New crystal form of riociguat and preparation method thereof

A crystal form, Leo's technology, applied in the field of medicine, can solve the problems of solvent toxicity and unsuitability for medicinal use, and achieve the effects of stable chemical and physical properties, uniform crystal particles, and convenient manufacturing process

Pending Publication Date: 2020-09-22
江苏华阳制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Among them, DMSO solvate has solvent toxicity and is not suitable for pharmaceutical use

Method used

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  • New crystal form of riociguat and preparation method thereof
  • New crystal form of riociguat and preparation method thereof
  • New crystal form of riociguat and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Take 10g of riociguat and heat it to 70°C with 2 times the volume of DMSO to dissolve it, add 14 times the volume of ethyl acetate, stir at 70°C for 0.5h, then cool to 10°C, stir for 4h, and filter to obtain Cake A; add 14 times the volume of ethyl acetate to filter cake A, heat to reflux, beat for 1 hour, cool to 10°C, stir for 4 hours, and filter to obtain filter cake B; filter cake B is vacuum-dried at 40°C for 18 hours to obtain profit The new crystal form of Ociguat is 4.6g.

Embodiment 2

[0024] Take 10g of riociguat and heat it to 80°C with 2 times the volume of DMSO to dissolve it, add 14 times the volume of ethyl acetate, stir at 80°C for 0.5h, then cool to 15°C, stir for 5h, and filter to obtain Cake A; add 14 times the volume of ethyl acetate to filter cake A, heat to reflux, beat for 1 hour, cool to 15°C, stir for 5 hours, and filter to obtain filter cake B; vacuum-dry filter cake B at 45°C for 20 hours to obtain profit The new crystal form of Ociguat is 4.2g.

Embodiment 3

[0026] Take 10g of riociguat and heat it to 75°C with 2 times the volume of DMSO to dissolve it, add 14 times the volume of ethyl acetate, stir at 75°C for 0.5h, then cool to 12°C, stir for 4.5h, and filter to obtain Filter cake A; add 14 times the volume of ethyl acetate to filter cake A, heat to reflux, beat for 1 hour, cool to 12°C, stir for 4.5 hours, and filter to obtain filter cake B; filter cake B is vacuum-dried at 42°C for 19 hours, Obtained 6.0g of the new crystal form of riociguat.

[0027] The new crystal form of Riociguat obtained by adopting the above-mentioned embodiments 1-3 shows the pattern of the peak shown in the following table in the X-ray powder diffraction pattern in units of 2 θ degrees:

[0028]

[0029] The riociguat crystalline powder obtained in the above-mentioned Example 3 was taken to conduct an investigation experiment on factors affecting stability (including strong light irradiation, high temperature, and high humidity). Among them, the r...

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Abstract

The invention discloses a new crystal form of riociguat and a preparation method thereof. The crystal form has peak values at the positions of 6.73, 9.05, 14.29, 17.73, 19.73, 20.29, 20.99, 25.54, 27.30 and 32.67 (2[theta]+ / -0.2) in an X-ray powder diffraction pattern. The preparation method of the crystal form comprises the following steps: firstly, heating and dissolving riociguat with DMSO, then adding ethyl acetate, stirring at a controlled temperature, and filtering to obtain filter cake A; and adding ethyl acetate, heating to reflux, pulping, cooling, stirring, filtering to obtain filtercake B, and drying in vacuum to obtain the new crystal form of the riociguat. The new crystal form of the riociguat prepared by the method has stable chemical and physical properties and uniform crystal particles, is suitable for long-term storage, and is convenient for the preparation process of preparations.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a new crystal form of riociguat and a preparation method thereof. Background technique [0002] Many drugs may have different crystal forms, and different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution rate, bioavailability, stability, and efficacy. Therefore, it is especially important to consider different crystal forms during drug research. Riociguat reported its preparation method and crystal form in U.S. Patent US10414766B2, and its different solvate crystal forms were reported in CN201480009667.6, including mono-DMSO solvate, sesquiguat-DMSO solvate, etc. . Among them, the DMSO solvate has solvent toxicity and is not suitable for pharmaceutical use. Therefore, there is a need in this field to systematically and comprehensively develop new crystal forms of riociguat, so as to find new crys...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04C07B2200/13
Inventor 徐进冯井胜何树青
Owner 江苏华阳制药有限公司
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