Crystal forms of demethyleneberberine hydrochloride and preparation method therefor

Patent metadata

Field	Value
Publication number	US-11242340-B2
Application number	US-201816960810-A
Country	US
Kind code	B2
Filing date	Jul 12, 2018
Priority date	Feb 6, 2018
Publication date	Feb 8, 2022
Grant date	Feb 8, 2022

Abstract

Provided are four crystal forms, A, B, C and D, of demethyleneberberine hydrochloride, and a preparation method therefor, and further provided are X-ray powder diffraction characteristic absorption peaks, infrared absorption peaks and DSC spectra of the four crystal forms. The X-ray powder diffraction characteristic diffraction peaks of the crystal forms are at about 8.205°, 8.805°, 10.817°, 14.835°, 15.479°, 16.668°, 17.492°, 18.529°, 20.656°, 21.536°, 23.538°, 25.657°, 26.192°, and 28.808°. A preparation method for the four crystal forms of the demethyleneberberine hydrochloride is also involved. The preparation method has a simple process, a high yield and a low cost; and has a high product purity and a stable quality.

First claim

The invention claimed is:

1. A crystal form of demethyleneberberine hydrochloride selected from:
A) a crystal form designated as crystal form A, characterized in that, it has characteristic diffraction peaks at 6.838, 8.300, 12.477, 13.667, 16.269, 16.642, 17.761, 18.247, 18.749, 20.389, 20.739, 21.926, 22.530, 23.983, 24.819, 25.774, 26.413, 26.592, 28.552, 30.333, and 38.312° in an X-ray powder diffraction spectrum represented by Cu-Kα radiation and 20±0.2° diffraction angle; one thermal absorption peak at 240±3° C. in a DSC thermogram; and characteristic infrared absorption peaks at 422.8 cm −1 , 454.3 cm −1 , 466.6 cm −1 , 505.6 cm −1 , 581.8 cm −1 , 617.7 cm −1 , 658.5 cm −1 , 739.3 cm −1 , 774.6 cm −1 , 820.3 cm −1 , 871.8 cm −1 , 892.6 cm −1 , 917.5 cm −1 , 962.6 cm −1 , 983.2 cm −1 , 999.7 cm −1 , 1,050.0 cm −1 , 1,067.8 cm −1 , 1,110.5 cm −1 , 1,140.5 cm −1 , 1,203.4 cm −1 , 1,244.5 cm −1 , 1,268.1 cm −1 , 1,293.8 cm −1 , 1,337.1 cm −1 , 1,363.8 cm −1 , 1,390.5 cm −1 , 1,455.5 cm −1 , 1,493.9 cm −1 , 1,515.6 cm −1 , 1,530.5 cm −1 , 1,567.1 cm −1 , 1,605.6 cm −1 , 1,638.0 cm −1 , 1,769.6 cm −1 , 2,726.3 cm −1 , 2,847.6 cm −1 , 2,945.2 cm −1 , 3,024.2 cm −1 , 3,065.1 cm −1 , 3,086.0 cm −1 , and 3,150.6 cm −1 ;
B) a crystal form designated as crystal form B, characterized in that, it has characteristic diffraction peaks at 6.838, 8.300, 12.477, 13.667, 16.269, 16.642, 17.761, 18.247, 18.749, 20.389, 20.739, 21.926, 22.530, 23.983, 24.819, 25.774, 26.413, 26.592, 28.552, 30.333, and 38.312° in an X-ray powder diffraction spectrum represented by Cu-Kα radiation and 20±0.2° diffraction angle; two thermal absorption peaks at 147±3° C. and 220±3° C. respectively in a DSC thermogram; and characteristic infrared absorption peaks at 421.5 cm −1 , 448.0 cm −1 , 464.4 cm −1 , 506.1 cm −1 , 523.9 cm −1 , 543.5 cm −1 , 568.8 cm −1 , 583.9 cm −1 , 618.9 cm −1 , 649.1 cm −1 , 676.8 cm −1 , 718.3 cm −1 , 742.1 cm −1 , 777.5 cm −1 , 833.0 cm −1 , 859.8 cm −1 , 878.7 cm −1 , 924.5 cm −1 , 960.4 cm −1 , 977.7 cm −1 , 1,018.9 cm −1 , 1,060.0 cm −1 , 1,107.7 cm −1 , 1,138.4 cm −1 , 1,170.1 cm −1 , 1,207.4 cm −1 , 1,243.9 cm −1 , 1,268.6 cm −1 , 1,366.8 cm −1 , 1,388.7 cm −1 , 1,422.7 cm −1 , 1,445.5 cm −1 , 1,457.3 cm −1 , 1,492.8 cm −1 , 1,517.8 cm −1 , 1,533.9 cm −1 , 1,568.8 cm −1 , 1,610.9 cm −1 , 1,636.9 cm −1 , 1,735.5 cm −1 , 2,646.6 cm −1 , 2,849.8 cm −1 , 2,952.5 cm −1 , 2,993.5 cm −1 , 3,089.6 cm −1 , and 3,364.3 cm −1 ;
C) a crystal form designated as crystal form C, characterized in that, it has characteristic diffraction peaks at 3.260, 8.515, 9.715, 12.147, 13.219, 14.789, 17.607, 18.306, 20.728, 21.261, 24.633, 25.430, 25.837, 26.416, 27.606, 28.147, and 37.695° in an X-ray powder diffraction spectrum represented by Cu-Kα radiation and 20±0.2° diffraction angle; one thermal absorption peak at 253±3° C. in a DSC thermogram; and characteristic infrared absorption peaks at 422.8 cm −1 , 441.6 cm −1 , 452.2 cm −1 , 505.0 cm −1 , 526.2 cm −1 , 584.6 cm −1 , 637.3 cm −1 , 652.0 cm −1 , 665.7 cm −1 , 699.9 cm −1 , 723.4 cm −1 , 742.0 cm −1 , 774.1 cm −1 , 814.2 cm −1 , 828.2 cm −1 , 869.6 cm −1 , 891.7 cm −1 , 915.6 cm −1 , 964.5 cm −1 , 980.6 cm −1 , 998.8 cm −1 , 1,065.8 cm −1 , 1,108.5 cm −1 , 1,139.7 cm −1 , 1,192.2 cm −1 , 1,216.5 cm −1 , 1,241.0 cm −1 , 1,273.9 cm −1 , 1,287.4 cm −1 , 1,308.2 cm −1 , 1,343.5 cm −1 , 1,356.5 cm −1 , 1,389.3 cm −1 , 1,420.2 cm −1 , 1,437.9 cm −1 , 1,456.1 cm −1 , 1,510.2 cm −1 , 1,565.5 cm −1 , 1,580.9 cm −1 , 1,604.3 cm −1 , 1,618.6 cm −1 , 1,633.2 cm −1 , 2,697.9 cm −1 , 2,842.7 cm −1 , 2,946.1 cm −1 , 3,005.3 cm −1 , and 3,066.4 cm −1 ; and
D) a crystal form designated as crystal form D, characterized in that, it has characteristic diffraction peaks at about 6.034, 8.699, 12.589, 18.108, 21.854, 24.224, 25.146 and 26.172° in an X-ray powder diffraction spectrum represented by Cu-Kα radiation and 2θ diffraction angle; two thermal absorption peaks at 131±3° C. and 190±3° C. respectively in a DSC thermogram; and characteristic infrared absorption peaks at 422.8 cm −1 , 454.3 cm −1 , 466.6 cm −1 , 505.6 cm −1 , 581.8 cm −1 , 617.7 cm −1 , 658.5 cm −1 , 739.3 cm −1 , 774.6 cm −1 , 820.3 cm −1 , 871.8 cm −1 , 892.6 cm −1 , 917.5 cm −1 , 962.6 cm −1 , 983.2 cm −1 , 999.7 cm −1 , 1,050.0 cm −1 , 1,067.8 cm −1 , 1,110.5 cm −1 , 1,140.5 cm −1 , 1,203.4 cm −1 , 1,244.5 cm −1 , 1,268.1 cm −1 , 1,293.8 cm −1 , 1,337.1 cm −1 , 1,363.8 cm −1 , 1,390.5 cm −1 , 1,455.5 cm −1 , 1,493.9 cm −1 , 1,515.6 cm −1 , 1,530.5 cm −1 , 1,567.2 cm −1 , 1,605.6 cm −1 , 1,638.0 cm −1 , 1,769.6 cm −1 , 2,726.3 cm −1 , 2,847.6 cm −1 , 2,945.2 cm −1 , 3,024.2 cm −1 , 3,065.1 cm −1 , 3,086.0 cm −1 , and 3,150.6 cm −1 .

2. A method for preparing the crystal foil is of demethyleneberberine hydrochloride according to claim 1 , comprising the following steps:
(1) adding 4 g of phloroglucinol into 100 ml of 40%-60% sulfuric acid, and stirring, so that the phloroglucinol is dissolved;
(2) adding 5 g of berberine hydrochloride into the solution obtained in the step (1), and stirring for 2 h at 80° C.-100° C.;
(3) adding the solution obtained in the step (2) into 100 ml of saturated salt solution, and stirring for 2 h;
(4) filtering the mixed solution obtained in the step (3) by suction-filtration, dissolving filter cake with 100 ml of methanol in water bath at 70° C., and recrystallizing;
(5) filtering the solution obtained in the step (4) by suction-filtration, dissolving filter cake with 100 ml of methanol in water bath at 70° C., recrystallizing, and performing suction-filtration;
(6) drying a yellow solid obtained in the step (5) by vacuum drying for 24 h at room temperature, so that a crystal form B of demethyleneberberine hydrochloride is obtained;
(7) filtering the solution obtained in the step (4) by suction-filtration, dissolving filter cake with 100 ml of ethanol in water bath at 80° C., recrystallizing, and performing suction-filtration;
(8) drying a yellow solid obtained in the step (7) by vacuum drying for 24 h at room temperature, so that a crystal form C of demethyleneberberine hydrochloride is obtained;
(9) filtering the solution obtained in the step (4) by suction-filtration, dissolving 1 g of filter cake with 12 ml of ethanol in water bath at 80° C. while stirring, performing suction-filtration and collecting filter cake;
(10) drying a yellow solid obtained in the step (9) by vacuum drying for 24 h at room temperature, so that a crystal form A of demethyleneberberine hydrochloride is obtained;
(11) filtering the solution obtained in the step (4) by suction-filtration, dissolving 1 g of filter cake with 30 ml of deionized water in water bath at 74° C. while stirring, recrystallizing, and performing suction-filtration; and
(12) drying a yellow solid obtained in the step (11) by vacuum freeze-drying for 48 h, so that a crystal form D of demethyleneberberine hydrochloride is obtained.

3. The method for preparing the crystal forms of demethyleneberberine hydrochloride according to claim 2 , wherein the step (5) further comprises: adding a small amount of seed crystals, adding 10-20 vol. % of diethyl ether, adding 10-20 vol. % of xylene, and adding 10-20 vol. % of toluene.

4. The method for preparing the crystal form of demethyleneberberine hydrochloride according to claim 2 , wherein the step (7) further comprises: adding a small amount of seed crystals, adding 10-20 vol. % of diethyl ether, adding 10-20 vol. % of xylene, and adding 10-20 vol. % of toluene.

5. A pharmaceutical composition comprising crystal form A, B, C and/or D of demethyleneberberine hydrochloride according claim 1 .

6. The pharmaceutical composition, according to claim 5 , formulated as a tablet, capsule, pill or as a sustained-release agent, or for injection, or as a microparticle administration system.

Assignees

• Univ China Pharma

Inventors

• Zhang Yubin
• Zhang Yuanqiang
• Zhang Miao
• Li Qingxia

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D455/03 Primary

  containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine · CPC title

• C07D455/04 Primary

  containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine · CPC title