CN103694165A - Gimeracil amorphous cured product and preparation method thereof - Google Patents

Abstract

The present invention provides a method for preparing a gimeracil amorphous cured product. According to the gimeracil amorphous cured product, gimeracil is dissolved in a suitable solvent to make the gimeracil be cured through a certain method so as to form a powdery solid, and the X-ray diffraction detection result shows that at least 90% of the solid exists in the amorphous form. The gimeracil amorphous cured product has good flowability and good bulk density so as to make manufacturing and preparation of the gimeracil-containing drug be easy, can meet preparation process requirements without crushing operation, and has good bioavailability. In addition, the preparation method is suitable for industrial production.

Description

Gimeracil amorphous solidified product and preparation method thereof

technical field

The invention relates to the field of medicinal chemistry, in particular to an amorphous cured product of gimeracil and a preparation method thereof.

Background technique

Gimeracil is one of the main components of the oral anti-cancer compound drug S-1 Capsules. S-1 Capsules was developed by Japan Dapeng Pharmaceutical Co., Ltd. and has been approved for the treatment of various cancers such as gastric cancer, non-small cell cancer, and colon cancer. The treatment mainly consists of the active ingredient tegafur and two biochemical modulators gimeracil and oteracil potassium.

Gimeracil itself does not have anti-tumor activity. After taking it, the drug stays in the gastrointestinal tract, inhibits the degradation of 5-fluorouracil by inhibiting dihydropyrimidine dehydrogenase DPD, and maintains the concentration of 5-fluorouracil in plasma and tumor tissues for a long time. concentration, thereby enhancing the antitumor activity.

Gimeracil, also known as Gimeracil, Gimeracil, chemical name 5-chloro-2,4-dihydroxypyridine or 5-chloro-4-hydroxy-2(1H)-pyridone, the structural formula is as follows:

Regarding the preparation method of gimeracil, bibliographical reports mainly contain two preparation methods:

(1) Synthetic route 1:

Den Henog H J, Kolder C R. Migration of halogen atoms in halogeno-derivatives of 2,4- dihydroxypyridine [J]. Rec Trav Chim, 1953, 72:853-858.

In this method, 2,4-dihydroxypyridine (2) is used as a raw material to obtain products through chlorination, addition, hydrolysis and other steps.

(2) Synthetic route 2:

CONVENIENT AND PRACTICAL SYNTHESIS OF 5-CHLORO-

4-HYDROXY-2(lH)-PYRIDINON [J] HETER℃YCLES.,1993,36:145-148

Using malononitrile, trimethyl orthoacetate and 1,1-dimethoxytrimethylamine as starting materials, 5-chloro-2,4- Dihydroxypyridine. The raw material of this route is easy to obtain, the operating conditions are simple, and it is more suitable for industrial production.

(3) Hao Linghua et al. "Synthesis of Gymast", Journal of Shenyang Pharmaceutical University, 22(6), November 2005, 420-421.

(4) In addition, Wang Haipu et al.'s literature "Preparation and Identification of Polymorphs of Jimerasidium" (Chinese Journal of Medicinal Chemistry, 81[18-1], February 2008, 44-47) and invention patent application (application No. 200710020907.4, Invention name: 5-Chloro-4-hydroxy-2(1H)-pyridone crystal form and its preparation method and application, application date 2007.04.03, publication number CN101033211, publication date 2007.09.12) discovered and obtained Jimei Two crystal forms of pyrimidine: granular P crystal and short needle L crystal.

Since different crystal forms have differences in solubility, dissolution rate, stability, etc., different crystal forms will have a significant impact on the bioavailability of its oral preparation S-1 Capsules.

Contents of the invention

The technical problem to be solved by the present invention is to provide an amorphous cured product of gimeracil that is easy to operate and easy to obtain, so that it has good fluidity and bulk density, so as to facilitate the manufacture and preparation of pharmaceutical compositions.

The amorphous cured product of gimeracil disclosed in the present invention means that gimeracil is dissolved and solidified by a certain method to form a powdery solid, and at least 90% of the solid exists in an amorphous form according to X-ray diffraction (as shown in Figure 1) .

Another technical problem to be solved by the present invention is to disclose the preparation method of the above-mentioned amorphous solidified product of gimeracil.

The preparation method of the above-mentioned gimeracil amorphous solidified product disclosed by the present invention includes the following steps: adding 5-10 times solvent to the gimeracil solid to dissolve, cooling to -80°C to -30°C to solidify, and vacuum freezing at -100°C-0°C Dry for 24-48 hours, and then heat up to -10°C-0°C to dry, that is, at least 90% of which is in the form of amorphous form by X-ray diffraction.

Another technical problem to be solved by the present invention is to disclose the application of gimeracil's amorphous cured product in the preparation of pharmaceutical compositions.

As one of the main components of the compound preparation, the amorphous solidified product of gimeracil of the present invention can be formulated into various medically acceptable oral preparations with pharmaceutical excipients in a certain ratio. The pharmaceutical excipients of the present invention include: diluents, disintegrants, binders and lubricants, etc., such as: lactose, microcrystalline cellulose, starch, croscarmellose sodium, polyvinylpyrrolidone , sodium lauryl sulfate, magnesium stearate, etc.

The gimeracil amorphous cured product disclosed by the invention has good flow performance and bulk density performance, is easy to prepare for preparation, and has good bioavailability.

Description of drawings: Figure 1 is an X-ray diffraction pattern.

The content of the present invention will be described in further detail in the form of embodiments below, but it should not be understood that the scope of the above subject of the present invention is limited to the following embodiments. Without departing from the above-mentioned technical premise of the present invention, any corresponding replacement or modification made according to common technical knowledge and customary means in this field shall be included in the scope of the present invention .

Example 1:

Gimeracil (5g) was added to a lyophilized vial, and medicinal ethanol (30mL) was added to dissolve at 25°C-30°C, then cooled to -70°C and rotated to solidify. Maintain -60°C to -50°C for vacuum freeze-drying, and in the final stage, the temperature can be raised to -10°C to 0°C for drying. The obtained gimeracil amorphous cured product, wherein about 92% exists in an amorphous form.

Example 2:

Replace ethanol (30mL) with isopropanol (40mL), and the others are the same as in Example 1. The obtained gimeracil amorphous cured product, wherein about 90% exists in an amorphous form.

Example 3:

Gimeracil (5g) was added to a lyophilized vial, and ethyl acetate (30mL) was added to dissolve at 20°C-25°C, then cooled to -20°C and rotated to solidify. Maintain -10°C to -0°C for vacuum freeze-drying, and in the final stage, the temperature can be raised to 0°C-5°C for drying. The obtained gimeracil amorphous cured product, wherein about 95% exists in an amorphous form.

Example 4:

Gimeracil (5g) was added to a lyophilized bottle, and chloroform (40mL) was added to dissolve at 25°C-30°C, then cooled to -20°C and rotated to solidify. Maintain -10°C to -0°C for vacuum freeze-drying, and in the final stage, the temperature can be raised to 0°C-5°C for drying. Gained celecoxib amorphous cured product, wherein about 94% exists in an amorphous form.

Example 5:

Use several pharmaceutical excipients to make Gimeracil amorphous solidified product into S-Tegio capsules containing 20 mg of Tegafur according to the following method

Name of raw material Amount of raw and auxiliary materials (g/1000 preparation units) Gimeracil 5.8 Tegafur 20 Oteracil Potassium 19.6 Polyvinylpyrrolidone 10 Magnesium stearate 1 lactose 10 microcrystalline cellulose 20 5% SDS aqueous solution Appropriate amount

The manufacturing method of the capsule containing gimeracil amorphous solidified product is to mix tegafur, oteracil potassium, gimeracil amorphous solidified product with lactose, polyvinylpyrrolidone and microcrystalline cellulose, and mix them with lauryl sulfate Sodium aqueous solution is used as a wetting agent for wet granulation, dried and granulated, mixed evenly with magnesium stearate, and then packed into capsules.

Embodiment 6:

Use several pharmaceutical excipients to make Gimeracil amorphous solidified product into S-Tegio capsules containing 25 mg of Tegafur as follows

Name of raw material Amount of raw and auxiliary materials (g/1000 preparation units) Gimeracil 7.25 Tegafur 25 Oteracil Potassium 24.5 Polyvinylpyrrolidone 10 Magnesium stearate 1 lactose 10 microcrystalline cellulose 20 5% SDS aqueous solution Appropriate amount

The manufacturing method is the same as in Example 5.

Claims (3)

1. the unformed cured article of gimeracil, is characterized in that it is to exist with amorphous form that this solid detects at least 90% through X-ray diffraction.

2. the preparation method of the unformed cured article of gimeracil as claimed in claim 1, it is characterized in that the method comprises the following steps: to add 5-10 times of dissolution with solvents in gimeracil solid, being cooled to-80 ℃ to-30 ℃ solidifies,-100 ℃ of-0 ℃ of vacuum lyophilization 24-48 hour, then be warming up to-10 ℃-0 ℃ and be dried, obtain.

3. method as claimed in claim 2, solvent for use includes but not limited to methyl alcohol, ethanol, Virahol, propyl carbinol, ethyl acetate, methylene dichloride, acetone, acetonitrile.

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