CN103772298A - Erlotinib hydrochloride polymorphic substance and preparation method thereof - Google Patents
Erlotinib hydrochloride polymorphic substance and preparation method thereof Download PDFInfo
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- CN103772298A CN103772298A CN201210442310.XA CN201210442310A CN103772298A CN 103772298 A CN103772298 A CN 103772298A CN 201210442310 A CN201210442310 A CN 201210442310A CN 103772298 A CN103772298 A CN 103772298A
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- polymorphic form
- hydrochloric acid
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- erlotinid hydrochloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
Abstract
The invention provides an erlotinib hydrochloride polymorphic substance. According to the polymorphic substance, in an X-ray powder diffraction atlas, characteristic peaks appear in the positions when an angle 2 theta is 5.6 degrees, 10.4 degrees, 11.0 degrees, 11.3 degrees, 21.2 degrees, 24.5 degrees and 26.9 degrees, and do not appear in the positions when the angle 2 theta is at the range of 6-10 degrees. The novel erlotinib hydrochloride polymorphic substance provided by the invention creates a chance to find an erlotinib solid form with more stability, better drug effect and lower cost; the method for preparing the erlotinib hydrochloride polymorphic substancecan, provided by the invention, is suitable for large-scale production.
Description
Technical field:
The present invention relates to the polymorphic form of medical compounds, particularly a kind of polymorphic form of hydrochloric acid Erlotinib, in addition, the invention still further relates to the preparation method of this polymorphic form.
Background technology:
Hydrochloric acid Erlotinib is a kind of target therapeutic agent, can, specifically for tumour cell effect, suppress formation and the growth of tumour.It is a kind of micromolecular compound, can suppress the signal transduction path of Human epidermal growth factor receptor (EGFR); Be the key ingredient of Urogastron (can claim again HER1) signal transduction pathway, in the formation of kinds of tumor cells and growth, all played the part of important role.Hydrochloric acid Erlotinib suppresses tumor growth by the active mode that suppresses Tyrosylprotein kinase, and Tyrosylprotein kinase is one of intracellular important component part of EGFR.
Erlotinid hydrochloride has multiple solid form, and the crystalline texture of having nothing in common with each other and physical properties are as fusing point, and X-penetrates knot diffractogram, infrared attraction collection of illustrative plates, NMR spectrum.Solid form produces different calorifics effects, and as fusing point, DSC is for distinguishing different crystal formations.The polymorphous discovery of erlotinid hydrochloride provides a kind of synthetic efficiency of active medicine of improving, by stable erlotinid hydrochloride solid form, improves liquidity, and solvability.Therefore the research of the various solid form to erlotinid hydrochloride is a lot.
WO0134574A1 (open day: two kinds of crystal formations of erlotinid hydrochloride are disclosed 2008-12-31), crystal form A and crystal form B, in this piece of document embodiment, described crystal form A, B with and composition thereof preparation method.US7148231B2 (day for announcing: 2006-12-12) discloses the third crystal formation of erlotinid hydrochloride, and the preparation of crystal formation E, in this file, only makes the erlotinid hydrochloride material (crystal formation E) of crystallization.WO9630347A1 (open day: the preparation method of erlotinid hydrochloride is disclosed 1996-10-03) and in the super proliferative disease for the treatment of as the purposes of medicine, wherein embodiment 20 has described erlotinid hydrochloride and has been dissolved in after trichloromethane and ether by corresponding erlotinid hydrochloride free alkali, use the titration of 1M hydrochloric acid diethyl ether solution, and be settled out its hydrochloride product.The product fusing point obtaining is 228-230 ℃, and the fusing point of the erlotinid hydrochloride crystal form B described in the embodiment 4 of this numerical value and US7148231B2 is close.CN101016266A (open day: 2007-08-15) disclose unbodied erlotinid hydrochloride and preparation method thereof.WO2009/002538A2 (open day: 2008-12-31) disclose the amorphous and multiple crystal formation of erlotinid hydrochloride, its preparation method and become hydrochloride by transformation of crystal.CN101987834A (open day: adopt 2011-03-23) and use the low melting point organic solvent miscible with water or its mixture to dissolve erlotinid hydrochloride, add again water, stir, lyophilize, obtains a kind of 5.6 ± 0.1,9.8 ± 0.1,11.3 ± 0.1,18.8 ± 0.1,22.8 ± 0.1, there is the crystal habit at X-ray diffraction peak 23.5 ± 0.1,24.2 ± 0.1 degree 2 θ positions.
The different crystal forms of medicine affects stripping and the bioavailability of medicine, so still need the crystal formation of Tarceva to study.
Summary of the invention:
The object of the present invention is to provide a kind of erlotinid hydrochloride polymorphic form, to by a kind of new solid form is provided, is the erlotinid hydrochloride solid form create openings that searching is more stable, drug effect is better, cost is lower.
A kind of erlotinid hydrochloride polymorphic form provided by the invention, uses Cu-K
αradiation, its X-ray powder diffraction collection of illustrative plates 2 θ (°) there is diffraction peak at 5.6 places, and there is no diffraction peak between 6～10, typically 5.6,10.4,11.0,11.3,21.2,24.5, there is diffraction peak at 26.9 places, further typically following 2 θ (°) there is diffraction peak position: 5.6,10.4,10.6,11.0,11.3,14.9,17.0,17.4,19.1,19.7,21.2,23.4,24.5,26.9,26.9,28.7.Concrete crystal formation as shown in Figure 1.
For the XRD figure spectrum of several erlotinid hydrochloride crystal formations of the prior art be presented at 2 θ (°) between 6-10, all have diffraction peak to occur, polymorphic form of the present invention does not have diffraction peak to occur in this interval, this is the most significant feature of its difference prior art.
2 θ positional number value representations described herein fluctuate in ± 0.1 scope, above-mentioned numerical value determine, its degree of confidence is 0.99.The uncertainty that those skilled in the art know relative intensity depends on measuring condition very much, and relative intensity value can change or preferably in 10% scope, change in 30% scope for example.
Infrared data simultaneously, measures the error of institute's value all in 5%.
IR (infrared) atlas analysis is at 3258cm
-1, 1623cm
-1, 1570cm
-1, 1530cm
-1, 1514cm
-1, 1484cm
-1, 1465cm
-1, 1448cm
-1, 1432cm
-1, 1395cm
-1, 1371cm
-1, 1324cm
-1, 1280cm
-1, 1244cm
-1, 1213cm
-1there is charateristic avsorption band.
Another object of the present invention is to provide a kind of preparation method of hydrochloric acid Erlotinib polymorphic form.The method is that hydrochloric acid Erlotinib and pure water are mixed, is heated to dissolve, and insulation, cooling and stirring crystallization, suction filtration, washing, obtains hydrochloric acid Erlotinib polymorphic form.
Wherein, the amount of pure water used is 1～200 times of hydrochloric acid Erlotinib quality, preferably 55～70 times; The pH value adopting is 4.8～7.5, preferably 5.0～6.0.
Regulating PH material used is hydrochloric acid and Erlotinib.
Complete for crystallization, the solution after preliminary crystallization can be placed in to ice-water bath, be stirred to crystallization complete.Or filtrate is concentrated, then further crystallization.
Pure water recrystallization method of the present invention environmental protection, low toxicity, simple to operate, with low cost, product is without poisonous molten residual, suitable large production.
Accompanying drawing explanation:
Fig. 1 is the X-ray powder diffraction figure of embodiment 1 product;
Fig. 2 is the IR spectrogram of embodiment 1 product;
Fig. 3 is the X-ray powder diffraction figure of embodiment 2 products;
Fig. 4 is the IR spectrogram of embodiment 2 products;
Fig. 5 is the X-ray powder diffraction figure of embodiment 3 products;
Fig. 6 is the IR spectrogram of embodiment 3 products.
Embodiment:
Following content is in conjunction with concrete preferred implementation further description made for the present invention, can not assert that specific embodiment of the invention is confined to these explanations.For general technical staff of the technical field of the invention, without departing from the inventive concept of the premise, can also make some simple deduction or replace, all should be considered as belonging to protection scope of the present invention.
In summary of the invention of the present invention and specific embodiment, instrument used and test sample condition are respectively: XRD:
Instrument: Rigaku motor (Rigaku) D/max-γ B powder x-ray diffraction;
Condition: Cu-K
αray, 40kV, 100mA.
IR：
Instrument: Thermo Nicolet AVATAR370FT-IR;
Condition: KBr pressed disc method, data point interval: 2; Scanning times: 32; Resolving power: 4.
embodiment 1:
Hydrochloric acid Erlotinib 1g is stirred to whole dissolvings by the pure water 55ml reflux that hydrochloric acid is adjusted to pH5.0, stops heating, be cooled to 60～70 ℃ of insulation crystallizatioies after 2 hours, then under ice-water bath stirring and crystallizing 5h.Suction filtration after crystallization, with a small amount of pure water drip washing filter cake, filter cake is placed in 55 ℃ of vacuum drying ovens and is dried to constant weight, obtains hydrochloric acid Erlotinib polymorphic form sample 0.88g, and purity is greater than 99.5%, and its XRD is shown in Fig. 1, and data represent as follows:
IR (seeing Fig. 2) atlas analysis is at 3258cm
-1, 1623cm
-1, 1570cm
-1, 1530cm
-1, 1514cm
-1, 1484cm
-1, 1465cm
-1, 1448cm
-1, 1432cm
-1, 1395cm
-1, 1371cm
-1, 1324cm
-1, 1280cm
-1, 1244cm
-1, 1213cm
-1there is charateristic avsorption band.
embodiment 2:
Hydrochloric acid Erlotinib 1g is stirred to whole dissolvings by the pure water 65ml reflux that hydrochloric acid is adjusted to pH5.5, stops heating, be cooled to 60～70 ℃ of insulation crystallizatioies after 2 hours, then under ice-water bath stirring and crystallizing 6h.Suction filtration after crystallization, with a small amount of pure water drip washing filter cake, filter cake is placed in 55 ℃ of vacuum drying ovens and is dried to constant weight.Obtain hydrochloric acid Erlotinib polymorphic form 0.85g, purity is greater than 99.7%, and its XRD is shown in Fig. 3, and data represent as follows:
IR (seeing Fig. 4) atlas analysis is at 3258cm
-1, 1623cm
-1, 1570cm
-1, 1530cm
-1, 1514cm
-1, 1484cm
-1, 1465cm
-1, 1448cm
-1, 1432cm
-1, 1395cm
-1, 1371cm
-1, 1324cm
-1, 1280cm
-1, 1244cm
-1, 1213cm
-1there is charateristic avsorption band.
embodiment 3:
Hydrochloric acid Erlotinib 1g is stirred to whole dissolvings by the pure water 70ml reflux that hydrochloric acid is adjusted to pH6.0, stops heating, be cooled to 60～70 ℃ of insulation crystallizatioies after 2 hours, then under ice-water bath stirring and crystallizing 4h.Suction filtration after crystallization, with a small amount of pure water drip washing filter cake, filter cake is placed in 55 ℃ of vacuum drying ovens and is dried to constant weight.Obtain hydrochloric acid Erlotinib polymorphic form 0.89g, purity is greater than 99.9%, and its XRD is shown in Fig. 5, and data represent as follows:
IR (seeing Fig. 6) atlas analysis is at 3258cm
-1, 1623cm
-1, 1570cm
-1, 1530cm
-1, 1514 cm
-1, 1484cm
-1, 1465cm
-1, 1448cm
-1, 1432cm
-1, 1395cm
-1, 1371cm
-1, 1324cm
-1, 1280cm
-1, 1244cm
-1, 1213cm
-1there is charateristic avsorption band.
Claims (9)
1. an erlotinid hydrochloride polymorphic form, is characterized in that, its X-ray powder diffraction collection of illustrative plates 2 θ (°) there is diffraction peak at 5.6 places, and there is no diffraction peak between 6～10.
2. a kind of erlotinid hydrochloride polymorphic form as claimed in claim 1, is characterized in that, its X-ray powder diffraction collection of illustrative plates 2 θ (°) be 5.6,10.4,11.0,11.3, there is diffraction peak at 21.2,24.5,26.9 places.
3. a kind of erlotinid hydrochloride polymorphic form as claimed in claim 1, is characterized in that, its X-ray powder diffraction collection of illustrative plates 2 θ (°) be 5.6,10.4,10.6,11.0,11.3,14.9,17.0,17.4,19.1,19.7,21.2,23.4,24.5, there is diffraction peak at 26.9,26.9,28.7 places.
4. a kind of erlotinid hydrochloride polymorphic form as claimed in claim 1, is characterized in that, infared spectrum is at 3258cm
-1, 1623cm
-1, 1570cm
-1, 1530cm
-1, 1514cm
-1, 1484cm
-1, 1465cm
-1, 1448cm
-1, 1432cm
-1, 1395cm
-1, 1371cm
-1, 1324cm
-1, 1280cm
-1, 1244cm
-1, 1213cm
-1there is characteristic absorbance at place.
5. one kind as claim 1, the preparation method of the erlotinid hydrochloride polymorphic form described in 2,3 or 4, it is characterized in that, its step is that hydrochloric acid Erlotinib and pure water are mixed, and is heated to dissolve, insulation, cooling and stirring crystallization, this crystal is hydrochloric acid Erlotinib polymorphic form.
6. the preparation method of erlotinid hydrochloride polymorphic form as claimed in claim 5, is characterized in that, the amount of pure water used is 1～200 times of hydrochloric acid Erlotinib quality.
7. the preparation method of erlotinid hydrochloride polymorphic form as claimed in claim 6, is characterized in that, the amount of pure water used is 55～70 times of hydrochloric acid Erlotinib quality.
8. the preparation method of erlotinid hydrochloride polymorphic form as claimed in claim 5, is characterized in that, the pH value of pure water is adjusted to 4.5～7.0 with hydrochloric acid.
9. the preparation method of erlotinid hydrochloride polymorphic form as claimed in claim 8, is characterized in that, the pH value of pure water is adjusted to 5.0～6.0 with hydrochloric acid.
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| CN201210442310.XA CN103772298A (en) | 2012-10-25 | 2012-10-25 | Erlotinib hydrochloride polymorphic substance and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007060691A2 (en) * | 2005-11-23 | 2007-05-31 | Natco Pharma Limited | A novel process for the preparation of erlotinib |
| WO2008122776A2 (en) * | 2007-04-04 | 2008-10-16 | Cipla Limited | Process for preparation of erlotinib and its pharmaceutically acceptable salts |
| CN101735156A (en) * | 2008-11-20 | 2010-06-16 | 上海医药工业研究院 | Poly-crystal L of erlotinib hydrochloride, preparation method and application thereof |
| CN101987834A (en) * | 2010-06-13 | 2011-03-23 | 博瑞生物医药技术(苏州)有限公司 | Novel erlotinib hydrochloride of crystalline form, preparation method and pharmaceutical application thereof |
-
2012
- 2012-10-25 CN CN201210442310.XA patent/CN103772298A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007060691A2 (en) * | 2005-11-23 | 2007-05-31 | Natco Pharma Limited | A novel process for the preparation of erlotinib |
| WO2008122776A2 (en) * | 2007-04-04 | 2008-10-16 | Cipla Limited | Process for preparation of erlotinib and its pharmaceutically acceptable salts |
| CN101735156A (en) * | 2008-11-20 | 2010-06-16 | 上海医药工业研究院 | Poly-crystal L of erlotinib hydrochloride, preparation method and application thereof |
| CN101987834A (en) * | 2010-06-13 | 2011-03-23 | 博瑞生物医药技术(苏州)有限公司 | Novel erlotinib hydrochloride of crystalline form, preparation method and pharmaceutical application thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Application publication date: 20140507 |
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