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Preparation method of micro-powder capecitabine

A technology of capecitabine and micropowder, which is applied in the preparation of micropowder capecitabine and the field of capecitabine preparation, which can solve the problem that the particle size of capecitabine is not easy to control and large particle size is not good for capecitabine Dissolution of bine, crystal form change of capecitabine, etc., to achieve clinical drug safety, facilitate granulation of preparations, and ensure quality uniformity

Active Publication Date: 2014-01-15
QILU PHARMA HAINAN +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The micronized capecitabine obtained by the above method is mechanically pulverized, and the capecitabine particles obtained by sieving will generate a large amount of static electricity in the pulverization process, and the fluidity is extremely poor, which causes difficulties for sieving and granulation; Mechanical pulverization will change the crystal form of capecitabine
The capecitabine granules obtained by the crystallization method are the second-class solvents, such as dichloromethane, toluene, n-hexane, methanol, etc., which have certain toxicity and are restricted in drug production.
The particle size of capecitabine obtained by the existing crystallization method is not easy to control, and the large particle size is not conducive to the dissolution of capecitabine

Method used

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  • Preparation method of micro-powder capecitabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Add 20kg of crude capecitabine and 100L of ethyl acetate to a 200L reactor, heat up to 70°C to dissolve; cool down to 50°C, add 2kg of capecitabine seed crystals (particle size d(0.1)≥1μm, d(0.9) ≤30μm), keep stirring for 2 hours until a large number of crystals precipitate, cool to 0°C, centrifuge, and dry to obtain 20.4kg of micropowdered capecitabine, with a yield of 92.7%, a purity of 99.92%, and a melting point of 117-119°C.

[0054] Gained micropowder type capecitabine is measured through X-ray powder diffraction pattern, uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angle is at 5.0°±0.2°, 10.5°±0.2°, 15.2°±0.2° °, 17.1°±0.2°, 17.8°±0.2°, 18.7°±0.2°, 19.3°±0.2°, 20.0°±0.2°, 20.3°±0.2°, 21.2°±0.2°, 21.9°±0.2°, 28.4°±0.2° has a characteristic peak, such as figure 2 shown.

[0055] The obtained powder is measured by a laser particle size analyzer, and its particle size range is d (0.1): 2.216 μm, d (0.5): 6.341 μm, d (0.9): 25.616 μm, and ...

Embodiment 2

[0061] Add 200g capecitabine crude product and 2L ethyl acetate to a 3L flask, heat up to 60°C to dissolve; cool down to 40°C, add 4g capecitabine seed crystals (particle size d(0.1)≥1μm, d(0.9)≤ 30 μm), kept stirring for 6 hours until a large number of crystals were precipitated, cooled to -5°C, filtered with suction, and dried to obtain 185g of micropowdered capecitabine with a yield of 90.7%, a purity of 99.94%, and a melting point of 118-120°C.

[0062] The obtained powder is measured by a laser particle size analyzer, and its particle size range is d (0.1): 2.296 μm, d (0.5): 5.859 μm, d (0.9): 18.119 μm, and the results are as follows Figure 4 shown.

Embodiment 3

[0080] As described in Example 1, the difference is that the capecitabine seed crystal particle size is d(0.1) ≥ 1 μm, d(0.9) ≤ 20 μm; the obtained micronized capecitabine particle size is d(0.1) ≥ 1 μm, d(0.9)≤30μm. The obtained micropowder type capecitabine has a purity of 99.93%, determined by X-ray powder diffraction pattern, using Cu-Kα radiation, and the X-ray powder diffraction represented by 2θ angle is at 5.0°±0.2°, 10.5°±0.2°, 15.2°±0.2°, 17.1°±0.2°, 17.8°±0.2°, 18.7°±0.2°, 19.3°±0.2°, 20.0°±0.2°, 20.3°±0.2°, 21.2°±0.2°, 21.9° ±0.2°, 28.4°±0.2° have characteristic peaks.

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Abstract

The invention relates to a preparation method of micro powder capecitabine, the method is as follows: adding a capecitabine crude product into ethyl acetate, dissolving by heating, cooling to a condition that capecitabine reaches a saturation state in the ethyl acetate, adding capecitabine seed crystal, and obtaining the micro powder capecitabine by thermal insulation crystallization, cooling, filtration and drying. The micro powder capecitabine prepared by the method is high in purity and uniform in particle size, does not generate static electricity, does not agglomerate, good in fluidity, easy for scale production, can well ensure the quality homogeneity of a preparation, and makes clinical medication safer.

Description

technical field [0001] The invention relates to a preparation method of capecitabine with a specific particle size, in particular to a preparation method of micronized capecitabine, which belongs to the field of medicinal chemistry. Background technique [0002] Capecitabine, the chemical name is 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine nucleoside, as shown in structural formula I: [0003] [0004] Capecitabine is a new type of oral flucytosine nucleoside analogue, which is non-cytotoxic, and is metabolized to 5-fluorouracil (5-FU) by enzymes in the body, thereby exerting anti-tumor effects. It is mainly used clinically for the treatment of Advanced breast cancer, colorectal cancer and other solid tumors. [0005] The dosage form of capecitabine is an oral solid preparation, and when preparing the oral solid preparation of capecitabine, it is necessary to properly handle the particle size of the capecitabine raw material. [0006] US2010130734A1 discloses tha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/06C07H1/06
Inventor 冷传新张明会倪刚范传文林栋王会成
Owner QILU PHARMA HAINAN
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