CN101891635B - Crystal forms of citric acid nolvadex and preparation method of crystal form A - Google Patents
Crystal forms of citric acid nolvadex and preparation method of crystal form A Download PDFInfo
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- CN101891635B CN101891635B CN200910118404.XA CN200910118404A CN101891635B CN 101891635 B CN101891635 B CN 101891635B CN 200910118404 A CN200910118404 A CN 200910118404A CN 101891635 B CN101891635 B CN 101891635B
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Abstract
The invention discloses two crystal forms of (Z)-N,N-dimethyl-2-[4-(1,2- diphenyl-1- butenyl) phenoxyl]-ethylamine citrate and a preparation method of crystal form A and a method for transforming a crystal form B to the crystal form A. The invention further provides difference of infrared characteristic absorption peaks of the two crystal forms, which is as follows: the infrared absorption of the crystal form A only has one characteristic peak at 1700-1750 cm <-1>; and the infrared absorption of the crystal form B has two characteristic peaks at 1700-1750 cm<-1>, the characteristic peaks also exist at about 3400 cm <-1>, and other characteristic peaks of the crystal form A and the crystal form B are basically identical.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, 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 (Tamoxifen Citrate), 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, has two isomer of Z and E type.Both physicochemical property are different, and physiologically active is also different, and E type has weak estrogen activity, and Z-type has estrogenic antagonist.
If there is estrogen receptor (ER) in breast cancer cell, oestrogenic hormon enters in tumour cell, with its combination, impels the DNA of tumour cell and synthesizing of m-RNA, Tumor Cell Growth Stimulated.And tamoxifen Z-type isomer enters in cell, with ER competition combination, form receptor complex, stop the performance of estrogen effect, thereby suppress the propagation of breast cancer cell.
Tamoxifen Citrate now at home, abroad listing, be used for the treatment of women's recurrent and metastatic breast cancer; As the assisting therapy shifting 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
-1also there is charateristic avsorption band in left and right, both can be made a distinction.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 identical (USP30-NF25).The present invention is devoted to the research of Tamoxifen Citrate crystal form A, has finally obtained the preparation method of reliable and stable crystal form A, and is converted into the method for crystal form A by crystal form B, has realized 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 the type into A, this crystal through infrared analysis at 1700-1750cm
-1place has and itself and B crystal formation can be distinguished to the unique charateristic avsorption band coming, 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 and itself and A crystal formation can be distinguished to the charateristic avsorption band coming, and sees Fig. 2.
Another object of the present invention is the preparation method who discloses Tamoxifen Citrate crystal form A.
The preparation method of Tamoxifen Citrate crystal form A of the present invention, its process comprises: be that to be dissolved in respectively mass volume ratio (grams per milliliter) be in the solvent of 1: 5～1: 30 for the Citric Acid of 1: 2～2: 1 and tamoxifen by amount of substance ratio, mix Citric Acid and tamoxifen solution, and add 0～5% crystal seed, and water bath heat preservation stirs, and holding temperature is 20～50 DEG C, stir 0～60 minute, filter, dry 6 hours of lower 43 DEG C of normal pressure, obtains 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 is the method that discloses the method Tamoxifen Citrate crystal form B of the present invention that is converted into crystal form A by Tamoxifen Citrate crystal form B and be 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 0～5% crystal seed, recrystallization temperature is 0～50 DEG C, filter, dry 6 hours of lower 43 DEG C of normal pressure, obtains 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.
Brief description of the drawings
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 formation infrared absorpting light spectra of the embodiment of the present invention 2 Tamoxifen Citrates.
Fig. 3 is the A crystal formation infrared absorpting light spectra of the embodiment of the present invention 2 Tamoxifen Citrates.
Embodiment
Embodiment 1
21g Citric Acid is placed in to 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 to 1000ml beaker simultaneously, adds 700.6ml methyl alcohol, be stirred to dissolving in 40 DEG C of heating in water bath.Above two reaction solutions are mixed, and add 281.5mg crystal seed, 40 DEG C of water bath heat preservations stir 50 minutes, filter, normal pressure lower 43 DEG C dry 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 formation (seeing Fig. 2) of 20g Tamoxifen Citrate is placed in to 2000ml there-necked flask, adds 1000ml ethanol, heated and stirred, to dissolving, adds 100mg crystal seed, and 15 DEG C of crystallizatioies filter, and dry 6 hours of lower 43 DEG C of normal pressure, obtains 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. prepare the method for Tamoxifen Citrate crystal form A for one kind, its process comprises: amount of substance is dissolved in respectively in solvent than the Citric Acid and the tamoxifen that are 1:2～2:1, mix the solution of Citric Acid and tamoxifen, the mass volume ratio of Citric Acid and tamoxifen and solvent is 1:5～1:30, described mass volume ratio example is all the ratio of grams per milliliter, and add 0～5% crystal seed, crystal seed described in it is Tamoxifen Citrate crystal form A standard substance, described in it, in 0～5% crystal seed, do not comprise 0%, water bath heat preservation stirs, holding temperature is 20～50 DEG C, stir 0～60 minute, filter, dry 6 hours of lower 43 DEG C of normal pressure, obtain A N-type waferN.
2. the method for claim 1, it is characterized in that: the amount of substance ratio of Citric Acid and tamoxifen is 1: 1, the mass volume ratio of Citric Acid used and tamoxifen and solvent is all 1:20, and crystallization holding temperature is 40 DEG C, crystal seed is 0.5%, and churning time is 50 minutes.
3. preparation method as claimed in claim 1, its solvent for use is methyl alcohol, ethanol, acetone, in ether one or several.
4. the method for claim 1, is characterized in that: 21g Citric Acid is placed in to 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 to 1000ml beaker simultaneously, adds 700.6ml methyl alcohol, be stirred to dissolving in 40 DEG C of heating in water bath, above two reaction solutions are mixed, and add 281.5mg crystal seed, 40 DEG C of stirrings of water bath heat preservation 50 minutes, filter, dry 6 hours of lower 43 DEG C of normal pressure, obtains crystalline powder.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410069629.1A CN103896786B (en) | 2009-05-21 | 2009-05-21 | The crystal formation of Tamoxifen Citrate and the preparation method of crystal form A |
| CN200910118404.XA 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 | 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 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410069629.1A Division CN103896786B (en) | 2009-05-21 | 2009-05-21 | The crystal formation of Tamoxifen Citrate and the preparation method of crystal form A |
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| Publication Number | Publication Date |
|---|---|
| CN101891635A CN101891635A (en) | 2010-11-24 |
| CN101891635B true CN101891635B (en) | 2014-06-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910118404.XA Active CN101891635B (en) | 2009-05-21 | 2009-05-21 | Crystal forms of citric acid nolvadex and preparation method of crystal form A |
| 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 |
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| Application Number | Title | Priority Date | Filing Date |
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| 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 |
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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 |
| MX2020002649A (en) | 2017-09-11 | 2020-09-25 | Atossa Therapeutics Inc | Methods for making and using endoxifen. |
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- 2009-05-21 CN CN200910118404.XA patent/CN101891635B/en active Active
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| CN103896786A (en) | 2014-07-02 |
| CN103896786B (en) | 2015-11-25 |
| CN101891635A (en) | 2010-11-24 |
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