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Preparation technology of apixaban solid amorphous dispersoid

A preparation process and apixaban technology are applied in the field of preparation of apixaban solid amorphous dispersions, and can solve the problems of unfavorable industrial production of apixaban solid amorphous dispersions, low solubility, potential environmental pollution, etc. problems, to achieve the effect of reducing energy consumption, improving solubility, and reducing waste liquid

Active Publication Date: 2019-07-23
HISUN PHARMACEUTICAL (HANGZHOU) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The low solubility of apixaban requires the use of a large amount of organic solvents in the preparation of the existing solid amorphous dispersion of apixaban, which not only has potential environmental pollution, but also It is very unfavorable to realize the industrialized production of apixaban solid amorphous dispersion, therefore, there is an urgent need for a preparation process of apixaban solid amorphous dispersion with less solvent usage and suitable for scale-up production

Method used

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  • Preparation technology of apixaban solid amorphous dispersoid
  • Preparation technology of apixaban solid amorphous dispersoid
  • Preparation technology of apixaban solid amorphous dispersoid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Add 5g of apixaban and 15g of vinylpyrrolidone-vinyl acetate copolymer (PVP-VA64) into a 1L screw-top reagent bottle containing 120g of dichloromethane and acetic acid mixed solvent (1.0% by mass of acetic acid). Seal at 25°C, stir with a magnet until the solution is clear, spray dry the solution, the air inlet temperature of spray drying is 120°C, the air outlet temperature is 58-62°C, and then heat and dry under vacuum at 60°C for 8 hours to obtain api Shaban solid amorphous dispersion 10.2g.

[0037] The X-ray powder diffraction spectrum of the apixaban solid amorphous dispersion obtained in the present embodiment is as follows figure 1 shown.

Embodiment 2

[0039] Add 5g of apixaban and 45g of vinylpyrrolidone-vinyl acetate copolymer (PVP-VA64) into a 1L screw-top reagent bottle containing 150g of tetrahydrofuran and acetic acid mixed solvent (accounting for 1.0% by mass of acetic acid), at 25°C Bottom seal, stir with a magnet until the solution is clear, spray dry the solution, the air inlet temperature of the spray drying is 110°C, the air outlet temperature is 62-67°C, and then heat and dry under vacuum at 40°C for 12 hours to obtain apixaban Solid amorphous dispersion 23.2 g.

Embodiment 3

[0041]Add 5g of apixaban and 5g of polyvinylpyrrolidone (PVP-K30) into a 1L screw-top reagent bottle containing 80g of a mixed solvent of methanol and acetic acid (2.0% by mass of acetic acid), seal it at 25°C, and stir with a magnet Until the solution is clear, the solution is spray-dried, the air inlet temperature of the spray drying is 100°C, the air outlet temperature is 57-62°C, and then heated and dried under vacuum at 60°C for 8 hours to obtain apixaban solid amorphous dispersion 5.6 g.

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Abstract

The invention discloses a preparation technology of apixaban solid amorphous dispersoid. The preparation technology comprises the following steps of (a) dissolving apixaban and a pharmaceutically-accepted polymer in a solvent, so as to obtain a solution; and (b) performing spray drying on the solution obtained in the step (a) to remove the solvent so as to obtain the apixaban solid amorphous dispersoid, wherein the solvent is prepared through mixing acetic acid with an organic solvent A, and the mass ratio of acetic acid in the solvent is 0.1%-2.0% and is preferably 1.0%-2.0%. Compared with apreparation technology of a conventional apixaban solid amorphous dispersoid, the technology disclosed by the invention can significantly reduce the usage quantity of the organic solvent, reduce energy consumption and cost, and facilitate industrial production.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparations, in particular to a preparation process of apixaban solid amorphous dispersion. Background technique [0002] Apixaban is a coagulation factor Xa inhibitor effective in the treatment of thromboembolic disorders, and its compound name is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo Piperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazol[3,4-c]pyridine-3-carboxamide, the structural formula is shown in formula I: [0003] [0004] Apixaban is slightly soluble in dimethyl sulfoxide, very slightly soluble in ethanol (99.5%), and almost insoluble in water (0.028mg / ml). [0005] Patent CN102802608A discloses a solid amorphous dispersion of apixaban in a solubility-improved form, that is, a spray-dried dispersion, which contains apixaban and a polymer, and discloses apixaban in a mixed solvent of tetrahydrofuran and water The solubility is only 1.0g. [0006] The low solubility of apixaban makes the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/14A61K31/4545A61P7/02
CPCA61K31/4545A61K9/146A61P7/02
Inventor 张宏伟吴志会袁承烨朱世雄高华
Owner HISUN PHARMACEUTICAL (HANGZHOU) CO LTD