CN104744445A - Crystal form of tyrosine kinase inhibitor - Google Patents
Crystal form of tyrosine kinase inhibitor Download PDFInfo
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- CN104744445A CN104744445A CN201410839991.2A CN201410839991A CN104744445A CN 104744445 A CN104744445 A CN 104744445A CN 201410839991 A CN201410839991 A CN 201410839991A CN 104744445 A CN104744445 A CN 104744445A
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- crystal formation
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- maleate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a crystal form of a tyrosine kinase inhibitor, relating to a new crystal form of an Afatinib bimaleate medicament for treating non-small cell lung cancer, as well as a preparation method and a pharmaceutical composition and the like thereof, a peak appears at the 2theta of 5.45 degrees in an X-ray powder diffraction pattern of the new crystal form, and the relative intensity is greater than 90%; and the crystal form has the physicochemical properties of good mobile phase, low hygroscopicity and the like, and can be used for a pharmaceutical preparation.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to crystal formation that the medicine Ah method of Tyrosylprotein kinase can be suppressed for Buddhist nun and preparation method thereof.
Background technology
Ah method is for Buddhist nun's 2-maleate (Afatinib dimaleate), it is the irreversible inhibitor of EGF-R ELISA (EGFR) and human epidermal growth factor receptor 2 (HER2) Tyrosylprotein kinase, be approved for the diseases such as treatment advanced Non-small cell lung (NSCLC), its chemistry (2E)-4-by name [(the chloro-4-fluorophenyl of 3-) is amino]-6-{ [4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] is amino }-7-((S)-tetrahydrofuran (THF)-3-base oxygen base)-quinazoline 2-maleate; Its structure is such as formula shown in (1):
The document such as PCT application WO2005037824 and WO2013052157 discloses the multiple crystal formation such as crystal form A, crystal form B, purposes etc. of Ah method for Buddhist nun's 2-maleate; But crystal formation is the important factor affecting drug quality, huge difference may be there is in the different crystal forms of same medicine in the physico-chemical properties such as outward appearance, mobility, solubleness, stability in storage, thus the storage of medicine shifted, apply, stability, bioavailability, curative effect etc. have an impact; Therefore, in order to obtain effective crystal formation, need comprehensively to investigate, to be met the crystal formation of production requirement for the crystallization behavior of Buddhist nun's 2-maleate Ah method.
Summary of the invention
Summary of the invention
First aspect provides the crystal formation I of Ah method for Buddhist nun's 2-maleate.
Second aspect provides the preparation method of Ah method for the crystal formation I of Buddhist nun's 2-maleate.
The third aspect provides the application of the crystal formation I of Ah method for Buddhist nun's 2-maleate in the medicine of preparation treatment nonsmall-cell lung cancer.
Fourth aspect provides and comprises the pharmaceutical composition of Ah method for the crystal formation I of Buddhist nun's 2-maleate.
Term definition
" crystal formation " refers to ordered arrangement and/or the conformation of the uniqueness of the molecule of compound in lattice.
In the present invention, 2 θ values in X-ray powder diffraction pattern are all to spend (°) for unit.
X-ray powder diffraction " substantially as shown in the figure " to refer in X-ray powder diffraction pattern at least 90%, or at least 95%, or the peak display of at least 99% is in the drawings.
When " relative intensity " refers to that the intensity at the last the first peak in all diffraction peaks of X-ray powder diffraction pattern (XRPD) is 100%, the ratio of the intensity at the intensity at other peak and the last the first peak.
When mentioning spectrogram or/and when there are data in the drawings, " peak " refers to the feature that can not belong to background noise that those skilled in the art can identify.
" good solvent " refers in this solvent, Ah method is greater than 1 grams per liter for the solubleness of Buddhist nun's 2-maleate, or be greater than 2 grams per liters, or be greater than 3 grams per liters, or be greater than 4 grams per liters, or be greater than 5 grams per liters, or be greater than 6 grams per liters, or be greater than 7 grams per liters, or be greater than 8 grams per liters, or be greater than 9 grams per liters, or be greater than 10 grams per liters, or be greater than 15 grams per liters, or be greater than 20 grams per liters, or be greater than 30 grams per liters, or be greater than 40 grams per liters, or be greater than 50 grams per liters, or be greater than 60 grams per liters, or be greater than 70 grams per liters, or be greater than 80 grams per liters, or be greater than 90 grams per liters, or be greater than 100 grams per liters.
" poor solvent " refers to the solvent that can promote solution supersaturation and/or crystallization.In certain embodiments, Ah method is less than 0.001 grams per liter for the solubleness of Buddhist nun's 2-maleate in poor solvent, is less than 0.1 grams per liter, is less than 0.0 grams per liter, be less than 0.3 grams per liter, be less than 0.4 grams per liter, be less than 0.5 grams per liter, be less than 0.6 grams per liter, be less than 0.7 grams per liter, be less than 0.8 grams per liter, be less than 1 grams per liter, be less than 2 grams per liters, be less than 3 grams per liters, be less than 4 grams per liters, be less than 5 grams per liters, be less than 6 grams per liters, be less than 7 grams per liters, be less than 8 grams per liters, be less than 9 grams per liters, or be less than 10 grams per liters.
In certain embodiments, Ah method is greater than its solubleness in poor solvent for the solubleness of Buddhist nun's 2-maleate in good solvent, and therefore good solvent and poor solvent are comparatively speaking in system.In certain embodiments, with the solubleness in good solvent for calculating basis, Ah method differs about 10% for the solubleness of Buddhist nun's 2-maleate in good solvent and poor solvent, or 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90%.In certain embodiments, Ah method is approximately higher by 10% than the solubleness in poor solvent for the solubleness of Buddhist nun's 2-maleate in good solvent, or 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90%.
In the context of the present invention, when using or no matter whether use the wording such as " approximately " or " about ", represent that the numerical value of each numeral likely there will be the difference of 1%, 2%, 5%, 7%, 8% or 10%.
Detailed Description Of The Invention
First aspect, contriver is by having researched and developed the crystal formation I of Ah method for Buddhist nun's 2-maleate.
Have peak in the position that 2 θ are 5.45 degree in the X-ray powder diffraction pattern of Ah method for the crystal formation I of Buddhist nun's 2-maleate, its relative intensity is greater than 90%, or is greater than 99%, or is 100%.
In some embodiments, have peak in the position that 2 θ are 5.45 degree in the X-ray powder diffraction pattern of Ah method for the crystal formation I of Buddhist nun's 2-maleate, its relative intensity is greater than 99%.
In some embodiments, be 5.45,10.92 at 2 θ in the X-ray powder diffraction pattern of Ah method for the crystal formation I of Buddhist nun's 2-maleate, there is peak the position of 19.85 degree, wherein diffraction angle 2 θ is that the relative intensity at the peak of 5.45 degree is greater than 90%, or is greater than 99%, or is 100%.
In some embodiments, be 5.45,10.92 at 2 θ in the X-ray powder diffraction pattern of Ah method for the crystal formation I of Buddhist nun's 2-maleate, 19.85,22.05, there is peak the position of 25.57 degree, wherein diffraction angle 2 θ is that the relative intensity at the peak of 5.45 degree is greater than 90%, or is greater than 99%, or is 100%.
In some embodiments, Ah method is for being 5.45,10.92 at 2 θ in the X-ray powder diffraction pattern of Buddhist nun's 2-maleate crystal formation I, 11.39,17.52,19.85,22.05,25.57, there is peak the position of 26.14,27.93 degree, and wherein diffraction angle 2 θ is that the relative intensity at the peak of 5.45 degree is greater than 90%, or be greater than 99%, or be 100%.
In some embodiments, Ah method is for being 5.45,6.22 at 2 θ in the X-ray powder diffraction pattern of Buddhist nun's 2-maleate crystal formation I, 7.32,10.92,11.39,13.05,14.92,17.52,19.85,22.05,25.57, there is peak one place or the many places of the position of 26.14,27.93 degree, and wherein diffraction angle 2 θ is that the relative intensity at the peak of 5.45 degree is greater than 90%, or be greater than 99%, or be 100%.
In some embodiments, Ah method is for being 5.45,6.22,7.32 at 2 θ in the X-ray powder diffraction pattern of Buddhist nun's 2-maleate crystal formation I, 10.92,11.39,13.05,14.92,16.82,17.52,19.85,22.05,25.57,26.14,27.93, there is peak a place or the many places of the position of 29.64 degree, wherein diffraction angle 2 θ is that the relative intensity at the peak of 5.45 degree is greater than 90%, or is greater than 99%, or is 100%.
In some embodiments, Ah method for Buddhist nun's 2-maleate crystal formation I X-ray powder diffraction pattern substantially as shown in Figure 1, wherein diffraction angle 2 θ is that the relative intensity at the peak of 5.45 degree is greater than 90%, or is greater than 99%, or is 100%.
Ah method can also otherwise characterize for Buddhist nun's 2-maleate crystal formation I, such as, in some embodiments, has weightlessness, weightless 4.41% in the thermogravimetric analysis (TGA) of Ah method for the crystal formation I of Buddhist nun's 2-maleate between 50 DEG C-125 DEG C; In certain embodiments, its TGA as shown in Figure 2.
The X-ray powder diffraction peak of described crystal formation, 2 θ of its X-ray powder diffraction or diffraction peak measured experimental error, between a machine and another machine and between a sample and another sample, measuring of 2 θ of X-ray powder diffraction or diffraction peak may slightly difference, the numerical value of described experimental error or difference may be about +/-0.2 unit, or about +/-0.1 unit, therefore the numerical value of described 2 θ or diffraction peak can not be considered as absolute.
The thermogravimetric analysis (TGA) of described crystal formation has experimental error, between a machine and another machine and between a sample and another sample, weightless temperature and weightless amount may slightly difference, the numerical value of experimental error or difference may be about +/-0.1 unit, about +/-0.05 unit, or approximately +/-0.01 unit, therefore the numerical value of described weightless temperature and weightless amount can not be considered as absolute.
Through observing, Ah method provided by the invention has good mobility, prevented from caking for the crystal formation I of Buddhist nun's 2-maleate, is easy to transfer; On the other hand, crystal formation I also has and lower draws moist, is conducive to operating in production technique, can be used for pharmaceutical preparation.
Second aspect, additionally provides the preparation method of described Ah method for Buddhist nun's 2-maleate crystal formation I here.
A kind of Ah method of preparation comprises for the method for Buddhist nun's 2-maleate crystal formation I: be dissolved in good solvent by Ah method for Buddhist nun's 2-maleate, cooling, and crystallize out is collected crystal, except desolventizing, obtained product.
In some embodiments, be dissolved in good solvent described in and comprise heating for dissolving in good solvent; Described Heating temperature is the arbitrary value of room temperature to the reflux temperature of solvent; In some embodiments, Ah method is dissolved in good solvent for Buddhist nun's 2-maleate by reflux.
In some embodiments, described cooling also comprises and adds poor solvent.
Described good solvent is selected from: alcoholic solvent, ketones solvent, esters solvent, alkane solvents, ether solvent, DMF, water, or its combination; Described alcoholic solvent is selected from methyl alcohol, ethanol, its combination; Described ketones solvent is selected from acetone, butanone, its combination; Described esters solvent is selected from ethyl acetate, isopropyl acetate or its combination; Described alkane solvents is selected from methylene dichloride, trichloromethane, toluene or its combination; Described ether solvent is selected from tetrahydrofuran (THF), dioxane or its combination.
Described cooling refers to temperature to be comparatively low to moderate crystallize out temperature, in some embodiments, temperature is reduced to 30 DEG C-subzero 5 DEG C; In some embodiments, temperature is reduced to 25 DEG C-15 DEG C; In some embodiments, temperature is reduced to 25 DEG C-20 DEG C; In some embodiments, temperature is reduced to 15 DEG C-5 DEG C; In some embodiments, temperature is reduced to 5 DEG C-subzero 5 DEG C; In some embodiments, temperature is reduced to-5 DEG C-0 DEG C.
In some embodiments, Ah method is dissolved in methylene dichloride for Buddhist nun's 2-maleate reflux, is then cooled to 25 DEG C-20 DEG C, crystallize out, except desolventizing, obtains crystal formation I.
In some embodiments, be dissolved in methylene dichloride by Ah method for Buddhist nun's 2-maleate reflux, be then cooled to 25 DEG C-20 DEG C, crystallize out, then solid-liquid separation, 12 hours-18 hours air-dry solvents placed in atmosphere by gained solid, obtain crystal formation I.
The third aspect, this provides the application of the crystal formation I of Ah method for Buddhist nun's 2-maleate in the medicine of preparation treatment nonsmall-cell lung cancer.
Fourth aspect, this provides and comprises the pharmaceutical composition of Ah method for the crystal formation I of Buddhist nun's 2-maleate.
Described Ah method can mix with the pharmaceutically acceptable inert excipient of at least one or carrier for Buddhist nun's 2-maleate crystal formation I, is prepared into the various solid dosages of oral pharmaceutical, comprises capsule, tablet etc.; Solid dispersion etc. can also be prepared into various vehicle or carrier, then be prepared into various solid preparation.
In some embodiments, described inert excipient or carrier comprise Microcrystalline Cellulose, lactose or polyvidone.
In some embodiments, Ah method contains Magnesium Stearate for the pharmaceutical composition of the crystal formation I of Buddhist nun's 2-maleate.
In some embodiments, Ah method contains colloid silica for the pharmaceutical composition of the crystal formation I of Buddhist nun's 2-maleate.
Ah method accounts for about 0.1% to 99.5% for the treatment significant quantity weight percent of Buddhist nun's 2-maleate crystal formation I at whole mixture, in certain embodiments for the weight percent of about 0.5% to 95% weight is present in said medicine preparation.
Accompanying drawing explanation
Fig. 1 shows the X-ray powder diffraction pattern (XRPD) of Ah method for the crystal formation I of Buddhist nun's 2-maleate;
Fig. 2 shows the TGA figure of Ah method for the crystal formation I of Buddhist nun's 2-maleate.
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
In the present invention, g represents gram, and mL represents milliliter.
In the present invention, X-ray powder diffraction testing conditions is: INSTRUMENT MODEL: PANalytical Empyrean; Cu target k α, wavelength
sweep limit: 3 °-40 °; In X-ray powder diffraction pattern, ordinate zou is the diffracted intensity (Intensity) represented with counting (counts), and X-coordinate is diffraction angle 2 θ (2Theta) that expenditure (°) represents.
Thermogravimetric analysis (TGA) testing conditions is: INSTRUMENT MODEL: TA Q500; Under nitrogen atmosphere, with 10 DEG C/min of intensifications, temperature range is 25 DEG C to 300 DEG C.
Embodiment 1
1.0g Ah method is joined in 8mL methylene dichloride for Buddhist nun's 2-maleate, 40 DEG C are heated 45 minutes, slow cooling to 23 DEG C, be incubated 23 DEG C-20 DEG C and stir filtration after 30 minutes, 12 hours-18 hours air-dry solvents placed in atmosphere by filter cake, obtain product 0.86g, its XRPD figure, TGA figure is shown in Fig. 1, Fig. 2, called after crystal formation I respectively.
Embodiment 2
To get the lactose and Microcrystalline Cellulose that partly mix in advance, add Ah method for Buddhist nun's 2-maleate crystal formation I, add suitable quantity of water, mixing, sieves; Then add polyvidone, add suitable quantity of water, mixing, sieves, and mixes 30 minutes further, 60 DEG C of dryings; Then Magnesium Stearate is added, colloid silica, mixing; Then by mixture compressing tablet, dressing.
Capsule forms
Embodiment 3
Draw moist test:
According to the regulation of existing Chinese Pharmacopoeia, contrived experiment, investigates drawing of crystal formation I moist; Result shows that drawing of crystal formation I is moist extremely low, as shown in table 1 below:
Table 1: crystal formation I draws moist investigation result
Test result: drawing of crystal formation I is moist lower.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (10)
1. Ah method is for the crystal formation I of Buddhist nun's 2-maleate, is 5.45,10.92 at 2 θ in the X-ray powder diffraction pattern of described crystal formation I, 19.85,22.05, there is peak the position of 25.57 degree, wherein diffraction angle 2 θ is that the relative intensity at the peak of 5.45 degree is greater than 90%, or is greater than 99%, or is 100%.
2. crystal formation I according to claim 1 is 5.45,10.92 at 2 θ in its X-ray powder diffraction pattern, 11.39,17.52,19.85,22.05,25.57,26.14, and there is peak the position of 27.93 degree.
3. crystal formation I according to claim 1 is 5.45,6.22 at 2 θ in its X-ray powder diffraction pattern, 7.32,10.92,11.39,13.05,14.92,17.52,19.85,22.05,25.57,26.14, and there is peak the position of 27.93 degree.
4. crystal formation I according to claim 1 is 5.45,6.22 at 2 θ in its X-ray powder diffraction pattern, 7.32,10.92,11.39,13.05,14.92,16.82,17.52,19.85,22.05,25.57,26.14,27.93, and there is peak the position of 29.64 degree.
5. crystal formation I according to claim 1, substantially as shown in Figure 1, wherein diffraction angle 2 θ is that the relative intensity at the peak of 5.45 degree is greater than 90% to its X-ray powder diffraction pattern, or is greater than 99%, or is 100%.
6. the arbitrary described crystal formation I of claim 1-5, its thermogravimetric analysis has weightlessness between 50 DEG C-125 DEG C, and weightless 4.41%.
7. the arbitrary described crystal formation I of claim 1-5, its thermogravimetric analysis as shown in Figure 2.
8. the preparation method of the arbitrary described crystal formation I of claim 1-7, comprising: be dissolved in good solvent by Ah method for Buddhist nun's 2-maleate, be cooled to 30 DEG C-subzero 5 DEG C, crystallize out, collects crystal, except desolventizing, obtain product.
9. preparation method according to claim 8, described good solvent is selected from: alcoholic solvent, ketones solvent, esters solvent, alkane solvents, ether solvent, DMF, water, or its combination; Described alcoholic solvent is selected from methyl alcohol, ethanol or its combination; Described ketones solvent is selected from acetone, butanone or its combination; Described esters solvent is selected from ethyl acetate, isopropyl acetate or its combination; Described alkane solvents is selected from methylene dichloride, trichloromethane, toluene or its combination; Described ether solvent is selected from tetrahydrofuran (THF), dioxane or its combination.
10. preparation method according to claim 8, Ah method is dissolved in methylene dichloride for Buddhist nun's 2-maleate reflux, is then cooled to 25 DEG C-20 DEG C, crystallize out, then solid-liquid separation, 12 hours-18 hours air-dry solvents placed in atmosphere by gained solid, obtain crystal formation I product.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410839991.2A CN104744445A (en) | 2013-12-30 | 2014-12-29 | Crystal form of tyrosine kinase inhibitor |
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| CN2013107510053 | 2013-12-30 | ||
| CN201310751005 | 2013-12-30 | ||
| CN201410839991.2A CN104744445A (en) | 2013-12-30 | 2014-12-29 | Crystal form of tyrosine kinase inhibitor |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016051380A1 (en) * | 2014-10-01 | 2016-04-07 | Sun Pharmaceutical Industries Limited | Crystalline form of afatinib dimaleate |
| CN105669658A (en) * | 2016-04-05 | 2016-06-15 | 北京民康百草医药科技有限公司 | Refinement method of afatinib |
| WO2016166720A3 (en) * | 2015-04-17 | 2017-02-02 | Hetero Research Foundation | Polymorphs of afatinib and its salts and process for the preparation of quinazolinyl derivatives |
| WO2016199076A3 (en) * | 2015-06-12 | 2017-03-09 | Fresenius Kabi Oncology Ltd. | Polymorphic forms of afatinib free base and afatinib dimaleate |
| WO2017093789A1 (en) * | 2015-12-03 | 2017-06-08 | Mylan Laboratories Ltd. | Polymorphic forms of afatinib dimaleate |
| CN109824657A (en) * | 2019-03-26 | 2019-05-31 | 石药集团中奇制药技术（石家庄）有限公司 | Two maleic acid Afatinib novel crystal forms of one kind and its preparation method and application |
| US10525059B2 (en) | 2015-08-21 | 2020-01-07 | Fresenius Kabi Oncology, Ltd. | Pharmaceutical compositions comprising Afatinib |
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| CN101402631A (en) * | 2003-10-17 | 2009-04-08 | 贝林格尔.英格海姆国际有限公司 | Amino quinazoline 2-maleate, production method and uses thereof |
| WO2013052157A1 (en) * | 2011-10-06 | 2013-04-11 | Ratiopharm Gmbh | Crystalline forms of afatinib di-maleate |
| CN103476770A (en) * | 2010-11-25 | 2013-12-25 | 拉蒂欧制药有限责任公司 | Novel salts and polymorphic forms of afatinib |
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| CN101402631A (en) * | 2003-10-17 | 2009-04-08 | 贝林格尔.英格海姆国际有限公司 | Amino quinazoline 2-maleate, production method and uses thereof |
| CN103476770A (en) * | 2010-11-25 | 2013-12-25 | 拉蒂欧制药有限责任公司 | Novel salts and polymorphic forms of afatinib |
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3201190A4 (en) * | 2014-10-01 | 2018-03-14 | Sun Pharmaceutical Industries Ltd | Crystalline form of afatinib dimaleate |
| WO2016051380A1 (en) * | 2014-10-01 | 2016-04-07 | Sun Pharmaceutical Industries Limited | Crystalline form of afatinib dimaleate |
| US10011591B2 (en) | 2014-10-01 | 2018-07-03 | Sun Pharmaceutical Industries Limited | Crystalline form of afatinib dimaleate |
| US10329281B2 (en) | 2015-04-17 | 2019-06-25 | Hetero Labs Ltd | Polymorphs and process for the preparation of quinazolinyl derivatives |
| WO2016166720A3 (en) * | 2015-04-17 | 2017-02-02 | Hetero Research Foundation | Polymorphs of afatinib and its salts and process for the preparation of quinazolinyl derivatives |
| WO2016199076A3 (en) * | 2015-06-12 | 2017-03-09 | Fresenius Kabi Oncology Ltd. | Polymorphic forms of afatinib free base and afatinib dimaleate |
| US10800763B2 (en) | 2015-06-12 | 2020-10-13 | Fresenius Kabi Oncology Ltd. | Polymorphic forms of Afatinib free base and Afatinib dimaleate |
| US11390612B2 (en) | 2015-06-12 | 2022-07-19 | Fresenius Kabi Oncology Ltd. | Polymorphic forms of Afatinib free base and Afatinib dimaleate |
| US10525059B2 (en) | 2015-08-21 | 2020-01-07 | Fresenius Kabi Oncology, Ltd. | Pharmaceutical compositions comprising Afatinib |
| US11883403B2 (en) | 2015-08-21 | 2024-01-30 | Fresenius Kabi Oncology Ltd. | Pharmaceutical compositions comprising Afatinib |
| WO2017093789A1 (en) * | 2015-12-03 | 2017-06-08 | Mylan Laboratories Ltd. | Polymorphic forms of afatinib dimaleate |
| CN105669658B (en) * | 2016-04-05 | 2018-06-29 | 北京民康百草医药科技有限公司 | A kind of process for purification of Afatinib |
| CN105669658A (en) * | 2016-04-05 | 2016-06-15 | 北京民康百草医药科技有限公司 | Refinement method of afatinib |
| CN109824657A (en) * | 2019-03-26 | 2019-05-31 | 石药集团中奇制药技术（石家庄）有限公司 | Two maleic acid Afatinib novel crystal forms of one kind and its preparation method and application |
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