CN104678006A - Method for analyzing substances relevant to sunitinib malate - Google Patents
Method for analyzing substances relevant to sunitinib malate Download PDFInfo
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Abstract
The invention relates to a method for analyzing substances relevant to sunitinib malate. The method is carried out on a high performance liquid chromatography; a Poroshell120 Bonus RP chromatographic column is adopted; an ammonium acetate aqueous solution and an organic solvent-acetonitrile act as flow phases; a liquid phase diode array detector (DAD) or an ultraviolet (UV) detector are used for performing gradient elution detection; a relevant substance B, a relevant substance C, a relevant substance E and other relevant substances are separated and detected effectively. The method has the characteristics of good specificity, high accuracy, easiness, convenience and rapidness.
Description
Technical field
The present invention relates to field of medicine and chemical technology, relate more specifically to a kind of method of detection medicinal chemicals Sunitinib malate related substance of optimization.
Background technology
Sunitinib malate, chemistry N-(2-diethylaminethyl)-5 [(Z)-(the fluoro-2-oxygen of 5--1 hydrogen-indoles-3-subunit) methyl]-2 by name, 4-dimethyl-1 hydrogen-pyrrole-3-carboxamide malate, its chemical structural formula is:
Be a kind of Mutiple Targets receptor tyrosine kinase (RTK) inhibitor, it is mainly used in standard treatment not being responded to the gastrointestinal stromal tumors and metastatic renal cell cancer that maybe can not tolerate by oral treatment.This medicine is ratified listing by U.S. FDA and European EMEA at present, and commodity are Sutent.China granted patent CN 1329390C discloses the preparation method of Sunitinib malate.
Degraded related substance B also containing Sutent in usual Sunitinib malate bulk drug and technique preparation process introduce related substance C and related substance E, and other related substances.
The structural formula of related substance B, C and E is in table 1
Table 1
In order to ensure that the safe handling of medicine needs to carry out quality control to medicine usually, and related substance is the project that most medicine must detect.At present, the quality standard of Sunitinib malate is not all recorded in current edition " European Pharmacopoeia " and Pharmacopeial Forum, " American Pharmacopeia " and its Pharmacopeial Forum and Chinese Pharmacopoeia 2010 editions.Therefore the effective detection method developing related substance B, C, E and other unknown impurities is very important.
In order to ensure detection method to medicine in production phase and applicability and the validity of depositing the phase in stage, usually need to verify analytical approach, comprise the experiment such as specificity, preci-sion and accuracy, see Chinese Pharmacopoeia 2010 editions second annex Ⅹ Ⅸ A drug standard analytical approach verification guide principle (Chinese Pharmacopoeia Commission. Pharmacopoeia of People's Republic of China [S]. Beijing: China Medical Science Press, 2010:194 ~ 195).In the investigation process of specificity, usually need to be accelerated the failure medicine by methods such as acid (alkali) hydrolysis, high temperature, strong illumination or oxidations, study the possible catabolite of medicine and degradation pathway, and check analysis method has specificity.
High performance liquid chromatography is adopted usually to have internal standard method, external standard method, the major component Self-control method of the correction up factor, the major component Self-control method of the not correction up factor and area normalization method, see Chinese Pharmacopoeia 2010 editions second annex V D high performance liquid chromatography (Chinese Pharmacopoeia Commission. Pharmacopoeia of People's Republic of China [S]. Beijing: China Medical Science Press, 2010:29 ~ 31).Be that in hypothesis testing sample, all mensuration components are all detected by the related substance in area normalization method exactly working sample, and under identical UV detect wavelength, there is identical response factor.But in fact, different compounds often has different response factor under identical UV detect wavelength, and this is well known to those skilled in the art.Therefore areas of peak normalization method measuring error is large, is usually only applicable to investigate roughly the impurity content in test sample.
Wherein, when the major component Self-control method of the not correction up factor refers to and measures impurity content, if there is no impurity reference substance, the major component Self-control method of the not correction up factor can also be adopted.With the major component Self-control method configuration contrast solution after regulating detection sensitivity of the correction up factor, get need testing solution and contrast solution is appropriate, sample introduction respectively, the former writing time, unless otherwise specified, should be 2 times of major component chromatographic peak retention time, measure each impurity on need testing solution chromatogram peak area and with the peak area ratio of contrast solution major component comparatively, calculate impurity content.
Prior art State Food and Drug Administration import drugs registered standard, Sunitinib malate capsule (standard number: JX20060174), in disclose the detection method of the related substance of Sunitinib malate.Described method octadecylsilane chemically bonded silica is that filling agent is (as Supelco Discovery C18,150 × 4.6mm, 5 μm), column temperature is 45 DEG C, determined wavelength is 268nm, and with the ammonium acetate buffer solution of 0.05mol/L (pH 5.0) for mobile phase A, acetonitrile is Mobile phase B, by following gradient elution
In highly effective liquid phase chromatographic system, Sunitinib malate related substance is detected, calculate the content of all related substances by area normalization method.Therefore there is specificity difference in described method, accuracy is low and working time is long, inefficient problem.
In order to solve the technical matters existed in existing Sunitinib malate related substance detection method, the invention provides a kind of accurate, quick and easy Sunitinib malate bulk drug Related substance method.
Summary of the invention
Summary of the invention
The present inventor, by repeatedly testing, screens dissimilar chromatographic column, attempts different mobile phase conditions, and final acquisition is a kind of is suitable for the analytical approach detecting related substance in Sunitinib malate bulk drug.Described method is carried out on high performance liquid chromatography, detecting device is liquid phase diode array detector (DAD) or ultraviolet (UV) detecting device, wash-out is carried out as mobile phase using ammonium acetate aqueous solution and organic solvent acetonitrile, Poroshell 120Bonus RP chromatographic column is adopted to carry out chromatographic resolution detection, the method has superior specificity, high sensitivity, pin-point accuracy and efficient feature, solves problems of the prior art.
Wherein, the particle diameter of the filler particles of Poroshell 120Bonus RP chromatographic column is about 2.7 μm, wherein particle is made up of the interior solid core of 1.7 μm of diameters and the porous outer layer that is coated on 0.5 μm of interior solid core thick, and wherein Stationary liquid is the n-octadecane hydrocarbon be bonded on described filler particles.Special construction due to the filler particles of this chromatographic column makes it show superior specificity when detecting related substance B, C and E of Sunitinib malate bulk drug.Poroshell 120Bonus RP chromatographic column is selected to be through the result of repeatedly screening as the application chromatographic column of the analytical approach of Sunitinib malate bulk drug related substance.
Term definition
Term " filler particles " refers in liquid-phase chromatographic column field, liquid-phase chromatographic column (can be different materials by loading the particle having Stationary liquid on the surface in pillar, as silica gel) to prepare and obtain, the attribute such as structure, size, resistance to pressure of particle all can have influence on the usefulness such as the specificity when analyzing detection specific components of liquid-phase chromatographic column.
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 investigated a certain chromatographic peak 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); " " refer to the relative retention time of the chromatographic peak in HPLC detection, do not have unit, usually using the main peak in corresponding collection of illustrative plates as reference peak, the relative retention time of main peak is 1 to RRT.
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 is carried out on high performance liquid chromatograph;
Detecting device is diode array detector (DAD) or ultraviolet absorption detector (UV), and determined wavelength is 268nm;
Liquid-phase chromatographic column is Poroshell 120Bonus RP reverse-phase chromatographic column, and chromatogram column temperature is 20 DEG C ~ 30 DEG C;
Mobile phase by form as the ammonium acetate solution of damping fluid and organic solvent acetonitrile, and carries out gradient elution, and the flow velocity of mobile phase is about 0.9mL/min ~ 1.1mL/min;
Injection Sunitinib malate need testing solution and Sunitinib malate reference substance solution detect, and calculate the content of related substance by the major component Self-control method of the not correction up factor.
In certain embodiments, Poroshell 120Bonus RP reverse-phase chromatographic column is that the filler particles being about 2.7 μm by particle diameter is filled, wherein filler particles is made up of the interior solid core of 1.7 μm of diameters and the porous outer layer that is coated on 0.5 μm of interior solid core thick, and wherein Stationary liquid is the n-octadecane hydrocarbon be 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 to carry out being separated detection to detecting sample, and described gradient elution mode can be
Time (min) ammonium acetate solution (v/v, %) acetonitrile (v/v, %)
0 90 10
12 37 63
In certain embodiments, high performance liquid chromatograph can be Agilent 1260, Agilent 1290 or Waters UPLC.
In certain embodiments, the configuration of need testing solution carries out under lucifuge condition.The mixed solution of the test sample water and acetonitrile of getting appropriate Sunitinib malate dissolves, dilution, and ultimate density is about 0.10mg/mL ~ 1.0mg/mL, and more preferably need testing solution concentration is about 0.50mg/mL; Reference substance solution is that the mixed solution of the test sample water and acetonitrile getting appropriate Sunitinib malate dissolves, and dilution, ultimate density is about 0.2 μ g/mL ~ 2.0 μ g/mL, and more preferably reference substance solution concentration is about 1.0 μ g/mL.In wherein said water and the mixed solution of acetonitrile, the volume ratio of water and acetonitrile can be 7:3.
In certain embodiments, related substance method provided by the invention, is characterized in that:
High performance liquid chromatograph: Agilent 1260;
Detecting device is diode array detector (DAD), and determined wavelength is 268nm;
Liquid-phase chromatographic column is Poroshell 120Bonus RP 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, %)
0 90 10
12 37 63
Injection Sunitinib malate need testing solution and Sunitinib malate reference substance solution detect, and calculate the content of related substance by the major component Self-control method of the not correction up factor;
Wherein, Poroshell 120Bonus RP reverse-phase chromatographic column is that the filler particles being about 2.7 μm by particle diameter is filled, wherein filler particles is made up of the interior solid core of 1.7 μm of diameters and the porous outer layer that is coated on 0.5 μm of interior solid core thick, wherein Stationary liquid is the n-octadecane hydrocarbon be 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 mixed solution of water, Sunitinib malate reference substance solution is the acetonitrile of Sunitinib malate concentration about 1.0 μ g/mL and the mixed solution of water, in wherein said water and the mixed solution of acetonitrile, the volume ratio of water and acetonitrile can be 7:3.
Analytical approach provided by the present invention is suitable for detecting the related substance in Sunitinib malate bulk drug, is particularly suitable for the related substance B, related substance C and the related substance E that detect wherein.
Accompanying drawing explanation
Fig. 1 shows the detection chromatogram of the blank solution in embodiment 1
Fig. 2 shows the detection chromatogram of the Sunitinib malate reference substance solution in embodiment 1
Fig. 3 shows the detection chromatogram of the Sunitinib malate need testing solution in embodiment 1
Fig. 4 shows the detection chromatogram of the spiked solution in embodiment 1
Fig. 5 shows the detection chromatogram not destroying solution in embodiment 2
Fig. 6 shows that the acid in embodiment 2 destroys the detection chromatogram of solution
Fig. 7 shows that the alkali in embodiment 2 destroys the detection chromatogram of solution
Fig. 8 shows the detection chromatogram of the Oxidative demage solution in embodiment 2
Fig. 9 shows that the illumination in embodiment 2 destroys the detection chromatogram of solution
Figure 10 shows the detection chromatogram of the high temperature solution in embodiment 2
Figure 11 shows the chromatogram that the Oxidative demage solution contrast detection method in embodiment 5 detects
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting 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 preparation:
Blank solution (dilution): the mixed solution of preparation water and acetonitrile, volume ratio is 7:3.
Sunitinib malate need testing solution: under lucifuge condition, gets Sunitinib malate test sample 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: under lucifuge condition, it is appropriate that precision pipettes Sunitinib malate need testing solution, and putting in volumetric flask, is the solution of about 1.0 μ g/mL by appropriate diluted to Sunitinib malate concentration.
Spiked solution: get Sunitinib malate test sample, related substance B, related substance C and related substance E appropriate, accurately weighed, being placed in volumetric flask diluent preparing, to become containing Sunitinib malate concentration be about 0.50mg/mL, containing related substance B concentration be about 1.6 μ g/mL, related substance C concentration is the solution that about 0.6 μ g/mL and related substance E concentration are respectively about 0.6 μ g/mL.
Sample detection:
Chromatographic condition is as follows:
High performance liquid chromatograph: Agilent 1260;
Detecting device is diode array detector (DAD), and determined wavelength is 268nm;
Liquid-phase chromatographic column is Poroshell 120Bonus RP 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, %)
0 90 10
12 37 63
Wherein, Poroshell 120Bonus RP reverse-phase chromatographic column is that the filler particles being about 2.7 μm by particle diameter is filled, wherein filler particles is made up of the interior solid core of 1.7 μm of diameters and the porous outer layer that is coated on 0.5 μm of interior solid core thick, wherein Stationary liquid is the n-octadecane hydrocarbon be 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, each sample introduction 1 pin, record chromatogram.The retention time (RT) of main peak in report Sunitinib malate need testing solution, Sunitinib malate reference substance solution and spiked solution; The degree of separation of the peak purity of main peak, the relative retention time (RRT) of related substance B, C and E and peak area in Sunitinib malate need testing solution and spiked solution, main peak and related substance B, C and E and adjacent peak.Fig. 1 shows that blank solution detects noiseless to Sunitinib malate test sample; Fig. 2 shows that Sunitinib malate reference substance solution detects in chromatogram, and reference substance has good response, highly sensitive; Fig. 3 shows that the good and Fig. 4 of the degree of separation of main peak and each known list assorted (related substance B, C and E) and adjacent peak in Sunitinib malate test sample shows that related substance (related substance B, C and E) peak area that there will be a known of respectively interpolation in spiked solution enlarges markedly, and peak area and impurity level have linear relationship.Testing 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 (related substance B, C and E) the retention time place of main peak and each known list; In need testing solution and spiked solution chromatogram, main peak and each known list assorted (related substance B, C and E) and the degree of separation of adjacent peak are 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 chromatogram, the peak purity factor of main peak is all greater than 0.990; Compared with need testing solution, in spiked solution chromatogram, 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:
Dilution: the mixed solution of preparation water and acetonitrile, volume ratio is 7:3.
Test sample stock solution: under lucifuge condition, gets test sample 135mg, accurately weighed in 50mL volumetric flask, with dilution ultrasonic dissolution and constant volume, shakes up, to obtain final product.
Do not destroy need testing solution: under lucifuge condition, precision pipettes gets in test sample stock solution 5mL to 25mL volumetric flask, uses dilution constant volume, shakes up, to obtain final product.
Acid destroys solution: under lucifuge condition, precision pipettes in test sample stock solution 5mL to 25mL volumetric flask, adds the hydrochloric acid solution 1mL of 6mol/L, shakes up, sealing, after placing 24h at room temperature, adds 6mol/L sodium hydroxide solution 1mL and neutralizes, let cool, use dilution constant volume, shake up, to obtain final product;
Alkali destroys solution: under lucifuge condition, precision pipettes in test sample stock solution 5mL to 25mL volumetric flask, adds the sodium hydroxide solution 1mL of 6mol/L, shakes up, sealing, after placing 24h at room temperature, adds 6mol/L hydrochloric acid solution 1mL and neutralizes, let cool, use dilution constant volume, shake up, to obtain final product;
Oxidative demage solution: under lucifuge condition, precision pipettes in test sample stock solution 5mL to 25mL volumetric flask, adds 15% hydrogen peroxide 1mL, after placing 24h at room temperature, uses dilution constant volume, shakes up, to obtain final product;
Illumination destroys solution: get test sample appropriate, tiling is in measuring cup, under putting visible ray 4500Lux ± 500Lux, ultraviolet light 1.7W*h/m2 condition, illumination 13 angel visible illumination level total amount reaches 1200000Lux, and ultraviolet ray intensity reaches more than 200W/m2, then gets above-mentioned sample 27mg, accurately weighed, put in 100mL volumetric flask, under lucifuge condition, use dilution constant volume, shake up, to obtain final product;
High temperature solution: get test sample appropriate, tile in measuring cup, place 24h in 105 DEG C of baking ovens, taking-up lets cool, and then gets above-mentioned sample and is about 27mg, accurately weighed, puts in 100mL measuring bottle, under lucifuge condition, uses dilution constant volume, shakes up, to obtain final product;
Sample detection:
Chromatographic condition is as embodiment 1;
Get above-mentioned unbroken solution and each destruction solution each sample introduction 1 pin, record chromatogram.Report the degree of separation of main peak and adjacent peak in each destruction solution, main peak peak purity and total assorted peak area percentage composition.
Fig. 5, Fig. 6, Fig. 7, Fig. 8, Fig. 9 and Figure 10 are the chromatogram not destroying solution, acid destruction solution, alkali destruction solution, Oxidative demage solution, illumination destruction solution and high temperature solution respectively, the result of the measured in solution under showing non-failure condition and under each failure condition.
Testing result is in table 2.
Table 2
| Solution title | Total assorted (%) | The main peak purity factor | Main peak and adjacent peak degree of separation |
| 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 solution | 0.34 | 1.000 | 1.6 |
According to the result of collection of illustrative plates 5-10 and table 4, the method for the invention is detecting without in the Sunitinib malate solution destroyed and the Sunitinib malate solution through destroying, and 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 degree of separation are good, and >=1.5.Therefore method of the present invention is at mensuration Sunitinib malate, or even all has good specificity during the related substance of Sunitinib malate degraded sample, can the content of related substance of Sunitinib malate effectively in detection control preservation process.
Embodiment 3 Precision Experiment
Solution preparation:
Dilution: the mixed solution of preparation water and acetonitrile, volume ratio is 7:3.
Sunitinib malate need testing solution: under lucifuge condition, gets Sunitinib malate test sample appropriate, accurately weighed, puts in volumetric flask, becomes Sunitinib malate concentration to be the solution of about 0.50mg/mL, parallel preparation 6 parts by appropriate diluent preparing.
Sunitinib malate reference substance solution: under lucifuge condition, it is appropriate that precision pipettes Sunitinib malate need testing solution, and putting in volumetric flask, is the solution of about 1.0 μ g/mL by appropriate diluted to Sunitinib malate concentration.
Sample detection:
Chromatographic condition is as embodiment 1;
Get Sunitinib malate reference substance solution sample introduction 2 pin, get 6 parts of Sunitinib malate need testing solution each sample introduction 1 pins.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 major component Self-control method of the not correction up factor, and record the retention time of each impurity and the relative standard deviation of retention time.
Testing result is in table 3
Table 3
According to testing result, method provided by the invention is in the Precision Experiment detecting Sunitinib malate related substance, the retention time of each impurity is basicly stable, the major component Self-control method of the not correction up 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 preparation:
Dilution: the mixed solution of preparation water and acetonitrile, volume ratio is 7:3.
Sunitinib malate need testing solution: under lucifuge condition, get Sunitinib malate test sample and be about 27mg, accurately weighed, put in 50mL volumetric flask, make ultrasonic dissolution with appropriate dilution and be diluted to scale, being mixed with the solution that Sunitinib malate concentration is about 0.50mg/mL.
Sunitinib malate reference substance solution: under lucifuge condition, precision pipettes 1mL Sunitinib malate need testing solution in 50mL volumetric flask, uses dilution constant volume, shakes up; Precision pipettes in above-mentioned solution 5mL to 50mL volumetric flask again, uses dilution constant volume, is mixed with the solution that Sunitinib malate concentration is about 1.0 μ g/mL.
Related substance B, C and E storing solution: get that related substance B is about 16mg, related substance C is about 6mg and related substance E is about 6mg, accurately weighed, put in 1000mL volumetric flask, dissolve with dilution and be diluted to scale, shaking up.
Mark-on solution: under lucifuge condition, the test sample getting Sunitinib malate is about 27mg, accurately weighed, is placed in the volumetric flask of 50mL; Accurate 5mL related substance B, C and E storing solution that pipettes is in the volumetric flask of above-mentioned 50mL again, by diluted to scale, be mixed with Sunitinib malate concentration be about 0.50mg/mL, be about 1.6 μ g/mL containing related substance B concentration, related substance C concentration is the solution that about 0.6 μ g/mL and related substance E concentration are respectively about 0.6 μ g/mL, parallel preparation 3 parts.
Sample detection:
Chromatographic condition is as embodiment 1;
Get the Sunitinib malate reference substance solution, Sunitinib malate need testing solution and the mark-on solution that prepare to detect by the chromatographic condition of embodiment 1, every part of sample feeding 1 pin, the peak area at peak is contrasted in record Sunitinib malate reference substance solution, record the peak area of related substance B, related substance C and related substance E in Sunitinib malate need testing solution and mark-on solution, and be calculated as follows the recovery of standard addition of each impurity:
Theoretical amount (mg)=W
x× P
x
In formula: W
sTDfor the sample weighting amount of Sunitinib malate in Sunitinib malate reference substance solution, mg;
Wx is the weighing of related substance B, related substance C and related substance E;
A
sTDfor contrasting peak-to-peak area in Sunitinib malate reference substance solution;
A
sfor the peak area of related substance in Sunitinib malate need testing solution (related substance B, C or E);
A
xfor the peak area of related substance (related substance B, C or E) in each mark-on solution; D
stdfor the extension rate of Sunitinib malate reference substance solution;
D
xfor the extension rate of each mark-on solution;
P
stdfor the content of Sunitinib malate test sample, be 99.4%, w/w;
P
xfor the content of related substance B (98.7%, w/w), related substance C (99.7%, w/w) and related substance E (99.2%, w/w);
Experimental result is 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 of Sunitinib malate detect, sample introduction 1 pin, record chromatogram.As Figure 11, show that the impurity that Oxidative demage produces cannot be separated with main peak.
In sum,
The method of the related substance of Sunitinib malate of the present invention has good specificity, and precision is good, and accuracy is high and detection speed is fast, is applicable to the control of the related substance between production and storage life.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, 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 (9)
1. a Sunitinib malate Related substance method, is characterized in that:
Described method is carried out on high performance liquid chromatograph;
Detecting device is diode array detector or ultraviolet absorption detector, and determined wavelength is 268nm;
Liquid-phase chromatographic column is Poroshell 120Bonus RP reverse-phase chromatographic column, and chromatogram column temperature is 20 DEG C ~ 30 DEG C;
Mobile phase by form as the ammonium acetate solution of damping fluid and organic solvent acetonitrile, and carries out gradient elution, and the flow velocity of mobile phase is about 0.9mL/min ~ 1.1mL/min;
Injection Sunitinib malate need testing solution and Sunitinib malate reference substance solution detect, and calculate the content of related substance by the major component Self-control method of the not correction up factor.
2. analytical approach according to claim 1, wherein said Poroshell 120Bonus RP reverse-phase chromatographic column is that the filler particles being about 2.7 μm by particle diameter is filled, wherein filler particles is made up of the interior solid core of 1.7 μm of diameters and the porous outer layer that is coated on 0.5 μm of interior solid core thick, and wherein Stationary liquid is the n-octadecane hydrocarbon be bonded on described filler particles.
3. analytical approach according to claim 1, the concentration of wherein said ammonium acetate solution is about 3.45g/L ~ 4.20g/L, pH about 5.5 ~ 6.0.
4. analytical approach according to claim 1, wherein said gradient elution, gradient is as follows:
Time (min) ammonium acetate solution (v/v, %) acetonitrile (v/v, %)
0 90 10
12 37 63
5. analytical approach according to claim 1, wherein said Sunitinib malate need testing solution is that the mixed solution getting Sunitinib malate test sample water and acetonitrile dissolves, dilution, and ultimate density is about 0.10mg/mL ~ 1.0mg/mL; The mixed solution that described Sunitinib malate reference substance solution gets Sunitinib malate test sample water and acetonitrile dissolves, and dilution, ultimate density is about 0.2 μ g/mL ~ 2.0 μ g/mL.
6. analytical approach according to claim 5, in wherein said water and the mixed solution of acetonitrile, the volume ratio of water and acetonitrile is 7:3.
7. a Sunitinib malate Related substance method, is characterized in that:
Described method is carried out on high performance liquid chromatograph;
Detecting device is diode array detector, and determined wavelength is 268nm;
Liquid-phase chromatographic column is Poroshell 120Bonus RP 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, %)
0 90 10
12 37 63
Injection Sunitinib malate need testing solution and Sunitinib malate reference substance solution detect, and calculate the content of related substance by the major component Self-control method of the not correction up factor;
Wherein, Poroshell 120Bonus RP reverse-phase chromatographic column is that the filler particles being about 2.7 μm by particle diameter is filled, wherein filler particles is made up of the interior solid core of 1.7 μm of diameters and the porous outer layer that is coated on 0.5 μm of interior solid core thick, wherein Stationary liquid is the n-octadecane hydrocarbon be 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 mixed solution of water, Sunitinib malate reference substance solution is the acetonitrile of Sunitinib malate concentration about 1.0 μ g/mL and the mixed solution of water, in wherein said water and the mixed solution of acetonitrile, the volume ratio of water and acetonitrile is 7:3.
8., according to the arbitrary described analytical approach of claim 1-7, wherein said high performance liquid chromatograph is Agilent 1260, Agilent 1290 or Waters UPLC.
9. analytical approach according to claim 8, wherein said method is related substance B, related substance C and related substance E for detecting in Sunitinib malate bulk drug.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105572264A (en) * | 2016-02-26 | 2016-05-11 | 中国医学科学院肿瘤医院 | UPLC-MS/MS method for detecting concentrations of tafetinib and active metabolite SCR868 in human plasma |
| WO2022151841A1 (en) * | 2021-01-15 | 2022-07-21 | 浙江海正药业股份有限公司 | Determination method for related substances in favipiravir |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105572264A (en) * | 2016-02-26 | 2016-05-11 | 中国医学科学院肿瘤医院 | UPLC-MS/MS method for detecting concentrations of tafetinib and active metabolite SCR868 in human plasma |
| WO2022151841A1 (en) * | 2021-01-15 | 2022-07-21 | 浙江海正药业股份有限公司 | Determination method for related substances in favipiravir |
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