CN105085473B - Lenalidomide crystal form and preparation method thereof and medical usage - Google Patents
Lenalidomide crystal form and preparation method thereof and medical usage Download PDFInfo
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- CN105085473B CN105085473B CN201410169124.2A CN201410169124A CN105085473B CN 105085473 B CN105085473 B CN 105085473B CN 201410169124 A CN201410169124 A CN 201410169124A CN 105085473 B CN105085473 B CN 105085473B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
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Abstract
The invention discloses lenalidomide crystal form and preparation method thereof and medical usages.Specifically, the present invention relates to a kind of novel crystal forms α of lenalidomide and preparation method thereof, and the compound crystal form containing therapeutically effective amount pharmaceutical composition and be used to prepare the medical usage in treatment Huppert's disease and myelodysplastic syndrome in the crystal form.The crystal form α of lenalidomide provided by the invention, in powder x-ray diffraction map 2 θ ± 0.2 ° be 10.1,12.4,21.5, there is diffractive features peak at 22.9 and 32.4, the method for preparing the crystal form includes the following steps: 1) to dissolve by heating the lenalidomide of any solid forms in organic solvent；2) lysate of lenalidomide is cooling, it is added dropwise to addition crystal seed crystallization in anti-solvent；3) crystal form α is obtained by filtration.The stable crystal form is easy to get, and is very suitable to preparation patent medicine application.
Description
Technical field
The present invention relates to a kind of novel crystal forms of lenalidomide and preparation method thereof, and the compound containing therapeutically effective amount
Pharmaceutical composition and medical usage.
Background technique
Lenalidomide (Lenalidomide) also known as Lenalidomide, chemical name 3- (4- amino -1- oxo -1,3- dihydro -
2H- iso-indoles -2- base) piperidine-2,6-diones.Have such as flowering structure:
On June 7th, 1999 such as Muller in periodical Bioorganic&Medicinal Chemistry Letters,
Publish an article on Vol.9, Issue11, P1625-1630 " Amio-substituted thalidomide analogs:
Potent inhibitors of TNF-α production ", it was recently reported that 3- (substituted-dihydro iso-indoles -2- base) piperidines -2,6-
Diketone series compound.In December, 2005 3- (4- amino -1- oxo -1,3- dihydro -2H- iso-indoles -2- base) piperidines -2,6- two
Ketone (lenalidomide) goes through to list as a kind of immunomodulator with antitumor property in the U.S., multiple for treating
The diseases such as myeloma and myeloproliferative disorder are comprehensive.
Lenalidomide has polymorphic, and Yuan Yan company GELGENE CORPORATION is public in patent WO2005023192A
8 kinds of crystal forms for having opened lenalidomide are crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G and crystal form H respectively；
GENERICS company discloses a kind of novel crystal forms of lenalidomide in patent WO2010061209, and DR.REDDY`S company is in patent
A kind of novel crystal forms form1 of lenalidomide is disclosed in WO2010129636, SCINOPHRAM company WO2011034504 is disclosed
Lenalidomide novel crystal forms, NATCOPHARM company disclose lenalidomide novel crystal forms form-1 in patent WO2011111053；
HETERO RESEARCH FOUNDATION discloses a kind of novel crystal forms of lenalidomide, Nanjing in patent WO2012127493
Di Ka Kevin company discloses lenalidomide novel crystal forms IV in patent CN101817813, and Chongqing Inst. of Pharmaceutical Industry is limited
Company discloses lenalidomide novel crystal forms I in patent CN102453021.
Summary of the invention
The purpose of the present invention is to provide lenalidomide novel crystal forms α, and the preparation process of the crystal form is simple, crystal form physical chemistry
Property is stablized, and various forms preparation is suitable for.
The purpose of the present invention is to provide a kind of crystal form α of lenalidomide, in powder x-ray diffraction map 2 θ ±
0.2 ° is to have diffractive features peak at 10.1,12.4,21.5,22.9 and 32.4.
It preferably, is 10.1,12.4,17.3,18.1 in 2 θ ± 0.2 ° in the crystal form powder x-ray diffraction map,
There is diffractive features peak at 18.4,19.7,21.5,22.9,24.5,25.6,26.6,27.9 and 32.4.
Preferably, the crystal form powder x-ray diffraction map is as shown in Figure 1.
Another object of the present invention is to provide a kind of methods for preparing the lenalidomide crystal form α, include the following steps:
1) lenalidomide of any solid forms is dissolved by heating in organic solvent；
2) lysate of lenalidomide is cooling, it is added dropwise to addition crystal seed crystallization in anti-solvent；
3) crystal form α is obtained by filtration,
It wherein dissolves by heating temperature and is generally 80 DEG C to reflux temperature, preferably reflux temperature；The preferred room temperature of crystallization temperature is extremely
60 DEG C, preferably 40 DEG C -50 DEG C, most preferably 45 DEG C；Crystal seed is obtained by other methods, additional amount be inventory 0.5%~
1.0%.
Preferably, the organic solvent in the step 1) is organic acid, more preferably includes the carboxylic acid of carbon atom number 1-4.
Preferably, the anti-solvent in the step 2) is alcohols solvent, and the more preferably alcohols including carbon atom number 2-5 is molten
Agent.
Preferably, the organic acid is selected from formic acid or acetic acid, most preferably acetic acid.
Preferably, the anti-solvent is selected from propyl alcohol or n-butanol, more preferable n-butanol.
It is raw material that the preparation approach of crystal seed, which is using the crystal form C provided in patent WO2005023192A, small using grinding 3
When or high-temperature fusion quickly turn brilliant method and be prepared.
It includes the lenalidomide crystal form α that another object of the present invention, which is also resided in and provided a kind of, and is mixed with one or more
The composition of pharmaceutical excipient.
Composition of the invention includes being suitable for the administration routes, preferably oral administration route such as oral and injection.Dosage form includes
Tablet, capsule, dispersing agent and suspension, preferably capsule.
Tablet or capsule is made in the composition.
Another object of the present invention also resides in that provide the crystal form α of the lenalidomide more in preparation treatment as active constituent
Application in hair property myeloma and myelodysplastic syndrome drug.
Stable crystal form of the invention is easy to get, and drug forming effect is good when applying in the formulation, can reach formulation requirements.
Detailed description of the invention
Fig. 1 is the XRD spectrum of lenalidomide crystal form α of the present invention.
Specific embodiment
Embodiment one
Lenalidomide 1.0g and acetic acid 10.0ml are placed in a reaction flask, is heated to flowing back, is completely dissolved solid, is being stirred
45 DEG C are naturally cooled under conditions of mixing, 100ml n-butanol is preheated to 45 DEG C, the acetic acid solution of lenalidomide is added dropwise, and are added
Crystal seed insulated and stirred crosses filter solid and obtains crystal form α to solid is precipitated.Through detecting, XRD spectrum is as shown in Figure 1.
Embodiment two
Lenalidomide 1.0g and acetic acid 10.0ml are placed in a reaction flask, is heated to flowing back, is completely dissolved solid fastly,
45 DEG C are naturally cooled under conditions of stirring, and 150ml isopropanol is preheated to 35 DEG C, the acetic acid solution of lenalidomide is added dropwise, adds
The crystal seed insulated and stirred for entering 1% obtains crystal form α to solid, excessively filter solid is precipitated.Through detecting, XRD spectrum is kissed substantially with Fig. 1
It closes.
Experimental example a sample stability test
Example one and two gained crystal form samples of embodiment are in acceleration (30 DEG C, RH65% and 40 DEG C, RH75%) condition
Test sample stability after lower placement one month, data result are shown in Tables 1 and 2:
1.30 DEG C of RH65% stability result statistics of table
2.40 DEG C of RH75% stability result statistics of table
By stability test as can be seen that crystal form of the present invention is good in the performance of various investigation condition stability inferiors, meet medicine
Product application.
Claims (13)
1. a kind of crystal form α of lenalidomide, it is characterized in that, it in 2 θ ± 0.2 ° is 10.1,12.4 in powder x-ray diffraction map,
There is diffractive features peak at 17.3,18.1,18.4,19.7,21.5,22.9,24.5,25.6,26.6,27.9 and 32.4.
2. the crystal form α of lenalidomide according to claim 1, it is characterized in that, the XRPD diffracting spectrum of the crystal form α is as schemed
Shown in 1.
3. a kind of method for the crystal form α for preparing lenalidomide as described in claim 1, includes the following steps:
1) lenalidomide of any solid forms is dissolved by heating in organic acid solvent；
2) lysate of lenalidomide is cooling, it is added dropwise to addition crystal seed crystallization in alcohols anti-solvent；
3) crystal form α is obtained by filtration.
4. the method for the crystal form α according to claim 3 for preparing lenalidomide as described in claim 1, feature exist
In the carboxylic acid that the organic acid solvent in the step 1) is carbon atom number 1-4.
5. the method for the crystal form α according to claim 3 for preparing lenalidomide as described in claim 1, feature exist
In the alcohols solvent that the alcohols anti-solvent in the step 2) is carbon atom number 2-5.
6. the method for the crystal form α according to claim 4 for preparing lenalidomide as described in claim 1, feature exist
In the organic acid is selected from formic acid or acetic acid.
7. the method for the crystal form α according to claim 6 for preparing lenalidomide as described in claim 1, feature exist
In the organic acid is acetic acid.
8. the method for the crystal form α according to claim 5 for preparing lenalidomide as described in claim 1, feature exist
In the anti-solvent is selected from propyl alcohol or n-butanol.
9. the method for the crystal form α according to claim 8 for preparing lenalidomide as described in claim 1, feature exist
In the anti-solvent is n-butanol.
10. the crystal form α comprising the lenalidomide as described in claim 1-2 any one, and it is mixed with one or more medicinal taxes
The composition of shape agent.
11. composition according to claim 10, which is characterized in that the composition be made tablet, capsule, dispersing agent or
Suspension.
12. composition according to claim 11, which is characterized in that capsule is made in the composition.
13. the crystal form α of lenalidomide described in claim 1-2 any one treats multiple bone in preparation as active constituent
Application in myeloma and myelodysplastic syndrome drug.
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| CN105085473B true CN105085473B (en) | 2019-06-18 |
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| KR102147068B1 (en) * | 2017-05-10 | 2020-08-24 | 주식회사 경보제약 | Novel crystal form of lenalidomide and preparation of the same |
| EP3789385A4 (en) * | 2018-06-01 | 2021-06-16 | Shanghai Bocimed Pharmaceutical Co., Ltd. | Method for preparing lenalidomide |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102453021A (en) * | 2010-10-22 | 2012-05-16 | 重庆医药工业研究院有限责任公司 | Novel crystal form of lenalidomide and preparation method thereof |
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| UA83504C2 (en) * | 2003-09-04 | 2008-07-25 | Селджин Корпорейшн | Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione |
| CA2793312C (en) * | 2010-03-08 | 2016-06-14 | Natco Pharma Limited | Anhydrous lenalidomide form-i |
| EP2688649B1 (en) * | 2011-03-23 | 2019-04-10 | Hetero Research Foundation | A polymorph of lenalidomide |
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| CN102453021A (en) * | 2010-10-22 | 2012-05-16 | 重庆医药工业研究院有限责任公司 | Novel crystal form of lenalidomide and preparation method thereof |
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Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: Jiangsu best Pharmaceutical Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: Jiangsu best Pharmaceutical Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. |
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