CN103864664A - Bazedoxifene acetate new crystal form and preparation method thereof - Google Patents
Bazedoxifene acetate new crystal form and preparation method thereof Download PDFInfo
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- CN103864664A CN103864664A CN201210549315.2A CN201210549315A CN103864664A CN 103864664 A CN103864664 A CN 103864664A CN 201210549315 A CN201210549315 A CN 201210549315A CN 103864664 A CN103864664 A CN 103864664A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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Abstract
The invention relates to the crystal form (E type) a selective estrogen acceptor conditioning agent 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-benzyl)-3-methyl-1H-indol-5-ol monoacetate (bazedoxifene acetate), and preparation method of the E-type crystal and application of the E-type crystal to medicine preparation.
Description
Technical field
The present invention relates to new crystal (E type) of a kind of medicine BZA and preparation method thereof and the application in pharmacy, belong to medical technical field.
Technical background
Chemistry 1-[4-(2-azepan-1-base-oxyethyl group)-benzyl by name of BZA]-2-(4-hydroxyl-phenyl)-3-Methyl-1H-indole-5-phenol acetic acid, structural formula is suc as formula shown in [I].
It belongs to a class medicine of selective estrogen receptor modulators.Conform to its classification, WAY 140424 demonstrates the avidity for estrogen receptor, and demonstrates the estrogen effect of tissue selectivity.In the preclinical models stimulating in uterus at BZA, demonstrate stimulation little or that do not demonstrate uterus reaction.BZA prevents bone mass loss and reduces the effect that demonstrates estrogen agonist class aspect cholesterol in osteopenic ovariectomized mouse model on the contrary.In MCF-7 clone (people's breast cancer cell line), BZA has played estrogen antagonist.These data show that BZA is estrogenic and be antiestrogenic in uterus and breast tissue in bone and cardiovascular lipid parameter, and therefore it has the many various disease of estrogen receptor or the prospects of disease class situation of relating to for the treatment of.
In Chinese patent 101977897, having reported the preparation of BZA A crystal formation and having characterized DSC data is the salt of 176 DEG C; In Chinese patent 1938271, having reported the preparation of BZA B crystal formation and having characterized DSC data is the salt of 181 DEG C; In United States Patent (USP) 20100310870, having reported the preparation of BZA C crystal formation (amorphous) and having characterized DSC data is the salt of 190 DEG C; In world patent 2010151541, reported BZA D crystal formation preparation and to have characterized DSC data be the salt of 166 DEG C.
As everyone knows, the polymorphous form of the crystal of certain drug is often the determinative of following aspect: easiness, stability, solubleness, the stability of storage, the easiness that becomes agent and the property of medicine in vivo of the preparation of medicine.Thereby form when polycrystalline form wherein identical material composition and obtain the peculiar different thermodynamic behaviour of specific polycrystalline form and stability with different lattice arrangement crystallizations.A kind of different polymorph can due to have better solvability and/or better pharmacokinetics become in use preferably.
The present invention just provides the BZA crystal formation E of a kind of difference and existing bibliographical information.This stable crystal form is good, and water absorbability is low, is applicable to make various stable pharmaceutical preparations.
Summary of the invention
The invention provides a kind of BZA E crystal formation, can identify by one or more solid-state analytical procedures.The powder x-ray diffraction data that for example it has.2 θ are 7.789,9.877, and 11.687,11.920,12.766,13.359,15.361,16.258,16.623,17.665,19.478,19.862,20.490,22.537,23.250,23.592,24.051,25.018,25.446,26.058,26.648,27.030,28.018,28.618,29.622 have charateristic avsorption band, as Fig. 4.
Also can identify E type by its dsc (DSC) figure.E type is by locating to show that at approximately 153 DEG C peaked DSC figure characterizes, as Fig. 6.
The E crystal formation of BZA can be prepared by the following method:
Get WAY 140424 free alkali, add in the large polar solvent of tetrahydrofuran (THF) and ethanol mixing, be stirred to dissolving, add WAY 140424 molar weight 0.5-5 acetic acid doubly, then add low polar solvent sherwood oil or hexanaphthene, stirring and crystallizing, suction filtration, vacuum-drying, obtains crystalline powder, by BZA and solvent for this powder, be heated to dissolve again, under dissolved state, maintain 0.5 hour, then naturally cooling crystallize out, filter, be dried to constant weight, obtain crystal formation E.Solvent carries out recrystallization.
Wherein large polar solvent is the mixing solutions that tetrahydrofuran (THF) and ethanol volume ratio are 1: 2 to 1: 10, preferably 1: 3.
Wherein recrystallization solvent is methyl alcohol, ethanol, acetone, butanone, ethanol carbinol mixture or acetone butanone mixture.
In crystallisation step, the mass volume ratio of BZA and solvent (grams per milliliter) is 1: 15-1: 100.
As the WAY 140424 bar acetate E crystal formation that above-mentioned steps obtained can be prepared into multiple oral or injection type with pharmaceutically acceptable auxiliary material as activeconstituents.
As the WAY 140424 bar acetate E crystal formation that above-mentioned steps obtained, can be for the preparation of regulating oestrogenic hormon and treating osteoporotic medicine.
Brief description of the drawings
Fig. 1: the HPLC figure of BZA crystal formation E of the present invention
Fig. 2: the HNMR figure of BZA crystal formation E of the present invention
Fig. 3: the MS figure of BZA crystal formation E of the present invention
Fig. 4: the X-ray powder diffraction figure of BZA crystal formation E of the present invention.
Fig. 5: the TGA curve of BZA crystal formation E of the present invention.
Fig. 6: dsc (DSC) figure of BZA crystal formation E of the present invention.
Embodiment
To explain more specifically technical scheme of the present invention below in conjunction with specific embodiment, but not limit protection scope of the present invention.
Embodiment 1: the preparation of BZA crystal formation E
Get WAY 140424 10g, add tetrahydrofuran (THF) 50ml, ethanol 100ml, is stirred to dissolving, add 1 gram of acetic acid, then add sherwood oil 150ml, stirring and crystallizing 4 hours, suction filtration obtains pale solid, and dry 12 hours of 40 DEG C, vacuum, obtains crystalline powder, add ethanol 200ml, heated and stirred is to refluxing, after 0.5 hour again, stop heating, naturally cooling, stirring and crystallizing 3 hours, suction filtration obtains pale solid, and dry 12 hours of 40 DEG C, vacuum, obtains crystalline powder.Measure through X-ray powder diffraction, show that the crystal formation generating is crystal formation E.
Embodiment 2: the preparation of BZA crystal formation E
Get WAY 140424 10g, add tetrahydrofuran (THF) 30ml, ethanol 300ml, is stirred to dissolving, add 1.5 grams of acetic acid, then add sherwood oil 150ml, stirring and crystallizing 4 hours, suction filtration obtains pale solid, and dry 12 hours of 40 DEG C, vacuum, obtains crystalline powder, add acetone 150ml, heated and stirred is to refluxing, after 0.5 hour again, stop heating, naturally cooling, stirring and crystallizing 3 hours, suction filtration obtains pale solid, and dry 12 hours of 40 DEG C, vacuum, obtains crystalline powder.Measure through X-ray powder diffraction, show that the crystal formation generating is crystal formation E.
Embodiment 3: the preparation of BZA crystal formation E
Get WAY 140424 10g, add tetrahydrofuran (THF) 40ml, ethanol 120ml, is stirred to dissolving, add 5 grams of acetic acid, then add sherwood oil 150ml, stirring and crystallizing 4 hours, suction filtration obtains pale solid, and dry 12 hours of 40 DEG C, vacuum, obtains crystalline powder, add acetone 200ml, heated and stirred is to refluxing, after 0.5 hour again, stop heating, naturally cooling, stirring and crystallizing 3 hours, suction filtration obtains pale solid, and dry 12 hours of 40 DEG C, vacuum, obtains crystalline powder.Measure through X-ray powder diffraction, show that the crystal formation generating is crystal formation E.
Embodiment 4: the preparation of BZA crystal formation E
Get WAY 140424 10g, add tetrahydrofuran (THF) 40ml, ethanol 120ml, is stirred to dissolving, add 1.5 grams of acetic acid, then add sherwood oil 150ml, stirring and crystallizing 4 hours, suction filtration obtains pale solid, and dry 12 hours of 40 DEG C, vacuum, obtains crystalline powder, add butanone 300ml, heated and stirred is to refluxing, after 0.5 hour again, stop heating, naturally cooling, stirring and crystallizing 3 hours, suction filtration obtains pale solid, and dry 12 hours of 40 DEG C, vacuum, obtains crystalline powder.Measure through X-ray powder diffraction, show that the crystal formation generating is crystal formation E.
Embodiment 5: the preparation of BZA crystal formation E
Get WAY 140424 10g, add tetrahydrofuran (THF) 50ml, ethanol 100ml, is stirred to dissolving, add 1.5 grams of acetic acid, then add sherwood oil 150ml, stirring and crystallizing 4 hours, suction filtration obtains pale solid, and dry 12 hours of 40 DEG C, vacuum, obtains crystalline powder, add methyl alcohol 500ml, heated and stirred is to refluxing, after 0.5 hour again, stop heating, naturally cooling, stirring and crystallizing 3 hours, suction filtration obtains pale solid, and dry 12 hours of 40 DEG C, vacuum, obtains crystalline powder.Measure through X-ray powder diffraction, show that the crystal formation generating is crystal formation E.
Embodiment 6: the preparation of BZA crystal formation E tablet
Tablet formulation:
Preparation technology:
It is 30 revs/min that above-mentioned materials is fully mixed to rear mixing machine speed, and mixing time is 15 minutes, and 30 orders are granulated, and 60 DEG C dry, and dried particles is crossed the whole grain of 30 eye mesh screens.The particle obtaining is mixed with 2g croscarmellose sodium, 1g Magnesium Stearate, and mixing machine speed is 10 revs/min, and mixing time is 20 minutes, compressing tablet.
Embodiment 6: the preparation of BZA crystal formation E capsule.
Tablet formulation:
After above-mentioned materials is fully mixed, wet granulation, encapsulating capsule.
Claims (12)
1. crystal formation E of a BZA (formula I) and preparation method thereof, is characterized in that: reflection angle 2 θ of the X-ray powder diffraction pattern of this crystal are 9.88,11.68,11.92,12.77,13.36,15.63,17.66,19.48,19.86,20.49,23.25 there is charateristic avsorption band
2. crystal formation E as claimed in claim 1: its X-diffracting spectrum as shown in Figure 4.
3. crystalline form E as claimed in claim 1, as shown in Figure 6, DSC tangential temperature is 153 DEG C to its dsc figure.
4. the preparation method of crystal formation E as claimed in claim 1, the steps include: to get WAY 140424 free alkali, add in the large polar solvent of tetrahydrofuran (THF) and ethanol mixing, be stirred to dissolving, add WAY 140424 molar weight 0.5-5 acetic acid doubly, add again low polar solvent sherwood oil or hexanaphthene, stirring and crystallizing, suction filtration, vacuum-drying, obtain crystalline powder, then this powder is carried out to recrystallization with solvent.
5. the preparation method of crystal formation E as claimed in claim 4, is characterized in that the mixing solutions that large polar solvent tetrahydrofuran (THF) and ethanol volume ratio are 1: 2 to 1: 10, preferably 1: 3.
6. the preparation method of crystal formation E as claimed in claim 4, the molar weight that it is characterized in that adding acetic acid is that the 0.5-5.0 of WAY 140424 molar weight doubly measures.
7. the preparation method of crystal formation E as claimed in claim 4, is characterized in that little polar solvent is sherwood oil or hexanaphthene.
8. the preparation method of crystal formation E as claimed in claim 4, is characterized in that re-crystallization step is BZA and solvent, is heated to dissolve, under dissolved state, maintain 0.5 hour, then naturally cooling crystallize out, filters, be dried to constant weight, obtain crystal formation E.
9. the preparation method of crystal formation E as claimed in claim 4, is characterized in that recrystallization solvent is methyl alcohol, ethanol, acetone, butanone, ethanol carbinol mixture or acetone butanone mixture.
10. the preparation method of crystal formation E as claimed in claim 4, is characterized in that in re-crystallization step, the mass volume ratio (grams per milliliter) of BZA and solvent is 1: 15-1: 100.
11. 1 kinds of drug regimens, is characterized in that it comprises crystal formation E claimed in claim 1 as activeconstituents and acceptable auxiliary material pharmaceutically.
The purposes of 12. crystal formation E claimed in claim 1, it is characterized in that can be for the preparation of estrogen regulating and osteosporosis resistant medicament.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201210549315.2A CN103864664A (en) | 2012-12-18 | 2012-12-18 | Bazedoxifene acetate new crystal form and preparation method thereof |
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| CN201210549315.2A CN103864664A (en) | 2012-12-18 | 2012-12-18 | Bazedoxifene acetate new crystal form and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370796A (en) * | 2014-11-21 | 2015-02-25 | 扬子江药业集团有限公司 | Preparation method of bazedoxifene acetate polycrystalline type B |
| CN105669518A (en) * | 2014-12-04 | 2016-06-15 | 上海医药集团股份有限公司 | Preparation method of bazedoxifene acetate and crystal form A |
| CN109851547A (en) * | 2018-12-27 | 2019-06-07 | 北京鑫开元医药科技有限公司 | A kind of Preparation method and use of bazedoxifene acetate Form D |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1938271A (en) * | 2004-04-07 | 2007-03-28 | 惠氏公司 | Crystalline polymorph of bazedoxifene acetate |
| WO2010151541A1 (en) * | 2009-06-23 | 2010-12-29 | Wyeth Llc | Polymorphic form d of bazedoxifene acetate and methods of preparing same |
| WO2012007451A1 (en) * | 2010-07-14 | 2012-01-19 | Sandoz Ag | Crystalline compound of 1-[4-(2-azepan-1-ylethoxy)benzyl]-2-(4-hydroxyphenyl)-3-methyl-1h-indol-5-ol and lactic acid |
| WO2012037187A2 (en) * | 2010-09-14 | 2012-03-22 | Dr. Reddy's Laboratories Ltd. | Preparation of crystalline bazedoxifene and its salts |
-
2012
- 2012-12-18 CN CN201210549315.2A patent/CN103864664A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1938271A (en) * | 2004-04-07 | 2007-03-28 | 惠氏公司 | Crystalline polymorph of bazedoxifene acetate |
| WO2010151541A1 (en) * | 2009-06-23 | 2010-12-29 | Wyeth Llc | Polymorphic form d of bazedoxifene acetate and methods of preparing same |
| WO2012007451A1 (en) * | 2010-07-14 | 2012-01-19 | Sandoz Ag | Crystalline compound of 1-[4-(2-azepan-1-ylethoxy)benzyl]-2-(4-hydroxyphenyl)-3-methyl-1h-indol-5-ol and lactic acid |
| WO2012037187A2 (en) * | 2010-09-14 | 2012-03-22 | Dr. Reddy's Laboratories Ltd. | Preparation of crystalline bazedoxifene and its salts |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370796A (en) * | 2014-11-21 | 2015-02-25 | 扬子江药业集团有限公司 | Preparation method of bazedoxifene acetate polycrystalline type B |
| CN104370796B (en) * | 2014-11-21 | 2016-09-14 | 扬子江药业集团有限公司 | A kind of preparation method of bazedoxifene acetate polymorph b |
| CN105669518A (en) * | 2014-12-04 | 2016-06-15 | 上海医药集团股份有限公司 | Preparation method of bazedoxifene acetate and crystal form A |
| CN109851547A (en) * | 2018-12-27 | 2019-06-07 | 北京鑫开元医药科技有限公司 | A kind of Preparation method and use of bazedoxifene acetate Form D |
| CN109851547B (en) * | 2018-12-27 | 2020-09-08 | 北京鑫开元医药科技有限公司 | Preparation method and application of bazedoxifene acetate crystal form D |
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Application publication date: 20140618 |