CN101987834A - Novel erlotinib hydrochloride of crystalline form, preparation method and pharmaceutical application thereof - Google Patents
Novel erlotinib hydrochloride of crystalline form, preparation method and pharmaceutical application thereof Download PDFInfo
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- CN101987834A CN101987834A CN 201010200498 CN201010200498A CN101987834A CN 101987834 A CN101987834 A CN 101987834A CN 201010200498 CN201010200498 CN 201010200498 CN 201010200498 A CN201010200498 A CN 201010200498A CN 101987834 A CN101987834 A CN 101987834A
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Abstract
The invention aims to provide a novel crystalline form of erlotinib hydrochloride which has characteristic peaks at the positions of 5.6+/-0.1, 9.8+/-0.1, 11.3+/-0.1, 18.8+/-0.1, 22.8+/-0.1, 23.5+/-0.1, and 24.2+/-0.12[theta] in an X-ray powder diffraction figure, and a preparation method thereof. The novel crystalline form of erlotinib hydrochloride is prepared by dissolving the erlotinib hydrochloride with acetonitrile, then adding water to the solution, stirring the solution until the solution is uniformly clear, and finally freeze-drying the solution, preferably under the freezing conditions of -40 DEG C to -60 DEG C and 0.01 to 1 mbar, more preferably, -53 DEG C and 0.5 mbar.
Description
Technical field
The present invention relates to a kind of Erlotinib hydrochloride, its preparation method and the purposes in the preparation medicine thereof of novel crystalline form attitude.
Background technology
Erlotinib hydrochloride (erlotinib hydrochloride), its chemical substance are called N-(3-acetylene phenyl)-[6,7-two (2-methoxy ethoxy)] quinazoline-4-amine hydrochlorate, and structural formula is as follows.
Erlotinib hydrochloride is the medicine that is used for the treatment of the non-small cell tumour of FDA approval.It can be treated and prevention and Tyrosylprotein kinase such as the receptor related disease of epidermal growth factor, as cancer, and especially nonsmall-cell lung cancer, the rectum cancer, tolerance nonsmall-cell lung cancer, pancreas cancer, ovarian cancer, a cancer or neck cancer.
US5747498 discloses erlotinib and preparation method thereof.
Erlotinib has a plurality of solid form, has different crystalline texture and physical properties such as fusing point, x-ray diffraction pattern, infrared absorption pattern, NMR spectrum.A kind of solid form produces different calorifics effects, and as fusing point, TGA, DSC is used to distinguish different crystal formations.The polymorphous discovery of erlotinib provides a kind of chance to improve active medicine synthetic efficient, and the erlotinib solid form by stable improves liquidity solvability.Therefore a lot of to the research of the various solid form of erlotinib.WO01/34574 discloses hydrochloric acid 6, two (2-methoxyl group-oxyethyl group)-quinazolines of 7--4-yl]-two kinds of crystal formations of (3-acetylene phenyl) amine, crystal form A and crystal form B, described among this piece document embodiment pure crystal form A, B with and preparation process of mixture.US2004/0162300 discloses the third crystal formation of Erlotinib hydrochloride, and the preparation of crystal formation E in this file, only makes crystalline Erlotinib hydrochloride material (crystal formation E).The preparation method of Erlotinib hydrochloride is disclosed among the WO96/30347 and in the super proliferative disease of preparation treatment as the purposes of medicine, after wherein embodiment 20 has described Erlotinib hydrochloride and has been dissolved in trichloromethane and ether by corresponding erlotinib free base, use the titration of 1M hydrochloric acid diethyl ether solution, and be settled out its hydrochloride product.The product fusing point that obtains is 228-230 ℃, and the fusing point of the Erlotinib hydrochloride crystal form B described in this numerical value and the US2004/40162300 embodiment 4 is close.CN101016266A discloses extremely preparation method of unbodied Erlotinib hydrochloride.WO2009/002538 discloses the amorphous and multiple crystal formation of erlotinib, its preparation method and change into hydrochloride by crystal formation.
Instruct the amorphous and crystal habit of many medicines to show different solubleness and different bioavailabilities in many files, thereby produced higher biological activity.To some treatment illness, perhaps a kind of bioavailability is better than another kind of bioavailability.Generally speaking, the medicine of crystal habit is better than not having crystal habit in nature above-mentioned, has better physical and chemical stability, and very big benefit is arranged aspect preparation.Therefore still need the multiple solid form of erlotinib is studied.
Summary of the invention
The object of the present invention is to provide a kind of Erlotinib hydrochloride of new crystal habit.It is in X-ray powder diffraction figure (see figure 1) 5.6 ± 0.1,9.8 ± 0.1,11.3 ± 0.1,18.8 ± 0.1, and there is characteristic peak 22.8 ± 0.1,23.5 ± 0.1,24.2 ± 0.12 θ positions.In the hope of by a kind of new solid form is provided, be searching erlotinib solid form create openings more stable, preparation preferably.
Another object of the present invention is to provide a kind of preparation method of Erlotinib hydrochloride of this new crystal habit.
Mostly the Erlotinib hydrochloride of the crystal habit of existing bibliographical information is to make by solvent method, and the present invention then is the Erlotinib hydrochloride that makes new crystal habit by lyophilization.Lyophilize is meant the drying of low temperature, low pressure, nothing liquefaction, removes moisture or other solvents by distillation from scars, makes sample reach the exsiccant process.Look the efficient of Freeze Drying Equipment time of drying, sample loading amount and character etc. and decide.Than solvent method, freeze-drying crystallization process method is simpler, and is easy to operate.
The Erlotinib hydrochloride preparation method of new crystal habit is as follows: the erlotinib hydrochloride, use low melting point organic solvent or its mixture dissolving miscible with water, and add entry again, stir, lyophilize obtains the erlotinib hydrochloride of novel crystalline form attitude.Described low melting point is meant the evaporable solvent that can distil in lyophilize.More specifically, at-40 to-60 ℃, lyophilize under 0.01 to 1mbar.More preferably at-53 ℃, lyophilize under the 0.5mbar.
Organic solvent in the aforesaid method is low-melting alcohols, ketone, ethers, nitrile, furans or its mixture miscible with water.Be preferably methyl alcohol, ethanol, acetone, tetrahydrofuran (THF), acetonitrile or its mixture.It more preferably is acetonitrile.
Description of drawings
The X-ray powder diffraction figure of Fig. 1 embodiment 1 product
The X-ray powder diffraction figure of Fig. 2 embodiment 2 products
Embodiment
Embodiment 1
Get 10g erlotinib hydrochloride, with 150 milliliters of acetonitrile dissolvings, add 500 ml waters again, stirring is evenly clarified solution, is frozen into solid with liquid nitrogen bath.Sample on freeze drier, in temperature-53 ℃, the freezing erlotinib hydrochloride (canescence crystalline powder) that can obtain the novel crystalline form attitude in 24 hours under the pressure 0.5mbar.
Its X-ray powder diffraction data are as follows:
Embodiment 2
Get 10g erlotinib hydrochloride, with 150 milliliters of acetonitrile dissolvings, add 500 ml waters again, stirring is evenly clarified solution, then with solution 40 ℃ of solvents that following pressure reducing and steaming is about 100 milliliters on Rotary Evaporators.Be frozen into solid with liquid nitrogen bath again.Sample on freeze drier, in temperature-53 ℃, the freezing erlotinib hydrochloride (canescence crystalline powder) that can obtain the novel crystalline form attitude in 24 hours under the pressure 0.5mbar.
Its X-ray powder diffraction data are as follows:
Embodiment 3
Get 10g erlotinib hydrochloride, with 120 milliliters of dissolve with ethanol, add 500 ml waters again, stirring is evenly clarified solution, then with solution 40 ℃ of solvents that following pressure reducing and steaming is about 80 milliliters on Rotary Evaporators.Be frozen into solid with liquid nitrogen bath again.Sample on freeze drier, about temperature-45 ℃, the freezing erlotinib hydrochloride (canescence crystalline powder) that can obtain the novel crystalline form attitude in 24 hours under the pressure 0.65mbar.
Embodiment 4
Get 10g erlotinib hydrochloride, with 150 milliliters of acetone solutions, add 500 ml waters again, stirring is evenly clarified solution, then with solution 40 ℃ of solvents that following pressure reducing and steaming is about 60 milliliters on Rotary Evaporators.Be frozen into solid with liquid nitrogen bath again.Sample on freeze drier, in temperature-60 ℃, the freezing erlotinib hydrochloride (canescence crystalline powder) that can obtain the novel crystalline form attitude in 24 hours under the pressure 0.4mbar.
Claims (7)
1. the Erlotinib hydrochloride of a crystal habit is characterized in that, it is in its X-ray powder diffraction Fig. 5 .6 ± 0.1,9.8 ± 0.1,11.3 ± 0.1,18.8 ± 0.1,22.8 ± 0.1, and there is characteristic peak 23.5 ± 0.1,24.2 ± 0.12 θ positions.
2. erlotinib hydrochloride method for preparing crystal habit as claimed in claim 1, it is characterized in that, the erlotinib hydrochloride, with low melting point organic solvent or its mixture dissolving miscible with water, add entry again, stir, lyophilize obtains the erlotinib hydrochloride of novel crystalline form attitude.
3. method according to claim 2 is characterized in that, at-40 to-60 ℃, and lyophilize under 0.01 to the 1mbar condition.
4. method according to claim 3 is characterized in that, at-53 ℃, and lyophilize under the 0.5mbar condition.
5. according to claim 2 or 3 or 4 described methods, it is characterized in that described organic solvent is low-melting alcohols, ketone, ethers, nitrile, furans or its mixture miscible with water.
6. method according to claim 5 is characterized in that, described organic solvent is methyl alcohol, ethanol, acetone, acetonitrile, tetrahydrofuran (THF) or its mixture.
7. method according to claim 6 is characterized in that, described organic solvent is an acetonitrile.
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| CN2010102004988A CN101987834B (en) | 2010-06-13 | 2010-06-13 | Novel erlotinib hydrochloride of crystalline form, preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772298A (en) * | 2012-10-25 | 2014-05-07 | 鲁南制药集团股份有限公司 | Erlotinib hydrochloride polymorphic substance and preparation method thereof |
| RU2610337C1 (en) * | 2015-12-10 | 2017-02-09 | Индивидуальный предприниматель Михайлов Олег Ростиславович | CRYSTALLINE β-MODIFICATION OF N-(3-ETHYLPHENYL)-6,7-BIS(2 METHOXYETHOXY)QUINAZOLINE-4-AMINE HYDROCHLORIDE, METHOD FOR PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION BASED THEREON |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040162300A1 (en) * | 2003-02-17 | 2004-08-19 | Bubendorf Andre Gerard | Novel [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride polymorph |
| WO2009002538A2 (en) * | 2007-06-25 | 2008-12-31 | Plus Chemicals S.A. | Amorphous erlotinib, processes for the preparation thereof, and processes to prepare additional forms of erlotinib |
-
2010
- 2010-06-13 CN CN2010102004988A patent/CN101987834B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040162300A1 (en) * | 2003-02-17 | 2004-08-19 | Bubendorf Andre Gerard | Novel [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride polymorph |
| WO2009002538A2 (en) * | 2007-06-25 | 2008-12-31 | Plus Chemicals S.A. | Amorphous erlotinib, processes for the preparation thereof, and processes to prepare additional forms of erlotinib |
Non-Patent Citations (1)
| Title |
|---|
| 《Acta crystallographica section E》 20080531 S.Selvanayagam, et al. Erlotinib hydrochloride: an anticancer agent o931 1 第64卷, 第part 5期 2 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772298A (en) * | 2012-10-25 | 2014-05-07 | 鲁南制药集团股份有限公司 | Erlotinib hydrochloride polymorphic substance and preparation method thereof |
| RU2610337C1 (en) * | 2015-12-10 | 2017-02-09 | Индивидуальный предприниматель Михайлов Олег Ростиславович | CRYSTALLINE β-MODIFICATION OF N-(3-ETHYLPHENYL)-6,7-BIS(2 METHOXYETHOXY)QUINAZOLINE-4-AMINE HYDROCHLORIDE, METHOD FOR PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION BASED THEREON |
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| CN101987834B (en) | 2012-07-18 |
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