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Eplerenone crystalline form exhibiting enhanced dissolution rate

A technology of eplerenone and crystal form, which can be used in the preparation of steroids, medical preparations containing active ingredients, drug combinations, etc., and can solve problems such as gynecomastia

Inactive Publication Date: 2004-12-29
PHARMACIA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, spironolactone has antiandrogenic activity and may cause gynecomastia and impotence in men

Method used

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  • Eplerenone crystalline form exhibiting enhanced dissolution rate
  • Eplerenone crystalline form exhibiting enhanced dissolution rate
  • Eplerenone crystalline form exhibiting enhanced dissolution rate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0366] Embodiment 1: prepare butanone compound by high-purity eplerenone raw material and prepare by this solvate Eplerenone Crystalline Form L

[0367] A. Preparation of Butanone Compounds

[0368] Under magnetic stirring at 900 rpm, 437 mg of high-purity eplerenone (purity > 99%, and the total content of diepoxide and 11,12-epoxide < 0.2%) was dissolved by heating to boiling on a hot plate. In 10ml butanone. Under continuous magnetic stirring, the resulting solution was cooled to room temperature. Once at room temperature, the solution was transferred to a 1°C bath and stirring was continued for 1 hour. The butanate solid was collected from the cold solution by vacuum filtration.

[0369] B. Preparation of eplerenone crystalline form L

[0370] The butanate solid prepared as described above was dried in an oven at 100° C. under normal pressure for 4 hours. The dried solid was confirmed to be pure Form L by DSC and XRPD analysis.

Embodiment 2

[0371] Example 2: Preparation of additional solvates from high-purity starting materials

[0372] According to substantially the same method as in Example 1, the following solvents were used instead of butanone to prepare additional solvates: n-propanol, 2-pentanone, acetic acid, acetone, butyl acetate, chloroform, ethanol, isobutanol , isobutyl acetate, isopropanol, methyl acetate, ethyl propionate, n-butanol, n-octanol, propyl acetate, propylene glycol, tert-butanol, tetrahydrofuran, and toluene.

Embodiment 3

[0373] Example 3: Preparation of Butanone Compounds by Vapor Diffusion Growth

[0374] A stock solution was formed by dissolving 400 mg of eplerenone (>99.9% purity) in 20 ml of methyl ethyl ketone by warming on a hot plate. 8 ml of this stock solution was diluted to 10 ml with butanone, and the resulting solution was referred to as an 80% diluted sample. 4 ml of this stock solution was diluted to 10 ml with butanone (40% diluted sample). 2 ml of this stock solution was diluted to 10 ml with butanone (20% diluted sample). Each diluted sample in a 20 ml scintillation vial was transferred to a dry jar containing a small amount of hexane as an anti-solvent. The dry jar was sealed and the hexane vapor was allowed to diffuse into the butanone solution. Crystals of eplerenone butanate grew in 80% of the diluted samples within 24 hours.

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Abstract

A novel crystalline form (Form H) of the aldosterone receptor antagonist drug eplerenone is provided having a relatively rapid dissolution rate in aqueous media. Also provided are novel solvated crystalline forms of eplerenone that, when desolvated, can yield Form H eplerenone. Also provided is amorphous eplerenone. Pharmaceutical compositions are provided comprising Form H eplerenone, optionally accompanied by one or more other solid state forms of eplerenone, in a total unit dosage amount of eplerenone of about 10 to about 1000 mg, and further comprising one or more pharmaceutically acceptable excipients. Processes are provided for preparing Form H eplerenone and for preparing compositions comprising Form H eplerenone. A method for prophylaxis and / or treatment of an aldosterone-mediated condition or disorder is also provided, comprising administering to a subject a therapeutically effective amount of eplerenone, wherein at least a fraction of the eplerenone present is Form H eplerenone.

Description

[0001] This application is a divisional application of the application number 00805778.8, and the filing date of the application number 00805778.8 is December 4, 2000. field of invention [0002] The present invention relates to pharmaceutically active agents which are aldosterone receptor antagonists, more particularly the present invention relates to the aldosterone receptor antagonist eplerenone. In particular, the present invention relates to a new crystalline form of eplerenone, a method for preparing the crystalline form, a pharmaceutical composition comprising the crystalline form, the use of the crystalline form for the treatment and / or prevention of aldosterone-mediated disorders and / or diseases, including Process for a plethora of related disorders and diseases such as hypertension, and the use of the crystalline form for the preparation of medicaments. Background of the invention [0003] The compound 9,11-epoxy-17-hyd...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/58A61P1/16A61P9/04A61P9/12A61P43/00C07J71/00C07J75/00
CPCC07J71/0015A61P1/16A61P13/08A61P25/24A61P43/00A61P9/04A61P9/12A61K31/585
Inventor K·巴顿T·B·波尔查德特M·V·卡洛斯S·德赛L·J·菲罗H·T·戈德S·甘泽C·R·利特勒P·S·穆迪帕利M·A·皮茨D·R·皮利保斯卡斯Y·-L·L·邢G·L·斯塔尔J·J·维佐雷克C·Y·彦
Owner PHARMACIA CORP
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