Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1987-12-10
1989-09-05
Lone, Werren B.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540320, 540331, A61K 3143, C07D49904, C07D49948
Patent
active
048639150
DESCRIPTION:
BRIEF SUMMARY
This invention relates to .beta.-lactam antibiotics and in particular to crystalline anhydrous amoxycillin, to a process for its preparation from crystalline solvates of amoxycillin, and to pharmaceutically acceptable antibacterial compositions comprising crystalline anhydrous amoxycillin. The invention also relates to novel crystalline solvates of amoxycillin and processes for preparing them.
The crystalline anhydrous amoxycillin of the invention is active against Gram-positive and Gram-negative bacteria and is useful as a therapeutic and prophylactic agent against bacterial infections in animals including man.
6-[D(-)-.alpha.-Amino-p-hydroxyphenylacetamido]penicillanic acid, hereinafter referred to as amoxycillin, is an important penicillin antibiotic which was first disclosed in British Patent Specification No. 1,241,844 and which, as ordinarily prepared, exists as a stable crystalline trihydrate. Whilst the bound water can be removed from the trihydrate by vigorous drying, the resulting material is essentially amorphous and has poor stability.
Despite extensive attempts, including the use of those conditions employed to form the anhydrates of ampicillin, described in, for example, British Patent Specification No. 1,382,409, no crystalline anhydrate of amoxycillin has ever been described. It has been suggested that this is due to steric or structural reasons arising from the structure of amoxycillin itself. For example, Boles et al attributed their failure to crystallize forms of amoxycillin other than the trihydrate at least partly to the fact that stabilization by benzene ring overlap would be reduced in crystalline anhydrous amoxycillin compared to crystalline anhydrous ampicillin, without any corresponding increase in hydrogen bonding, whilst hydrogen bonding in crystalline amoxycillin trihydrate is increased, relative to that in crystalline ampicillin trihydrate, by the presence of the --OH group in the benzene ring ("The Structure of Amoxycillin Trihydrate and a Comparison with the Structures of Ampicillin" Acta Cryst. (1978) B34, 461-466).
European Patent Application Publication No. 0 131 147 describes the preparation of anhydrous crystalline sodium amoxycillin by removing solvent molecules from a solvate (preferably crystalline) of sodium amoxycillin. Solvates of salts of amoxycillin are also known from British Patent Specification No. 1 465 694, which describes a process for the preparation of a crystalline solvate of an alkali metal or alkaline earth metal salt of amoxycillin in which the bound solvent is a pharmaceutically acceptable amide.
No crystalline solvate (other than the trihydrate) of amoxycillin has previously been characterised. However, British Patent Specification No. 1,286,199 describes a process in which amoxycillin trihydrate is treated with a C.sub.1-4 alkanol such as methanol or ethanol and the resultant gel dried to produce a solid which is stated to be crystalline, is unstable and has a minimum water content of about 3 to 5% w/w. As far as we are aware, no crystalline anhydrous solvate of amoxycillin has previously been described.
It has now been discovered that crystalline anhydrous solvates of amoxycillin (free acid) may be prepared and that subsequent removal of bound solvent gives a stable, anhydrous form (i.e. anhydrate) of amoxycillin having a distinctive infra-red spectrum, and a multiple-line X-ray powder diffractogram characteristic of a crystalline solid.
Accordingly, the present invention provides crystalline anhydrous amoxycillin.
In accordance with a further aspect of the invention there is provided a crystalline solvate (other than the trihydrate) of amoxycillin, more particularly a crystalline anhydrous solvate of amoxycillin.
In accordance with a particular aspect, the invention provides crystalline anhydrous amoxycillin monomethanolate.
The invention also provides a process for the preparation of crystalline, anhydrous amoxycillin, which process comprises removing bound solvent molecules from a crystalline solvate of amoxycillin, which advantageously is cr
REFERENCES:
patent: 3299046 (1967-01-01), Alburn et al.
patent: 3479338 (1969-11-01), Adams
patent: 3926958 (1975-12-01), Callander
patent: 4222939 (1980-09-01), Clark et al.
Chemical Abstracts, vol. 97, No. 17, 144668z, Oct. 1982.
Beecham Group p.l.c.
Clarke Vera C.
Lone Werren B.
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