Industrialization method for preparing tamoxifen citrate polycrystalline type A

A citric acid and polymorphic technology, applied in the field of medicinal chemistry, can solve problems such as difficult realization, increased impurities, and difficult industrialization

Inactive Publication Date: 2019-04-02
UTOPHARM SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] First of all, during the industrialization of the first method, the impurities will increase significantly due to the long-term high-temperature heating of the raw material drug
For example, when feeding 200g in our research, the newly generated impurities reached 1.6% due to high-temperature heating and melting. What's more unfavorable is that it is difficult to achieve industrially after heating to 150°C and then quenching to minus 72°C, and the process of stirring and cooling The product will agglomerate to form a large ball, which is difficult to discharge and the crystal transformation is not complete, so this method is difficult to realize industrialization

Method used

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  • Industrialization method for preparing tamoxifen citrate polycrystalline type A
  • Industrialization method for preparing tamoxifen citrate polycrystalline type A
  • Industrialization method for preparing tamoxifen citrate polycrystalline type A

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] The preparation of embodiment 1 tamoxifen citrate crystal form A:

[0046] Add 10.00 g of the crystal form of tamoxifen citrate into DMF (20ml), heat to dissolve at 60°C, and then slowly add it to xylene (200ml) pre-cooled at -20°C, at -10±5°C, After continuing to stir for 2-3 hours, filter, wash with a small amount of DMF:xylene (1:10), and dry at 60°C to obtain about 9.41g of polymorph A of tamoxifen citrate, mp: 143-145°C, HPLC 99.85%, maximum simple 0.05%, HPLC: 99.72%.

Embodiment 2

[0047] The preparation of embodiment 2 tamoxifen citrate crystal form A:

[0048] Add 10.00g of tamoxifen citrate to DMF (15ml), heat to dissolve at 60°C, then add it to pre-cooled toluene (200ml) with stirring, continue to stir at -10±5°C for 2 hours, then filter , washed with a small amount of DMF:toluene (1:10), and dried at 60°C to obtain about 9.28g of polymorph A of tamoxifen citrate, mp: 143-145°C.

Embodiment 3

[0049] The preparation of embodiment 3 tamoxifen citrate crystal form A:

[0050] Add 10.00g of tamoxifen citrate methanol solvate into DMF (15ml), heat to dissolve at 60°C, then add it to pre-cooled xylene (200ml) with stirring, and continue stirring at -10±5°C After 2 hours, filter, wash with a small amount of xylene, and dry at 60°C to obtain about 9.05 g of polymorph A of tamoxifen citrate, mp: 143-145°C.

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Abstract

The invention discloses an industrialization method for preparing non-solvate tamoxifen citrate polycrystalline type A, the tamoxifen citrate is shown in the formula I, and the non-solvate tamoxifen citrate polycrystalline type A is conformed by melting point, X-ray diffraction powder pattern (XRD), differential thermal analysis (DSC)), infrared (IR) and thermal weight loss (TG) and the like. Thepolycrystalline type A prepared by the method is high in purity, and the purity of the product is greater than 99.50%; AND the preparation method is simple to operate and high in yield, and is suitable for industrial mass production.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to an industrialized method for preparing polymorphic form A of tamoxifen citrate for treating advanced breast cancer and ovarian cancer. Background technique [0002] Since 2016, the state has required a consistent evaluation of the quality and efficacy of domestically marketed drugs and foreign original drugs. Differences in drug crystal forms often have an important impact on its in vivo activity. Therefore, in order to achieve the same curative effect as the reference preparation in drug development, it is often required that the pharmaceutical crystal form of the generic drug should be consistent with the reference preparation. [0003] Tamoxifen Citrate (Tamoxifen Citrate; compound I; chemical name: (Z)-N,N-dimethyl-2-[4-(1,2-diphenyl-1-butenyl)benzene Oxy]-ethylamine citrate) is a drug used to treat advanced breast and ovarian cancer. The structural formula is as follows: [0004] ...

Claims

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Application Information

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IPC IPC(8): C07C217/16C07C213/08C07C59/265C07C51/41
CPCC07C213/08C07B2200/13C07C51/412C07C217/16C07C59/265
Inventor 罗军芝曾玉平年静
Owner UTOPHARM SHANGHAI
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