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A crystal form of dirithromycin compound and its crystal preparation method

A dirithromycin compound technology, applied in the field of dirithromycin compound crystal form and its crystallization preparation, can solve the problem of unsatisfactory solubility, crystal form and fluidity, large amount of mixed organic solvents, and difficulty in solvent recovery To achieve the effect of facilitating the implementation of large-scale industrialization, improving bioavailability, and shortening the experimental cycle

Active Publication Date: 2020-06-12
GUANGZHOU DAGUANG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Patent US5556839 discloses a crystal form of dirithromycin (we call it crystal form I in this patent) and a preparation method thereof. The purity of dirithromycin obtained by this method is relatively high, but the solubility, The crystal form and its fluidity are not ideal
At the same time, in the above-mentioned patents, the preparation methods of crystals all involve two or more toxic organic solvents, such as dioxane, isooctane, etc., and the use of mixed organic solvents is relatively large, making the recovery of solvents Very difficult; at the same time, the yield of the crystallization process product is not high

Method used

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  • A crystal form of dirithromycin compound and its crystal preparation method
  • A crystal form of dirithromycin compound and its crystal preparation method
  • A crystal form of dirithromycin compound and its crystal preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] At room temperature, add 1.05 g of dierythromycin solid to 30 ml of acetonitrile, and form a suspension at a stirring rate of 250r / min. The temperature is raised to 50°C, and the solid is completely dissolved. Continue to stir the solution, and then place it in an ultrasonic system , Then cool the mixture from 50°C to 0°C at a cooling rate of 1.5°C / min, turn on the ultrasonic generator 5 minutes after the start of the temperature drop, and open the device for 10 minutes; continue to stir for 5 hours after the end of the temperature drop, and the stirring rate will be maintained during the experiment No change; suction filtration, drying the obtained product at 77° C. under vacuum conditions for 24 hours to obtain a new crystal form of dierythromycin. The X-ray powder diffraction pattern of the new crystal form product is as follows figure 1 As shown, it is at the diffraction angle 2θ=5.84, 7.23, 7.70, 8.90, 9.93, 10.17, 10.67, 11.42, 13.09, 14.70, 15.33, 16.16, 17.59, 18....

Embodiment 2

[0031] Add 1.50g of dry dierythromycin solid to 30ml of acetonitrile, form a suspension at a stirring rate of 450r / min, heat to 74°C, the solids are completely dissolved, continue to stir the solution, and then cool down at a rate of 0.4°C / min Cool the mixture from 74°C to 5°C, turn on the ultrasonic generator 70min after the start of the temperature drop, and turn on the ultrasonic generator for 15 minutes. After the temperature drop, the temperature will be kept constant, and the crystal will be stirred for 3h. The stirring rate will remain unchanged during the experiment; To obtain a crystal slurry, the obtained product is dried at 95° C. under vacuum conditions for 24 hours to a constant weight to obtain a new crystal form of dierythromycin. The X-ray powder diffraction pattern of the product is at diffraction angle 2θ = 5.76, 7.23, 7.70, 8.89, 9.94, 10.19, 10.66, 11.38, 13.14, 14.65, 15.42, 16.20, 17.64, 18.19, 18.88, 19.85, 20.60, 21.51, 22.76 , There is a characteristic ...

Embodiment 3

[0033] At room temperature, add 2.53g of dierythromycin solid to 60ml of acetonitrile, and form a suspension at a stirring rate of 400r / min. The temperature is increased to 74°C, the solid is completely dissolved, the solution is continuously stirred, and then cooled at 1.0°C / min Cool the mixture from 74°C to 0°C at a rate. Turn on the ultrasonic generator 45min after the start of the cooling. The open time is 13min. After the cooling process is over, the temperature is kept constant and the crystal is stirred for 4h. The stirring rate remains unchanged during the experiment; The crystal slurry is suction filtered, and the obtained product is dried at 85° C. under vacuum conditions for 24 hours to constant weight to obtain a new crystal form of dierythromycin. The X-ray powder diffraction pattern of the product is at diffraction angle 2θ = 5.84, 7.33, 7.72, 8.94, 9.99, 10.09, 10.66, 11.37, 13.14, 14.65, 15.36, 16.02, 17.67, 18.20, 18.80, 19.82, 20.62, 21.51, 22.72 , There is a ...

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Abstract

The invention relates to a crystal form of a dirithromycin compound and a crystallizing preparation method of the crystal form of the dirithromycin compound. The crystal form of the dirithromycin compound is defined by using a diffraction angle 2 theta of an X-ray powder diffraction spectrum and a characteristic peak of DSC. The preparation method comprises the steps of adding dirithromycin solid into acetonitrile at room temperature, and stirring to prepare 0.035-0.05g / ml suspension; heating a system up to 50-74 DEG C, so as to realize complete dissolution; continuously stirring the solution, then putting the suspension into an ultrasonic system for carrying out ultrasonic treatment, cooling to 0-5 DEG C at a constant cooling rate, separating out crystals, continuously stirring and enabling the crystals to grow for 3-5h; filtering crystal slurry, washing, and drying to obtain a dirithromycin crystal form product. The new crystal form product has a rodlike appearance, and is higher in dissolving property, better in fluidity and higher in bulk density. Furthermore, the new crystal form product has the advantages of simple and stable technology, short experimental period, the purity of more than 99.5% and the yield of more than 90%, and is beneficial to large-scale enterprise production.

Description

Technical field [0001] The invention belongs to the technical field of medicine separation, and particularly relates to a crystal form of a dierythromycin compound and a crystal preparation method thereof. Background technique [0002] The chemical name of dirithromycin is erythromycin 9-deoxy-11-deoxy-9,11-[imino[2-(2-methoxyethoxy)ethylene]oxy]- [9S, 16R]. The molecular formula is C 42 H 78 N 2 O 14 , The molecular weight is 835.086, and the appearance is white crystalline powder. The structural formula is as formula (I). [0003] [0004] Dirithromycin was first synthesized by Thomae, a subsidiary of Boehringer Ingelheim in Germany. In 1985, it transferred the license to Lilly Corporation of the United States. In 1993, Lilly's dirithromycin (we call it crystal form I) , Prepared by reaction crystallization, the product is tablet or capsule) has been approved for marketing in France, Italy and Spain, and approved for sale in the United States in 1995. Dirithromycin is a 14-me...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H17/08C07H1/06
CPCC07B2200/13C07H1/06C07H17/08
Inventor 郝红勋韩政阳陈文展侯宝红陈伟翰林兴尹秋响王永莉谢闯肖燕
Owner GUANGZHOU DAGUANG PHARMA
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