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Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation

a technology of zoledronate sodium salt and crystal form, which is applied in the field of polymorphs of zoledronic acid and zoledronate sodium salt, amorphous zoledronate sodium salt, can solve the problems of not being able to repeat the last crystallization step exactly, and there is nothing in the literature that discloses polymorphs or different crystal forms of zoledronic acid

Inactive Publication Date: 2005-03-10
TEVA PHARM USA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The patent text describes new polymorphs of zolendronic acid and zolendronate sodium salt, as well as methods for making them and pharmaceutical compositions containing them. The new polymorphs have different physical properties and can be used in the treatment of bone-related diseases such as osteoporotic fractures. The patent also describes the crystalline forms of zolendronic acid and zolendronate sodium salt, which can be easily distinguished from each other using powder X-ray diffraction patterns. The new polymorphs have improved stability and can better absorb water compared to other forms of zolendronic acid."

Problems solved by technology

Moreover, the last step of crystallization could not be repeated exactly since the detailed experimental parameters are not given (different cooling regimes, for instance, can produce different polymorphs when crystallized in the same solvent).
However, the paper does not describe any procedure to obtain the forms mentioned therein, nor does it give any additional data by which they can be identified.
Moreover, there is nothing in the literature that discloses polymorphs or different crystal forms of zoledronic acid.

Method used

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  • Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation
  • Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation
  • Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation

Examples

Experimental program
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Effect test

example 10

Sodium hydroxide (pearls, 91.1 g) was added to a suspension of Zoledronic acid crystal form XII (200.0 g) in water (2000 ml) at room temperature (pH=14) to obtain a clear solution. Then the pH of the solution was adjusted to pH 1 by addition of 32% aqueous HCl (300 ml). The solution was then cooled gradually to 5° C. and the white precipitate was filtered, washed with cold water (2×150 ml) and dried in a vacuum oven at 50° C. for 24 hours to obtain 161.7 g (84%) of Zoledronic acid crystal form I (LOD by TGA=6.7%). Purity by HPLC 99.9%.

Preparation of ZLD-Ac Crystal Form II

example 11

A 250 ml three-necked flask equipped with a mechanical stirrer, a reflux condenser and a dropping funnel, was loaded with 1-Imidazoleacetic acid hydrochloride (4.9 g, 0.03 mole), phosphorous acid (4.9 g, 0.06 mole) and Silicon oil (Merck) (27 ml). The suspension was heated to 75° C. and phosphorous oxychloride (10.5 ml, 0.11 mole) was added drop-wise during 30 minutes. The reaction mixture was then heated to 80° C. for 27 hours. Then water (27 ml) and toluene (30 ml) were added at 80° C. The mixture was stirred vigorously for about 15 minutes. Then the toluene phase (containing the silicon oil) and the aqueous phase were separated. The aqueous phase was put in a clean flask and heated to 90° C. for 16 hours. Then it was cooled to room temperature and absolute Ethanol (27 ml) was added during the cooling process to obtain a white precipitate immediately. The mixture was stirred at 5° C. for 4 hours. The white product was then filtered, washed with absolute Ethanol (2×15 ml) and drie...

example 12

Zoledronic acid crystal form I (2.0 g) was stirred in Toluene (20 ml) at reflux temperature for 14 hours. Then the suspension was cooled to room temperature, filtered, washed with Toluene (1×15 ml) and dried in a vacuum oven at 50° C. for 24 hours to obtain 1.6 g of Zoledronic acid crystal form II.

Preparation of ZLD-Ac Crystal Form XII

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Abstract

The invention relates to polymorphs of zoledronic acid and zoledronate sodium salts, amorphous zoledronate sodium salt, processes for making the polymorphs and amorphous zoledronate sodium salt and pharmaceutical compositions containing the polymorphs and amorphous zoledronate sodium salt.

Description

FIELD OF THE INVENTION The invention relates to polymorphs of zoledronic acid and zoledronate sodium salts, amorphous zoledronate sodium salt, processes for making the polymorphs and amorphous zoledronate sodium salt and pharmaceutical compositions containing the polymorphs and amorphous zoledronate sodium salt. BACKGROUND OF THE INVENTION Zoledronic acid is a bisphosphonic acid, which is an inhibitor of osteoclastic bone resorption. Zoledronic acid, designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl)phosphonic acid is marketed in the U.S. under the name Zometa® (zoledronic acid for injection). Zometa® is available in vials as a sterile powder for reconstitution for intravenous infuision. The prescribing information for Zometa® states that each vial of Zometa® contains 4.264 mg of zoledronic acid monohydrate (corresponding to 4 mg zoledronic acid on an anhydrous basis). U.S. Pat. No. 4,939,130 discloses a method for making substituted alkanediphosphonic acids. Exa...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/675C07F9/6506
CPCC07F9/65061C07F9/6506
Inventor ARONHIME, JUDITHLIFSHITZ-LIRON, REVITAL
Owner TEVA PHARM USA INC
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