CN108250139A - A Pa is for Buddhist nun's B crystal form and its preparation method and application - Google Patents
A Pa is for Buddhist nun's B crystal form and its preparation method and application Download PDFInfo
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- CN108250139A CN108250139A CN201611238708.6A CN201611238708A CN108250139A CN 108250139 A CN108250139 A CN 108250139A CN 201611238708 A CN201611238708 A CN 201611238708A CN 108250139 A CN108250139 A CN 108250139A
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- CN
- China
- Prior art keywords
- buddhist nun
- crystal form
- replaces
- illustrative plates
- collection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- WNAREMVCTOCTGN-UHFFFAOYSA-N CN(Cc1ccncc1)c1ncccc1C(NC1C=CC(C2(CCCC2)C#N)=CC1)=O Chemical compound CN(Cc1ccncc1)c1ncccc1C(NC1C=CC(C2(CCCC2)C#N)=CC1)=O WNAREMVCTOCTGN-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention provides a kind of formula (I) Ah pa for Buddhist nun B crystal form and its preparation method and application,Wherein Ah pa has diffraction maximum for the XRPD collection of illustrative plates of the B crystal form of Buddhist nun at 2 θ=6.17,10.66,12.35,14.62,18.56,20.21,20.84,21.21 °, wherein 2 θ values error ranges are ± 0.2.Ah pa provided by the invention has good high-temperature stability and high wet stability for Buddhist nun's B crystal form.
Description
Technical field
The present invention relates to molecular targeted antitumor drug nicotinamide derivative Ah pas to replace Buddhist nun, and in particular to Ah pa replaces Buddhist nun B
Crystal form and its preparation method and application.
Background technology
Nicotinamide derivative Ah pa replaces Buddhist nun (Apatinib), molecular formula C24H23N5O, chemical name are N- [4- (1- cyanogen
Cyclopentyl) phenyl] -2- (4- picolyls) amino-Niacinamide is a kind of molecular targeted antitumor drug.It is made
For a kind of typical small molecule vascular endothelial growth factor tyrosine kinase inhibitor, available for treating Advanced Non-Small Cell lung
The tumor diseases such as cancer, gastric cancer, liver cancer and breast cancer.
Chinese invention patent CN101676267 discloses above-mentioned nicotinamide derivative Ah pa for Buddhist nun (as shown in formula (I))
And its salt preparation method and the application in antitumor drug.But CN101676267 does not disclose formula (I)
The solid-state form of compound also has no other open reports.
Therefore, it in order to promote exploitation of formula (I) compound as solid-state medical substance, in production, packaging, storage or uses
Ensure the quality and drug effect of formula (I) compound in the process, need the solid-state form of at least one compound, especially need to have
There is the Ah pa of superior physicochemical characteristics for Buddhist nun's crystal form, it is made to be conducive to use in drug processing and pharmaceutical composition.
Polymorphism refers to solid matter there are two or more different space arrangement mode, so as to more
The phenomenon that solid state of the different physicochemical properties of kind is the build-in attribute of compound.Effective ingredient there are two kinds or
Two or more different crystal forms states of matter, referred to as polymorph in pharmaceuticals.Between same drug different crystal forms due to arrangement architecture or
The difference of the mode of action, bioavilability may also can be there are difference, in addition its stability, mobility, compressibility also may be used
It can meeting difference.These physicochemical properties generate certain influence to the application of drug, the effect of so as to influence drug.
Invention content
The present invention provides a kind of Ah pa for the novel crystal forms (hereinafter referred to as " Ah pa replaces Buddhist nun's B crystal form ") of Buddhist nun, which is characterized in that
Use Cu-K α1Ray radiate, with the X-ray powder diffraction pattern that 2 θ angles represent 2 θ=6.17,10.66,12.35,
14.62nd, there is diffraction maximum at 18.56,20.21,20.84,21.21 °, wherein 2 θ values error ranges are ± 0.2 °.
Ah pa according to the present invention replaces Buddhist nun's B crystal form, has the XRPD collection of illustrative plates substantially the same with Figure of description Fig. 1.
Ah pa according to the present invention is monohydrate for Buddhist nun's B crystal form, is respectively provided with substantially the same with attached drawing 2-6 infrared
Spectrum, Raman spectrum, DSC collection of illustrative plates, TGA collection of illustrative plates and dynamic water absorption collection of illustrative plates.
The present invention also provides a kind of methods for preparing Ah pa and replacing Buddhist nun's B crystal form, include the following steps：
By Ah pa for Buddhist nun with 1:1 to 1:The ratio of 50g/mL is added in solvent, is stirred at room temperature or is shaken, Ran Houli
The heart is separated by filtration solid, dry, so as to obtain Ah pa for Buddhist nun's B crystal form solid.
Ah pa as described above replaces the preparation method of Buddhist nun's B crystal form, wherein the solvent is any one in water or alcohols
Solvent or two or more solvents are with the mixed solvent of arbitrary proportion.
Ah pa as described above replaces the preparation method of Buddhist nun's B crystal form, wherein, the alcohols solvent is methanol.
In the preparation method for replacing Buddhist nun's B crystal form in preferred Ah pa, it is stirred at room temperature or shaking table shakes 24 hours, Ran Houli
The heart is separated by filtration solid, vacuum drying, so as to obtain Ah pa for Buddhist nun's B crystal form solid.
It should be understood that those of ordinary skill in the art can be according to its knowledge and experience, to what is used in the method for the present invention
Temperature and the dosage of agents useful for same are adjusted, and the scheme of these adjustment is also contained in the method for the present invention.
Ah pa provided by the invention is monohydrate for Buddhist nun's B crystal form, has excellent thermal stability and high wet stability, can
To be applied in the drug for the treatment of late tumor.
Therefore, the present invention also provides application of the above-mentioned Ah pa for Buddhist nun's B crystal form in the drug for treating tumour is prepared.
In some embodiments, the tumour includes non-small cell lung cancer, gastric cancer, liver cancer and breast cancer.
The present invention also provides pharmaceutical composition, it includes Ah pa according to the present invention for Buddhist nun's B crystal form and one kind or more
Kind pharmaceutically acceptable carrier, excipient or diluent.Ah pa with the present invention is a kind of small for the composition of Buddhist nun's B crystal form
Molecule vascular endothelial growth factor tyrosine kinase inhibitor, can be used in treat advanced Non-small cell lung, gastric cancer, liver cancer with
And the diseases such as entity or liquid tumors of breast cancer and any other type.
Description of the drawings
Fig. 1 is the XRPD collection of illustrative plates that Ah pa provided by the invention replaces Buddhist nun's B crystal form；
Fig. 2 is the infrared spectrum that Ah pa provided by the invention replaces Buddhist nun's B crystal form；
Fig. 3 is the Raman spectrum that Ah pa provided by the invention replaces Buddhist nun's B crystal form；
Fig. 4 is the DSC collection of illustrative plates that Ah pa provided by the invention replaces Buddhist nun's B crystal form；
Fig. 5 is the TGA collection of illustrative plates that Ah pa provided by the invention replaces Buddhist nun's B crystal form；
Fig. 6 is that Ah pa provided by the invention adsorbs collection of illustrative plates for the dynamic water of Buddhist nun's B crystal form；
Fig. 7 replaces Buddhist nun's B crystal form compared with unbodied stability for Ah pa provided by the invention.
Specific embodiment
Below according to embodiment, and with reference to attached drawing, the detailed description present invention.In from detailed description below, the present invention
Above-mentioned aspect and other aspects of the present invention will be apparent.The scope of the present invention is not limited to the following example.
1 to 5 Ah pa of embodiment replaces the preparation of Buddhist nun's B crystal form
1g Ah pas are weighed (to buy from Shanghai Han Xiang bio tech ltd, purity for Buddhist nun's raw material>98%) it is placed in container
In, the solvent (analysis pure) that is separately added into table 1, be stirred at room temperature or shaking table concussion for 24 hours, then with 12000 revs/min from
The heart 5 minutes.A layer solid vacuum drying is removed, obtains white solid, as Ah pa replaces Buddhist nun's B crystal form.It weighs and calculates its yield, as a result
It is shown in table 1.
1 Ah pa of table replaces the preparation of Buddhist nun's B crystal form
Embodiment 6 characterizes Ah pa by XRPD and replaces Buddhist nun's B crystal form
The measurement of X-ray powder diffraction (XRPD) collection of illustrative plates uses German Brooker company D8Advance X-ray diffractions
Instrument is detected at room temperature, and specific acquisition information is as follows：Radiographic source is Cu-K α1Ray, scanning range (2 θ ranges) are from 3 °
It is 12 °/minute, scanning step 0.02, slit width 0.01 to 40 °, sweep speed.It is directly suppressed using glass slide in test board
Sample is handled.Thereafter XRPD collection of illustrative plates uses similar measuring method.
Measure the XRPD collection of illustrative plates that Ah pa according to prepared by 1 the method for embodiment replaces Buddhist nun's B crystal form, 2 θ=6.17,
10.66th, there is at 12.35,14.62,18.56,20.21,20.84,21.21 ° feature Cu-K α1Diffraction maximum, as shown in Figure 1.Its
In 2 θ values error ranges be ± 0.2 °.After testing, 2 θ value error ranges may be ± 0.15 °.
Specific list derived from the distinctive X-ray diffraction peak of the spectrogram is shown in table 2.
XRPD diffraction peak lists in 2 Fig. 1 of table
| Number | 2θ±0.2(°) |
| 1 | 6.17 |
| 2 | 10.66 |
| 3 | 12.35 |
| 4 | 14.62 |
| 5 | 18.56 |
| 6 | 20.21 |
| 7 | 20.84 |
| 8 | 21.21 |
The Ah pa prepared according to embodiment 2-5 the methods is for Buddhist nun's B crystal form, XRPD collection of illustrative plates and collection of illustrative plates base shown in attached drawing 1
This is identical.
It will be understood by those skilled in the art that these diffraction maximums do not represent A Pa for the detailed of diffraction maximum shown by Buddhist nun's B crystal form
Situation.2 θ values of X-ray powder diffraction figure are can to change with machine and between the variation in sample preparation and batch
And slight change, cited value are not intended as absolute value.It will also be appreciated that peak relative intensity may with orientation effect and
Become, therefore the intensity shown in the XRPD traces contained by the present invention is exemplary, be not used to absolutely relatively.
Embodiment 7 replaces Buddhist nun's B crystal form by infrared spectrum characterization Ah pa
Using 750 infrared spectrometers of Nicolet-Magna FT-IR of Buddhist nun's usury company of the U.S., root is detected at room temperature
The infrared spectrum of Buddhist nun's B crystal form is replaced according to the Ah pa prepared by 1 the method for embodiment, detection range is：4000~350cm-1.Gained
Infrared spectrum as shown in Figure 2,3352,2232,1656,1590,1515,1253,1136cm-1There is stronger absorption peak at place.
Detection replaces Buddhist nun's B crystal form, obtained infrared spectrum and collection of illustrative plates base shown in attached drawing 2 according to Ah pa prepared by embodiment 2-5 the methods
This is identical.
Embodiment 8 replaces Buddhist nun's B crystal form by Raman Characterization Ah pa
Using the DXR micro-Raman spectroscopies of power ＆ light company of the U.S., detected at room temperature according to 1 the method institute of embodiment
The Ah pa of preparation replaces the Raman spectrum of Buddhist nun's B crystal form, and detection range (Raman shift) is：3500~50cm-1.Gained Raman spectrum is such as
Shown in attached drawing 3,3056,2229,1659,1516,1406,1320,1249,997,860cm-1There is stronger absorption peak at place.Inspection
The Ah pa prepared according to embodiment 2-5 the methods is surveyed for Buddhist nun's B crystal form, obtained Raman spectrum and collection of illustrative plates shown in attached drawing 3 are basic
It is identical.
Embodiment 9 characterizes Ah pa by DSC-TGA and replaces Buddhist nun's B crystal form
Q2000 the and Q500 thermal analyzers of TA companies of the U.S. are used respectively, are tested at standard conditions according to 1 institute of embodiment
State DSC the and TGA collection of illustrative plates that the Ah pa prepared by method replaces Buddhist nun's B crystal form.DSC test conditions be 10 DEG C/min of heating rate, temperature
25 DEG C to 210 DEG C of range.TGA test conditions be 10 DEG C/min of heating rate, 30 DEG C to 400 DEG C of temperature range.Obtained DSC
With TGA collection of illustrative plates respectively as shown in attached drawing 4 and Fig. 5.The result shows that Ah pa of the invention is monohydrate for Buddhist nun's B crystal form.
The Ah pa that detection is prepared according to embodiment 2-5 the methods replaces Buddhist nun's B crystal form, obtain DSC collection of illustrative plates and TGA collection of illustrative plates with it is upper
It is essentially identical to state result.
Embodiment 10 replaces Buddhist nun's B crystal form by dynamic water absorption representation Ah pa
Using the dynamic water adsorption instrument (Intrinsic DVS) of SMS companies of Britain, the side according to embodiment 1 is detected
Ah pa prepared by method adsorbs collection of illustrative plates for the dynamic water of Buddhist nun's B crystal form.Obtained dynamic water absorption collection of illustrative plates shows in attached drawing Fig. 6
Go out.According to Ah pa prepared by embodiment 2-5 the methods for Buddhist nun's B crystal form, obtained dynamic water adsorbs collection of illustrative plates and attached drawing 6 for detection
Shown collection of illustrative plates is essentially identical.
11 Ah pa of embodiment is for Buddhist nun's B crystal form compared with unbodied stability
At room temperature, the Ah pa prepared according to 1 the method for embodiment is respectively placed in for Buddhist nun's B crystal form with amorphous samples
Sample is taken out under the damp condition of RH=68%, after preserving 7 days and carries out XRPD tests, it is steady to the crystal form of temperature to investigate sample
It is qualitative.The collection of illustrative plates of test result is summarized as shown in Figure 7.The result shows that compared to amorphous raw material powder, according to the application reality
Apply the Ah pa prepared by 1 the method for example has outstanding humidity stability for Buddhist nun's B crystal form, places for a long time at ambient temperature
Without crystal phenomenon, be conducive to the preparation and storage of bulk pharmaceutical chemicals and pharmaceutical preparation.
The Ah pa of the present invention is better than amorphous products for Buddhist nun's B crystal form stability.It is as it is known to the person skilled in the art, unstable
It is fixed amorphous to be changed into other crystal forms under certain condition, therefore the crystal form stablized has in the production process of pharmaceutical preparation
It is advantageous.Due to the stability that Ah pa has for Buddhist nun's B crystal form, can be kept in the drug process of various solid dosages
Stablize, can determine the crystal form of the active constituents of medicine in the drug finally obtained, it can be ensured that known bioavilability, no
The drug effect difference brought because of crystal transfer can occur.
Those skilled in the art is it should be understood that although for illustrative purposes, this document describes the tools of the present invention
Body embodiment, but it can be carry out various modifications without departing from the spirit and scope of the present invention.Therefore, it is of the invention specific
Embodiment and embodiment should not be considered as limiting the scope of the invention.The present invention is limited only by the appended claims.This Shen
Please in quote all documents be fully incorporated herein by reference.
Claims (9)
1. a kind of Ah pa of formula (I) replaces the B crystal form of Buddhist nun, which is characterized in that
Use Cu-K α1Ray radiate, with the X-ray powder diffraction pattern that 2 θ angles represent 2 θ=6.17,10.66,12.35,
14.62nd, there is diffraction maximum at 18.56,20.21,20.84,21.21 °, wherein 2 θ values error ranges are ± 0.2 °.
2. Ah pa as described in claim 1 replaces Buddhist nun's B crystal form, which is characterized in that it has the XRPD substantially the same with attached drawing 1
Collection of illustrative plates.
3. Ah pa as described in claim 1 replaces Buddhist nun's B crystal form, which is characterized in that the A Pa is monohydrate for Buddhist nun's B crystal form,
And it is respectively provided with the infrared spectrum substantially the same with attached drawing 2-6, Raman spectrum, DSC collection of illustrative plates, TGA collection of illustrative plates and dynamic water
Adsorb collection of illustrative plates.
4. Ah pa as described in any one of claim 1 to 3 replaces the preparation method of Buddhist nun's B crystal form, which is characterized in that including following
Step：
By Ah pa for Buddhist nun with 1:1 to 1:The ratio of 50g/mL is added in solvent, is stirred at room temperature or is shaken, be then centrifuged for or
Solid is separated by filtration, it is dry, so as to obtain Ah pa for Buddhist nun's B crystal form solid.
5. Ah pa as claimed in claim 4 replaces the preparation method of Buddhist nun's B crystal form, which is characterized in that the solvent is water or alcohols
In any one solvent or two or more solvents with the mixed solvent of arbitrary proportion.
6. Ah pa as claimed in claim 5 replaces the preparation method of Buddhist nun's B crystal form, which is characterized in that the alcohols solvent is methanol.
7. Ah pa as described in any one of claim 1 to 3 answering in the drug for treating tumour is prepared for Buddhist nun's B crystal form
With.
8. the use as claimed in claim 7, wherein the tumour includes non-small cell lung cancer, gastric cancer, liver cancer and breast cancer.
9. a kind of pharmaceutical composition, it includes Ah pas as described in any one of claim 1 to 3 to replace Buddhist nun's B crystal form and one kind
Or a variety of pharmaceutically acceptable carriers, excipient or diluent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611238708.6A CN108250139A (en) | 2016-12-28 | 2016-12-28 | A Pa is for Buddhist nun's B crystal form and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611238708.6A CN108250139A (en) | 2016-12-28 | 2016-12-28 | A Pa is for Buddhist nun's B crystal form and its preparation method and application |
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| Publication Number | Publication Date |
|---|---|
| CN108250139A true CN108250139A (en) | 2018-07-06 |
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ID=62720290
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611238708.6A Withdrawn CN108250139A (en) | 2016-12-28 | 2016-12-28 | A Pa is for Buddhist nun's B crystal form and its preparation method and application |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019034048A1 (en) * | 2017-08-15 | 2019-02-21 | 江苏恒瑞医药股份有限公司 | Crystal form of vegfr inhibitor and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541708A (en) * | 2014-10-28 | 2016-05-04 | 华东理工常熟研究院有限公司 | New crystal form of apatinib sulfate |
| CN105622498A (en) * | 2014-10-28 | 2016-06-01 | 华东理工常熟研究院有限公司 | New crystal of apatinib sulfate |
| CN105801476A (en) * | 2016-04-13 | 2016-07-27 | 上海宣创生物科技有限公司 | Crystal form II of Apatinib mesylate as well as preparation method and application of crystal form II |
| CN106243031A (en) * | 2016-07-26 | 2016-12-21 | 江苏恒瑞医药股份有限公司 | A kind of Ah handkerchief is for the preparation method of Buddhist nun |
-
2016
- 2016-12-28 CN CN201611238708.6A patent/CN108250139A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541708A (en) * | 2014-10-28 | 2016-05-04 | 华东理工常熟研究院有限公司 | New crystal form of apatinib sulfate |
| CN105622498A (en) * | 2014-10-28 | 2016-06-01 | 华东理工常熟研究院有限公司 | New crystal of apatinib sulfate |
| CN105801476A (en) * | 2016-04-13 | 2016-07-27 | 上海宣创生物科技有限公司 | Crystal form II of Apatinib mesylate as well as preparation method and application of crystal form II |
| CN106243031A (en) * | 2016-07-26 | 2016-12-21 | 江苏恒瑞医药股份有限公司 | A kind of Ah handkerchief is for the preparation method of Buddhist nun |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019034048A1 (en) * | 2017-08-15 | 2019-02-21 | 江苏恒瑞医药股份有限公司 | Crystal form of vegfr inhibitor and preparation method thereof |
| CN110637010A (en) * | 2017-08-15 | 2019-12-31 | 江苏恒瑞医药股份有限公司 | VEGFR inhibitor crystal form and preparation method thereof |
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