Azithromycin monohydrate isopropanol clathrate and methods for the manufacture thereof

Abstract

A novel form of azithromycin and processes for preparation of pure azithromycin monohydrate isopropanol clathrate (3 molecules of isopropanol for every 10 molecules of azithromycin monohydrate) has been obtained. Preparation of the novel form of azithromycin comprises the steps of dissolving azithromycin in isopropanol, followed by the slow addition of water to the organic solution.

Description

FIELD OF THE INVENTION[0001]This invention relates to a new form of azithromycin, namely azithromycin monohydrate isopropanol clathrate, which has improved properties over amorphous azithromycin, azithromycin monohydrate and azithromycin dihydrate. This invention also relates processes for the manufacture of azithromycin monohydrate isopropanol clathrate.BACKGROUND OF THE INVENTION[0002]Azithromycin, 9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, is a semi-synthetic macrolide antibiotic which can be classified as a member of the second-generation erythromycin antibacterial agent. Azithromycin has the following structure (I): [0003]The spectrum of azithromycin's antibacterial activity has been reported by Aronoff, et al (J. Antimicrob. Chemother, 1987, 19, 275). Its mode of action has been reviewed by Retsema, et al (Antimicrob. Ag. Chemother, 1987, 31, 1939)n, and its pharmacology has been reviewed by a number of investigators (J. Antimicrob. Chemother., 1993, 31, Suppl. E, 1-198)....

AI Technical Summary

Benefits of technology

[0036]According to this invention, azithromycin monohydrate isopropanol clathrate contains three molecules of isopropanol for every ten molecules of azithromycin monohydrate. The process comprises the dissolution of azithromycin in isopropanol to which water is added slowly while stirring, resulting in the precipitation of crystalline azithromycin monohydrate isopropanol clathrate. The volume of solvent used is such as to be sufficient to dissolve azithromycin. The addition of the water is carried out between 0° and 30° C. and preferably between 15° C. to 25° C. The product is filtered and washed with a mixture of water-isopropanol and dried under vacuum (1-10 mm Hg) at 50° C. to 60° C. for 12-24 hours to obtain azithromycin monohydrate isopropanol clathrate in high yields. Extension of vacuum drying does not reduce either the water content or the isopropanol content of azithromycin monohydrate isopropanol clathrate.

Problems solved by technology

It is not a crystalline product and therefore can not be made in pure form per se in commercial scale.

Furthermore, these patents do not provide a description of the drying process (temperature or pressure).

This is an undesirable property since it complicates formulation of azithromycin drug product and can adversely effect its stability on long term storage.

Excess loss of water, caused by higher temperature vacuum drying, could result in the formation of azithromycin monohydrate.

It is clear that anhydrous and monohydrate forms of azithromycin are not suitable for formulation.

The processes referred to in Canadian Patent 1 314 876 for the preparation of azithromycin dihydrate, while producing a non-hygroscopic form of azithromycin, have a number of disadvantages:1. Water immiscibility of the organic solvent mixture (tetrahydrofuran plus hexane) can cause problems in obtaining pure material since crystallisation processes are known to afford pure material when the anti-solvent is miscible with the solvent used to dissolve the crude product.2. The drying process must be very carefully controlled since an increase in temperature will cause the transformation of the non-hygroscopic dihydrate to the hygroscopic monohydrate.3. The use of low boiling point solvents is complicated by their toxicity and possibility of formation of explosive peroxide during solvent recovery.

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