CN106018655A - Method for detecting substances relevant with palbociclib raw material - Google Patents
Method for detecting substances relevant with palbociclib raw material Download PDFInfo
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- CN106018655A CN106018655A CN201610618387.6A CN201610618387A CN106018655A CN 106018655 A CN106018655 A CN 106018655A CN 201610618387 A CN201610618387 A CN 201610618387A CN 106018655 A CN106018655 A CN 106018655A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
Abstract
The invention provides a method for detecting substances relevant with a palbociclib raw material. The method is carried out by virtue of a high performance liquid chromatography and comprises the following steps: (1) preparing a palbociclib sample solution; and (2) injecting the sample solution obtained in the step (1) into a high performance liquid chromatographic instrument, carrying out gradient elution by adopting a flow phase A and a flow phase B as flow phases, and recording a chromatogram map, wherein a fixed phase filler of a chromatographic column of the high performance liquid chromatography is fluobenzene-base bonded silica gel or benzene-base bonded silica gel, the prepared flow phase A is 0.05%-0.3% deionized water solution, and the volume ratio of acidy buffer liquid to methanol is (0-10) to (90-100) in the prepared flow phase B. According to the method, the substances relevant with the palbociclib raw material can be detected under the same liquid phase. The method has the advantages that the operation is simple and convenient, the separation degree is high, the specificity is strong, and the detection result is accurate and credible.
Description
Technical field
The invention belongs to pharmaceutical analysis field.Specifically, the present invention relates to a kind of employing high effective liquid chromatography for measuring
Pabuk former times profit cloth raw material has the detection method of related substance.
Technical background
Pabuk former times profit cloth (Palbociclib) is that a kind of height researched and developed by Pfizer pharmaceutical Co. Ltd is selective thin
Born of the same parents cyclin-dependent kinase CDK4 and CDK6 reversibility antagonist.Its chemical entitled 6-acetyl group-8-cyclopenta-5-first
Base-2-{ [5-(1-piperazinyl)-2-pyridine radicals] amino }-7,8-dihydroquinazoline-7-ketone, the entitled 6-acetyl-of English language Chemical
8-cyclopentyl-5-methyl-2 - {[5- (1-piperazinyl) -2-pyridinyl] amino} -7,8-
Dihydro-quinazolin-7 ketone, its molecular weight is 447.53, and molecular formula is C24H29N7O2。
Pabuk former times profit cloth can block cell cycle from the G1 phase to the process of S phase by suppression CDK4/6, thus suppresses DNA to close
Become.Preclinical study data show, Palbociclib has tumor cell and subtracts the effect of going out and cell growth inhibiting effect, is
First Breast cancer immunotherapy medicine of the listing at present ratified by FDA for 2015, the most above-mentioned (advises for conventional capsule agent
Lattice 75mg, 100mg and 125mg).
Breast carcinoma be breast glandular epithelium under multiple cancerigenic factor effect, producer suddenly change, cause normal cell
Become cancerous cell.The pernicious increment of cancerous cell makes the normal configuration of mammary gland tissue be destroyed, and extrudes and corrodes normal structure.Breast
Adenocarcinoma is one of modal malignant tumor of women (male rare but exist), is only second to uterus carcinoma, and it is the most diffusible arrives other
Position, is also the major disease that serious harm patient is physically and mentally healthy, increase society's medical burden.
The early treatment of breast carcinoma includes operative treatment, endocrine therapy, chemotherapy, radiotherapy and molecular targeted therapy, although
So, still having a lot of patient that transfer and recurrence can occur, its main mechanism includes tumor drug resistance, the activation of signal path and cancer base
The activation etc. of cause.At present, the relation of tumor microenvironment and host is paid close attention in more research, and wherein immune system is important composition
One of part.Therefore for the immune system of patient, breast is become by regulating its effect in tumor is alleviation and host
The foundation of adenocarcinoma successive treatment.Pabuk former times profit cloth blocks cell cycle from the G1 phase to the process of S phase by suppression CDK4/6, thus
The synthesis of suppression DNA.Its preclinical test data show that Pabuk former times profit cloth has tumor cell and subtracts the effect of going out and suppression cell life
Long effect.
At present in Pabuk former times profit cloth Material synthesis technique, the initiation material that may contain in final raw produce, intermediate
And the known impurities of degraded has 7, respectively 4-(6-aminopyridine-3-base) piperazine-1-carboxylic acid tert-butyl ester (SM1), 6-are bromo-
2-chloro-8-cyclopenta-5-methvl-pyridinium also [2,3-D] pyrimidine-7 (8H)-one (SM2), tert-butyl group 4-(6-(6-bromo-8-ring penta
Base-5-methyl-7-oxygen-7,8-dihydropyridine [2,3-d] pyrimidine-2-yl amino) pyridine-3-yl) piperazine-1-carboxylate
(PALB01), tert-butyl group 4-(6-(6-(1-vinyl butyl ether)-8-cyclopenta-5-methyl-7-oxygen-7,8-dihydropyridine [2,3-
D] pyrimidine-2-yl amino) pyridine-3-yl) piperazine-1-carboxylate (PALB02), 8-cyclopenta-5-methyl-2-((5-(piperazine
Piperazine-1-base) pyridine-2-base) amino)-6-vinylpyridine also [2,3-d] pyrimidine-7(8H)-ketone (PF-06651464), 8-
Cyclopenta-5-methyl-2-(5-piperazine-1-base-pyridine-2-base amino)-8H-pyrido [2,3-d] pyrimidin-7-ones (PF-
00447880), 4-[6-(6-acetyl group-8-cyclopenta-5-methyl-7-oxo-7,8-dihydro pyrido [2,3-d] pyrimidine-2-
Base amino)-pyridin-3-yl]-piperazine-1-carboxylate (PF-00310864).
A kind of Pabuk former times profit cloth raw material involved in the present invention have the detection method of related substance be primarily directed to above wherein
Pabuk former times profit cloth known impurities effectively detects and separates.Wherein, 4-(6-aminopyridine-3-base) piperazine-1-carboxylic acid uncle
The bromo-2-of butyl ester, 6-chloro-8-cyclopenta-5-methvl-pyridinium also [2,3-D] pyrimidine-7 (8H)-one is initiation material；Tert-butyl group 4-
(6-(6-bromo-8-cyclopenta-5-methyl-7-oxygen-7,8-dihydropyridine [2,3-d] pyrimidine-2-yl amino) pyridine-3-yl) piperazine
Piperazine-1-carboxylate, tert-butyl group 4-(6-(6-(1-vinyl butyl ether)-8-cyclopenta-5-methyl-7-oxygen-7,8-dihydropyridine [2,
3-d] pyrimidine-2-yl amino) pyridine-3-yl) piperazine-1-carboxylate is synthetic intermediate；8-cyclopenta-5-methyl-2-
((5-(piperazine-1-base) pyridine-2-base) amino)-6-vinylpyridine also [2,3-d] pyrimidine-7(8H)-ketone, 8-cyclopenta-
5-methyl-2-(5-piperazine-1-base-pyridine-2-base amino)-8H-pyrido [2,3-d] pyrimidin-7-ones, 4-[6-(6-second
Acyl group-8-cyclopenta-5-methyl-7-oxo-7,8-dihydro pyrido [2,3-d] pyrimidine-2--amino)-pyridin-3-yl]-
Piperazine-1-carboxylate is catabolite.
At present, Chinese Pharmacopoeia and foreign pharmacopeia do not include Pabuk former times profit cloth raw material relevant substance-measuring method.Disclosed
Patent in, not inquiring the relevant testing conditions having related substance.Chinese patent application CN 105541832 A discloses one
The preparation method of isethionate Pabuk former times profit cloth, another Chinese patent application CN 105418603 A disclose a kind of high-purity
Degree Pabuk former times profit cloth and the preparation method of reaction intermediate, Chinese patent CN 105748435 A disclose a kind of Pabuk former times profit
Cloth pharmaceutical composition and preparation method thereof, Chinese patent CN 104887641 A disclose a kind of Pabuk former times profit cloth intra-gastric floating tablet
And preparation method thereof.Above four four patents the Pabuk former times profit relevant substance detecting method of cloth crude drug is not carried out research and
Illustrate.Additionally, in PCT Patent Application WO/2016/0662420A1, WO/2016/0662429A1, US20160024084 etc.
Pabuk former times profit cloth crude drug relevant substance-measuring method is not studied.Detection method provided by the present invention can be to above-mentioned
One or more in seven kinds of impurity effectively detect.
Summary of the invention
It is an object of the invention to provide a kind of employing high effective liquid chromatography for measuring Pabuk former times profit cloth crude drug and have related substance
Detection method, thus accurate and effective measures and has related substance, precisely control product quality in Pabuk former times profit cloth raw material.
For above-mentioned purpose, the present invention provides technical scheme as follows:
The present invention provides a kind of Pabuk former times profit to be furnished with the detection method of related substance, and wherein said Pabuk former times profit is furnished with related substance and includes
4-(6-aminopyridine-3-base) piperazine-1-carboxylic acid tert-butyl ester, the bromo-2-of 6-chloro-8-cyclopenta-5-methvl-pyridinium also [2,3-D]
Pyrimidine-7 (8H)-one, tert-butyl group 4-(6-(6-bromo-8-cyclopenta-5-methyl-7-oxygen-7,8-dihydropyridine [2,3-d] pyrimidine-
2-yl amino) pyridine-3-yl) piperazine-1-carboxylate, tert-butyl group 4-(6-(6-(1-vinyl butyl ether)-8-cyclopenta-5-first
Base-7-oxygen-7,8-dihydropyridine [2,3-d] pyrimidine-2-yl amino) pyridine-3-yl) piperazine-1-carboxylate is, 8-cyclopenta-
5-methyl-2-((5-(piperazine-1-base) pyridine-2-base) amino)-6-vinylpyridine also [2,3-d] pyrimidine-7(8H)-
Ketone, 8-cyclopenta-5-methyl-2-(5-piperazine-1-base-pyridine-2-base amino)-8H-pyrido [2,3-d] pyrimidin-7-ones,
4-[6-(6-acetyl group-8-cyclopenta-5-methyl-7-oxo-7,8-dihydro pyrido [2,3-d] pyrimidine-2--amino)-pyrrole
Pyridine-3-base] one or more in-piperazine-1-carboxylate, the method is to use high performance liquid chromatography to carry out
, comprise the steps:
(1) preparation Pabuk former times profit cloth sample solution, described Pabuk former times profit cloth sample solution includes need testing solution；
(2) step (1) gained sample solution is injected high performance liquid chromatograph, use mobile phase A and Mobile phase B as flowing phase
Carry out gradient elution, and record chromatogram；
Wherein, the preparation method of described need testing solution comprises the steps: that precision weighs Pabuk former times profit cloth crude drug sample, adds
Diluent dissolves and is diluted to the concentration of Pabuk former times profit cloth is 0.2mg/ml～2mg/ml, obtains need testing solution；
The chromatographic column fixed phase filler of described high performance liquid chromatography is fluorophenyl interval silica gel or phenyl bonded silica, preferably
Fixing phase filler is fluorophenyl bonded silica gel.
The preparation method of described impurity sample-adding solution comprises the steps: that precision weighs Pabuk former times profit cloth reference substance, adds dilute
Releasing liquid and dissolving and be diluted to the concentration of Pabuk former times profit cloth is 20ug/ml～5mg/ml, obtains Pabuk former times profit cloth reference substance deposit
Liquid；Separately take 4-(6-aminopyridine-3-base) piperazine-1-carboxylic acid tert-butyl ester, the bromo-2-of 6-chloro-8-cyclopenta-5-methyl-pyrrole respectively
Pyridine also [2,3-D] pyrimidine-7 (8H)-one, tert-butyl group 4-(6-(6-bromo-8-cyclopenta-5-methyl-7-oxygen-7,8-dihydropyridine
[2,3-d] pyrimidine-2-yl amino) pyridine-3-yl) piperazine-1-carboxylate, tert-butyl group 4-(6-(6-(1-vinyl butyl ether)-8-
Cyclopenta-5-methyl-7-oxygen-7,8-dihydropyridine [2,3-d] pyrimidine-2-yl amino) pyridine-3-yl) piperazine-1-carboxylate
For, 8-cyclopenta-5-methyl-2-((5-(piperazine-1-base) pyridine-2-base) amino)-6-vinylpyridine also [2,3-d] is phonetic
Pyridine-7(8H)-ketone, 8-cyclopenta-5-methyl-2-(5-piperazine-1-base-pyridine-2-base amino)-8H-pyrido [2,3-
D] pyrimidin-7-ones, 4-[6-(6-acetyl group-8-cyclopenta-5-methyl-7-oxo-7,8-dihydro pyrido [2,3-d] pyrimidine-
2-base amino)-pyridin-3-yl]-piperazine-1-carboxylate's standard substance, accurately weighed, dissolve also with diluent respectively
Being diluted to concentration is 20ug/ml～5mg/ml, obtains each impurity reference substance solution mother solution；Precision measures Pabuk former times Li Buduo photo
Storing solution and Pabuk former times profit cloth each impurity reference substance mother solution, mixing, add diluted, obtain Pabuk former times profit cloth impurity sample-adding molten
Liquid；
Preferably, wherein said diluent is water: acetonitrile: perchloric acid=60:40:0.05.
Preferably, wherein the concentration of Pabuk former times profit cloth is 1.0mg/ml in Pabuk former times profit cloth need testing solution.
Preferably, wherein Pabuk former times profit cloth each impurity reference substance mother liquid concentration is 100ug/ml.
Preferably, in high performance liquid chromatography detecting step (2), first own control solution is injected liquid chromatograph
Instrument, first injects chromatograph of liquid by contrast solution, regulates detection sensitivity, and the peak height making main constituent chromatographic peak is full scale
20%；Again need testing solution and impurity are loaded solution and are injected separately into chromatograph of liquid, use mobile phase A and Mobile phase B as stream
Move and carry out gradient elution mutually, and record chromatogram；Preferably, the amount of sample solution in chromatograph of liquid of injecting is 2ul.
The detection method of the present invention measures under same liquid-phase condition has related substance, described inspection in Pabuk former times profit cloth raw material
Survey method is easy and simple to handle, and Pabuk former times profit cloth main peak retention time is more suitable, and wherein an impurity all can effectively be detected, point
From degree height, assay method specificity is strong, and testing result is the most credible, for quality control, the impurity research of Pabuk former times profit cloth raw material
Provide a kind of easy reasonably detection method.The inventive method has the mensuration of related substance be applicable to Pabuk former times profit cloth crude drug
And sample survey.
Detailed description of the invention
The following example is the present invention to be explained further and illustrates, but is not intended to it and limits this by any way
Bright scope.
By great many of experiments and exploration, the Pabuk former times profit cloth raw material of the present invention has the detection method of related substance effectively to divide
From the relative seven kinds of known impurities of Pabuk former times profit cloth, method is reliable, measures accurately.
Embodiment 1
The Pabuk former times profit relevant substance detecting method of cloth raw material of the present invention
1. detecting instrument and testing conditions
Instrument: wear peace Ultimate3000；Wear peace VWD-3100
Chromatographic column: fluorobenzene pilum (1.7um, 2.1mm × 100mm)
Flowing phase: A:0.05%(v/v) high chloro acid solution
B: methanol
Flow velocity: 0.4ml/min；Detection wavelength: 220nm；
Column temperature: 55 DEG C；Automatic sampler temperature is 25 DEG C.
2. solution preparation: take Pabuk former times profit cloth material sample, adds diluent dissolving and makes every 1ml containing about Pabuk former times profit cloth
The need testing solution of 1mg.
Precision measures need testing solution 1ml, puts in 100ml volumetric flask, is diluted to scale by mobile phase A, shakes up, as certainly
Body contrast solution.
Take Pabuk former times profit cloth reference substance about 100mg, put in 50ml measuring bottle, dissolve with diluent and be diluted to scale, shake up,
It is Pabuk former times profit cloth reference substance storing solution；Separately take SM1, SM2, PALB01, PALB02, PF-06651464, PF-respectively
00447880, each 10mg of PF-00310864 standard substance, accurately weighed, puts in 10ml measuring bottle, dissolves with diluent and is diluted to carve
Degree, shakes up, is each dirt solution mother solution；Precision measures Pabuk former times profit cloth reference substance storing solution 5.0ml and each dirt solution is female
Liquid 1.0ml, puts in 10ml measuring bottle and mixes, by diluted to scale, shake up, and is worth Pabuk former times profit cloth impurity sample-adding solution.
3. assay method: go own control solution 2ul to inject chromatograph of liquid, regulate detection sensitivity, make main constituent color
The peak height of spectral peak is about the 20% of monitor full scale.Separately take need testing solution and the impurity sample-adding each 2ul of solution injects liquid chromatograph
Instrument, carries out gradient elution, 3 ~ 4 times of record chromatogram to main constituent peak retention time according to table 1.
The present invention is easy and simple to handle, and Pabuk former times profit cloth main peak retention time is about about 11 minutes, and the detection time is more suitable,
Seven kinds of known impurities all can effectively be detected, and separating degree all meets the requirements (more than 1.5), and assay method specificity is strong, inspection
Survey result the most credible.
Claims (10)
1. the detection method having related substance in Pabuk former times profit cloth raw material, relevant in wherein said Pabuk former times profit cloth raw material
Material include PF-00447880, PF-06651464, PF-00310864 one or more, the method be use high-efficient liquid phase color
Spectrometry is carried out, and comprises the steps:
(1) preparation Pabuk former times profit cloth sample solution, described Pabuk former times profit cloth sample solution includes need testing solution；
(2) step (1) gained sample solution is injected high performance liquid chromatograph, use mobile phase A and Mobile phase B as flowing
Carry out gradient elution mutually, and record chromatogram；
Wherein, the preparation method of described need testing solution comprises the steps: that precision weighs Pabuk former times profit cloth material sample, adds dilute
Releasing liquid and dissolving and be diluted to the concentration of Pabuk former times profit cloth is 0.2mg/ml～2.0mg/ml, obtains need testing solution；
The chromatographic column fixed phase filler of described high performance liquid chromatography is fluorophenyl bonded silica gel or phenyl bonded silica, preferably
Fixing phase filler is fluorophenyl bonded silica gel；
Mobile phase A be formulated as 0.05% ~ 0.5% acidic buffer；The acidic buffer of the preparation 0.05% ~ 0.3% of Mobile phase B
Liquid amasss: methanol volume=0 ~ 10:100 ~ 90.
2. according to the detection method described in claim 1, wherein mobile phase A be formulated as 0.05% acidic buffer.
3. according to the detection method described in claim 1 or 2, wherein Mobile phase B be formulated as 0.05% buffer volume: first
Alcohol volume=0:100.
4., according to the detection method according to any one of claim 3, the gradient elution of wherein said high performance liquid chromatography is suitable
Sequence is as follows:
When 0 minute, flowing is mutually: 90～100 volume % mobile phase A+0～10 volume % Mobile phase B；
When 0-30 minute, flowing is mutually: 45～55 volume % mobile phase A+45～55 volume % Mobile phase B；
When 30-45 minute, flowing is mutually: 0～10 volume % mobile phase A+90～100 volume % Mobile phase B；
When 45-55 minute, flowing is mutually: 90～100 volume % mobile phase A+0～10 volume % Mobile phase B；
Preferably, the gradient elution order of described high performance liquid chromatography is as follows:
When 0 minute, flowing is mutually: 97 volume % mobile phase A+3 volume % Mobile phase B；
When 0-30 minute, flowing is mutually: 50 volume % mobile phase A+50 volume % Mobile phase B；
When 30-45 minute, flowing is mutually: 3 volume % mobile phase A+97 volume % Mobile phase B；
During 45-55 minutes, flowing is mutually: 97 volume % mobile phase A+3 volume % Mobile phase B.
5., according to the detection method according to any one of claim 1 to 4, the acid of wherein said acidic buffer is high chlorine
Acid, phosphoric acid, trifluoroacetic acid, preferably perchloric acid；
Preferably, the concentration of acidic buffer is 0.05% ~ 0.3%(v/v), preferably 0.05%；
Preferably, the pH of acidic buffer is 2.0 ~ 7.0, and the pH of the phase that preferably flows is 2.3；
Preferably, the flow velocity of flowing phase is 0.3～0.5ml/min, and the flow velocity of the phase that preferably flows is 0.4ml/min.
6. according to the detection method according to any one of claim 1 to 5, the chromatograph of wherein said high performance liquid chromatography
Post column temperature is 40～65 DEG C, preferably 55 DEG C；
Preferably, auto injection room temperature is 4 ~ 30 DEG C, preferably 25 DEG C；
Preferably, detection wavelength is 220nm.
7., according to the detection method according to any one of claim 1 to 6, wherein said Pabuk former times profit cloth sample solution also wraps
Include own control solution and/or impurity sample-adding solution；
The preparation method of described own control solution comprises the steps: that precision measures need testing solution 1ml, puts 100ml capacity
In Ping, add diluted to scale, shake up, obtain own control solution；
The preparation method of described impurity sample-adding solution comprises the steps: that precision weighs Pabuk former times profit cloth reference substance, adds diluent
Dissolving and being diluted to the concentration of Pabuk former times profit cloth is 0.2mg/ml～2mg/ml, obtains Pabuk former times profit cloth reference substance storing solution；
Separately take PF-00447880, PF-06651464, PF-00310864 respectively, accurately weighed, dissolve with diluent respectively and be diluted to
Concentration is 20ug/ml～5mg/ml, obtains each impurity reference substance solution mother solution；Precision measures Pabuk former times profit cloth reference substance deposit
Liquid and Pabuk former times Li Butan each impurity reference substance solution mother solution, mixing, add diluted, obtain Pabuk former times profit cloth impurity sample-adding
Solution；
Preferably, wherein said diluent is water: acetonitrile: perchloric acid=60:40:0.05.
8. according to the detection method according to any one of claim 1 to 7, wherein Pabuk in Pabuk former times profit cloth need testing solution
Former times profit cloth concentration is 1mg/ml.
9. according to the detection method described in claim 7 or 8, wherein Pabuk former times profit cloth each impurity reference substance solution mother liquid concentration
It is 100 μ g/ml.
10. according to the detection method according to any one of claim 7 to 9, wherein, at high performance liquid chromatography detecting step
(2) in, first sample own control solution is injected chromatograph of liquid, regulate detector sensitivity, make main constituent chromatographic peak
Peak height is the 20% of monitor full scale；Again need testing solution and impurity are loaded solution and are injected separately into chromatograph of liquid, use
Mobile phase A carries out gradient elution with Mobile phase B mutually as flowing, and records chromatogram；Preferably, inject in chromatograph of liquid
The amount of sample solution is 2 μ l.
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| CN106970177A (en) * | 2017-06-06 | 2017-07-21 | 北京元延医药科技股份有限公司 | The analyzing detecting method of Pa Boxini intermediates and its impurity |
| CN111239299A (en) * | 2020-03-30 | 2020-06-05 | 重庆三圣实业股份有限公司 | Method for separating and measuring palbociclib and impurities thereof |
| CN114544847A (en) * | 2022-03-09 | 2022-05-27 | 上海皓元医药股份有限公司 | Method for detecting genotoxic impurities in starting raw material for synthesizing thuja occidentalis |
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Cited By (5)
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|---|---|---|---|---|
| CN106970177A (en) * | 2017-06-06 | 2017-07-21 | 北京元延医药科技股份有限公司 | The analyzing detecting method of Pa Boxini intermediates and its impurity |
| CN111239299A (en) * | 2020-03-30 | 2020-06-05 | 重庆三圣实业股份有限公司 | Method for separating and measuring palbociclib and impurities thereof |
| CN111239299B (en) * | 2020-03-30 | 2022-05-27 | 重庆三圣实业股份有限公司 | Method for separating and measuring palbociclib and impurities thereof |
| CN114544847A (en) * | 2022-03-09 | 2022-05-27 | 上海皓元医药股份有限公司 | Method for detecting genotoxic impurities in starting raw material for synthesizing thuja occidentalis |
| CN114544847B (en) * | 2022-03-09 | 2023-11-03 | 上海皓元医药股份有限公司 | Method for detecting genotoxic impurities in starting raw material for synthesizing piperaquine Bai Xi |
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