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A method of preparing micro-powder-type capecitabine

A capecitabine and micropowder technology, which is applied in the field of preparing micropowder capecitabine, can solve problems such as unfavorable industrial production, difficult manual control, and inability to achieve, and achieves convenient preparation granulation, improved dissolution, and simple operation. Effect

Active Publication Date: 2017-03-15
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The particle size of the micropowder type capecitabine obtained by this method is relatively small, but in this process, factors such as detection of supersaturation, solubility curve, addition of crystal seeds with specific particle size requirements, strict control of cooling conditions, etc. It is conducive to industrial production, and can only achieve a d(0.9) of 18-30 μm particle size, and cannot achieve a smaller particle size

Method used

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  • A method of preparing micro-powder-type capecitabine
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  • A method of preparing micro-powder-type capecitabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Put 150g of capecitabine crude product and 300ml of tetrahydrofuran into a 1000ml reaction flask, dissolve at 25℃, add 600ml methyl tert-butyl ether dropwise with stirring, stop stirring after addition, keep for 1.5 hours for crystallization, stir and cool to -10℃ , Suction filtration, and blast drying to obtain 137 g of micronized capecitabine, with a yield of 91.4%, a purity of 99.89%, and a melting point of 117.5-119°C.

[0032] The obtained micronized capecitabine was measured by X-ray powder diffraction pattern, using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angles was at 4.9°±0.2°, 10.3°±0.2°, 11.7°±0.2 °, 15.0°±0.2°, 17.0°±0.2°, 17.6°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 20.2°±0.2°, 20.5°±0.2°, 21.0°±0.2°, 21.7°±0.2°, 22.7°±0.2°, 23.9°±0.2°, 25.0°±0.2°, 25.6°±0.2°, 26.2°±0.2°, 27.1° ±0.2°, 28.2°±0.2°, 29.5°±0.2°, 30.8°±0.2°, 31.5°±0.2°, 31.9°±0.2°, 32.8°±0.2°, 33.1°±0.2°, 33.7°±0.2 °, 34.3°±0.2°, 32.5°±0.2°, 35.9°±0.2°, 36.3°±...

Embodiment 2

[0034] Put 150g of capecitabine crude product and 150ml of tetrahydrofuran into a 1000ml reaction flask, dissolve at 25℃, add 300ml methyl tert-butyl ether dropwise with stirring, stop stirring after addition, keep for 1.5 hours for crystallization, stir and cool to -10℃ , Suction filtration, and blast drying to obtain 138 g of micronized capecitabine, with a yield of 92.0%, a purity of 99.8%, and a melting point of 117-119°C.

[0035] The obtained micronized capecitabine was measured by a laser particle size analyzer, and its particle size was: d(0.1)=1.403μm, d(0.5)=4.565μm, d(0.9)=9.645μm, the result is as follows Figure 4 Shown.

[0036] The capecitabine prepared in Examples 1 to 2 was prepared with reference to the Xeloda prescription that has been marketed to prepare capecitabine tablets. The in vitro dissolution test method: Take this product according to the second method of Annex XC of the 2010 edition of the Chinese Pharmacopoeia. Purified water, pH 1.2 hydrochloric acid...

Embodiment 3

[0038] Put 150g of crude capecitabine and 300ml of tetrahydrofuran into a 1000ml reaction flask, dissolve at 30°C, add 600ml methyl tert-butyl ether dropwise with stirring, stop stirring after addition, keep crystallization for 1.5 hours, stir and cool to -10°C , Suction filtration, and blast drying to obtain 136.4 g of micronized capecitabine, with a yield of 90.9%, a purity of 99.87%, and a melting point of 118-119°C.

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Abstract

The invention discloses a method of preparing micro-powder-type capecitabine. The method includes the steps of adding a capecitabine crude product to tetrahydrofuran to dissolve the capecitabine crude product, and under stirring, adding an ether solvent, performing temperature-maintained crystallization, and reducing the temperature, suction-filtering the solution and drying the solution to obtain the micro-powder-type capecitabine. Particle size of the product is d (0.1) <= 2 [mu]m, d (0.5) <= 5 [mu]m and d (0.9) <= 12 [mu]m. The method has simple operations and high stability and is beneficial to industrial modeled production.

Description

Technical field [0001] The invention relates to a method for preparing micronized capecitabine, which belongs to the field of medicinal chemistry. Background technique [0002] Capecitabine, chemical name: 1-(5-deoxy-β-D-ribofuranosyl)-5-fluoro-1,2-dihydro-2-oxo-4-pyrimidine carbamate, its The structural formula is as follows: [0003] [0004] Capecitabine was developed by the Swiss Roche Pharmaceutical Company and is currently the most biologically active oral fluorouracil drug, which can reach or exceed the efficacy of other fluorouracil drugs administered intravenously. Capecitabine has an ingenious structure design and unique activation mechanism, which successfully improves its anti-tumor specificity. The dosage form of capecitabine is an oral solid preparation. When preparing the capecitabine oral solid preparation, the particle size of the capecitabine raw material needs to be appropriately processed. [0005] US2010130734A1 discloses that capecitabine has a particle size ...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/06
CPCC07B2200/13C07H1/06C07H19/06
Inventor 杜云锋陈成效宇文礼张小勇樊长莹李保勇
Owner 山东安信制药有限公司
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