CN108459107A - Utilize the remaining method of hydrazine hydrate in liquid chromatography and mass spectrometry drug - Google Patents
Utilize the remaining method of hydrazine hydrate in liquid chromatography and mass spectrometry drug Download PDFInfo
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- CN108459107A CN108459107A CN201810388112.7A CN201810388112A CN108459107A CN 108459107 A CN108459107 A CN 108459107A CN 201810388112 A CN201810388112 A CN 201810388112A CN 108459107 A CN108459107 A CN 108459107A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- 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
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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
- G01N30/04—Preparation or injection of sample to be analysed
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Abstract
The invention belongs to hydrazine hydrate residues detection technical fields, and in particular to and it is a kind of using the remaining method of hydrazine hydrate in liquid chromatography and mass spectrometry drug, have the advantages that measure quick, accurate, easy, sensitive.
Description
Technical field
The invention belongs to hydrazine hydrate residues detection technical fields, and in particular to a kind of to utilize liquid chromatography and mass spectrometry drug
The middle remaining method of hydrazine hydrate.
Background technology
Hydrazine hydrate is a kind of strong reductant, the extensive use in bulk pharmaceutical chemicals synthesis.Based on structure-toxicity Correlation Theory,
The caution structure library with genetoxic risk is compareed, identifies and determines that diazanyl is genetoxic caution structure, hydrazine hydrate, which has, to be lost
Pass risk of toxicity.The genetoxic risk of drug in order to control needs the residual quantity to hydrazine hydrate in drug to be detected.But it reflects
It is larger in the polarity of hydrazine hydrate, in general liquid phase Reversed-phase Chromatographic System without reserve；And diazanyl is without UV absorption, unavailable
UV detectors detect.So the residues detecton of hydrazine hydrate mainly uses derivatization method and the chromatography of ions (IC-ED) at present, together
When also have been reported that with hilic systems combination nitrogen chemical luminescence detector detect hydrazine hydrate, the pre-treatment of such method is comparatively laborious,
And have the shortcomings that analysis time is long, sensitivity is not high.
Therefore the present invention provides a kind of method measurement drug using LC-MS according to problems of the prior art
The method of middle hydrazine hydrate content has the advantages that measure quick, accurate, easy, sensitive.
Invention content
The present invention provides the following technical solutions：
It is a kind of using the remaining method of hydrazine hydrate in liquid chromatography and mass spectrometry drug, including：
S1：Instrument and solvent：
1. instrument：Liquid chromatography mass combined instrument and chromatographic work station；
2. solvent：For reagent product, hydrazine reference substance solution, acetonitrile, ammonium formate, formic acid and ultra-pure water；
S2：Configure solution：
1. 100 μ g/ml hydrazine stock solutions；
2. 10 μ g/ml hydrazine stock solutions；
3. 0.2 μ g/ml hydrazine stock solutions；
4. reference substance solution；
5. test solution；
S3：Chromatographic column and mass spectrographic preparation：
Chromatographic column uses hydrophilic reservation chromatographic column, the hydrophilic reservation chromatographic column：Packing material size is 1.7 μm, column length
100mm, diameter 2.1mm；Mobile phase is buffer solution：Acetonitrile=30:70,40 DEG C of column temperature；Sample size μ L, retention time 5min；
Mass spectrum column：ESI+, quota ion m/z=33.1.
Preferably, the configuration method of each solution is in the S2：
1. 100 μ g/ml hydrazine stock solutions：Precision pipettes in 1ml hydrazines to 10mL volumetric flasks, adds buffer solution-acetonitrile dissolving
Afterwards, it is settled to scale；
2. 10 μ g/ml hydrazine stock solutions：Precision pipettes 100 μ g/ml hydrazines stock solutions of 1mL to 10mL volumetric flasks, adds buffering
Liquid-dilution in acetonitrile is simultaneously settled to scale；
3. 0.2 μ g/ml hydrazine stock solutions：Precision pipettes 1mL hydrazines stock solution 2 and arrives 50mL volumetric flasks, adds buffer solution-acetonitrile
It dilutes and is settled to scale；
4. reference substance solution：Precision pipettes 1mL10 μ g/ml hydrazines stock solutions to 100mL volumetric flasks, with buffer solution-acetonitrile
It dilutes and is settled to scale；
5. test solution：Take KP0467 samples about 15mg (lot numbers：P05157-003-P1), accurately weighed, it is placed in
In 100ml volumetric flasks, scale is dissolved and is settled to buffer solution-acetonitrile, as test solution.
Preferably, acetonitrile is chromatographic grade acetonitrile in the S1；Ammonium formate is chromatographic grade ammonium formate, and the formic acid is chromatographic grade
Formic acid.
Preferably, mobile phase buffer solution is the mixed liquor of 0.1% formic acid/10mM formic acid aqueous ammoniums in the S3, is used
The mobile phase carries out isocratic elution to the hydrophilic reservation chromatographic column, and the flow velocity for controlling the mobile phase is 0.3ml/min.
The beneficial effects of the invention are as follows：
The present invention is applicable in Liquid Chromatography/Mass Spectrometry can be accurate, accurately determines whether the hydrazine hydrate in drug complies with standard,
And it is fairly simple for the sample pre-treatments of drug, it is easy to operate；In addition, the stabilization of the specificity and test result of the present invention
Stronger, the repeated multiple times measurement suitable for laboratory of property.
Description of the drawings
Attached drawing is used to provide further understanding of the present invention, and a part for constitution instruction, the reality with the present invention
It applies example to be used to explain the present invention together, not be construed as limiting the invention.In the accompanying drawings：
Fig. 1 is that the specificity in embodiment 2 measures spectrogram；
Fig. 2 is hydrazine canonical plotting obtained in embodiment 4；
Specific implementation mode
The specific implementation mode of the present invention is described below in conjunction with the accompanying drawings.
Embodiment 1
It is a kind of using the remaining method of hydrazine hydrate in liquid chromatography and mass spectrometry drug, including：
S1：Instrument and solvent：
1. instrument：Liquid chromatography mass combined instrument and chromatographic work station；
2. solvent：For reagent product, hydrazine reference substance solution, acetonitrile, ammonium formate, formic acid and ultra-pure water；
S2：Configure solution：
1. 100 μ g/ml hydrazine stock solutions；
2. 10 μ g/ml hydrazine stock solutions；
3. 0.2 μ g/ml hydrazine stock solutions；
4. reference substance solution；
5. test solution；
S3：Chromatographic column and mass spectrographic preparation：
Chromatographic column uses hydrophilic reservation chromatographic column, hydrophilic reservation chromatographic column：Packing material size is 1.7 μm, column length 100mm, directly
Diameter 2.1mm；Mobile phase is buffer solution：Acetonitrile=30:70,40 DEG C of column temperature；Sample size μ L, retention time 5min；
Mass spectrum column：ESI+, quota ion m/z=33.1.
Specifically, the configuration method of each solution is in S2：
1. 100 μ g/ml hydrazine stock solutions：Precision pipettes in 1ml hydrazines to 10mL volumetric flasks, adds buffer solution-acetonitrile dissolving
Afterwards, it is settled to scale；
2. 10 μ g/ml hydrazine stock solutions：Precision pipettes 100 μ g/ml hydrazines stock solutions of 1mL to 10mL volumetric flasks, adds buffering
Liquid-dilution in acetonitrile is simultaneously settled to scale；
3. 0.2 μ g/ml hydrazine stock solutions：Precision pipettes 1mL hydrazines stock solution 2 and arrives 50mL volumetric flasks, adds buffer solution-acetonitrile
It dilutes and is settled to scale；
4. reference substance solution：Precision pipettes 1mL10 μ g/ml hydrazines stock solutions to 100mL volumetric flasks, with buffer solution-acetonitrile
It dilutes and is settled to scale；
5. test solution：Take KP0467 samples about 15mg (lot numbers：P05157-003-P1), accurately weighed, it is placed in
In 100ml volumetric flasks, scale is dissolved and is settled to buffer solution-acetonitrile, as test solution.
Acetonitrile is chromatographic grade acetonitrile in S1；Ammonium formate is chromatographic grade ammonium formate, and formic acid is chromatographic grade formic acid.
Mobile phase buffer solution is the mixed liquor of 0.1% formic acid/10mM formic acid aqueous ammoniums in S3, uses flowing relative hydropathic
The flow velocity for retaining chromatographic column and carrying out isocratic elution, and control mobile phase is 0.3ml/min.
Embodiment 2
Specificity measures：Blank solvent, reference substance solution and test solution in Example 1 respectively, in embodiment 1
In testing conditions under carry out liquid chromatograph mass spectrography detection, the interference of determination sample and solvent to hydrazine.As a result such as Fig. 1
It is shown, there is the spectrogram in Fig. 1 to can be seen that blank solvent and sample are noiseless.
Embodiment 3
Quantitative limit detection limit measures：
Hydrazine reference substance solution is appropriate in Example 1, is diluted step by step with buffer solution-acetonitrile.Precision measures 10 μ L injections
Liquid chromatography mass combined instrument, is measured.
It measures detection and is limited to 0.002 μ g/ml (S/N >=3)；Quantitatively it is limited to 0.01 μ g/ml (S/N >=10).
Embodiment 4
Linear relationship measures：Precision pipettes in embodiment 1 in appropriate hydrazine storing solution to 10ml volumetric flasks, with blank solution
Simultaneously constant volume is diluted, 0.01 μ g/mL, 0.02 μ g/mL, 0.04 μ g/mL, 0.1 μ g/mL, 0.15 μ g/mL and 0.2 μ g/mL lines are configured to
Property solution, then respectively it is accurate measure 10 μ L0.01 μ g/mL, 0.02 μ g/mL, 0.04 μ g/mL, 0.1 μ g/mL, 0.15 μ g/mL and
0.2 μ g/mL linear solvents distinguish sample introduction, and record chromatogram is as shown in Figure 2.
Linear regression is carried out to peak area with hydrazine concentration.Linear relationship is shown in Table 1, Fig. 2, and the hydrazine known to table 1 and Fig. 2 exists
In the concentration range of 10~200ng/mL, linear relationship is good, and related coefficient is more than 0.999, meets and receives standard.
Table 1：The linear relationship of hydrazine
Embodiment 5
It is loaded recovery test
Precision weighs 11 parts of test sample in embodiment 1, and every part of 1.5mg is respectively placed in 10ml volumetric flasks, wherein two parts add
Enter the dissolving of buffer solution-acetonitrile and constant volume, as blank test solution, 3 groups of remaining nine parts of sample point, every group 3 parts, and point
0.05ml is not added, then 10 μ g/ml hydrazine storing solutions of 0.1ml, 0.15ml dissolve simultaneously constant volume respectively with buffer solution-acetonitrile,
As 50%, 100%, 150% rate of recovery solution.
Precision measures reference substance solution, test solution and each 10 μ L of rate of recovery solution, sequentially determining, and determination data is whole
Reason is recorded in table 2, and the rate of recovery of hydrazine meets acceptable mark between 80%~120% known to the data in table 2
It is accurate.
Rate of recovery calculation formula：
2 hydrazine of table is loaded recovery test result (n=9)
Embodiment 6
Sample introduction precision：Precision measures 10 μ L of reference substance solution in embodiment 1, injects liquid chromatography mass spectrometric coupled HPLC instrument, even
6 needle of continuous sample introduction, records hydrazine peak area, calculates RSD%.Measurement result is recorded in table 3, by table 3 the result shows that hydrazine
Peak area RSD be 2.6% (n=6) and the RSD of retention time is 0.3% (n=6), meet the requirements.
Repeatability：Parallel 6 parts of preparation limit concentration rate of recovery solution measures solution as precision, accurate respectively to measure
10 μ L, inject liquid chromatography mass spectrometric coupled HPLC instrument, and measurement result records in table 4.By time for showing the hydrazine peak of investigation in table 4
Yield RSD is 4.9%, is less than 20% (n=6), meets the requirements.
3 sample introduction Precision test result (n=6) of table
4 repetitive test result (n=6) of table
Embodiment 7
According to the fresh configuration reference substance solution of the method in embodiment 1, sample mark-on solution (100% rate of recovery solution),
Then respectively at 0h, 1h, 2h, 4h, 6h, 8h, 12h, 15h time points measure 10 μ l of above-mentioned solution, sample detection.Then it will count
In table 5 according to result record.The hydrazine solution prepared in the embodiment of the present invention 1 known to the data in table 5 and sample solution room
There is good stability of solution, and RSD is respectively less than 20%, meets and receives standard under the conditions of temperature in 15 hours.
5 stability of solution measurement result of table
Embodiment 8
Test sample 1.5mg is weighed according to the method precision in embodiment 1, is placed in 10mL volumetric flasks, buffer solution-second is added
Nitrile dissolves, and measures after constant volume, and the parallel double of test sample is parallel 1 and parallel 2, and containing for hydrazine hydrate in test sample is calculated by external standard method
Amount.
Precision measures above-mentioned 10 μ L of prepared test solution, is labeled as 3, is injected separately into liquid chromatography mass spectrometric coupled HPLC
Instrument records the data in chromatogram.Chromatographic peak of the chromatogram of test solution in addition to solvent peak is integrated, by external standard
Method calculates hydrazine hydrate residual quantity in test sample.Last result of calculation is recorded in table 6.
The determination of residual amount result of hydrazine hydrate in 10 drug A of table
Explanation：" ND " expression is not detected
It can be seen that hydrazine hydrate residual is not detected in three batches of samples by the data in table 6, be below limit 1000ppm and receive
Standard, therefore meet the requirements.
By embodiment 2- embodiments 7 it can be seen that the accuracy of the method provided by the invention for measuring hydrazine hydrate, sensitivity
It is stronger and fairly simple to the pre-treatment of sample with specificity, save operational time cost.
Note：Reagent source in the embodiment of the present invention 1 is：
Hydrazine reference substance solution is purchased from national non-ferrous metal and electronic material Institute of Analysis；
Acetonitrile (chromatographic grade, Merck)；
Ammonium formate (chromatographic grade, Aladdin)；
Formic acid (chromatographic grade, ACS), water are that ultra-pure water is made in laboratory by oneself.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, although with reference to aforementioned reality
Applying example, invention is explained in detail, for those skilled in the art, still can be to aforementioned each implementation
Technical solution recorded in example is modified or equivalent replacement of some of the technical features.All essences in the present invention
With within principle, any modification, equivalent replacement, improvement and so on should all be included in the protection scope of the present invention god.
Claims (4)
1. a kind of utilizing the remaining method of hydrazine hydrate in liquid chromatography and mass spectrometry drug, which is characterized in that including：
S1：Instrument and solvent：
1. instrument：Liquid chromatography mass combined instrument and chromatographic work station；
2. solvent：For reagent product, hydrazine reference substance solution, acetonitrile, ammonium formate, formic acid and ultra-pure water；
S2：Configure solution：
1. 100 μ g/ml hydrazine stock solutions；
2. 10 μ g/ml hydrazine stock solutions；
3. 0.2 μ g/ml hydrazine stock solutions；
4. reference substance solution；
5. test solution；
S3：Chromatographic column and mass spectrographic preparation：
Chromatographic column uses hydrophilic reservation chromatographic column, the hydrophilic reservation chromatographic column：Packing material size is 1.7 μm, column length 100mm, directly
Diameter 2.1mm；Mobile phase is buffer solution：Acetonitrile=30：70,40 DEG C of column temperature；Sample size μ L, retention time 5min；
Mass spectrum column：ESI+, quota ion m/z=33.1.
2. according to claim 1 utilize the remaining method of hydrazine hydrate in liquid chromatography and mass spectrometry drug, which is characterized in that
The configuration method of each solution is in the S2：
1. 100 μ g/ml hydrazine stock solutions：Precision pipettes in 1ml hydrazines to 10mL volumetric flasks, fixed after adding buffer solution-acetonitrile dissolving
Hold to scale；
2. 10 μ g/ml hydrazine stock solutions：Precision pipettes 100 μ g/ml hydrazines stock solutions of 1mL to 10mL volumetric flasks, adds buffer solution-
Dilution in acetonitrile is simultaneously settled to scale；
3. 0.2 μ g/ml hydrazine stock solutions：Precision pipettes 1mL hydrazines stock solution 2 and arrives 50mL volumetric flasks, adds buffer solution-dilution in acetonitrile
And it is settled to scale；
4. reference substance solution：Precision pipettes 1mL10 μ g/ml hydrazines stock solutions to 100mL volumetric flasks, with buffer solution-dilution in acetonitrile
And it is settled to scale；
5. test solution：Take KP0467 samples about 15mg (lot numbers：P05157-003-P1), accurately weighed, it is placed in 100ml appearances
In measuring bottle, scale is dissolved and is settled to buffer solution-acetonitrile, as test solution.
3. according to claim 1 utilize the remaining method of hydrazine hydrate in liquid chromatography and mass spectrometry drug, which is characterized in that
Acetonitrile is chromatographic grade acetonitrile in the S1；Ammonium formate is chromatographic grade ammonium formate, and the formic acid is chromatographic grade formic acid.
4. according to claim 1 utilize the remaining method of hydrazine hydrate in liquid chromatography and mass spectrometry drug, which is characterized in that
Mobile phase buffer solution is the mixed liquor of 0.1% formic acid/10mM formic acid aqueous ammoniums in the S3, using the mobile phase to described
Hydrophilic reservation chromatographic column carries out isocratic elution, and the flow velocity for controlling the mobile phase is 0.3ml/min.
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| CN201810388112.7A CN108459107A (en) | 2018-04-26 | 2018-04-26 | Utilize the remaining method of hydrazine hydrate in liquid chromatography and mass spectrometry drug |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109884203A (en) * | 2019-03-07 | 2019-06-14 | 通化东宝药业股份有限公司 | A kind of detection method and a kind of method for detecting cianazide in phosphoric acid Xi Gelieting of cianazide |
| CN112461956A (en) * | 2020-11-12 | 2021-03-09 | 湖南新合新生物医药有限公司 | Method for detecting content of hydrazine substances in steroid hormone substances |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109884203A (en) * | 2019-03-07 | 2019-06-14 | 通化东宝药业股份有限公司 | A kind of detection method and a kind of method for detecting cianazide in phosphoric acid Xi Gelieting of cianazide |
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| CN112461956A (en) * | 2020-11-12 | 2021-03-09 | 湖南新合新生物医药有限公司 | Method for detecting content of hydrazine substances in steroid hormone substances |
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Application publication date: 20180828 |