Process for the purification of roxithromycin

Details Process for the purification of roxithromycin Process for the purification of roxithromycin

1999-08-11

2001-03-20

Peselev, Elli (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S007200, C536S007400, C536S127000

Reexamination Certificate

active

06204368

ABSTRACT:

The present invention refers to a process for the purification of roxithromycin by crystallisation of methanol, possibly in the presence of water.
AT9400151 describes a process for the purification of roxithromycin by crystallisation with a halogenated solvent, namely chloroform. The usage of chloroform at an industrial level is not advisable as it is considered a hazardous solvent for the environment and, it is also not advisable to use it in the last step of the synthesis route since it is considered as potentially cancerous.
U.S. Pat. No. 4,349,545 describes a process for the purification of roxithromycin by crystallisation with acetone and water, where the product is dissolved in warm acetone and the crystallisation caused by addition of water. Mixtures of acetone and water are not efficient in the reduction of the impurity (impurity A) which appears immediately after the roxithromycin peak in the high-pressure liquid chromatography system of the European Pharmacopoeia. The reduction of this impurity is crucial since the European Pharmacopoeia establishes an individual limit of impurities at 0.5% and this impurity may have levels higher than 2% in the impure roxithromycin.
ES2026824 and ES2024371 describe processes of purification by column chromatography, which are expensive when applied to an industrial scale.
A simple process is described to purify the roxitromycin without the disadvantages mentioned above. The purification method consists of dissolving the impure roxithromycin in methanol and then start the crystallisation by cooling off or by addition of water. The present invention also takes advantage of roxithromycin solubility in methanol. Surprisingly, the roxithromycin solubility in methanol is low in comparison to other common alcohols, namely ethanol and isopropyl alcohol, or even to other common organic solvents such as acetone.
The crystallisation method consists of dissolving the impure roxithromycin at a temperature near to that of the reflux temperature of methanol and then slowly cooling until the mixture becomes turbid. Turbidity occurs at a temperature around 51° C. After turbidity it may be possible to seed the mixture with roxithromycin of good quality. The mixture is stirred for approximately 30 minutes, maintaining the range of the turbidity temperature. Thereafter, the mixture is cooled slowly, in a controlled fashion until approximately 0° C. Preferably the cooling off should follow the following cooling pattern, 3° C. in the first hour, 4° C. in the second hour, 6° C. between the third and the fifth hour and 9° C. in the remaining period. The solution is filtered and the purified solid washed with a mixture of methanol and water, previously cooled to approximately 0° C. The solid is dried at a temperature between 40° and 60° C.
The purification method herein described allows reducing in an efficient way the impurities present in the roxithromycin, especially the impurity A.
Optionally, the roxithromycin may also be dissolved at a temperature of approximately 40° C. and maintaining this temperature, water added slowly until the mixture is turbid. Thereafter, the mixture is stirred at approximately 40° C. for one hour and then cooled to approximately 0° C. The solution is filtered and the purified solid washed with a mixture of methanol and water previously cooled to approximately 0° C. The solid is dried at a temperature between 40° and 60° C.
It is also possible to purify the roxithromycin by suspension in methanol. In this case impure roxithromycin is suspended in methanol, and stirred for about 2 hours at a temperature of around 40° C. The suspension is cooled slowly to approximatley 0° C. with good stirring. Thereafter it is filtered and the purified solid is washed with methanol previously cooled to approximately 0° C. The solid is dried at a temperature between 40°and 60° C.
Another methanol purification method consists of dissolving, at room temperature, the impure roxithromycin in methanol and then, at this temperature, concentrate the solution under vacuum until having destined the adequate volume of solvent. The mixture is cooled off slowly to about 0° C. and stirred for 1 hour at this temperature. The solution is filtered and the solid is washed with methanol previously cooled to approximately 0° C. The solid is dried at a temperature between 40° and 60° C.


REFERENCES:
patent: 4349545 (1982-09-01), Gouin d'Ambrieres et al.
patent: 5959088 (1999-09-01), Miwa et al
patent: 9400151 (1997-03-01), None
patent: 0284203A3 (1988-09-01), None
patent: 0284203A2 (1988-09-01), None
patent: 2024371 (1992-02-01), None
patent: 2026824 (1992-05-01), None
patent: 2036472 (1993-05-01), None

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