CN105085490A - New sunitinib malate crystal form and preparation method therefor - Google Patents
New sunitinib malate crystal form and preparation method therefor Download PDFInfo
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- CN105085490A CN105085490A CN201410193624.XA CN201410193624A CN105085490A CN 105085490 A CN105085490 A CN 105085490A CN 201410193624 A CN201410193624 A CN 201410193624A CN 105085490 A CN105085490 A CN 105085490A
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- sunitinib malate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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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
Abstract
The present invention relates to a new sunitinib malate crystal form and a preparation method therefor. The sunitinib malate is detected by Cu-Ka radiation to form an X-ray powder diffraction pattern, wherein characteristic peaks of Form VIII are at approximately 3.15 degree, 9.43 degree, 10.07 degree, 12.63 degree, 14.85 degree, 15.74 degree, 17.65 degree, 18.96 degree and 20.53 degree(2 theta). Characteristic peaks of Form IX are at approximately 3.09 degree, 7.63 degree, 9.15 degree, 9.63 degree, 12.16 degree, 12.84 degree, 15.21 degree, 16.13 degree, 18.36 degree, 18.93 degree, 22.47 degree and 27.39 degree(2 theta). The present invention further provides a method for preparing the Form VIII and the Form IX of the sunitinib malate. The sunitinib malate crystal form prepared by the preparation method is good in solubility, high in stability, and is suitable for industrial production.
Description
Technical field
The present invention relates to new pharmaceutically acceptable crystal formation of sunitinib malate and preparation method thereof.
Technical background
Sutent is represented by formula I, chemical name is N-[2-(diethylamino) ethyl]-5-[-(5-fluoro-1,2-dihydro-2-oxo--3H-indoles-3-subunit) methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide is a kind of novel many targetings tyrosine kinase inhibitor (TKI).
Polymorphism is defined as a kind of substance to be existed with two or more different crystalline structure.Crystal formation can affect the different aspect of the solid state properties of medicine, such as its solubleness, stability, dissolution rate, degree of crystallinity, bioavailability, and affects preparation and the character thereof of pharmaceutical preparation.
Therefore, in order to pursue better solvability, bioavailability or stability, for the different crystal forms of sunitinib malate, carried out a large amount of screening operations.
Patent WO2003016305 discloses and protects Sutent L MALIC ACID anhydrous crystal forms Form I, patent CN100364991 and discloses and protect Form II and preparation method thereof.Point out in the description, Form I has agent of low hygroscopicity, water-soluble.Further research finds that oxysuccinic acid Form I is thermodynamically more stable than Form II.Form I is preferential crystal formation.Point out in specification sheets, at 25 DEG C, measure Form I solubleness in water is 5mg/mL, and this solubleness is relatively low, may produce adverse influence to the bioavailability of medicine.
Patent WO2009104021 discloses and protects Sutent oxysuccinic acid Form III and Form IV, gives its XRPD collection of illustrative plates and DSC data.Patent WO2010010454 then discloses and protects the crystalline form III different from WO2009104021, IV and new crystalline form V, VI and VII.Above-mentioned patent does not all provide the character such as stability, water absorbability, solvability, granularity of crystal.
In sum, screen the sunitinib malate crystal formation obtained at present and there is certain defect.Can for improving its physics and chemistry character to the further screening of crystal formation, and then the clinical needs meeting medicine provide and better select and chance.Sutent Buddhist nun malate new crystal provided by the invention, the solubleness in water or in water-bearing media is significantly increased, and has relative good stability, and its technique is applicable to scale operation.
Summary of the invention
For making up the deficiencies in the prior art, obtain be sure oing functional pharmaceutically acceptable sunitinib malate crystal formation, we have screened various different solvent and crystallization method, finally obtain two kinds of new crystal formations.The invention provides above-mentioned two kinds of sunitinib malates and preparation method thereof.
Described sunitinib malate crystal formation VIII, in its XRD figure spectrum, 2 θ values have following characteristics peak: 3.15 °, 9.43 °, 10.07 °, 12.63 °, 14.85 °, 15.74 °, 17.65 °, 18.96 °, 20.53 °, 2 θ value tolerance range are ± 0.2o.
Dsc analysis collection of illustrative plates is presented at 166 DEG C ~ 167 DEG C places and there is endotherm(ic)peak at 176 ~ 178 DEG C of places.
Described sunitinib malate crystal formation Ⅸ, in its XRD figure spectrum, 2 θ values have following characteristics peak: 3.09 °, 7.63,9.15 °, 9.63 °, 12.16 °, 12.84 °, 15.21 °, 16.13 °, 18.36 °, 18.93 °, 22.47 °, 27.39 °, 2 θ value tolerance range are ± 0.2 °.
Dsc analysis collection of illustrative plates is presented at 158 DEG C ~ 161 DEG C places and there is endotherm(ic)peak at 176 ~ 178 DEG C of places
Present invention also offers above-mentioned sunitinib malate crystal formation preparation method, described in specific as follows:
The preparation method of sunitinib malate crystal formation VIII is: Sutent free alkali and oxysuccinic acid are pressed mole mass ratio 1:1 ~ 1.5:1, and preferred 1:1 ~ 1.2:1 adds organic solvent, heating for dissolving.Filtrate is cooled to 0 DEG C to 10 DEG C after filtration, preferably 5 DEG C, makes it to separate out solid.Continue to be cooled to-10 DEG C to-30 DEG C, preferably-25 DEG C.The sunitinib malate solid that collecting by filtration is separated out.
Describedly prepare organic solvent in the method for sunitinib malate crystal formation VIII and be selected from ethers, preferred tetrahydrofuran (THF).
Heating temperature is 70 DEG C to 90 DEG C, preferably 85 DEG C.Rate of cooling is 0.5-2 DEG C/min, preferably 1 DEG C/min.
The preparation method of sunitinib malate crystal formation Ⅸ is: sunitinib malate heated and stirred in water extremely dissolved completely.Is precooled to 0 DEG C to-10 DEG C filtrate adding after filtration, in the organic solvent of preferred-5 DEG C, makes it to separate out solid.Continue to stir 1h to 3h, preferred 2h.The sunitinib malate solid that collecting by filtration is separated out.
Describedly prepare organic solvent in the method for sunitinib malate crystal formation Ⅸ and be selected from ethers, preferred tetrahydrofuran (THF).
Sutent of the present invention has good solubleness, thermostability and lower water absorbability.
Comparative data is as follows:
Solubleness (mg/ml) in water:
| 25℃ | 35℃ | 45℃ | |
| Sunitinib malate Form I | 5.7 | 8.0 | 12.0 |
| Sunitinib malate Form VIII | 28.9 | 36.3 | 50.6 |
| Sunitinib malate Form Ⅸ | 31.2 | 42.5 | 59.6 |
Accompanying drawing explanation
Fig. 1 is X-ray powder diffraction (XRPD) figure of the sunitinib malate Form VIII obtained according to the embodiment of the present invention 1.
Fig. 2 is dsc (DSC) figure of the sunitinib malate Form VIII obtained according to the embodiment of the present invention 1.
Fig. 3 is X-ray powder diffraction (XRPD) figure of the sunitinib malate Form Ⅸ obtained according to the embodiment of the present invention 2.
Fig. 4 is dsc (DSC) figure of the sunitinib malate Form Ⅸ obtained according to the embodiment of the present invention 2.
Specific implementation method
In order to more detailed explanation the present invention, provide and followingly prepare example, but scope of the present invention is not limited to this.
Analyzing and testing condition of the present invention is as follows:
1, DSC is measured by the SDTQ600 of TA company of the U.S., and test condition is 120ml/minN
2, heat-up rate 10 DEG C/min.
2, X-ray powder diffraction data uses X ' PertProMPD (Multi-PurposeDiffractometer) to measure, light pipe type: EmpyreanXRDtubeCuLFFHR; Electric current and voltage: 45kV, 40mA; The vertical goniometer of goniometer: PW3050/60, radius 240mm; Slit: DS=2 °, SS=1/2 °, mask=15mm, RS=5.0mm; The super detector of detector: X ' Celerator; Scan pattern: continuous sweep; Sweep limit: 3 ° of-40 ° of 2 θ; Often walk gate time: 20s; Scanning total time: 6min.
Embodiment 1: sunitinib malate Form VIII
By 100mg Sutent free alkali and the mixing of 34mgL-oxysuccinic acid, add 4ml tetrahydrofuran (THF) and 0.5ml water, be heated to 65 DEG C and make it dissolve completely, filter.Filtrate is cooled to 5 DEG C, is cooled to-25 DEG C after 2min with the speed of 1 DEG C/min, suction filtration after maintenance 3h, obtains 93.5mg sunitinib malate Form VIII after 50 DEG C of vacuum-dryings are about 6h.
Embodiment 2: sunitinib malate Form VIII
By 2.00g Sutent free alkali and the mixing of 0.68gL-oxysuccinic acid, add 80ml tetrahydrofuran (THF) and 10ml water, be heated to 65 DEG C and make it dissolve completely, filter.Filtrate is cooled to 5 DEG C, is cooled to-25 DEG C after 2min with the speed of 1 DEG C/min, suction filtration after maintenance 3h, obtains 1.98g sunitinib malate Form VIII after 50 DEG C of vacuum-dryings are about 6h.
Embodiment 3: sunitinib malate Form Ⅸ
120mg sunitinib malate is added in 4ml water, is heated to 65 DEG C and makes it dissolve completely, filter.Filtrate being added under agitation is precooled in the tetrahydrofuran (THF) of-5 DEG C, has solid to separate out.Suction filtration after continuation stirring 2h, obtains 90.2mg sunitinib malate Form Ⅸ after 50 DEG C of vacuum-dryings are about 6h.
Embodiment 4: sunitinib malate Form Ⅸ
2.4g sunitinib malate is added in 80ml water, is heated to 65 DEG C and makes it dissolve completely, filter.Filtrate being added under agitation is precooled in the tetrahydrofuran (THF) of-5 DEG C, has solid to separate out.Suction filtration after continuation stirring 2h, obtains 1.83g sunitinib malate Form Ⅸ after 50 DEG C of vacuum-dryings are about 6h.
Claims (12)
1. a sunitinib malate new crystal VIII, is characterized in that the X-ray powder diffraction pattern of described crystal formation comprises the characteristic peak shown in following 2 θ angles: 3.15 °, 9.43 °, 10.07 °, 12.63 °, 14.85 °, 15.74 °, 17.65 °, 18.96 °, 20.53 °.
2. sunitinib malate new crystal VIII as claimed in claim 1, is characterized in that it has X-ray powder diffraction pattern as shown in Figure 1.
3. sunitinib malate new crystal VIII as claimed in claim 1, is characterized in that described crystal formation dsc analysis collection of illustrative plates is presented at 166 DEG C ~ 167 DEG C places and 176 ~ 178 DEG C of places and has endotherm(ic)peak (accompanying drawing 2).
4. prepare a method for claim 1 sunitinib malate new crystal VIII, comprise the following steps:
Under (a) room temperature by Sutent free alkali with oxysuccinic acid with molar mass than 1:1 ~ 1.5:1, preferred 1.2:1 is mixed to form suspension in organic solvent;
B suspension described in step (a) is heated to dissolve completely and filter by ();
C filtrate described in step (b) is cooled to 0 DEG C to 10 DEG C by (), preferably 5 DEG C.Separate out solid.
D () is cooled to-10 DEG C to-30 DEG C by cooling filtrate continuation described in step (c), preferably-25 DEG C.
E () obtains sunitinib malate new crystal VIII by after gained solid vacuum-drying in step (d).
5. method as claimed in claim 4, the solvent described in step (a) is the mixture of organic solvent and water.Wherein the mass ratio of organic solvent and water is 5:1 ~ 10:1, preferred 8:1.
6. method as claimed in claim 4, organic solvent is ethers, preferred tetrahydrofuran (THF).
7. method as claimed in claim 4, the described rate of cooling of step (d) is 0.5-2 DEG C/min, preferably 1 DEG C/min.
8. a sunitinib malate new crystal Ⅸ, is characterized in that the X-ray powder diffraction pattern of described crystal formation comprises the characteristic peak shown in following 2 θ angles: 3.09 °, 7.63,9.15 °, 9.63 °, 12.16 °, 12.84 °, 15.21 °, 16.13 °, 18.36 °, 18.93 °, 22.47 °, 27.39 °.
9. sunitinib malate new crystal Ⅸ as claimed in claim 8, is characterized in that it has X-ray powder diffraction pattern as shown in Figure 3.
10. sunitinib malate new crystal Ⅸ as claimed in claim 8, is characterized in that described crystal formation dsc analysis collection of illustrative plates is presented at 158 DEG C ~ 161 DEG C places and 176 ~ 178 DEG C of places and has endotherm(ic)peak (accompanying drawing 4).
11. 1 kinds of methods preparing claim 8 sunitinib malate new crystal Ⅸ, comprise the following steps:
A sunitinib malate heated and stirred in water is extremely dissolved and is filtered by () completely;
B organic solvent is cooled to 0 DEG C to-10 DEG C by (), preferably-5 DEG C.；
C filtrate described in step (a) adds in organic solvent described in step (b) by (), separate out solid, continues to stir 1h to 3h, preferred 2h.
D () obtains sunitinib malate new crystal Ⅸ by after gained solid vacuum-drying in step (c).
12. methods as claimed in claim 11, organic solvent is ethers, preferred tetrahydrofuran (THF).
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| CN201410193624.XA CN105085490A (en) | 2014-05-09 | 2014-05-09 | New sunitinib malate crystal form and preparation method therefor |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009156837A2 (en) * | 2008-06-26 | 2009-12-30 | Medichem, S.A. | Amorphous form of a 3-pyrrole substituted 2-indolinone malate salt |
| CN101983195A (en) * | 2008-02-21 | 2011-03-02 | 基因里克斯(英国)有限公司 | Novel polymorphs and processes for their preparation |
| WO2011092664A1 (en) * | 2010-01-29 | 2011-08-04 | Ranbaxy Laboratories Limited | Crystalline forms of l-malic acid salt of sunitinib |
| CN102164913A (en) * | 2008-07-24 | 2011-08-24 | 麦迪凯姆股份公司 | Crystalline forms of a 3-pyrrole substituted 2-indolinone malate salt |
| CN102203085A (en) * | 2008-07-10 | 2011-09-28 | 基因里克斯(英国)有限公司 | Processes for the preparation of crystalline forms of sunitinib malate |
| CN102272124A (en) * | 2008-11-13 | 2011-12-07 | 力奇制药公司 | New crystal form of sunitinib malate |
| WO2012059941A1 (en) * | 2010-11-04 | 2012-05-10 | Ind-Swift Laboratories Limited | Process for preparation of sunitinib malate and salts thereof |
-
2014
- 2014-05-09 CN CN201410193624.XA patent/CN105085490A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101983195A (en) * | 2008-02-21 | 2011-03-02 | 基因里克斯(英国)有限公司 | Novel polymorphs and processes for their preparation |
| WO2009156837A2 (en) * | 2008-06-26 | 2009-12-30 | Medichem, S.A. | Amorphous form of a 3-pyrrole substituted 2-indolinone malate salt |
| CN102203085A (en) * | 2008-07-10 | 2011-09-28 | 基因里克斯(英国)有限公司 | Processes for the preparation of crystalline forms of sunitinib malate |
| CN102164913A (en) * | 2008-07-24 | 2011-08-24 | 麦迪凯姆股份公司 | Crystalline forms of a 3-pyrrole substituted 2-indolinone malate salt |
| CN102272124A (en) * | 2008-11-13 | 2011-12-07 | 力奇制药公司 | New crystal form of sunitinib malate |
| WO2011092664A1 (en) * | 2010-01-29 | 2011-08-04 | Ranbaxy Laboratories Limited | Crystalline forms of l-malic acid salt of sunitinib |
| WO2012059941A1 (en) * | 2010-11-04 | 2012-05-10 | Ind-Swift Laboratories Limited | Process for preparation of sunitinib malate and salts thereof |
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Application publication date: 20151125 |