Empagliflozin crystal forms, preparation methods and uses thereof, and pharmaceutical composition

A technology of empagliflozin and composition, which is applied in the direction of drug combination, preparation of sugar derivatives, chemical instruments and methods, etc., can solve the problem of unfavorable crystal form stability preparation storage stability, affecting preparation operability, crystal form A Low purity and other issues, to achieve the effect of improving bioavailability, reducing sieving time, and good fluidity

Inactive Publication Date: 2016-03-09
HANGZHOU PUSHAI PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The inventors found in the research that there are the following defects in the crystal form A: the purity of the crystal form A is low, and it is a needle crystal
Needle crystals generally have poor fluidity, low bulk density, and are difficult to filter and dry, which affects the operability of preparation processing; in addition, needle crystals need to be pulverized before they can be used in solid dosage forms of pharmaceutical preparations, and pulverization will affect the crystal form. Destruction, which is not conducive to the stability of the crystal form and the storage stability of the preparation

Method used

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  • Empagliflozin crystal forms, preparation methods and uses thereof, and pharmaceutical composition
  • Empagliflozin crystal forms, preparation methods and uses thereof, and pharmaceutical composition
  • Empagliflozin crystal forms, preparation methods and uses thereof, and pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0075] Preparation Example 1 Preparation of empagliflozin

[0076] Empagliflozin was prepared by referring to the preparation method of the examples of the patent document WO2006 / 117359A1. Specifically: take 2.85g of (R)-3-(4-methylphenylsulfonyloxy)-tetrahydrofuran and add 3.00g of 1-chloro-4-(β-D-glucopyranose-1-yl )-2-(4-Hydroxybenzyl)-benzene and 4.36 g of cesium carbonate in a mixture of 38 mL of dimethylformamide. The mixture was stirred at 75° C. for 5 hours, then an additional 4.40 g of cesium carbonate and 2.87 g of (R)-3-(4-methylphenylsulfonyloxy)-tetrahydrofuran were added. After stirring for another 16 hours at 75°C, the mixture was cooled to room temperature and brine was added. The resulting mixture was extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous sodium sulfate. The residue was purified by column (dichloromethane / methanol 1:0→5:1). Yield is 2.1 g, yield 57%. Mass spectrometry (ESI + ): m / z=451 / 453 (Cl)[M+H] ...

preparation example 2

[0077] Preparation example 2 Preparation of Crystal Form A of Empagliflozin

[0078] The crystal form A of empagliflozin was prepared by referring to the preparation method of the example of patent document WO2006 / 117359A1. Specifically: 2.1 g of empagliflozin was dissolved in 50 mL of ethyl acetate (containing 0.5-3% water) heated to 50°C. The solution was cooled slowly (about 1-4 hours) to room temperature. After 72 hours, it was filtered and rinsed twice with ethyl acetate (containing 0.5-3% water) to obtain a white solid, which was dried overnight at 45° C., and its XRPD pattern was as follows: Figure 5 As shown, it is consistent with the crystal form A disclosed in the patent document WO2006 / 117359A1.

Embodiment 1

[0080] Get 29.01mg of the crystal form A of empagliflozin prepared in Preparation Example 2 in a 20mL glass vial, add 5.8mL of ethyl acetate, and stir for 3 hours in a water bath at 80°C, and the system basically dissolves (the empagliflozin in the solution The dosage of crystal form A is 1 time of its solubility in ethyl acetate at 80°C), and after hot filtration, the filtrate is directly placed at 4°C and stirred, and a white solid is precipitated in 2 hours; after centrifugation, empagliflozin is obtained. Form I, the yield is 24.26mg, the yield is 76%.

[0081] Its XRPD pattern is as follows figure 1 Shown is the crystal form I of empagliflozin.

[0082] Its TGA / DSC spectrum is as follows figure 2 As shown, the melting point is 149°C, the weight loss is 1.1% before 50°C, and the weight loss is 8.8% at 50-150°C, which is about one molecule of empagliflozin combined with 0.5 ethyl acetate molecules.

[0083] Its FT-IR spectrum is as image 3 Shown, compared with the FT-...

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Abstract

The present invention relates to new empagliflozin crystal forms, wherein the new empagliflozin crystal forms have a variety of improved characteristics compared with the known crystal form, and are suitable for pharmaceutical preparations. The present invention further relates to preparation methods of the new crystal forms, a pharmaceutical composition of the new crystal form, and uses of the new crystal forms in preparation of drugs for treatment and / or prevention of type II diabetes.

Description

technical field [0001] This application relates to the technical field of medicinal chemical crystallization. Specifically, the application relates to a glucopyranosyl-substituted benzene derivative, especially to a new crystal form of empagliflozin, as well as a preparation method, pharmaceutical composition and use of the new crystal form. Background technique [0002] The English name of empagliflozin is Empagliflozin, also known as BI-10773, and its molecular formula is C 23 h 27 ClO 7 , the molecular weight is 450.91, and the chemical structural formula is as follows: [0003] [0004] Empagliflozin, jointly developed by Boehringer Ingelheim and Eli Lilly and Company, is a glucopyranosyl-substituted benzene derivative belonging to a class of sodium-glucose symporter (SGLT2) inhibitors for the treatment of type II diabetes agent. The results of the four phase III clinical studies of empagliflozin have reached the main treatment index. Compared with patients takin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/12A61K31/351C07H15/203C07H1/06A61K31/7048A61P3/10A61P3/04A61P3/00
Inventor 劳海萍盛晓红盛晓霞贾强
Owner HANGZHOU PUSHAI PHARMA TECH
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