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Gimeracil crystal form and preparation method thereof

A kind of technology of crystal form and characteristic peak, which is applied in the field of crystal form and preparation of Gimoster A

Active Publication Date: 2013-07-17
HANGZHOU MINSHENG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The clinical application of 5-FU has a history of more than 40 years, and it is still the drug of choice for various tumors such as the gastrointestinal tract. However, the drug still has some shortcomings, which limit its clinical application, mainly as follows: (1) Short half-life in vivo, nonlinear elimination, difficult to obtain objective and stable curative effect; (2) severe side effects, mainly gastrointestinal and bone marrow toxicity
[0017] However, the content of the raw material drug synthesized by the above-mentioned literature is generally only about 99%, especially the content of a single impurity cannot stably reach the standard of the drug, The above-mentioned documents did not study the method of using the preparation of crystals to obtain high-purity products, and did not study the conversion between crystal forms
In addition, the preparation of the crystal form needs to be dissolved in an alkaline solution first, and the solution needs to be strictly temperature controlled, the pH carefully adjusted, and placed for up to 12 hours, so the operation is very inconvenient and time-consuming and labor-intensive.

Method used

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  • Gimeracil crystal form and preparation method thereof
  • Gimeracil crystal form and preparation method thereof
  • Gimeracil crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] 10 grams of gimostert heated and dissolved in 500 milliliters of water are synthesized by the method provided in the literature of "The Synthesis of Gymaster" (Chinese Journal of Medicinal Chemistry, 81 [18-1], February 2008, 44-47), Add 1 gram of activated carbon, heat to reflux, vacuum filter while it is hot, let it stand without stirring, cool with ice water to precipitate white needle-shaped crystals, cool to 10°C and filter with suction, wash the filter cake with a small amount of water, drain and filter The cake was dried in an oven at 60°C for 5 hours. Obtained 9.4 g of dry Gimostel white needle-like crystals—type A crystals, HPLC 99.82%, yield 99.4%. Powder X-ray Diffraction see figure 2 , melting point 277.11-277.61°C ( Figure 6 ), see the infrared spectrum Figure 11 .

[0084] Example 2 Preparation of Gimerost Type A Crystals in Ethanol Solution

Embodiment 2

[0085] Heat and dissolve 10 grams of P-type crystal Gimostel in 350 ml of 94% ethanol-water solution, let it stand without stirring, cool with ice water to precipitate crystals, and filter the precipitated crystals after cooling to 10°C, and use a small amount of ethanol in the same proportion Wash with aqueous solution, and dry the filter cake in an oven at 60°C for 5 hours. Obtained dry gimoster type A crystals, the content and yield are shown in the table below. Gimostel uses 90%, 80%, 70%, 60%, 50%, 30%, 20% ethanol-water solution and water respectively to prepare Gimostil A-type crystals according to the above process conditions, and the content and yield Rates are shown in the table below. Crystal powder X-ray diffraction see figure ( figure 2 ).

[0086]

[0087]

[0088] Example 3 Preparation of Gimerost P-type Crystals in Ethanol Solution

Embodiment 3

[0089]Heat and dissolve 10 g of crystal form A gimostel in 350 ml of 94% ethanol-water solution, add P-type crystal seed crystals and stir vigorously, the precipitated crystals are cooled to 10°C, then suction filtered, and washed with a small amount of ethanol water solution in the same proportion , The filter cake was dried in an oven at 60°C for 5 hours. The dry Gymast P-type crystals were obtained, and the contents and yields are shown in the table below. Gimostel uses 90%, 80%, 70%, 60%, 50%, 40%, 30% ethanol-water solution and water respectively to prepare Gimostel P-type crystals according to the above process conditions, and the content and yield Rates are shown in the table below. Crystal powder X-ray diffraction see Figure 4 .

[0090]

[0091] Example 4 Preparation of Gymast P-type Crystals in Pure Water

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Abstract

The invention relates to a Gimeracil needle crystal (A crystal form) and a preparation method thereof, and a method for mutual transformation between the needle crystal (A crystal form) and a granular crystal (P crystal form). The preparation of the A crystal form, the transformation between the A crystal form and the P crystal form, or the purification of the A crystal form and the P crystal form adopts aqueous solution of any one of ethanol, methanol, acetone and tetrahydrofuran, or mixed solution of more than one of the ethanol, the methanol, the acetone and the tetrahydrofuran, or pure water, preferably the aqueous solution of ethanol or the pure water, and optimally preferable the pure water. By adopting the solvent in the method for crystallization, not only the transformation and simultaneously the purification of different crystal forms can be finished well, but also low-content water or even the pure water can be used as a crystallization solvent, thus the Gimeracil needle crystal and the methods have the advantages of low cost, nontoxicity, environmental protection, few organic residues and the like. Particularly the pure water is used, thus not only the purification effect is good, but also the yield is higher, and the yield is 35 percent higher than that of using absolute ethyl alcohol.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a crystal form of Gimerost A and a preparation method thereof. Background technique [0002] Fluterazine Capsules is a compound anticancer drug developed by Dapeng Pharmaceutical Co., Ltd. of Japan. It consists of three components: Tegafur, Gimeracil and Potassium Oxonate. The ratio is 1:0.4:1. Fluterazine capsules are available in two specifications, 20mg and 25mg, based on the tegafur contained in each capsule. The drug is approved in Japan for the treatment of gastric cancer and head and neck cancer. [0003] Among the three components of fluterazine capsules, tegafur is the prodrug of 5-fluorouracil (5-FU), which is transformed into 5-FU in the body after taking it to play an anti-tumor effect. The clinical application of 5-FU has a history of more than 40 years, and it is still the drug of choice for various tumors such as the gastrointe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/69A61P35/00
Inventor 王树龙蔡剑颜子富
Owner HANGZHOU MINSHENG PHARM CO LTD
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