CN105181844A - Method for determining content and associated substances of sorafenib tosylate in high-performance liquid phase chromatography - Google Patents
Method for determining content and associated substances of sorafenib tosylate in high-performance liquid phase chromatography Download PDFInfo
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- CN105181844A CN105181844A CN201510578004.2A CN201510578004A CN105181844A CN 105181844 A CN105181844 A CN 105181844A CN 201510578004 A CN201510578004 A CN 201510578004A CN 105181844 A CN105181844 A CN 105181844A
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Abstract
The invention discloses a method for determining content and associated substances of sorafenib tosylate. The method comprises the following steps: taking a reverse high-performance liquid phase chromatography, preparing a test solution and a reference solution, respectively measuring 10 micro liters of the test solution and 10 micro liters of reference solution, injecting the solution into a chromatograph, recording a chromatogram, calculating at a peak area according to an external standard method, and drying to complete the test on the content of the sorafenib tosylate and other substances. The method has the advantages that the blank that no method for testing and analyzing the content and associated substances of the sorafenib tosylate is provided at present is filled, the sorafenib tosylate and impurities can be separated by virtue of an acetonitrile-trifluoroacetic acid aqueous solution, the research development and production requirement can be met, and the associated substances in a sorafenib tosylate active ingredient can be more strictly and effectively controlled.
Description
Technical field
The present invention relates to Pharmaceutical Analysis field, be specifically related to a kind of method of high effective liquid chromatography for measuring Sorafenib Tosylate content and related substance.
Background technology
Sorafenib Tosylate, English name SorafenibTosylate; Sorafenib is a kind of multi-kinase inhibitor, has dual antitumor activity, can Tumor suppression propagation and Angiogenesis.(comprising: hepatocellular carcinoma at people's tumour transplatation animal model, kidney, breast cancer, colon cancer, cancer of pancreas and lung cancer model) preclinical study in, Sorafenib shows antitumor activity widely, and inducing apoptosis of tumour cell, the growth of effective Tumor suppression.A kind of new type anticancer medicine of Sorafenib Tosylate Pian Shi Bayer A.G development, get permission listing early than on Dec 20th, 2005 in the U.S., in the world, more than 50 country is approved for treatment advanced renal cell carcinoma at present.This product is in Huo State Food and Drug Administration approval of import September 12 in 2006 China, and specification is 200mg.
The content assaying method of existing a lot of bibliographical information Sorafenib Tosylate at present, the Related substance method for Sorafenib Tosylate bulk drug also rarely has research.Invention disclosed patent in 2007 method of-N-picoline-2-formamide " prepare 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl) phenyl] is amino } carbonyl) is amino] phenoxy group } " (publication number 101052619, publication date on October 10th, 2007), be referred to 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl) phenyl] amino } carbonyl) is amino] phenoxy group } HPLC method for detecting purity after the preparation of-N-picoline-2-carboxamide tosylat, under phosphate buffer-ethanol/acetonitrile=4/6 system, carry out linear gradient elution.But for some other known impurities of Sorafenib Tosylate, the method can not reach and be separated and control effectively.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, a kind of method of high effective liquid chromatography for measuring Sorafenib Tosylate content and related substance is now provided.
For achieving the above object, technical scheme of the present invention is: a kind of method of high effective liquid chromatography for measuring Sorafenib Tosylate content, its innovative point is: described chromatographic condition is: selecting with octadecyl silane is filling agent, column length 250mm, determined wavelength 235nm, column temperature 40 DEG C, flow velocity 1.0ml/min; The detecting device adopted is UV-detector; Adopt reversed-phased high performace liquid chromatographic to carry out wash-out by degree such as grade, described mobile phase is trifluoroacetic acid aqueous solution and polar organic solvent, and described trifluoroacetic acid aqueous solution is A phase, and described polar organic solvent is B phase, and in described mobile phase, the organic solvent of B phase is acetonitrile.
Further, the concentration of the trifluoroacetic acid in described A phase trifluoroacetic acid aqueous solution is 0.1 ~ 1%.
Further, described B phase is 45 ~ 55% with A phase mixed volume ratio.
Further, the concrete operation step of described mensuration Sorafenib Tosylate content is as follows:
(1) choose 14mg Sorafenib Tosylate, precise weighing, be positioned in 100ml measuring bottle, add mobile phase and dissolve and be diluted to scale, shake up, as test liquid;
(2) separately get Sorafenib Tosylate 14mg, precise weighing, be positioned in 100ml measuring bottle, being mixed with containing Sorafenib concentration is 0.1mg/ml, in contrast liquid;
(3) measure test liquid and contrast solution 10 μ l respectively, injecting chromatograph, record chromatogram, gives money as a gift with calculated by peak area by external standard method, to obtain final product.
Another object of the present invention is the method for openly a kind of high effective liquid chromatography for measuring Sorafenib Tosylate related substance, its innovative point is: described chromatographic condition is: selecting with octadecyl silane is filling agent, column length 250mm, determined wavelength 235nm, column temperature 40 DEG C, flow velocity 1.0ml/min; The detecting device adopted is UV-detector; Adopt reversed-phased high performace liquid chromatographic to carry out wash-out by gradient, described mobile phase is trifluoroacetic acid aqueous solution and polar organic solvent, and described trifluoroacetic acid aqueous solution is A phase, and described polar organic solvent is B phase, and in described mobile phase, the organic solvent of B phase is acetonitrile.
Further, the concentration of the trifluoroacetic acid in described A phase trifluoroacetic acid aqueous solution is 0.1 ~ 1%.
Further, described A phase is arranged according to Gradient program with the volume ratio of B phase.
Further, the concrete operation step of described mensuration Sorafenib Tosylate related substance is as follows:
(4) 14mg Sorafenib Tosylate is got, precise weighing, be positioned in 10ml measuring bottle, add mixed solvent, described mixed solvent is the mixing of water, acetonitrile and ethanol, and the mixed volume of described water, acetonitrile and ethanol is than being 250:450:300, by ultrasonic, Sorafenib Tosylate is fully dissolved, shakes up, as need testing solution;
(5) precision measures need testing solution 1ml, is positioned in 100ml measuring bottle, is diluted to scale, shakes up with the mixed solvent in step (4); Precision measures the solution 1ml of step (5) first stage acquisition again, and be positioned in 10ml measuring bottle, the mixed solvent in optional step (4) carries out being diluted to scale, shakes up, in contrast solution;
(6) get contrast solution 10 μ l injection liquid chromatography, regulate detection sensitivity, make major component chromatogram peak height be 10 ~ 20% of full scale;
(7) precision measures need testing solution and each 10 μ l of contrast solution, respectively injection liquid chromatography, record chromatogram.
Beneficial effect of the present invention is as follows: present invention employs reversed-phased high performace liquid chromatographic, by preparing test liquid and contrast liquid, and measure test liquid and contrast solution 10 μ l respectively, injecting chromatograph, record chromatogram, to give money as a gift with calculated by peak area by external standard method, namely the test of Sorafenib Tosylate content and other materials is completed, the present invention filled up current Sorafenib Tosylate content and related substance the vacancy that there is no of method for testing and analyzing, Sorafenib Tosylate can be reached with its impurity by acetonitrile-trifluoroacetic acid aqueous solution system and be separated, the demand that the present invention can meet research and development and produce, more strict effectively to control can be carried out by related substance effectively in Sorafenib Tosylate bulk drug.
Accompanying drawing explanation
Fig. 1 Sorafenib Tosylate content system flexibility.
Fig. 2 Sorafenib Tosylate related substance system flexibility.
Fig. 3 is the chromatogram of embodiment 1.
Fig. 4 is the chromatogram of embodiment 2.
Embodiment
By particular specific embodiment, embodiments of the present invention are described below, person skilled in the art scholar the content disclosed by this instructions can understand other advantages of the present invention and effect easily.
Embodiment 1
The concrete operation step of high effective liquid chromatography for measuring Sorafenib Tosylate content is as follows:
(1) choose 14mg Sorafenib Tosylate, precise weighing, be positioned in 100ml measuring bottle, add mobile phase and dissolve and be diluted to scale, shake up, as test liquid;
(2) separately get Sorafenib Tosylate 14mg, being configured to containing BAY 43-9006 concentration is 0.1mg/ml, in contrast liquid;
(3) measure test liquid and contrast solution 10 μ l respectively, injecting chromatograph, record chromatogram, gives money as a gift with calculated by peak area by external standard method, to obtain final product.
Embodiment 2
The concrete operation step of high effective liquid chromatography for measuring Sorafenib Tosylate related substance is as follows:
(4) 14mg Sorafenib Tosylate is got, precise weighing, be positioned in 10ml measuring bottle, add mixed solvent, described mixed solvent is the mixing of water, acetonitrile and ethanol, and the mixed volume of described water, acetonitrile and ethanol is than being 250:450:300, by ultrasonic, Sorafenib Tosylate is fully dissolved, shakes up, as need testing solution;
(5) precision measures need testing solution 1ml, is positioned in 100ml measuring bottle, is diluted to scale, shakes up with the mixed solvent in step (4); Precision measures the solution 1ml of step (5) first stage acquisition again, and be positioned in 10ml measuring bottle, the mixed solvent in optional step (4) carries out being diluted to scale, shakes up, in contrast solution;
(6) get contrast solution 10 μ l injection liquid chromatography, regulate detection sensitivity, make major component chromatogram peak height be 10 ~ 20% of full scale;
(7) precision measures need testing solution and each 10 μ l of contrast solution, respectively injection liquid chromatography, record chromatogram.
Elution process for carry out wash-out according to Gradient program, shown in table specific as follows:
The following items of Sorafenib Tosylate content assaying method is verified:
1, system flexibilityanalyze this chromatographic condition with Sorafenib Tosylate whether to meet the requirements.Under this condition, between each impurity and main peak and impurity, degree of separation meets the requirements as seen from Figure 1, and peak purity and single-point threshold value all meet the requirements.
, typical curveprepare the test liquid of each concentration gradient, precision measures 10 μ l respectively, injecting chromatograph, record chromatogram.With concentration (μ g/ml) for horizontal ordinate, peak area (A) is ordinate, draws regression curve, calculates regression coefficient.From result, the assay of this product has good linear in the concentration range of Sorafenib Tosylate concentration 50.23-150.7 μ g/ml.
, repeatabilitysample thief 6 parts, accurately weighed respectively, measure by high performance liquid chromatography content assaying method, investigate the repeatability of assay method.From result, the repeatability of this product assay high performance liquid chromatography is good.
, the recoveryget Sorafenib Tosylate and be about 14mg, totally 9 parts, accurately weighed, put in the measuring bottle of 200ml, separately get each three parts of Sorafenib Tosylate reference substance 8mg, 10mg, 12mg and be set up and state in measuring bottle, add the flowing mutual-assistance and dissolve and be diluted to scale, shake up, as 80%, 100%, 120% need testing solution.According to the high effective liquid chromatography for measuring of assay, calculate measured amount and the recovery.From result, the recovery of this product high performance liquid chromatography assay is good.
5, stability of solutionget the test liquid of this product assay, respectively at 0,1,2,4,6,8,12,24 hour sample introduction, investigate the stability of solution of this product assay liquid phase method, from result, the high performance liquid chromatography solution of this product assay is stable in 24 hours.
, Intermediate precisionwith repeated result for intermediate precision degrees of data group 1, experimental result is intermediate precision degrees of data group 2 separately.Investigate the Intermediate precision of this product assay high performance liquid chromatography, from result, the Intermediate precision of this product assay high performance liquid chromatography is good.
The following items of Sorafenib Tosylate Related substances separation method is verified:
1, system suitability experimentunder the above-mentioned chromatographic condition determined, use Sorafenib Tosylate and its impurity more respectively, impurity peak sequence is p-toluenesulfonic acid, picolinamide phenyl ether, SLFN-SM1, PAPE-urethanes, PAPE-urea, PAPE-carbamic acid isopropyl ester, CTF-aniline, SLFN-I12, des-chloro compound, CTF-urethanes, the chloro-3-TF-compound of 2-, Sorafenib, CTF-urea, and whether potpourri is analyzed this chromatographic condition and met the requirements.Under this condition, between each impurity and main peak and impurity, degree of separation meets the requirements as seen from Figure 2, and peak purity and single-point threshold value all meet the requirements.
, specificityget this product appropriate, destroy respectively under each severe conditions, investigate the separation case destroying product and major component peak.
Acid destroys: get Sorafenib Tosylate 14mg, accurately weighed, puts in 10ml measuring bottle, adds 1mol/L hydrochloric acid 0.5ml, place 36 hours, and add the neutralization of 1mol/L sodium hydroxide solution, solubilizer dissolves and is diluted to scale, shakes up.
Alkali destroys: get Sorafenib Tosylate 14mg, accurately weighed, puts in 10ml measuring bottle, adds 1mol/L sodium hydroxide solution 0.5ml, place 36 hours, and add the neutralization of 1mol/L hydrochloric acid, solubilizer dissolves and is diluted to scale, shakes up.
Oxidative demage: get Sorafenib Tosylate 14mg, accurately weighed, put in 10ml measuring bottle, add 30% hydrogen peroxide 0.5ml, place 36 hours, solubilizer dissolves and is diluted to scale, shakes up.
High temperature: get Sorafenib Tosylate 14mg, accurately weighed, put in crucible, put in 150 DEG C of baking ovens and place 8 hours, be transferred in 10ml measuring bottle, solubilizer dissolves and is diluted to scale, shakes up.
Illumination destroys: get Sorafenib Tosylate 14mg, accurately weighed, put in 50ml measuring bottle, solubilizer dissolves and is diluted to scale, shakes up.48h is placed under 4500 ± 500LUX intensity of illumination.
Get the sample under each failure condition, according to the liquid-phase condition sample introduction of related substance, record chromatogram, result is visible, and the impurity peaks that this product generates under each failure condition all can be separated well with major component peak.The impurity that this product generates under each failure condition is all little, and the impurity peaks of degraded all has larger absorption near determined wavelength 235nm.
, the response of intermediate and typical curveget this product synthetic mesophase picolinamide phenyl ether, test liquid (1) that side reaction product PAPE-urethanes, side reaction product PAPE-urea, Sorafenib Tosylate are mixed with gradient concentration respectively, (2), (3), (4), (5), (6), (7).Get and draw each test liquid 10 μ l respectively, injecting chromatograph, record chromatogram.With concentration (μ g/ml) for horizontal ordinate, peak area is ordinate, draws regression curve, calculates regression coefficient.From above result, this product and each step intermediate are all in good linear within the scope of 0.201 ~ 9.514 μ g/ml, and the response factor of each intermediate and Sorafenib Tosylate is basically identical.
Intermediate 1 low concentration typical curve
Sorafenib Tosylate low concentration typical curve
Side reaction product 1 low concentration typical curve
Side reaction product 2 typical curve
4, stability of solutionget the test liquid of this product determination of related substances, respectively at 0,1,2,4,6,8,12,24 hour sample introduction, investigate the stability of solution of this product Related substances separation liquid phase method, from result, this solution is stable in 24 hours.
5, durabilitybecause the chromatographic condition of this product is gradient elution, and define corresponding chromatographic column model, column temperature, mobile phase ratio, still these conditions are done corresponding fine setting, investigate the durability of chromatographic condition.
As seen from the figure, result shows, under using same brand different batches chromatographic column condition, each chromatogram parametric results of this product, without significant change, proves that this product is to same brand different batches chromatographic column good tolerance; But when using different brands chromatographic column, main peak and previous magazins' layout degree are poor, chromatographic condition is pointed out to need regulation chromatographic column brand and model; Under different determined wavelength, this product major component normalization content results has significant change, and the area ratio of main peak and the impurity peaks of prompting this product is more responsive to wavelength variations, and affect impurity correction factor and quantitative, therefore mensuration wavelength needs to be defined in 235nm; Under different in flow rate condition, each chromatographic parameter of this product, without significant change, proves that this product is to different in flow rate good tolerance; During pH of buffer change, appearance time also has significant change.
, quantitative limit and detectabilityget this product reference substance appropriate, accurately weighed, add after mobile phase is made into Sorafenib Tosylate solution, then precision to measure test liquid appropriate, stepwise dilution, sample introduction is investigated, and result shows this product and is quantitatively limited to 0.4ng/ml, detects and is limited to 0.15ng/ml.
Sorafenib Tosylate bulk drug, in the treatment for the treatment of advanced renal cell carcinoma, has important effect.Current content and Related substance method there is no bibliographical information, and we are by great many of experiments, and the detection method found out, have passed through strict method validation.The demand that can meet research and development and produce, for the listing early of Sorafenib Tosylate medicine provides necessary support.
Above-described embodiment is preferred embodiment of the present invention; it is not the restriction to technical solution of the present invention; as long as without the technical scheme that creative work can realize on the basis of above-described embodiment, all should be considered as falling within the scope of the rights protection of patent of the present invention.
Claims (8)
1. a method for high effective liquid chromatography for measuring Sorafenib Tosylate content, is characterized in that: described chromatographic condition is: selecting with octadecyl silane is filling agent, column length 250mm, determined wavelength 235nm, column temperature 40 DEG C, flow velocity 1.0ml/min; The detecting device adopted is UV-detector; Adopt reversed-phased high performace liquid chromatographic to carry out wash-out by degree such as grade, described mobile phase is trifluoroacetic acid aqueous solution and polar organic solvent, and described trifluoroacetic acid aqueous solution is A phase, and described polar organic solvent is B phase, and in described mobile phase, the organic solvent of B phase is acetonitrile.
2. the method for a kind of high effective liquid chromatography for measuring Sorafenib Tosylate content according to claim 1, is characterized in that: the concentration of the trifluoroacetic acid in described A phase trifluoroacetic acid aqueous solution is 0.1 ~ 1%.
3. the method for a kind of high effective liquid chromatography for measuring Sorafenib Tosylate content according to claim 1, is characterized in that: described B phase is 45 ~ 55% with A phase mixed volume ratio.
4. the method for a kind of high effective liquid chromatography for measuring Sorafenib Tosylate content according to claim 1, is characterized in that: the concrete operation step of described mensuration Sorafenib Tosylate content is as follows:
(1) take 14mg Sorafenib Tosylate, precise weighing, be positioned in 100ml measuring bottle, add mobile phase and dissolve and be diluted to scale, shake up, as test liquid;
(2) separately get Sorafenib Tosylate 14mg, precise weighing, be positioned in 100ml measuring bottle, being mixed with containing Sorafenib concentration is 0.1mg/ml, in contrast liquid;
(3) measure test liquid and contrast solution 10 μ l respectively, injecting chromatograph, record chromatogram, gives money as a gift with calculated by peak area by external standard method, to obtain final product.
5. the method for a high effective liquid chromatography for measuring Sorafenib Tosylate related substance, it is characterized in that: described chromatographic condition is: selecting with octadecyl silane is filling agent, column length 250mm, determined wavelength 235nm, column temperature 40 DEG C, flow velocity 1.0ml/min; The detecting device adopted is UV-detector; Adopt reversed-phased high performace liquid chromatographic to carry out wash-out by gradient, described mobile phase is trifluoroacetic acid aqueous solution and polar organic solvent, and described trifluoroacetic acid aqueous solution is A phase, and described polar organic solvent is B phase, and in described mobile phase, the organic solvent of B phase is acetonitrile.
6. the method for a kind of high effective liquid chromatography for measuring Sorafenib Tosylate related substance according to claim 5, is characterized in that: the concentration of the trifluoroacetic acid in described A phase trifluoroacetic acid aqueous solution is 0.1 ~ 1%.
7. the method for a kind of high effective liquid chromatography for measuring Sorafenib Tosylate content according to claim 5, is characterized in that: described A phase is arranged according to Gradient program with the volume ratio of B phase.
8. the method for a kind of high effective liquid chromatography for measuring Sorafenib Tosylate content according to claim 5, is characterized in that: the concrete operation step of described mensuration Sorafenib Tosylate related substance is as follows:
(4) 14mg Sorafenib Tosylate is got, precise weighing, be positioned in 10ml measuring bottle, add mixed solvent, described mixed solvent is the mixing of water, acetonitrile and ethanol, and the mixed volume of described water, acetonitrile and ethanol is than being 250:450:300, by ultrasonic, Sorafenib Tosylate is fully dissolved, shakes up, as need testing solution;
(5) precision measures need testing solution 1ml, is positioned in 100ml measuring bottle, is diluted to scale, shakes up with the mixed solvent in step (4); Precision measures the solution 1ml of step (5) first stage acquisition again, and be positioned in 10ml measuring bottle, the mixed solvent in optional step (4) carries out being diluted to scale, shakes up, in contrast solution;
(6) get contrast solution 10 μ l injection liquid chromatography, regulate detection sensitivity, make major component chromatogram peak height be 10 ~ 20% of full scale;
(7) precision measures need testing solution and each 10 μ l of contrast solution, respectively injection liquid chromatography, record chromatogram.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105651877A (en) * | 2015-12-30 | 2016-06-08 | 神威药业集团有限公司 | Detection method of sorafenib and related substances thereof |
| CN106226421A (en) * | 2016-07-14 | 2016-12-14 | 合肥华方医药科技有限公司 | A kind of Sorafenib Tosylate has the detection method of related substance |
| CN106932502A (en) * | 2015-12-31 | 2017-07-07 | 上海奥博生物医药技术有限公司 | The assay method of 4- Chloro-2-Pyridyles methyl formate content in a kind of Sorafenib |
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| CN105651877A (en) * | 2015-12-30 | 2016-06-08 | 神威药业集团有限公司 | Detection method of sorafenib and related substances thereof |
| CN106932502A (en) * | 2015-12-31 | 2017-07-07 | 上海奥博生物医药技术有限公司 | The assay method of 4- Chloro-2-Pyridyles methyl formate content in a kind of Sorafenib |
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Application publication date: 20151223 |