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Salt, crystal and pharmaceutical composition of trelagliptin compound and applications thereof

A composition and drug technology, applied in the directions of drug combination, organic chemistry, organic chemistry methods, etc., can solve the problems such as the inability to maintain a crystalline state of troxagliptin succinate

Active Publication Date: 2016-03-16
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] After further research on the solid form of trexagliptin succinate, we found that trexagliptin succinate cannot maintain the original crystalline state in the presence of organic solvents or water residues

Method used

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  • Salt, crystal and pharmaceutical composition of trelagliptin compound and applications thereof
  • Salt, crystal and pharmaceutical composition of trelagliptin compound and applications thereof
  • Salt, crystal and pharmaceutical composition of trelagliptin compound and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1: Trexagliptin hemisuccinate hydrate crystal form I and its preparation

[0081] Take 15.00g (41.97mmol) trexagliptin and place it in a round-bottomed flask, add 200mL tetrahydrofuran and 100mL isopropanol, stir and heat to 40°C, the solid gradually dissolves during heating; weigh 2.47g (20.91mmol) of succinic acid Added to the trexagliptin solution, white solids precipitated after the addition, continued to stir for 60 minutes, stopped heating, naturally cooled to room temperature and stirred for 2 hours. After filtering, the filter cake was washed twice with isopropanol, sucked dry, and dried in vacuum at 40° C. to obtain trexagliptin hemisuccinate hydrate crystal form I.

[0082] The crystalline form I of trexagliptin hemisuccinate hydrate prepared as above was identified via the triclinic unit cells of space group P1, which were characterized by single crystal X-ray structures at 296K The following parameters were analyzed analytically: α=85.883(2)°, β=8...

Embodiment 2

[0092] Example 2: Preparation of trexagliptin hemisuccinate hydrate crystal form I

[0093] Take 15.0g (41.97mmol) trexagliptin in a round bottom flask, add 150mL tetrahydrofuran, stir and heat to 50°C, the solid gradually dissolves during the heating process; weigh 2.47g (20.91mmol) of succinic acid and dissolve it in 50mL isopropyl alcohol; add the succinic acid solution to the trexagliptin solution, a white solid precipitates during the addition process, continue to stir for 20min, stop heating, naturally cool to room temperature and stir for 2h. After filtering, the filter cake was washed twice with isopropanol, sucked dry, and dried in vacuum at 50° C. to obtain trexagliptin hemisuccinate hydrate crystal form I.

[0094] After testing, the characteristic diffraction lines of X-ray powder diffraction are all the same as those in Example 1.

Embodiment 3

[0095] Example 3: Preparation of trexagliptin hemisuccinate hydrate crystal form I

[0096] Take 15.0g (41.97mmol) trexagliptin and place it in a round bottom flask, add 100mL tetrahydrofuran and 50mL isopropanol, stir and heat to 70°C, the solid gradually dissolves during the heating process; weigh 2.47g (20.91mmol) succinic acid Added to the trexagliptin solution, a white solid precipitated, continued to stir for 30 minutes, stopped heating, naturally cooled to room temperature and stirred for 2 hours. After filtering, the filter cake was washed twice with isopropanol, sucked dry, and dried in vacuum at 50° C. to obtain trexagliptin hemisuccinate hydrate crystal form I.

[0097] After testing, the characteristic diffraction lines of X-ray powder diffraction are all the same as those in Example 1.

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Abstract

The invention provides a novel dipeptidyl peptidase IV inhibitor trelagliptin compound, hemi-succinate, hydrates and novel crystal-form drugs thereof, a pharmaceutical composition containing them and applications thereof in preparing medications for treating diabetic diseases. A novel crystal form provided by the invention contains 0.5 succinate molecule, so that the intake of inactive ingredients is reduced, then the relative toxicity is low, and the effective composition content is high, therefore, the novel crystal-form is safer and more effective when applied to preparations, and more applicable to the clinical application of high-dose preparations. Compared with the succinate crystal form of existing trelagliptin, the novel crystal form provided by the invention is good in stability and conducive to the wet granulation of solid preparations or the preparation of liquid preparations, and facilitates the manufacturing, storage and transportation of medications; and the novel crystal form provided by the invention is high in purity and safer in usage of medication.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a hemisuccinate salt of the hypoglycemic drug trexagliptin and its crystal or crystal form, and also relates to a preparation method of the salt and its crystal or crystal form, its pharmaceutical composition and Its application in the preparation of medicines for treating diabetes diseases. Background technique [0002] With the continuous improvement of people's living standards, the prevalence of diabetes is gradually increasing, and it has become one of the chronic diseases that seriously threaten human health. In recent years, dipeptidyl peptidase-Ⅳ inhibitor (DPP-Ⅳ inhibitor), as a new target drug for diabetes, has attracted more and more attention and has been widely used in clinic. DPP-Ⅳ inhibitors are the first new type 2 diabetes drugs that can control blood sugar levels by improving the body's own ability. They can be used as single drugs or in combinati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04A61P3/10
CPCC07B2200/13C07D401/04
Inventor 李国琴周新波胡秀荣郑鹛赵琛吕裕斌
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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