CN101891635A - 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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- CN101891635A CN101891635A CN200910118404XA CN200910118404A CN101891635A CN 101891635 A CN101891635 A CN 101891635A CN 200910118404X A CN200910118404X A CN 200910118404XA CN 200910118404 A CN200910118404 A CN 200910118404A CN 101891635 A CN101891635 A CN 101891635A
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- tamoxifen
- tamoxifen citrate
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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 the pharmaceutical chemistry field, be specifically related to the 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)-and N, N-dimethyl-2-[4-(1,2-phenylbenzene-1-butylene base) phenoxy group]-the ethamine citrate.
Chemical structural formula:
Tamoxifen is non-steroid estrogen antagonist medicine, 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 the E type has weak estrogen activity, and the Z type then has estrogenic antagonist.
If estrogen receptor (ER) is arranged in the breast cancer cell, then oestrogenic hormon enters in the tumour cell, combines with it, impels the DNA of tumour cell and synthesizing of m-RNA, stimulates growth of tumour cell.And tamoxifen Z type isomer enters in the cell, combines with the ER competition, forms receptor complex, stops the performance of estrogen effect, thereby suppresses the propagation of breast cancer cell.
Tamoxifen Citrate now at home, external listing, be used for the treatment of women's recurrent and metastatic breast cancer; As the assisting therapy that shifts behind the mammary cancer surgery, prevention of recurrence.According to related data, Tamoxifen Citrate has two kinds of crystal formations now, and according to Infrared spectroscopy, crystal form A is at 1700-1750cm
-1Have only a charateristic avsorption band, crystal form B is at 1700-1750cm
-1There are two charateristic avsorption bands at the place, and at 3400cm
-1About also have charateristic avsorption band, 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
Purpose of the present invention provides the crystal formation of two kinds of Tamoxifen Citrates.
The crystal formation of first kind of Tamoxifen Citrate disclosed by the invention, this crystal formation are named the type into A, this crystal through infrared analysis at 1700-1750cm
-1The place has and itself and B crystal formation can be distinguished the unique charateristic avsorption band that comes, and sees Fig. 1.
The crystal formation of second kind of Tamoxifen Citrate disclosed by the invention, this crystal formation are named and are Type B, this crystal through infrared analysis at 1700-1750cm
-1, 3400cm
-1About locate to have the charateristic avsorption band that itself and the difference of A crystal formation can be come, see Fig. 2.
Another object of the present invention is the preparation method who discloses the Tamoxifen Citrate crystal form A.
The preparation method of Tamoxifen Citrate crystal form A of the present invention, its process comprises: with the amount of substance ratio is that to be dissolved in mass volume ratio (grams per milliliter) respectively be in 1: 5～1: 30 the solvent for 1: 2～2: 1 Citric Acid and tamoxifen, mix Citric Acid and tamoxifen solution, and add 0～5% crystal seed, and water bath heat preservation stirs, and holding temperature is 20～50 ℃, stirred 0～60 minute, filter, the following 43 ℃ of dryings of normal pressure 6 hours get the A N-type waferN.
The amount of substance ratio of above-mentioned Citric Acid and tamoxifen is 1: 1, the mass volume ratio of Citric Acid and tamoxifen and solvent (grams per milliliter) all is 1: 20, the crystallization holding temperature is 40 ℃, crystal seed is 0.5%, and churning time is 50 minutes, wherein, solvent is a methyl alcohol, ethanol, acetone, in the ether one or several.
Another purpose of the present invention is to disclose the method that the method Tamoxifen Citrate crystal form B of the present invention that is converted into crystal form A by the Tamoxifen Citrate crystal form B is converted into crystal form A, its process comprises: it is in 1: 5～1: 100 the solvent that the Type B crystal is dissolved in mass volume ratio (grams per milliliter), heating for dissolving, the crystal seed of adding 0～5%, recrystallization temperature is 0～50 ℃, filter, the following 43 ℃ of dryings of normal pressure 6 hours get the 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 ℃, and wherein, solvent is a methyl alcohol, ethanol, acetone, in the ether one or several.
Description of drawings
Fig. 1 is the A crystal formation infrared absorpting light spectra of the embodiment of the invention 1 Tamoxifen Citrate.
Fig. 2 is the B crystal formation infrared absorpting light spectra of the embodiment of the invention 2 Tamoxifen Citrates.
Fig. 3 is the A crystal formation infrared absorpting light spectra of the embodiment of the invention 2 Tamoxifen Citrates.
Embodiment
Embodiment 1
The 21g Citric Acid is placed the 2000ml there-necked flask, add 420ml methyl alcohol, be stirred to dissolving in 40 ℃ of heating in water bath; Simultaneously the 35.3g tamoxifen is placed the 1000ml beaker, add 700.6ml methyl alcohol, be stirred to dissolving in 40 ℃ of heating in water bath.Above two reaction solutions are mixed, and add the 281.5mg crystal seed, water bath heat preservation stirred 50 minutes for 40 ℃, filtered, and the following 43 ℃ of dryings of normal pressure 6 hours get 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 (see figure 2) of 20g Tamoxifen Citrate is placed the 2000ml there-necked flask, adding 1000ml ethanol, heated and stirred adds the 100mg crystal seed to dissolving, and 15 ℃ of crystallizatioies filter, and the following 43 ℃ of dryings of normal pressure 6 hours get crystalline powder.Measure this powder infrared spectrogram, according to infrared absorption spectrum, what obviously generate is crystal form A, sees Fig. 3
The above only is a specific embodiment of the present invention, and this embodiment only produces any constraint to the present invention as an illustration and not.
Claims (9)
1. the crystal form A of a Tamoxifen Citrate, it is characterized in that: infrared spectrogram is at 1700-1750cm
-1Has only a charateristic avsorption band.
2. the crystal form B of a Tamoxifen Citrate, it is characterized in that: infrared spectrogram is at 1700-1750cm
-1There are two charateristic avsorption bands at the place, and at 3400cm
-1About also have charateristic avsorption band.
3. the crystal form A of the described Tamoxifen Citrate of claim 1～2 and B, it is characterized in that: other charateristic avsorption bands of infared spectrum are identical substantially.
4. method for preparing the described Tamoxifen Citrate crystal form A of claim 1, its process comprises: with the amount of substance ratio is that to be dissolved in mass volume ratio respectively be in 1: 5～1: 30 the solvent for 1: 2～2: 1 Citric Acid and tamoxifen, the solution that mixes Citric Acid and tamoxifen, and add 0～5% crystal seed, and water bath heat preservation stirs, and holding temperature is 20～50 ℃, stirred 0～60 minute, filter, the following 43 ℃ of dryings of normal pressure 6 hours get the A N-type waferN.
5. method as claimed in claim 4, it is characterized in that: the amount of substance ratio of Citric Acid and tamoxifen is 1: 1, and the mass volume ratio of used Citric Acid and tamoxifen and solvent all is 1: 20, and the crystallization holding temperature is 40 ℃, crystal seed is 0.5%, and churning time is 50 minutes.
6. method that the described Tamoxifen Citrate crystal form B of claim 2 is converted into the described Tamoxifen Citrate crystal form A of claim 1, its process comprises: it is in 1: 5～1: 100 the solvent that the Type B crystal is dissolved in mass volume ratio, heating for dissolving, the crystal seed of adding 0～5%, 0～50 ℃ of crystallization, filter, the following 43 ℃ of dryings of normal pressure 6 hours get the A N-type waferN.
7. method as claimed in claim 6 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 ℃.
8. as the arbitrary described method of claim 4～7, said crystal seed is Tamoxifen Citrate crystal form A standard substance, and the ratio of all quality volumes all is the ratio of grams per milliliter.
9. as the described preparation method of claim 4～7, its solvent for use is a methyl alcohol, ethanol, acetone, in the ether one or several.
Priority Applications (2)
| 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 |
| CN201410069629.1A CN103896786B (en) | 2009-05-21 | 2009-05-21 | The crystal formation of Tamoxifen Citrate and the preparation method of crystal form A |
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 Child Applications (1)
| 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101891635A true CN101891635A (en) | 2010-11-24 |
| CN101891635B 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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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109293519A (en) * | 2017-07-25 | 2019-02-01 | 北京斯利安药业有限公司 | A kind of preparation method of tamoxifen citrate crystal form A |
| CN111328280A (en) * | 2017-09-11 | 2020-06-23 | 阿托萨治疗学公司 | Methods of making and using endoxifen |
-
2009
- 2009-05-21 CN CN200910118404.XA patent/CN101891635B/en active Active
- 2009-05-21 CN CN201410069629.1A patent/CN103896786B/en active Active
Non-Patent Citations (4)
| Title |
|---|
| THE OFFICIAL COMPENDIA OF STANDARDS: "《USP-NF》", 31 December 2007 * |
| 中华人民共和国卫生部药典委员会: "《药品红外光谱集》", 31 December 1996 * |
| 徐峰等: "抗雌激素药三苯氧胺制备方法的进展", 《浙江化工》 * |
| 梅和珊等: "他莫昔芬合成路线图解", 《中国医药工业杂志》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109293519A (en) * | 2017-07-25 | 2019-02-01 | 北京斯利安药业有限公司 | A kind of preparation method of tamoxifen citrate crystal form A |
| 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 |
| CN111328280A (en) * | 2017-09-11 | 2020-06-23 | 阿托萨治疗学公司 | Methods of making and using endoxifen |
| US11572334B2 (en) | 2017-09-11 | 2023-02-07 | Atossa Therapeutics, Inc. | Methods for making and using endoxifen |
| US11680036B1 (en) | 2017-09-11 | 2023-06-20 | Atossa Therapeutics, Inc. | Methods for making and using endoxifen |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101891635B (en) | 2014-06-04 |
| CN103896786B (en) | 2015-11-25 |
| CN103896786A (en) | 2014-07-02 |
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