CN110146605A - A kind of analysis method measuring specific gene toxic impurities in Glipizide bulk pharmaceutical chemicals and its sustained release tablets - Google Patents
A kind of analysis method measuring specific gene toxic impurities in Glipizide bulk pharmaceutical chemicals and its sustained release tablets Download PDFInfo
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- CN110146605A CN110146605A CN201910317999.5A CN201910317999A CN110146605A CN 110146605 A CN110146605 A CN 110146605A CN 201910317999 A CN201910317999 A CN 201910317999A CN 110146605 A CN110146605 A CN 110146605A
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- Prior art keywords
- glipizide
- specific gene
- methanol
- pharmaceutical chemicals
- bulk pharmaceutical
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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
Abstract
The invention discloses a kind of analysis methods of specific gene toxic impurities in measurement Glipizide bulk pharmaceutical chemicals and its sustained release tablets, the following steps are included: weighing determinand powder first into a measuring bottle, it is subsequently added into methanol, it is ultrasonic sufficiently to extract, it finally takes out and lets cool, constant volume is set scale and is shaken up, and supernatant is taken to analyze after high speed centrifugation as test sample；Test sample is analyzed using high performance liquid chromatography-tandem mass method, starts chromatography collecting computer system acquisition data；Specific gene toxic impurities reference substance is taken, methanol dissolution is added and is made into reference substance solution, while carrying out high performance liquid chromatography-tandem mass analysis, then calculates the content of the specific gene toxic impurities in sample to be tested.The advantages of present invention has specificity strong, and analysis is quick, strong interference immunity, high sensitivity.
Description
Technical field
Present invention relates particularly to a kind of high performance liquid chromatography-tandem mass analysis methods, especially quickly measure lattice column pyrrole
The analysis method of specific gene toxic impurities in piperazine bulk pharmaceutical chemicals and its sustained release tablets.
Background technique
Glipizide is second generation sulfonylurea oral hypoglycemic agents, is suitable for discontented through diet control and physical training curative effect
Light, the moderate patients with NIDDM of meaning.Glipizide bulk pharmaceutical chemicals/Glipizide sustained release tablets method for detecting impurities has report
Road, impurity number and control standard referring especially to European Pharmacopoeia (9.0 editions, 9 impurity), United States Pharmacopeia (41 editions, 3 impurity) and
Chinese Pharmacopoeia (version in 2015,1 impurity).Having not yet to see has genotoxicity caution structure impurity in Glipizide bulk pharmaceutical chemicals
Report.
The regulation of international coordination meeting (ICH) M7 (R1) is required according to human medicine registration technology, and there is genotoxicity
The impurity of caution structure, if not carrying out bacterial mutation test proves it without genotoxicity, as genotoxic potential impurity, people exists
When long-term administration, daily intake is no more than 1.5 μ g.Glipizide bulk pharmaceutical chemicals/Glipizide sustained release tablets are in production process
In if touching ethyl alcohol or the reagent containing micro ethanol, can degrade and be formed with the miscellaneous of urethane structure
Matter.In the carcinogenic substance list of international cancer research institution, the World Health Organization, urethanes belongs to 2 class carcinogenic substances.And lattice
Column pyrazine clinical administration maximum dose be 20 mg, so in Glipizide the impurity to greatest extent be 75ppm.
Summary of the invention
The purpose of the present invention is to overcome the above shortcomings, provide it is a kind of analysis quickly, strong interference immunity, high sensitivity
Measurement Glipizide bulk pharmaceutical chemicals and its sustained release tablets in specific gene toxic impurities analysis method.
The purpose of the present invention is achieved through the following technical solutions: in a kind of measurement Glipizide bulk pharmaceutical chemicals and its sustained release tablets
The analysis method of specific gene toxic impurities, comprising the following steps:
A, Glipizide bulk pharmaceutical chemicals 20mg is weighed, is set in 20mL measuring bottle, scale is dissolved and be diluted to methanol, is shaken up, is made dense
Degree is the test solution of 1mg/mL；
B, the Glipizide sustained release tablets powder for being equivalent to 20mg Glipizide is weighed, sets in 20mL measuring bottle, is dissolved with methanol, is surpassed
Sound is let cool, and with methanol dilution to scale, is shaken up, and is made the test solution that concentration is 1mg/mL, after high speed centrifugation, is taken
Clear liquid is analyzed as test sample；
C, urethanes impurity 1.5mg is weighed, is set in 200mL measuring bottle, scale is dissolved and be diluted to methanol, is shaken up, is made
The reference substance stock solution for being 7.5 μ g/mL at concentration；Precision measures 2mL, sets in 200mL measuring bottle, with methanol dilution to scale, shakes
It is even, it is made into the reference substance solution that concentration is 75 ng/mL；
D, test sample is analyzed using high performance liquid chromatography-tandem mass method, while starts chromatography collecting computer system acquisition number
According to；The content of the specific gene toxic impurities is calculated using external standard method；
High performance liquid chromatography-tandem mass analysis method:
Bulk pharmaceutical chemicals are detected, chromatographic condition includes: mobile phase: 3.5 aqueous acetic acid of pH: acetonitrile=30:70v/v；Chromatography
Column: water generation octadecyl silane chromatographic column, internal diameter 4.6mm, 150 mm of column length, 5 μm of packing material size；Flow velocity: 0.4-
0.6 mL/min；Sampling volume: 30 μ L；Column temperature: 32-38 °C；Runing time: 10 min.Mass Spectrometry Conditions include: Aeroassisted
Electric spray ion source, cation, more reactive ion monitorings, MRM, 393 → 347；Fragmentation voltage: 120 V, collision energy: 10 V；
Dry gas stream amount: dry temperature degree: 9-10 L/min 350 °C, is atomized chamber pressure: 45 Psi, capillary voltage: 4000 V.
Tablet is detected, chromatographic condition includes: mobile phase A: 3.5 aqueous acetic acid of pH: acetonitrile=75:25 (v/v),
Mobile phase B: 3.5 aqueous acetic acid of pH: acetonitrile=50:50 (v/v)；Gradient elution program:
Chromatographic column: water generation octadecyl silane chromatographic column, internal diameter 4.6mm, 150 mm of column length, 5 μm of packing material size；Stream
Speed: 0.4-0.6 mL/min；Sampling volume: 20 μ L；Column temperature: 32-38 °C；Runing time: 25 min.Mass Spectrometry Conditions include: gas
Dynamic auxiliary electric spray ion source, cation, more reactive ion monitorings, MRM, 393 → 347；Fragmentation voltage: 120 V, impact energy
Amount: 10 V；Dry gas stream amount: dry temperature degree: 9-10 L/min 350 °C, is atomized chamber pressure: 45 Psi, capillary electricity
Pressure: 4000 V.
Compared with the prior art, the present invention has the following advantages:
1, the present invention uses high performance liquid chromatography-tandem mass, can effectively improve the recognition capability of impurity, improve the special of analysis
Attribute and sensitivity, its content of Accurate Determining；
2, the present invention solves the survey of potential specific gene toxic impurities in Glipizide bulk pharmaceutical chemicals and Glipizide sustained release tablets
Determine problem；
3, method of the invention easy, can be analyzed quickly and accurately potential in Glipizide bulk pharmaceutical chemicals and Glipizide sustained release tablets
Specific gene toxic impurities (Glipizide urethanes impurity) content.
Detailed description of the invention:
Fig. 1 is 1 solvent blank solution chromatogram of embodiment；
Fig. 2 is 1 reference substance chromatogram of embodiment；
The sample chromatogram figure of Fig. 3 embodiment 1；
Fig. 4 is 2 solvent blank solution chromatogram of embodiment；
Fig. 5 is 2 reference substance chromatogram of embodiment；
The sample chromatogram figure of Fig. 6 embodiment 2；
Specific embodiment:
It in order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below will be to the skill in the embodiment of the present invention
Art scheme is clearly and completely described, it is clear that and described embodiment is a module embodiments of the invention, rather than all
Embodiment.The elements and features described in one embodiment of the invention can be with one or more other embodiment party
Elements and features shown in formula combine.It should be noted that being omitted for purposes of clarity, in explanation unrelated to the invention
, the expression and description of component known to persons of ordinary skill in the art and processing.Based on the embodiments of the present invention, this field
Those of ordinary skill's every other embodiment obtained under the premise of not making the creative labor, belongs to guarantor of the present invention
The range of shield.
A kind of analysis method measuring specific gene toxic impurities in Glipizide bulk pharmaceutical chemicals and its sustained release tablets, including it is following
Step: weighing determinand powder into a measuring bottle first, is subsequently added into methanol, and ultrasound is sufficiently extracted, finally takes out and let cool, fixed
Accommodating scale simultaneously shakes up, and supernatant is taken to analyze after high speed centrifugation as test sample；Using high performance liquid chromatography-tandem mass method point
Test sample is analysed, chromatography collecting computer system acquisition data are started；Specific gene toxic impurities reference substance is taken, methanol dissolution is added
It is made into reference substance solution, while carrying out high performance liquid chromatography-tandem mass analysis, then calculates the specific gene in sample to be tested
The content of toxic impurities.
Embodiment one
The assay of urethanes impurity in Glipizide bulk pharmaceutical chemicals:
(1), instrument and condition:
High performance liquid chromatography-tandem mass instrument: the triple quadrupole rods tandem mass spectrometry systems of 1260 high performance liquid chromatography -6410B of Agilent
System and MassHunter work station；
Chromatographic column: water generation Sunfire C18, internal diameter 4.6mm, 150 mm of column length, 5 μm of packing material size；
(2), experimental procedure:
Precision weighs Glipizide bulk pharmaceutical chemicals 20mg, sets in 20mL measuring bottle, and scale is dissolved and be diluted to methanol, is shaken up, is made
Concentration is the test solution of 1mg/mL, and sample introduction is analyzed；
Precision weighs urethanes impurity 1.5mg, sets in 200mL measuring bottle, and scale is dissolved and be diluted to methanol, is shaken up,
The reference substance stock solution that concentration is 7.5 μ g/mL is made；Precision measures 2mL, sets in 200mL measuring bottle, with methanol dilution to scale,
It shakes up, is made into the reference substance solution that concentration is 75 ng/mL, sample introduction is analyzed；
Chromatographic condition includes: mobile phase: 3.5 aqueous acetic acid of pH: acetonitrile=30:70 (v/v)；Chromatographic column: water generation
Sunfire C18, internal diameter 4.6mm, 150 mm of column length, 5 μm of packing material size；Flow velocity: 0.5 mL/min；Sampling volume: 30 μ
L；Column temperature: 35 °C；Runing time: 10 min.Mass Spectrometry Conditions include: Aeroassisted electric spray ion source (ESI), and cation is more
Reactive ion monitors (MRM, 393 → 347)；Fragmentation voltage: 120 V, collision energy: 10 V；Dry gas stream amount: 9.5 L/
Dry temperature degree: min 350 °C, is atomized chamber pressure: 45 Psi, capillary voltage: 4000 V.
Methodological study:
Sample introduction reproducibility: taking reference substance solution continuously into 6 needles, to calculate the %RSD of urethanes impurity peak area, is 1.6,
Less than 5, the precision of illustration method is good；
Specificity: the retention time of this method urethanes impurity liquid quality detection is 5.15 min or so；
Repeatability: 6 parts of samples are prepared in parallel, the %RSD of urethanes impurity determination result is less than 3；
Measurement result:
Urethanes impurity content is respectively 18 ppm, 35 ppm and 67 ppm in 3 batches of Glipizide test samples, but is lower than
75 ppm to greatest extent of the impurity in sample.
Embodiment two
The assay of urethanes impurity in Glipizide sustained release tablets:
(1), instrument and condition:
High performance liquid chromatography-tandem mass instrument: the triple quadrupole rods tandem mass spectrometry systems of 1260 high performance liquid chromatography -6410B of Agilent
System and MassHunter work station；
Chromatographic column: water generation Sunfire C18, internal diameter 4.6mm, 150 mm of column length, 5 μm of packing material size；
(2), experimental procedure:
Precision weighs the column pyrazine sustained release tablets powder for being equivalent to 20mg Glipizide lattice, sets in 20mL measuring bottle, adds 20.0 mL first
Alcohol is vortexed 5 minutes, and high speed centrifugation, taking supernatant, sample introduction is analyzed；
Precision weighs urethanes impurity 1.5mg, sets in 200mL measuring bottle, and scale is dissolved and be diluted to methanol, is shaken up,
The reference substance stock solution that concentration is 7.5 μ g/mL is made；Precision measures 2mL, sets in 200mL measuring bottle, with methanol dilution to scale,
It shakes up, is made into the reference substance solution that concentration is 75 ng/mL, sample introduction is analyzed；
Chromatographic condition includes: mobile phase A: 3.5 aqueous acetic acid of pH: acetonitrile=75:25 (v/v), Mobile phase B: 3.5 acetic acid of pH
Aqueous solution: acetonitrile=50:50 (v/v)；
Gradient elution program
Chromatographic column: water generation Sunfire C18, internal diameter 4.6mm, 150 mm of column length, 5 μm of packing material size；Flow velocity: 0.5 mL/
min；Sampling volume: 20 μ L；Column temperature: 35 °C；Runing time: 25 min.Mass Spectrometry Conditions include: Aeroassisted electron spray ion
Source (ESI), cation, more reactive ions monitor (MRM, 393 → 347)；Fragmentation voltage: 120 V, collision energy: 10 V；It is dry
Throughput: dry temperature degree: 9.5 L/min 350 °C, are atomized chamber pressure: 45 Psi, capillary voltage: 4000 V；
System suitability:
Reference substance solution is taken continuously into 5 needles, to calculate the %RSD of urethanes impurity peak area, %RSD meets less than 10.0
It is required that；
Measurement result:
Urethanes impurity content is respectively 30 ppm, 30 ppm and 32 ppm in 3 batches of Glipizide sustained release tablets test samples,
But lower than 75 ppm to greatest extent of the impurity in sample.
The present invention uses high performance liquid chromatography-tandem mass, being capable of Accurate Determining Glipizide bulk pharmaceutical chemicals and Glipizide
The content of genotoxicity impurity urethanes in sustained release tablets；It solves in Glipizide bulk pharmaceutical chemicals and Glipizide sustained release tablets
The measuring method problem of trace genotoxicity impurity.
It, can be quick by high performance liquid chromatography-tandem mass for the specific genotoxicity impurity existing for trace
Accurately it detected.The advantages of present invention has specificity strong, and analysis is quick, strong interference immunity, high sensitivity.
Finally, it should be noted that although the present invention and its advantage have been described in detail above it should be appreciated that not
Can be carried out in the case where beyond the spirit and scope of the present invention being defined by the claims appended hereto various changes, substitution and
Transformation.Moreover, the scope of the present invention is not limited only to the specific reality of process, equipment described in specification, means, method and steps
Apply example.One of ordinary skilled in the art holds from the disclosure it will be readily understood that can be used according to the present invention
The row function essentially identical to corresponding embodiment described herein obtains the result essentially identical with it, existing and future
Process, equipment, means, method or step to be developed.Therefore, the attached claims are intended to wrap in the range of them
Include such process, equipment, means, method or step.
Claims (1)
1. the analysis method of specific gene toxic impurities, feature exist in a kind of measurement Glipizide bulk pharmaceutical chemicals and its sustained release tablets
In: the following steps are included:
A, Glipizide bulk pharmaceutical chemicals 20mg is weighed, is set in 20mL measuring bottle, scale is dissolved and be diluted to methanol, is shaken up, is made dense
Degree is the test solution of 1mg/mL；
B, the Glipizide sustained release tablets powder for being equivalent to 20mg Glipizide is weighed, sets in 20mL measuring bottle, is dissolved with methanol, is surpassed
Sound is let cool, and with methanol dilution to scale, is shaken up, and is made the test solution that concentration is 1mg/mL, after high speed centrifugation, is taken
Clear liquid is analyzed as test sample；
C, urethanes impurity 1.5mg is weighed, is set in 200mL measuring bottle, scale is dissolved and be diluted to methanol, is shaken up, is made
The reference substance stock solution for being 7.5 μ g/mL at concentration；Precision measures 2mL, sets in 200mL measuring bottle, with methanol dilution to scale, shakes
It is even, it is made into the reference substance solution that concentration is 75 ng/mL；
D, test sample is analyzed using high performance liquid chromatography-tandem mass method, while starts chromatography collecting computer system acquisition number
According to；The content of the specific gene toxic impurities is calculated using external standard method；
High performance liquid chromatography-tandem mass analysis method:
Bulk pharmaceutical chemicals are detected, chromatographic condition includes: mobile phase: 3.5 aqueous acetic acid of pH: acetonitrile=30:70v/v；Chromatography
Column: octadecyl silane chromatographic column, internal diameter 4.6mm, 150 mm of column length, 5 μm of packing material size；Flow velocity: 0.4-0.6
mL/min；Sampling volume: 30 μ L；Column temperature: 32-38 °C；Runing time: 10 min；
Mass Spectrometry Conditions include: Aeroassisted electric spray ion source, cation, more reactive ions monitorings, MRM, and 393 → 347；Fragmentation
Voltage: 120 V, collision energy: 10 V；Dry gas stream amount: dry temperature degree: 9-10 L/min 350 °C, is atomized chamber pressure:
45 Psi, capillary voltage: 4000 V；
Tablet is detected, chromatographic condition includes: mobile phase A: 3.5 aqueous acetic acid of pH: acetonitrile=75:25 (v/v), flowing
3.5 aqueous acetic acid of phase B:pH: acetonitrile=50:50 (v/v)；Gradient elution program:
Chromatographic column: octadecyl silane chromatographic column, internal diameter 4.6mm, 150 mm of column length, 5 μm of packing material size；Flow velocity:
0.4-0.6 mL/min；Sampling volume: 20 μ L；Column temperature: 32-38 °C；Runing time: 25 min；
Mass Spectrometry Conditions include: Aeroassisted electric spray ion source, cation, more reactive ions monitorings, MRM, and 393 → 347；Fragmentation
Voltage: 120 V, collision energy: 10 V；Dry gas stream amount: dry temperature degree: 9-10 L/min 350 °C, is atomized chamber pressure:
45 Psi, capillary voltage: 4000 V.
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| CN201910317999.5A CN110146605A (en) | 2019-04-19 | 2019-04-19 | A kind of analysis method measuring specific gene toxic impurities in Glipizide bulk pharmaceutical chemicals and its sustained release tablets |
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| CN108732290A (en) * | 2018-05-22 | 2018-11-02 | 威海迪素制药有限公司 | A kind of detection method of Glipizide genotoxicity impurity |
| CN111679027A (en) * | 2020-07-16 | 2020-09-18 | 广东华南药业集团有限公司 | Method for separating and measuring glipizide and impurities thereof by liquid chromatography |
| CN115389653A (en) * | 2022-08-01 | 2022-11-25 | 北京悦康科创医药科技股份有限公司 | Method for detecting genotoxic impurities in cefuroxime sodium |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108732290A (en) * | 2018-05-22 | 2018-11-02 | 威海迪素制药有限公司 | A kind of detection method of Glipizide genotoxicity impurity |
| CN111679027A (en) * | 2020-07-16 | 2020-09-18 | 广东华南药业集团有限公司 | Method for separating and measuring glipizide and impurities thereof by liquid chromatography |
| CN115389653A (en) * | 2022-08-01 | 2022-11-25 | 北京悦康科创医药科技股份有限公司 | Method for detecting genotoxic impurities in cefuroxime sodium |
| CN115389653B (en) * | 2022-08-01 | 2023-09-12 | 北京悦康科创医药科技股份有限公司 | Method for detecting genotoxic impurities in cefuroxime sodium |
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