CN111689961A

CN111689961A - Novel crystal form of lis ciguat and preparation method thereof

Info

Publication number: CN111689961A
Application number: CN202010483794.7A
Authority: CN
Inventors: 徐进; 冯井胜; 何树青
Original assignee: Jiangsu Huayang Pharmaceutical Co ltd
Current assignee: Jiangsu Huayang Pharmaceutical Co ltd
Priority date: 2020-06-01
Filing date: 2020-06-01
Publication date: 2020-09-22

Abstract

The invention discloses a novel crystal form of linagliptin and a preparation method thereof, wherein the crystal form has a peak value at a 2 theta +/-0.2 position by using an X-ray powder diffraction pattern, and the 2 theta is 6.73, 9.05, 14.29, 17.73, 19.73, 20.29, 20.99, 25.54, 27.30 and 32.67. The preparation method of the crystal form comprises the steps of heating and dissolving the Lioqiguat in DMSO, adding ethyl acetate, controlling the temperature, stirring, and filtering to obtain a filter cake A; adding ethyl acetate, heating to reflux, pulping, cooling, stirring, filtering to obtain filter cake B, and vacuum drying to obtain new crystal form of li ciguat. The novel crystal form of the linociguat 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.

Description

Novel crystal form of lis ciguat and preparation method thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a novel crystal form of li ciguat and a preparation method thereof.

Background

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, therapeutic effect, and the like. Therefore, in summary of pharmaceutical research processes, it is particularly important to consider different crystalline forms. Lioqiguat is reported in US patent US10414766B2 for its preparation and crystalline forms, and CN201480009667.6 for its different solvates including mono-DMSO solvate, sesqui-DMSO solvate etc. Wherein DMSO solvate has solvent toxicity and is not suitable for medicinal use. Therefore, there is a need in the art to systematically and comprehensively develop a new crystalline form of riociguat, thereby finding a new crystalline form with better solubility and suitable for pharmaceutical use. The application discovers a new crystal form with better stability, and provides a new and better choice for preparing the pharmaceutical preparation containing riociguat.

Disclosure of Invention

The invention provides a novel crystal form of Li ciguat and a preparation method thereof aiming at the defects in the background art, and the novel crystal form of Lioqiguat prepared by the method has good stability, is suitable for long-term storage and is suitable for pharmaceutical preparations.

In order to achieve the purpose, the technical solution of the invention is as follows:

a novel crystalline form of ciguat Li having a peak at 2 θ ± 0.2 according to an X-ray powder diffraction pattern, wherein the 2 θ is 6.73, 9.05, 14.29, 17.73, 19.73, 20.29, 20.99, 25.54, 27.30 or 32.67.

A method for preparing a novel crystal form of linagliptin , comprising the following steps:

step (I): heating the Lioqiguat to be clear by using 2 times volume of DMSO;

step (II): adding ethyl acetate with volume 14 times of that of the solution in the step (I), controlling the temperature, stirring for 0.5h, cooling, stirring for 4-5h, and filtering to obtain a filter cake A;

step (three): adding 14 times volume of ethyl acetate into the filter cake A obtained in the step (II), heating to reflux, pulping for 1h, cooling, stirring for 4-5h, and filtering to obtain a filter cake B;

step (IV): and (3) drying the filter cake B in the step (III) at 40-45 ℃ for 18-20h in vacuum to obtain the novel crystal form of the Lioqiguat.

Preferably, the temperature of the solution clear of the DMSO added in the step (one) is 70-80 ℃.

Preferably, the stirring temperature after adding the ethyl acetate in the step (two) is 70-80 ℃.

Preferably, the cooling temperature in the step (two) is 10-15 ℃.

Preferably, the cooling temperature in the step (three) is 10-15 ℃.

Compared with the prior art, the invention has the following beneficial effects:

the novel crystal form of the linociguat 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.

Drawings

Other features, objects and advantages of the present invention will become more apparent upon reading of the following detailed description of non-limiting embodiments thereof, with reference to the accompanying drawings.

FIG. 1 shows the X-ray powder diffraction pattern (intensity (count) -angle 2 θ (︒)) of the novel crystal form of rit ciguat.

Detailed Description

The novel crystal form of the linagliptin and the solvent used in the preparation method thereof provided by the invention can be purchased from the market. Detection conditions for X-ray powder diffraction in the present invention: the instrument comprises the following steps: SmartLab 3KW X-ray Diffractometer; conditions are as follows: cu K alpha, 40kV and 40 mA.

In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments.

Example 1

Heating 10g of Lioqiguat with 2 times volume of DMSO to 70 ℃ for dissolving, adding 14 times volume of ethyl acetate, controlling the temperature at 70 ℃, stirring for 0.5h, then cooling to 10 ℃, stirring for 4h, and filtering to obtain a filter cake A; adding ethyl acetate with volume of 14 times into the filter cake A, heating to reflux, pulping for 1h, cooling to 10 ℃, stirring for 4h, and filtering to obtain a filter cake B; and (3) drying the filter cake B at 40 ℃ for 18h in vacuum to obtain 4.6g of the new rilociguat crystal form.

Example 2

Heating 10g of Lioqiguat with 2 times volume of DMSO to 80 ℃ for dissolving, adding 14 times volume of ethyl acetate, controlling the temperature to 80 ℃, stirring for 0.5h, then cooling to 15 ℃, stirring for 5h, and filtering to obtain a filter cake A; adding ethyl acetate with volume of 14 times into the filter cake A, heating to reflux, pulping for 1h, cooling to 15 ℃, stirring for 5h, and filtering to obtain a filter cake B; and (3) drying the filter cake B at 45 ℃ for 20h in vacuum to obtain 4.2g of the new rilociguat crystal form.

Example 3

Heating 10g of Lioqiguat with 2 times volume of DMSO to 75 ℃ for dissolving, adding 14 times volume of ethyl acetate, controlling the temperature to be 75 ℃, stirring for 0.5h, then cooling to 12 ℃, stirring for 4.5h, and filtering to obtain a filter cake A; adding ethyl acetate with volume of 14 times to the filter cake A, heating to reflux, pulping for 1h, cooling to 12 ℃, stirring for 4.5h, and filtering to obtain a filter cake B; and (3) drying the filter cake B at 42 ℃ for 19h in vacuum to obtain 6.0g of the new rilociguat crystal form.

The novel crystalline form of rio ciguat obtained using the above examples 1-3 exhibits a pattern of peaks expressed in degrees 2 θ in the X-ray powder diffraction pattern as shown in the following table:

the crystalline powder of riociguat obtained in example 3 was examined for the effect of stability (including strong light irradiation, high temperature and high humidity). The related substances related to the invention are determined by referring to high performance liquid chromatography (appendix VD of 2010-ban, China pharmacopoeia, second part, VD), and the detection conditions and the method are as follows: the column was kromasil C18(150 x 4.6mm,5 μm); phosphate buffer solution (5 mmol/L potassium dihydrogen phosphate solution and 5mmol/L dipotassium hydrogen phosphate solution) is used as a mobile phase A, and acetonitrile is used as a mobile phase B; the detection wavelength is 230 nm; the linear gradient elution was performed as follows:

1. test for influence factor of strong light

Riociguat crystalline powder is taken out, placed in a light box of a fluorescent lamp with the light intensity of 4500 +/-500 Lx for 10 days, sampled respectively on the 5 th day and the 10 th day, and compared with the result of the 0 day. The results are shown in the following table:

note: the temperature changes by 20-25 ℃, and the relative humidity changes by 55-65%.

2. High temperature (60 ℃ C.) influential factor test

Riociguat crystalline powder is placed in a clean container, placed at 60 ℃ and 75% relative humidity for 10 days, sampled respectively on days 5 and 10, and compared with the results on day 0. The results are shown in the following table:

3. high humidity influence factor test

Riociguat crystalline powder was taken out and placed in a dry container (25 ℃ C., relative humidity 92.5%) containing a saturated potassium nitrate solution for 10 days, and samples were taken on the 5 th and 10 th days, respectively, and the results on the 0 th day were compared. The results are shown in the following table:

the test result shows that the riociguat crystal form obtained by the invention has no change in appearance under the conditions of illumination, high temperature and high humidity, the content of related substances basically has no change under the conditions of illumination, high temperature and high humidity, and the crystal form stability is good. By combining the above factors, the riociguat crystal form obtained by the invention is suitable for pharmaceutical application.

The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

1. A novel crystal form of Ri ciguat, which is characterized in that: it has a peak at 2 theta + -0.2 position with X-ray powder diffraction pattern, said 2 theta being 6.73, 9.05, 14.29, 17.73, 19.73, 20.29, 20.99, 25.54, 27.30 and 32.67.

2. The process for preparing a novel crystalline form of linagliptin according to claim 1, comprising the steps of:

step (I): heating the Lioqiguat to be clear by using 2 times volume of DMSO;

step (II): adding ethyl acetate with volume 14 times of that of the solution in the step (I), controlling the temperature, stirring for 0.5h, then cooling, stirring for 4-5h, and filtering to obtain a filter cake A;

3. The process for preparing a novel crystalline form of rit ciguat as claimed in claim 2, wherein: in the step (I), the temperature of the added DMSO solution is 70-80 ℃.

4. The process for preparing a novel crystalline form of rit ciguat as claimed in claim 2, wherein: and (2) stirring the mixture after adding the ethyl acetate in the step (II) at the temperature of between 70 and 80 ℃.

5. The process for preparing a novel crystalline form of rit ciguat as claimed in claim 2, wherein: the cooling temperature in the step (II) is 10-15 ℃.

6. The process for preparing a novel crystalline form of rit ciguat as claimed in claim 2, wherein: the cooling temperature in the step (III) is 10-15 ℃.