to dissolve and dilute the hydroxychloroquine side chains to prepare a uniform solution containing 0.19-0.30 g of hydroxychloroquine side chains per 1mL as a test solution;
(4) measurement of
Precisely measuring the mixed reference substance solution and the test substance solution with the same volume respectively, and injecting into a gas chromatograph for measurement and calculation respectively to obtain the final product.
2. The method according to claim 1, wherein in the step (1), the flow rate of the nitrogen is 1.5-3.5 mL/min, and the split ratio is 25: 1-35: 1.
3. The method according to claim 1, wherein in the step (2) and the step (3), the solvent is DMF, DMSO or N-methylpyrrolidone.
4. The method of claim 1, wherein in step (2), the content of hydroxychloroquine in the mixed control solution is 0.04-0.06 g, the content of ethylamine ethanol in the mixed control solution is 0.004-0.006 g, and the content of ethylamine in the mixed control solution is 0.04-0.06 g, and the content of ethylamine ethanol in the mixed control solution is 0.004-0.006 g.
5. The method according to claim 1, wherein in the step (3), 0.22 to 0.26g of the homogeneous solution containing hydroxychloroquine side chains per 1mL is used as the test solution.
6. The method according to claim 1, wherein in the step (4), the volume of the mixed control solution and the test solution is 0.6-1 μ L.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102718707A (en) * | 2012-06-27 | 2012-10-10 | 武汉武药科技有限公司 | Hydroxychloroquine derivative and preparation method thereof |
| CN103472154A (en) * | 2013-09-27 | 2013-12-25 | 武汉武药科技有限公司 | Method for analysis of hydroxychloroquine sulfate raw material and preparation by high performance liquid chromatography |
| AU2015303835A1 (en) * | 2014-08-12 | 2017-03-02 | Monash University | Lymph directing prodrugs |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102718707A (en) * | 2012-06-27 | 2012-10-10 | 武汉武药科技有限公司 | Hydroxychloroquine derivative and preparation method thereof |
| CN103472154A (en) * | 2013-09-27 | 2013-12-25 | 武汉武药科技有限公司 | Method for analysis of hydroxychloroquine sulfate raw material and preparation by high performance liquid chromatography |
| AU2015303835A1 (en) * | 2014-08-12 | 2017-03-02 | Monash University | Lymph directing prodrugs |
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| 5-（N-乙基-N-2-羟乙基胺）-2戊胺的合成;余丹 等;《化学与生物工程》;20150531;第31卷(第05期);54-56 * |
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