阅读说明：本技术 硫酸羟氯喹水合物、其晶型、其制备方法及其应用 (Hydroxychloroquine sulfate hydrate, crystal form thereof, preparation method and application thereof ) 是由 颜国明 洪鸣凰 齐明辉 任国宾 尹超 俞伟 李�杰 于 2020-11-16 设计创作，主要内容包括：本发明公开了一种硫酸羟氯喹水合物、其晶型、其制备方法及其应用。本发明的硫酸羟氯喹水合物,尤其是水合物的晶型B、C、D具有较好的吸湿稳定性,易于工业化生产,及后续的制剂操作,质量稳定可靠、具有较好的成药前景。(The invention discloses hydroxychloroquine sulfate hydrate, a crystal form thereof, a preparation method and application thereof. The hydroxychloroquine sulfate hydrate, especially the crystal form B, C, D of the hydrate, has good moisture absorption stability, is easy for industrial production and subsequent preparation operation, has stable and reliable quality and good patent medicine prospect.)

1. The hydroxychloroquine sulfate hydrate is characterized in that the hydroxychloroquine sulfate hydrate is a monohydrate, a dihydrate or a hemihydrate of hydroxychloroquine sulfate.

2. The hydrate of hydroxychloroquine sulfate of claim 1, wherein when said hydrate of hydroxychloroquine sulfate is hydroxychloroquine sulfate monohydrate, said hydroxychloroquine sulfate monohydrate is form B having characteristic diffraction peaks at 9.1 ± 0.2 °, 10.3 ± 0.2 °, 13.9 ± 0.2 °, 15.4 ± 0.2 °, 16.8 ± 0.2 °, 18.1 ± 0.2 °, 19.5 ± 0.2 °, 20.0 ± 0.2 °, 20.9 ± 0.2 °, 22.0 ± 0.2 °, 22.5 ± 0.2 °, 24.2 ± 0.2 °, 24.4 ± 0.2 °, 25.4 ± 0.2 °, 25.8 ± 0.2 °, 26.6 ± 0.2 °, 27.2 ± 0.2 °, 28.5 ± 0.2 ° and 32.0 ± 0.2 ° in an X-ray powder diffraction pattern expressed in terms of 2 Θ;

and/or, when the hydroxychloroquine sulfate hydrate is hydroxychloroquine sulfate dihydrate, the hydroxychloroquine sulfate dihydrate is form C, which has characteristic diffraction peaks at 9.2 ± 0.2 °, 10.0 ± 0.2 °, 10.4 ± 0.2 °, 11.3 ± 0.2 °, 12.4 ± 0.2 °, 17.1 ± 0.2 °, 17.9 ± 0.2 °, 18.6 ± 0.2 °, 20.9 ± 0.2 °, 21.6 ± 0.2 °, 25.6 ± 0.2 ° and 27.1 ± 0.2 ° in an X-ray powder diffraction pattern expressed by 2 θ angles;

and/or, when the hydroxychloroquine sulfate hydrate is hydroxychloroquine sulfate hemihydrate, the hydroxychloroquine sulfate hemihydrate is form D having characteristic diffraction peaks at 9.4 ± 0.2 °, 10.2 ± 0.2 °, 10.6 ± 0.2 °, 14.9 ± 0.2 °, 15.1 ± 0.2 °, 17.5 ± 0.2 °, 21.1 ± 0.2 °, 22.4 ± 0.2 ° and 24.0 ± 0.2 ° in an X-ray powder diffraction pattern expressed in terms of 2 θ angle.

3. The hydroxychloroquine sulfate hydrate of claim 2, wherein when said hydroxychloroquine sulfate hydrate is of form B, it has an X-ray powder diffraction pattern expressed in terms of 2 Θ angles having characteristic peaks at 9.1 ± 0.2 °, 10.3 ± 0.2 °, 11.6 ± 0.2 °, 12.0 ± 0.2 °, 13.4 ± 0.2 °, 13.9 ± 0.2 °, 14.5 ± 0.2 °, 15.4 ± 0.2 °, 15.7 ± 0.2 °, 16.1 ± 0.2 °, 16.8 ± 0.2 °, 18.1 ± 0.2 °, 19.5 ± 0.2 °, 20.0 ± 0.2 °, 20.9 ± 0.2 °, 22.0 ± 0.2 °, 22.5 ± 0.2 °, 23.2 ± 0.2 °, 23.5 ± 0.2 °, 24.2 ± 0.2 °, 24.4 ± 0.2 °, 25.25 ± 0.2 °,2 ± 0.25 ± 0.2 °,2 ± 0.29 ± 0.28 ± 0 °,2 ± 0.2 °,2 ± 0.29 ± 0 ° 2 ° and 2 ± 0.29 ± 0 ° 2 ± 0.2 ° 2 ± 0.29 ± 0 ° 2;

and/or, when the hydroxychloroquine sulfate hydrate is the crystal form C, the X-ray powder diffraction pattern thereof expressed by 2 theta angles has characteristic diffraction peaks at 9.2 +/-0.2 °, 10.0 +/-0.2 °, 10.4 +/-0.2 °, 11.3 +/-0.2 °, 12.4 +/-0.2 °, 14.4 +/-0.2 °, 15.2 +/-0.2 °, 17.1 +/-0.2 °, 17.9 +/-0.2 °, 18.6 +/-0.2 °, 20.9 +/-0.2 °, 21.6 +/-0.2 °, 21.9 +/-0.2 °, 23.0 +/-0.2 °, 24.0 +/-0.2 °, 25.6 +/-0.2 ° and 27.1 +/-0.2 °;

and/or, when the hydroxychloroquine sulfate hydrate is the crystal form D, the X-ray powder diffraction pattern expressed by 2 theta angles has characteristic diffraction peaks at 9.4 +/-0.2 degrees, 10.2 +/-0.2 degrees, 10.6 +/-0.2 degrees, 11.5 +/-0.2 degrees, 13.1 +/-0.2 degrees, 14.9 +/-0.2 degrees, 15.1 +/-0.2 degrees, 17.5 +/-0.2 degrees, 19.4 +/-0.2 degrees, 21.1 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.1 +/-0.2 degrees, 24.0 +/-0.2 degrees, 26.4 +/-0.2 degrees and 27.6 +/-0.2 degrees.

4. The hydroxychloroquine sulfate hydrate of claim 3, wherein when said hydroxychloroquine sulfate hydrate is form B, said hydroxychloroquine sulfate hydrate exhibits the following 2 θ values and peak relative intensities in an X-ray powder diffraction pattern expressed in terms of 2 θ angles as shown in the following Table:

and/or, when the hydroxychloroquine sulfate hydrate is in a crystal form B, the corresponding weight loss of the thermogravimetric analysis curve is 4.140% before 150 ℃;

and/or when the hydroxychloroquine sulfate hydrate is in a crystal form B, the water content of the crystal form is 3.73% as determined by Karl Fischer water analysis;

and/or, when the hydroxychloroquine sulfate hydrate is the crystal form C, the 2 theta values and the peak relative intensities in an X-ray powder diffraction pattern expressed by 2 theta angles are shown in the following table:

and/or, when the hydroxychloroquine sulfate hydrate is in the crystal form C, the corresponding weight loss of the thermogravimetric analysis curve before 150 ℃ is 8.176%;

and/or when the hydroxychloroquine sulfate hydrate is in a crystal form C, the water content of the crystal form is 7.98% as determined by Karl Fischer water analysis;

and/or, when the hydroxychloroquine sulfate hydrate is in a form D, the 2 theta values and the peak relative intensities in an X-ray powder diffraction pattern expressed by 2 theta angles are shown in the following table:

and/or, when the hydroxychloroquine sulfate hydrate is in a crystal form D, the corresponding weight loss of the thermogravimetric analysis curve before 150 ℃ is 2.422%;

and/or when the hydroxychloroquine sulfate hydrate is in a crystal form D, the water content of the crystal form is 2.13% as determined by Karl Fischer water analysis.

5. The hydroxychloroquine sulfate hydrate of claim 4, wherein when said hydroxychloroquine sulfate hydrate is form B, an X-ray powder diffraction pattern expressed in terms of 2 θ angles is shown in figure 2;

and/or, when the hydroxychloroquine sulfate hydrate is in the form B, the differential scanning calorimetry analysis curve is shown in figure 3;

and/or, when the hydroxychloroquine sulfate hydrate is in the form B, the thermogravimetric analysis curve is shown in figure 4;

and/or, when the hydroxychloroquine sulfate hydrate is in the form C, the X-ray powder diffraction pattern of the hydroxychloroquine sulfate hydrate expressed by the 2 theta angle is shown in figure 5;

and/or, when the hydroxychloroquine sulfate hydrate is in the form of crystal form C, a differential scanning calorimetry analysis curve is shown in fig. 6;

and/or, when the hydroxychloroquine sulfate hydrate is in the form of the crystal form C, the thermogravimetric analysis curve is shown in figure 7;

and/or, when the hydroxychloroquine sulfate hydrate is in a crystal form D, an X-ray powder diffraction pattern expressed by a 2 theta angle is shown in figure 8;

and/or, when the hydroxychloroquine sulfate hydrate is in the form of crystal form D, the differential scanning calorimetry analysis curve is shown in figure 9;

and/or, when the hydroxychloroquine sulfate hydrate is in the form D, the thermogravimetric analysis curve is shown in figure 10.

6. A process for the preparation of the hydrate of hydroxychloroquine sulfate according to any of claims 2 to 5, wherein when said hydrate of hydroxychloroquine sulfate is of form B, said process comprises the following steps: amorphous hydroxychloroquine sulfate is suspended in a first organic solvent for crystal transformation to obtain a crystal form B of hydroxychloroquine sulfate monohydrate; the first organic solvent is an ether solvent, a ketone solvent, a chloroalkane solvent, an ester solvent, 3-methyl-1-butanol or a combination thereof; the first organic solvent contains water, and the content of the water is 0.05-4 wt%;

or, when the hydroxychloroquine sulfate hydrate is in the crystal form C, the preparation method comprises the following steps: dissolving hydroxychloroquine sulfate in water, and carrying out crystallization to obtain a crystal form C of hydroxychloroquine sulfate dihydrate;

or, when the hydroxychloroquine sulfate hydrate is in a crystal form D, the preparation method comprises the following steps: and drying the crystal form C of the hydroxychloroquine sulfate dihydrate to obtain a crystal form D of the hydroxychloroquine sulfate hemihydrate.

7. The method of claim 6, wherein when the hydroxychloroquine sulfate hydrate is form B, the first organic solvent is m-xylene, anisole, phenetole, 2-methyltetrahydrofuran, 1, 4-dioxane, acetone, cyclohexanone, dichloromethane, 1, 2-dichloroethane, isopropyl acetate, dimethyl carbonate, 3-methyl-1-butanol, or a combination thereof;

and/or, when the hydroxychloroquine sulfate hydrate is in a crystal form B, the mass-to-volume ratio of the hydroxychloroquine sulfate amorphous form to the first organic solvent is 15-60 mg/mL;

and/or, when the hydroxychloroquine sulfate hydrate is in the crystal form B, the suspension is carried out under the stirring or shaking condition;

and/or when the hydroxychloroquine sulfate hydrate is in a crystal form B, the temperature of crystal transformation is 20-40 ℃;

and/or when the hydroxychloroquine sulfate hydrate is in a crystal form B, the crystal transformation time is 24-72 hours;

and/or, when the hydroxychloroquine sulfate hydrate is in the crystal form B, the preparation method further comprises a post-treatment step, wherein the post-treatment step is drying;

and/or, when the hydroxychloroquine sulfate hydrate is in the crystal form C, the mass-volume ratio of hydroxychloroquine sulfate to water is 0.5-2.5 g/mL;

and/or when the hydroxychloroquine sulfate hydrate is in a crystal form C, the crystallization mode is solvent volatilization;

and/or when the hydroxychloroquine sulfate hydrate is in a crystal form C, the crystallization temperature is 10-40 ℃;

and/or, when the hydroxychloroquine sulfate hydrate is in a crystal form D, the drying is blast drying;

and/or when the hydroxychloroquine sulfate hydrate is in a crystal form D, the drying temperature is 40-70 ℃;

and/or, when the hydroxychloroquine sulfate hydrate is in the form of the crystal form D, the drying time is 0.3-1 hour.

8. The preparation method according to claim 7, wherein when the hydroxychloroquine sulfate hydrate is form B, the mass to volume ratio of hydroxychloroquine sulfate to organic solvent is 37.5 mg/mL;

and/or, when the hydroxychloroquine sulfate hydrate is in a crystal form B and the post-treatment is drying, the drying temperature is 30-60 ℃; the drying time is 18-36 hours;

and/or when the hydroxychloroquine sulfate hydrate is in the crystal form C, the mass-to-volume ratio of hydroxychloroquine sulfate to water is 1.3025 g/mL;

and/or, when the hydroxychloroquine sulfate hydrate is in a crystal form D, the drying temperature is 60 ℃;

and/or, when the hydroxychloroquine sulfate hydrate is form D, the drying time is 0.5 hours.

9. A pharmaceutical composition comprising a hydrate of hydroxychloroquine sulfate as in any one of claims 1 to 5, and a pharmaceutically acceptable carrier.

10. Use of a hydrate of hydroxychloroquine sulfate as claimed in any one of claims 1 to 5 or a pharmaceutical composition as claimed in claim 9 for the manufacture of a medicament for the treatment of lupus erythematosus or rheumatoid arthritis.

Technical Field

The invention relates to hydroxychloroquine sulfate hydrate, a crystal form thereof, a preparation method and application thereof.

Background

Hydroxychloroquine Sulfate (Hydroxychloroquine Sulfate), chemical name: 2- [ [4- [ (7-chloro-4-quinolinyl) amino ] pentyl, ethylamino ] ethanol sulfate having CAS number: 747-36-40. Hydroxychloroquine sulfate was developed by Winthrop and first introduced into the United states in 1956, and was introduced into the market in France, Denmark, Japan, Germany, Finland and many other countries and regions. The American FDA approves the hydroxychloroquine sulfate tablet at 29/5 of 1998 to treat lupus erythematosus and rheumatoid arthritis. Hydroxychloroquine sulfate has become more and more widely used in the clinical application of the rheumatism field due to its unique action mechanism and better safety. After 90 years in the 20 world, hydroxychloroquine sulfate is selected for clinical treatment of more than 90% of rheumatism, and the structure of the hydroxychloroquine sulfate is as follows:

patent CN108727263A discloses a hydroxychloroquine sulfate crystal form a, which has characteristic diffraction peaks at 2 θ values of 16.9 °, 17.1 °, 17.5 °, 19.9 °, 21.3 °, 23.5 °, 23.9 °, and 26.7 °, and is obtained by mixing and crystallizing hydroxychloroquine, ethyl acetate, and/or ethanol, and a sulfuric acid aqueous solution with a mass fraction of 40-60%.

Polymorphism is the phenomenon that the same drug molecule exists in different crystal forms due to different crystal arrangement and filling modes. Because of the obvious difference of physicochemical properties of different polymorphic forms of the same medicine, such as solubility, dissolution rate, bioavailability, stability, fluidity, compression resistance and other mechanical properties, the properties have certain influence on the application of the medicine. Therefore, it is necessary to improve various properties of hydroxychloroquine sulfate by deeply researching the crystal form of hydroxychloroquine sulfate and related preparation methods.

Disclosure of Invention

The invention aims to overcome the defect of poor hygroscopicity of the hydroxychloroquine sulfate crystal form in the prior art, and provides a hydroxychloroquine sulfate hydrate, the hydroxychloroquine sulfate crystal form and a preparation method thereof. The hydroxychloroquine sulfate hydrate, especially the crystal form B, C, D of the hydrate, has good moisture absorption stability, is easy for industrial production and subsequent preparation operation, has stable and reliable quality and good patent medicine prospect.

The invention provides a hydroxychloroquine sulfate hydrate, which is a monohydrate, a dihydrate or a hemihydrate of hydroxychloroquine sulfate.

The invention also provides a hydroxychloroquine sulfate monohydrate crystal form B, which has characteristic diffraction peaks at 9.1 +/-0.2 degrees, 10.3 +/-0.2 degrees, 13.9 +/-0.2 degrees, 15.4 +/-0.2 degrees, 16.8 +/-0.2 degrees, 18.1 +/-0.2 degrees, 19.5 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.9 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.5 +/-0.2 degrees, 24.2 +/-0.2 degrees, 24.4 +/-0.2 degrees, 25.4 +/-0.2 degrees, 25.8 +/-0.2 degrees, 26.6 +/-0.2 degrees, 27.2 +/-0.2 degrees, 28.5 +/-0.2 degrees and 32.0 +/-0.2 degrees according to an X-ray powder diffraction pattern expressed by a 2 theta angle.

In one embodiment, the hydroxychloroquine sulfate monohydrate of form B, having, in an X-ray powder diffraction pattern expressed in terms of 2 Θ angles, the ± 0.2 ° at diffraction peaks at 9.1 ± 0.2 °, 10.3 ± 0.2 °, 11.6 ± 0.2 °, 12.0 ± 0.2 °, 13.4 ± 0.2 °, 13.9 ± 0.2 °, 14.5 ± 0.2 °, 15.4 ± 0.2 °, 15.7 ± 0.2 °, 16.1 ± 0.2 °, 16.8 ± 0.2 °, 18.1 ± 0.2 °, 19.5 ± 0.2 °, 20.0 ± 0.2 °, 20.9 ± 0.2 °, 22.0 ± 0.2 °, 22.5 ± 0.2 °, 23.2 ± 0.2 °, 23.5 ± 0.2 °, 24.2 ± 0.2 °, 24.4 ± 0.2 °, 25.4 ± 0.2 °, 25.8 ± 0.2 °, 26.2 °, 23.2 ± 0.2 °, 23.5 ± 0 ± 0.2 °,2 ± 0.29 ± 0.30 °,2 ± 0.30 ± 0 ± 0.30 °,2 ° and 29 ± 0 ± 0.30.30 °.

In one embodiment, the hydroxychloroquine sulfate monohydrate in crystalline form B, having peak widths and peak height relative intensities in an X-ray powder diffraction pattern expressed in terms of 2 Θ angles, is as shown in table 1:

TABLE 1

In one embodiment, the hydroxychloroquine sulfate monohydrate in crystalline form B has an X-ray powder diffraction pattern expressed in terms of 2 Θ angles substantially as shown in figure 2.

In one embodiment, the hydroxychloroquine sulfate monohydrate, in crystalline form B, has a Differential Scanning Calorimetry (DSC) curve substantially as shown in figure 3.

In one embodiment, the hydroxychloroquine sulfate monohydrate is in crystalline form B having a thermogravimetric analysis (TGA) curve corresponding to a weight loss of 4.140% before 150 ℃.

In one embodiment, the hydroxychloroquine sulfate monohydrate, form B, has a thermogravimetric analysis (TGA) curve substantially as shown in figure 4.

In one embodiment, the hydroxychloroquine sulfate monohydrate in form B has a water content of 3.73% as determined by karl fischer moisture (KF) analysis.

The invention provides a preparation method of a hydroxychloroquine sulfate monohydrate crystal form B, which comprises the following steps: amorphous hydroxychloroquine sulfate is suspended in a first organic solvent for crystal transformation to obtain a crystal form B of hydroxychloroquine sulfate monohydrate; the organic solvent in the first organic solvent is an ether solvent, a ketone solvent, a chloroalkane solvent, an ester solvent, 3-methyl-1-butanol or a combination thereof; the first organic solvent contains water, and the content of the water may be 0.05 to 4 wt%.

In the preparation method of the hydroxychloroquine sulfate monohydrate crystal form B, the organic solvent can be m-phenyl dimethyl ether, anisole, phenetole, 2-methyltetrahydrofuran, 1, 4-dioxane, acetone, cyclohexanone, dichloromethane, 1, 2-dichloroethane, isopropyl acetate, dimethyl carbonate, 3-methyl-1-butanol or a combination thereof.

In the preparation method of the hydroxychloroquine sulfate monohydrate crystal form B, the mass-to-volume ratio of the hydroxychloroquine sulfate amorphous form to the organic solvent may be 15-60mg/mL, for example 37.5 mg/mL.

In the preparation method of the hydroxychloroquine sulfate monohydrate crystal form B, the crystal transformation temperature can be a crystal transformation temperature conventional in the art, such as 20-40 ℃, for example, 25 ℃.

In the preparation method of the hydroxychloroquine sulfate monohydrate crystal form B, the time for crystal transformation is not particularly limited as long as crystals can be precipitated, for example, 24 to 72 hours, for example, 24, 48 or 63 hours.

In the preparation method of the hydroxychloroquine sulfate monohydrate crystal form B, the suspension can be carried out under the condition of stirring or shaking.

The preparation method of the hydroxychloroquine sulfate monohydrate crystal form B can further comprise post-treatment, and the post-treatment can be conventional post-treatment in the field, such as drying. The drying operation and conditions may be conventional in the art, and the drying is preferably vacuum drying. The drying temperature is preferably from 30 to 60 c, for example 35 c. The drying time is preferably 18 to 36 hours, for example 24 hours.

The preparation method of the hydroxychloroquine sulfate monohydrate crystal form B can further comprise the following steps: (1) carrying out rotary evaporation on a 2,2, 2-trifluoroethanol solution of the hydroxychloroquine sulfate crystal form A to remove a solvent to obtain an amorphous hydroxychloroquine sulfate; (2) suspending the obtained hydroxychloroquine sulfate amorphous form in the aqueous organic solvent for crystal transformation to obtain the crystal form B of hydroxychloroquine sulfate monohydrate. The mass volume of the hydroxychloroquine sulfate crystal form A and the 2,2, 2-trifluoroethanol solution is preferably 0.1-0.5g/mL, such as 0.33 g/mL. The rotary evaporation temperature may be as conventional in such operations as are conventional in the art, preferably from 40 to 70 ℃ and further for example 60 ℃.

The invention also provides a hydroxychloroquine sulfate dihydrate crystal form C, which has characteristic diffraction peaks at 9.2 +/-0.2 degrees, 10.0 +/-0.2 degrees, 10.4 +/-0.2 degrees, 11.3 +/-0.2 degrees, 12.4 +/-0.2 degrees, 17.1 +/-0.2 degrees, 17.9 +/-0.2 degrees, 18.6 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.6 +/-0.2 degrees, 25.6 +/-0.2 degrees and 27.1 +/-0.2 degrees in an X-ray powder diffraction pattern expressed by a 2 theta angle.

In one embodiment, the hydroxychloroquine sulfate dihydrate of form C, having an X-ray powder diffraction pattern expressed in terms of 2 Θ angles, has characteristic diffraction peaks at 9.2 ± 0.2 °, 10.0 ± 0.2 °, 10.4 ± 0.2 °, 11.3 ± 0.2 °, 12.4 ± 0.2 °, 14.4 ± 0.2 °, 15.2 ± 0.2 °, 17.1 ± 0.2 °, 17.9 ± 0.2 °, 18.6 ± 0.2 °, 20.9 ± 0.2 °, 21.6 ± 0.2 °, 21.9 ± 0.2 °, 23.0 ± 0.2 °, 24.0 ± 0.2 °, 25.6 ± 0.2 ° and 27.1 ± 0.2 °.

In one embodiment, the hydroxychloroquine sulfate dihydrate form C has a peak width and a peak height relative intensity in an X-ray powder diffraction pattern expressed in terms of 2 Θ angles as shown in table 2:

TABLE 2

In one embodiment, the hydroxychloroquine sulfate dihydrate in form C has an X-ray powder diffraction pattern, expressed in terms of 2 Θ angles, substantially as shown in figure 5.

In one embodiment, the hydroxychloroquine sulfate dihydrate in form C has a Differential Scanning Calorimetry (DSC) curve substantially as shown in figure 6.

In one embodiment, the hydroxychloroquine sulfate dihydrate form C has a thermogravimetric analysis (TGA) curve corresponding to a weight loss of 8.176% before 150 ℃.

In one embodiment, the hydroxychloroquine sulfate dihydrate form C has a thermogravimetric analysis (TGA) curve substantially as shown in figure 7.

In one embodiment, the hydroxychloroquine sulfate dihydrate form C has a water content of 7.98% as determined by karl fischer moisture (KF) analysis.

The invention provides a preparation method of a hydroxychloroquine sulfate dihydrate crystal form C, which comprises the following steps: and dissolving hydroxychloroquine sulfate in water, and carrying out crystallization to obtain the crystal form C of hydroxychloroquine sulfate dihydrate.

In the preparation method of the hydroxychloroquine sulfate dihydrate crystal form C, the mass-to-volume ratio of hydroxychloroquine sulfate to water can be 0.5-2.5g/mL, such as 1.3025 g/mL.

In the preparation method of the hydroxychloroquine sulfate dihydrate crystal form C, the crystallization mode can be a crystallization mode conventional in the art, such as solvent volatilization.

In the preparation method of the hydroxychloroquine sulfate dihydrate crystal form C, the crystallization temperature can be a crystallization temperature conventional in the art, for example, 10-40 ℃.

The invention provides a hydroxychloroquine sulfate hemihydrate crystal form D, which has characteristic diffraction peaks at 9.4 +/-0.2 degrees, 10.2 +/-0.2 degrees, 10.6 +/-0.2 degrees, 14.9 +/-0.2 degrees, 15.1 +/-0.2 degrees, 17.5 +/-0.2 degrees, 21.1 +/-0.2 degrees, 22.4 +/-0.2 degrees and 24.0 +/-0.2 degrees in an X-ray powder diffraction pattern expressed by a 2 theta angle.

In one embodiment, form D of the hydroxychloroquine sulfate hemihydrate, having characteristic diffraction peaks at 9.4 ± 0.2 °, 10.2 ± 0.2 °, 10.6 ± 0.2 °, 11.5 ± 0.2 °, 13.1 ± 0.2 °, 14.9 ± 0.2 °, 15.1 ± 0.2 °, 17.5 ± 0.2 °, 19.4 ± 0.2 °, 21.1 ± 0.2 °, 22.4 ± 0.2 °, 23.1 ± 0.2 °, 24.0 ± 0.2 °, 26.4 ± 0.2 ° and 27.6 ± 0.2 °, in an X-ray powder diffraction pattern expressed in terms of 2 Θ angles.

In one embodiment, the hydroxychloroquine sulfate hemihydrate, in crystal form D, exhibits a peak width and a peak height relative intensity in an X-ray powder diffraction pattern expressed in terms of 2 Θ angles as shown in table 3:

TABLE 3

In one embodiment, the hydroxychloroquine sulfate hemihydrate, in crystalline form D, has an X-ray powder diffraction pattern, expressed in terms of 2 Θ angles, substantially as shown in figure 8.

In one embodiment, the hydroxychloroquine sulfate hemihydrate, in crystalline form D, has a Differential Scanning Calorimetry (DSC) curve substantially as shown in figure 9.

In one embodiment, the hydroxychloroquine sulfate hemihydrate, form D, has a thermogravimetric analysis (TGA) curve corresponding to a weight loss of 2.422% prior to 150 ℃.

In one embodiment, the hydroxychloroquine sulfate hemihydrate, form D, has a thermogravimetric analysis (TGA) curve substantially as shown in figure 10.

In one embodiment, the hydroxychloroquine sulfate hemihydrate is in crystalline form D having a water content of 2.13% as determined by karl fischer moisture (KF) analysis.

The invention also provides a preparation method of the hydroxychloroquine sulfate hemihydrate crystal form D, which comprises the following steps: and drying the crystal form C of the hydroxychloroquine sulfate dihydrate to obtain a crystal form D of the hydroxychloroquine sulfate hemihydrate.

In the preparation method of the hydroxychloroquine sulfate hemihydrate crystal form D, the drying operation and conditions may be conventional in the art, for example, the drying may be air-blast drying. The drying temperature may be 40 to 70 ℃, for example 60 ℃. The drying time may be 0.3 to 1 hour, for example 0.5 hour.

The invention also provides a pharmaceutical composition, which comprises the hydroxychloroquine sulfate hydrate and a pharmaceutically acceptable carrier.

The invention also provides an application of the hydroxychloroquine sulfate hydrate or the pharmaceutical composition in preparing a medicament for treating lupus erythematosus or rheumatoid arthritis.

In the present invention, the X-ray powder diffraction patterns are all measured using the Ka line of the Cu target.

In the present invention, said form a of hydroxychloroquine sulfate can be synthesized according to examples 2-19 of patent CN 108727263A.

On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

The reagents used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the hydroxychloroquine sulfate hydrate, especially the crystal form B, C, D of the hydrate, has good moisture absorption stability, simple and feasible preparation method, easy industrial production and subsequent preparation operation, stable and reliable quality and good patent medicine prospect.

Terms and definitions

In the present invention, the term "pharmaceutical composition" refers to a formulation of duloxetine hydrochloride form D of the present invention with carriers, excipients and/or vehicles generally accepted in the art for the delivery of biologically active compounds to organisms (e.g. humans). The purpose of the pharmaceutical composition is to facilitate the administration of duloxetine hydrochloride form D of the present invention to an organism.

In the present invention, the term "pharmaceutically acceptable carrier" refers to carriers and diluents which do not significantly irritate the organism and do not impair the biological activity and performance of the active compound, and includes, but is not limited to, any carrier, excipient, vehicle, glidant, sweetener, diluent, preservative, dye/colorant, taste-modifying enhancer, surfactant, wetting agent, dispersing agent, disintegrating agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifier which can be used in humans or livestock animals. Non-limiting examples of such excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, and the like.

Administration of a compound of the invention in pure form or in a suitable pharmaceutical composition may be carried out by any acceptable mode of administration providing agents of similar use. The pharmaceutical compositions of the present invention can be prepared by combining a compound of the present invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into solid, semi-solid, liquid or gaseous formulations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

Drawings

FIG. 1 is an amorphous X-ray powder diffraction (XRPD) pattern of hydroxychloroquine sulfate prepared in example 1;

FIG. 2 is an X-ray powder diffraction (XRPD) pattern of form B of hydroxychloroquine sulfate monohydrate prepared in example 2;

FIG. 3 is a Differential Scanning Calorimetry (DSC) curve of form B of hydroxychloroquine sulfate monohydrate prepared in example 2;

FIG. 4 is a thermogravimetric analysis (TGA) curve of form B of hydroxychloroquine sulfate monohydrate prepared in example 2;

FIG. 5 is an X-ray powder diffraction (XRPD) pattern of form C of hydroxychloroquine sulfate dihydrate prepared in example 5;

FIG. 6 is a Differential Scanning Calorimetry (DSC) curve of form C of hydroxychloroquine sulfate dihydrate prepared in example 5;

FIG. 7 is a thermogravimetric analysis (TGA) curve of form C of hydroxychloroquine sulfate dihydrate prepared in example 5;

FIG. 8 is an X-ray powder diffraction (XRPD) pattern of form D of hydroxychloroquine sulfate hemihydrate prepared as in example 6;

FIG. 9 is a Differential Scanning Calorimetry (DSC) curve of form D of hydroxychloroquine sulfate hemihydrate prepared in example 6;

FIG. 10 is a thermogravimetric analysis (TGA) curve of crystalline form D of hydroxychloroquine sulfate hemihydrate made in example 6.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

The reagents and methods employed in the examples of the invention are conventional in the art. It will be clear to those skilled in the art that, unless otherwise specified, temperatures are expressed in degrees Celsius (C.) and operating temperatures are carried out at ambient temperature, which is between 10℃ and 30℃, preferably between 20℃ and 25℃.

The detection method comprises the following steps:

1. x-ray powder diffraction (XRPD)

A Rigaku Ultima IV powder diffractometer was used, which was irradiated with Cu-Ka (40kV, 40mA) at room temperature using a D/tex Ultra detector. The scan range is from 3 ° to 45 ° in the 2 θ interval, and the scan speed is 20 °/min.

The differences in measurements associated with such X-ray powder diffraction analysis results arise from a number of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors in determining peak position), and (e) properties of the substance (e.g., preferred orientation errors). Calibration errors and sample height errors often result in a shift of all peaks in the same direction. When a flat holder is used, small differences in sample height will result in large shifts in XRPD peak positions. Systematic studies show that sample height differences of 1mm can result in peak shifts of 2 θ up to 1 °. These shifts can be identified from the X-ray diffraction patterns and can be eliminated by compensating for them (using the system calibration factor for all peak position values) or recalibrating the instrument. As described above, measurement errors from different instruments can be corrected by applying a system calibration factor to make the peak positions consistent.

2. Differential Scanning Calorimetry (DSC)

Using a TA Q2000 differential scanning calorimeter, N₂The gas flow rate is 50mL/min, and the temperature rise rate is 10 ℃/min.

3. Thermogravimetric analysis (TGA)

Using a TA Q500 thermogravimetric analyzer, N₂The gas flow rate is 50mL/min, and the temperature rise rate is 10 ℃/min.

4. Karl Fischer moisture (KF) analysis

A Mettler Toledo V20 Karl Fischer moisture meter is adopted, after the instrument is balanced and calibrated, a finely ground crystal form B powder sample is accurately weighed and placed in a titration cell, the solvent is a solvent (absolute methanol) for single-component titration, stirring is carried out for 5min, so that all water in the sample is dissolved out, and after the Karl Fischer titrant is titrated to an end point, the recorded sample quality is input. Repeating for 3 times, taking the average value as the measurement result, and obtaining the result which is accurate to 2 bits after the decimal point.

Due to differences in the detection instruments and variations in the detection conditions, there may be detection errors in XRPD, DSC, TGA, and KF. Detection errors should be taken into account when screening and determining various crystal forms.

Example 1: preparation of hydroxychloroquine sulfate amorphous form

Taking 3g of hydroxychloroquine sulfate crystal form A (synthesized according to example 2 of patent CN 108727263A), adding 9mL of 2,2, 2-trifluoroethanol, stirring, dissolving, placing in a rotary evaporator, performing rotary evaporation at the temperature of 60 ℃ and the rotating speed of 100rpm, and performing rotary drying to obtain the title product. The product was in an amorphous state as detected by XRPD, and its XRPD pattern is shown in FIG. 1.

Example 2: preparation of crystal form B of hydroxychloroquine sulfate monohydrate

300mg of the hydroxychloroquine sulfate amorphous prepared in example 1 was taken, 8mL of m-xylylene ether (water containing impurities, water content 0.1 wt%) was added, the mixture was put in a shaker at 25 ℃ and 250rpm, shaken for 48 hours, and then filtered. The sample obtained by filtration was dried in a vacuum oven (degree of vacuum-0.1 MPa) at 35 ℃ for 24h to give the title product. The XRPD detected product was form B, which has the following peak widths and peak heights relative intensities in the X-ray powder diffraction pattern expressed in terms of 2 θ angles:

the XRPD pattern is shown in figure 2.

The DSC spectrum is shown in figure 3.

The TGA profile is shown in fig. 4, showing a corresponding weight loss of 4.140% for the sample before 150 ℃. Calculating the ratio of the hydroxychloroquine sulfate to the water according to the molecular weight of the hydroxychloroquine sulfate to be 1: 1.04.

the sample was analyzed for water content by karl fischer moisture (KF) of 3.73%. The ratio of hydroxychloroquine sulfate to water is 1:0.94 according to the molecular weight of hydroxychloroquine sulfate.

The moisture analysis result and the TGA test result both show that the ratio of hydroxychloroquine sulfate to water in the crystal form B is close to 1:1, which indicates that the crystal form B is a monohydrate.

Example 3: preparation of crystal form B of hydroxychloroquine sulfate monohydrate

300mg of the hydroxychloroquine sulfate amorphous prepared in example 1 was taken, 8mL of 3-methyl-1-butanol (containing impurity water and 0.1 wt% of water) was added, and the mixture was put in a shaker at 25 ℃ and 250rpm, shaken for 24 hours and then filtered. The sample obtained by filtration was dried in a vacuum oven (degree of vacuum-0.1 MPa) at 35 ℃ for 24h to give the title product. The XRPD detection result shows that the product is hydroxychloroquine sulfate monohydrate crystal form B, and the identification data are basically the same as in example 2.

Example 4: preparation of crystal form B of hydroxychloroquine sulfate monohydrate

300mg of the hydroxychloroquine sulfate amorphous prepared in example 1 was taken, 8mL of acetone (containing impurity water and 3 wt% of water) was added, the mixture was placed in a shaker at 25 ℃ and 250rpm, shaken for 63 hours, and then filtered. The sample obtained by filtration was dried in a vacuum oven (degree of vacuum-0.1 MPa) at 35 ℃ for 24h to give the title product. The XRPD detection result shows that the product is hydroxychloroquine sulfate monohydrate crystal form B, and the identification data are basically the same as in example 2.

Example 5: preparation of crystal form B of hydroxychloroquine sulfate monohydrate

300mg of the hydroxychloroquine sulfate amorphous prepared in example 1 was taken, 20mL of anisole (containing impurity water and 0.1 wt% of water) was added, the mixture was placed on a shaker at 25 ℃ and 250rpm, shaken for 48 hours, and then filtered. The sample obtained by filtration was dried in a vacuum oven (degree of vacuum-0.1 MPa) at 35 ℃ for 24h to give the title product. The XRPD detection result shows that the product is hydroxychloroquine sulfate monohydrate crystal form B, and the identification data are basically the same as in example 2.

Example 6: preparation of crystal form B of hydroxychloroquine sulfate monohydrate

300mg of the hydroxychloroquine sulfate amorphous prepared in example 1 was taken, 5mL of phenetole (containing impurity water, water content 0.1 wt%) was added, the mixture was placed in a shaker at 25 ℃ and 250rpm, shaken for 48 hours, and then filtered. The sample obtained by filtration was dried in a vacuum oven (degree of vacuum-0.1 MPa) at 35 ℃ for 24h to give the title product. The XRPD detection result shows that the product is hydroxychloroquine sulfate monohydrate crystal form B, and the identification data are basically the same as in example 2.

Example 7: preparation of crystal form B of hydroxychloroquine sulfate monohydrate

300mg of the hydroxychloroquine sulfate amorphous prepared in example 1 was taken, 8mL of 2-methyltetrahydrofuran (containing impurity water and water content of 2 wt%) was added, the mixture was placed in a shaker at 25 ℃ and 250rpm, shaken for 48 hours, and then filtered. The sample obtained by filtration was dried in a vacuum oven (degree of vacuum-0.1 MPa) at 35 ℃ for 24h to give the title product. The XRPD detection result shows that the product is hydroxychloroquine sulfate monohydrate crystal form B, and the identification data are basically the same as in example 2.

Example 8: preparation of crystal form B of hydroxychloroquine sulfate monohydrate

300mg of the hydroxychloroquine sulfate amorphous prepared in example 1 was taken, 8mL of 1, 4-dioxane (containing impurity water and water content of 2 wt%) was added, the mixture was placed in a shaker at 25 ℃ and 250rpm, shaken for 48 hours and then filtered. The sample obtained by filtration was dried in a vacuum oven (degree of vacuum-0.1 MPa) at 35 ℃ for 24h to give the title product. The XRPD detection result shows that the product is hydroxychloroquine sulfate monohydrate crystal form B, and the identification data are basically the same as in example 2.

Example 9: preparation of crystal form B of hydroxychloroquine sulfate monohydrate

300mg of the hydroxychloroquine sulfate amorphous prepared in example 1 was taken, 8mL of cyclohexanone (containing impurity water and having a water content of 0.5 wt%) was added, the mixture was placed in a shaker at 25 ℃ and 250rpm, shaken for 63 hours, and then filtered. The sample obtained by filtration was dried in a vacuum oven (degree of vacuum-0.1 MPa) at 35 ℃ for 24h to give the title product. The XRPD detection result shows that the product is hydroxychloroquine sulfate monohydrate crystal form B, and the identification data are basically the same as in example 2.

Example 10 preparation of Hydroxychloroquine sulfate monohydrate form B

300mg of the hydroxychloroquine sulfate amorphous prepared in example 1 was taken, 8mL of dichloromethane (containing impurity water and 0.1 wt% of water) was added, the mixture was placed on a shaker at 25 ℃ and 250rpm, shaken for 48 hours, and then filtered. The sample obtained by filtration was dried in a vacuum oven (degree of vacuum-0.1 MPa) at 35 ℃ for 24h to give the title product. The XRPD detection result shows that the product is hydroxychloroquine sulfate monohydrate crystal form B, and the identification data are basically the same as in example 2.

Example 11 preparation of Hydroxychloroquine sulfate monohydrate form B

300mg of the hydroxychloroquine sulfate amorphous prepared in example 1 was taken, 8mL of 1, 2-dichloroethane (containing water as an impurity and 0.05 wt% of water) was added, the mixture was placed in a shaker at 25 ℃ and 250rpm, shaken for 48 hours, and then filtered. The sample obtained by filtration was dried in a vacuum oven (degree of vacuum-0.1 MPa) at 35 ℃ for 24h to give the title product. The XRPD detection result shows that the product is hydroxychloroquine sulfate monohydrate crystal form B, and the identification data are basically the same as in example 2.

Example 12 preparation of Hydroxychloroquine sulfate monohydrate form B

300mg of the hydroxychloroquine sulfate amorphous prepared in example 1 was taken, 8mL of isopropyl acetate (containing impure water and having a water content of 0.2 wt%) was added, the mixture was placed on a shaker at 25 ℃ and 250rpm, shaken for 48 hours, and then filtered. The sample obtained by filtration was dried in a vacuum oven (degree of vacuum-0.1 MPa) at 35 ℃ for 24h to give the title product. The XRPD detection result shows that the product is hydroxychloroquine sulfate monohydrate crystal form B, and the identification data are basically the same as in example 2.

Example 13 preparation of Hydroxychloroquine sulfate monohydrate form B

300mg of the hydroxychloroquine sulfate amorphous prepared in example 1 was taken, 8mL of dimethyl carbonate (containing impurity water and 0.2 wt% of water) was added, the mixture was placed on a shaker at 25 ℃ and 250rpm, shaken for 48 hours, and then filtered. The sample obtained by filtration was dried in a vacuum oven (degree of vacuum-0.1 MPa) at 35 ℃ for 24h to give the title product. The XRPD detection result shows that the product is hydroxychloroquine sulfate monohydrate crystal form B, and the identification data are basically the same as in example 2.

Example 14: preparation of crystal form C of hydroxychloroquine sulfate dihydrate

5.21g of hydroxychloroquine sulfate form A (synthesized according to example 2 of patent CN 108727263A) were weighed, dissolved in 4mL of purified water with stirring, filtered and evaporated to dryness in the open at room temperature to give the title product. The product is a hydroxychloroquine sulfate dihydrate crystal form C detected by XRPD, and the peak width and the peak height relative intensity in an X-ray powder diffraction pattern expressed by a 2 theta angle are as follows:

the XRPD pattern is shown in figure 5.

The DSC spectrum is shown in figure 6.

The TGA profile is shown in fig. 7, showing that the corresponding weight loss of the sample before 150 ℃ is 8.176%. Calculating the ratio of the hydroxychloroquine sulfate to the water according to the molecular weight of the hydroxychloroquine sulfate to be 1: 2.13.

the water content of the sample was 7.98% by karl fischer moisture (KF) analysis. Calculating the ratio of the hydroxychloroquine sulfate to the water according to the molecular weight of the hydroxychloroquine sulfate to be 1: 2.08.

the moisture analysis result and the TGA test result both show that the ratio of hydroxychloroquine sulfate to water in the crystal form C is close to 1:2, which indicates that the crystal form C is a dihydrate.

Example 15: preparation of hydroxychloroquine sulfate hemihydrate in crystal form D

The hydroxychloroquine sulfate dihydrate form C was dried in a 60 ℃ forced air drying oven for 0.5h to give the title product. The XRPD detection result shows that the product is hydroxychloroquine sulfate hemihydrate crystal form D, and the peak width and the peak height relative intensity in an X-ray powder diffraction pattern expressed by a 2 theta angle are as follows:

the XRPD pattern is shown in figure 8.

The DSC spectrum is shown in figure 9.

The TGA profile is shown in fig. 10, showing that the corresponding weight loss of the sample before 150 ℃ is 2.422%. Calculating the ratio of the hydroxychloroquine sulfate to the water according to the molecular weight of the hydroxychloroquine sulfate to be 1: 0.61.

the water content of the sample was 2.13% by karl fischer moisture (KF) analysis. Calculating the ratio of the hydroxychloroquine sulfate to the water according to the molecular weight of the hydroxychloroquine sulfate to be 1: 0.53.

the moisture analysis result and the TGA test result both show that the ratio of hydroxychloroquine sulfate to water in the crystal form D is close to 1:0.5, which indicates that the crystal form D is hemihydrate.

Effect example 1: comparison of hygroscopicity of hydroxychloroquine sulfate in different crystal forms

About 30mg of hydroxychloroquine sulfate crystal form a (synthesized according to example 2 of patent CN 108727263A) and the hydroxychloroquine sulfate hydrate crystal form B, C, D of the present invention were precisely weighed on a DVS built-in balance, and DVS analysis was performed using a dynamic moisture adsorption tester (DVS Intrinsic, Surface Measurement Systems), at a temperature: 25 ℃; gas: nitrogen gas; airflow: 200+70 sccm; humidity range (RH%): 50-70% (higher humidity range is not determined because the moisture content is more than 70% and the phenomenon of deliquescence occurs); 10% RH one step. And (4) judging the standard: the change in body weight was less than 0.02% in 10 minutes and the maximum time per step was limited to 360 minutes. The percent weight gain was calculated from the test results. The results are shown in Table 4:

table 4: results of testing hygroscopicity of hydroxychloroquine sulfate in different crystal forms

Crystal form	A	B	C	D
					Weight gain (%)	7.96	0.55	2.78	3.87

The result shows that the hygroscopicity of the hydroxychloroquine sulfate hydrate crystal form B, C, D is superior to that of the crystal form A in the conventional humidity range, and the hydroxychloroquine sulfate hydrate crystal form A is beneficial to links such as drug production, storage, subsequent preparation processing and the like.