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Crystal form of linagliptin and preparation method thereof

A crystal form and molecular crystallization technology, applied in the fields of active ingredients of heterocyclic compounds, metabolic diseases, organic chemistry, etc., can solve the problems of linagliptin's poor crystal form stability, incapable of large-scale production, and safety , to achieve the effect of good drug prospects, low hygroscopicity and high safety

Inactive Publication Date: 2019-05-14
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The object of the present invention is to provide a crystalline form of linagliptin, which solves the problems in the prior art that the crystalline form of linagliptin is not stable, has safety risks, cannot be produced on a large scale, etc.

Method used

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  • Crystal form of linagliptin and preparation method thereof
  • Crystal form of linagliptin and preparation method thereof
  • Crystal form of linagliptin and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1: Preparation of linagliptin crystal form.

[0057] Add 10 g of linagliptin solid to 40 mL of methyl ethyl ketone to form a suspension, and stir at a stirring speed of 300 r / min. Raise the temperature to 30°C at a heating rate of 3°C / min to obtain a linagliptin clear liquid, add 2ml of purified water to the above clear liquid at a constant temperature, then cool down to 20°C at a cooling rate of 0.5°C / min, and grow crystals at a constant temperature for 1.5h . Suction filtration, and dry the obtained wet crystalline product at 40°C and a vacuum of 0.1Mpa for 10h to obtain 9.00g of crystalline solid. The purity was 99.6%, and the yield was 90.0%.

[0058] The characterization data of the crystal form determined by XRD are shown in Table 1, and the XRD spectrum of its sample is shown in Table 1. figure 1 shown.

[0059] Table 1 XRD analysis data of the crystal form of the application

[0060]

[0061] The results of DSC analysis show that there are strong...

Embodiment 2

[0067] Embodiment 2: Preparation of linagliptin crystal form

[0068] Add 10 g of linagliptin solid into 40 mL of a mixed solvent of methanol and acetone (volume ratio = 1:1) and stir at a stirring speed of 200 r / min. Raise the temperature to 70°C at a heating rate of 2°C / min to obtain a linagliptin clarified liquid, add 1.6mL of purified water to the above clear liquid at a constant temperature, then cool down to 0°C at a cooling rate of 0.5°C / min, and grow crystals at a constant temperature of 0.5°C. h. Suction filtration, and dry the obtained wet crystalline product at 55°C and a vacuum of 0.08Mpa for 2h to obtain 9.12g of crystalline solid. The purity was 99.7%, and the yield was 91.2%.

[0069] After determination, its XRD pattern and figure 1 Basically the same, its DSC spectrum and figure 2 Basically the same, according to the KF moisture test, its water content is about 6.1%, and its TGA spectrum is consistent with that of image 3 The shape of the curve is basic...

Embodiment 3

[0070] Example 3: Preparation of linagliptin crystal form.

[0071] Add 10 g of linagliptin solid into 100 mL of n-propanol and stir at a stirring speed of 500 r / min. Raise the temperature to 50°C at a heating rate of 5°C / min to obtain a linagliptin clarified liquid, add 10 mL of purified water to the above clear liquid at a constant temperature, then cool down to 10°C at a cooling rate of 0.5°C / min, and grow crystals at a constant temperature for 2 hours. Suction filtration, and dry the obtained wet crystalline product at 35° C. and a vacuum of 0.1 Mpa for 5 hours to obtain 9.13 g of crystalline solid. The purity was 99.4%, and the yield was 91.3%.

[0072] After determination, its XRD pattern and figure 1 Basically the same, its DSC spectrum and figure 2 Basically the same, as shown by KF moisture content, its water content is about 8.0%, and its TGA spectrum is consistent with that of image 3 The shape of the curve is basically the same.

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Abstract

The invention discloses a crystal form of linagliptin and a preparation method thereof. For the crystal form, X-ray powder diffraction, expressed in 2 theta angle and using the alpha radiation of Cu-K(copper-potassium), has diffraction peaks at 23.1 plus or minus 0.2 degrees, 23.5 plus or minus 0.2 degrees, 24.6 plus or minus 0.2 degrees and 27.1 plus or minus 0.2 degrees. The preparation methodof the crystal form of the linagliptin includes the steps of preparing linagliptin solid into a suspension in a solvent and stirring, adding purified water therein after heating to 30-70 DEG C, cooling down to 0-20 DEG C and growing crystal at constant temperature for 0.5-2 hours, filtering crystal slurry, and drying to constant weight. The crystal form of the linagliptin has the advantages of good stability, high safety, and suitablility for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a crystal form of linagliptin and a preparation method thereof. Background technique [0002] Linagliptin, chemical name: 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)- 8-(3-(R)-amino-piperidin-1-yl)-xanthine, chemical formula: C 25 h 28 N 8 o 2 , relative molecular mass: 472.54, and the structural formula of the compound is as follows: [0003] [0004] Linagliptin is an oral tablet for type II diabetes developed by Boehringer Ingelheim International, Germany, which was approved by the FDA for marketing on May 2, 2011, and its sales product is named TRADJENTA. Linagliptin is a dipeptidyl peptidase 4 (DPP-4) inhibitor. Compared with other DPP-4 inhibitors, Linagliptin has better renal safety and has the advantage of effectively reducing glycosylated hemoglobin . [0005] German Boehringer Ingelheim International patent EP1532149 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/04A61P3/10A61K31/522
Inventor 王天明李宏名张生烈李正林郭军辉张娇王利春王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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