WO2020164565A1 - New crystal form of oxypiperone hydrochloride and preparation method therefor - Google Patents

Abstract

The present invention relates to a new crystal form III of oxypiperone hydrochloride and a preparation method therefor. The 2θ angle of the X-ray powder diffraction pattern of the oxypiperone hydrochloride crystal form III has characteristic peaks at 11.8°, 14.4°, 15.7°, 18.7°, 19.4°, 26.2°, and 28.8°. The oxypiperone hydrochloride crystal form III obtained in the present invention has high purity and good stability, and is very suitable for industrial production.

Description

A new crystal form of piperpirox hydrochloride and its preparation method

This application claims the priority of a Chinese patent application filed with the Chinese Patent Office on February 14, 2019 with the application number 201910113923.0 and the invention titled "A new crystalline form of hydroxypiperidone hydrochloride and its preparation method", the entire content of which is approved The reference is incorporated in this application.

Technical field

The invention specifically relates to a new crystal form of piperpyrone hydrochloride and a preparation method thereof.

Background technique

Hydroxypiperidone hydrochloride has a chemical name of 1-[(1-benzyl-4-hydroxypiperidin-4-yl)-methyl]-pyridine-2(1H)-one hydrochloride, and the structural formula is shown below.

CN102241667B discloses a piperpirox hydrochloride compound and a preparation method thereof. The compound can be used to prevent or treat central nervous system diseases related to 5-HT system dysfunction, including depression, mania, cognitive deficit, schizophrenia, Pain etc.

CN106892897A discloses a new crystal form I of the free base of piperpirox. The 2θ angles in the X-ray powder diffraction pattern of this crystal form are at 5.3°, 6.8°, 7.9°, 10.6°, 13.6°, 15.4°, 16.3°, 20.4° , There is a characteristic peak at 23.9°, and its differential scanning calorimetry analysis spectrum shows that the crystal form I has a melting endothermic peak at 146-150°C.

CN106928187A discloses a new crystal form II of piperpyrone hydrochloride and a preparation method thereof. The 2θ angles in the X-ray powder diffraction pattern of the crystal form are at 8.6°, 9.5°, 14.8°, 16.1°, 18.3°, 19.1°, 20.0° , There is a characteristic peak at 21.1°, and its thermogravimetric analysis pattern shows that the crystal form II has a weight loss of 5.1% at 73-145°C.

Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., which affect the stability, bioavailability and efficacy of the drug. This phenomenon is manifested in oral solid preparations. Especially obvious. Drug polymorphism is one of the important factors affecting the quality and clinical efficacy of drugs. Therefore, the development of a high-purity and stable crystal form is crucial for the production and application of drugs.

Summary of the invention

The invention provides a new crystal form of piperpirox hydrochloride with high purity, stability and good reproducibility and a preparation method thereof. In the present invention, the new crystal form is named crystal form III.

The hydroxypiperidone hydrochloride crystal form III of the present invention has the following characteristic peaks in the X-ray powder diffraction pattern detected by Cu-Kα radiation, and its 2θ angle value and relative intensity are shown in the following table:

2θ	Relative Strength(%)
11.8°	10.6
14.4°	100
15.7°	35.8
18.7°	61.4
19.4°	48.9
26.2°	32.3
28.8°	27.8

In one embodiment, the X-ray powder diffraction pattern of the crystal form III using Cu-Kα radiation has the following characteristic peaks, and the 2θ angle values and relative intensities are shown in the following table:

2θ	Relative Strength(%)
10.5°	7.5
11.8°	10.6
14.4°	100
15.7°	35.8

16.8°	6.3
18.7°	61.4
18.9°	20.5
19.1°	16.7
19.4°	48.9
21.2°	12.4
22.7°	15.6
25.2°	12.8
25.5°	16.9
26.2°	32.3
28.8°	27.8
31.6°	14.6
39.4°	5.9

In one embodiment, the hydroxypiperidone hydrochloride crystal form III of the present invention has an X-ray powder diffraction pattern as shown in FIG. 1 using Cu-Kα radiation detection.

In another embodiment, as shown by the differential scanning calorimetry (DSC) spectrum, the crystal form III has a melting endothermic peak at 224-243°C, and has a differential scanning volume as shown in Figure 2. Thermal analysis atlas.

The present invention also provides a method for preparing the above-mentioned hydroxypiperidone hydrochloride crystal form III, which comprises the following steps:

(a) Mix piperpyrone hydrochloride with a polar solvent and heat to dissolve it;

(b) cooling the solution obtained in step (a) to the crystallization temperature, stirring and crystallization;

(c) Filtration and drying to obtain hydroxypiperidone hydrochloride crystal form III.

In one embodiment, the polar solvent described in step (a) is one or more of methanol, ethanol, acetone and isopropanol, preferably ethanol or acetone.

In another embodiment, the weight ratio of piperpirox hydrochloride to polar solvent in step (a) is 1:4-20, preferably 1:6-15.

In another embodiment, in step (a), the moisture content of piperpirox hydrochloride is below 1.0%; the moisture content of the polar solvent is below 0.5%.

In another embodiment, the heating temperature in step (a) is 40°C to reflux temperature, preferably 50°C to reflux temperature.

In one embodiment, the crystallization temperature of step (b) is -10 to 30°C, preferably -5 to 10°C.

In another embodiment, the cooling process in step (b) adopts programmed cooling, and the programmed cooling rate is controlled at 10-15°C/h.

The method provided by the present invention for preparing the new crystal form III of ropipirone hydrochloride has simple process, simple operation and good reproducibility, and does not require special preparation conditions. The obtained new crystal form Ⅲ of ropipirone hydrochloride is anhydrous. With high purity and good stability, it is very suitable for industrial production and clinical applications.

Description of the drawings

Figure 1 is an X-ray powder diffraction pattern of the new crystalline form III of piperpirox hydrochloride obtained according to Example 1 of the present invention.

Fig. 2 is a differential scanning calorimetry analysis chart of the new crystalline form III of piperpirox hydrochloride obtained according to Example 1 of the present invention.

detailed description

The following specific preparation examples are intended to illustrate the present invention in detail by way of examples, but not to limit the present invention in any form.

The analytical instrument used in the present invention:

(1) X-ray powder diffraction analysis

Instrument model: X’Pert-Pro-MPD (Multi-Purpose Diffractometer)

Test method: fill the ground sample (100mg) in the groove of the glass plate, use a glass slide to scrape its plane and the glass surface flush, then place the sample in the X'Pert-Pro-MPD analyzer, Using the Cu-X-ray source with voltage and current of 45kV and 40mA, the scanning range is 3～50°(2θ), the step size is 0.0167°(2θ), the counting time per step: 50s, and the total scanning time: 20min.

(2) DSC thermal analyzer

Instrument model: Discovery DSC-250

Test method: Place the sample to be tested (about 2 mg) in the sample pan, keep it in equilibrium at 30°C, and then heat it to 260°C at a rate of 10°C/min.

Example 1

At room temperature, weigh out 2.0g of piperpyrone hydrochloride (moisture content 1.0%), add 30g acetone (moisture content 0.5%), heat to 55～65℃ to completely dissolve, control the cooling rate of 10～15℃/h, and put the solution When the temperature was lowered to 10°C, a white solid was precipitated, and the stirring was continued for 1 h, filtered, and dried to obtain a white crystalline form III of piperpirox hydrochloride.

Example 2

At room temperature, weigh out 2.0 g of piperpyrone hydrochloride (moisture content 0.8%), add 24 g of ethanol (moisture content 0.5%), heat to 80～90℃ to completely dissolve, control the cooling rate of 10～15℃/h, and reduce the solution When the temperature was lowered to 10°C, a white solid was precipitated, and the stirring was continued for 1 h, filtered, and dried to obtain a white crystalline form III of piperpirox hydrochloride.

Example 3

At room temperature, weigh 50g of hydroxypiperidone hydrochloride (moisture content 1.0%), add 600g ethanol (moisture content 0.5%), heat to 80～90℃ to completely dissolve, control the cooling rate of 10～15℃/h, and cool the solution When the temperature reached 10°C, a white solid precipitated, and the mixture was stirred for 1 h, filtered, and dried to obtain a white crystalline form III of hydroxypiperidone hydrochloride.

Example 4

Investigation on the stability of piperpyrone hydrochloride crystal form Ⅲ:

Stability test conditions: T=25±2℃, relative humidity RH=60±5%

Packing conditions: a layer of polyethylene bag, a layer of four-layer composite film, vacuumed and filled with nitrogen for protection, put in a fiber drum, and stored in a sealed airtight.

Investigation time: two years.

Stability investigation conclusion: X-ray powder diffraction analysis showed that the crystal forms of Examples 1 to 3 were unchanged, and the crystalline form III of piperpirox hydrochloride had good stability.

Claims (12)

1. A crystal form III of piperpyrone hydrochloride, which is characterized in that the characteristic peaks of the X-ray powder diffraction pattern of the crystal form III are expressed as follows in terms of 2θ angle and relative intensity:

   
2. The crystal form III of claim 1, wherein the characteristic peaks of the X-ray powder diffraction pattern of the crystal form III are expressed as follows in terms of 2θ angle and relative intensity:

   

   
3. The crystal form III according to claim 1 or 2, characterized in that it has an X-ray powder diffraction pattern as shown in FIG. 1.
4. The crystal form III according to any one of claims 1 to 3, wherein a differential scanning calorimetry analysis chart shows that the crystal form III has a melting endothermic peak at 224-243°C.
5. The crystal form III according to any one of claims 1 to 4, characterized in that it has a differential scanning calorimetry analysis pattern as shown in FIG. 2.
6. The crystal form according to any one of claims 1 to 5, which is used to prevent or treat central nervous system diseases related to 5-HT system dysfunction.
7. A method for preparing the hydroxypiperidone hydrochloride crystal form III of any one of claims 1-5, comprising the following steps:

   (a) Mix piperpyrone hydrochloride with a polar solvent and heat to dissolve it;

   (b) cooling the solution obtained in step (a) to the crystallization temperature, stirring and crystallization;

   (c) Filtration and drying to obtain hydroxypiperidone hydrochloride crystal form III.
8. 8. The method of claim 7, wherein the polar solvent in step (a) is one or more selected from methanol, ethanol, acetone and isopropanol, preferably ethanol or acetone.
9. 8. The method according to claim 7 or 8, wherein the water content of the oxypiperazone hydrochloride used in step a) is below 1.0%, and the water content of the polar solvent used is below 0.5%.
10. The method according to any one of claims 7 to 9, wherein the weight ratio of the piperpirox hydrochloride to the polar solvent is 1:4-20, preferably 1:6-15.
11. The method according to any one of claims 7 to 10, wherein the crystallization temperature is -10 to 30°C, preferably -5 to 10°C.
12. The method according to any one of claims 7 to 11, wherein the cooling process in step (b) adopts program cooling, and preferably, the program cooling rate is controlled at 10-15°C/h.

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