TW201730178A - New crystalline form of aripiprazole characterized in that the crystalline form has the property that the differential heat scan at a heating rate of 5 DEG C/min has an endothermic peak at a temperature of approximately 125 DEG C and close to 134 DEG C - Google Patents

Abstract

The present invention provides a novel crystalline form N of aripiprazole, a pharmaceutical composition thereof, and the use of the crystalline form N in the preparation of a medicament for the treatment of central nervous system disorders (particularly schizophrenia). This invention is characterized in that the crystalline form has the property that the differential heat scan at a heating rate of 5 DEG C/min has an endothermic peak at a temperature of approximately 125 DEG C and close to 134 DEG C. Also, the crystalline form has a powder X-ray diffraction spectrum which has the same peak position as that of the powder X-ray diffraction pattern shown in Figure 1.

Description

New crystal form of aripiprazole

The present invention relates to a novel crystalline form N of aripiprazole, a medical composition thereof and the use of the crystalline form N for the preparation of a medicament for the treatment of diseases of the central nervous system, in particular schizophrenia.

Aripiprazole, chemical name: 7-{4-[4-(2,3-dichlorophenyl)-1-pyridazinyl]-butoxy}-3,4-dihydroquinolone, is a kind Atypical psychotic drugs for the treatment of schizophrenia. The drug is marketed under the trade name Abilify in several countries including China, the United States and Europe.

Aripiprazole is a polymorphic substance which is diversified in crystal form by changes in crystallization solvent, crystallization mode, drying method, and the like. WO 03/026659 discloses Form I and Form II of the 4th Japan-Korea Separation Technology Symposium Proceedings (October 6-8, 1996), which can be crystallized or passed from an ethanol solution. The aripiprazole hydrate is prepared by heating at 80 ° C, but the aripiprazole crystal obtained by the method has obvious hygroscopicity; the crystal form of the II can be heated by heating the I crystal form at 130 ° C - 140 ° C. It is prepared in an hour, but the process is not easy to prepare a high-purity Form II crystal on a good reproducible industrial scale. The patent document also discloses seven crystal forms of hydrates A, B, C, D, E, F and G. It is known from the specification that in order to obtain the above-mentioned crystal forms, it is necessary to obtain an I crystal form first. Further, the aripiprazole of the crystal form I is placed at a relatively high temperature, and is obtained by heating or dispersing in an organic solvent for a long time and then heat-treating for a long time, although the prepared aripiprazole crystal form has low hygroscopicity. However, the process is cumbersome and consumes a large amount of cost, which is not conducive to large-scale industrial production of products. CN1760183 discloses two crystal forms of α and β, wherein the α crystal form is a 1/2 ethanol solvate of aripiprazole, which has certain limitations on the drying and processing process, and is not suitable for preparation into a medicine; and the β crystal form needs to be first The alpha form is prepared by specific conditions and the process is also unsuitable for large scale industrial production. It can be seen that the crystal form of aripiprazole is greatly affected by the preparation conditions, and the change of conditions will result in crystal forms with different characteristics. Different crystal forms have different dissolution rates. For formulations, a faster dissolution rate crystal form is suitable for preparing a fast release product, and a slower dissolution rate crystal form is suitable for preparing a sustained release product.

It is well known in the art that hydrates generally have a lower water solubility than anhydrous forms, which may facilitate the development of controlled release or sustained release pharmaceutical formulations. There are currently two known aripiprazole hydrates, both of which are reported in WO 03/026659, namely conventional hydrates, and hydrate A.

In the treatment of schizophrenia, aripiprazole rapid release preparation can quickly achieve efficacy and relieve symptoms, and its long-acting sustained-release preparation can significantly reduce the number of medications and increase patient compliance. In order to meet the release requirements and facilitate patient use, the present invention provides a novel aripiprazole crystal form N which is not only stable in process but also slower than the known two aripiprazole hydrates. The dissolution rate is more suitable for use in aripiprazole sustained release preparations.

It is an object of the present invention to provide a new crystalline form of aripiprazole, referred to as Form N.

Another object of the present invention is to provide a pharmaceutical composition of the aripiprazole Form N.

The aripiprazole crystal form N provided by the present invention is characterized in that the differential heat scan has an endothermic peak at approximately 125 ° C and approximately 134 ° C at a heating rate of 5 ° C / min.

In a specific embodiment, the crystalline form N of aripiprazole has a powder X-ray diffraction spectrum substantially identical to the peak position of the powder X-ray diffraction pattern shown in FIG.

In another embodiment, the crystalline form N of aripiprazole has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction pattern shown in FIG.

In one embodiment, the form N has an endothermic curve substantially the same as the differential thermal endothermic curve shown in FIG. 2 at a heating rate of 5 ° C/min.

In one embodiment, the differential heat scan of the crystalline form has an endothermic peak at 124 ° C - 126 ° C and 133 ° C - 135 ° C at a heating rate of 5 ° C / min.

In some embodiments, the differential thermal scan of the crystalline form has no endothermic peak near 71 ° C or no endothermic peak near 75 ° C at a heating rate of 5 ° C/min. In one embodiment, the differential thermal scan of the crystalline form has no endothermic peak at 70 ° C - 72 ° C or at 74 ° C - 76 ° C at a heating rate of 5 ° C / min. No endothermic peak.

In a specific embodiment, the crystal form further has the property that the diffraction spectrum of the X-ray powder expressed by degree 2θ is 12.6±0.1, 15.1±0.1, 17.4±0.1, 18.2±0.1, using Cu-Ka radiation. There are peaks at 18.7 ± 0.1, 22.5 ± 0.1, 23.2 ± 0.1, 24.8 ± 0.1, and 27.5 ± 0.1.

In a specific embodiment, the crystalline form N of aripiprazole is aripiprazole hydrate.

The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of aripiprazole crystal form N of the present invention in admixture with a pharmaceutically acceptable carrier. The pharmaceutical composition may be administered parenterally or parenterally, and may be administered to a patient in the form of a tablet, a capsule, a solution, a suspension or the like.

The "powder X-ray diffraction spectrum having the same peak position" as described herein, wherein "the peak position is the same" means that the positions of the peaks represented by degrees 2θ in the powder X-ray diffraction spectrum are substantially the same. It should be noted that the 2θ angle in the diffraction spectrum of the X-ray powder may sometimes have some measurement errors due to various factors, and the measured value may generally be ±0.3, preferably ±0.2, more preferably ±0.1. change. Therefore, herein, the 2 theta angle based on the measured value of a particular sample is understood to include the meaning of these tolerable errors.

As used herein, "the same powder X-ray diffraction spectrum" means that the positions of the peaks represented by degrees 2θ are substantially the same, and the relative intensities of the peak positions are substantially the same. The relative intensity is the ratio of the intensity of the other peaks to the intensity of the strongest peak when the intensity of the peak with the highest intensity among all the diffraction peaks of the powder X-ray diffraction spectrum is 100%.

As used herein, "substantially the same as the powder X-ray diffraction pattern shown in Figure 1" means at least 50%, or at least 60%, or at least 70%, or at least 80% of the powder X-ray diffraction spectrum, or At least 90%, or at least 95%, or at least 99% of the peaks appear in the given powder X-ray diffraction pattern.

It is to be noted that the absorption peak in the differential calorimetry analysis is an inherent physical property of the crystal form N of the present invention. However, in actual measurement, in addition to measurement errors, impurities may be mixed in an allowable amount. The possibility of a change in the melting point is also undeniable. Therefore, those skilled in the art can fully understand to what extent the measured value of the endothermic peak temperature in the present invention can be varied. For example, the conceivable error is, in some cases, about ±5 ° C, preferably. It is about ± 3 ° C, more preferably about ± 2 ° C, and most preferably about ± 1 ° C.

The analytical methods used in this article:

X-ray powder diffraction

Using a Bruker D8 advanced diffractometer, use a Cu Ka fill tube (40 kV, 40 mA) at room temperature as an X-ray source with a wide-angle goniometer, 0.6 mm divergence slit, 2.5° primary cable slit, 2.5 °Secondary Sola slits, 8 mm anti-scatter slits, 0.1 mm detector slits and LynxEye detectors. In the 2θ continuous scan mode, data acquisition was performed at a scan speed of 2.4°/min and a scan step of 0.02° in the range of 3°-40°.

Differential scanning calorimetry

Differential thermal analysis was performed using NETZSCH 200F3. The 3~5mg sample was placed in an aluminum pan and the blank aluminum crucible was used as a control. The temperature was scanned from room temperature to 180 °C at a heating rate of 5 °C/min. The atmosphere was high purity nitrogen with a flow rate of 40 mL/min.

The invention will be further described in conjunction with the following examples, and the present invention may be more fully understood by those of ordinary skill in the art.

Example 1: Preparation Method of Form N

2kg aripiprazole anhydrate was added to a 60L acetone-water (4:1 (V/V)) system, and the temperature was raised to 70 ° C. The system was completely clarified, the stirring was stopped, and the crystals were naturally cooled to room temperature to precipitate white. The needle crystals were blasted at 40 ° C until the moisture content of the material was between 3.9% and 4.4%, the weight was 1.9 kg, and the yield was 91%.

Example 2: Solid state characteristics of Form N

The new crystal form was solid-state characterized by X-ray powder diffraction and differential scanning calorimetry, and its solid state characteristic parameters and maps are as described herein.

Comparative Example 1: Preparation method and solid state characteristics of aripiprazole hydrate A

Aripiprazole hydrate A was prepared by the method of Example 1 of WO 03/026659. In WO 03/026659, hydrate A is solid-state characterized by X-ray powder diffraction and differential scanning calorimetry, and its solid state characteristic parameters and maps are as described in WO 03/026659, specifically shown in Figures 3 and 4.

Comparative Example 2: Preparation method and solid state characteristics of aripiprazole conventional hydrate

Aripiprazole conventional hydrate was prepared by the method of Reference Example 3 of WO 03/026659. Conventional hydrate B is solid-state characterized by X-ray powder diffraction and differential scanning calorimetry in WO 03/026659, the solid state characteristic parameters and maps of which are described in WO 03/026659 (pages 63-64), See Figure 5 and Figure 6 for details.

in conclusion:

In the example 1 and the crystal form obtained in Comparative Example 1 (see FIGS. 3 and 4), the characteristic peak-to-peak positions of the X-ray powder diffraction spectrum were different, and the peak intensities were different. In the differential thermal analysis, it had an endothermic peak of about 125 ° C and did not exhibit a weak peak of about 71 ° C.

In the example 1 and the crystal form obtained in Comparative Example 2 (see FIGS. 5 and 6), the characteristic peak-to-peak positions of the X-ray powder diffraction spectrum were different, and the peak intensities were different. In the differential thermal analysis, a gradual dehydration endothermic peak between about 60 ° C and 120 ° C and a weak peak of about 75 ° C were not exhibited.

Thus, the crystalline form N provided by the present invention is different from the known aripiprazole hydrate crystalline form disclosed or protected by the prior art.

Example 3: Comparison test of dissolution rate of aripiprazole crystal form N, hydrate A and conventional hydrate

Sample preparation: Aripiprazole Form N, hydrate A and conventional hydrate powder were respectively passed through a 100 mesh sieve, and an appropriate amount of the material (corresponding to 50 mg of aripiprazole) was taken to determine the dissolution rate of the sample.

Dissolution conditions: 0.25% aqueous sodium lauryl sulfate solution (900 mL), slurry method, 50 rpm, 37 ° C ± 0.5 ° C.

Sample detection: 3 ml was sampled at 15, 30, 60, 90, 120, 240, 360 minutes, immediately filtered through a 0.45 μm microporous membrane, 2 mL of the primary filtrate was discarded, and the concentration of the drug in the continuous filtrate was determined.

in conclusion:

Figure 7 is a graph showing the dissolution rate of Form N, hydrate A, and conventional hydrate of the present invention. As can be seen from Figure 7, the dissolution rate of the crystal form N of the present invention is significantly different from that of the two known hydrates. The crystalline form N has a slower release rate.

Example 4: Pharmaceutical composition comprising aripiprazole crystal form N of the invention

formula:

Preparation method: 1) sodium carboxymethyl cellulose, mannitol, polyoxyethylene 20 sorbitol monooleate, sodium dihydrogen phosphate monohydrate dissolved in an appropriate amount of water for injection; 2) added to the material obtained in step 1 Raspazole crystal form N, evenly dispersed; 3) Add the material of step 2 to the water for injection to adjust to the target concentration, and dispense.

The above is only a preferred embodiment of the present invention, and it should be understood that those skilled in the art can make a number of improvements and refinements without departing from the principles of the present invention. It is within the scope of the invention.

no.

Figure 1 shows a powder X-ray powder diffraction spectrum of aripiprazole Form N.

Figure 2 shows the differential thermal analysis of aripiprazole Form N.

Figure 3 shows a powder X-ray powder diffraction spectrum of hydrate A disclosed in WO 03/026659.

Figure 4 shows the differential thermal analysis of hydrate A disclosed in WO 03/026659.

Figure 5 shows a powder X-ray powder diffraction spectrum of a conventional hydrate disclosed in WO 03/026659.

Figure 6 shows a differential thermal analysis pattern of a conventional hydrate disclosed in WO 03/026659.

Figure 7 shows a comparison of the dissolution rates of different crystal forms of aripiprazole.

no.

Claims (11)

A crystal form N of aripiprazole characterized in that the crystal form has the following properties: at a heating rate of 5 ° C /min, the differential heat scan is near 125 ° C and close to 134 ° C There is an endothermic peak. The crystal form N of aripiprazole according to claim 1, wherein the crystal form has a powder X-ray diffraction spectrum substantially the same as the peak position of the powder X-ray diffraction pattern shown in Fig. 1. The crystal form N of aripiprazole according to claim 2, characterized in that the crystal form has a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction pattern shown in Fig. 1. The crystal form N of aripiprazole according to claim 2 or 3, characterized in that the crystal form has substantially the same thermal analysis as that shown in Fig. 2 at a heating rate of 5 ° C / min. The endothermic curve of the same endothermic curve. The crystalline form N of aripiprazole according to claim 1, which is a hydrate of aripiprazole. The crystal form N of aripiprazole according to claim 1, wherein the crystal form has a differential heat scan at 124 ° C - 126 ° C under a heating rate of 5 ° C / min. There is an endothermic peak at 133 ° C -135 ° C. The crystal form N of aripiprazole according to claim 1, wherein the crystal form has a heat absorption peak at a heating rate of 5 ° C / min, and has no endothermic peak at a temperature close to 71 ° C. Or there is no endothermic peak near 75 °C. The crystalline form N of aripiprazole according to claim 7, characterized in that the crystalline form has a differential heat scan at 70 ° C - 72 ° C at a heating rate of 5 ° C / min. There is no endothermic peak or no endothermic peak at 74 ° C -76 ° C. The crystal form N of aripiprazole according to claim 1, wherein the crystal form further has the following property: it uses Cu-Ka radiation, and the diffraction spectrum of the X-ray powder expressed by degree 2θ is 12.6± 0.1, 15.1 ± 0.1, 17.4 ± 0.1, 18.2 ± 0.1, 18.7 ± 0.1, 22.5 ± 0.1, 23.2 ± 0.1, 24.8 ± 0.1, 27.5 ± 0.1 with peaks. A pharmaceutical composition comprising the crystalline form N of aripiprazole according to any one of claims 1 to 9 and a pharmaceutical carrier. The use of the crystalline form N of aripiprazole according to any one of claims 1-9 for the preparation of a medicament for the treatment of diseases of the central nervous system.