CN105503717A - Cabozantinib malate compound and medicine composition therewith - Google Patents
Cabozantinib malate compound and medicine composition therewith Download PDFInfo
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- CN105503717A CN105503717A CN201410495691.7A CN201410495691A CN105503717A CN 105503717 A CN105503717 A CN 105503717A CN 201410495691 A CN201410495691 A CN 201410495691A CN 105503717 A CN105503717 A CN 105503717A
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- buddhist nun
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Abstract
The invention provides a cabozantinib malate compound in a new crystal form and a preparation method thereof. The cabozantinib malate compound in the new crystal form has excellent stability and is free of significant changes on maximum single impurity content and maximum total impurity content at a high temperature (40 DEG C) under high humidity with light irradiation.
Description
Technical field
The invention belongs to medicinal chemistry arts, relate to a kind of oxysuccinic acid card of novel crystalline forms particularly rich for Buddhist nun's compound and pharmaceutical composition thereof and preparation method.
Background technology
Card is rich is a kind of tyrosine kinase inhibitor for Buddhist nun (Cabozantinib), external biochemistry and/or cell detection show, card rich for Buddhist nun suppress RET, MET, VEGFR-1 ,-2 and-3, the tyrosine kinase activity of KIT, TRKB, FLT-3, AXL and TIE-2 acceptor.
Medullary thyroid carcinoma (MTC) patient being used for the treatment of progressive stage, transfer for Buddhist nun won by the card of in November, 2012 U.S. FDA approval Exelixis company exploitation; Commodity are called COMETRIQ
tM.The activeconstituents of COMETRIQ is the rich L MALIC ACID salt form for Buddhist nun of card, and its chemical structure is such as formula shown in-I.
Disclose the rich three kinds of solid forms for Buddhist nun's L MALIC ACID salt of card in CN102388024A, be respectively the crystallization of N-1 type, the crystallization of N-2 type, armorphous (unformed).
The different crystal forms existence form of solid pharmaceutical has obvious difference in stability, can show as the stable existence of crystal formation and the phenomenon of transformation of crystal.Different according to the stability of crystal-form substances, polymorph in pharmaceuticals can be divided into instability mode, metastable type and stable form.Possess the medicine of certain stability of crystal form, be conducive to ensureing that the curative effect at process of clinical application Chinese traditional medicine does not change, therefore, the medicine of clinical application needs to possess certain stability of crystal form.
Summary of the invention
The oxysuccinic acid card that the invention provides a kind of novel crystalline forms is rich for Buddhist nun's compound, and preparation method thereof.The oxysuccinic acid card of described novel crystalline forms is rich has good stability for Buddhist nun's compound, meets medicinal requirements.
The oxysuccinic acid card that the invention provides a kind of novel crystalline forms is rich for Buddhist nun's compound, chemical structure such as formula shown in I,
Its X-ray powder diffraction has diffraction peak at following spacing place: 13.30,11.44,10.22,9.42,8.11,7.57,6.62,5.83.
Preferably, the oxysuccinic acid card of novel crystalline forms provided by the invention is won for Buddhist nun's compound X-ray powder diffraction a place or many places in following spacing have diffraction peak: 4.70,4.55,4.22,3.92,3.85,3.77,3.41,3.31;
And/or
In following spacing, a place or many places have diffraction peak: 5.58,5.43,5.16,5.00,4.35,4.06.
Further preferably, the oxysuccinic acid card of novel crystalline forms provided by the invention win for Buddhist nun's compound X-ray powder diffraction pattern substantially as shown in Figure 1.
Spacing can be represented by d value, and its unit is dust.The 2 θ angles of Fig. 1, d value and Relative intensity data are as shown in table 1.According to Bragg equation 2dsin θ=n λ; Wherein λ is the wavelength of X-ray, and n is diffraction progression; In the present invention, Fig. 1 is obtained by Cu target diffraction, and wavelength X is 1.5406 dusts.There is error in the mensuration at 2 θ angles; Generally speaking the limit of error at 2 θ angles can regard as measuring error ± 0.2.
Still more preferably, the oxysuccinic acid card of novel crystalline forms provided by the invention is won and is had DSC collection of illustrative plates (differentialscanningcalorimetry, dsc) substantially as shown in Figure 2 for Buddhist nun's compound.Be preferably and have endotherm(ic)peak, more preferably for have endotherm(ic)peak at 125 ± 2 DEG C at 125 ± 5 DEG C.In Fig. 2, endotherm(ic)peak is oriented upwards (Endoup).
The rich Buddhist nun's compound that replaces of oxysuccinic acid card that thermogravimetric analysis (ThermogravimetricAnalysis, TGA) shows novel crystalline forms provided by the invention does not contain crystal water.
Table 1
The oxysuccinic acid card of novel crystalline forms provided by the invention is rich be may be used for preparing Therapeutic cancer medicine for Buddhist nun's compound; Preferably, cancer is medullary thyroid carcinoma; Be more preferably used in the medicine of medullary thyroid carcinoma (MTC) patient preparing treatment of advanced, transfer.
Present invention also offers a kind of oxysuccinic acid card containing described novel crystalline forms and win pharmaceutical composition for Buddhist nun's compound.
Preferably, the dosage form of described composition can be oral solid formulation (including but not limited to tablet, capsule) or parenteral formulations agent (including but not limited to injection).
Described composition also comprises pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier normally those of ordinary skill in the art specifically can be selected according to concrete form of medication.Available well known technology is as manufacture technics pharmaceutical compositions of the present invention such as conventional granulation, mixing, dissolving, formation capsule, freeze-drying.
Most preferably, the form of described pharmaceutical composition is be called the identical pharmaceutical preparation of the capsule of COMETRIQ with commercial goods; Pharmaceutically acceptable carrier is silicified microcrystalline cellulose, croscarmellose sodium, sodium starch glycollate, fumed silica and stearic acid.
Present invention also offers the oxysuccinic acid card preparing described novel crystalline forms and win method for Buddhist nun's compound, preferably its step is that cooling crystallization obtains by after being dissolved with solution heating that L MALIC ACID card wins for Buddhist nun.To be dissolved with the L MALIC ACID card solvent won for the solution of Buddhist nun be preferably volume ratio is (10 ~ 35): butanone, the water mixed liquid of 2.
Further preferably, its step is, 50 ~ 70 DEG C of heating be cooled to being dissolved with the solution that L MALIC ACID card wins for Buddhist nun 15 ~ 35 DEG C of crystallizatioies and obtain after 2 ~ 8 hours; Wherein the ratio for Buddhist nun and butanone won by oxysuccinic acid card is 1mol:(5 ~ 17.5) L.More preferably, after the solid that cooling crystallization obtains is pulverized, 40 ~ 50 DEG C of vacuum-drying 12 ~ 24h, the oxysuccinic acid card obtaining described novel crystalline forms is rich for Buddhist nun's compound.
Factors affecting stability test has been carried out for Buddhist nun's compound according to " Chinese Pharmacopoeia " to the oxysuccinic acid card of novel crystalline forms provided by the invention is rich, under result is presented at high temperature (40 DEG C), high humidity, illumination condition, the oxysuccinic acid card of novel crystalline forms provided by the invention is rich has satisfactory stability for Buddhist nun's compound, and the highest list is mixed, always assorted content is without considerable change.Simultaneously under high temperature, high humidity, illumination condition, the moisture that the oxysuccinic acid card of novel crystalline forms provided by the invention is won for Buddhist nun's compounds adsorb increases on a small quantity, for somewhat is drawn moist, meets medicinal requirements.
Accompanying drawing explanation
The XRPD collection of illustrative plates for Buddhist nun's compound won by the oxysuccinic acid card of Fig. 1 novel crystalline forms of the present invention
The DSC collection of illustrative plates for Buddhist nun's compound won by the oxysuccinic acid card of Fig. 2 novel crystalline forms of the present invention
The TGA collection of illustrative plates for Buddhist nun's compound won by the oxysuccinic acid card of Fig. 3 novel crystalline forms of the present invention
Embodiment
Mode below by embodiment further illustrates the present invention, but those skilled in the art understand, and following embodiment is only explain object of the present invention is described, is not limiting the scope of the invention.
If no special instructions, the operation steps in embodiment is routine operation.If no special instructions, in the present invention, room temperature refers to 25 ± 10 DEG C.
Embodiment 1
In reaction flask, add card and win for Buddhist nun's free alkali 5g (10mmol), L MALIC ACID 1.34g (10mmol); butanone 50mL, under nitrogen protection, 60 ± 10 DEG C of heated and stirred, add purified water 10mL; clearly molten, the lower 55 DEG C of backflow 4h of nitrogen protection, then add 0.5g gac; decolouring 1h, filtered while hot, filtrate room temperature crystallization stirs and spends the night; centrifugal; after solid fast-crushing, 40 ~ 50 DEG C of vacuum-drying 12h, obtain off-white color or white solid powder.
Get the pressed powder of acquisition, carry out X-ray powder diffraction, its XRPD collection of illustrative plates substantially as shown in Figure 1.
Embodiment 2
In reaction flask, add card and win for Buddhist nun's free alkali 5g (10mmol), L MALIC ACID 1.34g (10mmol); butanone 50mL, under nitrogen protection, 60 ± 10 DEG C of heated and stirred, add purified water 5mL; clearly molten, the lower 60 DEG C of backflow 6h of nitrogen protection, then add 0.5g gac; decolouring 1h, filtered while hot, filtrate room temperature crystallization stirs and spends the night; centrifugal; after solid fast-crushing, 40 ~ 50 DEG C of vacuum-drying 24h, obtain off-white color or white solid powder.
Get the pressed powder of acquisition, carry out X-ray powder diffraction, its XRPD collection of illustrative plates substantially as shown in Figure 1.
Embodiment 3
In reaction flask, add card and win for Buddhist nun's free alkali 5g (10mmol), L MALIC ACID 1.34g (10mmol); butanone 100mL, under nitrogen protection, 60 ± 10 DEG C of heated and stirred, add purified water 6mL; clearly molten, the lower 50 DEG C of backflow 8h of nitrogen protection, then add 0.5g gac; decolouring 1h, filtered while hot, filtrate room temperature crystallization stirs and spends the night; centrifugal; after solid fast-crushing, 40 ~ 50 DEG C of vacuum-drying 18h, obtain off-white color or white solid powder.
Get the pressed powder of acquisition, carry out X-ray powder diffraction, its XRPD collection of illustrative plates substantially as shown in Figure 1.
Embodiment 4
In reaction flask, add card and win for Buddhist nun's free alkali 5g (10mmol), L MALIC ACID 1.34g (10mmol); butanone 100mL, under nitrogen protection, 60 ± 10 DEG C of heated and stirred, add purified water 10mL; clearly molten, the lower 70 DEG C of backflow 2h of nitrogen protection, then add 0.5g gac; decolouring 1h, filtered while hot, filtrate room temperature crystallization stirs and spends the night; centrifugal; after solid fast-crushing, 40 ~ 50 DEG C of vacuum-drying 18h, obtain off-white color or white solid powder.
Get the pressed powder of acquisition, carry out X-ray powder diffraction, its XRPD collection of illustrative plates substantially as shown in Figure 1.
Embodiment 5
In reaction flask, add card and win for Buddhist nun's free alkali 5g (10mmol), L MALIC ACID 1.34g (10mmol); butanone 175mL, under nitrogen protection, 60 ± 10 DEG C of heated and stirred, add purified water 10mL; clearly molten, the lower 65 DEG C of backflow 5h of nitrogen protection, then add 0.5g gac; decolouring 1h, filtered while hot, filtrate room temperature crystallization stirs and spends the night; centrifugal; after solid fast-crushing, 40 ~ 50 DEG C of vacuum-drying 12h, obtain off-white color or white solid powder.
Get the pressed powder of acquisition, carry out X-ray powder diffraction, its XRPD collection of illustrative plates substantially as shown in Figure 1.
Embodiment 6
In reactor, add card successively rich for Buddhist nun's free alkali 100.3g (0.2mol), L MALIC ACID 26.9g (0.2mol), butanone 3L, temperature is adjusted to 70 DEG C, heated and stirred under nitrogen protection, during interior temperature to 65 ± 5 DEG C, add purified water 150mL, clearly molten, interior temperature to 65 ± 5 DEG C start timing, back flow reaction 5h under nitrogen protection, add 10g gac 5 again, 65 ± 5 DEG C of decolouring 1h, filtered while hot, filtrate proceeds in another reactor, when reaction solution is down to about 45 DEG C, start to separate out a small amount of white solid, room temperature crystallization stirs and spends the night, centrifugal, after taking out fast-crushing, 40 ~ 50 DEG C of vacuum-drying 24h, obtain off-white color or white solid powder 92.7g (yield 72.9%).
Get the pressed powder of acquisition, carry out X-ray powder diffraction, its XRPD collection of illustrative plates substantially as shown in Figure 1.
Embodiment 7
Example 6 obtains pressed powder and carries out dsc analysis, temperature elevating range 50 ~ 300 DEG C, temperature rise rate 10 DEG C/min, and obtain collection of illustrative plates as shown in Figure 2, in Fig. 2, endotherm(ic)peak upwards (Endoup).Fig. 2 has endotherm(ic)peak when being presented at about 125 DEG C.
Example 6 obtains pressed powder and carries out TGA analysis, temperature elevating range 25 ~ 600 DEG C, temperature rise rate 20 DEG C/min, obtains collection of illustrative plates as shown in Figure 3.Fig. 3 show embodiment 6 obtain in pressed powder containing have an appointment 3% planar water, embodiment 6 to obtain in pressed powder not containing crystal water.
Embodiment 8
Example 6 obtains pressed powder according to " Chinese Pharmacopoeia " (2010 editions, two) governing principle of annex XIXC, carried out the factors affecting stability test (comprising strong illumination test, high temperature test, high humidity test) of 10 days, result is as shown in table 2.Wherein HPLC testing conditions: chromatographic column is octadecylsilane chemically bonded silica (C18 post, 250 × 4.6mm, 5 μm); Column temperature is 25 DEG C; Determined wavelength is 242nm; Flow velocity is 1.0mL/min; Mobile phase A is 25mmol/L ammonium acetate solution (regulating pH to 4.8), and Mobile phase B is acetonitrile; Condition of gradient elution is as follows:
| Time (min) | B(％，V/V) |
| 0.01 | 15 |
| 30 | 50 |
| 60 | 20 |
Table 2
From data in table 2, outside the content of remove 60 DEG C of hot conditionss, the highest list is mixed, always mixing is significantly increased; Under all the other high temperature, high humidity, illumination condition, L MALIC ACID card provided by the invention is won has satisfactory stability for Buddhist nun.
Show under high temperature, high humidity, illumination condition, L MALIC ACID card provided by the invention is rich to be drawn moist for Buddhist nun for somewhat, meets medicinal requirements.
Claims (10)
1. the oxysuccinic acid card shown in formula I is rich for Buddhist nun's compound,
It is characterized in that: described compound is crystalline form, its X-ray powder diffraction has diffraction peak at following spacing place: 13.30,11.44,10.22,9.42,8.11,7.57,6.62,5.83.
2. compound according to claim 1, is characterized in that the place of X-ray powder diffraction in following spacing or many places have diffraction peak: 4.70,4.55,4.22,3.92,3.85,3.77,3.41,3.31.
3. compound according to claim 1, is characterized in that the place of X-ray powder diffraction in following spacing or many places have diffraction peak: 5.58,5.43,5.16,5.00,4.35,4.06.
4. compound according to claim 1, is characterized in that X-ray powder diffraction pattern substantially as shown in Figure 1.
5. compound according to claim 1, is characterized in that DSC collection of illustrative plates has endotherm(ic)peak at 125 ± 5 DEG C.
6. compound according to any one of Claims 1 to 5 is preparing the application in Therapeutic cancer medicine.
7., according to the application described in claim 5, it is characterized in that described cancer is medullary thyroid carcinoma.
8. contain the pharmaceutical composition of compound according to any one of Claims 1 to 5.
9. prepare a method for compound according to any one of Claims 1 to 5, it is characterized by by be dissolved with L MALIC ACID card win for Buddhist nun solution heating after, cooling crystallization obtain; Described to be dissolved with the L MALIC ACID card solvent won for the solution of Buddhist nun be volume ratio is (10 ~ 35): butanone, the water mixed liquid of 2.
10. prepare a method for compound according to any one of Claims 1 to 5, it is characterized by and, 50 ~ 70 DEG C of heating be cooled to being dissolved with the solution that L MALIC ACID card wins for Buddhist nun 15 ~ 35 DEG C of crystallizatioies and obtain after 2 ~ 8 hours; Wherein the ratio for Buddhist nun and butanone won by L MALIC ACID card is 1mol:(5 ~ 17.5) L.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410495691.7A CN105503717A (en) | 2014-09-24 | 2014-09-24 | Cabozantinib malate compound and medicine composition therewith |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410495691.7A CN105503717A (en) | 2014-09-24 | 2014-09-24 | Cabozantinib malate compound and medicine composition therewith |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107951850A (en) * | 2017-12-20 | 2018-04-24 | 深圳万乐药业有限公司 | A kind of malic acid card is won for the preparation method of Buddhist nun's piece |
| WO2020057622A1 (en) * | 2018-09-20 | 2020-03-26 | 苏州科睿思制药有限公司 | Cabozantinib malate crystal form, preparation method therefor and use thereof |
| WO2020075196A1 (en) * | 2018-10-11 | 2020-04-16 | Cipla Limited | Polymorphs of n-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-n'-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide, (s)- malate, methods of production and pharmaceutical uses thereof |
| CN115215797A (en) * | 2021-04-15 | 2022-10-21 | 成都苑东生物制药股份有限公司 | Novel crystal form of cabozantinib malate and preparation method thereof |
| US11814356B1 (en) | 2023-03-29 | 2023-11-14 | Apotex Inc. | Salt of cabozantinib |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107951850A (en) * | 2017-12-20 | 2018-04-24 | 深圳万乐药业有限公司 | A kind of malic acid card is won for the preparation method of Buddhist nun's piece |
| WO2020057622A1 (en) * | 2018-09-20 | 2020-03-26 | 苏州科睿思制药有限公司 | Cabozantinib malate crystal form, preparation method therefor and use thereof |
| CN112638880A (en) * | 2018-09-20 | 2021-04-09 | 苏州科睿思制药有限公司 | Cabotinib malate crystal form and preparation method and application thereof |
| CN112638880B (en) * | 2018-09-20 | 2022-03-25 | 苏州科睿思制药有限公司 | Cabotinib malate crystal form and preparation method and application thereof |
| WO2020075196A1 (en) * | 2018-10-11 | 2020-04-16 | Cipla Limited | Polymorphs of n-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-n'-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide, (s)- malate, methods of production and pharmaceutical uses thereof |
| CN115215797A (en) * | 2021-04-15 | 2022-10-21 | 成都苑东生物制药股份有限公司 | Novel crystal form of cabozantinib malate and preparation method thereof |
| CN115215797B (en) * | 2021-04-15 | 2024-04-12 | 成都苑东生物制药股份有限公司 | Novel crystal form of cabozitinib malate and preparation method thereof |
| US11814356B1 (en) | 2023-03-29 | 2023-11-14 | Apotex Inc. | Salt of cabozantinib |
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Application publication date: 20160420 |