CN103896786B - The crystal formation of Tamoxifen Citrate and the preparation method of crystal form A - Google Patents
The crystal formation of Tamoxifen Citrate and the preparation method of crystal form A Download PDFInfo
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- CN103896786B CN103896786B CN201410069629.1A CN201410069629A CN103896786B CN 103896786 B CN103896786 B CN 103896786B CN 201410069629 A CN201410069629 A CN 201410069629A CN 103896786 B CN103896786 B CN 103896786B
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Abstract
The invention discloses the method that (Z)-N, N-dimethyl-2-[4-(1,2-phenylbenzene-1-butylene base) phenoxy group] two kinds of crystal formations of-ethamine citrate and the preparation method of crystal form A and crystal form B are converted into crystal form A.Invention further provides the difference of two kinds of crystal formation infrared signature absorption peaks: the infrared absorption of crystal form A is at 1700-1750cm
-1only has a charateristic avsorption band; And the infrared absorption of crystal form B is at 1700-1750cm
-1there are two charateristic avsorption bands at place, and at 3400cm
-1left and right also existing characteristics absorption peak, and both other charateristic avsorption bands are substantially identical.
Description
The application is the applying date is on May 21st, 2009, and application number is 200910118404.X, and denomination of invention is the divisional application of the application of the crystal formation of Tamoxifen Citrate and the preparation method of crystal form A.
Technical field
The invention belongs to medicinal chemistry art, be specifically related to two kinds of crystal form As and the B of Tamoxifen Citrate, the preparation method of crystal form A, and crystal form B is converted into the method for crystal form A.
Background technology
Tamoxifen Citrate (TamoxifenCitrate), its chemistry is by name: (Z)-N, N-dimethyl-2-[4-(1,2-phenylbenzene-1-butylene base) phenoxy group]-ethamine citrate.
Chemical structural formula:
Tamoxifen is non-steroid antiestrogen, and its structure is similar to oestrogenic hormon, there are Z and E type two isomer.Both physicochemical property are different, and physiologically active is also different, and E type has weak estrogen activity, and Z-type then has estrogenic antagonist.
If there is estrogen receptor (ER) in breast cancer cell, then oestrogenic hormon enters in tumour cell, with its combination, impels the synthesis of DNA and m-RNA of tumour cell, Tumor Cell Growth Stimulated.And tamoxifen Z-type isomer enters in cell, with ER competition binding, form receptor complex, stop the performance of estrogen effect, thus suppress the propagation of breast cancer cell.
Tamoxifen Citrate now goes on the market at home, abroad, is used for the treatment of women's recurrent and metastatic breast cancer; As the assisting therapy shifted after mammary cancer surgery, prevention of recurrence.According to related data, the existing two kinds of crystal formations of Tamoxifen Citrate, according to Infrared spectroscopy, crystal form A is at 1700-1750cm
-1only have a charateristic avsorption band, crystal form B is at 1700-1750cm
-1there are two charateristic avsorption bands at place, and at 3400cm
-1both can be made a distinction by left and right also existing characteristics absorption peak.Wherein the Tamoxifen Citrate ir data of domestic production requires to coincide (Chinese Pharmacopoeia 2005) with crystal form B, and this product infrared spectra data demand produced in USA and crystal form A coincide (USP30-NF25).The present invention is devoted to the research of Tamoxifen Citrate crystal form A, finally obtains the preparation method of reliable and stable crystal form A, and is converted into the method for crystal form A by crystal form B, achieves the Tamoxifen Citrate outlet U.S. of domestic production.
Summary of the invention
Object of the present invention provides the crystal formation of two kinds of Tamoxifen Citrates.
The crystal formation of the first Tamoxifen Citrate disclosed by the invention, this crystal formation is named as A type, this crystal through infrared analysis at 1700-1750cm
-1place has can distinguish itself and B crystal form the unique features absorption peak come, and sees Fig. 1.
The crystal formation of the second Tamoxifen Citrate disclosed by the invention, this crystal formation is named as Type B, this crystal through infrared analysis at 1700-1750cm
-1, 3400cm
-1left and right place has can distinguish itself and A crystal formation the charateristic avsorption band come, and sees Fig. 2.
Another object of the present invention is the preparation method disclosing Tamoxifen Citrate crystal form A.
The preparation method of Tamoxifen Citrate crystal form A of the present invention, its process comprises: by amount of substance ratio be 1: 2 ~ 2: 1 Citric Acid and tamoxifen to be dissolved in mass volume ratio (grams per milliliter) be respectively in the solvent of 1: 5 ~ 1: 30, mixing Citric Acid and tamoxifen solution, and adding the crystal seed of 0 ~ 5%, water bath heat preservation stirs, and holding temperature is 20 ~ 50 DEG C, stir 0 ~ 60 minute, filter, the lower 43 DEG C of dryings of normal pressure 6 hours, obtain A N-type waferN.
The amount of substance ratio of above-mentioned Citric Acid and tamoxifen is 1: 1, the mass volume ratio (grams per milliliter) of Citric Acid and tamoxifen and solvent is all 1: 20, crystallization holding temperature is 40 DEG C, crystal seed is 0.5%, and churning time is 50 minutes, wherein, solvent is methyl alcohol, ethanol, acetone, in ether one or several.
Another object of the present invention discloses the method that the method Tamoxifen Citrate crystal form B of the present invention being converted into crystal form A by Tamoxifen Citrate crystal form B is converted into crystal form A, its process comprises: it is in the solvent of 1: 5 ~ 1: 100 that Type B crystal is dissolved in mass volume ratio (grams per milliliter), heating for dissolving, add the crystal seed of 0 ~ 5%, recrystallization temperature is 0 ~ 50 DEG C, filter, the lower 43 DEG C of dryings of normal pressure 6 hours, obtain A N-type waferN.
The mass volume ratio (grams per milliliter) of above-mentioned Type B crystal and solvent is 1: 50, and crystal seed is 0.5%, and recrystallization temperature is 15 DEG C, and wherein, solvent is methyl alcohol, ethanol, acetone, in ether one or several.
Accompanying drawing explanation
Fig. 1 is the A crystal formation infrared absorpting light spectra of the embodiment of the present invention 1 Tamoxifen Citrate.
Fig. 2 is the B crystal form infrared absorpting light spectra of the embodiment of the present invention 2 Tamoxifen Citrate.
Fig. 3 is the A crystal formation infrared absorpting light spectra of the embodiment of the present invention 2 Tamoxifen Citrate.
Embodiment
Embodiment 1
21g Citric Acid is placed in 2000ml there-necked flask, adds 420ml methyl alcohol, be stirred to dissolving in 40 DEG C of heating in water bath; 35.3g tamoxifen is placed in 1000ml beaker simultaneously, adds 700.6ml methyl alcohol, be stirred to dissolving in 40 DEG C of heating in water bath.By above two reaction solutions mixing, and add 281.5mg crystal seed, water bath heat preservation 40 DEG C stirs 50 minutes, and filter, the lower 43 DEG C of dryings of normal pressure 6 hours, obtain crystalline powder.Measure this powder infrared spectrogram, according to infrared absorption spectrum, what obviously generate is crystal form A.
Embodiment 2
The B crystal form (see Fig. 2) of 20g Tamoxifen Citrate is placed in 2000ml there-necked flask, adds 1000ml ethanol, heated and stirred, to dissolving, adds 100mg crystal seed, 15 DEG C of crystallizatioies, and filter, the lower 43 DEG C of dryings of normal pressure 6 hours, obtain crystalline powder.Measure this powder infrared spectrogram, according to infrared absorption spectrum, what obviously generate is crystal form A, sees Fig. 3
The foregoing is only a specific embodiment of the present invention, this embodiment does not only produce any constraint to the present invention as explanation.
Claims (4)
1. the preparation method of the crystal form A of a Tamoxifen Citrate, its process comprises: it is in the solvent of 1: 50 that Type B crystal is dissolved in mass volume ratio, heating for dissolving, add the crystal seed of 0 ~ 5%, 15 DEG C of crystallizatioies, filter, the lower 43 DEG C of dryings of normal pressure 6 hours, A N-type waferN, wherein said solvent be in methyl alcohol, ethanol, acetone, ether one or several, the ratio of described quality volume is the ratio of grams per milliliter.
2. method according to claim 1, is characterized in that: the mass volume ratio of Type B crystal and solvent is 1: 50, and crystal seed is 0.5%, and recrystallization temperature is 15 DEG C.
3. the preparation method of the crystal form A of a kind of Tamoxifen Citrate according to claim 1 and 2, said crystal seed is Tamoxifen Citrate crystal form A standard substance, and the ratio of all quality volumes is all the ratio of grams per milliliter.
4. preparation method according to claim 1, is characterized in that: the B crystal form of 20g Tamoxifen Citrate is placed in 2000ml there-necked flask, adds 1000ml ethanol, heated and stirred, to dissolving, adds 100mg crystal seed, 15 DEG C of crystallizatioies, filter, the lower 43 DEG C of dryings of normal pressure 6 hours, obtain crystalline powder.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910118404.XA CN101891635B (en) | 2009-05-21 | 2009-05-21 | Crystal forms of citric acid nolvadex and preparation method of crystal form A |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910118404.XA Division CN101891635B (en) | 2009-05-21 | 2009-05-21 | Crystal forms of citric acid nolvadex and preparation method of crystal form A |
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| Publication Number | Publication Date |
|---|---|
| CN103896786A CN103896786A (en) | 2014-07-02 |
| CN103896786B true CN103896786B (en) | 2015-11-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410069629.1A Active CN103896786B (en) | 2009-05-21 | 2009-05-21 | The crystal formation of Tamoxifen Citrate and the preparation method of crystal form A |
| CN200910118404.XA Active CN101891635B (en) | 2009-05-21 | 2009-05-21 | Crystal forms of citric acid nolvadex and preparation method of crystal form A |
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| Application Number | Title | Priority Date | Filing Date |
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| CN200910118404.XA Active CN101891635B (en) | 2009-05-21 | 2009-05-21 | Crystal forms of citric acid nolvadex and preparation method of crystal form A |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109293519B (en) * | 2017-07-25 | 2021-09-28 | 北京斯利安药业有限公司 | Preparation method of tamoxifen citrate crystal form A |
| AU2018329202B2 (en) | 2017-09-11 | 2022-10-27 | Atossa Therapeutics, Inc. | Methods for making and using endoxifen |
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2009
- 2009-05-21 CN CN201410069629.1A patent/CN103896786B/en active Active
- 2009-05-21 CN CN200910118404.XA patent/CN101891635B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| Polymorphs of Tamoxifen Citrate: Detailed Structural Characterization of the Stable Form;ISRAEL GOLDBERG et al.;《Journal of Pharmaceutical Sciences》;19870331;第76卷(第3期);第259-264页 * |
| 苏德森等.第七节 药物的多晶型转变与无定型.《物理药剂学》.2004,第33-35页. * |
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| Publication number | Publication date |
|---|---|
| CN101891635A (en) | 2010-11-24 |
| CN103896786A (en) | 2014-07-02 |
| CN101891635B (en) | 2014-06-04 |
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