Rifapentine hydrohalides

Details Rifapentine hydrohalides Rifapentine hydrohalides

1991-01-08

1994-04-26

Bond, Robert T.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514255, 540458, A61K 31395, C07D49808

Patent

active

053067150

DESCRIPTION:

BRIEF SUMMARY
The object of this invention is an hydrohalic acid addition salt of rifapentine of the formula ##STR1## wherein X is chlorine or bromine.
A further particular object of this invention is an hydrohalic acid addition salt of rifapentine according to the above formula in the solid form.
Rifapentine is an antibacterial compound showing a long lasting action which is disclosed in U.S. Pat. No. 4,002,752 and particularly useful for the treatment of acute pulmonary infections. See also, M. Tsukamura et al., Kekkaku (Tuberculosis, Japan), 1986, 61/12, (633-639); P.E. Varlado et al., antimicrobial Agents Chemother, (USA), 1985, 27/4, (615-618); Yi Lu et al., Chin. J. antib. (China), 1987, 12/5, (341-344).
The process of manufacture of rifapentine disclosed in U.S. Pat. No. 4,002,752 yields a solid rifapentine free base in several different forms, having different solubility and bioavailability characteristics. The applicant have so far obtained six different forms of solid rifapentine (one crystalline modification, five solvates--two of which with ethanol, one with methanol, one with ethyl acetate and one with toluene--and the amorphous phase) by slightly changing the operation conditions, e.g. the type of solvent or the temperature of crystallization. Most frequently, when operating according to the general methods and solvents described in U.S. Pat. No. 4,002,752 in industrial or pilot scale preparations, a mixture of two or more of said solid forms is obtained which results in a product of inconstant physical and biological characteristics.
Moreover, it has been observed that some of said forms are relatively instable during storage or under the manipulations necessary for the manufacture of the final dosage units (e.g. capsules, tablets, film-coated tablets, sugar-coated tablets, suspensions and the like) and therefore it is very difficult to maintain the biological characteristics of the dosage forms of the antibiotic substance at a constant level of performance and quality to assure a reliable therapeutical effect. A further disadvantage of the presence of said relatively instable forms is that, in most cases, their modification during storage or under formulation manipulations promotes the transformation into the amorphous phase which is the solid form of rifapentine free base showing less favorable biological characteristics.
Therefore, it is desirable to provide rifapentine in a solid form displaying good and constant biological effects coupled with good stability of its physico-chemical characteristics.
According to the present invention it has been found that the new acid addition salts of rifapentine represented in formula I are solving such problems. Acid addition salts of rifapentine with strong mineral acids, in particular with hydrohalic acids, are not known in the prior art and, moreover, although several hydrazones of 3-formlyrifamycin SV with 1-aminopiperazines variously substituted in the position 4 are reported (see for instance: U.S. Pat. Nos. 3,342,810, 3,796,798, 4,002,754 and W. Germany Patent Application 2816274), no example of strong mineral acid addition salts thereof is disclosed.
The hydrohalides of rifapentine of formula I can be obtained by common procedures which consist in contacting rifapentine free base with a hydrohalic acid of the formula HX wherein X is chlorine or bromine.
The solid rifapentine hydrohalides are preferably obtained by contacting rifapentine free base with an excess of diluted aqueous hydrohalic acid of the formula HX as above defined at a temperature between 0.degree. and 40.degree. C., preferably at the room temperature, for a period of time sufficient for the completion of the salification process. The solid obtained is separated from the reaction mixture by filtration or centrifugation and, after washing with cool water, is recristallized from an organic solvent or a mixture thereof or is precipitated from an organic solution by addition of a non-solvent. The product obtained from crystallization is a stable monohydrohalide of rifapentine which, depending o

REFERENCES:
patent: 3342810 (1967-09-01), Maggi et al.
patent: 4002752 (1977-01-01), Cricchio et al.
Derwent Abstract of FR2309556.

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