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Solid compound of dapagliflozin as well as preparation method and application of solid compound

A complex, form of technology, applied in the field of medicine

Pending Publication Date: 2022-06-28
HINYE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In summary, the existing reports mainly involve research on the new crystal forms and solvates of dapagliflozin, and there is no data showing that these co-crystals can improve the pharmacological properties of the drug
In addition, there are no research reports on multi-drug complexes of dapagliflozin, such as multi-drug co-crystals or multi-drug amorphous

Method used

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  • Solid compound of dapagliflozin as well as preparation method and application of solid compound
  • Solid compound of dapagliflozin as well as preparation method and application of solid compound
  • Solid compound of dapagliflozin as well as preparation method and application of solid compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] The preparation method of the co-crystal represented by formula II formed by dapagliflozin and nateglinide:

[0069] Test 1: Add nateglinide (776mg, 2.4mmol, 1.0eq) and dapagliflozin (1.0g, 2.4mmol, 1.0eq) to 4mL of ethyl acetate, stir to dissolve at room temperature, and slowly add 50mL of n-hexane dropwise After dripping, the temperature was slowly lowered to 0°C, a white solid was precipitated, suction filtered, the filter cake was rinsed with 5 mL of n-hexane, and then dried under vacuum at 40°C to obtain 1.5 g of a white solid with a yield of 84.5%.

[0070] Test 2: Add nateglinide (776mg, 2.4mmol, 1.0eq) and dapagliflozin (1.0g, 2.4mmol, 1.0eq) to 4mL of ethanol, stir to dissolve at room temperature, slowly add 30mL of water dropwise at 60°C, After dripping, the temperature was slowly lowered to 0°C to precipitate a white solid, which was filtered off with suction. The filter cake was rinsed with 5 mL of water, and then dried under vacuum at 40°C to obtain 1.62 g ...

Embodiment 2

[0081] The preparation method of the co-crystal formed by dapagliflozin and candesartan cilexetil of the present embodiment:

[0082] Preparation method of dapagliflozin and candesartan medoxomil co-crystal form I

[0083] Dapagliflozin (816mg, 2.0mmol, 1.0eq) and candesartan medoxomil (1.22g, 2.0mmol, 1.0eq) were added to a mixed system of 5mL of dichloromethane and 2mL of methanol, stirred at room temperature to dissolve, and then rotated The solvent was removed to obtain an oily substance, which was dissolved by adding 5 mL of ethyl acetate, and then slowly added dropwise with 40 mL of n-hexane. After drying, 1.95 g of white solid was obtained, which was identified as the co-crystal form I of dapagliflozin and candesartan cilexetil, and the yield was 96.1%.

[0084] The X-ray powder diffraction (XRPD) data of the co-crystal form I of dapagliflozin and candesartan cilexetil obtained in this example are shown in Table 2, and the XRPD pattern is shown in Table 2. Figure 4 ....

Embodiment 3

[0100] The preparation method of the solid amorphous formed by dapagliflozin and alalogliptin:

[0101] Alalogliptin (250 mg, 0.65 mmol, 1.0 eq) and dapagliflozin (266 mg, 0.65 mmol, 1.0 eq) were added to 10 mL of dichloromethane, stirred at room temperature to dissolve, and then spun off the solvent to obtain an oily substance, which was added 10 mL of n-hexane was slurried at room temperature, the oily substance turned into a white solid, filtered with suction, the filter cake was rinsed with 5 mL of n-hexane, and then dried under vacuum at 45°C to obtain 0.50 g of a white solid with a yield of 96.9%.

[0102] The XRPD diagram of the solid amorphous of dapagliflozin and alalogliptin obtained in this example is as follows Figure 11 , Figure 11 X-ray powder diffraction showed no characteristic peaks, indicating that the obtained complex was amorphous.

[0103] Nuclear Magnetic Resonance Spectroscopy 1 H-NMR as Figure 12 .

[0104] 1 H NMR (400MHz, MeOD) δ 9.33 (d, J=1...

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Abstract

The invention discloses a dapagliflozin solid-form compound as well as a preparation method and application thereof. The compound is in a solid form formed by dapagliflozin, nateglinide, candesartan cilexetil, anagliptin or enalapril. The invention also comprises a preparation method and application of the dapagliflozin solid compound. According to the dapagliflozin solid compound, the two components are combined in a hydrogen bond or other non-covalent bond mode on the basis that original molecular covalent bonds are not damaged, a new eutectic or amorphous substance is formed, the two active components exist in a specific stoichiometric ratio, no organic solvent is contained, and the preparation method is simple. And good biocompatibility is achieved. Different from a mixture obtained by simply and physically mixing the two active ingredients, the compound provided by the invention can effectively improve various physicochemical properties of the medicine, improve the stability, solubility and bioavailability of the medicine and effectively improve the hygroscopicity of the medicine.

Description

technical field [0001] The invention belongs to the technical field of medicine, and particularly relates to a dapagliflozin solid form compound and a preparation method and application thereof. Background technique [0002] Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT-2) inhibitor for the treatment of type 2 diabetes mellitus, and is a new type of oral hypoglycemic drug. It can inhibit the reabsorption of glucose in the renal tubules, so that the excess blood sugar is excreted through the urine, thereby reducing the blood sugar of diabetic patients. Under normal circumstances, the daily glomerular filtration of glucose is 180g / d, but 100% of this glucose is filtered by the renal tubules. Sodium-glucose cotransporters (SGLT-1, SGLT-2) reabsorption on The reabsorption of glucose and sodium ions by SGLT-2 inhibitors can excrete 70-80 g / d glucose from the urine, thereby exerting a hypoglycemic effect and a hypotensive effect. The chemical structural formula of Dapa...

Claims

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Application Information

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IPC IPC(8): C07D309/10C07C233/63C07D403/10C07D401/04C07K5/062C07K1/107A61K31/351A61P3/10A61P5/48A61P9/04A61P9/12
CPCC07D309/10C07C233/63C07D403/10C07D401/04C07K5/06026A61P3/10A61P5/48A61P9/04A61P9/12C07B2200/13
Inventor 不公告发明人
Owner HINYE PHARM CO LTD
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