CN101968470B - Method for separating and measuring acetylcysteine enantiomers - Google Patents
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Abstract
The invention provides a method for separating and measuring acetylcysteine enantiomers. In the method, before acetylcysteine is added in a chromatographic column, a derivatization reagent is used to perform derivatization, wherein the derivatization reagent is N(alpha)-(5-fluoro-2,4-dinitrophenyl)-L-amino acid compound. The method for separation and measurement combines the high performance liquid chromatography (HPLC) or high performance liquid chromatography-mass spectrum (HPLC-MS), and the used chromatographic column uses octadecylsilane chemically bonded silica as filler. The method for separation and measurement comprises the following steps: (1) taking acetylcysteine or a preparation with acetylcysteine, dissolving in low-concentration acid solution, adjusting the pH value of the mixed solution to 6.0-8.0 with alkaline solution to obtain a sample solution for testing; (2) mixing the acetylcysteine solution with 1mol/L of carbonate solution, adding N(alpha)-(5-fluoro-2,4-dinitrophenyl)-L-amino acid compound to mix evenly; (3) reacting the solution obtained by the step (2) at 40-60 DEG C in a dark place, adding hydrochloric acid solution after the reaction; (4) adding the solution obtained by the step (3) in a drying solution with the prestored phosphorus pentoxide and potassium hydroxide, adding phosphate buffer solution-acetonitrile, dissolving residues through ultrasonic treatment, filtering to obtain filtrate which is used as a testing solution; and (5) adopting HPLC or HPLC-MS to separate and measure the testing solution prepared by the step (4).
Description
Technical field
The present invention relates to the analytical chemistry field, specially refer to the method for separation determination acetylcysteine enantiomter.
Background technology
Pre-column derivatization is the method that improves detection sensitivity, most ofly without uv absorption or the weak compound of uv absorption, adopts suitable derivatization method, can comprise the Accurate Determining of content and enantiomter.
Acetylcysteine is a kind of amino acids drug, is a kind of phlegm medicine that goes.Its chemistry ACETYLCYSTEINE by name, molecular formula is C
5H
9NO
3S, the chemistry of its enantiomter is called N-acetyl group-D-Cys.The relevant report of measuring without the acetylcysteine isomeride in existing technology, only have document HPLC Separation of DL-Amino Acide Derivatized with N
2-(5-Fluoro-2,4-Dinitrophenyl)-LAmino Acid Amides(Journal of Chromatography B 674(1995) 143-148) and the method for Chinese patent 200510057381.8 have the report other products the isomeride assay method.
Acetylcysteine is that end absorbs, and absorption is not strong, and the enantiomter of acetylcysteine is the impurity of acetylcysteine, is the important indicator of acetylcysteine quality control.If with chiral chromatographic column separating isomerism body impurity, the kind of mobile phase is very limited on the one hand, and the positive condition is available hardly; In addition, detection sensitivity also is difficult for reaching requirement.
Summary of the invention
The object of the present invention is to provide a kind of employing with derivatization reagent, to carry out pre-column derivatization at acetylcysteine, acetylcysteine is when being derivatized, its enantiomter also is derivatized, thereby realizes adopting general chromatographic column to carry out the method for acetylcysteine and enantiomter (impurity) separation determination thereof.
For achieving the above object, technical scheme of the present invention is:
A kind of method of separation determination acetylcysteine enantiomter, adopt acetylcysteine with derivatization reagent, to carry out derivatization before advancing post, and its derivatization reagent is N
α-(5-fluoro-2,4-dinitrophenyl)-L-amino acids, state derivatization reagent N
α-(5-fluoro-2,4-dinitrophenyl)-L-amino acids comprises N
α-(5-fluoro-2,4-dinitrophenyl)-L-propylamine acid amides, N
α-(5-fluoro-2,4-dinitrophenyl)-L-amphetamine acid amides, N
α-(5-fluoro-2,4-dinitrophenyl)-L-dried meat amine amide or N
α-(5-fluoro-2,4-dinitrophenyl)-L-figured silk fabrics amine amide, the mol ratio of acetylcysteine and derivatization reagent is: 1:1.5-1:50; The separation determination method therefor is that high performance liquid chromatography or high performance liquid chromatography are combined use with mass spectroscopy, its chromatographic column of using is with octadecylsilane key and the silica gel chromatographic column as filler, and the detection wavelength of chromatographic column is 200-380nm, and the optimum detection wavelength is 333 ± 3nm; In the method for described separation determination acetylcysteine enantiomter, in the condition of separation determination acetylcysteine enantiomter, mobile phase is ammonium acetate solution-acetonitrile system, ammonium acetate solution is mobile phase A, acetonitrile is Mobile phase B, wherein the concentration of ammonium acetate solution is 0.01-0.05mol/L, and with ammoniacal liquor or phosphorus acid for adjusting pH value to 5.0-8.0, ammonium acetate solution and acetonitrile are measured eluent gradient wash-out table by following isomeride and are carried out wash-out:
Isomeride is measured eluent gradient wash-out table
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 18 | 80 | 20 |
| 19 | 50 | 50 |
| 25 | 50 | 50 |
| 26 | 80 | 20 |
| 36 | 80 | 20 |
Wherein: after 18 minutes, for rinsing chromatographic column and balance chromatographic column, the number percent of mobile phase A, B is percent by volume.
Described method of separating and assaying follows these steps to carry out:
(1), get acetylcysteine or contain the preparation of acetylcysteine, with dilute acid soln, dissolve, with aqueous slkali, the pH value is transferred to 6.0-8.0, adding water shakes up, be mixed with the solution that contains acetylcysteine 4.1-16.4mg/L, as the test sample sample solution, wherein dilute acid soln is mineral acid such as watery hydrochloric acid, dilute sulfuric acid, dilute phosphoric acid solution, also can be organic acid such as formic acid, acetic acid solution, described aqueous slkali is inorganic alkali solution such as NaOH, potassium hydroxide, ammonia spirit;
(2), get acetylcysteine solution and mix with the 1mol/L carbonate solution, add N
α-(5-fluoro-2,4-dinitrophenyl)-L-amino acids mixes, and wherein carbonate solution is sodium bicarbonate, saleratus, sal tartari or sodium carbonate liquor, or they mix rear resulting composition in any proportion;
(3), by the solution of step (2) gained in 40-60C ° of lucifuge reaction 30-50 minute, after completion of the reaction, add the hydrochloric acid solution 10-30 μ l of 1-5mol/L, its top condition is: the hydrochloric acid solution 10 μ l that add 2mol/L;
(4), get the solution of step (3) gained, in the drying system of preset phosphorus pentoxide and potassium hydroxide, after being dried in solution solvent and fully volatilizing to the greatest extent, adding pH is 7.0 phosphate buffered solution-acetonitrile 1ml, the ratio of phosphate buffered solution and acetonitrile is 1:1, ultrasonic processing is dissolved residue, filters, and filtrate is as need testing solution;
(5), with high performance liquid chromatography or high performance liquid chromatography-prepared need testing solution of mass spectroscopy separation determination step (4).
Good effect of the present invention is:
1, the present invention adopts N
α-(5-fluoro-2,4-dinitrophenyl)-L-amino acids and acetylcysteine carry out pre-column derivatization, not only make the product after derivatization that stronger uv absorption is arranged, and can conveniently measure amino acid whose enantiomter;
2, the present invention has the not advantage such as interference measurement of reaction conditions gentleness, fast, the excessive derivatization reagent of reaction velocity;
3 and derivatization product of the present invention is stable, sensitivity for analysis is high, the acetylcysteine enantiomter quantitatively be limited to 4.844 * 10
-8G/ml;
4, the method has solved with common chromatographic column (C
18Chromatographic column) problem of the enantiomter impurity of separation determination acetylcysteine and preparation thereof.
The accompanying drawing explanation
Fig. 1, acetylcysteine enantiomter (L and D configuration) high-efficient liquid phase chromatogram;
The high-efficient liquid phase chromatogram of Fig. 2, acetylcysteine;
The high-efficient liquid phase chromatogram of Fig. 3, Acetylcysteine granules;
The high-efficient liquid phase chromatogram of Fig. 4, reagent blank.
Embodiment
Below in conjunction with embodiment, further illustrate the specific embodiment of the present invention.
(1), instrument and condition
The U.S. wears peace UltiMate 3000 highly effective liquid phase chromatographic systems and workstation, auto injection, chromatographic column adopting octadecylsilane chemically bonded silica post; Ultraviolet detects wavelength: 333nm.Mobile phase: as mobile phase A, acetonitrile is Mobile phase B take 0.02mol/L ammonium acetate solution (regulating the pH value as 6.8 with phosphoric acid or ammoniacal liquor), and according to the form below carries out linear gradient elution
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 18 | 80 | 20 |
| 19 | 50 | 50 |
| 25 | 50 | 50 |
| 26 | 80 | 20 |
| 36 | 80 | 20 |
(2), experimental procedure
Get D-acetylcysteine 11mg, be dissolved in water into 25ml solution, add L-acetylcysteine 82mg to dissolve and make mixed solution, get mixed solution 1ml and put in the 10ml measuring bottle, add 1mol/L hydrochloric acid solution 2ml, jolting makes to dissolve, and with the 1mol/L sodium hydroxide solution, to be neutralized to pH be 8.0, be diluted with water to scale, shake up, as sample solution; Separately get N
α-(5-fluoro-2,4-dinitrophenyl)-L-propylamine acid amides 10.0mg(0.037mmol), add acetone 1ml, shake up, as derivatization reagent solution.Extracting sample solution 40 μ l, derivatization reagent solution 160 μ l and 1mol/L sodium bicarbonate solution 20 μ l, put in the 2ml sample bottle, and are airtight, at 40 ℃, add thermal response 45 minutes; Add after completion of the reaction 2mol/L hydrochloric acid solution 10 μ l, in the drying under reduced pressure system of preset phosphorus pentoxide and potassium hydroxide, the solvent that is dried in solution is fully waved to the greatest extent.The mixture of acetonitrile-phosphate buffer 1ml that adds again ph=7.0, the ratio of phosphate buffer and acetonitrile is 1:1, and jolting is dissolved residue, filters, and filtrate is as need testing solution.Getting need testing solution analyzes under above-mentioned chromatographic condition.The chromatographic peak that the results are shown in Figure retention time 22.313 in 1, Fig. 1 and 23.860 minutes is excessive derivatization reagent peak; The chromatographic peak of retention time 12.713 minutes and 15.380 minutes is respectively the chromatographic peak of acetylcysteine (L configuration) and enantiomter (D-isomeride) thereof.Show that acetylcysteine and its isomeride and excessive derivatization reagent can reach baseline separation.
(1), instrument and condition
The U.S. wears peace UltiMate 3000 highly effective liquid phase chromatographic systems and workstation, auto injection, chromatographic column adopting octadecylsilane chemically bonded silica post; Ultraviolet detects wavelength: 333nm.Mobile phase: as mobile phase A, acetonitrile is Mobile phase B take 0.03mol/L ammonium acetate solution (regulating the pH value as 5.0 with phosphoric acid or ammoniacal liquor), and according to the form below carries out linear gradient elution
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 18 | 80 | 20 |
| 19 | 50 | 50 |
| 25 | 50 | 50 |
| 26 | 80 | 20 |
| 36 | 80 | 20 |
(2), experimental procedure
Get acetylcysteine 82mg and put in the 10ml measuring bottle, add 1mol/L sulfuric acid solution 2ml, jolting makes to dissolve, and with the 1mol/L potassium hydroxide solution, to be neutralized to PH be 6.0, is diluted with water to scale, shakes up, as sample solution; Separately get N
α-(5-fluoro-2,4-dinitrophenyl)-L-amphetamine acid amides 10.0mg(0.037mmol), add acetone 1ml, shake up, as derivatization reagent solution.Extracting sample solution 40 μ l, derivatization reagent solution 160 μ l and 1mol/L potassium bicarbonate solution 20 μ l, put in the 2ml sample bottle, and are airtight, at 40 ℃, add thermal response 45 minutes; Add after completion of the reaction 3mol/L hydrochloric acid solution 25 μ l, in the drying under reduced pressure system of preset phosphorus pentoxide and potassium hydroxide, the solvent that is dried in solution is fully waved to the greatest extent.The mixture of acetonitrile-phosphate buffer 1ml that adds again pH=7.0, the ratio of phosphate buffer and acetonitrile is 1:1, and jolting is dissolved residue, filters, and filtrate is as need testing solution.Getting need testing solution analyzes under above-mentioned chromatographic condition.The chromatographic peak that the results are shown in Figure retention time 22.320 in 2, Fig. 2 and 23.880 minutes is excessive derivatization reagent peak; The chromatographic peak of retention time 12.720 minutes and 15.413 minutes is respectively the chromatographic peak of acetylcysteine (L configuration) and enantiomter (D-isomeride) thereof.Show that acetylcysteine and its isomeride and excessive derivatization reagent can reach baseline separation, and the enantiomter impurity that contains in energy Accurate Determining acetylcysteine.
(1), instrument and condition
The U.S. wears peace UltiMate 3000 highly effective liquid phase chromatographic systems and workstation, auto injection, chromatographic column adopting octadecylsilane chemically bonded silica post; Ultraviolet detects wavelength: 333nm.Mobile phase: as mobile phase A, acetonitrile is Mobile phase B take 0.04mol/L ammonium acetate solution (regulating the pH value as 7.0 with phosphoric acid or ammoniacal liquor), and according to the form below carries out linear gradient elution
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 18 | 80 | 20 |
| 19 | 50 | 50 |
| 25 | 50 | 50 |
| 26 | 80 | 20 |
| 36 | 80 | 20 |
(2), experimental procedure
Get Acetylcysteine granules 82mg, put in the 10ml measuring bottle, add 1mol/L formic acid solution 2ml, jolting makes to dissolve, and with the 1mol/L ammonia spirit, to be neutralized to PH be 7.0, is diluted with water to scale, shakes up, as sample solution; Separately get N
α-(5-fluoro-2,4-dinitrophenyl)-L-dried meat amine amide 10.0mg(0.037mmol), add acetone 1ml, shake up, as derivatization reagent solution.Extracting sample solution 40 μ l, derivatization reagent solution 160 μ l and 1mol/L solution of potassium carbonate 20 μ l, put in the 2ml sample bottle, and are airtight, at 40 ℃, add thermal response 45 minutes; Add after completion of the reaction 5mol/L hydrochloric acid solution 15 μ l, in the drying under reduced pressure system of preset phosphorus pentoxide and potassium hydroxide, the solvent that is dried in solution is fully waved to the greatest extent.The mixture of acetonitrile-phosphate buffer 1ml that adds again ph=7.0, the ratio of phosphate buffer and acetonitrile is 1:1, and jolting is dissolved residue, filters, and filtrate is as need testing solution.Getting need testing solution analyzes under above-mentioned chromatographic condition.The chromatographic peak that the results are shown in Figure retention time 22.320 in 3, Fig. 3 and 23.873 minutes is excessive derivatization reagent peak; Retention time 12.753 minutes was the chromatographic peak of acetylcysteine (L configuration), the different Wei Chu peak, body position of purchasing of mapping, in interpret sample without the D-acetylcysteine.Show that acetylcysteine and its isomeride and excessive derivatization reagent can reach baseline separation, and the enantiomter impurity that contains in energy Accurate Determining acetylcysteine.
(1), instrument and condition
The U.S. wears peace UltiMate 3000 highly effective liquid phase chromatographic systems and workstation, auto injection, chromatographic column adopting octadecylsilane chemically bonded silica post; Ultraviolet detects wavelength: 333nm.Mobile phase: as mobile phase A, acetonitrile is Mobile phase B take 0.05mol/L ammonium acetate solution (regulating the pH value as 8.0 with phosphoric acid or ammoniacal liquor), and according to the form below carries out linear gradient elution
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 18 | 80 | 20 |
| 19 | 50 | 50 |
| 25 | 50 | 50 |
| 26 | 80 | 20 |
| 36 | 80 | 20 |
(2), experimental procedure
Prepare blank solution
Add 1mol/L hydrochloric acid solution 2ml, jolting makes to dissolve, and with the 1mol/L sodium hydroxide solution, to be neutralized to pH be 8.0, is diluted with water to scale, shakes up, as sample solution; Separately get N
α-(5-fluoro-2,4-dinitrophenyl)-L-propylamine acid amides 10.0mg(0.037mmol), add acetone 1ml, shake up, as derivatization reagent solution.Extracting sample solution 40 μ l, derivatization reagent solution 160 μ l and 1mol/L sodium bicarbonate solution 20 μ l, put in the 2ml sample bottle, and are airtight, at 40 ℃, add thermal response 45 minutes; Add after completion of the reaction 2mol/L hydrochloric acid solution 10 μ l, in the drying under reduced pressure system of preset phosphorus pentoxide and potassium hydroxide, the solvent that is dried in solution is fully waved to the greatest extent.The mixture of acetonitrile-phosphate buffer 1ml that adds again pH=7.0, the ratio of phosphate buffer and acetonitrile is 1:1, and jolting is dissolved residue, filters, and filtrate is as need testing solution.Getting need testing solution analyzes under above-mentioned chromatographic condition.The chromatographic peak that the results are shown in Figure retention time 22.327 in 4, Fig. 4 and 23.887 minutes is excessive derivatization reagent peak; In retention time 13 ~ 20 minutes, without chromatographic peak, show not interference measurement of derivatization reagent.
The above is only non-limiting enforcement side of the present invention; for the person of ordinary skill of the art; not breaking away from the invention design and not making under the prerequisite of creative work, can also make some distortion and improvement, these all belong to protection scope of the present invention.
Claims (6)
1. the method for a separation determination acetylcysteine enantiomter, it is characterized in that: acetylcysteine carries out derivatization with derivatization reagent before advancing post, and its derivatization reagent is N
α-(5-fluoro-2,4-dinitrophenyl)-L-amino acids, described derivatization reagent N
α-(5-fluoro-2,4-dinitrophenyl)-the L-amino acids is N
α-(5-fluoro-2,4-dinitrophenyl)-L-propylamine acid amides, N
α-(5-fluoro-2,4-dinitrophenyl)-L-amphetamine acid amides, N
α-(5-fluoro-2,4-dinitrophenyl)-L-dried meat amine amide or N
α-(5-fluoro-2,4-dinitrophenyl)-L-figured silk fabrics amine amide, the mol ratio of acetylcysteine and derivatization reagent is: 1:1.5～1:5; The separation determination method therefor is high performance liquid chromatography, and its chromatographic column of using is with the chromatographic column of octadecylsilane chemically bonded silica as filler, and the detection wavelength of chromatographic process is 333 ± 3nm; In the condition of separation determination acetylcysteine enantiomter, mobile phase is ammonium acetate solution-acetonitrile system, ammonium acetate solution is mobile phase A, acetonitrile is Mobile phase B, wherein the concentration of ammonium acetate solution is 0.01-0.05mol/L, and with the phosphorus acid for adjusting pH value to 5.0-8.0, ammonium acetate solution and acetonitrile are measured eluent gradient wash-out table by following isomeride and are carried out wash-out:
Isomeride is measured eluent gradient wash-out table
Wherein: after 18 minutes, for rinsing chromatographic column and balance chromatographic column, the number percent of mobile phase A, B is percent by volume.
2. the method for separation determination acetylcysteine enantiomter according to claim 1, it is characterized in that: described method of separating and assaying follows these steps to carry out:
(1), get acetylcysteine or contain the preparation of acetylcysteine, with dilute acid soln, dissolve, with aqueous slkali, the pH value is transferred to 6.0-8.0, add water and shake up, be mixed with the solution that contains acetylcysteine 4.1-16.4mg/L, as the test sample sample solution;
(2), get acetylcysteine solution and mix with the 1mol/L carbonate solution, add N
α-(5-fluoro-2,4-dinitrophenyl)-L-amino acids mixes, and wherein carbonate solution is sodium bicarbonate, saleratus, sal tartari or sodium carbonate liquor, or they mix rear resulting composition in any proportion;
(3), by the solution of step (2) gained in 40-60C ° of lucifuge reaction 30-50 minute, after completion of the reaction, add the hydrochloric acid solution 10-30 μ l of 1-5mol/L, its condition is: the hydrochloric acid solution 10 μ l that add 2mol/L;
(4), get the solution of step (3) gained, in the drying system of preset phosphorus pentoxide and potassium hydroxide, after being dried in solution solvent and fully volatilizing to the greatest extent, add pH and be 7.0 phosphate buffered solution-acetonitrile 1ml, wherein the ratio of phosphate buffered solution and acetonitrile is 1:1, ultrasonic processing is dissolved residue, filters, and filtrate is as need testing solution;
(5), with the prepared need testing solution of high efficiency liquid chromatography for separating and determining step (4).
3. the method for separation determination acetylcysteine enantiomter according to claim 2, it is characterized in that: described dilute acid soln is mineral acid or organic acid.
4. the method for separation determination acetylcysteine enantiomter according to claim 3, it is characterized in that: described mineral acid is watery hydrochloric acid, dilute sulfuric acid, dilute phosphoric acid solution.
5. the method for separation determination acetylcysteine enantiomter according to claim 3, it is characterized in that: described organic acid is formic acid, acetic acid solution.
6. the method for separation determination acetylcysteine enantiomter according to claim 2, it is characterized in that: described aqueous slkali is NaOH, potassium hydroxide, ammonia spirit.
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| CN102590387B (en) * | 2012-02-17 | 2014-02-12 | 成都金典药物科技开发有限公司 | Method for detecting impurity cystine in compound glycyrrhizin injection |
| CN105319309A (en) * | 2015-04-23 | 2016-02-10 | 北京紫萌同达科技有限公司 | Separation and detection method of glycyl-L-glutamine chiral isomer |
| CN108037209B (en) * | 2017-12-25 | 2021-05-07 | 浙江天宇药业股份有限公司 | Liquid chromatography analysis method of ticagrelor chiral intermediate |
| CN109261126B (en) * | 2018-08-13 | 2021-09-03 | 南京理工大学 | Method for regulating cysteine molecule separation capacity by applying strain |
| CN109725073B (en) * | 2018-12-12 | 2021-10-15 | 湖南华纳大药厂科技开发有限公司 | Separation and detection method of acetylcysteine enantiomer |
| CN110333302A (en) * | 2019-06-25 | 2019-10-15 | 武汉兴华智慧医药科技有限公司 | The detection method of N in acetylcysteine solution, N- diacetyl lanthionine |
| CN110642767B (en) * | 2019-09-20 | 2021-07-09 | 武汉远大弘元股份有限公司 | Separation and purification method of acetylcysteine enantiomer |
| CN114689707A (en) * | 2020-12-26 | 2022-07-01 | 四川汇宇制药股份有限公司 | Detection method of acetylcysteine enantiomer |
| CN114280179B (en) * | 2021-12-22 | 2024-03-15 | 北京美福润医药科技股份有限公司 | Pretreatment of exenatide and detection method of isomer in His amino acid eluent obtained by pretreatment |
| CN114563495B (en) * | 2022-02-28 | 2023-09-15 | 杭州民生药业股份有限公司 | Detection method of acetylcysteine and related substances thereof |
| CN115144498A (en) * | 2022-06-30 | 2022-10-04 | 浙江金华康恩贝生物制药有限公司 | Method for detecting content of enantiomers in acetylcysteine and acetylcysteine particles |
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