CN113075343B - Hydroxylamine and detection method of hydroxylamine salt - Google Patents
Hydroxylamine and detection method of hydroxylamine salt Download PDFInfo
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- 238000001514 detection method Methods 0.000 title claims abstract description 32
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 150000002443 hydroxylamines Chemical class 0.000 title abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 239000007788 liquid Substances 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 89
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 72
- 238000000034 method Methods 0.000 claims description 57
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 24
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 12
- 238000010828 elution Methods 0.000 claims description 12
- 235000019253 formic acid Nutrition 0.000 claims description 12
- 238000002347 injection Methods 0.000 claims description 11
- 239000007924 injection Substances 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 9
- 150000002500 ions Chemical class 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 238000011068 loading method Methods 0.000 claims description 6
- 239000003643 water by type Substances 0.000 claims description 5
- 238000004949 mass spectrometry Methods 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000000889 atomisation Methods 0.000 claims description 3
- 238000001360 collision-induced dissociation Methods 0.000 claims description 3
- 238000001819 mass spectrum Methods 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 230000005526 G1 to G0 transition Effects 0.000 claims description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 230000035945 sensitivity Effects 0.000 abstract description 12
- 238000001212 derivatisation Methods 0.000 abstract description 11
- 238000006243 chemical reaction Methods 0.000 abstract description 3
- 239000000523 sample Substances 0.000 description 66
- 238000002360 preparation method Methods 0.000 description 40
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 38
- 239000012490 blank solution Substances 0.000 description 25
- 239000003153 chemical reaction reagent Substances 0.000 description 21
- 239000012071 phase Substances 0.000 description 19
- 239000000047 product Substances 0.000 description 19
- 239000013558 reference substance Substances 0.000 description 17
- 238000005303 weighing Methods 0.000 description 17
- 239000011550 stock solution Substances 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 239000012086 standard solution Substances 0.000 description 14
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 9
- 238000007865 diluting Methods 0.000 description 9
- 239000012085 test solution Substances 0.000 description 7
- 238000011084 recovery Methods 0.000 description 6
- 229910021642 ultra pure water Inorganic materials 0.000 description 6
- 239000012498 ultrapure water Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000012488 sample solution Substances 0.000 description 5
- BXUJVINGXQGNFD-UHFFFAOYSA-N 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethanamine Chemical compound CCOC1=CC(C(N)CS(C)(=O)=O)=CC=C1OC BXUJVINGXQGNFD-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 238000001209 resonance light scattering Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 229960004099 azithromycin Drugs 0.000 description 3
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012088 reference solution Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 2
- 229960005101 febuxostat Drugs 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000009210 therapy by ultrasound Methods 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- 125000000923 (C1-C30) alkyl group Chemical group 0.000 description 1
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 description 1
- OCNWYKFGWLGNHZ-UHFFFAOYSA-N 1-butylpiperidin-4-one Chemical compound CCCCN1CCC(=O)CC1 OCNWYKFGWLGNHZ-UHFFFAOYSA-N 0.000 description 1
- BDVKAMAALQXGLM-UHFFFAOYSA-N 1-ethylpiperidin-4-one Chemical compound CCN1CCC(=O)CC1 BDVKAMAALQXGLM-UHFFFAOYSA-N 0.000 description 1
- VPGLFNOKHAIGEC-UHFFFAOYSA-N 1-phenylpiperidin-4-one Chemical compound C1CC(=O)CCN1C1=CC=CC=C1 VPGLFNOKHAIGEC-UHFFFAOYSA-N 0.000 description 1
- YGDZKYYCJUNORF-UHFFFAOYSA-N 1-propylpiperidin-4-one Chemical compound CCCN1CCC(=O)CC1 YGDZKYYCJUNORF-UHFFFAOYSA-N 0.000 description 1
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 239000005916 Methomyl Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007674 genetic toxicity Effects 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- UHXUZOCRWCRNSJ-QPJJXVBHSA-N methomyl Chemical compound CNC(=O)O\N=C(/C)SC UHXUZOCRWCRNSJ-QPJJXVBHSA-N 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000005429 oxyalkyl group Chemical group 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- 229960005224 roxithromycin Drugs 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
Abstract
The invention belongs to the field of analytical chemistry, and particularly relates to a detection method of hydroxylamine and a salt thereof. In the presence of alkali, hydroxylamine or a salt thereof in a sample to be detected reacts with the compound of the formula (C) in a reaction solvent to generate the compound of the formula (D), the derivatization reaction is completed rapidly, and the compound of the formula (D) is detected by a liquid chromatograph-mass spectrometer, so that the content of the hydroxylamine or the salt thereof is calculated. The detection method provided by the invention is efficient, convenient, high in sensitivity, good in specificity and high in accuracy, and is particularly suitable for detecting samples with low limitation of hydroxylamine or hydroxylamine salt.
Description
Technical Field
The invention relates to the field of analytical chemistry, in particular to a detection method of hydroxylamine and salts thereof.
Background
Hydroxylamine hydrochloride is mainly used as a reducing agent and an imaging agent, is used for preparing oxime in organic synthesis, and is also used as a raw material for synthesizing anticancer drugs (hydroxyurea), sulfa drugs (neonolamine) and pesticides (methomyl). In recent years for the synthesis of antibiotics such as: azithromycin, clarithromycin, roxithromycin and other medicines.
Hydroxylamine and its salt have strong genetic toxicity and genetic mutation effect, and detecting its residue in medicine and controlling its limit is one important aspect of ensuring medicine safety and effectiveness and medicine quality. Regarding the detection of hydroxylamine, the current methods are: resonance light scattering, gas chromatography, liquid chromatography, ion chromatography, and the like.
The resonance light scattering method is a constant spectrum analysis method, and can not meet the detection requirement for trace substances. The method for detecting hydroxylamine hydrochloride by using a resonance light scattering method is disclosed in the Yingming Hua publication, "resonance light scattering method for measuring hydroxylamine hydrochloride", wherein the detection limit is 0.04 mug/ml, and the sensitivity of the sample with a very low limit cannot meet the requirement, so that the method is only suitable for analyzing the sample with a higher limit.
Ding Hongwei A method for detecting hydroxylamine hydrochloride by gas chromatography is disclosed in the publication of pre-column derivatization-GC method determination of hydroxylamine hydrochloride in risperidone, but the detection limit of the method is 1.85 mug/ml, the quantitative limit is 3.70 mug/ml, the sensitivity of the sample with low limit can not meet the requirement, and the method is only suitable for analysis of the sample with high limit.
Zhao Tan, mao Yana et al, high performance liquid chromatography for measuring the content of hydroxylamine nitrate solution, disclose a method for detecting hydroxylamine nitrate by liquid chromatography with a detection limit of 82.78ng/g (i.e. about 0.08 μg/ml), which is not suitable for analysis of samples with very low limits, but only for samples with high limits.
Pan Sai, shi Chaoou et al disclose a method for detecting hydroxylamine hydrochloride by ion chromatography in which the detection limit is 0.012 mug/ml, the tolerance of ion chromatography (amperometric detector) to sample matrix and organic matters is weak, the requirement on the injected solution is high, the pretreatment of the sample is complicated, the method is suitable for a system containing only a small amount of organic matters in the solution, and the detection requirement on the sample is high.
Because hydroxylamine and its salts have strong genotoxicity and mutagenic effect, the content of hydroxylamine and its salts in the medicine needs to be strictly controlled below a limit level. For medicines with large daily dose, the control limit of hydroxylamine and its salt is low, and when the prior art is difficult to quantitatively detect the sample with low limit of hydroxylamine and its salt, a convenient, simple and high-sensitivity detection method of hydroxylamine, its salt and hydroxylamine derivatives is needed.
Disclosure of Invention
The invention provides a method for detecting hydroxylamine and salts thereof, which comprises the following steps:
in the presence of alkali, hydroxylamine or a salt thereof in a sample to be tested reacts with a compound of formula (C) in a reaction solvent to generate a compound of formula (D); then a chromatographic column taking octadecylsilane chemically bonded phase as a stationary phase is adopted, the mobile phase consists of a mobile phase A and a mobile phase B, wherein an aqueous solution containing volatile acid is taken as the mobile phase A, and an organic solvent is taken as the mobile phase B; gradient elution is carried out in a liquid chromatograph-mass spectrometer system, and a spectrogram is recorded;
wherein R is selected from the group consisting of substituted or unsubstituted C1-C30 alkyl, substituted or unsubstituted C1-C30 oxyalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C6-C14 aryl, and substituted or unsubstituted C1-C9 heteroaryl.
In some embodiments, the compound of formula (C) is N-phenyl-4-piperidone.
In some embodiments, the compound of formula (C) is N-benzyl-4-piperidone.
In some embodiments, the compound of formula (C) is N-ethyl-4-piperidone.
In some embodiments, the compound of formula (C) is N-propyl-4-piperidone.
In some embodiments, the compound of formula (C) is N-butyl-4-piperidone.
In some embodiments, the base is an aqueous ammonia solution.
In some embodiments, the reaction solvent is at least one of methanol, ethanol, dichloromethane, acetonitrile, tetrahydrofuran, acetone, isopropanol.
In some embodiments, the chromatographic column is 2.1 x 150mm,3.5 μm.
In some embodiments, the chromatographic column is a Waters XBridge TM C18，2.1*150mm，3.5μm。
In some embodiments, the volatile acid is formic acid.
In some embodiments, the volatile acid is trifluoroacetic acid.
In some embodiments, the volatile acids are formic acid and trifluoroacetic acid.
In some embodiments, the volatile acid is present in an amount of 0.05% to 0.2% by volume.
In some embodiments, the volatile acid is present in an amount of 0.1% by volume.
In some embodiments, the mobile phase has a flow rate of 0.1ml/min to 0.5ml/min.
In some embodiments, the mobile phase has a flow rate of 0.2ml/min to 0.4ml/min.
In some embodiments, the mobile phase has a flow rate of 0.3ml/min.
In some embodiments, the elution procedure for the gradient elution is as follows:
in some embodiments, the detection conditions for the compound of formula (D) are:
chromatographic column: waters XBiridge TM C18，2.1*150mm，3.5μm；
Mobile phase a:0.1% formic acid in water;
mobile phase B: acetonitrile;
elution mode: gradient elution;
mobile phase ratio:
flow rate: 0.3mL/min;
column temperature: not controlled;
sample tray temperature: not controlled;
sample injection amount: 1 mu L-10 mu L;
a detector: a mass spectrum detector;
mass spectrometry conditions: electrospray ion source, positive ion detection, SIM mode, and number of extracted ions as derivative product [ M+H ]] + Peak, m/z=205.0, run time 5.00min-11.00min; the temperature of the drying gas is 300-400 ℃; the flow rate of the drying gas is 10L/min-15L/min; the atomization gas pressure is 1500Torr-2320Torr; the capillary voltage is 2500V-3500V; peak width is 0.1min; gain factor 1.0; collision induced dissociation 70V.
In some embodiments, the sample loading is 2 μl to 8 μl.
In some embodiments, the sample loading is 3 μl to 5 μl.
In some embodiments, the sample loading is 4 μl.
In some embodiments, the drying gas temperature is 350 ℃.
In some embodiments, the drying gas flow rate is 12.0L/min.
In some embodiments, the atomizing gas pressure is 1811Torr.
In some embodiments, the capillary voltage is 3000V.
Compared with the prior art, the invention has the advantages that: the method has high sensitivity, good specificity and high accuracy, and is particularly suitable for detecting samples with low limitation of hydroxylamine or the salt thereof.
Description of the terminology:
in the invention, mg represents milligrams, g represents grams,% represents percentages, mm represents millimeters, pH represents pH, min represents minutes, h represents hours, DEG C represents degrees Celsius, HPLC represents high performance liquid chromatography, MS represents mass spectrometry, torr represents pressure unit "Torr", V represents voltage unit "volts", mu L represents microliters, mu g represents micrograms, ppm represents million%, S/N represents signal to noise ratio, EP tube is a microcentrifuge tube, RSD represents relative standard deviation, N/A represents no data, MΩ represents megaohms; APSTB03 represents 1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine, which has the CAS number: 253168-94-4.
In the description of the present invention, it should be understood that the terms "first," "second," and the like are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. In the description of the present invention, the meaning of "a plurality" is two or more, unless explicitly defined otherwise. In the description of the present specification, the descriptions of the terms "some implementations," "some embodiments," "examples," "particular examples," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
Detailed Description
The embodiment of the invention discloses a method for separating and detecting hydroxylamine and salts thereof. Those skilled in the art can, with the benefit of this disclosure, suitably modify the implementation of the process parameters. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included in the present invention. While the method of the present invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that variations and modifications can be made in the method described herein without departing from the spirit and scope of the invention.
The present invention will be described in detail with reference to examples.
Example 1 apparatus, reagents, controls, derivatization reagents and derivatization reactions
Instrument: a liquid chromatograph-mass spectrometer, an analytical balance of one ten thousandth.
Reagent: methanol.
Control: hydroxylamine hydrochloride has a structural formula shown as a compound of a formula E.
Derivatization agent: the structural formula of the N-benzyl-4-piperidone is shown as a compound of a formula F.
Derivatization reaction:
example 2 Process parameters
Chromatographic conditions:
chromatographic column: waters XBiridge TM C18，2.1*150mm，3.5μm；
Mobile phase a:0.1% formic acid aqueous solution (1 mL formic acid is added into 1000mL ultrapure water, and shaking, ultrasonic treatment for 10min and degassing are carried out to obtain the product);
mobile phase B: acetonitrile;
elution mode: gradient elution;
mobile phase ratio:
flow rate: 0.3mL/min; column temperature: not controlled; sample tray temperature: not controlled; sample injection amount: 1 μl; a detector: a mass spectrum detector;
mass spectrometry conditions: electrospray ion source (ESI source), positive ion detection, SIM mode, and number of extracted ions as derivative product [ M+H ]] + Peak, m/z=205.0, run time 5.00min-11.00min, drying gas temperature 350 ℃, drying gas flow rate 12.0L/min, atomizing gas pressure 1811Torr, capillary voltage 3000V (+), peak width 0.1min, gain factor 1.0, collision induced dissociation 70V.
EXAMPLE 3 verification of hydroxylamine residual method in Azithromycin
1.1 instruments, reagents, controls and test articles
Instrument: an analytical balance of ten parts per million, a high performance liquid chromatography-mass spectrometry coupling instrument;
reagent: acetonitrile (HPLC grade), methanol (HPLC grade), formic acid (HPLC grade), aqueous ammonia solution (HPLC grade), N-benzyl-4-piperidone (AR grade), ultrapure water (resistivity. Gtoreq.18.2 mΩ);
control: hydroxylamine hydrochloride;
test article: azithromycin.
1.2 preparation of solutions
Blank solution: taking about 100mg of N-benzyl-4-piperidone, precisely weighing, transferring into a 100mL volumetric flask, transferring 20mL of ammonia water solution into the volumetric flask, dissolving with methanol, fixing the volume, and shaking uniformly;
control stock solution 1: taking about 26mg of hydroxylamine hydrochloride, precisely weighing, dissolving in 50mL volumetric flask, fixing volume with methanol, and shaking; transferring 1.0mL of the solution into a 100mL volumetric flask, diluting with methanol to constant volume, and shaking uniformly;
control solution: taking about 100mg of N-benzyl-4-piperidone, precisely weighing, transferring 20mL of ammonia water solution into a volumetric flask of 100mL, transferring 1.0mL of reference substance stock solution 1 into the volumetric flask, diluting with methanol to constant volume, and shaking uniformly;
sensitivity solution: transferring 3.0mL of the reference substance solution into a 10mL volumetric flask, fixing the volume by using a blank solution, and shaking uniformly;
test solution: taking about 25mg of a sample to be tested, precisely weighing, putting the sample into a 5mL volumetric flask, diluting the sample with a blank solution to a certain volume, and shaking the sample uniformly; 2 parts were prepared in parallel.
1.3 System applicability
1.3.1 preparation of solution:
blank solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 3;
control solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 3;
sensitivity solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 3;
1.3.2 operation
After the system is balanced, taking the chromatographic conditions described by the method for each solution, feeding a blank solution into 1 needle, feeding a sensitivity solution into 2 needles, feeding a reference solution into 3 needles, and recording a chromatogram. Reporting the signal to noise ratio (S/N) of hydroxylamine derivative product in the sensitivity solution; the separation degree of the hydroxylamine derivative product peak and the nearest neighbor peak in the first needle of the control solution, and the peak area, the peak area average value and the RSD value of the hydroxylamine derivative product of 3 needles of continuous injection are adopted.
1.3.3 results
TABLE 1 System applicability results
1.4 specificity
1.4.1 preparation of solution:
blank solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 3;
control solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 3;
test solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 3;
adding a standard solution to a test sample: taking about 25mg of a sample to be tested, precisely weighing the sample into a 5mL volumetric flask, dissolving the sample in a reference substance solution, and fixing the volume; preparing 3 parts in parallel;
1.4.2 operation
Taking chromatographic conditions described by the method for each solution on the premise of qualified system applicability, and recording a chromatogram after each 1 needle. Reporting retention time, peak area and separation degree of hydroxylamine derivative products in blank solution, reference solution, test sample addition solution and adjacent peaks; the individual recovery rates of the test sample addition solutions were calculated according to the following formulas, and the recovery rate average value and RSD value thereof were calculated.
Wherein:
C S adding the hydroxylamine hydrochloride reference substance solution into the sample to be tested to obtain the concentration of the hydroxylamine hydrochloride reference substance solution, and μg/mL;
v is the volume of hydroxylamine hydrochloride reference substance solution added into the sample adding standard solution, and mL;
C S+T adding the hydroxylamine hydrochloride residual quantity measured in the standard solution to the test sample;
C i residual hydroxylamine hydrochloride measured in the sample solution;
is the average value of the residual quantity of hydroxylamine hydrochloride measured in the test solution;
A i peak area of hydroxylamine derivative product in the sample solution;
A S is the average value of peak areas of hydroxylamine derivative products in 3 reference substance solutions;
A S+T adding the peak area of hydroxylamine derivative product in the standard solution to the test sample;
W T the sample is the sample weighing amount of the sample in the sample solution, mg;
W S weighing the hydroxylamine hydrochloride in the reference substance solution to obtain mg;
W S+T adding a sample weighing amount of the sample in the standard solution to the sample, wherein the sample weighing amount is mg;
D T is the dilution multiple of the sample solution;
D S is the dilution multiple of the reference substance solution;
D S+T and adding dilution factors of the test sample into the standard solution for the test sample.
1.4.3 results
TABLE 2 specific results
TABLE 3 recovery results
1.5 detection limit
1.5.1 preparation of solutions
Blank solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 3;
detection limit solution: transferring 1.0mL of the reference substance solution into a 250mL volumetric flask, fixing the volume by using a blank solution, and shaking uniformly; 1 part of the composition is prepared;
quantitative limiting solution: transferring 1.0mL of the reference substance solution into a 200mL volumetric flask, fixing the volume by using a blank solution, and shaking uniformly; 1 part was prepared.
1.5.2 operation
And taking 1 needle of blank solution sample injection under the premise of qualified system applicability, detecting 3 needles of limited and quantitative solution continuous sample injection, and recording a chromatogram. Peak area, signal to noise ratio (S/N) of hydroxylamine derived products are reported.
1.5.3 results
TABLE 4 limit of detection results
TABLE 5 quantitative limit results
1.6 durability-solution stability
1.6.1 preparation of solution:
control solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 3;
sensitivity solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 3;
adding a standard solution to a test sample: the preparation method was the same as in example 3 item 1.4.1, and 1 part was prepared.
1.6.2 operation
And placing the prepared reference substance solution, sensitivity solution and 100% sample adding standard solution in a sample tray, and placing at room temperature. According to the chromatographic conditions described by the method, the reference substance solution is injected into 1 needle at 0h, 4h and 11h respectively; feeding 1 needle into each of the sensitivity solution at 0h, 5h and 11 h; the sample is added with the standard solution and 1 needle is injected in 0h, 3h and 9h respectively. The peak area ratio of hydroxylamine derived product to 0h peak area was calculated at each time point.
1.6.3 results
TABLE 6 solution stability results
Example 4 verification of hydroxylamine residual method in febuxostat
1.1 instruments, reagents, controls and test articles
Instrument: an analytical balance of ten parts per million, a high performance liquid chromatography-mass spectrometry coupling instrument;
reagent: acetonitrile (HPLC grade), methanol (HPLC grade), formic acid (HPLC grade), aqueous ammonia solution (HPLC grade, purity 25% -28%), N-benzyl-4-piperidone (AR grade), ultrapure water (homemade);
control: hydroxylamine hydrochloride;
test article: febuxostat.
1.2 preparation of solutions
Derivatizing reagent: taking about 189mg of N-benzyl-4-piperidone, precisely weighing, transferring into a 100mL volumetric flask, transferring 4.0mL of ammonia water solution into the volumetric flask, dissolving with methanol, fixing the volume, and shaking uniformly;
blank solution: transferring 1.0mL of methanol into an EP tube, transferring 1.0mL of derivatization reagent into the EP tube, capping, shaking uniformly, and standing for 10min;
control stock solution 1: taking about 65mg of hydroxylamine hydrochloride, precisely weighing, dissolving in 50mL volumetric flask, fixing volume with methanol, and shaking; transferring 1.0mL of the solution into a 50mL volumetric flask, diluting with methanol to constant volume, and shaking uniformly;
control stock solution 2: transferring 1.0mL of control stock solution into a volumetric flask with 1to 100mL, diluting with methanol to constant volume, and shaking;
control solution: transferring 1.0mL of control stock solution 2 into an EP tube, transferring 1.0mL of derivative reagent into the EP tube, capping, shaking uniformly, and standing for 10min;
sensitivity solution: transferring 3.0mL of control stock solution into a volumetric flask with volume of 2 to 10mL, and shaking uniformly with methanol to fix the volume; transferring 1.0mL of the solution into an EP tube, transferring 1.0mL of the derivatization reagent into the EP tube, capping, shaking uniformly, and standing for 10min;
test solution: taking about 25mg of a sample to be tested, precisely weighing, putting the sample into a 5mL volumetric flask, diluting the sample with methanol to a certain volume, and shaking the sample uniformly; transferring 1.0mL of the solution into an EP tube, transferring 1.0mL of the derivatization reagent into the EP tube, capping, shaking uniformly, and standing for 10min; 2 parts were prepared in parallel.
Mobile phase a: transferring 1.0mL of formic acid into 1.0L of ultrapure water, covering, shaking, and performing ultrasonic treatment for 10min to obtain the final product;
mobile phase B: acetonitrile.
1.3 System applicability
1.3.1 preparation of solution:
blank solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 4;
control solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 4;
detection limit solution: the preparation method was the same as 1.2 in example 4, and 1 part was prepared.
1.3.2 operation
After the system is balanced, taking the chromatographic conditions described by the method for each solution, feeding a blank solution into 1 needle, feeding a detection limit solution into 2 needles, feeding a reference solution into 3 needles, and recording a chromatogram. Reporting the signal to noise ratio (S/N) of the hydroxylamine derivative product in the detection limit solution; the separation degree of the hydroxylamine derivative product peak and the nearest neighbor peak in the first needle of the control solution, and the peak area, the peak area average value and the RSD value of the hydroxylamine derivative product of 3 needles of continuous injection are adopted.
1.3.3 results
TABLE 7 System applicability results
1.4 specificity
1.4.1 preparation of solution:
blank solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 4;
control solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 4;
test solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 4;
adding a standard solution to a test sample: taking about 25mg of a test sample, precisely weighing the test sample into a 5mL volumetric flask, and dissolving and fixing the volume by using a reference substance stock solution 2; transferring 1.0mL of the solution into an EP tube, transferring 1.0mL of the derivative reagent into the EP tube, shaking uniformly, capping, and standing for 10min to obtain the final product; preparing 3 parts in parallel;
1.4.2 operation
Same as in example 3, item 1.4.2.
1.4.3 results
TABLE 8 specificity results
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TABLE 9 recovery results
1.5 detection limit
1.5.1 preparation of solution:
blank solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 4;
detection limit solution: transferring 0.4mL of control stock solution into a volumetric flask with volume of 2 to 250mL, and shaking uniformly with a blank solution to fix the volume; 1 part of the composition is prepared;
1.5.2 operation
Taking 1 needle of blank solution sample injection under the premise of qualified system applicability, detecting 3 needles of limited solution continuous sample injection, and recording a chromatogram. The peak area, signal to noise ratio (S/N) of hydroxylamine derivative product in the detection limit solution is reported.
1.5.3 results
TABLE 10 limit of detection results
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1.5 durability-solution stability
1.6.1 preparation of solution:
control solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 4;
adding a standard solution to a test sample: the preparation method was the same as 1.4.1 in example 4, and 1 part was prepared.
1.6.2 operation
And placing the prepared reference substance solution and 100% of the sample adding standard solution in a sample tray, and placing the sample tray at room temperature. According to the chromatographic conditions described by the method, the reference substance solution is injected into 1 needle in 0h, 4h and 12h respectively; the sample is added with the standard solution and 1 needle is injected in 0h, 2h and 10h respectively. The peak area ratio of hydroxylamine derived product to 0h peak area was calculated at each time point.
1.6.3 results
TABLE 11 solution stability results
EXAMPLE 5 detection of hydroxylamine residue in Apostite intermediate APSTB03 (CAS number: 253168-94-4)
1.1 instruments, reagents, controls and test articles
Instrument: an analytical balance of ten parts per million, a high performance liquid chromatography-mass spectrometry coupling instrument;
reagent: acetonitrile (HPLC grade), methanol (HPLC grade), formic acid (HPLC grade), aqueous ammonia solution (HPLC grade, purity 25% -28%), N-benzyl-4-piperidone (AR grade), ultrapure water (homemade);
control: hydroxylamine hydrochloride;
test article: apremilast intermediate APSTB03.
1.2 preparation of solutions
Derivatizing reagent: taking about 189mg of N-benzyl-4-piperidone, precisely weighing, transferring into a 100mL volumetric flask, transferring 4.0mL of ammonia water solution into the volumetric flask, dissolving with methanol, fixing the volume, and shaking uniformly;
blank solution: transferring 1.0mL of methanol into an EP tube, transferring 1.0mL of derivatization reagent into the EP tube, capping, shaking uniformly, and standing for 10min;
control stock solution 1: taking about 65mg of hydroxylamine hydrochloride, precisely weighing, dissolving in 50mL volumetric flask, fixing volume with methanol, and shaking; transferring 1.0mL of the solution into a 50mL volumetric flask, diluting with methanol to constant volume, and shaking uniformly;
control stock solution 2: transferring 1.0mL of control stock solution into a volumetric flask with 1to 100mL, diluting with methanol to constant volume, and shaking;
control solution: transferring 1.0mL of control stock solution 2 into an EP tube, transferring 1.0mL of derivative reagent into the EP tube, capping, shaking uniformly, and standing for 10min;
detection limit solution: transferring 3.0mL of control stock solution into a volumetric flask with volume of 2 to 10mL, and shaking uniformly with methanol to fix the volume; transferring 1.0mL of the solution into an EP tube, transferring 1.0mL of the derivatization reagent into the EP tube, capping, shaking uniformly, and standing for 10min;
test solution: taking about 25mg of a sample to be tested, precisely weighing, putting the sample into a 5mL volumetric flask, diluting the sample with methanol to a certain volume, and shaking the sample uniformly; transferring 1.0mL of the solution into an EP tube, transferring 1.0mL of the derivatization reagent into the EP tube, capping, shaking uniformly, and standing for 10min; 2 parts were prepared in parallel.
Mobile phase: the water phase (1.0 mL of formic acid is removed to 1.0L of ultrapure water, covered tightly, shaken well and sonicated for 10min to obtain the aqueous phase); organic phase (acetonitrile).
1.3 System applicability
1.3.1 preparation of solution:
blank solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 5;
control solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 5;
detection limit solution: the preparation method is the same as 1.2 in example 5, and 1 part of the composition is prepared.
1.3.2 operation
Same as in example 3, item 1.4.2.
1.3.3 results
TABLE 12 System applicability results
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1.4 specificity
1.4.1 preparation of solution:
blank solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 5;
control solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 5;
test solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 5;
adding a standard solution to a test sample: taking about 25mg of a test sample, precisely weighing the test sample into a 5mL volumetric flask, and dissolving and fixing the volume by using a reference substance stock solution 2; transferring 1.0mL of the solution into an EP tube, transferring 1.0mL of the derivative reagent into the EP tube, shaking uniformly, capping, and standing for 10min to obtain the final product; 3 parts were prepared in parallel.
1.4.2 operation
Taking chromatographic conditions described by the method for each solution on the premise of qualified system applicability, and recording a chromatogram after each 1 needle. Report the retention time, peak area, and degree of separation from adjacent peaks of hydroxylamine derivative product in blank solution, control solution, test sample solution, and test sample addition solution.
1.4.3 results
TABLE 13 specificity results
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1.4.4 recovery calculation
The recovery rate is calculated to be 94.4% (between 70.0% and 130.0%) by the single-needle test sample.
1.5 detection limit
1.5.1 preparation of solution:
blank solution: 1 part of the preparation method is prepared by the same method as 1.2 in the example 5;
detection limit solution: transferring 0.4mL of control stock solution into a volumetric flask with volume of 2 to 250mL, and shaking uniformly with a blank solution to fix the volume; 1 part was prepared.
1.5.2 operation
Taking 1 needle of blank solution sample injection under the premise of qualified system applicability, detecting 3 needles of limited solution continuous sample injection, and recording a chromatogram. The peak area, signal to noise ratio (S/N) of hydroxylamine derivative product in the detection limit solution is reported.
1.5.3 results
TABLE 14 limit of detection results
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Claims (8)
1. A detection method of hydroxylamine and salt thereof is characterized in that hydroxylamine or salt thereof in a sample to be detected reacts with a compound of formula C in a reaction solvent in the presence of alkali to generate a compound of formula D; a chromatographic column taking octadecylsilane chemically bonded phase as a stationary phase is adopted, and a mobile phase consists of a mobile phase A and a mobile phase B, wherein an aqueous solution containing volatile acid is taken as the mobile phase A, and an organic solvent is taken as the mobile phase B; gradient elution is carried out in a liquid chromatograph-mass spectrometer system;
，
wherein R is selected from benzyl;
the alkali is ammonia water solution; the reaction solvent is methanol;
the chromatographic column is Waters XBridgeTM C, 2.1 x 150mm and 3.5 μm;
the volatile acid is selected from formic acid;
the organic solvent of the mobile phase B is acetonitrile;
the elution procedure for the gradient elution is shown in the following table:
。
2. the method of claim 1, wherein the mobile phase has a flow rate of 0.1ml/min to 0.5ml/min.
3. The method of claim 1, wherein the mobile phase has a flow rate of 0.2ml/min to 0.4ml/min.
4. The method of claim 1, wherein the mobile phase has a flow rate of 0.3ml/min.
5. The method according to any one of claims 1to 4, wherein the detection conditions of the method are:
chromatographic column: waters XBridgeTM C18,2.1 x 150mm,3.5 μm;
mobile phase a:0.1% formic acid in water;
mobile phase B: acetonitrile;
elution mode: gradient elution;
mobile phase ratio:
flow rate: 0.3mL/min;
sample injection amount: 1-10 mu L;
a detector: a mass spectrum detector;
mass spectrometry conditions: electrospray ion source, positive ion detection, SIM mode, the number of extracted ions is the derivative product [ M+H ] + peak, M/z=205.0, and the running time is 5.00min-11.00min; the temperature of the drying gas is 300-400 ℃; the flow rate of the drying air is 10L/min-15L/min; the atomization gas pressure is 1500 Torr~2320Torr; the capillary voltage is 2500-2500V; peak width is 0.1min; gain factor 1.0; collision induced dissociation 70V.
6. The method of claim 5, wherein the sample loading is: 2 mu L to 8 mu L.
7. The method of claim 5, wherein the sample loading is: 3 mu L to 5 mu L.
8. The method of claim 5, wherein the sample loading is: 4. Mu.L; the temperature of the drying gas is 350 ℃; the flow rate of the drying gas is 12.0L/min; the atomization gas pressure is 1811 Torr; the capillary voltage was 3000V.
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