Crystalline form of aripiprazole

Abstract

The present invention relates to a crystalline form N of aripiprazole, pharmaceutical compositions thereof and the use of crystalline form N in the preparation of a medicament for the treatment of central nervous system diseases, especially schizophrenia.

Claims

1. A crystalline form N of aripiprazole, wherein the crystalline form is an aripiprazole hydrate that has the following properties: at a heating rate of 5 C./min, the crystalline form has endothermic peaks near 125 C. and near 134 C. during differential scanning calorimetry; and an X-ray powder diffraction pattern having peaks expressed in degrees 2 at 12.60.1, 15.10.1, 17.40.1, 18.20.1, 18.70.1, 22.50.1, 23.20.1, 24.80.1, and 27.50.1 by using a Cu-Ka radiation.

2. The crystalline form N of aripiprazole as claimed in claim 1, wherein the crystalline form has a powder X-ray diffraction pattern that is substantially the same as the powder X-ray diffraction pattern as shown in FIG. 1 in terms of peak positions.

3. The crystalline form N of aripiprazole as claimed in claim 2, wherein at a heating rate of 5 C./min, the crystalline form has an endothermic curve of differential thermal analysis that is substantially the same as the endothermic curve as shown in FIG. 2.

4. The crystalline form N of aripiprazole as claimed in claim 1, wherein at a heating rate of 5 C./min, the crystalline form has endothermic peaks at 124 C.-126 C. and at 133 C.-135 C. during differential scanning calorimetry.

5. The crystalline form N of aripiprazole as claimed in claim 1, wherein at a heating rate of 5 C./min, the crystalline form neither has an endothermic peak near 71 C. nor near 75 C. during differential scanning calorimetry.

6. The crystalline form N of aripiprazole as claimed in claim 5, wherein at a heating rate of 5 C./min, the crystalline form neither has an endothermic peak at 70 C.-72 C. nor at 74 C.-76 C. during differential scanning calorimetry.

7. A pharmaceutical composition, comprising the crystalline form N of aripiprazole according to claim 1 and a pharmaceutically acceptable carrier.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is the powder X-ray diffraction pattern of crystalline form N of aripiprazole.

(2) FIG. 2 is the differential thermal analysis of crystalline form N of aripiprazole.

(3) FIG. 3 is the powder X-ray diffraction pattern of hydrate A prepared according to the method in WO 03/026659.

(4) FIG. 4 is the differential thermal analysis pattern of hydrate A prepared according to the method in WO 03/026659.

(5) FIG. 5 is the powder X-ray diffraction pattern of the conventional hydrate prepared according to the method in WO 03/026659.

(6) FIG. 6 is the differential thermal analysis pattern of the conventional hydrate prepared according to the method in WO 03/026659.

(7) FIG. 7 is a comparison of the dissolution rates of different crystalline forms of aripiprazole.

DETAILED DESCRIPTION OF THE INVENTION

(8) The present invention will be further described with reference to the following examples, such that the present invention will be more comprehensively understood by a person skilled in the art, and these examples are not intend to limit the present invention in any way.

Example 1

Preparation Method of Crystalline form N

(9) 2 kg of aripiprazole an hydrate is added to a 60 L acetone-water (4:1 (V/V)) system, and the temperature is raised to 70 C. Stirring is stopped until the system is completely cleared. Crystals are precipitated by naturally cooling to room temperature, and same are filtered to obtain white needle crystals for air blast drying at 40 C. until the moisture content of the material is between 3.9% and 4.4%, which crystals are 1.9 kg by weight, and the yield is 91%.

Example 2

Solid State Characterization of Crystalline Form N

(10) The new crystalline forms are characterized as being in a solid state by X-ray powder diffraction and differential scanning calorimetry, and the solid state characterization parameters and patterns thereof are as described herein.

Comparison Example 1

Preparation Method and Solid-State Characterization of Hydrate A of Aripiprazole

(11) Hydrate A of aripiprazole is prepared according to the method in example 1 of WO 03/026659. Hydrate A is characterized as being in a solid state by X-ray powder diffraction and differential scanning calorimetry in WO 03/026659, and the solid state characterization parameters and patterns thereof are as described in WO 03/026659 (see FIG. 3 and FIG. 4 for details).

Comparison Example 2

Preparation Method and Solid-State Characterization of Conventional Hydrate of Aripiprazole

(12) The conventional hydrate of aripiprazole is prepared according to the method in reference example 3 of WO 03/026659. Hydrate B is characterized as being in a solid state by X-ray powder diffraction and differential scanning calorimetry in WO 03/026659, and the solid state characterization parameters and patterns thereof are as described in WO 03/026659 (pages 63-64, see FIG. 5 and FIG. 6 for details).

(13) Conclusions:

(14) Comparing the crystalline form obtained in example 1 with that obtained in comparison example 1 (see FIG. 3 and FIG. 4), the positions of the characteristic peaks in the X-ray powder diffraction pattern are different, and the peak intensities are different. The differential thermal analysis of example 1 has an endothermic peak at about 125 C. and does not show a weak peak at about 71 C.

(15) Comparing the crystalline form obtained in example 1 with that obtained in comparison example 2 (see FIG. 5 and FIG. 6), the positions of the characteristic peaks in the X-ray powder diffraction pattern are different, and the peak intensities are different. The differential thermal analysis of example 1 neither shows a gradual dehydration endothermic peak between about 60 C. and 120 C. nor a weak peak at about 75 C.

(16) Therefore, crystalline form N provided by the present invention is different from the known crystalline forms of aripiprazole hydrate disclosed or claimed by the existing documents.

Example 3

Comparison Test for the Dissolution Rate of Crystalline form N, Hydrate A and the Conventional Hydrate of Aripiprazole

(17) Sample preparation: Powders of crystalline form N, hydrate A and the conventional hydrate of aripiprazole are respectively sieved through a 100-mesh sieve, and the appropriate amount of sieved material (equivalent to 50 mg of aripiprazole) is taken and measured to determine the dissolution rate of each sample.

(18) Dissolution conditions: 0.25% sodium dodecyl sulfate solution (900 mL): slurry method: 50 rpm; 37 C.0.5 C.

(19) Sample detection: Samples of 3 ml are respectively taken at 15, 30, 60, 90, 120, 240, and 360 min, and immediately littered through a 0.45 m microporous membrane, 2 mL of the initial filtrate is discarded, and the drug concentration in the subsequent filtrate is measured.

(20) Conclusions:

(21) FIG. 7 shows comparison data regarding the dissolution rate of crystalline form N of the present invention, hydrate A, and the conventional hydrate. It can be seen from FIG. 7 that the dissolution rate of crystalline form N of the present invention is significantly different from that of the two known hydrates. Crystalline form N of the present invention has a slower release rate.

Example 4

Pharmaceutical Composition Comprising Crystalline Form N of Aripiprazole of the Present Invention

(22) Formula:

(23) TABLE-US-00001 Components Formulation amount Crystalline form N of aripiprazole 400 mg (based on aripiprazole) Sodium carboxymethylcellulose 20 mg Mannitol 80 mg Polyoxyethylene (20) sorbitan 20 mg monooleate Sodium dihydrogen phosphate 1.38 mg monohydrate Water for injection Appropriate amount, adjusted to 2 mL
Preparation Method

(24) 1) The sodium carboxymethylcellulose, mannitol, polyoxyethylene (20) sorbitan monooleate and sodium dihydrogen phosphate monohydrate are dissolved in an appropriate amount of water for injection;

(25) 2) crystalline form N of aripiprazole is added to the material obtained in step 1 and is dispersed uniformly; and

(26) 3) the water for injection is added to the material in step 2 to adjust and arrive at the target concentration, and same are then sub-packaged.

(27) The above description merely relates to preferred embodiments of the present invention, and it should be pointed out that, for a person of ordinary skill in the art, some improvements and modifications can also be made under the premise of not departing from the principle of the present invention, and these improvements and modifications should also be considered to be within the scope of protection of the present invention.