Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-09-25
1998-01-06
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540226, 540227, A61K 31545, C07D50136
Patent
active
057054967
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to benzathine salts of cefonicid, a member of the cephalosporin family of antibiotics.
BACKGROUND
Cefonicid is a cephalosporin antibiotic presently used as a parenterally administered drug in the treatment of bacterial infections. Cefonicid, whose chemical name is 7-D-mandelamido-3-(1-sulfomethyltetrazol-5-yl)-thiomethyl-3-cephem-4-carbo xylic acid, was first disclosed within a large generic class of compounds disclosed and claimed in U.S. Pat. No. 4,048,311. The structure of the disodium salt of cefonicid is: ##STR2## The disodium salt of cefonicid is only moderately stable at room temperature, requiring refrigeration and special handling for transport and storage.
It was later discovered that the monosodium salt of cefonicid was an unexpectedly more stable form of the antibiotic as compared to the disodium salt. Thus, the antibiotic in its monosodium salt form could be stored for longer periods of time without refrigeration than the disodium salt. This invention is described in U.S. Pat. No. 4,576,937. The monosodium salt of cefonicid is not a commercially practical antibiotic unless administered with a companion buffer.
Cefonicid is an extremely water soluble cephalosporin between pH 1 to 10 due to the presence of the sulfonic acid moiety. The molecule is extremely difficult, and for all practical purposes impossible, to extract into an organic phase. Thus, isolation by conventional methods of solvent extraction are difficult. Consequently, isolation and purification of cefonicid at present requires lengthy and cumbersome steps for sample preparation, purification by chromatography and final isolation by lyophilization. The benzathine salts of other cephalosporin antibiotics have been described in U.S. Pat. No. 4,737,492 and the European Patent Application EP 0399094. U.S. Pat. No. 4,737,492 describes the benzathine salt of cefamandole for use in opthamalic compositions. European Patent Application EP 0399094 describes an improved process for the preparation of ceftriaxone. The formation of the benzathine salt and crystallization of such an extremely water soluble cephalosporin as cefonicid and the resulting improvement in ease of sample isolation and purification of cefonicid is not known in the prior art.
SUMMARY OF THE INVENTION
One object of this invention is to provide an improved process for isolation and purification of cefonicid.
Another object of this invention is to provide a stable composition and pharmaceutically viable form of cefonicid which allows for easier storage and handling.
One feature of this invention is a novel salt form of cefonicid.
DETAILED DESCRIPTION OF THE INVENTION
Cephalosporins having acidic groups that impart a high degree of water solubility to the molecule are difficult to isolate via conventional methods of solvent extraction. Cefonicid, in particular, is extremely water soluble due to the presence of a sulfonic acid moiety. It has now been discovered that cefonicid may be readily isolated and/or purified by forming a benzathine salt of the free acid. This salt is readily isolated in a crystalline form via conventional filtration. Thus, the benzathine salt facilitates isolation of cefonicid.
The benzathine salt is the first known crystalline form of cefonicid. It has also been discovered that this form is more stable than the disodium salt of cefonicid and that crystallization of the salt yields a product of high purity. The enhanced stability allows for transport of cefonicid without refrigeration or special handling during storage. More importantly, this crystalline product need not be isolated via chromatography, thus eliminating a cumbersome process work-up step. This cefonicid salt is easily isolated via filtration. The salt can also be convened to Na, K, or Ca salts via conventional salt transfer means such as cation exchange resins or by addition of an organic solvent soluble salt of an organic acid or a strong base.
As used herein, benzathine refers to dibenzylethylene diamine. Cefonicid refers to
REFERENCES:
patent: 4048311 (1977-09-01), Berges
patent: 4576937 (1986-03-01), Polansky
patent: 4737492 (1988-04-01), Gerson et al.
patent: 5276024 (1994-01-01), Schneider et al.
Dustman Wayne J.
Kinzig Charles M.
Lentz Edward T.
Shah Mukund J.
SmithKline Beecham Corporation
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