CN107014943B - A kind of detection method for replacing Buddhist nun's enantiomter according to Shandong - Google Patents
A kind of detection method for replacing Buddhist nun's enantiomter according to Shandong Download PDFInfo
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- CN107014943B CN107014943B CN201710424005.0A CN201710424005A CN107014943B CN 107014943 B CN107014943 B CN 107014943B CN 201710424005 A CN201710424005 A CN 201710424005A CN 107014943 B CN107014943 B CN 107014943B
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
Abstract
The invention discloses a kind of detection methods for replacing Buddhist nun's enantiomter according to Shandong, belong to Pharmaceutical Analysis technical field, include mainly the preparation of system suitability solution, the preparation of enantiomter reference substance solution, preparation, chromatographic condition and the system suitability of test solution and according to Shandong for Buddhist nun's enantiomerism body measurement this 5 steps.Detection method has higher accuracy, precision, durability is strong, the content for enantiomter in Buddhist nun's bulk pharmaceutical chemicals according to Shandong can be accurately reflected, it is suitble to be commercially used for replace the inspection and quality control of Buddhist nun's enantiomter according to Shandong, so as to provide rational foundation for the formulation of quality standard, so as to preferably control and grasp product quality, and improve the safety of clinical application.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical fields, and in particular to a kind of detection method for replacing Buddhist nun's enantiomter according to Shandong.
Background technology
Chronic lymphocytic leukemia（Chronic Lymphocytic Leukemia, CLL）It is the leaching because of morphological maturity
Bar cell can not normal apoptotic, a kind of chronic blood system caused by clonal expansion is pernicious swollen in lymphoid tissue instead
Tumor.CLL has certain Familial Occurrence, belongs to B cell non-Hodgkin lymphoma (Non-Hodgkin ' s Lymphoma, NHL)
In more typical one kind.Lymphoma mantle cell (Mantle Cell Lymphoma, MCL) is a kind of rare B cell NHL, about
The 5%-10% for accounting for whole NHL, the hardly possible for having both malignant lymphoma are curative and aggressive.MCL is not easy to diagnose, and about 85% patient is true
It was in for III~IV phase when examining；And easily recurrence, it is the minimum hypotype lymthoma of long term survival rate.It is weary clinically often to show as high fever
Power, spleen and enlargement of lymph nodes, gastrointestinal tract involve and the infiltration to nervous system.The first-line treatment scheme of CLL is the side FCR at present
Case, i.e. fludarabine（F）, cyclophosphamide（C）And Rituximab（R）The scheme of triple combination's treatment, the program have a constant current modulation
Effect, but be that 38%, 3 or 4 grade of adverse reaction happens occasionally without progression of disease survival rate.MCL often select anthracycline or containing large dosage of Ah
The drug of sugared cytidine, however it is mostly insensitive to conventional chemotherapy medicine, although having compared with drug for treating, total life of patient
Depositing the phase is not obviously prolonged；Although also using the Regimen Chemotherapy MCL of drug and monoclonal antibody combined chemotherapy, it is more toxic, infects
Incidence is about 14%, and 3~4 grades of adverse reaction rates are up to 87%.Therefore, the drug of feasible therapeutic scheme and highly effective and safe
Need to be released.
By Pharmacyclics companies and Janssen Pharmaceutica（Jassen）That develops jointly replaces Buddhist nun according to Shandong（Ibrutinib, quotient
Name of an article Imbruvica）As oral bruton's tyrosine kinase（BTK）Inhibitor class initiated new drug, in 2 months 2013 quilts
FDA authorizes breakthrough medicine qualification, and is approved as MCL and CLL respectively on November 13rd, 2013 and on 2 12nd, 2014
Medicine.It is 1- [(3 to replace the chemical name of Buddhist nun according to ShandongR) -3- [4- amino -3- (4- Phenoxyphenyls) -1HPyrazolo
[3,4-d] pyrimidine -1- bases] -1- piperidyls] -2- propylene -1- ketone, structural formula is as follows：
.Replace Buddhist nun in mirror symmetry, chemical name with according to Shandong for Buddhist nun's enantiomter according to Shandong
For 1- [(3S) -3- [4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases] -1- piperidyls] -2-
Propylene -1- ketone.
It is single enantiomer due to replacing Buddhist nun according to Shandong, the impurity content controlled in its bulk pharmaceutical chemicals is especially its enantiomter
Content has great importance for reducing its adverse reaction.Patent CN 104407067A disclose it is a kind of to according to Shandong for Buddhist nun and
The method that its isomers carries out HPLC detections, but there are some drawbacks for this method, and such as 1. run time is longer, single needle run time
35min or more；2. the computational methods of unlisted isomer impurities also do not carry out methodology validation；3. not carrying out the inspection of isomers
Survey the determination of limit and quantitative limit, percentage of the isomer impurities according to Shandong for Buddhist nun's bulk pharmaceutical chemicals（That is ee values）Also unknown.Thus may be used
See, the testing result of the prior art can not in actual response drug isomer impurities content.Based on this, the present invention provides one
Kind replaces Buddhist nun's enantiomerism body detecting method and its quality control standard according to Shandong.
Invention content
The purpose of the present invention is to provide a kind of detection methods for replacing Buddhist nun's enantiomter according to Shandong, with higher accurate
Degree, precision, durability is strong, the content for enantiomter in Buddhist nun's bulk pharmaceutical chemicals according to Shandong can be accurately reflected, so as to be quality mark
Accurate formulation provides rational foundation, so as to preferably control and grasp product quality, and improves the safety of clinical application
Property.
To achieve the above object, the present invention adopts the following technical scheme that：
A kind of detection method for replacing Buddhist nun's enantiomter according to Shandong comprising following steps：
1）The preparation of system suitability solution：Using methanol as solvent, will match for Buddhist nun's enantiomter reference substance according to Shandong
The isomers stock solution of a concentration of 0.5mg/mL is made；Another take replaces Buddhist nun's reference substance according to Shandong, according to mass volume ratio 5:1（W/V）
Prepared isomers stock solution is added, then methanol is added to be dissolved to a concentration of 0.5mg/mL for replacing Buddhist nun in solution according to Shandong, as
System suitability solution；
2）The preparation of enantiomter reference substance solution：Using methanol as solvent, Buddhist nun's enantiomter reference substance will be replaced according to Shandong
It is configured to the isomers mother liquor of a concentration of 0.25mg/mL；Then accurate to measure the isomers mother liquor, using methanol as solvent, by body
Product ratio 1:100 are diluted, using the solution after dilution as enantiomter reference substance solution；
3）The preparation of test solution：Precision is weighed replaces Buddhist nun's sample to be tested according to Shandong, is configured to using methanol as solvent a concentration of
The solution of 0.5mg/mL, as test solution；
4）Chromatographic condition and system suitability：Using Féraud door chiral column（LUX Cellulose-4, specification 250 ×
4.6mm）；With n-hexane-propylene glycol-diethylamine（90:10:0.1, V/V/V）For mobile phase, flow 1.2ml/min；Detection wavelength
For 260nm；Take step 1）The system suitability solution of preparation carries out system suitability, and Buddhist nun is replaced with according to Shandong for Buddhist nun according to Shandong
The separating degree of enantiomter is answered>5.0, theoretical cam curve by according to Shandong for 5000 should be not less than based on Ni Feng；
5）Buddhist nun's enantiomerism body measurement is replaced according to Shandong：Take step 2）Prepared enantiomter reference substance solution and step 3）
Each 10 μ L of prepared test solution are injected separately into liquid chromatograph, chromatogram are recorded, by external standard method with calculated by peak area pair
Reflect the content of isomers.
The present invention also provides a kind of quality control standards for replacing Buddhist nun's enantiomter according to Shandong, wherein different for Buddhist nun's mapping according to Shandong
The assay of structure body is carried out by above-mentioned detection method, measured to must not exceed 0.5% according to Shandong for the content of Buddhist nun's enantiomter.
If stringenter control product quality, ensure drug safety, the standard of the enantiomter inspection can be improved as must not
Cross 0.1%.
Detection method has higher accuracy, precision, and durability is strong, can accurately reflect former for Buddhist nun according to Shandong
The content for expecting enantiomter in medicine is suitble to be commercially used for replace the inspection and quality control of Buddhist nun's enantiomter according to Shandong, can be with
Rational foundation is provided for the formulation of quality standard, so as to preferably control and grasp product quality, and is conducive to improve
The safety of clinical application.
Description of the drawings
Fig. 1 is the separating degree chromatogram that Buddhist nun and its enantiomter are replaced according to Shandong, wherein tR6.426min is to replace Buddhist nun according to Shandong
Enantiomter, tR8.233min is to replace Buddhist nun according to Shandong.The Detection wavelength of detector A channel 1 is 260nm.
Specific implementation mode
It is as follows for the detection method of Buddhist nun's enantiomter according to Shandong：
1）The preparation of system suitability solution：Precision is weighed replaces Buddhist nun enantiomter reference substance 25mg according to Shandong, by it
It is placed in 50mL volumetric flasks, scale is dissolved and be diluted to methanol, as isomers stock solution；Another precision is weighed replaces Buddhist nun according to Shandong
Reference substance 25mg, is placed in 50mL volumetric flasks, and prepared isomers stock solution 5mL is then added, then adds methanol dissolving simultaneously
It is diluted to scale, as system suitability solution；
2）The preparation of enantiomter reference substance solution：Precision is weighed replaces Buddhist nun enantiomter reference substance 25mg according to Shandong, will
It is placed in 100mL volumetric flasks, and scale is dissolved and be diluted to methanol, is shaken up, and obtains isomers mother liquor；Precision measures obtained by 1mL
Isomers mother liquor is placed in 100mL measuring bottles, is added methanol dilution to scale, is shaken up, as enantiomter reference substance solution；
3）The preparation of test solution：Precision is weighed replaces Buddhist nun sample to be tested 25mg according to Shandong, is placed in 50mL volumetric flasks, adds first
Alcohol dissolves and is diluted to scale, shakes up, as test solution；
4）Chromatographic condition and system suitability：Using LUX Cellulose-4 chiral columns（250×4.6mm）；With just
Hexane-propylene glycol-diethylamine（90:10:0.1, V/V/V）For mobile phase, flow 1.2ml/min；Detection wavelength is 260nm；It takes
Step 1）The 10 μ L of system suitability solution of preparation inject liquid chromatograph, and Buddhist nun's enantiomerism is replaced with according to Shandong for Buddhist nun according to Shandong
The separating degree of body is answered>5, theoretical cam curve by according to Shandong for 5000 should be not less than based on Ni Feng；
5）Buddhist nun's enantiomerism body measurement is replaced according to Shandong：Take step 2）The enantiomter reference substance solution and step 3 of preparation）System
Each 10 μ L of standby test solution are injected separately into liquid chromatograph, record chromatogram；As shown and compareing in test solution collection of illustrative plates
The peak of the corresponding retention time in enantiomter peak in product solution collection of illustrative plates, by external standard method containing with calculated by peak area enantiomter
Amount.
It is used to be synthesized by the following method for Buddhist nun's enantiomter reference substance according to Shandong：
It is as follows：
1）Under nitrogen protection, by Ph3P（58.0g 224mmol）、(R) -3 hydroxy piperidine of -1- tert-butoxycarbonyls
（36.0g 179mmol）It is dissolved in 300mL tetrahydrofurans, is cooled to 0 DEG C, DIAD is then added in 20-30min（50.0g,
250mmol）Tetrahydrofuran solution 80mL, stir 10min, at 0 ~ 5 DEG C be added 4- amino -3- (4- Phenoxyphenyls) -
1H- pyrazolos [3,4-d] pyrimidine（56.0g 184mmol）Tetrahydrofuran solution 300mL, stir 5h at room temperature, then plus
Water 100mL is extracted, and is divided and is removed water layer, by organic layer through anhydrous Na2SO4It is concentrated after drying, then through column chromatography for separation, vacuum is dry
It is dry, obtain (3S) -4- amino -3- (4- Phenoxyphenyls) -1- (1- tert-butoxycarbonylpiperidines) -1H- pyrazolos [3,4-d] are phonetic
The white solid 53.2g of pyridine；
2）Step 1 is added in the reaction bulb of 1L）Obtained (3S) -4- amino -3- (4- Phenoxyphenyls) -1- (uncles 1-
Butoxy carbonyl piperidine) -1H- pyrazolos [3,4-d] pyrimidine（42.8g 100mmol）, stir and be dissolved in 500mL methanol, then
It is slowly added to 12M hydrochloric acid solution 30mL at room temperature, stirs 5h, there are a large amount of solids to be precipitated, then in 6M NaOH solutions 60mL
With, it filtering, obtained solid is washed 3 times with ethyl acetate, dry, obtain (S) -3- (4- Phenoxyphenyls) -1- (3- piperidyls) -
1H- pyrazolos [3,4-d] pyridine -4- amine 30.9g；
3）1 L dichloromethane is added in the reaction bulb of 2L, be then added (S) -3- (4- Phenoxyphenyls) -1- (3- piperazines
Piperidinyl) -1H- pyrazolos [3,4-d] pyridine -4- amine（32.8g 100mmol）And acryloyl chloride（11.1g 125mmol）, in 25-
At 35 DEG C, triethylamine is added dropwise（13.1 g, 130mmol）, it is stirred to react 4h, is then extracted with dichloromethane, is concentrated, gained slightly produces
Product are added isopropanol 240mL and are recrystallized, and obtain 1- [(3S) -3- [4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,
4-d] pyrimidine -1- bases] -1- piperidyls] and -2- propylene -1- ketone white solid 34.4g, related data is as follows：
mp：155.0~157.5℃.MS (ESI+, m/z)：903 [M+1]+。
1H NMR (500 MHz, 300 K, DMSO)：δ8.39 (s, 1H), δ 3.6 (s, 2H), δ 7.44 (d, 1H), δ
6.98 (d, 1H), δ 6.98（D, 1H), δ 7.44 (d, 1H), δ 6.92 (d, 1H), δ 7.22 (d, 1H), δ 6.98 (d, 1H), δ 7.22
(d, 1H), δ 6.92 (d, 1H), δ 3.40 (m, 1H), δ 3.70 (d, 2H), δ 1.5 (m, 2H), δ 1.8 (t, 2H), δ 3.0 (t,
2H), δ 6.62 (m, 1H), δ 6.12 (m, 1H), δ 5.50 (m, 1H).
13C NMR (125 MHz, DMSO)：δ157.1（s）, δ 131.4（s）, δ 97.5（s）, δ 167.7（s）, δ 155.5
（s）, δ 129.6（s）, δ 126.7（t）, δ 117.8（t）, δ 156.1（s）, δ 117.8（t）, δ 126.7（t）, δ 156.1（s）, δ
117.3（t）, δ 128.2（t）, δ 121.6（s）, δ 128.2（t）, δ 117.3（t）, δ 55.9（d）, δ 27.3（d）, δ 20.3（d）, δ
46.2（d）, δ 47.6（d）, δ 168.3（s）, δ 130.8（d）, δ 129.1（t）.
In order to make content of the present invention easily facilitate understanding, With reference to embodiment to of the present invention
Technical solution is described further, but the present invention is not limited only to this.
The selection of 1 mobile phase of experimental example
Table 1 is according to Shandong for the selection of chromatographic condition in the detection of Buddhist nun's enantiomter
By table 1 as it can be seen that when mobile phase is n-hexane-ethyl alcohol-diethylamine (90:10:0.1, V/V/V) when, obtained
Main peak peak type is good in HPLC collection of illustrative plates, and retention time is suitable, and the separation of main peak and impurity peaks has reached preferable effect.Therefore,
By n-hexane-ethyl alcohol-diethylamine (90:10:0.1, V/V/V) it is determined as replacing the mobile phase item of Buddhist nun's enantiomter detection according to Shandong
Part.
The selection of 2 Detection wavelength of experimental example
It takes according to Shandong for Buddhist nun and replaces Buddhist nun's enantiomter reference substance appropriate according to Shandong, dissolved respectively with methanol and be diluted to concentration about
For the solution of 10 μ g/mL, according to UV-VIS spectrophotometry (Chinese Pharmacopoeia version in 2015), respectively in 200~400nm wavelength
Scanning in range.Scanning result finds have absorption maximum, therefore, take at 259nm wavelength for Buddhist nun and its enantiomter according to Shandong
It is whole to select 260nm to replace the Detection wavelength of Buddhist nun's enantiomter detection according to Shandong.
3 methodological study of embodiment
1. method specificity is tested
Separating degree is tested：It takes and replaces Buddhist nun and its enantiomter reference substance appropriate according to Shandong, be made into a certain concentration with ethyl alcohol respectively
Solution, the 10 μ l of sample introduction under selected chromatographic condition record chromatogram；The mixed solution for preparing the two again, in above-mentioned chromatostrip
Sample introduction under part, records chromatogram, and gained chromatogram is as shown in Figure 1.
By Fig. 1 results as it can be seen that it is 5.6 to replace Ni Feng and the separating degree at its enantiomter peak according to Shandong, separating degree is good.
2. accuracy test
It takes according to Shandong for Buddhist nun's enantiomter reference substance about 25mg, it is accurately weighed, it is placed in 10mL measuring bottles, simultaneously with methanol dissolving
It is diluted to scale, precision pipettes 1.0mL and is placed in 100mL measuring bottles, is settled to scale with methanol dilution, shakes up, as isomers
Concentrated solution；It weighs and replaces totally three parts of Buddhist nun's raw material about 25mg according to Shandong, it is accurately weighed, it is respectively placed in three 50mL measuring bottles, and add respectively
Enter above-mentioned isomers concentrated solution 4mL, 5mL and 6mL, 80%, 100% and 120% three concentration points are made, uses methanol dilution
It to scale, shakes up, as determination of recovery rates test solution.Each concentration point is parallel three parts another.
10 μ l of above-mentioned test solution are taken respectively, inject liquid chromatograph, chromatogram are recorded, by external standard method in terms of peak area
It calculates, the rate of recovery is calculated according to measured amount and the amount of being actually added into.Test result is shown in Table 2.
Table 2 replaces Buddhist nun's enantiomter accuracy test according to Shandong
By 2 result of table as it can be seen that this method accuracy is good, meet test request.
3. precision test
3.1 repetitive test
It takes according to Shandong for Buddhist nun's enantiomter reference substance about 25mg, it is accurately weighed, it is placed in 10mL volumetric flasks, is dissolved with methanol
And it is diluted to scale, precision pipettes 1.0mL and is placed in 100mL volumetric flasks, and scale is settled to methanol dilution, dense as isomers
Solution；It takes and replaces Buddhist nun's sample about 25mg according to Shandong, it is totally 6 parts, accurately weighed, it is respectively placed in 6 50mL volumetric flasks, and be separately added into
Isomers concentrated solution 5mL is stated, scale is dissolved and be diluted to methanol, as test solution.
Another precision is weighed replaces Buddhist nun enantiomter reference substance 25mg according to Shandong, is placed in 100mL volumetric flasks, precision pipettes 1mL
Into 100mL volumetric flasks, scale is dissolved and is diluted to methanol, as enantiomter reference substance solution.
Precision measures 6 parts of test solutions and each 10 μ L of enantiomter reference substance solution, injects in liquid chromatograph, note
Record chromatogram.Test result shows that the content of enantiomter is respectively in 6 samples（%）0.49、0.48、0.49、0.47、
0.50,0.48, the RSD% of 6 measurement results is 1.46%, it was demonstrated that this method has certain precision.
3.2 system precision
It takes according to Shandong for Buddhist nun's enantiomter reference substance 25mg, it is accurately weighed, it is placed in 100mL volumetric flasks, is dissolved with methanol
To scale, precision pipettes the 1.0mL solution and sets in 100mL volumetric flasks, with methanol constant volume to scale, is configured to a concentration of 2.5 μ g/
The solution of mL, continuous sample introduction 5 times, 10 μ L, record peak area, and evaluate result, test result is shown in Table 3 every time.
3 system Precision test result of table
By table 3 as it can be seen that this method system precision is good, meet test request.
4. linearity and range
It takes and replaces Buddhist nun's enantiomter reference substance appropriate according to Shandong, it is accurately weighed, it is dissolved with methanol and is diluted successively, concentration is made
The ranging from series standard solution of 0.05 μ of μ g/mL~10.02 g/mL.It is accurate respectively to measure 10 μ L according to chromatographic condition, inject liquid
Chromatography records chromatogram, and with concentration C (μ g/mL) for abscissa, peak area A is ordinate, carries out linear regression, and count
Regression equation and related coefficient are calculated, the results are shown in Table 4.
Table 4 replaces Buddhist nun's enantiomter linearity and range test result according to Shandong
Table 4 the result shows that, it is linear for Buddhist nun's enantiomter according to Shandong in the range of the 0.05 μ g/mL of μ g/mL~10.02
Relationship is good.
5. quantitative limit and detection limit
Conditioning instrumentation sensitivity, with methanol be configured to it is certain density according to Shandong replace Buddhist nun's enantiomerism liquid solution, gradually dilute
10 μ L of sample introduction afterwards make 2-3 times of a height of baseline noise of main peak, record chromatogram, and get Yi Lu examines for the minimum of Buddhist nun's enantiomter
Survey is limited to 0.3ng.
Conditioning instrumentation sensitivity, with methanol be configured to it is certain density according to Shandong replace Buddhist nun's enantiomerism liquid solution, gradually dilute
10 μ L of sample introduction afterwards make 10 times or so of a height of baseline noise of main peak, record chromatogram, and get Yi Lu replaces the minimum of Buddhist nun's enantiomter
Quantitatively it is limited to 1.0ng.
6. solution stability testing
6.1 replace Buddhist nun's enantiomter standard solution stability test according to Shandong
It takes according to Shandong for Buddhist nun's isomer control product about 25mg, it is accurately weighed, 100mL volumetric flasks are placed in, with methanol dissolving and dilute
It releases to scale, precision pipettes in 1mL solution to 100mL volumetric flasks, with methanol constant volume to scale, as standard solution.Respectively
10 μ L were drawn in 0,2,4,8,16,24 hour and inject liquid chromatograph, recorded chromatogram, test result is shown in Table 5.
5 standard solution stability of table
It is had good stability by table 5 as it can be seen that being placed at room temperature for 24 hours for the methanol solution of Buddhist nun's enantiomter according to Shandong.
6.2 replace Buddhist nun's test solution stability test according to Shandong
It weighs according to Shandong for Buddhist nun's raw material about 25mg, it is accurately weighed, it is placed in 50mL volumetric flasks, is dissolved with methanol and be diluted to quarter
Degree, is made into the test solution that concentration is about 0.5mg/mL, drew 10 μ L respectively at 0,2,4,8,16,24 hour, injects liquid phase
Chromatograph, records chromatogram, and test result is shown in Table 6.
Table 6 replaces Buddhist nun's test solution stability according to Shandong
It is had good stability by table 6 as it can be seen that being placed at room temperature for 24 hours for the methanol solution of Buddhist nun's test sample according to Shandong.
7. serviceability test
By changing mobile phase ratio, flow velocity holds come when assessing determination condition small variations, measurement result is impregnable
By degree.Under each condition, it takes respectively and replaces Buddhist nun and its enantiomter reference substance appropriate according to Shandong, it is accurately weighed, it is molten with methanol
It solves and dilutes and be made containing the solution for replacing 2.5 μ g of Buddhist nun 0.5mg and isomers according to Shandong in every mL, as test solution；Separately take isomery
Body impurity reference substance is appropriate, accurately weighed, uses methanol to dissolve and dilutes the solution containing 2.5 μ g is made in every 1mL as isomers
Reference substance solution, accurate respectively to measure in isomer control product solution and each 10 μ L injections liquid chromatograph of test solution, note
Chromatogram is recorded, result is evaluated.The results show that this method good tolerance, meets test request.
Embodiment 4 replaces the detection and its quality examination of Buddhist nun's enantiomter according to Shandong
1）The preparation of system suitability solution：It takes according to Shandong for Buddhist nun's enantiomter reference substance 25mg, it is accurately weighed, it sets
In 50mL volumetric flasks, scale is dissolved and is diluted to methanol, as isomers stock solution；Another take replaces Buddhist nun's reference substance according to Shandong
25mg, it is accurately weighed, it sets in 50ml measuring bottles, isomers storing solution 5mL is added, scale is dissolved and be diluted to methanol, as being
System applicability solution；
2）The preparation of enantiomter reference substance solution：It takes according to Shandong for Buddhist nun's enantiomter reference substance 25mg, it is accurately weighed,
It is placed in 100mL measuring bottles, scale is dissolved and be diluted to methanol, is shaken up；Precision measures 1mL, is placed in 100mL measuring bottles, uses first
Alcohol is diluted to scale, shakes up, as enantiomter reference substance solution；
3）The preparation of test solution：It takes according to Shandong for Buddhist nun's sample to be tested 25mg, it is accurately weighed, it sets in 50mL volumetric flasks, uses
Methanol dissolves and is diluted to scale, shakes up, as test solution；
4）Chromatographic condition and system suitability：Using LUX Cellulose-4 chiral columns（250×4.6mm）, with just
Hexane-propylene glycol-diethylamine（90:10:0.1, V/V/V）For mobile phase, flow 1.2mL/min, Detection wavelength 260nm；It takes
Step 1）The 10 μ L of system suitability solution of preparation inject liquid chromatograph, and Buddhist nun's enantiomerism is replaced with according to Shandong for Buddhist nun according to Shandong
The separating degree of body is answered>5.0, theoretical cam curve by according to Shandong for 5000 should be not less than based on Ni Feng；
5）Buddhist nun's enantiomerism body measurement is replaced according to Shandong：Take step 2）The enantiomter reference substance solution and step 3 of preparation）System
Each 10 μ L of standby test solution are injected separately into liquid chromatograph, record chromatogram；As shown and compareing in test solution collection of illustrative plates
The peak of the corresponding retention time in enantiomter peak in solution collection of illustrative plates, by external standard method with the content of calculated by peak area enantiomter.
It is detected using enantiomter content in three batches of samples of above-mentioned detection method pair, and carries out stability test,
As a result it is shown in Table 7, table 8 respectively.
Table 7 is according to Shandong for the inspection result of enantiomter in Buddhist nun's sample
Table 8 is according to Shandong for the inspection result of enantiomter in Buddhist nun's stability sample
By test result as it can be seen that by acceleration and long-term stable experiment, enantiomerism is not detected in each batch sample
Body is stringenter control product quality, ensures drug safety, the standard of enantiomter inspection can must not rise to
0.1%.
The foregoing is merely presently preferred embodiments of the present invention, all equivalent changes done according to scope of the present invention patent with
Modification should all belong to the covering scope of the present invention.
Claims (2)
1. a kind of detection method for replacing Buddhist nun's enantiomter according to Shandong, it is characterised in that：Include the following steps：
1）The preparation of system suitability solution：Using methanol as solvent, will be configured to for Buddhist nun's enantiomter reference substance according to Shandong
The isomers stock solution of a concentration of 0.5mg/mL；Another take replaces Buddhist nun's reference substance according to Shandong, according to 5 mg of mass volume ratio:1 mL is added
Prepared isomers stock solution, then methanol is added to be dissolved to a concentration of 0.5mg/mL for replacing Buddhist nun in solution according to Shandong, as system
Employment and suitability test (E ＆ ST) solution；
2）The preparation of enantiomter reference substance solution：Using methanol as solvent, will be prepared for Buddhist nun's enantiomter reference substance according to Shandong
At the isomers mother liquor of a concentration of 0.25mg/mL；Then accurate to measure the isomers mother liquor, using methanol as solvent, by volume
1:100 are diluted, using the solution after dilution as enantiomter reference substance solution；
3）The preparation of test solution：Precision is weighed replaces Buddhist nun's sample to be tested according to Shandong, is configured to using methanol as solvent a concentration of
The solution of 0.5mg/mL, as test solution；
4）Chromatographic condition and system suitability：It is flowing with n-hexane-propylene glycol-diethylamine using Féraud door chiral column
Phase, Detection wavelength 260nm；Take step 1）The system suitability solution of preparation carries out system suitability, is replaced according to Shandong
Buddhist nun should meet regulation with according to Shandong for the separating degree of Buddhist nun's enantiomter；
5）Buddhist nun's enantiomerism body measurement is replaced according to Shandong：Take step 2）Prepared enantiomter reference substance solution and step 3）It is made
Each 10 μ L of standby test solution are injected separately into liquid chromatograph, record chromatogram, different with calculated by peak area mapping by external standard method
The content of structure body：
The Féraud door chiral column is specially LUX Cellulose-4, and specification is 250 × 4.6mm；
The flow of the mobile phase is 1.2mL/min, and the volume ratio of n-hexane-propylene glycol-diethylamine is 90 in mobile phase:10:
0.1。
2. the detection method of Buddhist nun's enantiomter is replaced according to Shandong according to claim 1, it is characterised in that：According to Shandong for Buddhist nun and according to Shandong
Separating degree for Buddhist nun's enantiomter is answered>5.0, theoretical cam curve by according to Shandong for 5000 should be not less than based on Ni Feng.
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| CN112630346B (en) * | 2020-12-16 | 2022-11-01 | 河北合佳医药科技集团股份有限公司 | Quantitative analysis method for residual solvent in ibrutinib |
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