Crystal form of chidamide, preparation method and use thereof

Abstract

The present invention belongs to the field of pharmaceutical chemistry, and disclosed are two crystal forms of Childamide, that is, Chidamide crystal form A and Chidamide crystal form B, and the method for preparing the new crystal forms of Chidamide. The Chidamide crystal form A and Chidamide crystal form B of the present invention can be used for preparing drugs for treating diseases related to cell differentiation and proliferation.

Claims

1. Chidamide crystal form A, which is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2 of about 4.18, 6.61, 8.42, 12.69, 17.85, 18.34, 19.27, 20.10, 20.59, 21.58, 23.70, 23.96, 25.52, 27.00, 27.90, 29.59, and 29.94; its infrared spectrum has characteristic absorption peaks at about 3412, 3282, 3199, 3043, 1654, 1615, 1524, 1514, 1497, 1442, 1418, 1332, 1296, 1234, 1198, 1183, 1166 and 1027 cm.sup.1; and its differential scanning calorimetry pattern has a endothermic peak at about 239.4 C.

2. A method for preparing chidamide crystal form A having an X-ray powder diffraction pattern of the chidamide crystal form A with characteristic peaks at 2of about 4.18, 6.61, 8.42, 12.69, 17.85, 18.34, 19.27, 20.10, 20.59, 21.58, 23.70, 23.96, 25.52, 27.00, 27.90, 29.59, and 29.94; an infrared spectrum with characteristic absorption peaks at about 3412, 3282, 3199, 3043, 1654, 1615, 1524, 1514, 1497, 1442, 1418, 1332, 1296, 1234, 1198, 1183, 1166 and 1027 cm.sup.1; and a differential scanning calorimetry pattern with an endothermic peak at about 239.4 C., the method comprising: Step 1: chidamide is added to 2 mol/L dilute hydrochloric acid solution, dissolved by stirring at room temperature and diluted with water; to the resultant solution is added dropwise 2 mol/L NaOH solution, stirred for 30 min, and then filtered; wherein the weight ratio between chidamide and the dilute hydrochloric acid solution in Step 1 is in the range from 1:4.2 to 1:4.4, the weight ratio between chidamide and water is in the range from 1:25 to 1:30, and the weight ratio between chidamide and NaOH solution is in the range from 1:2.5 to 1:2.7; Step 2: the resultant solid is collected, and added to water; to the mixture is added dropwise 2 mol/L NaOH solution, stirred for 60 min, and then filtered; the resultant solid is collected, washed with water to a pH value from 5 to 7, and then dried; wherein the weight ratio between chidamide and water in Step 2 is in the range from 1:15 to 1:25, and the weight ratio between chidamide and NaOH solution is in the range from 1:1.5 to 1:2.0.

3. A pharmaceutical formulation for the treatment of cell differentiation and proliferation-related diseases, which is characterized in that the pharmaceutical formulation comprises the chidamide crystal form A according to claim 1, and pharmaceutically acceptable excipients.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is the HPLC chromatogram of the solid prepared according to Example 2 of patent ZL 03139760.3;

(2) FIG. 2 is the .sup.1H NMR spectrum of the solid prepared according to Example 2 of patent ZL 03139760.3;

(3) FIG. 3 is the X-ray powder diffraction pattern of the chidamide crystal form A provided in Example 1 of the present invention, which is obtained by irradiation with cooper K ray. In the X-ray powder diffraction pattern, the ordinate represents diffraction intensity expressed in counts per second (cps), and the abscissa represents diffraction angle 2 expressed in degree;

(4) FIG. 4 is an infrared spectrum pattern of the chidamide crystal form A provided by Example 1 of the present invention. The ordinate represents light transmittance (T) expressed in percentage (%); and the abscissa represents wave number expressed in cm.sup.1;

(5) FIG. 5 is the differential scanning calorimetry (DSC) pattern of the chidamide crystal form A provided by Example 1 of the present invention. The ordinate represents heat flow rate expressed in cal/sec, and the abscissa represents temperature expressed in C.;

(6) FIG. 6 is the X-ray powder diffraction pattern of the chidamide crystal form B provided in Example 3 of the present invention, which is obtained by irradiation with cooper K ray. In the X-ray powder diffraction pattern, the ordinate represents diffraction intensity expressed in counts per second (cps), and the abscissa represents diffraction angle 2 expressed in degree;

(7) FIG. 7 is the infrared spectrum of the chidamide crystal form B provided by Example 3 of the present invention. The ordinate represents light transmittance (T) expressed in percentage (%); and the abscissa represents wave number expressed in cm.sup.1;

(8) FIG. 8 is the differential scanning calorimetry (DSC) pattern of the chidamide crystal form B provided by Example 3 of the present invention. The ordinate represents heat flow rate expressed in cal/sec, and the abscissa represents temperature expressed in C.

EXAMPLES

(9) The crystal forms of chidamide, and the preparation methods and the use thereof are disclosed in the Examples of the present invention. The present invention can be implemented by properly modifying the processing parameters by those skilled in the art with reference to the content herein. Particularly, it should be noted that all similar replacements and modifications are apparent to those skilled in the art, all of which are regarded to be included in the present invention. The method of the present invention has been described by preferred examples, and it is apparent that modification, or proper change and the combination thereof can be made to the method described herein by those skilled in the art, without departing from the content, spirit and scope of the invention, in order to achieve and apply the techniques disclosed in the present invention.

(10) For better understanding the present invention, it will be further described with reference to specific examples below. The percentage described herein refers to the weight percentage, unless otherwise indicated. All numerical ranges, such as measurement units, reaction conditions, and the physical states or percentages of compounds, described in the specification are provided for clear reference. Expected results can also be achieved by those skilled in the art when the present invention is practiced with temperatures, concentrations or quantities, etc. outside the range or different from individual values.

(11) Experiment Methods

(12) Test conditions for X-ray powder diffraction: Instrument: D/MAX-1200 (Japan); radiation source: Cu-K (40 kV, 40mA).

(13) Test conditions for infrared spectrum: Instrument: FT-IR NICOLET 6700 (US); KBr disc.

(14) Test conditions for differential scanning calorimetry: Instrument: DSC 204 (Germany); temperature ramp rate: 10 C./min; flow rate of nitrogen: 20 mL/min.

(15) Test conditions for proton magnetic resonance: Instrument: AV-400 (Germany); Solvent: DMSO-d6.

Example 1

Preparation of Chidamide Crystal Form A

(16) 4.84 kg chidamide (about 95% purity) was added to 20.91 kg 2 mol/L dilute hydrochloric acid solution, and dissolved by stirring at room temperature. Subsequently, 137.8 kg water was added and stirred for 5 min. To the resulted solution, 21.35 kg 2 mol/L NaOH solution was added dropwise, stirred for 30 min, and filtered. The resultant solid was added to 96.70 kg water, and subsequently, 8.39 kg 2 mol/L NaOH solution was added dropwise. The mixture was stirred for 60 min, filtered, and washed to a pH value of 5-7 with water. The resultant solid was dried under vacuum at 80 C. for 24 h to obtain 4.32 kg chidamide crystal form A with a purity of 99.2%. The X-ray powder diffraction pattern, infrared spectrum, and differential scanning calorimetry pattern of the crystal form were shown in FIG. 3, FIG. 4 and FIG. 5, respectively.

Example 2

Preparation of Chidamide Crystal Form B

(17) 1 g chidamide crystal form A was added to 10 mL dimethyl sulfoxide, and dissolved by stirring at room temperature. To the resultant solution, 100 mL water was added dropwise, stirred for 30 min, and filtered. The resultant solid was dried under vacuum at 80 C. for 24 h to obtain the chidamide crystal form B with a purity of 99.2%. The X-ray powder diffraction pattern, infrared spectrum, and differential scanning calorimetry pattern of the crystal form were shown in FIG. 6, FIG. 7 and FIG. 8, respectively.

Example 3

Preparation of Tablets of the Chidamide Crystal Form A

(18) Formula (1000 tablets):

(19) TABLE-US-00001 Chidamide crystal form A 5 g Soluble starch 50 g Lactose 20 g Microcrystalline cellulose 20 g Sodium carboxymethyl starch 8 g Talc powder 0.5 g

(20) The preparation process: chidamide crystal form A, lactose, soluble starch, microcrystalline cellulose and sodium carboxymethyl starch were each weighed out at the prescribed amount, and mixed uniformly. The mixture was wetted by a suitable amount of water to prepare the soft dough. Wet particulates were prepared using a 20-mesh sieve, and dried at 60 C. Particulates were sieved by using an 18-mesh sieve. Subsequently, talc powder was added at the prescribed amount and mixed uniformly. The tablets were obtained after being tabletted.

Example 4

Preparation of Capsules of the Chidamide Crystal Form A

(21) Formula (1000 capsules):

(22) TABLE-US-00002 Chidamide crystal form A 5 g Microcrystalline cellulose 55 g Lactose 35 g Sodium carboxymethyl starch 5 g Magnesium stearate 0.5 g

(23) The preparation process: the chidamide crystal form A was screened by passing through a 100-mesh sieve, and the microcrystalline cellulose, lactose, sodium carboxymethyl starch and magnesium stearate were screened by passing through a 80-mesh screen. The microcrystalline cellulose, lactose and sodium carboxymethyl starch were weighed out at the prescribed amounts, and mixed uniformly. Subsequently, the mixture was mixed with the chidamide crystal form A uniformly using equal increase method. After mixed with prescribed amount of magnesium stearate, the capsules were filled.

Example 5

Preparation of Granules of the Chidamide Crystal Form A

(24) Formula (1000 bags):

(25) TABLE-US-00003 Chidamide crystal form A 5 g Soluble starch 500 g Lactose 200 g Microcrystalline cellulose 175 g Sodium carboxymethyl starch 100 g

(26) The preparation process: chidamide crystal form A, lactose, soluble starch, microcrystalline cellulose and sodium carboxymethyl starch were each weighed out at the prescribed amounts, and mixed uniformly. The mixture was wetted by a suitable amount of water to prepare soft dough. Wet particulates were prepared using a 20-mesh screen, and dried at 60 C. Particulates were sieved by using an 18-mesh screen. After being filled, the granules were obtained.

Example 6

Preparation of Tablets of the Chidamide Crystal Form B

(27) Formula (1000 tablets):

(28) TABLE-US-00004 Chidamide crystal form B 5 g Soluble starch 50 g Lactose 20 g Microcrystalline cellulose 20 g Sodium carboxymethyl starch 8 g Talc powder 0.5 g

(29) The preparation process: chidamide crystal form B, lactose, soluble starch, microcrystalline cellulose and sodium carboxymethyl starch were each weighed out at the prescribed amount, and mixed uniformly. The mixture was wetted by a suitable amount of water to prepare soft dough. Wet particulates were sieved by using a 20-mesh screen, and dried at 60 C. Particulates were sieved by using an 18-mesh screen. Subsequently, talc powder was added at the prescribed amount and mixed uniformly. The tablets were obtained after being tabletted.

Example 7

Preparation of Capsules of the Chidamide Crystal Form B

(30) Formula (1000 capsules):

(31) TABLE-US-00005 Chidamide crystal form B 5 g Microcrystalline cellulose 55 g Lactose 35 g Sodium carboxymethyl starch 5 g Magnesium stearate 0.5 g

(32) The preparation process: the chidamide crystal form B was screened by passing through a 100-mesh sieve, and microcrystalline cellulose, lactose, sodium carboxymethyl starch and magnesium stearate were screened by passing through an 80-mesh screen. Microcrystalline cellulose, lactose and sodium carboxymethyl starch were weighed out at the prescribed amounts, and mixed uniformly. Subsequently, the mixture was mixed with the chidamide crystal form A uniformly using equal increase method. After mixed with prescribed amount of magnesium stearate, the capsules were filled.

Example 8

Preparation of Granule of the Chidamide Crystal Form B

(33) Formula (1000 bags):

(34) TABLE-US-00006 Chidamide crystal form B 5 g Soluble starch 500 g Lactose 200 g Microcrystalline cellulose 175 g Sodium carboxymethyl starch 100 g

(35) The preparation process: chidamide crystal form B, lactose, soluble starch, microcrystalline cellulose and sodium carboxymethyl starch were each weighed out at the prescribed amounts, and mixed uniformly. The mixture was wetted by a suitable amount of water to prepare soft dough. Wet particulates were sieved by using a 20-mesh screen, and dried at 60 C. Particulates were sieved by using an 18-mesh screen. After being filled, the granules were obtained.

(36) The above examples are only described for understanding the methods and principal concepts of the present invention. It should be noted that some improvements and modifications can be made to the present invention by those skilled in the art without departing from the principles of the present invention. These improvements and modifications also fall within the scope of the claims of the present invention.