CN105585602A - Fidaxomicin compound - Google Patents

Abstract

The invention belongs to the technical field of medicines and particularly relates to a fidaxomicin compound and a preparation method thereof. The fidaxomicin compound is high in purity and good in stability.

Description

A kind of feldamycin compound

Technical field

The invention belongs to medical technical field, be specifically related to feldamycin novel crystal forms and preparation method thereof, the invention still further relates to the application that uses this feldamycin composition therapeuticing disease.

Background technology

Feldamycin (fidaxomicin) is the macrolides antimicrobial of a kind of novel narrow spectrum of being researched and developed by Op-timer drugmaker in recent years. Obtain FDA approval in U.S.'s listing on May 27th, 2011, commodity are called Dificid. This drug main will be used for the treatment of clostridium difficile (Clostridiumdifficile has another name called difficulty and distinguishes clostridium) induced diarrhea (CDAD).

Its structure is as follows:

Molecular formula: C52H74Cl2O18 molecular weight: 1058.04

Feldamycin is a class multi-crystalline compounds, and common is white needles, flakes crystallization or amorphous powder etc., is soluble in methyl alcohol, ethanol, ethyl acetate etc., is slightly soluble in benzene, carrene, chloroform, acetone, propyl alcohol, is insoluble to hexane, water.

In research process, repeat the method for prior art, the feldamycin impurity number obtaining is more, and total impurities is higher. The feldamycin that the present invention obtains, has advantages of: purity is high, and maximum contaminant is less than 1 ‰; Good stability.

Summary of the invention

One object of the present invention, discloses a kind of feldamycin compound crystal.

Another object of the present invention, discloses the preparation method of feldamycin compound crystal.

Another object of the present invention, discloses the pharmaceutical composition of feldamycin.

Now in conjunction with object of the present invention, content of the present invention is specifically described.

The invention provides a kind of feldamycin compound, this feldamycin compound crystal, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: CuKa target, tube voltage 40KV, tube current 100mA. X-ray powder diffraction characteristic absorption peak (2 θ) and D value are as follows,

In the present invention, the mensuration of 2 θ values is used light source, and precision is ± 0.2 °, therefore represents that above-mentioned got value has allowed certain reasonably error range, and its error range is ± 0.2 °.

Another object of the present invention, discloses the preparation method of feldamycin compound crystal,

Bibliographical information, feldamycin has multiple preparation method, and because of its process for purification difference, fusing point has relatively big difference; Quantity and the total amount of impurity are larger. The inventor is by a large amount of experiments, the relationship between quality of the feldamycin crystal of exploring refining solvent and obtain, by feldamycin is dissolved in ethanol-acetic acid-heated in water solution, then add cooling stage by stage, obtain the preparation method of feldamycin compound crystal of the present invention. Astoundingly, this feldamycin compound crystal has advantages of: purity is high, and maximum contaminant is less than 1 ‰; Good stability.

This preparation method screens from a large amount of single or mixed solvents, does not have method to instruct and draws. The partial solvent of testing has, water; Methyl alcohol, ethanol, propyl alcohol, isopropyl alcohol, butanols, isobutanol, propane diols etc.; The ketone reagent such as acetone; The ethers such as ether and diisopropyl ether reagent; Ester class, as ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, ethyl butyrate, methyl butyrate etc.; Acetonitrile; Carrene, chloroform, hexane, heptane, toluene, oxolane, DMF etc. Use their single or mixed solvent, mixed solvent can be two kinds, three kinds or four kinds of solvent, the ratio difference of various solvents in mixed solvent.

Specifically comprise the following steps: that feldamycin adds in the mixed liquor of 6-8 times of (weight or measurement (WM) ratio) ethanol-acetic acid-water=5-9:0.5-1:1-2, be heated to 50 DEG C-55 DEG C, filter while hot, 30 DEG C-35 DEG C insulation 3-4 hour of filtrate, 10 DEG C-15 DEG C, then be incubated 3-4 hour, crystallization, filter, drying obtains above-mentioned feldamycin compound crystal.

Feldamycin used, the method providing according to existing document is synthetic, and the chemical constitution of synthetic feldamycin is through proton nmr spectra, and elementary analysis, proves that chemical constitution is correct.

Another object of the present invention, provides the composition of the feldamycin that comprises feldamycin compound crystal and one or more pharmaceutically acceptable carriers composition.

Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid-carrier on galenic pharmacy are combined, and make it at random on galenic pharmacy acceptable adjuvant and excipient and be combined and be prepared into particulate or microballoon. Said composition is for the preparation of oral formulations.

The amount of the active ingredient (the compounds of this invention) containing in pharmaceutical composition and unit dosage form can specifically be applied according to the situation of patient's the state of an illness, diagnosis, the amount of compound used or concentration regulate in a wider scope, 1%～50%(weight that the weight range of reactive compound is composition).

Stability test

Inventor is studied the chemical stability of feldamycin compound crystal of the present invention, investigation condition is high temperature (60 DEG C ± 2 DEG C), strong illumination (4500Lx ± 500lx), high humidity (92.5%, RH) investigating index is outward appearance, content and related substance (optical isomer).

Outward appearance, content is without change.

Result: under high light, high temperature, super-humid conditions from 0-10 days, outward appearance, optical isomer, content do not change, and illustrate that chemical stability is good, are applicable to manufacture and the long term storage of pharmaceutical preparation.

Detailed description of the invention:

Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention. Embodiment is only indicative, never means that it limits the scope of the invention by any way.

Embodiment 1

In the 3000ml reaction bulb that stirring, thermometer, condenser are housed, Ethanol-Acetic Acid-water (5:0.5:1) mixed liquor that adds 200 grams of feldamycins and 1200ml, starts stirring, and heat temperature raising is heated to 50 DEG C-55 DEG C, filter while hot, 30 DEG C-35 DEG C insulations of filtrate 3 hours, 10 DEG C-15 DEG C, then be incubated 3 hours, crystallization, filter, drying obtains above-mentioned feldamycin compound crystal, 172.6 grams. Purity 99.94%.

Embodiment 2

In the 3000ml reaction bulb that stirring, thermometer, condenser are housed, Ethanol-Acetic Acid-water (8:1:2) mixed liquor that adds 200 grams of feldamycins and 1600ml, starts stirring, and heat temperature raising is heated to 50 DEG C-55 DEG C, filter while hot, 30 DEG C-35 DEG C insulations of filtrate 3 hours, 10 DEG C-15 DEG C, then be incubated 3 hours, crystallization, filter, drying obtains above-mentioned feldamycin compound crystal, 173 grams. Purity 99.99%.

Claims (5)

1. feldamycin compound shown in formula I,

（Ⅰ）

The crystal of described feldamycin compound, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has the following 2 θ angles of diffraction and D value,

The error of the 2 θ angles of diffraction is ± 0.2.

2. the preparation method of feldamycin compound crystal described in claim 1, by feldamycin is dissolved in ethanol-acetic acid-heated in water solution, then cooling obtains stage by stage.

3. the preparation method of feldamycin compound crystal described in claim 2, it is characterized in that comprising the following steps: that feldamycin adds in the mixed liquor of 6-8 times of (weight or measurement (WM) ratio) ethanol-acetic acid-water=5-9:0.5-1:1-2, be heated to 50 DEG C-55 DEG C, filter while hot 30 DEG C-35 DEG C insulation 3-4 hour of filtrate, 10 DEG C-15 DEG C, be incubated again 3-4 hour, crystallization, filters, and drying obtains above-mentioned feldamycin compound crystal.

4. a composition that contains the feldamycin of feldamycin compound crystal and one or more pharmaceutically acceptable carrier compositions described in claim 1.

5. composition claimed in claim 4, is characterized in that said composition is for the preparation of oral formulations.