CN105218522B

CN105218522B - A kind of dextrorotation Iprazole compound and its pharmaceutical composition

Info

Publication number: CN105218522B
Application number: CN201410294728.XA
Authority: CN
Inventors: 陈庆财; 赵俊; 赵小伟; 王孝雯; 赵骞; 付锐; 吕伟
Original assignee: Jiangsu Aosaikang Pharmaceutical Co Ltd
Current assignee: Jiangsu Aosaikang Pharmaceutical Co Ltd
Priority date: 2014-06-25
Filing date: 2014-06-25
Publication date: 2019-04-02
Anticipated expiration: 2034-06-25
Also published as: CN105218522A

Abstract

The present invention provides a kind of new the dextrorotation Iprazole compound of crystal form and the preparation method of the novel crystal forms and contain the pharmaceutical composition of the crystal form.The dextrorotation Iprazole compound of crystal form of the present invention is basicly stable under high temperature, high humidity and illumination condition；In accelerated test condition stability inferior and draw moist also without significant changes, while drawing and moist meeting medicinal requirements.

Description

A kind of dextrorotation Iprazole compound and its pharmaceutical composition

Technical field

The invention belongs to medicinal chemistry arts, a kind of dextrorotation Iprazole compound more particularly to crystal form and its Pharmaceutical composition and preparation method.

Background technique

Iprazole (Ilaprazole), systematic naming method are 5- (1 hydrogen-pyrroles -1- base) -2- [[(4- methoxyl group -3- first Base) -2- pyridyl group]-methyl]--1 hydrogen of sulfinyl-benzimidazole；Its enteric coatel tablets can be used for treating duodenal ulcer.

Dextrorotation Iprazole chemical structure is shown in formula I, is R configuration.Left or right rotation is disclosed in CN101098867A Iprazole Acidinhibitor it is all stronger than raceme.

Disclosed in WO2008/083319A1 dextrorotation Iprazole crystal form Form A form and left-handed Iprazole Form A, Form O, amorphous forms.

Summary of the invention

The present invention provides the preparation sides of a kind of dextrorotation Iprazole compound of new crystal form and the novel crystal forms Method and pharmaceutical composition containing the crystal form.

The present invention may be implemented by following technical solution:

A kind of dextrorotation Iprazole compound that structure is shown in formula I, is crystal form, and X-ray powder diffraction figure exists With diffraction maximum at following interplanar distance: 11.21,8.91,7.32,4.83,4.16,4.10,3.63.

Its X-ray powder diffraction figure is at following interplanar distance with diffraction maximum: 5.90,5.58,5.46,3.90,3.10. Interplanar distance can also indicate that unit is angstrom by d value.

It is further preferred that the dextrorotation Iprazole compound of the crystal form, there is X substantially as shown in Figure 1 to penetrate Line powder diagram；2 angles θ, d value and Relative intensity data are as shown in table 1 in Fig. 1.According to Bragg equation 2dsin θ=n λ； Wherein λ is the wavelength of X-ray, and n is diffraction progression；Fig. 1 is obtained by Cu target diffraction in the present invention, and wavelength X is 1.5406 angstroms. 2θ There are errors for the measurement at angle；In general the error range at 2 angles θ may be regarded as measurement error ± 0.2.

Table 1

It is further preferred that the dextrorotation Iprazole compound of the crystal form, has DSC substantially as shown in Figure 2 Map has an endothermic peak at about 180 DEG C.The heating rate of DSC map shown in Fig. 2 is 10 DEG C/min, and temperature elevating range is 50~300 DEG C, endothermic peak is upward (Endo up) in map.

The present invention also provides a kind of methods for preparing the crystal form dextrorotation Iprazole compound, comprising: will be right Rotation Iprazole is dissolved in methylene chloride, and methyl tertiary butyl ether(MTBE) is added dropwise, and the dextrorotation Iprazole is obtained by filtration in stirring and crystallizing Compound.

Preferably, it dissolves and is carried out at room temperature with the process of crystallization, the room temperature refers to 15~30 DEG C.

Preferably the volume ratio of methylene chloride and methyl tertiary butyl ether(MTBE) is 1:(0.5~10)；It is further preferably 1:(1 ~5).

Preferably every 1 gram of dextrorotation Iprazole is dissolved in (3~15) mL methylene chloride；It is further preferably every 1 gram of dextrorotation Iprazole is dissolved in (3~8) mL methylene chloride.

The pharmaceutical composition of the present invention also provides a kind of dextrorotation Iprazole compound containing the crystal form.It is excellent Selection of land, the dosage form of the composition can for oral solid formulation (including but not limited to enteric coatel tablets, capsulae enterosolubilis) or Parenteral formulations agent (such as freeze dried injection).

According to the present invention, the composition further includes pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier is usual It is that those of ordinary skill in the art can be specifically chosen according to specific form of medication.It can be with it is well known that technology be as usual The techniques such as rule granulation, mixing, dissolution, formation capsule, freeze-drying manufacture pharmaceutical composition of the invention.It can be by the present composition The form for various administration routes is made, for example, oral administration, intravenous etc..

The present invention also provides the dextrorotation Iprazole compounds of the crystal form in preparing proton pump inhibitor drug Application.

The present invention has investigated the factors such as high temperature, high humidity and illumination to the dextrorotation Iprazole of crystal form of the present invention The dextrorotation Iprazole chemical combination of crystal form of the present invention under the conditions of accelerated test has also been investigated in the influence for closing object stability The stability of object with draw it is moist.The result shows that novel crystal forms of the present invention are basicly stable under high temperature, high humidity and illumination condition； Under the conditions of accelerated test the stability of novel crystal forms of the present invention and draw it is moist also without significant changes, while according to " middle traditional Chinese medicines Allusion quotation " 2010 editions two annex XIX J, novel crystal forms of the present invention are slightly to draw moist, meet medicinal requirements.

Detailed description of the invention

The X-ray powder diffraction pattern of the dextrorotation Iprazole compound of Fig. 1 crystal form of the present invention

The DSC map of the dextrorotation Iprazole compound of Fig. 2 crystal form of the present invention

The dextrorotation Iprazole A crystal form that Fig. 3 is prepared according to WO2008/083319A1 embodiment 2

Specific embodiment

It is further illustrated below by the mode of embodiment, but skilled in the art realises that, following embodiments are not pair The limitation of the scope of the present invention, any improvements and changes made on the basis of the present invention, all in protection scope of the present invention Within.

Embodiment 1

It takes dextrorotation Iprazole crude product (1.0g) to be dissolved in methylene chloride (5mL), methyl tertiary butyl ether(MTBE) is slowly added dropwise at room temperature (15mL) is stirred at room temperature 30 minutes, and filtering, filter cake is washed with methyl tertiary butyl ether(MTBE), and 30 DEG C of vacuum drying obtain white solid 0.78g。

The X-ray powder diffraction collection of gained white solid is basic as shown in Figure 1, its DSC map is substantially as shown in Figure 2.

Embodiment 2

It takes dextrorotation Iprazole crude product (1.0g) to be dissolved in methylene chloride (3mL), methyl tertiary butyl ether(MTBE) is slowly added dropwise at room temperature (15mL) is stirred at room temperature 20 minutes, and filtering, filter cake is washed with methyl tertiary butyl ether(MTBE), and 30 DEG C of vacuum drying obtain white solid. The X-ray powder diffraction collection of gained white solid is substantially as shown in Figure 1.

Embodiment 3

It takes dextrorotation Iprazole crude product (1.0g) to be dissolved in methylene chloride (8mL), methyl tertiary butyl ether(MTBE) is slowly added dropwise at room temperature (15mL) is stirred at room temperature 40 minutes, and filtering, filter cake is washed with methyl tertiary butyl ether(MTBE), and 30 DEG C of vacuum drying obtain white solid. The X-ray powder diffraction collection of gained white solid is substantially as shown in Figure 1.

Embodiment 4

It takes dextrorotation Iprazole crude product (1.0g) to be dissolved in methylene chloride (10mL), methyl tertiary butyl ether(MTBE) is slowly added dropwise at room temperature (15mL) is stirred at room temperature 50 minutes, and filtering, filter cake is washed with methyl tertiary butyl ether(MTBE), and 30 DEG C of vacuum drying obtain white solid. The X-ray powder diffraction collection of gained white solid is substantially as shown in Figure 1.

Embodiment 5

It takes dextrorotation Iprazole crude product (1.0g) to be dissolved in methylene chloride (15mL), methyl tertiary butyl ether(MTBE) is slowly added dropwise at room temperature (15mL) is stirred at room temperature 1 hour, and filtering, filter cake is washed with methyl tertiary butyl ether(MTBE), and 30 DEG C of vacuum drying obtain white solid. The X-ray powder diffraction collection of gained white solid is substantially as shown in Figure 1.

Embodiment 6

It is prepared for dextrorotation Iprazole A crystal form according to WO2008/083319A1 embodiment 2, has investigated illumination, relative humidity The influence of (temperature is 25 DEG C), temperature (relative humidity is 65 ± 5%) to dextrorotation Iprazole A crystal form and novel crystal forms of the present invention. The results are shown in Table 1.(0d represents initial time, 5d and 10d respectively represent 5 days after with 10 days after)

Table 1

It is tested from influence factor, no matter novel crystal forms of the present invention are obviously than A crystalline substance under high temperature, high humidity or light conditions Type is stablized.In terms of appearance, relative to novel crystal forms of the present invention, A crystal form is more easy to change, becomes faint yellow to brown from off-white color.

Embodiment 7

It is prepared for dextrorotation Iprazole A crystal form according to WO2008/083319A1 embodiment 2, has investigated accelerated test condition Under (30 DEG C ± 2 DEG C, RH65 ± 5%), dextrorotation Iprazole A crystal form and novel crystal forms stability of the present invention.It the results are shown in Table 2.

Table 2

Accelerated test sees that novel crystal forms stability of the present invention is substantially better than A crystal form；Draw moist aspect and is slightly better than A crystal form.

Claims

1. a kind of dextrorotation Iprazole compound that structure is shown in formula I, it is characterised in that the dextrorotation Iprazole compound For crystal form,

Its X-ray powder diffraction figure has diffraction maximum at following interplanar distance: 11.21,8.91,7.32,5.90,5.58, 5.46、4.83、4.16、4.10、3.90、3.63、3.10。

2. dextrorotation Iprazole compound according to claim 1, it is characterised in that have X substantially as shown in Figure 1 to penetrate Line powder diagram.

3. dextrorotation Iprazole compound according to claim 1, it is characterised in that have DSC substantially as shown in Figure 2 Map.

4. a kind of method for preparing dextrorotation Iprazole compound according to any one of claims 1 to 3, it is characterised in that: Dextrorotation Iprazole is dissolved in methylene chloride, methyl tertiary butyl ether(MTBE) is added dropwise, the dextrorotation Ai Pu is obtained by filtration in stirring and crystallizing Prazole compounds.

5. according to the method described in claim 4, it is characterized by: every 1 gram of dextrorotation Iprazole is dissolved in (3~15) mL dichloromethane Alkane.

6. according to the method described in claim 5, it is characterized by: every 1 gram of dextrorotation Iprazole is dissolved in (3~8) mL dichloromethane Alkane.

7. according to the method described in claim 4, it is characterized by: the volume ratio of methylene chloride and methyl tertiary butyl ether(MTBE) is 1: (0.5~10).

8. according to the method described in claim 7, it is characterized by: the volume ratio of methylene chloride and methyl tertiary butyl ether(MTBE) is 1:(1 ~5).

9. dextrorotation Iprazole compound according to any one of claims 1 to 3 is in preparing proton pump inhibitor drug Using.

10. containing the pharmaceutical composition of dextrorotation Iprazole compound according to any one of claims 1 to 3.

11. pharmaceutical composition according to claim 10, it is characterised in that described pharmaceutical composition is enteric coatel tablets, enteric glue Capsule or freeze dried injection.