CN104678006B - A kind of Sunitinib malate Related substance method - Google Patents
A kind of Sunitinib malate Related substance method Download PDFInfo
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- CN104678006B CN104678006B CN201410499808.9A CN201410499808A CN104678006B CN 104678006 B CN104678006 B CN 104678006B CN 201410499808 A CN201410499808 A CN 201410499808A CN 104678006 B CN104678006 B CN 104678006B
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Abstract
The present invention relates to a kind of Sunitinib malate Related substance method, described method carries out on high performance liquid chromatography, do you adopt Poroshell120? Bonus? RP chromatographic column, ammonium acetate aqueous solution and organic solvent acetonitrile are as moving phase, liquid phase diode-array detector (DAD) or ultraviolet (UV) detector carry out gradient elution detection, effectively be separated and detect relevant substance B, about substance C, have related substance E and other have related substance. It is good that analytical procedure of the present invention has specificity, accuracy rate height and simple and efficient feature.
Description
Technical field
The present invention relates to field of medicine and chemical technology, the detection medicinal chemicals Sunitinib malate relating more specifically to a kind of optimization has the method for related substance.
Background technology
Sunitinib malate, chemistry N-(2-diethylamine ethyl) by name-5 [(Z)-(the sub-base of fluoro-2-oxygen-1 hydrogen of 5--indoles-3-) methyl]-2,4-dimethyl-1 hydrogen-pyrrole-3-carboxamide malate, its chemical structural formula is:
Being a kind of Mutiple Targets receptor tyrosine kinase (RTK) inhibitor, it is mainly used in being treated by oral administration standard treatment does not respond the gastrointestinal stromal tumors that maybe can not tolerate and metastatic renal cell cancer. This medicine is at present by U.S. FDA and Europe EMEA approval listing, and commodity are Sutent. China granted patent CN1329390C discloses the preparation method of Sunitinib malate.
The relevant substance B of degraded and the technique preparation process that also contain Sutent in usual Sunitinib malate bulk drug are introduced relevant substance C and have related substance E, and other have related substance.
About the structural formula of substance B, C and E in table 1
Table 1
Usually need medicine is carried out quality control to ensure the safe handling of medicine, and have related substance to be the project that most medicine must detect. At present, the quality standard of Sunitinib malate is not all recorded in existing version " European Pharmacopoeia " and pharmacopeia forum, " American Pharmacopeia " and its pharmacopeia forum and Chinese Pharmacopoeia 2010 editions. Therefore develop the effective detection method about substance B, C, E and other unknown impurities to be very important.
In order to guarantee detection method to medicine in production phase and suitability and the validity of depositing the phase in stage, usually need analytical procedure to be verified, comprise the experiment such as specificity, preci-sion and accuracy, see Chinese Pharmacopoeia 2010 editions the 2nd annex �� �� A drug standard analytical procedure checking governing principle (the state-promulgated pharmacopoeia council. People's Republic of China's pharmacopeia [S]. Beijing: China Medical Science Press, 2010:194��195). In the investigation process of specificity, it usually needs accelerated the failure medicine by the method such as acid (alkali) hydrolysis, high temperature, strong illumination or oxidation, study the possible degraded product of medicine and degradation pathway, and verify that analytical procedure has specificity.
High performance liquid chromatography is adopted usually to have marker method, external standard method, the principal constituent Self-control method adding correction factor, the principal constituent Self-control method not adding correction factor and area normalization method, see Chinese Pharmacopoeia 2010 editions the 2nd annex V D high performance liquid chromatography (the state-promulgated pharmacopoeia council. People's Republic of China's pharmacopeia [S]. Beijing: China Medical Science Press, 2010:29��31). The related substance that has accurately measured in sample by area normalization method assumes that all mensuration components are all detected in testing sample, and has identical response factor under identical ultraviolet detection wavelength. But in fact, different compounds often has different response factor under identical ultraviolet detection wavelength, and this is well known to those skilled in the art. Therefore areas of peak normalization method measuring error is big, is usually only applicable to investigate roughly the foreign matter content in trial-product.
Wherein, the principal constituent Self-control method not adding correction factor refers to when measuring foreign matter content, if not having impurity reference substance, it is also possible to adopt the principal constituent Self-control method not adding correction factor. After configuring contrast solution with the principal constituent Self-control method adding correction factor and regulate detection sensitivity, get need testing solution and contrast solution appropriate, enter sample respectively, the former writing time, unless otherwise specified, should be 2 times of principal constituent chromatographic peak retention time, measure each impurity on need testing solution color atlas peak area and with the peak area ratio of contrast solution principal constituent relatively, calculate foreign matter content.
Prior art State Food and Drug Administration import drugs registered standard, Sunitinib malate capsule (standard number: JX20060174), in disclose the detection method having related substance of Sunitinib malate. Described method octadecylsilane chemically bonded silica is that weighting agent is (such as SupelcoDiscoveryC18,150 �� 4.6mm, 5 ��m), post temperature is 45 DEG C, determined wavelength is 268nm, and taking the ammonium acetate buffer solution (pH5.0) of 0.05mol/L as mobile phase A, acetonitrile is Mobile phase B, by following gradient elution
Sunitinib malate there is is related substance to detect by highly effective liquid phase chromatographic system, calculates all content having related substance by area normalization method. Therefore there is specificity difference in described method, accuracy is low and working time is excessively long, inefficient problem.
Having, in order to solve existing Sunitinib malate, the technical problem existed in related substance detection method, the present invention provides a kind of accurate, quick and easy Sunitinib malate bulk drug Related substance method.
Summary of the invention
Invention general introduction
The present inventor, by repeatedly testing, screens dissimilar chromatographic column, attempts different moving phase conditions, and a kind of being suitable for of final acquisition detects the analytical procedure having related substance in Sunitinib malate bulk drug. Described method carries out on high performance liquid chromatography, detector is liquid phase diode-array detector (DAD) or ultraviolet (UV) detector, wash-out is carried out as moving phase using ammonium acetate aqueous solution and organic solvent acetonitrile, Poroshell120BonusRP chromatographic column is adopted to carry out chromatographic separation detection, the method has superior specificity, highly sensitive, split hair caccuracy and efficient feature, solves problems of the prior art.
Wherein, the particle diameter of the filler particles of Poroshell120BonusRP chromatographic column is about 2.7 ��m, wherein particle is made up of the porous outer layer of the interior solid core of 1.7 �� m diameter He 0.5 �� m-thick being coated on interior solid core, and wherein stationary phase is the Octadecane hydrocarbon being bonded on described filler particles. Owing to the special construction of the filler particles of this chromatographic column makes it show superior specificity when detecting relevant substance B, C and E of Sunitinib malate bulk drug. Selection Poroshell120BonusRP chromatographic column has the application chromatographic column of the analytical procedure of related substance to be through the result repeatedly screened as Sunitinib malate bulk drug.
Term definition
Term " filler particles " refers in liquid-phase chromatographic column field, liquid-phase chromatographic column is the particle having stationary phase on the surface by loading in pillar (can be different materials, such as silica gel) preparation and obtain, the attributes such as the structure of particle, size, resistance to pressure all can have influence on liquid-phase chromatographic column analyzing the usefulness such as specificity when detecting specific components.
During term " peak purity " refers to that HPLC detects, for judging the investigation parameter whether a certain chromatographic peak is just caused by a material, it is generally acknowledged that namely peak purity thinks that between 0.990��1.000 a certain chromatographic peak investigated is pure, this chromatographic peak is the chromatographic peak of certain one matter.
Term " RT " refers to the retention time of the chromatographic peak in HPLC detection, and unit is minute (min); " RRT " refers to the relative retention time of the chromatographic peak in HPLC detection, it does not have unit, usually using the main peak in corresponding collection of illustrative plates as with reference to peak, the relative retention time of main peak is 1.
Term " v/v " refers to volume ratio, and " w/w " refers to mass ratio.
Detailed Description Of The Invention
The Related substance method of Sunitinib malate bulk drug provided by the invention, is characterized in that:
Described method carries out on high performance liquid chromatograph;
Detector is diode-array detector (DAD) or ultraviolet absorption detector (UV), and determined wavelength is 268nm;
Liquid-phase chromatographic column is Poroshell120BonusRP reverse-phase chromatographic column, and chromatogram column temperature is 20 DEG C��30 DEG C;
Moving phase by as damping fluid ammonium acetate solution and what organic solvent acetonitrile formed, and carry out gradient elution, the flow velocity of moving phase is about 0.9mL/min��1.1mL/min;
Injection Sunitinib malate need testing solution and Sunitinib malate reference substance solution detect, and calculate, by the principal constituent Self-control method not adding correction factor, the content having related substance.
In certain embodiments, Poroshell120BonusRP reverse-phase chromatographic column is that the filler particles being about 2.7 ��m by particle diameter is filled, wherein filler particles is made up of the porous outer layer of the interior solid core of 1.7 �� m diameter He 0.5 �� m-thick being coated on interior solid core, and wherein stationary phase is the Octadecane hydrocarbon being bonded on described filler particles.
In certain embodiments, ammonium acetate solution concentration is about 3.45g/L��4.20g/L, pH about 5.5��6.0.
In certain embodiments, method of the present invention adopts the mode of gradient elution that detection sample is carried out separation detection, and described gradient elution mode can be
Time (min) ammonium acetate solution (v/v, %) acetonitrile (v/v, %)
09010
123763
In certain embodiments, high performance liquid chromatograph can be Agilent1260, Agilent1290 or WatersUPLC.
In certain embodiments, carry out when the configuration of need testing solution is lucifuge. The mixing solutions of the trial-product water and acetonitrile of getting appropriate Sunitinib malate dissolves, dilution, and final concentration is about 0.10mg/mL��1.0mg/mL, it is more preferable to need testing solution concentration is about 0.50mg/mL; The mixing solutions that reference substance solution is the trial-product water and acetonitrile of getting appropriate Sunitinib malate dissolves, and dilution, final concentration is about 0.2 �� g/mL��2.0 �� g/mL, it is more preferable to reference substance solution concentration is about 1.0 �� g/mL. In wherein said water and the mixing solutions of acetonitrile, the volume ratio of water and acetonitrile can be 7:3.
In certain embodiments, relevant substance method provided by the invention, is characterized in that:
High performance liquid chromatograph: Agilent1260;
Detector is diode-array detector (DAD), and determined wavelength is 268nm;
Liquid-phase chromatographic column is Poroshell120BonusRP reverse-phase chromatographic column, and chromatogram column temperature is 25 DEG C;
Flow velocity is about 1.0mL/min;
Gradient elution:
Time (min) ammonium acetate solution (v/v, %) acetonitrile (v/v, %)
09010
123763
Injection Sunitinib malate need testing solution and Sunitinib malate reference substance solution detect, and calculate, by the principal constituent Self-control method not adding correction factor, the content having related substance;
Wherein, Poroshell120BonusRP reverse-phase chromatographic column is that the filler particles being about 2.7 ��m by particle diameter is filled, wherein filler particles is made up of the porous outer layer of the interior solid core of 1.7 �� m diameter He 0.5 �� m-thick being coated on interior solid core, wherein stationary phase is the Octadecane hydrocarbon being bonded on described filler particles, pillar length is 50mm, and pillar interior diameter is 4.6mm;
Wherein ammonium acetate solution concentration is about 3.85g/L, pH about 5.7;
Wherein, Sunitinib malate need testing solution is that Sunitinib malate concentration is about the acetonitrile of 0.50mg/mL and the mixing solutions of water, Sunitinib malate reference substance solution is the acetonitrile of Sunitinib malate concentration about 1.0 �� g/mL and the mixing solutions of water, in wherein said water and the mixing solutions of acetonitrile, the volume ratio of water and acetonitrile can be 7:3.
Analytical procedure provided by the present invention is suitable for detecting has related substance in Sunitinib malate bulk drug, is particularly suitable for detecting relevant substance B wherein, about substance C with there is related substance E.
Accompanying drawing explanation
Fig. 1 shows the detection color atlas of the blank solution in embodiment 1
Fig. 2 shows the detection color atlas of the Sunitinib malate reference substance solution in embodiment 1
Fig. 3 shows the detection color atlas of the Sunitinib malate need testing solution in embodiment 1
Fig. 4 shows the detection color atlas of the spiked solution in embodiment 1
Fig. 5 shows the detection color atlas not destroying solution in embodiment 2
Fig. 6 shows the detection color atlas of the acid destruction solution in embodiment 2
Fig. 7 shows that the alkali in embodiment 2 destroys the detection color atlas of solution
Fig. 8 shows the detection color atlas of the Oxidative demage solution in embodiment 2
Fig. 9 shows that the illumination in embodiment 2 destroys the detection color atlas of solution
Figure 10 shows that the high temperature in embodiment 2 destroys the detection color atlas of solution
Figure 11 shows the color atlas of the detection of the Oxidative demage solution comparison and detection method in embodiment 5
Embodiment
In order to make the technician of this area understand the technical scheme of the present invention better, below disclose further some unrestricted embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
Embodiment 1 system flexibility is tested
Solution is prepared:
Blank solution (diluent): the mixing solutions of preparation water and acetonitrile, volume ratio is 7:3.
Sunitinib malate need testing solution: when lucifuge, gets Sunitinib malate trial-product appropriate, accurately weighed, puts in volumetric flask, becomes Sunitinib malate concentration to be the solution of about 0.50mg/mL by appropriate diluent preparing.
Sunitinib malate reference substance solution: when lucifuge, it is appropriate that precision pipettes Sunitinib malate need testing solution, puts in volumetric flask, is the solution of about 1.0 �� g/mL by appropriate diluted to Sunitinib malate concentration.
Spiked solution: get Sunitinib malate trial-product, about substance B, about substance C with there is related substance E appropriate, accurately weighed, being placed in volumetric flask diluent preparing one-tenth is about 0.50mg/mL containing Sunitinib malate concentration, is about 1.6 �� g/mL containing related substance B concentration, about substance C concentration is about 0.6 �� g/mL and has related substance E concentration to be respectively the solution of about 0.6 �� g/mL.
Sample detection:
Chromatographic condition is as follows:
High performance liquid chromatograph: Agilent1260;
Detector is diode-array detector (DAD), and determined wavelength is 268nm;
Liquid-phase chromatographic column is Poroshell120BonusRP reverse-phase chromatographic column, and chromatogram column temperature is 25 DEG C;
Flow velocity is about 1.0mL/min;
Gradient elution:
Time (min) ammonium acetate solution (v/v, %) acetonitrile (v/v, %)
09010
123763
Wherein, Poroshell120BonusRP reverse-phase chromatographic column is that the filler particles being about 2.7 ��m by particle diameter is filled, wherein filler particles is made up of the porous outer layer of the interior solid core of 1.7 �� m diameter He 0.5 �� m-thick being coated on interior solid core, wherein stationary phase is the Octadecane hydrocarbon being bonded on described filler particles, pillar length is 50mm, and pillar interior diameter is 4.6mm;
Wherein ammonium acetate solution concentration is about 3.85g/L, pH about 5.7;
Get blank solution, Sunitinib malate need testing solution, Sunitinib malate reference substance solution and spiked solution, respectively enter sample 1 pin, record color atlas. The retention time (RT) of main peak in report Sunitinib malate need testing solution, Sunitinib malate reference substance solution and spiked solution; The peak purity of main peak in Sunitinib malate need testing solution and spiked solution, about the relative retention time (RRT) of substance B, C and E and peak area, main peak and the resolution about substance B, C and E and adjacent peak. Fig. 1 shows that blank solution is noiseless to the detection of Sunitinib malate trial-product; Fig. 2 shows that in Sunitinib malate reference substance solution detection color atlas, reference substance has good response value, highly sensitive; Fig. 3 shows that the resolution of main peak and each known list assorted (about substance B, C and E) and adjacent peak in Sunitinib malate trial-product is all good and Fig. 4 shows that related substance (about substance B, C and the E) peak area that there will be a known of respectively interpolation in spiked solution significantly increases, and peak area and impurity level have linear relationship. Detected result is in table 1.
Table 1
Experimentally result and collection of illustrative plates,
Blank solution, need testing solution are compared with spiked solution, and blank solution is noiseless at assorted (about substance B, C and E) the retention time place of main peak and each known list; In need testing solution and spiked solution color atlas, the resolution of main peak and each known list assorted (about substance B, C and E) and adjacent peak is all not less than 1.5; Need testing solution is consistent with the main peak retention time in spiked solution and contrast solution; In need testing solution and spiked solution color atlas, the peak purity factor of main peak is all greater than 0.990; Compared with need testing solution, in spiked solution color atlas, the peak area at the peak at the retention time place of impurity B, impurity C, impurity E obviously strengthens. Therefore, method specificity provided by the invention is good.
Embodiment the last 2 is degraded breaking test
Destruction sample solution is prepared:
Diluent: the mixing solutions of preparation water and acetonitrile, volume ratio is 7:3.
Trial-product stock solution: when lucifuge, gets trial-product 135mg, accurately weighed to, in 50mL volumetric flask, holding with diluent ultrasonic dissolution is also fixed, shake even, to obtain final product.
Not destroying need testing solution: when lucifuge, precision pipettes gets in trial-product stock solution 5mL to 25mL volumetric flask, surely holds with diluent, shakes even, to obtain final product.
Acid destroys solution: when lucifuge, precision pipettes in trial-product stock solution 5mL to 25mL volumetric flask, adds the hydrochloric acid soln 1mL of 6mol/L, shakes even, sealing, after placing 24h, adds 6mol/L sodium hydroxide solution 1mL and neutralizes, let cool in room temperature, surely hold with diluent, shake even, to obtain final product;
Alkali destroys solution: when lucifuge, precision pipettes in trial-product stock solution 5mL to 25mL volumetric flask, adds the sodium hydroxide solution 1mL of 6mol/L, shakes even, sealing, after placing 24h, adds 6mol/L hydrochloric acid soln 1mL and neutralizes, let cool in room temperature, surely hold with diluent, shake even, to obtain final product;
Oxidative demage solution: when lucifuge, precision pipettes in trial-product stock solution 5mL to 25mL volumetric flask, adds 15% hydrogen peroxide 1mL, after placing 24h, surely holds with diluent in room temperature, shakes even, to obtain final product;
Illumination destroys solution: get trial-product appropriate, tiling is in weighing bottle, when putting visible ray 4500Lux �� 500Lux, UV-light 1.7W*h/m2, the visible intensity of illumination total amount of illumination 13 angel reaches 1200000Lux, and ultraviolet ray intensity reaches more than 200W/m2, then gets above-mentioned sample 27mg, accurately weighed, put in 100mL volumetric flask, when lucifuge, surely hold with diluent, shake even, to obtain final product;
High temperature destroys solution: get trial-product appropriate, and tiling to, in weighing bottle, placing 24h in 105 DEG C of baking ovens, and taking-up lets cool, and then gets above-mentioned sample and is about 27mg, accurately weighed, puts in 100mL measuring bottle, when lucifuge, surely holds with diluent, shakes even, to obtain final product;
Sample detection:
Chromatographic condition is such as embodiment 1;
Get above-mentioned unbroken solution and each destruction solution respectively enters sample 1 pin, record color atlas. Report resolution, the main peak peak purity of main peak and adjacent peak in each destruction solution and peak area percentage composition of always mixing.
Fig. 5, Fig. 6, Fig. 7, Fig. 8, Fig. 9 and Figure 10 do not destroy the color atlas that solution, acid destruction solution, alkali destruction solution, Oxidative demage solution, illumination destruction solution and high temperature destroy solution, the result of the measured in solution under showing non-failure condition and under each failure condition.
Detected result is in table 2.
Table 2
| Solution title | Total assorted (%) | The main peak purity factor | Main peak and adjacent peak resolution |
| Do not destroy solution | 0.37 | 1.0000 | 1.5 |
| Acid destroys solution | 1.06 | 1.000 | 1.5 |
| Alkali destroys solution | 1.45 | 1.000 | 2.5 |
| Oxidative demage solution | 6.72 | 1.000 | 2.7 |
| Illumination destroys solution | 0.36 | 1.000 | 1.5 |
| High temperature destroys solution | 0.34 | 1.000 | 1.6 |
Result according to collection of illustrative plates 5-10 and table 4 it will be seen that the method for the invention in detection without, in the Sunitinib malate solution destroyed and the Sunitinib malate solution through destroying, the peak purity of main peak is very high, shows that main peak does not include other impurity peaks; Main peak and other impurity chromatographic peak resolution are good, and >=1.5. Therefore the method for the present invention is at mensuration Sunitinib malate, or even Sunitinib malate having of sample of degraded all has good specificity during related substance, it is possible to the content having related substance of the Sunitinib malate in effective detection control preservation process.
Embodiment 3 precision is tested
Solution is prepared:
Diluent: the mixing solutions of preparation water and acetonitrile, volume ratio is 7:3.
Sunitinib malate need testing solution: when lucifuge, gets Sunitinib malate trial-product appropriate, accurately weighed, puts in volumetric flask, becomes Sunitinib malate concentration to be the solution of about 0.50mg/mL by appropriate diluent preparing, parallel preparation 6 parts.
Sunitinib malate reference substance solution: when lucifuge, it is appropriate that precision pipettes Sunitinib malate need testing solution, puts in volumetric flask, is the solution of about 1.0 �� g/mL by appropriate diluted to Sunitinib malate concentration.
Sample detection:
Chromatographic condition is such as embodiment 1;
Get Sunitinib malate reference substance solution and enter sample 2 pin, get 6 parts of Sunitinib malate need testing solutions and respectively enter sample 1 pin. Calculate the content of each impurity in 6 parts of Sunitinib malate need testing solutions, content average and total assorted relative standard deviation value by the principal constituent Self-control method not adding correction factor, and record the retention time of each impurity and the relative standard deviation of retention time.
Detected result is in table 3
Table 3
According to detected result, method provided by the invention is in detection Sunitinib malate has the precision of related substance to test, the retention time of each impurity is substantially stable, the principal constituent Self-control method not adding correction factor is adopted to calculate the content of each impurity, the content of each impurity is basically identical, total assorted relative standard deviation is less than 5.0%, has extraordinary precision.
Embodiment 4 accuracy is tested
Solution is prepared:
Diluent: the mixing solutions of preparation water and acetonitrile, volume ratio is 7:3.
Sunitinib malate need testing solution: when lucifuge, get Sunitinib malate trial-product and it is about 27mg, accurately weighed, put in 50mL volumetric flask, make ultrasonic dissolution with appropriate diluent and it is diluted to scale, be mixed with the solution that Sunitinib malate concentration is about 0.50mg/mL.
Sunitinib malate reference substance solution: when lucifuge, precision pipettes 1mL Sunitinib malate need testing solution in 50mL volumetric flask, surely holds with diluent, shakes even; Precision pipettes in above-mentioned solution 5mL to 50mL volumetric flask again, surely holds with diluent, is mixed with the solution that Sunitinib malate concentration is about 1.0 �� g/mL.
About substance B, C and E storing solution: get that relevant substance B is about 16mg, relevant substance C is about 6mg and has related substance E to be about 6mg, accurately weighed, put in 1000mL volumetric flask, dissolve with diluent and be diluted to scale, shake even.
Adding mark solution: when lucifuge, the trial-product getting Sunitinib malate is about 27mg, accurately weighed, is placed in the volumetric flask of 50mL; Precision pipettes 5mL about substance B, C and E storing solution in the volumetric flask of above-mentioned 50mL again, by diluted to scale, it is mixed with Sunitinib malate concentration to be about 0.50mg/mL, be about 1.6 �� g/mL containing related substance B concentration, about substance C concentration be about 0.6 �� g/mL and have related substance E concentration to be respectively the solution of about 0.6 �� g/mL, parallel preparation 3 parts.
Sample detection:
Chromatographic condition is such as embodiment 1;
Get the Sunitinib malate reference substance solution, the Sunitinib malate need testing solution that prepare and add mark solution and detect by the chromatographic condition of embodiment 1, every part of sample feeding 1 pin, record Sunitinib malate reference substance solution compares the peak area at peak, record Sunitinib malate need testing solution is marked about substance B, about substance C and the peak area having related substance E in solution with adding, and is calculated as follows the recovery of standard addition of each impurity:
Theoretical amount (mg)=Wx��Px
In formula: WSTDFor the sample weighting amount of Sunitinib malate in Sunitinib malate reference substance solution, mg;
Wx is about substance B, about substance C and the weighing having related substance E;
ASTDFor Sunitinib malate reference substance solution compares peak peak area;
ASFor Sunitinib malate need testing solution has the peak area of related substance (about substance B, C or E);
AXThe peak area having related substance (about substance B, C or E) in mark solution for respectively adding; DStdFor the extension rate of Sunitinib malate reference substance solution;
DXFor respectively adding the extension rate of mark solution;
PStdFor the content of Sunitinib malate trial-product, it is 99.4%, w/w;
PXFor relevant substance B (98.7%, w/w), relevant substance C (99.7%, w/w) and the content having related substance E (99.2%, w/w);
Experimental result is such as table 4
Table 4
Embodiment 5 comparative example
In Example the last 2 degradation experiment, Oxidative demage solution is as test fluid, by prior art State Food and Drug Administration import drugs registered standard, Sunitinib malate capsule (standard number: JX20060174), disclosed in the detection method of related substance that has of Sunitinib malate detect, enter sample 1 pin, record color atlas. Such as Figure 11, show that the impurity that Oxidative demage produces cannot be separated with main peak.
In sum,
The method of related substance that has of Sunitinib malate of the present invention has good specificity, and precision is good, and accuracy height and detection speed are fast, applicable in the control having related substance produced and between preservation period.
The method of the present invention is described by better embodiment, and methods and applications as herein described obviously can be changed in content of the present invention, spirit and scope or suitably change and combination by related personnel, realize and apply the technology of the present invention. Those skilled in the art can use for reference content herein, and suitable improving technique parameter realizes. Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (6)
1. a Sunitinib malate Related substance method, is characterized in that:
Described method carries out on high performance liquid chromatograph;
Detector is diode-array detector or ultraviolet absorption detector, and determined wavelength is 268nm;
Liquid-phase chromatographic column is Poroshell120BonusRP reverse-phase chromatographic column, and chromatogram column temperature is 20 DEG C��30 DEG C;
Moving phase by as damping fluid ammonium acetate solution and what organic solvent acetonitrile formed, and carry out gradient elution, the flow velocity of moving phase is 0.9mL/min��1.1mL/min;
Injection Sunitinib malate need testing solution and Sunitinib malate reference substance solution detect, and calculate, by the principal constituent Self-control method not adding correction factor, the content having related substance;
Wherein said Poroshell120BonusRP reverse-phase chromatographic column is that the filler particles being about 2.7 ��m by particle diameter is filled, wherein filler particles is made up of the porous outer layer of the interior solid core of 1.7 �� m diameter He 0.5 �� m-thick being coated on interior solid core, and wherein stationary phase is the Octadecane hydrocarbon being bonded on described filler particles;
The concentration of wherein said ammonium acetate solution is 3.45g/L��4.20g/L, pH5.5��6.0;
Gradient program is as follows:
Wherein said method is the relevant substance B for detecting in Sunitinib malate bulk drug, relevant substance C or has related substance E.
2. analytical procedure according to claim 1, wherein said Sunitinib malate need testing solution is that the mixing solutions getting Sunitinib malate trial-product water and acetonitrile dissolves, dilution, and final concentration is 0.10mg/mL��1.0mg/mL; The mixing solutions that described Sunitinib malate reference substance solution gets Sunitinib malate trial-product water and acetonitrile dissolves, and dilution, final concentration is 0.2 �� g/mL��2.0 �� g/mL.
3. in analytical procedure according to claim 2, wherein said water and the mixing solutions of acetonitrile, the volume ratio of water and acetonitrile is 7:3.
4. a Sunitinib malate Related substance method, is characterized in that:
Described method carries out on high performance liquid chromatograph;
Detector is diode-array detector, and determined wavelength is 268nm;
Liquid-phase chromatographic column is Poroshell120BonusRP reverse-phase chromatographic column, and chromatogram column temperature is 25 DEG C;
Flow velocity is about 1.0mL/min;
Gradient elution:
Injection Sunitinib malate need testing solution and Sunitinib malate reference substance solution detect, and calculate, by the principal constituent Self-control method not adding correction factor, the content having related substance;
Wherein, Poroshell120BonusRP reverse-phase chromatographic column is that the filler particles being about 2.7 ��m by particle diameter is filled, wherein filler particles is made up of the porous outer layer of the interior solid core of 1.7 �� m diameter He 0.5 �� m-thick being coated on interior solid core, wherein stationary phase is the Octadecane hydrocarbon being bonded on described filler particles, pillar length is 50mm, and pillar interior diameter is 4.6mm;
Wherein ammonium acetate solution concentration is about 3.85g/L, pH about 5.7;
Wherein, Sunitinib malate need testing solution is that Sunitinib malate concentration is about the acetonitrile of 0.50mg/mL and the mixing solutions of water, Sunitinib malate reference substance solution is the acetonitrile of Sunitinib malate concentration about 1.0 �� g/mL and the mixing solutions of water, in wherein said water and the mixing solutions of acetonitrile, the volume ratio of water and acetonitrile is 7:3;
Wherein said method is the relevant substance B for detecting in Sunitinib malate bulk drug, relevant substance C or has related substance E.
5., according to the arbitrary described analytical procedure of claim 1-4, wherein said high performance liquid chromatograph is Agilent1260, Agilent1290 or WatersUPLC.
6. analytical procedure according to claim 5, wherein said method is the relevant substance B for detecting in Sunitinib malate bulk drug, about substance C with there is related substance E.
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Non-Patent Citations (5)
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| B.Sandhya 等.RP-HPLC METHOD DEVELOPMENT AND VALIDATION FOR THE ANALYISIS OF SUNITINIB IN PHARMACEUTICAL DOSAGE FORMS.《International Journal of Science Innovations and Discoveries》.2011,第1卷(第3期),441-450. * |
| Marie-Christine Etienne-Grimaldi 等.A routine feasible HPLC analysis for the anti-angiogenic tyrosine kinase inhibitor,sunitinib, and its main metabolite, SU12662, in plasma.《Journal of Chromatography B》.2009,第877卷3757-3761. * |
| Quantification of sunitinib in human plasma by high-performance liquid chromatography–tandem mass spectrometry;Patton Minkin 等;《Journal of Chromatography B》;20080912;第874卷;84-88 * |
| 冯亚宁 等.HPLC法测定苹果酸舒尼替尼胶囊中主药的含量.《中国药房》.2012,第23卷(第41期),3910-3911. * |
| 张亚明.高效液相色谱双波长法测定人血浆中舒尼替尼的浓度.《中国医药》.2011,第6卷(第12期),1461-1463. * |
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