CN107515257A - The method of methanesulfonates in derivatization HPLC UV methods measure methanesulfonic acid - Google Patents

The method of methanesulfonates in derivatization HPLC UV methods measure methanesulfonic acid Download PDF

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CN107515257A
CN107515257A CN201710499848.7A CN201710499848A CN107515257A CN 107515257 A CN107515257 A CN 107515257A CN 201710499848 A CN201710499848 A CN 201710499848A CN 107515257 A CN107515257 A CN 107515257A
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derivatization
methanesulfonates
hplc
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reaction
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CN107515257B (en
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郑枫
柳文媛
周洁
冯锋
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China Pharmaceutical University
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China Pharmaceutical University
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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
    • 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
    • G01N2030/067—Preparation by reaction, e.g. derivatising the sample

Abstract

The invention discloses a kind of method that derivatization HPLC UV methods determine methanesulfonates in methanesulfonic acid, this method has the product absorbed more by force to generation after methanesulfonates derivatization using dithiocarbamates derivatization reagent in ultraviolet region；Derivative reaction liquid is separated in ultraviolet region based on the principle of reversed-phased high performace liquid chromatographic as sample introduction sample and determines the derivatization product of methanesulfonates, so as to realize the qualitative or quantitative detection to methanesulfonates.The present invention has ultraviolet absorption characteristic based on methanesulfonates and generation product after the reaction of dithiocarbamates derivatization reagent, the method for establishing methanesulfonates in a kind of simple, general derivatization HPLC UV methods measure methanesulfonic acid.The result of Method validation shows that this method specificity and sensitivity are good.

Description

The method of methanesulfonates in derivatization HPLC-UV methods measure methanesulfonic acid
Technical field
The invention belongs to drugs analysis detection field, is related to a kind of method of derivatization HPLC-UV methods measure methanesulfonates, More particularly to a kind of method that derivatization HPLC-UV methods determine methanesulfonates in methanesulfonic acid.
Background technology
Latent gene toxic impurities (potential genotoxic impurities) are strong mutagenic agents and carcinogen, DNA mutation, chromosome breakage or DNA restructuring can be caused, it is also possible to cause the generation of human tumor[1,2].In recent years, With the gradual perfection of genotoxicity impurity regulation, food and drug administration (FDA) and European FAD (EMEA) the regulatory requirements more and more higher of the department to genotoxicity impurity such as[3,4].If the control of genotoxicity impurity is not in medicine When, clinical hidden danger is may result in, while new drug Time To Market can be also influenceed, therefore, in medicine production process, for potential The control of genotoxicity impurity is particularly significant[5,6]。
Methanesulfonates is a kind of common latent gene toxic impurities, is increasingly closed in recent years by Drug Administration department Note, this mainly contains excessive ethyl methane sulfonate with the general Luo Saiyin of Roche Holding Ag's production in 2007 and had by city is removed from European market Close[7-10].Through investigation, the ethyl methane sulfonate main source remained in general Luo Sai is the ethyl methane sulfonate contained in raw material methanesulfonic acid Residual[11].During pharmaceutical synthesis, methanesulfonic acid is used for salt-forming reaction frequently as ion balance, and this kind of anti-into salt Should be typically all in the final step of pharmaceutical production[12,13], therefore the methanesulfonates remained in methanesulfonic acid is methanesulfonic acid in bulk drug The main source of ester[14,15].Methyl mesylate (MMS) and ethyl methane sulfonate (EMS) are two kinds of common methanesulfonates gene poison Property impurity, European Pharmacopoeia 8.0 recorded gas chromatography-mass spectrum (GC-MS) method be used for detect methyl mesylate and first in methanesulfonic acid The standard method of sulfonic acid, this method need to derive determinand into the alkane iodide of chemical conversion volatile, then liquid-liquid extraction, It can be analyzed[16-18].And other are commonly used in most of methods for determining methyl mesylate and ethyl methane sulfonate also all It is to be based on mass spectrometry method, although mass detector is a kind of sensitive and general detector, but fancy price limits it Widely use[2,5,19-23]。
HPLC- UV detection (HPLC-UV) method is the conventional means of Control of drug quality, develops a kind of letter It is significant that single, sensitive, stable HPLC-UV methods are used for methyl mesylate and ethyl methane sulfonate in methanesulfonic acid.But should The exploitation of method faces a significant challenge, i.e., methanesulfonates lacks the chromophoric group that can be used for ultraviolet detection, therefore we are uncommon Prestige passes through liquid phase Derivative, using nucleophilic substitution, introduces chromophoric group to solve this problem.Triethylamine and piperidines It is reported and is used for liquid chromatography-mass spectrography (LC-MS) method and capillary chromatography-mass spectrum (CE-MS) method measure as derivatization reagent The content of methanesulfonates[19-21].However, the product (quaternary ammonium salt) of these derivatization reagents can cause to trail due to silicone hydroxyl effect Phenomenon, reduce detection sensitivity.Five fluorine thiophenols and rhodanate are strong nucleopilic reagents, are used as derivatization reagent and are used for gas phase color Spectrum-mass spectrum (GC-MS) method determines methanesulfonates content[22,23].But five fluorine thiophenols easily aoxidize, detect, can produce for HPLC Interference.And rhodanate derivatization can produce a variety of derivatization products, cause muting sensitivity.
The content of the invention
The purpose of the present invention is in view of the shortcomings of the prior art, there is provided derivatization HPLC-UV methods determine the side of methanesulfonates Method.
It is a further object of the present invention to provide the method that derivatization HPLC-UV methods determine methanesulfonates in methanesulfonic acid.
The purpose of the present invention can be achieved through the following technical solutions：
A kind of method of derivatization HPLC-UV methods measure methanesulfonates, including：Derived using dithiocarbamates Change reagent and the derivatization product for having stronger absorption in ultraviolet region 272-284nm is generated to methanesulfonates derivatization, utilize HPLC reversed phase partition chromatographies determine the derivatization product of methanesulfonates in ultraviolet region 272-284nm, so as to realize to first sulphur The qualitative or quantitative detection of acid esters.
Preferably, the method for described derivatization HPLC-UV methods measure methanesulfonates, is comprised the steps of：
(1) reaction system pH to 7-8, is adjusted with sodium hydroxide, under the conditions of 80-100 DEG C, uses aminodithioformic acid Salt derivatization reagent generates the product for having stronger absorption in ultraviolet region 272-284nm to methanesulfonates derivative reaction；
(2), using HPLC-UV methods, based on reversed phase partition chromatography principle in ultraviolet region 272-284nm determination steps (1) the methanesulfonates derivatization product obtained in, so as to realize the qualitative or quantitative detection to methanesulfonates.
Described methanesulfonates is alkyl-substituted methanesulfonates, appointing preferably in methyl mesylate and ethyl methane sulfonate Meaning is a kind of.
Described dithiocarbamates derivatization reagent is selected from sodium diethyldithiocarbamate, dibenzyl two Any one in thiocarbamic acid sodium and ehtyl potassium xanthate, preferably sodium diethyldithiocarbamate, diethyl Nabam generates with methanesulfonates derivatization has the derivatization absorbed more by force to produce in ultraviolet region 275-277nm Thing.
Described reaction system is DMA or dimethyl sulfoxide, preferably DMA.
Preferably, the condition of described derivative reaction：Using DMA as reaction system, with diethyl two Thiocarbamic acid sodium is derivatization reagent, adjusts reaction system pH to 7 with sodium hydroxide, is performed the derivatization under the conditions of 80 DEG C Reaction；Wherein, sodium diethyldithiocarbamate concentration is 0.2-2mg/mL, preferably 0.2mg/mL, reaction time 1- 5h, preferably 1h.
Described HPLC-UV methods：Using HPLC chromatogram instrument；Using reversed phase partition chromatography；It is mutually solid with non-polar linkage Determine phase, using polarity mobile phase, Detection wavelength is located at 272-284nm, is preferably 275-277nm, more preferably 277 nm.
Preferably, the instrument that described HPLC-UV methods use is Shimadzu LC 20AT liquid chromatographs, the chromatograph It is configured with online vacuum degassing machine, binary gradient pump, automatic sampler, column oven, DAD detectors and LC-solution chromatograms Work station；Chromatographic column uses 250mm × 4.6mm, 5 μm of GL Sciences IntertSustain C18 posts；Sample size： 20 μL；Flow rate of mobile phase：1.0mL/min；Eluent gradient：A phases are acetonitrile, and B phases are 5mmol/L ammonium acetate solutions, 0min 60% A phases, 16min 60%A phases, 21min 80%A phases, 26min 80%A phases, 27min 60%A phases, 34min 60%A phases；Post Temperature：30℃；Detection wavelength：277nm.
The application of the qualitative and quantitative detection of method of the present invention methanesulfonates in for methanesulfonic acid sample.
The method of methanesulfonates, is comprised the steps of in a kind of derivatization HPLC-UV methods measure methanesulfonic acid：
(1) methanesulfonic acid sample, water, are taken：Add in reaction system, adjusted with sodium hydroxide anti-after acetonitrile mixed solution dissolving System pH to 7~8 is answered, under the conditions of 80 DEG C~100 DEG C, is performed the derivatization using dithiocarbamates derivatization reagent React 1-5h and obtain reaction solution；
(2) reaction solution after, being terminated using the reaction of step (1) derivedization is existed as sample introduction sample using HPLC-UV methods The derivatization product of 272-284nm measure wherein methanesulfonates, so as to realize in methanesulfonic acid methanesulfonates it is qualitative or quantitative Detection.
Described methanesulfonates is selected from alkyl-substituted methanesulfonates, preferably in methyl mesylate and ethyl methane sulfonate Any one.
Described dithiocarbamates derivatization reagent is selected from sodium diethyldithiocarbamate, dibenzyl two Any one in thiocarbamic acid sodium and ehtyl potassium xanthate, preferably sodium diethyldithiocarbamate.
Described reaction system is DMA or dimethyl sulfoxide, preferably DMA.
Described water：Acetonitrile mixed solution is mixed by isometric water and acetonitrile.Described methanesulfonic acid and water：Acetonitrile The amount ratio of mixed solution is 5mg：4μL.Final concentration of 50mg/mL of the methanesulfonic acid in reaction system.
Preferably, the condition of described derivative reaction：Using DMA as reaction system, with diethyl two Thiocarbamic acid sodium is derivatization reagent, adjusts reaction system pH to 7 with sodium hydroxide, is performed the derivatization under the conditions of 80 DEG C Reaction；Wherein, sodium diethyldithiocarbamate concentration is 0.2mg/mL, reaction time 1h.
Preferably, described HPLC-UV methods：Using HPLC chromatogram instrument；Using reversed phase partition chromatography；With non-polar linkage It is mutually stationary phase, using polarity mobile phase, Detection wavelength is located at 272-284nm, preferably 275-277nm, is more preferably 277nm。
Preferably, the instrument that described HPLC-UV methods use is Shimadzu LC 20AT liquid chromatographs, the chromatograph It is configured with online vacuum degassing machine, binary gradient pump, automatic sampler, column oven, DAD detectors and LC-solution chromatograms Work station；Chromatographic column uses 250mm × 4.6mm, 5 μm of GL Sciences IntertSustain C18 posts；Sample size： 20 μL；Flow rate of mobile phase：1.0mL/min；Eluent gradient：A phases are acetonitrile, and B phases are 5mmol/L ammonium acetates, 0 min 60%A Phase, 16min 60%A phases, 21min 80%A phases, 26min 80%A phases, 27min 60%A phases, 34 min 60%A phases；Post Temperature：30℃；Detection wavelength：277nm.
Beneficial effects of the present invention：
Alkyl derivatized product of the invention based on dithiocarbamates derivatization reagent has UV absorption Feature, establish a kind of method of simple, general derivatization HPLC-UV measure methanesulfonates.The result of Method validation shows Show that methanesulfonic acid and other impurities will not interfere to analysis in methanesulfonic acid, this method specificity is good.In addition, the inspection of method Survey is limited to 0.01 μ g/mL, is quantitatively limited to 0.03 μ g/mL, the good (r of linear relationship>0.999)；In a few days distinguish with day to day precision Less than 4.8% and 6.8%；Average recovery rate (RSD between 88.7-103.8%<5.0%), without obvious matrix interference；And Derivatization product is good in 8h internal stabilities.
Brief description of the drawings
Fig. 1 be using sodium diethyldithiocarbamate as derivatization reagent, under the conditions of identical derivative reaction, different first The chromatogram of sulfonate derivatized product；A is the derivatization product chromatogram of methanesulfonates mixing stock solution, and b is first first The derivatization product chromatogram of sulfonic acid sample, c are the derivatization product chromatogram of second batch methanesulfonic acid sample, and d is the 3rd batch of first The derivatization product chromatogram of sulfonic acid sample, e are sodium diethyldithiocarbamate blank solution.
Fig. 2 is influence of the reaction dissolvent to methanesulfonates derivative reaction：A is shadow of the organic solvent to derivatization efficiency Ring；B is influence of the pH value to derivatization efficiency.
Fig. 3 is influence of the reaction condition to methanesulfonates derivative reaction：A is reaction temperature and reaction time to methanesulfonic acid The influence of active carbon efficiency；B is the influence of reaction temperature and reaction time to ethyl methane sulfonate derivatization efficiency；C is two Influence of the sodium diethyldithiocarbamate concentration to derivatization efficiency.
Embodiment
Technical scheme is described further with reference to embodiment.
1.1. instrument
Shimadzu LC 20AT liquid chromatographs (are contained in line vacuum degasser, binary gradient pump, automatic sampler, post Incubator, DAD detectors and LC-solution chromatographic work stations)；The LC-TOF Liquid Chromatography-Tandem Mass Spectrometry instrument of Aglient 6520 (it is contained in line vacuum degasser, high pressure binary gradient pump, automatic sampler, column oven, DAD detectors, electron spray (ESI) interface With Agilent Mass Hunter Acquisition Software Ver.A.01.00 work stations)；METTLER TOLEDO AB135-S assay balances (plum Teller swedish company)；Sartorious BS110 assay balances (the limited public affairs of Beijing Sai Duolisi Department).
1.2. reagent
Methyl mesylate (99.0%), ethyl methane sulfonate (98.5%), methanesulfonic acid (99.0%), diethyl-dithio amino Formic acid sodium trihydrate (99.0%), dibenzyl aminodithioformic acid sodium X hydrates (98.0%), ehtyl potassium xanthate (98.0%), acetonitrile (chromatographically pure), DMF (chromatographically pure), DMA (chromatographically pure), diformazan Sulfoxide (DMSO), dimethyl pyrrolidone (chromatographically pure), acetone (analysis is pure), ammonium acetate, sodium hydroxide (analysis is pure), purifying Water, acetonitrile (chromatographically pure).
1.3. the preparation of solution
The preparation of methanesulfonates stock solution and series mixing stock solution：
Methyl mesylate stock solution：Methyl mesylate about 25mg is taken, it is accurately weighed, it is placed in 25mL measuring bottles, with N, N- bis- Methylacetamide is diluted to scale, shakes up.
Ethyl methane sulfonate stock solution：Ethyl methane sulfonate about 25mg is taken, it is accurately weighed, it is placed in 25mL measuring bottles, with N, N- bis- Methylacetamide is diluted to scale, shakes up.
Serial methanesulfonates mixing stock solution：Precision pipettes equivalent methyl mesylate stock solution and ethyl methane sulfonate reserve Liquid, it is placed in 10mL measuring bottles, adds DMA constant volume to scale, be diluted to containing same concentrations methanesulfonic acid first A series of mixing stock solutions of ester and ethyl methane sulfonate (the μ g/mL of concentration 1.5,2.5,5,10,25,100,250).
The preparation of derivatization test solution：
Sodium diethyldithiocarbamate (DDTC), dibenzyl aminodithioformic acid sodium (DBDTC) and ethyl xanthan Sour potassium (PEX) test solution：Mentioned reagent about 20mg is taken respectively, it is accurately weighed, it is placed in 10mL measuring bottles, uses DMA Scale is diluted to, is shaken up.
10mol/L sodium hydroxides (NaOH) solution：NaOH 20.0g are taken, it is accurately weighed, it is placed in 50mL measuring bottles, it is dilute with water Release to scale, shake up.Need Fresh.
1.4.HPLC-UV condition
Chromatographic column uses 250mm × 4.6mm, 5 μm of GL Sciences IntertSustain C18 posts；Mobile phase stream Speed： 1.0mL/min；Eluent gradient：A phases are acetonitrile, and B phases are 5mmol/L ammonium acetates, 0min 60%A phases, 16min 60% A phases, 21min 80%A phases, 26min 80%A phases, 27min 60%A phases, 34min 60%A phases；Column temperature：30℃；Detect ripple It is long：277nm.
The comparison of the derivatization reagent of embodiment 1
Precision pipette three times, every time 100 μ L concentration be 250 μ g/mL methanesulfonates mixing stock solution, be respectively placed in three In individual 5mL measuring bottles, 200 μ L water and 500 μ L dithiocarbamates derivatization test solution are sequentially added, add N, N- diformazans Yl acetamide is diluted to scale, vortex 10s, shakes up.80 DEG C of heating water bath 1h, taking-up are let cool to room temperature, after filtering, take 20 μ L to note Enter the analysis of HPLC-DAD sample introductions.
HPLC-DAD conditions：Shimadzu LC 20AT liquid chromatographs (be contained in line vacuum degasser, binary gradient pump, Automatic sampler, column oven, DAD detectors and LC-solution chromatographic work stations)；Chromatographic condition is the same as described in 1.4；DAD is swept Retouch wavelength：200-400nm.
3 kinds of derivatization reagents and the derivatization product ultraviolet maximum absorption wavelength of methyl mesylate generation are respectively 275nm (ehtyl potassium xanthate tries by (sodium diethyldithiocarbamate), 276nm (dibenzyl aminodithioformic acid sodium) and 277nm Liquid).Three kinds of derivatization reagents and the derivatization product ultraviolet maximum absorption wavelength of ethyl methane sulfonate generation are respectively 277nm (two Sodium diethyldithiocarbamate), 272nm (dibenzyl aminodithioformic acid sodium) and 284nm (ehtyl potassium xanthate test solution). 3 kinds of dithiocarbamate derivatives all have stronger ultraviolet detection sensitivity, wherein sodium diethyldithiocarbamate Sensitivity is most strong, and sodium diethyldithiocarbamate is most common commercialization dithiocar-bamate reagent, so, Present invention selection sodium diethyldithiocarbamate carries out follow-up study.
The identification of the derivatization product of embodiment 2
Precision pipettes the methanesulfonates mixing stock solution that 100 μ L concentration are 250 μ g/mL, is placed in 5mL measuring bottles, adds successively Enter 200 μ L water and 500 μ L DDTC derivatization test solutions, add DMA to be diluted to scale, be vortexed 10 s, shakes up. 80 DEG C of heating water bath 1h, taking-up are let cool to room temperature, after filtering, take 20 μ L injection HPLC-MS sample introduction analyses.
HPLC-MS conditions：Agilent 6224-TOF high performance liquid chromatography-exact mass spectra combined instrument；Chromatographic condition is the same as 1.4 It is described；Mass ion source：ESI(+)；Scanning range：m/z 90-230；Dry gas (N2) flow velocity：8.0L/min；Dry gas Temperature：325℃；Capillary voltage：3.5kV；Resolution ratio：200,000.
High performance liquid chromatography exact mass spectra measurement result is：The measure at methyl mesylate and DDTC derivatization product peak point Error of the son amount between 164.0555, and the calculated value (164.0562) of diethyldithiocar bamic acid methyl esters be 4.27 ppm, the product for showing reaction generation is diethyldithiocar bamic acid methyl esters；The derivative of ethyl methane sulfonate and DDTC The measure molecular weight for changing product peak is 178.0712, the calculated value with diethyldithiocar bamic acid ethyl ester (178.0719) error between is 3.93ppm, and the product for showing reaction generation is diethyldithiocar bamic acid ethyl ester.
The optimization of the derivatization solvent of embodiment 3
Nucleophilic substitution is very fast in non-protonic solvent medium-rate, therefore this experimental selection includes N, N- dimethyl second Six kinds of non-protonic solvents including acid amides, N,N-dimethylformamide, acetonitrile, acetone, 1-METHYLPYRROLIDONE, dimethyl sulfoxide Optimize.
Precision pipettes six times, the 5 μ g/mL methanesulfonates mixing stock solutions of 100 μ L every time, is respectively placed in six 5mL measuring bottles In, 200 μ L water and 500 μ L DDTC derivatization reagents are added, respectively plus six kinds of above-mentioned non-protonic solvents are diluted to scale, whirlpool 10s is revolved, is shaken up.80 DEG C of heating water bath 1h, taking-up are let cool to room temperature, after filtering, take 20 μ L injection HPLC-UV sample introduction analyses.
Fig. 2A is shown, when being performed the derivatization to methyl mesylate and ethyl methane sulfonate, ethyl methane sulfonate derivatization product Generation substantially influenceed by reaction dissolvent.When reaction dissolvent is DMA and dimethyl sulfoxide, derivatization Peak areas is higher.And the blank interference of DMA is small compared with dimethyl sulfoxide, so selection N, N- dimethyl second Acid amides carries out follow-up study as derivative reaction solvent.
The investigation of the derivatization solution pH of embodiment 4
Six parts of methanesulfonic acids about 250mg is taken, it is accurately weighed, it is respectively placed in 5mL measuring bottles, adds 200 μ L water：Acetonitrile mixing is molten Liquid (50:50, v/v) dissolve, add different amounts of sodium hydroxide solution by six parts of solution be respectively adjusted to pH value 3.0,4.0, 5.0th, 6.0,7.0,8.0, add the DDTC derivatizations examination of 100 μ L 5 μ g/mL methanesulfonates mixing stock solutions and 500 μ L Liquid, add DMA to be diluted to scale, vortex 10s, shake up.80 DEG C of heating water bath 1h, taking-up are let cool to room temperature, mistake After filter, 20 μ L injection HPLC-UV sample introduction analyses are taken.
Fig. 2 B are shown, when being performed the derivatization to methyl mesylate and ethyl methane sulfonate, methanesulfonates derivatization product Generation is substantially influenceed by pH value of solution.When reacting solution pH value is 3-4, derivatization peak areas is seldom, and pH is 7- When 8, derivatization peak areas substantially increases and reaches platform.Because too high pH may damage chromatographic column, so selection 7 is made For sample solution pH value.
The investigation of the derivatization temperature and time of embodiment 5
Precision pipettes six times, the 5 μ g/mL methanesulfonates mixing stock solutions of 100 μ L every time, is respectively placed in six 5mL measuring bottles In, 200 μ L water and 500 μ L DDTC derivatization test solutions are added, respectively plus six kinds of above-mentioned non-protonic solvents are diluted to scale, whirlpool 10s is revolved, is shaken up.20 μ L injection HPLC-UV sample introduction analyses are taken after 60 DEG C of heating water baths 0.5,1,2,3,4,5h respectively.Same method Investigate change of the derivatization peak areas when reacting for 80 DEG C and 100 DEG C.
It is smaller that Fig. 3 A show that methyl mesylate derivatization peak areas is affected by temperature between 80 DEG C -100 DEG C；By Fig. 3 B It can be seen that ethyl methane sulfonate derivatization peak areas is optimal at 80 DEG C, and its lifting trend is more slow after 1h.Cause This selection derivative reaction temperature is 80 DEG C, reaction time 1h.
The investigation of the derivatization reagent concentration of embodiment 6
Precision pipettes ten times, the 5 μ g/mL methanesulfonates mixing stock solutions of 100 μ L every time, is respectively placed in ten 5mL measuring bottles In, the DDTC derivatization test solutions of 200 μ L water and different volumes are added, adds DMA to be diluted to scale, is configured to DDTC concentration is respectively 0.2,0.4,0.6,0.8,1.0,1.2,1.4,1.6,1.8,2.0mg/mL sample solution, vortex 10s, Shake up.80 DEG C of heating water bath 1h, taking-up are let cool to room temperature, after filtering, take 20 μ L injection HPLC-UV sample introduction analyses.
Fig. 3 C show that methyl mesylate and ethyl methane sulfonate derivatization peak areas are with the increasing of derivatization reagent concentration Add and increase, gradually tend to saturation after concentration is more than 0.2mg/mL, therefore select end of the derivatization reagent in sample solution Concentration is 0.2mg/mL.
The Method validation of embodiment 7 and application
7.1. specificity
Precision pipettes 100 μ L 5 μ g/mL methanesulfonates mixing stock solutions, is placed in 5mL measuring bottles, add 200 μ L water and 500 μ L DDTC derivatization test solutions, add DMA to be diluted to scale, vortex 10s, shake up.80 DEG C of heating water baths 1h, taking-up are let cool to room temperature, after filtering, take 20 μ L injection HPLC-UV sample introduction analyses.Chromatogram is by a in Fig. 1.
The methanesulfonic acid about 250mg of three different batches is weighed respectively, it is accurately weighed, it is respectively placed in 5mL measuring bottles, adds 200 μ L water：Acetonitrile mixed solution (50:50, v/v) dissolving and 500 μ L DDTC derivatization test solutions, are adjusted with sodium hydroxide solution PH value is 7.0, adds DMA to be diluted to scale, vortex 10s, shakes up.80 DEG C of heating water bath 1h, taking-up are let cool To room temperature, after filtering, 20 μ L injection HPLC-UV sample introduction analyses are taken.Chromatogram is shown in b, c, d in Fig. 1.
Precision pipettes 100 μ L blank acetonitrile, is placed in 5ml measuring bottles, adds 200 μ L water and 500 μ L DDTC derivatizations Test solution, add DMA to be diluted to scale, vortex 10s, shake up.80 DEG C of heating water bath 1h, taking-up are let cool to room temperature, After filtering, 20 μ L injection HPLC-UV sample introduction analyses are taken.E in chromatogram such as Fig. 1.
Above-mentioned chromatogram derivedization product chromatographic peak and derivatization reagent chromatographic peak, methanesulfonic acid chromatographic peak separating degree are good Good, other impurities peak does not also disturb the measure of methyl mesylate and ethyl methane sulfonate, and the specificity of illustration method is good.
7.2. linearity and range
The accurate methanesulfonates series mixing stock solution for pipetting 100 μ L respectively, is placed in 5mL measuring bottles, add 200 μ L water and 500 μ L DDTC derivatization test solutions, add DMA to be diluted to scale, vortex 10s, shake up, be made containing methanesulfonic acid Methyl esters and ethyl methane sulfonate concentration are respectively 0.03,0.05,0.1,0.2,0.5,2,5 μ g/mL methanesulfonates reference substance solution. Above-mentioned 80 DEG C of heating water bath 1h of solution, taking-up are let cool to room temperature, after filtering, take 20 μ L injection HPLC-UV sample introduction analyses.
With methanesulfonates concentration C (μ g/mL) for abscissa, derivatization peak areas (A) is ordinate, using a most young waiter in a wineshop or an inn Multiplication carries out linear regression analysis, calculates equation of linear regression and coefficient correlation.As a result show, methyl mesylate and methanesulfonic acid second The ester range of linearity is 0.03~5 μ g/mL, and the good (r of each determinand linear relationship>0.999).It the results are shown in Table 1.
7.3. test limit and quantitative limit
With signal to noise ratio 3:1 is the test limit of method, with signal to noise ratio 10:1 is the quantitative limit of method.As a result show, methanesulfonic acid The detection of methyl esters and ethyl methane sulfonate is limited to 0.01 μ g/mL, is quantitatively limited to 0.03 μ g/mL.Specifically it is shown in Table 1.
7.4. precision test (withinday precision and day to day precision)
By the methanesulfonates reference substance solution that method compound concentration under 7.2. items is 0.05 μ g/mL, above-mentioned 80 DEG C of water of solution Bath heating 1h, taking-up let cool to room temperature, after filtering, take 20 μ L injections HPLC-UV to repeat sample introduction 6 times, calculate derivatization product peak RSD between area is as withinday precision；Same concentration sample repeats sample introduction 6 times daily for three days on end, calculates derivatization product Calculated by peak area RSD values are as day to day precision.As shown in Table 1, the withinday precision of the method and day to day precision are good, RSD is respectively smaller than 4.8% and 6.8%.
7.5. derivative stability
By the methanesulfonates reference substance solution that method compound concentration under 7.2. items is 0.05 μ g/mL, above-mentioned 80 DEG C of water of solution Bath heating 1h, taking-up takes 20 μ L injection HPLC-UV sample introduction analyses respectively when letting cool 0,1,2,4,6,8h, with determinand peak area The stability of derivative is investigated in change.As shown in Table 1, when derivatization product room temperature is placed, the RSD of peak area is small in 0~8h In 4.1%, that is, have good stability.
The methodology result of the test of table 1
X- testing concentrations (μ g/mL), y- peak areas, the coefficient correlation of r- regression equations.
7.6. average recovery
In order to evaluate the accuracy of this method, average recovery of each methanesulfonates in methanesulfonic acid is calculated respectively.
Reference substance solution：The methanesulfonates of various concentrations (0.03,0.05,0.5,5 μ g/mL) is prepared by 7.2 lower methods Reference substance solution, it is not added with methanesulfonic acid background, each 3 parts of concentration level.Above-mentioned 80 DEG C of heating water bath 1h of solution, taking-up are let cool to room Temperature, after filtering, take 20 μ L injection HPLC-UV sample introduction analyses.
Rate of recovery sample solution：12 parts of methanesulfonic acids about 250mg is taken, it is accurately weighed, it is respectively placed in 5mL measuring bottles, then essence The close methanesulfonates mixing stock solution for pipetting 100 μ L various concentrations is configured to concentration containing methanesulfonates as 0.03,0.05,0.5,5 μ g/mL four groups of rate of recovery sample solutions, every group of three parts of sample；Every part of sample adds 200 μ L water：Acetonitrile mixed solution (50: 50, v/v) dissolving and 500 μ L DDTC derivatization test solutions, it is 7.0 with sodium hydroxide solution regulation pH value, adds N, N- dimethyl second Acid amides is diluted to scale, vortex 10s, shakes up.Above-mentioned 80 DEG C of heating water bath 1h of solution, taking-up are let cool to room temperature, after filtering, take 20 μ L injection HPLC-UV sample introduction analyses.
Blank sample solution：Methanesulfonic acid about 250mg is weighed, it is accurately weighed, it is respectively placed in 5mL measuring bottles, adds 200 μ L Water：Acetonitrile mixed solution (50:50, v/v) dissolving and 500 μ L DDTC derivatization test solutions, pH value is adjusted with sodium hydroxide solution For 7.0, add DMA to be diluted to scale, vortex 10s, shake up.80 DEG C of heating water bath 1h, taking-up are let cool to room Temperature, after filtering, take 20 μ L injection HPLC-UV sample introduction analyses.
Average recovery=(rate of recovery sample solution peak area-blank sample solution peak area)/reference substance solution peak face Product × 100%.
As shown in Table 2, the average recovery of methyl mesylate and ethyl methane sulfonate is between 88.73~103.8%, and RSD is respectively less than 5.0%.
The average recovery result of the test of table 2
Embodiment 8
Precision pipettes 100 μ L 5 μ g/mL methanesulfonates mixing stock solutions, is placed in 5ml measuring bottles, add 200 μ L water and 500 μ L DDTC derivatization test solutions, add DMA to be diluted to scale, vortex 10s, shake up.80 DEG C of heating water baths 1h, taking-up are let cool to room temperature, after filtering, take 20 μ L injection HPLC-UV sample introduction analyses.
Methanesulfonic acid about 250mg is weighed, it is accurately weighed, it is respectively placed in 5mL measuring bottles, adds 200 μ L water：Acetonitrile mixed solution (50:50, v/v) dissolving and 500 μ L DDTC derivatization test solutions, it is 7.0 with sodium hydroxide solution regulation pH value, adds N, N- bis- Methylacetamide is diluted to scale, vortex 10s, shakes up.80 DEG C of heating water bath 1h, taking-up are let cool to room temperature, after filtering, take 20 μ L Inject the analysis of HPLC-UV sample introductions.
By external standard method containing according to methyl mesylate in the calculated by peak area methanesulfonic acid of derivatization product and ethyl methane sulfonate Measure (μ g/g), determine the methanesulfonic acid sample of three batches of separate sources altogether, as a result as shown in table 3.
Measurement result of the inventive method of table 3 in three batches of methanesulfonic acid samples
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Claims (10)

  1. A kind of 1. method of derivatization HPLC-UV methods measure methanesulfonates, it is characterised in that this method uses dithiocarbamates first Barbiturates derivatization reagent generates to methanesulfonates derivatization has the derivatization absorbed more by force to produce in ultraviolet region 272-284nm Thing, the derivatization product of methanesulfonates is determined in ultraviolet region 272-284nm using HPLC reversed phase partition chromatographies, so as to realize Qualitative or quantitative detection to methanesulfonates.
  2. 2. the method for derivatization HPLC-UV methods measure methanesulfonates according to claim 1, it is characterised in that comprising following Step：
    (1) reaction system pH to 7-8, is adjusted with sodium hydroxide, under the conditions of 80-100 DEG C, uses dithiocarbamates Derivatization reagent generates the product for having stronger absorption in ultraviolet region 272-284nm to methanesulfonates derivative reaction；
    (2), using HPLC-UV methods, based on reversed phase partition chromatography principle in ultraviolet region 272-284nm determination steps (1) The methanesulfonates derivatization product of acquisition, so as to realize the qualitative or quantitative detection to methanesulfonates.
  3. 3. the method for derivatization HPLC-UV methods measure methanesulfonates according to claim 2, it is characterised in that described first Sulphonic acid ester is alkyl-substituted methanesulfonates, preferably any one in methyl mesylate and ethyl methane sulfonate；Described two Thiocarbamate class derivatization reagent is sodium diethyldithiocarbamate, dibenzyl aminodithioformic acid sodium and second Any one in base potassium xanthate；Described reaction system is DMAC N,N' dimethyl acetamide or dimethyl sulfoxide.
  4. 4. the method for derivatization HPLC-UV methods measure methanesulfonates according to claim 2, it is characterised in that described spreads out The condition of biochemical reaction：Using DMA as reaction system, using sodium diethyldithiocarbamate as derivatization Reagent, reaction system pH to 7 is adjusted with sodium hydroxide, reaction is performed the derivatization under the conditions of 80 DEG C；Wherein, diethyl-dithio Carbamic acid na concn is 0.2-2mg/mL, preferably 0.2mg/mL, reaction time 1-5h, preferably 1h.
  5. 5. the method for derivatization HPLC-UV methods measure methanesulfonates according to claim 2, it is characterised in that step (2) Described in HPLC-UV methods：Using HPLC chromatogram instrument；Using reversed phase partition chromatography；With non-polar linkage mutually for stationary phase, adopt With polarity mobile phase, Detection wavelength is located at 272-284nm, is preferably 275-277nm, more preferably 277nm；
    The instrument that described HPLC-UV methods use is Shimadzu LC 20AT liquid chromatographs, and the chromatograph is configured with online Vacuum degassing machine, binary gradient pump, automatic sampler, column oven, DAD detectors and LC-solution chromatographic work stations；Chromatogram Post uses 250mm × 4.6mm, 5 μm of GL Sciences IntertSustain C18 posts；Sample size：20μL；Mobile phase stream Speed：1.0mL/min；Eluent gradient：A phases are acetonitrile, and B phases are 5mmol/L ammonium acetates, 0min 60%A phases, 16min 60%A Phase, 21min 80%A phases, 26min 80%A phases, 27min 60%A phases, 34min 60%A phases；Column temperature：30℃；Detect ripple It is long：277nm.
  6. 6. application of the method in methanesulfonates in determining methanesulfonic acid any one of claim 1-5.
  7. 7. a kind of method of methanesulfonates in derivatization HPLC-UV methods measure methanesulfonic acid, it is characterised in that comprise the steps of：
    (1) methanesulfonic acid sample, water, are taken：Added after acetonitrile mixed solution dissolving in reaction system, reactant is adjusted with sodium hydroxide It is pH to 7-8, under the conditions of 80 DEG C -100 DEG C, reaction 1- is performed the derivatization using dithiocarbamates derivatization reagent 5h obtains reaction solution；
    (2) reaction solution after, being terminated using the reaction of step (1) derivedization is as sample introduction sample, using HPLC-UV methods in 272- The derivatization product of 284nm measure wherein methanesulfonates, so as to realize the qualitative or quantitative detection to methanesulfonates in methanesulfonic acid.
  8. 8. the method for methanesulfonates in derivatization HPLC-UV methods measure methanesulfonic acid according to claim 7, it is characterised in that Described methanesulfonates is alkyl-substituted methanesulfonates, preferably any one in methyl mesylate and ethyl methane sulfonate； Described dithiocarbamates derivatization reagent is sodium diethyldithiocarbamate, dibenzyl dithio amino first Any one in sour sodium and ehtyl potassium xanthate；Described reaction system is DMAC N,N' dimethyl acetamide or dimethyl sulfoxide.
  9. 9. the method for methanesulfonates, its feature in the derivatization HPLC-UV methods measure methanesulfonic acid according to claim 7 or 8 It is the condition of described derivative reaction：Using DMA as reaction system, with diethyl-dithio amino first Sour sodium is derivatization reagent, adjusts reaction system pH to 7 with sodium hydroxide, reaction is performed the derivatization under the conditions of 80 DEG C；Wherein, Sodium diethyldithiocarbamate concentration is 0.2mg/mL, reaction time 1h.
  10. 10. the method for methanesulfonates, its feature exist in derivatization HPLC-UV methods measure methanesulfonic acid according to claim 7 HPLC-UV methods described in step (2) use HPLC chromatogram instrument；Using reversed phase partition chromatography；It is mutually with non-polar linkage Stationary phase, using polarity mobile phase, Detection wavelength is located at 272-284nm, preferably 275-277nm, is more preferably 277nm；
    The instrument that described HPLC-UV methods use is Shimadzu LC 20AT liquid chromatographs, and the chromatograph is configured with online Vacuum degassing machine, binary gradient pump, automatic sampler, column oven, DAD detectors and LC-solution chromatographic work stations；Chromatogram Post uses 250mm × 4.6mm, 5 μm of GL Sciences IntertSustain C18 posts；Sample size：20μL；Mobile phase stream Speed：1.0mL/min；Eluent gradient：A phases are acetonitrile, and B phases are 5mmol/L ammonium acetates, 0min 60%A phases, 16min 60%A Phase, 21min 80%A phases, 26min 80%A phases, 27min 60%A phases, 34min 60%A phases；Column temperature：30℃；Detect ripple It is long：277nm.
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