CN110530998A - A kind of Laura is for Buddhist nun and containing Laura for the detection method in relation to substance in the preparation of Buddhist nun - Google Patents
A kind of Laura is for Buddhist nun and containing Laura for the detection method in relation to substance in the preparation of Buddhist nun Download PDFInfo
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- CN110530998A CN110530998A CN201910869894.0A CN201910869894A CN110530998A CN 110530998 A CN110530998 A CN 110530998A CN 201910869894 A CN201910869894 A CN 201910869894A CN 110530998 A CN110530998 A CN 110530998A
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- laura
- buddhist nun
- detection method
- detection
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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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
-
- 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
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
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- 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)
- Spectroscopy & Molecular Physics (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention discloses a kind of Laura for Buddhist nun and containing Laura for the detection method in relation to substance in the preparation of Buddhist nun.This method selects mobile phase appropriate, using HPLC rapidly and accurately detect Laura replace Buddhist nun impurity and catabolite situation, solve interference of all kinds of impurity generated in its synthesis and production process to product purity, the quality of bulk pharmaceutical chemicals and preparation can be reliably controlled comprehensively, provide a kind of effective analysis method for control of product quality.
Description
Technical field
Belong to drug for Buddhist nun and containing Laura the present invention relates to a kind of Laura for the detection method in relation to substance in the preparation of Buddhist nun
Analysis detection field.
Background technique
Laura replaces Buddhist nun (chemical name: Lorlatinib, trade name: Lorbrena), and chemical structural formula is as follows:
The medicine is novel, reversible, the potent small molecule ALK (anaplastic lymphoma kinase) of one kind and ROS1 (c-ros
Oncogene 1, receptor tyrosine kinase) inhibitor is to be passed through by Pfizer (Pfizer) company to a gram azoles
For ALK inhibitor obtained from Buddhist nun (Crizotinib) transformation.Enter clinical test within 2014, for the treatment of lung cancer, mainly
Buddhist nun is replaced for first generation ALK inhibitor gram azoles for Buddhist nun's drug resistance and second generation ALK inhibitor Ceritinib (Ceritinib) and Ai Le
(Alectinib) drug resistant Patients with Non-small-cell Lung.On June 5th, 2016, Pfizer discloses the I/ of the medicine in ASCO meeting
II phase clinical data.On May 7th, 2019, Pfizer Inc announce that product Laura replaces Buddhist nun's (trade name
LORVIQUA under) being allowed to have ready conditions by European Union's authorization, market sale is carried out.And before with trade name LORBRENA in beauty
State, Canada and Japanese market sale.
Country's drug also ununified examination criteria at present, therefore, in order to control Laura preferably for Buddhist nun's product
Quality needs to establish a set of simple and reliable and stablizes effective method and detect to the related substance of this product, solves synthesis work
The interference that all kinds of known or unknown impurities that skill introduces or degradation and formulation process generate measure product purity.
The present invention uses isocratic elution mode, effectively carries out content for the preparation of Buddhist nun to Laura for Buddhist nun and containing Laura and has
Substance detection is closed, can fast and accurately detect that Laura replaces the impurity and its catabolite of Buddhist nun, simple to operation, high sensitivity can
Preferably control product quality.The present invention realizes Laura and replaces the preparation of Buddhist nun in relation to the measurement of substance for Buddhist nun and containing Laura, guarantees
Laura controls for the quality of Buddhist nun, has important practical significance in the quality controlling party face of synthesis and production process.
Summary of the invention
It is an object of the invention to establish one kind to control Laura for Buddhist nun and containing Laura for substance related in the preparation of Buddhist nun
Detection method.The problem of the method overcome the drug ununified pharmaceutical standards, solve synthesis technology introduce or
The interference that all kinds of known or unknown impurities that degradation and formulation process generate measure product purity, preferably control Laura
For the quality of Buddhist nun's product.In view of normal-phase chromatography condition is not suitable for LC-MS instrument, can not further carry out Laura for Buddhist nun and
It replaces the preparation of Buddhist nun in relation to the separation of substance and structure-characterized detection containing Laura, therefore has studied reversed-phased high performace liquid chromatographic.It should
The advantages of method: 1, can efficiently separate related substance and being capable of quantified controlling；2, this method has universal applicability；
3, enough sensitivity can effectively control impurity.
The present invention provides a kind of Laura for Buddhist nun and containing Laura for substance detecting method related in the preparation of Buddhist nun, step is such as
Under: (1) it takes Laura to replace the formulation samples of Buddhist nun for Buddhist nun's bulk pharmaceutical chemicals or containing Laura, with flowing phased soln, prepares test liquid；(2) it uses
Reversed-phased high performace liquid chromatographic, chromatographic column are C18 column, and 15 DEG C~40 DEG C of column temperature, flow velocity is 0.5~1.5ml/min, is had with polarity
Solvent-inorganic salt buffer is mobile phase, using isocratic elution；(3) use UV detector, Detection wavelength 230~
260nm records chromatography, completes Laura for Buddhist nun and containing Laura for the detection in relation to substance in the preparation of Buddhist nun.
Further, in detection method of the present invention, Laura is taken to flow for Buddhist nun and containing Laura for the formulation samples of Buddhist nun
Dynamic phased soln simultaneously dilutes, and the test solution that every 1ml replaces 0.01~5mg of Buddhist nun containing Laura is made.
It wherein, is flowing with acetonitrile-phosphate buffer mixed solution or methanol-phosphate buffer mixed solution
The volume ratio of phase, the two is 1%:99%~15%:85%, and the preferred 1%:99%~10%:90% of volume ratio, optimal is 5%:
95%.
Further, phosphate buffering liquid concentration is 0.001~0.1mol/L, and pH value is 3.5~7.0, wherein concentration
It is preferred that 0.001~0.05mol/L, pH value is 5.0~6.5, and optimal concentration 0.01mol/L, optimal pH are 5.5 or 6.0.Phosphoric acid
The salt type of salt buffer includes: ammonium salt, sodium salt, sylvite, calcium salt, zinc salt, magnesium salts etc., wherein by testing preferred ammonium salt, sodium
Salt, sylvite, most preferably potassium phosphate buffer.
In detection method of the present invention, chromatographic column is ZORBAX SB-C18.
In detection method of the present invention, chromatogram column temperature is at 15 DEG C~40 DEG C.
In detection method of the present invention, Detection wavelength 254nm.
The present invention having the active effect that compared with the prior art
1, the superiority of liquid phase chromatogram condition is stronger in the present invention, suitable for bulk pharmaceutical chemicals and its related substance of various dosage forms
Detection can fast and accurately detect that Laura replaces the impurity and catabolite situation of Buddhist nun.In Laura for Buddhist nun's raw material and its preparation
In related substance detection, each peak shape is symmetrical, and separating degree is high, avoids and the problems such as leading peak, individual peak separating degrees are inadequate occurs.
2, the present invention carries out related substance detection to product using UV detector, establishes a kind of evaluation of quicklook
Effective prevention of chromatography peak purity.It can intuitively judge the purity of chromatographic peak, and judge the position that there is interference expense, can obtain
Whole spectral informations of " flowing ", quickly obtain the absorption spectrum of chromatographic component, and advantage is that the reservation of chromatography can not only be relied on
Time progress is qualitative, and can be qualitative according to the spectral information progress that it is provided, and substantially increases qualitative confidence level and inspection
Survey sensitivity.
3, detection method is accurate, simple to operation, favorable reproducibility, high sensitivity, can sufficiently meet related substance
The requirement of detection and decomposition product measurement controls the special impurities in sample better, guarantees product quality, real at work
It is strong with property.Be conducive in industrialized production, Laura is for Buddhist nun and containing Laura for the detection in relation to substance in the preparation of Buddhist nun, and energy is preferably
Product quality is controlled, guarantees drug safety.
Detailed description of the invention
Fig. 1 Laura replaces the liquid chromatogram of Buddhist nun's reference substance for one Laura of Buddhist nun's limit of impurities linear relationship chart Fig. 2-1. embodiment
Figure Fig. 2-2. Laura replaces the related substance liquid phase color of Buddhist nun's piece in relation to two Laura of liquid chromatogram Fig. 3 embodiment of substance for Buddhist nun's raw material
Spectrogram
Specific embodiment
Below will by embodiment, the invention will be further described, but these descriptions are not to the content of present invention
It is further to limit.
One Laura of embodiment replaces measurement of the Buddhist nun in relation to substance
1, chromatographic condition and system suitability are tested
The selection of 1.1 chromatographic conditions:
Instrument: Agilent 1260,25 DEG C of optimum column temperature, flow velocity 1.0ml/min, Detection wavelength 254nm.Liquid chromatogram
Column ZORBAX SB-C18 column (150mm × 4.6mm, 5 μm), 0.01mol/L K2HPO4Solution (pH5.5)-acetonitrile or
0.01mol/L K2HPO4Solution (pH5.5)-methanol is flowing phase composition, optimum proportioning are as follows: 95%:5%.20 μ l of sample volume.
Under the chromatographic condition, Laura is moderate for Buddhist nun's main peak retention time, and peak shape is preferable.
1.2 sensitivity determination
Take Laura appropriate for Buddhist nun, being configured to concentration with mobile phase is solution of every 1ml containing 0.2mg, then uses mobile phase respectively
It is diluted to a series of solution of various concentrations, respectively 10 μ l of sample introduction, is allowed to generate the signal that main peak is baseline noise three times.Through trying
It tests, detectability is 0.2ng (S/N >=3), if concentration 0.2mg/ml when with Related substances separation is calculated, limit of detection
It is 0.1%.The results show that this method high sensitivity, can sufficiently meet the requirement of Related substances separation measurement.
1.3 stability of solution
It takes with a test sample product solution, is measured respectively at 0,2,4,8,10,12 hour difference sample introduction, main peak peak area
And related substance-measuring result is basicly stable in 12 hours.
The experimental results showed that, the method simplicity is sensitive, favorable reproducibility above, and the matter of Buddhist nun can be preferably replaced to Laura in sample
Amount is detected.
The configuration of 1.4 test solutions；
It takes Laura appropriate for Buddhist nun's raw material, adds mobile phase to be configured to the solution of 0.2mg/ml, as test solution.
The preparation of 1.5 reference substance solutions:
It measures that above-mentioned 1.4 test solution is appropriate, mobile phase is added to be diluted to containing about the solution of 2 μ g in every 1ml, as control
Solution.The contrast solution concentration range exists: when in 1~20 μ g/ml, peak area and concentration are in good linear relationship, linear phase
Relationship number is 0.9999.See attached drawing 1
2, Laura replaces detection of Buddhist nun's raw material in relation to substance:
Test solution 10ul is taken, liquid chromatograph is injected, adjusts detection sensitivity, keeps principal component chromatography peak height about full
The 10% of range, then test solution 10ul is taken to inject liquid chromatograph, records chromatogram, in test solution chromatogram if any
Impurity peaks measure the sum of each impurity peak area, are not greater than the peak area of main peak in contrast solution.See attached drawing 2
Embodiment two: Laura replaces measurement of Buddhist nun's piece in relation to substance
This product 20 are taken, accurately weighed, finely ground, precision measures appropriate (be approximately equivalent to Laura and replace Buddhist nun 2mg), and mobile phase is added to match
It is set to the solution in every 1ml containing 0.2mg, is filtered, as test solution.Precision measures in right amount, and mobile phase is added to be diluted to every 1ml
In solution containing about 2 μ g, as contrast solution.Under the chromatographic condition of lower column selection:
UV detector (Agilent 1260) Detection wavelength 254nm, ZORBAX SB-C18 column (150mm × 4.6mm, 5 μ
M), 0.01mol/L K2HPO4Solution (pH5.5)-acetonitrile composition, optimum proportioning are as follows: 95%:5%.25 DEG C of chromatographic column column temperature,
Flow velocity 1.0ml/min.20 μ l of sample volume.It is calculated on theoretical tray by Laura for Ni Feng and is not less than 3000.
Measurement result is as shown in the table:
| Lot number | First | Second batch | Third batch |
| Related substance (%) | 0.12 | 0.13 | 0.15 |
Claims (10)
1. a kind of Laura is for Buddhist nun and containing Laura for related substance detecting method in the preparation of Buddhist nun, it is characterised in that detection method includes
Following steps:
(1) it takes Laura to replace the formulation samples of Buddhist nun for Buddhist nun's bulk pharmaceutical chemicals or containing Laura, with flowing phased soln, prepares test liquid, be made every
1ml replaces the test solution of 0.01~5mg of Buddhist nun containing Laura；
(2) HPLC is used, chromatographic column is C18 column, and flow velocity is 0.5~1.5ml/min, with the inorganic salt buffer of polar organic solvent-
The mixed solution of liquid is mobile phase, isocratic elution；
(3) UV detector is used, 230~260nm of Detection wavelength records chromatography, completes Laura for Buddhist nun and containing Laura for Buddhist nun's
In relation to the detection of substance in preparation.
2. detection method according to claim 1, which is characterized in that in the step (2), chromatogram column temperature 15 DEG C~
40℃。
3. detection method according to claim 1, which is characterized in that in the step (2), chromatographic column is selected from ZORBAX
SB-C18。
4. detection method according to claim 1, which is characterized in that in the step (2), buffer salt solution is selected from phosphoric acid
Salt buffer.
5. detection method according to claim 1, which is characterized in that in the step (2), the pH value of phosphate buffer
It is 3.5~7.0.
6. detection method according to claim 1, which is characterized in that polarity is organic molten in mobile phase in the step (2)
Agent-phosphate buffer volume ratio is 1%:99%~15%:85%.
7. detection method according to claim 1, which is characterized in that polarity is organic molten in mobile phase in the step (2)
Agent is selected from acetonitrile or methanol.
8. detection method according to claim 5, which is characterized in that phosphate buffering liquid concentration is 0.001~0.1mol/
L。
9. detection method according to claim 1, which is characterized in that in the step (2), flow velocity 1.0ml/min.
10. detection method according to claim 1, which is characterized in that in the step (3), Detection wavelength 254nm.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910869894.0A CN110530998A (en) | 2019-09-16 | 2019-09-16 | A kind of Laura is for Buddhist nun and containing Laura for the detection method in relation to substance in the preparation of Buddhist nun |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910869894.0A CN110530998A (en) | 2019-09-16 | 2019-09-16 | A kind of Laura is for Buddhist nun and containing Laura for the detection method in relation to substance in the preparation of Buddhist nun |
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| CN201910869894.0A Pending CN110530998A (en) | 2019-09-16 | 2019-09-16 | A kind of Laura is for Buddhist nun and containing Laura for the detection method in relation to substance in the preparation of Buddhist nun |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017175091A1 (en) * | 2016-04-08 | 2017-10-12 | Pfizer Inc. | Crystalline forms of lorlatinib maleate |
| CN107849060A (en) * | 2015-07-31 | 2018-03-27 | 辉瑞公司 | Laura replaces the crystal form of Buddhist nun's free alkali |
| CN109232607A (en) * | 2018-09-20 | 2019-01-18 | 沈阳药科大学 | Laura replaces the synthetic method of Buddhist nun |
| CN109651397A (en) * | 2019-01-25 | 2019-04-19 | 安庆多辉生物科技有限公司 | A kind of Laura is for Buddhist nun's intermediate and prepares the method that Laura replaces Buddhist nun |
| WO2019113071A1 (en) * | 2017-12-05 | 2019-06-13 | Icahn School Of Medicine At Mount Sinai | Compositions and methods for treating alk-mediated cancer |
| CN110568121A (en) * | 2019-07-11 | 2019-12-13 | 山东省药学科学院 | Eribulin and detection method of related substances in eribulin-containing preparation |
-
2019
- 2019-09-16 CN CN201910869894.0A patent/CN110530998A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107849060A (en) * | 2015-07-31 | 2018-03-27 | 辉瑞公司 | Laura replaces the crystal form of Buddhist nun's free alkali |
| WO2017175091A1 (en) * | 2016-04-08 | 2017-10-12 | Pfizer Inc. | Crystalline forms of lorlatinib maleate |
| WO2019113071A1 (en) * | 2017-12-05 | 2019-06-13 | Icahn School Of Medicine At Mount Sinai | Compositions and methods for treating alk-mediated cancer |
| CN109232607A (en) * | 2018-09-20 | 2019-01-18 | 沈阳药科大学 | Laura replaces the synthetic method of Buddhist nun |
| CN109651397A (en) * | 2019-01-25 | 2019-04-19 | 安庆多辉生物科技有限公司 | A kind of Laura is for Buddhist nun's intermediate and prepares the method that Laura replaces Buddhist nun |
| CN110568121A (en) * | 2019-07-11 | 2019-12-13 | 山东省药学科学院 | Eribulin and detection method of related substances in eribulin-containing preparation |
Non-Patent Citations (3)
| Title |
|---|
| ANURADHA N. D. ET AL.: "RP-HPLC Method Development And Validation For The Determination Of Lorlatinib In Bulk And Its Pharmaceutical Formulation", 《WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES》 * |
| CLAUDIA SPATARI ET AL.: "Bioanalytical assay for the quantification of the ALK inhibitor lorlatinib in mouse plasma using liquid chromatography-tandem mass spectrometry", 《JOURNAL OF CHROMATOGRAPHY B》 * |
| WEI CHEN ET AL.: "Pharmacokinetic Study and Tissue Distribution of Lorlatinib in Mouse Serum and Tissue Samples by Liquid Chromatography-Mass Spectrometry", 《JOURNAL OF ANALYTICAL METHODS IN CHEMISTRY》 * |
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Application publication date: 20191203 |