CN104961799A - Kyprolis crystal form A and method for preparing same - Google Patents
Kyprolis crystal form A and method for preparing same Download PDFInfo
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- CN104961799A CN104961799A CN201510344488.4A CN201510344488A CN104961799A CN 104961799 A CN104961799 A CN 104961799A CN 201510344488 A CN201510344488 A CN 201510344488A CN 104961799 A CN104961799 A CN 104961799A
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Abstract
The invention discloses a novel Kyprolis crystal form A. The novel Kyprolis crystal form A is characterized in that 2-theta values of X-ray powder diffraction patterns of the crystal form at positions of 6.4+/-0.2 degrees, 12.5+/-0.2 degrees, 12.7+/-0.2 degrees, 18.8+/-0.2 degrees, 19.7+/-0.2 degrees, 19.9 +/-0.2 degrees and 25.4+/-0.2 degrees have characteristic diffraction peaks. The novel Kyprolis crystal form A has the advantage of stable physical and chemical properties.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to a kind of Ka Feizuo meter crystal form A and preparation method thereof.
Background technology
Ka Feizuo meter is a kind of medicine for the treatment of multiple myeloma, and commodity are called Kyprolis, and English name is Carfilzomib, and structure is such as formula shown in I, and it is by method preparation disclosed in CN101883779.
A kind of novel peptide type compound for the treatment of multiple myeloma that Ka Feizuo meter is researched and developed by Onyx Pharmaceuticals company, ratifies listing on July 20th, 2012 by U.S. food Drug Administration (FDA).This product is s-generation proteasome inhibitor, can not injure composing type spheroid protein function and immunoproteasome in Selective depression blood tumor cell, thus make the easier apoptosis of cancer cells.This product has the few feature of untoward reaction because of the selectivity of height, and sharpest edges are then overcome the neurotoxicity that some proteasome inhibitor has, and common adverse reactions is pneumonia, anaemia, neutrophils reduce and thrombocytopenia.
CN101883779 discloses the crystal formation of a kind of Ka Feizuo meter, it has 6.10o in the X-ray powder diffraction in CuK α source, 8.10 o, 9.32 o, 10.10 o, 11.00 o, 12.14 o, 12.50 o, 13.64 o, 13.94o, 17.14 o, 17.52 o, 18.44 o, 20.38 o, 21.00 o, 22.26 o, 23.30 o, 24.66 o, 25.98 o, 26.02 o, 27.84 o, 28.00o, 28.16 o, 29.98 o, 30.46 o, 32.98 o, 33.22o, 34.52 o and 39.46o etc. 2 θ value tag diffraction peak, this crystal formation is by high temperature using a kind of good solvent (methyl alcohol, ethanol, acetonitrile or ethyl acetate) to dissolve Ka Feizuo meter, add water cure again and obtain.
The present inventor is in the process of research Ka Feizuo meter crystal formation, and a kind of new crystal of preparation card release Fei Zuo meter, is called for short Ka Feizuo meter crystal form A.The preparation of this crystal formation is simple, and physicochemical property are stablized, and easily preserve.。
Summary of the invention
The object of the present invention is to provide the new crystal of a kind of Ka Feizuo meter, this crystal formation preparation technology is easy, physical and chemical stability is excellent.
Ka Feizuo meter new crystal provided by the invention, is defined as Ka Feizuo meter crystal form A in this text.
Ka Feizuo meter crystal form A of the present invention, there is characteristic diffraction peak the position that its X-ray powder diffraction is 6.4 ± 0.2 °, 12.5 ± 0.2 °, 12.7 ± 0.2 °, 18.8 ± 0.2 °, 19.7 ± 0.2 °, 19.9 ± 0.2 °, 25.4 ± 0.2 ° in 2 θ values.
The Ka Feizuo meter crystal form A of the invention described above, also comprising its X-ray powder diffraction further in 2 θ values is that the position of 18.7 ± 0.2 °, 19.1 ± 0.2 °, 20.0 ± 0.2 °, 22.5 ± 0.2 ° and 22.7 ± 0.2 ° is to having characteristic diffraction peak.
In one embodiment, Ka Feizuo meter crystal form A of the present invention, its X-ray powder diffraction has characteristic diffraction peak as shown in Figure 1.
Ka Feizuo meter crystal form A of the present invention, its DSC scintigram has an endotherm(ic)peak between 93 ~ 108 DEG C, particularly reaches peak value at about 100 DEG C; It has another endotherm(ic)peak between 211 ~ 216 DEG C, particularly reaches peak value at about 213 DEG C
Ka Feizuo meter crystal form A of the present invention, its DSC scintigram has feature as shown in Figure 2.
The X-ray powder diffraction test of Ka Feizuo meter crystal form A of the present invention is under envrionment temperature and ambient moisture, has measured through the CuK α source (α=1.5406) of Japanese Shimadzu XRD-6000 type x-ray diffractometer.In test process, the impact for the treatment of process, instrument, test parameter, test operation etc. of sample during owing to being subject to many factors as tested granularity, the test of sample, the X-ray powder diffraction measured by same crystal formation go out peak position or peak intensity has certain difference.In X-ray powder diffraction the experimental error of diffraction peak 2 θ value can be ± 0.2 °." envrionment temperature " is generally 0 ~ 40 DEG C; " ambient moisture " is generally the relative humidity of 30% ~ 80%.
The dsc analysis condition of Ka Feizuo meter crystal form A of the present invention is under envrionment temperature and ambient moisture, completes through Switzerland Mettler 1100LF type instrument test.Purge with the flow velocity of 50ml/min with high-purity Ar gas, carry out temperature programming with the speed of 10 DEG C/min, temperature elevating range is that room temperature to 300 DEG C is tested." envrionment temperature " is generally 0 ~ 40 DEG C; " ambient moisture " is generally the relative humidity of 30% ~ 80%.
Object of the present invention additionally provides a kind of method preparing Ka Feizuo meter crystal form A, and the method comprises the following steps:
1) dissolved by the mixed solvent of Ka Feizuo meter acetonitrile and water, obtain Ka Feizuo meter solution, wherein, solvent temperature is 30 ~ 80 DEG C, and the volume ratio of acetonitrile and water is 1:0.1 ~ 0.5;
2) add water Ka Feizuo meter is solidified;
3) solid of precipitation is carried out filtering or centrifugation;
4) optional, under normal pressure or reduced pressure, carry out drying by being separated the solid obtained, drying temperature is 30 ~ 60 DEG C.During decompression, vacuum tightness is generally 300 ~ 760mmHg, preferably 650 ~ 760mmHg.
The method of the invention described above, rapid 2) amount adding water in reaches 1:1 ~ 1:4 for making the volume ratio of water and acetonitrile in whole solvent system.The concentration that Ka Feizuo meter dissolves is 0.05 ~ 0.5g/ml.
The method of the invention described above, rapid 2) in, the solidification of Ka Feizuo meter is generally complete under agitation.
The stability of Ka Feizuo meter crystal form A of the present invention, carried out stability study with the Ka Feizuo meter crystal form A that embodiment 1 is obtained, result is as following table.
As can be seen from the above table, Ka Feizuo meter crystal form A no hygroscopicity of the present invention, substantially without degraded, do not turn brilliant, its physics, chemical stability are better.
Ka Feizuo meter crystal form A preparation technology of the present invention is easy, adopts common equipment and mild conditions just can complete, is suitable for suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the x-ray diffraction pattern of Ka Feizuo meter crystal form A;
Fig. 2 is the DSC figure of Ka Feizuo meter crystal form A.
Embodiment
Below in conjunction with embodiment, the invention will be further described, and those skilled in the art can be made more fully to understand essence of the present invention, but the scope do not limited the present invention in any way.
X-ray powder diffraction figure of the present invention gathers on Japanese Shimadzu XRD-6000 type x-ray diffractometer.The parameter of X-ray powder diffraction analytical procedure of the present invention is specific as follows:
X ray reflection parameter: CuK α
CuK α source (α=1.5406)
Voltage: 40 kilovolts (KV)
Electric current: 30 milliampere(mA)s (mA)
Divergent slit: automatically
Scan pattern: continuously
Sweep limit: 3 ~ 40 degree
Sampling step length: 0.02 degree
Sweep velocity: 2 degrees/min
The DSC figure of Ka Feizuo meter crystal form A of the present invention gathers on Switzerland Mettler 1100LF type instrument.The parameter of dsc analysis method of the present invention is specific as follows:
Temperature range: room temperature ~ 300 DEG C
Scanning speed: 10 DEG C/min
Shielding gas: Ar gas 50ml/min
Embodiment
Following examples are used for understanding the present invention further, but do not limit the scope of the invention with this.
embodiment 1the preparation of Ka Feizuo meter crystal form A
10g Ka Feizuo meter is dissolved in the mixed solvent of 20ml acetonitrile and 2ml water at 30 ~ 40 DEG C, is added dropwise to 19.8ml water under stirring, after dripping, and temperature 30 ~ 40 DEG C of crystallizatioies 12 hours in keeping; A large amount of solid is separated out; Filter, filter cake at 700 ~ 760mmHg, drying under reduced pressure get Ka Feizuo meter crystal form A 9.7g, HPLC:99.87% at 40 ~ 50 DEG C.Test its X-ray powder diffraction, its XRPD the results are shown in Figure 1; Test DSC the results are shown in Figure 2.
embodiment 2the preparation of Ka Feizuo meter crystal form A
20g Ka Feizuo meter is dissolved in the mixed solvent of 200ml acetonitrile and 100ml water at 70 ~ 80 DEG C, is added dropwise to 700ml water under stirring, after dripping, is down to interior temperature 30 ~ 40 DEG C of crystallizatioies 10 hours; A large amount of solid is separated out; Filter, filter cake at 700 ~ 760mmHg, drying under reduced pressure get Ka Feizuo meter crystal form A 18.5g, HPLC:99.89% at 40 ~ 50 DEG C.。Through the test of X-ray powder diffraction, substantially identical with the XRPD of embodiment 1, be Ka Feizuo meter crystal form A.
embodiment 3the preparation of Ka Feizuo meter crystal form A
10g Ka Feizuo meter is dissolved in the mixed solvent of 20ml acetonitrile and 6ml water at 30 ~ 40 DEG C, is added dropwise to 34ml water under stirring, after dripping, and temperature 30 ~ 40 DEG C of crystallizatioies 12 hours in keeping; A large amount of solid is separated out; Filter, filter cake at 700 ~ 760mmHg, drying under reduced pressure get Ka Feizuo meter crystal form A 9.8g, HPLC:99.87% at 40 ~ 50 DEG C.Test its X-ray powder diffraction, its XRPD and Fig. 1 is basically identical.
Claims (10)
1. Yi Zhong Ka Feizuo meter crystal form A, is characterized in that X-ray powder diffraction has characteristic diffraction peak in the position that 2 θ values are 6.4 ± 0.2 °, 12.5 ± 0.2 °, 12.7 ± 0.2 °, 18.8 ± 0.2 °, 19.7 ± 0.2 °, 19.9 ± 0.2 °, 25.4 ± 0.2 °.
2. crystal form A according to claim 1, also comprising its X-ray powder diffraction further in 2 θ values is that the position of 18.7 ± 0.2 °, 19.1 ± 0.2 °, 20.0 ± 0.2 °, 22.5 ± 0.2 ° and 22.7 ± 0.2 ° is to having characteristic diffraction peak.
3. crystal form A according to claim 1, its X-ray powder diffraction has in fact the characteristic diffraction peak as Fig. 1.
4., according to the arbitrary described crystal form A of claim 1-3, its DSC scintigram has an endotherm(ic)peak with 211 ~ 216 DEG C respectively between 93 ~ 108 DEG C.
5. prepare a method for the Ka Feizuo meter crystal form A of claim 1, comprise and Ka Feizuo meter is dissolved in the mixed solvent of acetonitrile and water, then add water and make it solidify.
6. method according to claim 4, specifically comprises the following steps:
1) dissolved by the mixed solvent of Ka Feizuo meter acetonitrile and water, solvent temperature is 30 ~ 80 DEG C, obtains Ka Feizuo meter solution, and wherein, the volume ratio of acetonitrile and water is 1:0.1 ~ 0.5;
2) add water Ka Feizuo meter is solidified;
3) solid of precipitation is carried out filtering or centrifugation;
4) optional, under normal pressure or reduced pressure, carry out drying by being separated the solid obtained, drying temperature is 30 ~ 60 DEG C.
7. method according to claim 6, described solvent temperature is 50 ~ 70 DEG C.
8. temperature when adding water cure method according to claim 6, rapid 2) is 30 ~ 50 DEG C.
9. method according to claim 6, the drying temperature of step 4) is 40 ~ 50 DEG C.
10. the amount adding water method according to claim 5, rapid 2) reaches 1:1 ~ 1:4 for making the volume ratio of water and acetonitrile in whole solvent system.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017098532A1 (en) * | 2015-12-11 | 2017-06-15 | Mylan Laboratories Limited | Crystalline and amorphous forms of carfilzomib |
| CN111153964A (en) * | 2020-01-20 | 2020-05-15 | 安礼特（上海）医药科技有限公司 | Carfilzomib crystal form, preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101883779A (en) * | 2007-10-04 | 2010-11-10 | 欧尼斯治疗公司 | Synthesizing of crystalline peptide epoxy ketone protease inhibitors and amino acid ketone-epoxide |
| CN104402973A (en) * | 2014-11-24 | 2015-03-11 | 重庆泰濠制药有限公司 | Method for preparing carfilzomib amorphous crystal |
-
2015
- 2015-06-19 CN CN201510344488.4A patent/CN104961799B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101883779A (en) * | 2007-10-04 | 2010-11-10 | 欧尼斯治疗公司 | Synthesizing of crystalline peptide epoxy ketone protease inhibitors and amino acid ketone-epoxide |
| CN104402973A (en) * | 2014-11-24 | 2015-03-11 | 重庆泰濠制药有限公司 | Method for preparing carfilzomib amorphous crystal |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017098532A1 (en) * | 2015-12-11 | 2017-06-15 | Mylan Laboratories Limited | Crystalline and amorphous forms of carfilzomib |
| CN111153964A (en) * | 2020-01-20 | 2020-05-15 | 安礼特（上海）医药科技有限公司 | Carfilzomib crystal form, preparation method and application thereof |
| CN111153964B (en) * | 2020-01-20 | 2023-12-19 | 江苏希迪制药有限公司 | Carfilzomib crystal form, preparation method and application thereof |
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