Process for preparing a pure, pharmacopoeial grade amorphous...

Details Process for preparing a pure, pharmacopoeial grade amorphous... Process for preparing a pure, pharmacopoeial grade amorphous...

2000-05-19

2002-05-07

Berch, Mark L (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06384213

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of a pure pharmacopoeial grade amorphous form of cefuroxime axetil.
BACKGROUND OF THE INVENTION
Cefuroxime axetil is 1-acetoxyethyl ester of cefuroxime, a second generation cephalosporin antibiotic with a broad spectrum of activity against gram-positive and gram-negative microorganisms. This compound, as well as many other esters of cefuroxime, are disclosed and claimed in U.S. Pat. No. 4,267,320. This patent discloses conventional methods for preparing a mixture of the R and S isomers in crystalline form, as well as for separating the individual R and S diastereoisomers.
U.S. Pat. No. 4,562,181 and related U.S. Pat. Nos. 4,820,833, 4,994,567 and 5,013,833 all disclose that cefuroxime axetil in amorphous form essentially free from crystalline material and having a purity of at least 95% (not including residual solvents), has a higher bioavailability than the crystalline form while also having adequate chemical stability. These patents disclose that highly pure cefuroxime axetil can be recovered in substantially amorphous form from a solution containing cefuroxime axetil by spray drying, roller drying, or solvent precipitation. The preferred method is spray drying. In each case, crystalline cefuroxime axetil is dissolved in an organic solvent and the cefuroxime axetil is recovered from the solution in a highly pure, substantially amorphous form by one of the foregoing methods. The prior art processes for the preparation of amorphous form of cefuroxime axetil suffer from disadvantages and also are not convenient to operate at a large scale. These disadvantages include requiring large volume of solvents for dissolving cefuroxime axetil because of the poor solubility of cefuroxime axetil in the solvents utilized by the prior art. This is uneconomical on a commercial scale because large size reactors would be necessary. Furthermore, because of the poor solubility, cefuroxime axetil needs to be dissolved at higher temperature followed by concentration of the solution to reduce the volume. These disadvantages make the processes of the prior art operationally tedious and inefficient.
U.S. Pat. No. 5,847,118 (“the '118 patent”) discloses a method of preparing amorphous cefuroxime axetil which comprises dissolving crystalline cefuroxime axetil in a solvent such as formic acid, the solvent being present in an amount just sufficient to dissolve the crystalline cefuroxime axetil, and later adding the resulting cefuroxime axetil solution to water. All the examples of the patent only disclose dropwise addition of the cefuroxime axetil solution to water. As is shown by the present invention, certain advantages are realized if the cefuroxime axetil solution is added all at once (dumped) into the water instead of the dropwise addition disclosed by the '118 patent. Thus, it is observed that the crystallinity of the resulting product is greatly reduced, i.e., the product is much more completely amorphous by use of the dumping method of the present invention. Additionally, it has been determined that a specific volume of water is required in relationship to the weight of the crystalline cefuroxime axetil (starting material) for precipitation of an amorphous product that contains as little crystalline material as possible. Thus, it is believed that a sufficient amount of water is required, into which the cefuroxime axetil solution is added all at once. It is preferred that at least 25 times the volume of water in comparison to the weight of crystalline cefuroxime axetil be used.
SUMMARY OF THE INVENTION
It is an object of the present invention to obtain a pure, pharmacopoeial grade amorphous form of cefuroxime axetil by a process which is efficient and commercially viable. Cefuroxime Axetil in accordance with the invention has a purity by chromatographic analysis (chemical purity) of at least 95% w/w, preferably containing less than 3% w/w and is in pharmacopoeial grade amorphous form (meeting the specifications as per U.S. Pharmacopoeia 23).
Accordingly, the present invention provides a process for the preparation of a pure, pharmacopoeial grade amorphous form of cefuroxime axetil which comprises dissolving crystalline cefuroxime axetil in acetic acid including at least about 5% v/v water and recovering said amorphous form of cefuroxime axetil from said solution by the addition of water, the solution being dumped into the water and the water being present in a volume which is sufficient to precipitate the amorphous cefuroxime axetil. It is preferred that the volume of water into which the solution is dumped is at least 25 times the weight of the crystalline cefuroxime axetil.
In accordance with the present invention, cefuroxime axetil in crystalline form (the starting material) is dissolved in acetic acid containing at least about 5% v/v water at a temperature of at least about 50° C. After it is completely dissolved, the solution is added to precooled water (0-20° C.) under vigorous stirring, the water being present in a volume which is preferably at least 25 times the weight of the crystalline cefuroxime axetil. At least 30 times the volume of water is more preferred and at least 40 times is even more preferred. Precipitated cefuroxime axetil is filtered, washed with water and dried under vacuum.
Preferably, the volume of solvent is at least about 1.6 parts per part of the starting material. Higher volumes of solvents and generally up to 10 parts per part of the starting material can be used. Volumes higher than 10 parts are not useful from an economical point of view. The volume of solvent in relation to the amount of starting material can be adjusted based on the temperature and Is known to a person of ordinary skill in the art.
Generally, the product can be collected by any standard method known in the art such as by filtration, filtration under vacuum or decantation and drying.


REFERENCES:
patent: 4267320 (1981-05-01), Gregson et al.
patent: 4562181 (1985-12-01), Crisp et al.
patent: 4775750 (1988-10-01), White et al.
patent: 4820833 (1989-04-01), Crisp et al.
patent: 4994567 (1991-02-01), Crisp et al.
patent: 5013833 (1991-05-01), Crisp et al.
patent: 5847118 (1998-12-01), Karimian et al.
patent: 0 757 991 (1997-02-01), None
patent: WO 98/43980 (1998-10-01), None

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