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Polymorphic forms of rifaximin, processes for their production and uses thereofRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Polycyclo Ring System Having The Six-membered Hetero Ring As One Of The CyclosPolymorphic forms of rifaximin, processes for their production and uses thereof description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20050272754, Polymorphic forms of rifaximin, processes for their production and uses thereof. Brief Patent Description - Full Patent Description - Patent Application Claims
BACKGROUND [0001] Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an antibiotic belonging to the rifamycin class of antibiotics, e.g., a pyrido-imidazo rifamycin. Rifaximin exerts its broad antibacterial activity, for example, in the gastrointestinal tract against localized gastrointestinal bacteria that cause infectious diarrhea, irritable bowel syndrome, small intestinal bacterial overgrowth, Crohn's disease, and/or pancreatic insufficiency. It has been reported that rifaximin is characterized by a negligible systemic absorption, due to its chemical and physical characteristics (Descombe J. J. et al. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res, 14 (2), 51-56, (1994)). [0002] Rifaximin is described in Italian Patent IT 1154655 and EP 0161534, both of which are incorporated herein by reference in their entirety for all purposes. The EP patent discloses a process for rifaximin production using rifamycin O as the starting material (The Merck Index, XIII Ed., 8301). These patents generically describe purification strategies of rifaximin by crystallization in suitable solvents or solvent systems and summarily show in some examples that the resulting product can be crystallized from the 7:3 mixture of ethyl alcohol/water and dried both under atmospheric pressure and under vacuum. Neither patent discloses any experimental conditions, or further guidance for crystallization and drying or any indication that rifaximin exists in polymorphic forms. [0003] The identification and characterization of polymorphic forms, as well as the experimental conditions for obtaining polymorphs, is important for therapeutic compounds. Polymorphs of a compound can influence the pharmaco-toxicologic properties of the drug, such as bioavailability, solubility, stability, colour, compressibility, flowability and workability with consequent modification of the profiles of toxicological safety, clinical effectiveness and productive efficiency. [0004] In therapeutic practice, antibiotics may cause bacterial resistance to the same or other similar antibiotics. This is particularly relevant to rifaximin because it belongs to the rifamycin family along with rifampicin, which is the standard of care for the treatment of tuberculosis. The current short course treatment for tuberculosis is a combination therapy involving four active pharmaceutical ingredients: rifampicin, isoniazid, ethambutol and pyrazinamide, with rifampicin playing a pivotal role. Therefore, any drug which jeopardizes the efficacy of the therapy by selecting for resistance to rifampicin would be harmful. (Kremer L. et al. "Reemergence of tuberculosis: strategies and treatment," Expert Opin. Investig. Drugs, 11 (2), 153-157, (2002)). Thus, it is possible that the use of rifaximin might induce the selection resistant strains of M. tuberculosis and cross-resistance to rifampicin. Polymorphous forms may provide a mechanism to avoid this negative event because the quantity of systemically absorbed rifaximin may be controllable through the use of polymorphous forms. [0005] The known processes for the industrial preparation of rifaximin from rifamycin O did not provide the same product every time and are limited by the very long reaction times, from 16 to 72 hours, which are poorly suited to an industrial use. Moreover, the known processes do not provide for the in situ reduction of the oxidized rifaximin that may be formed in the reaction mixture. [0006] Therefore, there is a need in the art for improved forms of rifaximin and for processes for the industrial preparation of polymorphous forms of rifaximin. SUMMARY [0007] The presence of different polymorphs had not previously been ascertained for rifaximin and therefore the previously known conditions of obtaining rifaximin did not sufficiently describe how to obtain a pure polymorphic form of rifaximin. Described herein are novel rifaximin polymorphic compositions and novel methods of obtaining the rifaximin polymorphic compositions. The methods described here provide homogeneous products of rifaximin polymorphs. [0008] It has now been unexpectedly found that some polymorphic forms of rifaximin exist whose formation depends on the solvent as well as on the conditions of time and temperature at which both crystallization and drying are carried out. [0009] Presented herein, according to one aspect is a compound formula (I) 1 [0010] in polymorphic form .alpha.. [0011] According to one embodiment, the polymorph in Form .alpha. has an x-ray powder diffraction pattern peak position at about 11.8.degree.; 12.9.degree.; and 19.7.degree. degrees 2-.theta.. In a related embodiment, the polymorph in Form .alpha. has an x-ray powder diffraction pattern peak position at about 6.6.degree.; 7.4.degree.; 7.9.degree.; 8.8.degree.; 10.5.degree.; 11.1.degree.; 11.8.degree.; 12.9.degree.; 17.6.degree.; 18.5.degree.; 19.7.degree.; 21.0.degree.; 21.4.degree.; and 22.1.degree. degrees 2-.theta.. [0012] In one embodiment, the polymorph a has a water content (w/w) of from between about 0 to about 3.0%. [0013] In another embodiment, the C.sub.max of polymorph .alpha. is from between about 2.3 ng/ml to about 2.7 ng/ml. [0014] In one embodiment, the polymorph .alpha. has t.sub.max from between about 3.5 h to about 9.5 h. [0015] In another embodiment, polymorph .alpha. has a AUC.sub.0-24 h from between about 10 and about 20 ng.multidot.h/ml. [0016] In one embodiment, polymorph a has a AUC.sub.0-inf of between about 10 and 25 ng.multidot.h/ml. [0017] Presented herein, according to one aspect is a compound of formula (I) in polymorphic Form .beta.. [0018] In one embodiment, the polymorph in Form .beta. has an x-ray powder diffraction pattern peak position at about 5.4.degree.; 10.4.degree.; 18.3.degree., and 20.9.degree. degrees 2-.theta.. [0019] In another embodiment, the polymorph in Form .beta. has an x-ray powder diffraction pattern peak position at about 5.4.degree.; 6.4.degree.; 7.0.degree.; 7.8.degree.; 9.0.degree.; 10.4.degree.; 13.1.degree., 14.4.degree.; 17.1.degree.; 17.9.degree.; 18.3.degree.; 20.9.degree. degrees 2-.theta.. [0020] In one embodiment, the polymorph in Form .beta. has a water content of from between about 4.5 to about 100%. [0021] In another embodiment, the polymorphic Form .beta. has a C.sub.max between about 0.9 and about 1.3 ng/ml. [0022] According to one embodiment, the polymorphic Form .beta. has a t.sub.max between about 3.5 and about 4.5 h. Continue reading about Polymorphic forms of rifaximin, processes for their production and uses thereof... Full patent description for Polymorphic forms of rifaximin, processes for their production and uses thereof Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Polymorphic forms of rifaximin, processes for their production and uses thereof patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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