CN107991398A - The analysis determining method of pazopanib hydrochloride intermediate related impurities - Google Patents

The analysis determining method of pazopanib hydrochloride intermediate related impurities Download PDF

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Publication number
CN107991398A
CN107991398A CN201610947701.5A CN201610947701A CN107991398A CN 107991398 A CN107991398 A CN 107991398A CN 201610947701 A CN201610947701 A CN 201610947701A CN 107991398 A CN107991398 A CN 107991398A
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mobile phase
phosphate
chromatographic column
pazopanib hydrochloride
phosphate buffer
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Inventor
马超
吴兆春
周英兰
高永宏
王晓晖
李静新
管凯林
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Qilu Pharmaceutical Co Ltd
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Qilu Pharmaceutical Co Ltd
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography

Abstract

The analysis determining method of the entitled pazopanib hydrochloride intermediate related impurities of the present invention, belongs to Pharmaceutical Analysis technical field.3 kinds of high efficient liquid phase analysis methods that the present invention is established can effectively measure pazopanib hydrochloride intermediate compound I respectively：2,3 dimethyl, 6 amino 2H indazoles, intermediate II：6 amine of N (2 chlorine pyrimidine, 4 base) 2,3 dimethyl 2H indazoles and intermediate III：N (2 chlorine pyrimidine, 4 base) N, the content of 2,3 trimethyl 2H indazoles, 6 amine related impurities, is the monitoring of pazopanib hydrochloride synthetic reaction and the important means of Quality control of intermediates.

Description

The analysis determining method of pazopanib hydrochloride intermediate related impurities
Technical field
The invention belongs to Pharmaceutical Analysis technical field, specifically discloses 3 kinds of passes in measure pazopanib hydrochloride synthetic route The HPLC analytical method of the related impurities of key intermediate.This 3 kinds of key intermediates are respectively：
Intermediate compound I：2,3- dimethyl -6- amino -2H- indazoles；
Intermediate II：N- (2- chlorine pyrimidine-4-yl) -2,3- dimethyl -2H- indazole -6- amine；
Intermediate III：N- (2- chlorine pyrimidine-4-yl)-N, 2,3- trimethyl -2H- indazole -6- amine.
Background technology
Pazopanib hydrochloride, entitled the 5- ({ 4- ((2,3- dimethyl -2H- indazole -6- bases) (methyl) amino)-phonetic of chemistry Pyridine -2- bases } amino) -2- Methyl benzenesulfonyl amine hydrochlorates, molecular formula C21H23N7O2SHCl, molecular weight 473.98, it is tied Structure formula is as follows：
Pazopanib hydrochloride is second generation multiple receptor tyrosine kinases inhibitor, to vascular endothelial growth factor receptor, blood Platelet source property growth factor receptors etc. has obvious inhibitory action.Pazopanib hydrochloride is developed by GlaxoSmithKline PLC company, in U.S. Food and Drug Administration (FDA) approval is obtained in October, 2009 in the listing in the U.S., trade name Votrient, use It is antitumor kinase inhibitor evident in efficacy in diseases such as treatment advanced renal cell carcinoma, soft tissue sarcoma, advanced ovarian cancers.
The synthetic route of pazopanib hydrochloride patent WO02059110, WO03106416, WO2007064752, Had been reported that in many documents such as WO2009062658.Although technological parameter is different, synthetic route is basically identical, i.e., first By 2,3- dimethyl -6- amino -2H- indazoles (intermediate compound I), by substitution reaction generation N-, (2- chlorine is phonetic with 2,4- dichloro pyrimidines Pyridine -4- bases) -2,3- dimethyl -2H- indazole -6- amine (intermediate II), then by methylation reaction generate N- (2- chlorine pyrimidine - 4- yls)-N, 2,3- trimethyl -2H- indazole -6- amine (intermediate III), finally again with 5- amino 2- methyl benzamides by taking Generation reaction generation pazopanib hydrochloride.In the reaction scheme, intermediate compound I, II, III are to form the important composition of product structure Part, and in the synthetic route downstream of close reaction end, therefore should be regarded as key intermediate.
At present, pharmacopoeia of each country not yet records the quality standard of pazopanib hydrochloride, and wherein the analysis method of mesosome is in phase Close and be also rarely reported in document and patent.Quality control of intermediates improves important role for reaction monitoring and yield, together When also contribute to the quality of finished product.And comprehensive system from starting material to finished product particularly to the key during synthesis Intermediate carries out quality control, and the improvement of the quality research and synthesis technique for pazopanib hydrochloride is anticipated with important guidance Justice, and this area need the important process completed at present.To improve pilot process control, drug quality is effectively analyzed, is ensured Drug safety is, it is necessary to develop a kind of related impurities of convenient, effective detection pazopanib hydrochloride intermediate and the analysis of content Method.
The content of the invention
First aspect present invention provides one kind and measures pazopanib hydrochloride intermediate I i.e. with high-efficient liquid phase chromatogram technique analysis The method of 2,3- dimethyl -6- amino -2H- indazole related impurities contents.
Specifically, above-mentioned analysis method of the invention can be realized as follows：
(1) sample preparation
Test solution：Take this product appropriate, dissolve and dilute with acetonitrile water mixed solvent and be made in every 1ml containing about 0.2mg The solution of intermediate I.
(2) chromatographic condition
Instrument：High performance liquid chromatograph-UV detector
Chromatographic column：Use chromatographic column of the octadecylsilane bonded-phase silica for filler；Chromatographic column particle diameter is 3.5 μm； Chromatogram column length is 150mm；Chromatography column internal diameter is 4.6mm.
Mobile phase A：PH value be 5.0~6.0 phosphate buffer (preferable ph 5.3~5.7, most preferably 5.4)；Phosphoric acid Salt buffer is the potassium dihydrogen phosphate or phosphoric acid of 5~15mmol/L (preferred concentration 8~12mmol/L of value, most preferably 10mmol/L) Two aqueous solutions of potassium of hydrogen, is adjusted using the phosphoric acid solution (>=85%) or potassium hydroxide aqueous solution (1mol/L) of this area normal concentration PH value.
Mobile phase B：Acetonitrile.
The preferable gradient elution program according to the form below of the present invention one carries out：
Flow velocity：0.8ml/min~1.2ml/min, preferably 0.9ml/min~1.1ml/min, most preferably 1.0ml/min；
Column temperature：30 DEG C~40 DEG C, preferably 33 DEG C~37 DEG C, most preferably 35 DEG C；
Detection wavelength：215nm；
Sampling volume：10μl.
Preferable gradient elution program
Time (min) Mobile phase A (%) Mobile phase B (%)
0 91 9
12 91 9
30 30 70
35 30 70
36 91 9
45 91 9
(3) calculating of impurity
Intermediate compound I and the content of impurity are calculated according to area normalization method.
Second aspect of the present invention provides a kind of with high-efficient liquid phase chromatogram technique analysis measure pazopanib hydrochloride intermediate II That is the method for N- (2- chlorine pyrimidine-4-yl) -2,3- dimethyl -2H- indazole -6- amine related impurities contents.
Specifically, above-mentioned analysis method of the invention can be realized as follows：
(1) sample preparation
Test solution：Take this product appropriate, add acetonitrile water mixed solvent to dissolve and dilute and be made in every 1ml containing about 0.5mg The solution of intermediate II, as test solution.
(2) chromatographic condition
Instrument：High performance liquid chromatograph-UV detector
Chromatographic column：Use chromatographic column of the octyl silane group silica gel for filler；Chromatographic column particle diameter is 5 μm；Chromatographic column Length is 150mm；Chromatography column internal diameter is 4.6mm.
Mobile phase A：PH value be 5.0~6.0 phosphate buffer (preferable ph 5.2~5.6, most preferably 5.4)；Phosphoric acid Salt buffer is the potassium dihydrogen phosphate or phosphoric acid hydrogen of 5~15mmol/L (8~12mmol/L of preferable ph, most preferably 10mmol/L) Two aqueous solutions of potassium, pH is adjusted using the phosphoric acid solution (>=85%) or potassium hydroxide aqueous solution (1mol/L) of this area normal concentration Value.
Mobile phase B：Acetonitrile.
The preferable gradient elution program according to the form below of the present invention one carries out：
Flow velocity：0.8ml/min~1.2ml/min, preferably 0.9ml/min~1.1ml/min, most preferably 1.0ml/min；
Column temperature：30 DEG C~40 DEG C, preferably 33 DEG C~37 DEG C, most preferably 35 DEG C；
Detection wavelength：210nm；
Sampling volume：10μl.
Preferable gradient elution program
Time (min) Mobile phase A (%) Mobile phase B (%)
0 80 20
16 80 20
30 30 70
35 30 70
37 80 20
45 80 20
(3) calculating of impurity
Intermediate II and the content of impurity are calculated according to area normalization method.
Third aspect present invention provides a kind of with high-efficient liquid phase chromatogram technique analysis measure pazopanib hydrochloride intermediate III That is 2N- (2- chlorine pyrimidine-4-yl)-N, the method for 2,3- trimethyl -2H- indazole -6- amine related impurities contents.
Specifically, above-mentioned analysis method of the invention can be realized as follows：
(1) sample preparation
Test solution：Take this product appropriate, add acetonitrile water mixed solvent to dissolve and dilute and be made in every 1ml containing about 0.5mg The solution of intermediate III, as test solution.
(2) chromatographic condition
Instrument：High performance liquid chromatograph-UV detector
Chromatographic column：Use chromatographic column of the octyl silane group silica gel for filler；Chromatographic column particle diameter is 5 μm；Chromatographic column Length is 150mm；Chromatography column internal diameter is 4.6mm.
Mobile phase A：PH value be 3.0~4.0 phosphate buffer (preferable ph 3.3~3.7, most preferably 3.5)；Phosphoric acid Salt buffer is the potassium dihydrogen phosphate or phosphoric acid of 5~15mmol/L (preferred concentration is 8~12mmol/L, most preferably 10mmol/L) Two aqueous solutions of potassium of hydrogen, is adjusted using the phosphoric acid solution (>=85%) or potassium hydroxide aqueous solution (1mol/L) of this area normal concentration PH value.
Mobile phase B：Acetonitrile.
The preferable gradient elution program according to the form below of the present invention one carries out：
Flow velocity：0.8ml/min~1.2ml/min, preferably 0.9ml/min~1.1ml/min, most preferably 1.0ml/min；
Column temperature：30 DEG C~40 DEG C, preferably 33 DEG C~37 DEG C, most preferably 35 DEG C；
Detection wavelength：210nm；
Sampling volume：10μl
Preferable gradient elution program
Time (min) Mobile phase A (%) Mobile phase B (%)
0 75 25
17 75 25
30 30 70
35 30 70
36 75 25
45 75 25
(3) calculating of impurity
Intermediate III and the content of impurity are calculated according to area normalization method.
In conclusion the claimed analysis method of the present invention has following good effect：The analysis method foundation The theory (QBD) that quality comes from design has carried out accurate monitoring from synthetic route upstream to impurity spectrum, can efficiently separate centre Body I, intermediate II, intermediate III and its related impurities system, have many advantages, such as easy to operate, analysis time is moderate, make Follow-up impurity transfer law and process parameter optimizing research are more convenient, are provided effectively for the quality control of pazopanib hydrochloride Ensure.
Brief description of the drawings
The sample detection collection of illustrative plates of analysis method described in Fig. 1 embodiments 1；
The sample detection collection of illustrative plates of analysis method described in Fig. 2 embodiments 2；
The sample detection collection of illustrative plates of analysis method described in Fig. 3 embodiments 3.
Note：Numeral 1~40 in Fig. 1-3 represents corresponding 1~impurity of impurity 40 respectively.
Embodiment
The present invention is further illustrated below by specific embodiment.It should be understood to：The embodiment of the present invention is only For illustrating the present invention, rather than limitation of the present invention.The simple of the present invention is changed on the basis of technical solution of the present invention Protection scope of the present invention is belonged into or using the technical solution that obtained obtained by equivalent substitution of customary means or component.
The detection of the related impurities of 1 intermediate compound I of embodiment
(1) chromatographic condition
Instrument：High performance liquid chromatograph-UV detector
Chromatographic column：With octadecylsilane bonded-phase silica [XBridge C18(4.6 × 150mm, 3.5 μm)] it is filler
Mobile phase A：10mmol/L aqueous dibasic potassium phosphate solutions (with phosphorus acid for adjusting pH value to 5.4)
Mobile phase B：Acetonitrile.
Gradient elution program
Time (min) Mobile phase A (%) Mobile phase B (%)
0 91 9
12 91 9
30 30 70
35 30 70
36 91 9
45 91 9
Flow velocity：1.0ml/min；Column temperature：35℃；Detection wavelength：215nm；Sampling volume：10μl.
(2) sample preparation and detection
Take intermediate compound I appropriate, it is accurately weighed, add acetonitrile-water (1:9) ultrasonic dissolution and dilute be made in every 1ml containing about in The solution of mesosome I 0.5mg, as test solution.Precision measures 10 μ l injection liquid chromatographs, by the method for the invention It is detected.
(3) result calculates
Intermediate compound I and the content of impurity are calculated according to area normalization method, and records retention time and separating degree.The result is shown in Table 1, collection of illustrative plates is shown in Fig. 1.
The related impurities testing result of 1 intermediate compound I of table
Title Retention time (min) Content (%) Separating degree
Impurity 1 2.747 0.29 -
Impurity 2 4.102 0.04 6.6
Impurity 3 4.480 0.01 1.7
Impurity 4 5.130 0.02 3.2
Impurity 5 5.469 0.10 1.6
Impurity 6 6.471 0.02 4.2
Impurity 7 9.361 1.27 10.0
Intermediate compound I 10.092 96.96 2.1
Impurity 8 12.080 0.10 5.2
Impurity 9 17.379 0.43 1.8
Impurity 10 18.531 0.03 6.1
Impurity 11 19.195 0.04 4.2
Impurity 12 19.417 0.06 1.4
Impurity 13 19.689 0.04 1.7
Impurity 14 20.945 0.04 7.6
Impurity 15 21.212 0.01 1.4
Impurity 16 21.949 0.04 4.2
Impurity 17 22.128 0.01 1.2
Impurity 18 22.601 0.19 3.1
Impurity 19 23.001 0.30 2.5
Test result indicates that under chromatographic condition of the present invention, intermediate compound I with before its peak and peak rear impurity separating degree More than 1.5, the separating degree between each impurity is more than 1.0, and minimum impurity detected level is 0.01%, the separating effect of method and sensitivity Well.
The detection of the related impurities of 2 intermediate II of embodiment
(1) chromatographic condition
Instrument：High performance liquid chromatograph-UV detector
Chromatographic column：With octyl silane group silica gel [Thermo Hypersil C8(4.6 × 150mm, 5 μm)] it is filling Agent
Mobile phase A：10mmol/L aqueous dibasic potassium phosphate solutions (with phosphorus acid for adjusting pH value to 5.4)
Mobile phase B：Acetonitrile.
According to the form below carries out gradient elution：
Gradient elution program
Time (min) Mobile phase A (%) Mobile phase B (%)
0 80 20
16 80 20
30 30 70
35 30 70
37 80 20
45 80 20
Flow velocity：1.0ml/min；Column temperature：35℃；Detection wavelength：210nm；Sampling volume：10μl.
(2) sample preparation and detection
Take intermediate II appropriate, it is accurately weighed, add acetonitrile-water (1:1) ultrasonic dissolution and dilute be made every 1ml containing about The solution of 0.5mg intermediate IIs, as test solution.Precision measures 10 μ l injection liquid chromatographs, by side of the present invention Method is detected.
(3) result calculates
Intermediate II and the content of impurity are calculated according to area normalization method, and records retention time and separating degree.As a result 2 are shown in Table, collection of illustrative plates is shown in Fig. 2.
The related impurities testing result of 2 intermediate II of table
Title Retention time (min) Content (%) Separating degree
Impurity 20 2.006 0.11 -
Impurity 21 3.358 0.05 7.2
Impurity 22 7.296 0.16 14.6
Impurity 23 11.870 0.80 10.9
Intermediate II 15.095 97.60 5.5
Impurity 24 21.931 0.19 15.7
Impurity 25 22.936 0.89 4.5
Impurity 26 23.286 0.15 1.7
Impurity 27 23.941 0.06 3.4
Test result indicates that under chromatographic condition of the present invention, between each impurity peaks and intermediate II with before its peak, The separating degree of rear impurity is all higher than 1.5, and minimum impurity detected level is 0.05%, and the separating effect of method and sensitivity are good.
The detection of the related impurities of 3 intermediate III of embodiment
(1) chromatographic condition
Instrument：High performance liquid chromatograph-UV detector
Chromatographic column：With octyl silane group silica gel [Thermo Hypersil C8(4.6 × 150mm, 5 μm)] it is filling Agent
Mobile phase A：10mmol/L potassium dihydrogen phosphate aqueous solutions (with phosphorus acid for adjusting pH value to 3.5)
Mobile phase B：Acetonitrile.
Gradient elution program
Time (min) Mobile phase A (%) Mobile phase B (%)
0 75 25
17 75 25
30 30 70
35 30 70
36 75 25
45 75 25
Flow velocity：1.0ml/min；Column temperature：35℃；Detection wavelength：210nm；Sampling volume：10μl
(2) sample preparation and detection
Take intermediate III appropriate, it is accurately weighed, add acetonitrile-water (1:1) ultrasonic dissolution and dilute every 1ml is made containing about in The solution of mesosome III 0.2mg, as test solution.Precision measures 10 μ l injection liquid chromatographs, by side of the present invention Method is detected.
(3) result calculates
Intermediate III and the content of impurity are calculated according to area normalization method, and records retention time and separating degree.As a result 3 are shown in Table, collection of illustrative plates is shown in Fig. 3.
The related impurities testing result of 3 intermediate III of table
Title Retention time (min) Content (%) Separating degree
Impurity 28 1.935 0.05 -
Impurity 29 2.972 0.02 5.4
Impurity 30 4.486 0.04 5.9
Impurity 31 5.705 0.01 3.9
Impurity 32 7.026 0.02 3.6
Impurity 33 8.197 0.01 3.1
Impurity 34 11.056 0.01 4.6
Impurity 35 13.713 0.05 3.6
Intermediate III 15.557 98.95 2.6
Impurity 36 19.425 0.01 4.7
Impurity 37 21.500 0.01 2.0
Impurity 38 25.090 0.54 3.5
Impurity 39 27.196 0.26 2.4
Impurity 40 31.035 0.02 4.7
Test result indicates that under chromatographic condition of the present invention, between each impurity peaks and intermediate III and Qi Feng The separating degree of forward and backward impurity is all higher than 1.5, and minimum impurity detected level is 0.01%, and the separating effect of method and sensitivity are good.

Claims (10)

  1. A kind of 1. method of the related impurities content of high-efficient liquid phase chromatogram technique analysis measure pazopanib hydrochloride intermediate, in described Mesosome is 2,3- dimethyl -6- amino -2H- indazoles (intermediate compound I), it is characterised in that using octadecylsilane chemically bonded silica For the chromatographic column of filler, using phosphate buffer as mobile phase A, acetonitrile is Mobile phase B, gradient elution mode；It is wherein described Phosphate used in phosphate buffer is potassium dihydrogen phosphate or dipotassium hydrogen phosphate, the phosphate buffer pH value for 5.0~ 6.0, preferably 5.3~5.7, most preferably 5.4；The phosphate buffering liquid concentration is 5~15mmol/L, preferably 8~12mmol/L, Most preferably 10mmol/L.
  2. A kind of 2. method of the related impurities content of high-efficient liquid phase chromatogram technique analysis measure pazopanib hydrochloride intermediate, in described Mesosome is N- (2- chlorine pyrimidine-4-yl) -2,3- dimethyl -2H- indazole -6- amine (intermediate II), it is characterised in that using octane Base silane bonded silica gel is the chromatographic column of filler, and using phosphate buffer as mobile phase A, acetonitrile is Mobile phase B, gradient elution Mode；Phosphate used in wherein described phosphate buffer is potassium dihydrogen phosphate or dipotassium hydrogen phosphate, the phosphate buffer PH value is 5.0~6.0, preferably 5.2~5.6, most preferably 5.4；The phosphate buffering liquid concentration is 5~15mmol/L, preferably 8 ~12mmol/L, most preferably 10mmol/L.
  3. A kind of 3. method of the related impurities content of high-efficient liquid phase chromatogram technique analysis measure pazopanib hydrochloride intermediate, in described Mesosome is N- (2- chlorine pyrimidine-4-yl)-N, 2,3- trimethyl -2H- indazole -6- amine (intermediate III), it is characterised in that is used Octyl silane group silica gel is the chromatographic column of filler, and using phosphate buffer as mobile phase A, acetonitrile is Mobile phase B, gradient Type of elution；Phosphate used in wherein described phosphate buffer is potassium dihydrogen phosphate or dipotassium hydrogen phosphate, and the phosphate delays Fliud flushing pH value is 3.0~4.0, preferably 3.3~3.7, most preferably 3.5；The phosphate buffering liquid concentration is 5~15mmol/L, It is preferred that 8~12mmol/L, most preferably 10mmol/L.
  4. 4. a kind of method of the related impurities content of high-efficient liquid phase chromatogram technique analysis measure pazopanib hydrochloride intermediate, its feature It is, using phosphate buffer as mobile phase A, acetonitrile is Mobile phase B, gradient elution mode；Wherein described phosphate buffer Phosphate used is potassium dihydrogen phosphate or dipotassium hydrogen phosphate, and the phosphate buffering liquid concentration is 5~15mmol/L, preferably 8~ 12mmol/L, most preferably 10mmol/L；And：
    When the intermediate is 2,3- dimethyl -6- amino -2H- indazoles (intermediate compound I), using octadecylsilane bonded silica Glue is the chromatographic column of filler, and the phosphate buffer pH value is 5.0~6.0, preferably 5.3~5.7, most preferably 5.4；
    When the intermediate is N- (2- chlorine pyrimidine-4-yl) -2,3- dimethyl -2H- indazole -6- amine (intermediate II), use Octyl silane group silica gel is the chromatographic column of filler, the phosphate buffer pH value for 5.0~6.0, preferably 5.2~ 5.6, most preferably 5.4；
    When the intermediate is N- (2- chlorine pyrimidine-4-yl)-N, during 2,3- trimethyl -2H- indazole -6- amine (intermediate III), adopt With the chromatographic column that octyl silane group silica gel is filler, the phosphate buffer pH value for 3.0~4.0, preferably 3.3~ 3.7, most preferably 3.5.
  5. 5. the high-efficient liquid phase chromatogram technique analysis according to claim 1 or 2 or 3 or 4 measure pazopanib hydrochloride intermediate The method of related impurities content, it is characterised in that
    When the chromatographic column is octadecylsilane chemically bonded silica chromatographic column, the octadecylsilane chemically bonded silica chromatographic column Particle diameter be 3.5 μm, length 150mm, internal diameter 4.6mm；
    When the chromatographic column is octyl silane group silica gel chromatographic column, the grain of the octyl silane group silica gel chromatographic column Footpath is 5 μm, length 150mm, internal diameter 4.6mm.
  6. 6. the high-efficient liquid phase chromatogram technique analysis according to claim 1 or 4 measure the related miscellaneous of pazopanib hydrochloride intermediate The method of matter content, when the intermediate is intermediate compound I, it is characterised in that the flow velocity of the mobile phase for 0.8ml/min~ 1.2ml/min, preferably 0.9ml/min~1.1ml/min, most preferably 1.0ml/min；The column temperature of chromatographic column is 30 DEG C~40 DEG C, It is preferred that 33 DEG C~37 DEG C, most preferably 35 DEG C；Detection wavelength is 215nm；Sampling volume is 10 μ l.
  7. 7. the correlation of the high-efficient liquid phase chromatogram technique analysis measure pazopanib hydrochloride intermediate according to Claims 2 or 3 or 4 The method of impurity content, when the intermediate is intermediate II or intermediate III, it is characterised in that the stream of the mobile phase Speed is 0.8ml/min~1.2ml/min, preferably 0.9ml/min~1.1ml/min, most preferably 1.0ml/min；The column of chromatographic column Temperature is 30 DEG C~40 DEG C, preferably 33 DEG C~37 DEG C, most preferably 35 DEG C；Detection wavelength is 210nm；Sampling volume is 10 μ l.
  8. 8. the high-efficient liquid phase chromatogram technique analysis according to claim 1 or 4 measure the related miscellaneous of pazopanib hydrochloride intermediate The method of matter content, when the intermediate is intermediate compound I, it is characterised in that gradient is：
    Time (min) Mobile phase A (%) Mobile phase B (%) 0 91 9 12 91 9 30 30 70 35 30 70 36 91 9 45 91 9
  9. 9. the high-efficient liquid phase chromatogram technique analysis according to claim 2 or 4 measure the related miscellaneous of pazopanib hydrochloride intermediate The method of matter content, when the intermediate is intermediate II, it is characterised in that gradient is：
    Time (min) Mobile phase A (%) Mobile phase B (%) 0 80 20 16 80 20 30 30 70 35 30 70 37 80 20 45 80 20
  10. 10. the high-efficient liquid phase chromatogram technique analysis according to claim 3 or 4 measure the related miscellaneous of pazopanib hydrochloride intermediate The method of matter content, when the intermediate is intermediate III, it is characterised in that gradient is：
    Time (min) Mobile phase A (%) Mobile phase B (%) 0 75 25 17 75 25 30 30 70 35 30 70 36 75 25 45 75 25
CN201610947701.5A 2016-10-26 2016-10-26 The analysis determining method of pazopanib hydrochloride intermediate related impurities Withdrawn CN107991398A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112730725A (en) * 2019-10-28 2021-04-30 齐鲁制药有限公司 Analysis method for determining chloride ion content in pezopyr hydrochloride

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011069053A1 (en) * 2009-12-04 2011-06-09 Teva Pharmaceutical Industries Ltd. Process for the preparation of pazopanip hcl and crystalline forms of pazopanib hcl
US20160280689A1 (en) * 2013-11-05 2016-09-29 Laurus Labs Private Limited An improved process for the preparation of pazopanib or a pharmaceutically acceptable salt thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011069053A1 (en) * 2009-12-04 2011-06-09 Teva Pharmaceutical Industries Ltd. Process for the preparation of pazopanip hcl and crystalline forms of pazopanib hcl
US20160280689A1 (en) * 2013-11-05 2016-09-29 Laurus Labs Private Limited An improved process for the preparation of pazopanib or a pharmaceutically acceptable salt thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
D.Q. LIU ET AL.: "Analytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing process", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 *
MUSTY SHARADA, RAVICHANDRA BABU: "DETERMINATION AND CHARACTERIZATION OF PROCESS IMPURITIES IN PAZOPANIB HYDROCHLORIDE DRUG SUBSTANCE", 《INT J PHARM PHARM SCI》 *
Y. LI ET AL.: "Analytical control of process impurities in Pazopanib hydrochloride by impurity fate mapping", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 *
赵玲等: "HPLC法测定盐酸帕唑帕尼片含量和有关物质", 《中国药房》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112730725A (en) * 2019-10-28 2021-04-30 齐鲁制药有限公司 Analysis method for determining chloride ion content in pezopyr hydrochloride

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