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New crystal forms of (R)-7-chloro-N-(quinuclidinyl-3-yl)benzo[b]thienyl-2-formamide hydrochloride

A technology of hydrochloride and crystal form, which is applied in the direction of medical preparations containing active ingredients, organic active ingredients, nervous system diseases, etc. It can solve the problems of great influence of humidity, instability of crystal form I and crystal form II, etc. Achieve low cost, good stability, avoid changes in bioavailability and efficacy

Inactive Publication Date: 2016-05-25
CRYSTAL PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Encenicline hydrochloride has polymorphic forms. At present, only Envivo (EnVivo) pharmaceutical company discloses two hydrate crystal forms of Encenicline hydrochloride in patent CN103221411A, crystal form I and crystal form II, but the crystal form Form I and Form II are unstable and are greatly affected by humidity
No other pharmaceutical company has disclosed a new polymorphic form of Encenicline hydrochloride

Method used

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  • New crystal forms of (R)-7-chloro-N-(quinuclidinyl-3-yl)benzo[b]thienyl-2-formamide hydrochloride
  • New crystal forms of (R)-7-chloro-N-(quinuclidinyl-3-yl)benzo[b]thienyl-2-formamide hydrochloride
  • New crystal forms of (R)-7-chloro-N-(quinuclidinyl-3-yl)benzo[b]thienyl-2-formamide hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] The preparation method of the crystal form A of formula (I) compound hydrochloride:

[0070] Dissolve 202.2 mg of the compound of formula (I) in 5 mL of chloroform, add 1 N hydrochloric acid solution (hydrochloric acid concentration: 12 mol / L) dropwise, stir at room temperature for 30 minutes, filter off the chloroform, and place the resulting solid in an oven at 180°C 30 minutes, cooling at room temperature, the obtained solid is hydrochloride crystal form A.

[0071] The X-ray powder diffraction data of hydrochloride salt form A obtained in this example include but are not limited to the data in Table 1. Its XRPD pattern is as follows figure 1 , and its DSC graph is shown in figure 2 , and its TGA figure is shown in image 3 .

[0072] Table 1 X-ray powder diffraction data of crystal form A

[0073]

[0074]

Embodiment 2

[0076] The preparation method of the crystal form A of formula (I) compound hydrochloride:

[0077] Add 0.5ml of ethyl acetate to the 10.7mg patent CN103221411A disclosed formula (I) compound hydrochloride solid, place in a 1.5ml glass vial, then add formula (I) compound hydrochloride solid 9.9% in the vial mg, stirred at 80°C for 72 hours, centrifuged, and dried to form the hydrochloride crystal form A.

[0078] Table 2 shows the X-ray powder diffraction data of the hydrochloride crystal form A obtained in this example.

[0079] Table 2 X-ray powder diffraction data of crystal form A

[0080]

[0081]

Embodiment 3

[0083] The preparation method of the crystal form B of formula (I) compound hydrochloride:

[0084] Add the hydrochloride crystal form A of the compound of formula (I) prepared in Example 1 into 0.2 mL of a mixed solvent with a volume ratio of pure water and methanol of 7:93 until insoluble matter appears, and then add 10.0 mg of the Hydrochloride solid, stirred at room temperature for 48 hours.

[0085] The X-ray powder diffraction data of the crystal forms obtained in this example include but are not limited to the data in Table 3. Its XRPD pattern is as follows Figure 4 , and its DSC graph is shown in Figure 5 , and its TGA figure is shown in Image 6 .

[0086] Table 3 X-ray powder diffraction data of crystal form B

[0087]

[0088]

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PUM

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Abstract

The invention relates to new crystal forms of (R)-7-chloro-N-(quinuclidinyl-3-yl)benzo[b]thienyl-2-formamide hydrochloride and a preparation method thereof. The crystal forms provided by the invention have the advantages of favorable stability, lower hygroscopicity, developable technique, high treatability and the like. The preparation method is simple, is low in cost, and has important value for optimizing and developing the drug in future.

Description

technical field [0001] The invention relates to the field of chemical medicine, in particular to a new crystal form of hydrochloride of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and its Preparation. Background technique [0002] (R)-7-Chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide (Encenicline), as shown in the compound of formula (I), was first produced by Bayer HealthCare Research and development, and later authorized to EnVivo Pharmaceutical Company and Mitsubishi Tanabe Pharmaceutical Company for development. The drug is used to treat Alzheimer's disease and schizophrenia, and it is currently in the clinical phase III, and the hydrochloride of Encenicline is used clinically. [0003] [0004] Drug polymorphism refers to the existence of two or more different crystal forms of a drug. Polymorphism exists widely in pharmaceuticals. Different crystal forms of the same drug have significant differences in solubility, melting point, de...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02A61K31/439A61P25/28A61P25/18
CPCA61K31/439C07D453/02C07B2200/13
Inventor 陈敏华张炎锋刘凯张晓宇
Owner CRYSTAL PHARMATECH CO LTD
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