Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-03-21
1998-06-09
Sham, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514210, C07D49900, A61K 31425
Patent
active
057636036
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel crystalline penicillin derivative, crystalline 2.alpha.-methyl-2.beta.-(1,2,3-triazol-1-yl)-methylpenam-3.alpha.-carboxyl ic acid-1,1-dioxide, and its production and use in a medicine.
BACKGROUND ART
In EPOS 97 446 certain penicillin derivatives are disclosed; in particular, 2.alpha.-methyl-2.beta.-(l1,2,3-triazol-1-yl)-methylpenam-3.alpha.-carboxy lic acid-1,1-dioxide of the formula ##STR1## (hereinbelow "tazobactam") and its pharmaceutically acceptable salts, notably the sodium salt, are reported to be useful as .beta.-lactamase inhibitory agents in combination with known .beta.-lactam antibiotics, viz. increasing the antimicrobial activity of the .beta.-lactam antibiotics.
However, up to the present tazobactam sodium has been obtained in solid form only in the amorphous state, e.g. as a lyophilisate. Such solid forms are hygroscopic, possess inferior stability, and their purification require laborious, e.g. lyophilizing procedures.
Thus, there is a need for a crystalline modification of tazobactam sodium, which overcomes all these drawbacks.
Initial attempts to crystallize the product did not offer the required result: Due to the high solubility of tazobactam sodium in water it was not expected that the product could be crystallized from an aqueous medium. This assumption was supported by findings, according to which concentrated aqueous tazobactam sodium solutions could not be crystallized from methanol due to the solubility of the product in that solvent; moreover, attempts with methyl ethyl ketone/water 95:5 v/v and with ethyl acetate/water 95:5 v/v as solvent failed due to a separation of phases, without crystallization. Therefore, crystallization in the absence of water was attempted: Based on a known procedure, tazobactam was suspended in methanol, and one equivalent of sodium 2-ethylhexanoate solution in ethyl acetate added. To the resulting solution, a less polar solvent was added in order to cause crystallization. The following solvents were investigated: toluene, t-butylmethyl ether, diethyl ether, dimethoxy ethane, i-propanol and ethyl acetate. In all cases, amorphous materials were isolated, which were very hygroscopic and contained water and solvent residues.
DISCLOSURE OF THE INVENTION
However, contrary to expectation, it has surprisingly turned out that a crystalline modification of tazobactam sodium, viz. crystalline sodium 2.alpha.-methyl-2.beta.-(1,2,3-triazol-1-yl)-methylpenam-3.alpha.-carboxyl ate-1,1-dioxide monohydrate (crystalline tazobactam sodium monohydrate) can be prepared from an aqueous medium by a particular process which involves a careful balance between the water and one of the organic solvents acetone and ethanol. Thus the process of the present invention for producing crystalline sodium 2.alpha.-methyl-2.beta.-(1,2,3-triazol-1-yl)-methylpenam-3.alpha.-carboxyl ate-1,1-dioxide monohydrate (crystalline tazobactam sodium monohydrate) is characterized by adding to a concentrated aqueous solution of sodium 2.alpha.-methyl-2.beta.-(1,2,3-triazol-1-yl) -methylpenam-3.alpha.-carboxylate-1,1-dioxide (tazobactam sodium) a solvent selected from acetone and ethanol in an amount corresponding to a solvent to water ratio of between about 95:5 v/v and about 99:1 v/v and crystallizing the desired product from the solvent mixture.
The tazobactam sodium can be obtained in accordance with a method described, for example, in EPOS 97 446.
The concentrated aqueous solution of tazobactam sodium used for this crystallization process should contain about 0.1 to 0.4 g, preferably about 0.25 to 0.35 g of water per g of tazobactam equivalent present.
The ratio of acetone or ethanol to water is critical. Already at a ratio of 9:1 v/v it is not possible to crystallize the product even at -20.degree. C. Suitable ratios for crystallization are about 95:5 to 99:1 v/v. Preferred ratios are about 96:4 to 98:2, particularly about 97:3. The crystallization is preferably carried out at a temperature of about -10 .degree. to +30.degree. C., mor
REFERENCES:
patent: 4562073 (1985-12-01), Micetich et al.
patent: 4774238 (1988-09-01), Brown et al.
patent: 4912211 (1990-03-01), Bonfanti
Chemical Patents Index Basic Abstracts Journal, Section B:FARMDOC, 1988, Derwent Publications, week 8818, 29 Jun. 1988, 88-122648/18.
Sham Mukund J.
Sripada Pavanaram K.
Taiho Pharmaceutical Co. Ltd.
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