the term room temperature used in present application refers to a temperature range between 25 - 30 ° c . the term stripping in this application refers to removal of traces of the first solvent from residue by adding second solvent and distilling it to residue . in one embodiment , the present invention provides amorphous form of rifaximin . amorphous form of rifaximin of the present invention is characterized by its powder x - ray diffraction pattern . the xrpd of the amorphous rifaximin was measured on a rigaku dmax 2200 ultima * pc series x - ray powder diffractometer using a cu k α radiation source , and is characterized by its xrpd pattern as shown in fig1 . the amorphous rifaximin can be characterised by its ft - ir pattern , as shown in fig2 . amorphous rifaximin according to the present invention is conveniently prepared by a process , which comprises reaction of rifamycin s with 2 - amino - 4 - picoline in presence of a suitable solvent like dichloromethane , ethyl acetate , dichloroethylene , chloroform , in an inert atmosphere . all these solvents can be used alone or in mixture among them or with water in various ratios . further , iodine dissolved in suitable solvent like dichloromethane , ethyl acetate , dichloroethylene , chloroform , is added at room temperature to the above reaction mixture and then stirred . further , suitable reducing agent dissolved in water , is preferably added to the above reaction mass and stirred at room temperature and then cooled to 10 - 15 ° c . the reducing agent used preferably comprises at least one of ascorbic acid , isoascorbic acid , sulphur dioxide , dihydroxyacetone . further , ph of the reaction mass is adjusted between 1 . 5 - 2 . 5 , preferably to 2 . 0 - 2 . 2 under stirring . the reaction mass is preferably further stirred for 10 - 15 minutes and organic layer is separated . the separated organic layer is preferably washed with water , followed by washing with 10 % sodium thiosulphate or 10 % sodium metabisulphite and finally washed with water till ph of the organic layer is neutral . this separated organic layer is preferably further charcoalised , filtered , dried over sodium sulphate and concentrated under vacuum below 50 ° c . to residue . this residue contains rifaximin and can be further treated to obtain crystalline rifaximin ( as in the prior art ) or amorphous rifaximin ( in accordance with the invention ). in the prior art , to manufacture the form known as the β form , the residue would be treated with a water miscible solvent , followed by drying in air at 80 - 110 ° c . to manufacture the γ form in accordance with the prior art , the residue is treated with an organic acid and water , followed by drying in air at 100 - 110 ° c . i think it is best to maintain the temperatures , if they are the working temperatures , as we cannot add the information after filing . in accordance with the present invention , amorphous rifaximin is prepared by subjecting a residue containing rifaximin to a stripping step , followed by mixing with a mixture of water immiscible solvents , followed by drying at a temperature below 40 ° c .— the amorphous rifaximin may be recovered after the drying step . the drying can be carried out at the temperature somewhat below 40 ° c ., e . g ., at room temperature ( for example 25 ° c .). more specifically , the residue obtained is preferably stripped out to dryness with suitable water immiscible organic solvent and the material obtained is isolated by stirring with the same solvent used for stripping or a mixture of solvents , preferably at room temperature . further , the solid is filtered , washed with same solvents and dried below 40 ° c . to get amorphous rifaximin . the suitable solvent used for stripping of the product is a water immiscible organic solvent selected from n - heptane , n - hexane , di - isopropyl ether , dichloromethane , dichloroethylene , chloroform and ethyl acetate . the schematic representation for preparation of amorphous rifaximin is as follows : amorphous rifaximin according to the present invention can be characterized by various parameters like solubility , intrinsic dissolution , bulk density , tapped density . rifaximin is known to exist in 3 polymorphic forms namely α form , β form & amp ; γ form of which the α form is thermodynamically the most stable . hence , the amorphous form of rifaximin was studied in comparison with a form . further , when intrinsic dissolution of amorphous rifaximin is carried out against the α form , it is observed that the amorphous rifaximin has better dissolution profile than α form which is shown in table below ( this data is also shown graphically in fig3 ): dissolution medium : 1000 ml of 0 . 1m sodium dihydrogen phosphate monohydrate + 4 . 5 g of sodium lauryl sulphate . amorphous rifaximin exhibits bulk density in the range of 0 . 3 - 0 . 4 g / ml and tapped density is in the range of 0 . 4 - 0 . 5 g / ml while the a form rifaximin exhibits bulk density in the range of 0 . 2 - 0 . 3 g / ml & amp ; tapped density is in the range of 0 . 3 - 0 . 4 g / ml . these higher densities of amorphous rifaximin are advantageous in formulation specifically in tablet formulation , for example , it gives better compressibility . another aspect of the present invention is to provide conversion of amorphous rifaximin to crystalline γ form rifaximin which comprises dissolving amorphous rifaximin in an organic solvent , heating preferably to 40 - 60 ° c . and stirring the reaction mixture to get clear solution . to this organic solution , water may be added gradually preferably at 40 - 60 ° c . and stirred . the reaction mass may be cooled gradually to room temperature and stirred . the resulting solid may be filtered and washed with mixture of organic acid and water . the solid may be further washed with mixture of organic acid and water and then with water . the washed solid is dried at 100 - 110 ° c . to yield rifaximin γ form . preferably , the organic solvent used for dissolution and washing , is organic acid . the organic acid preferably can be acetic acid or formic acid . another embodiment of the present invention is to provide process for the conversion of amorphous rifaximin to crystalline β form rifaximin which comprises dissolving amorphous rifaximin in an organic solvent , heating preferably to 40 - 60 ° c . and stirring the reaction mixture to get clear solution . to this organic solution , water may be added gradually at 40 - 60 ° c . and stirred . the reaction mass may be cooled gradually to room temperature and stirred . the resulting solid may be filtered and washed with mixture of suitable organic solvent and water . the solid may be further washed with mixture of organic solvent and water and then with water . the washed solid is dried at 80 - 110 ° c . to yield rifaximin β form . preferably , the organic solvent used for dissolution and washing , comprises at least one of water miscible solvents preferably acetone , acetonitrile , c 1 - 4 alcohols . another embodiment of the present invention is to provide process for inter - conversion of γ form of rifaximin which comprises dissolving crystalline rifaximin in suitable solvent , heating preferably to 40 - 60 ° c . and stirred . water is added , preferably dropwise , preferably at 40 - 60 ° c . to the above mixture under stirring . the resulting mixture may be cooled gradually to room temperature and stirred . the solid obtained may be filtered , washed with mixture of solvents . further the above solid may be washed with water , dried at 80 - 110 ° c . to yield β form of rifaximin . suitable solvent used for dissolving and washing the product is selected from water miscible solvents selected from group comprising of acetone , acetonitrile , lower alcohols or mixtures thereof . yet another embodiment of the present invention is to provide conversion of crystalline form of rifaximin to amorphous rifaximin which comprises dissolving crystalline rifaximin in suitable solvent at room temperature and filtered . the filtrate may be washed with suitable solvent mentioned above and the solution may be concentrated , preferably under vacuum , preferably at 40 - 60 ° c . to get residue . the residue obtained is stripped out with suitable water immiscible organic solvent and then stirred in the same solvent or mixture of solvents used for dissolving at room temperature , filtered , washed with same solvent and dried below 40 ° c . to get amorphous rifaximin . the suitable solvent used for dissolving and stripping the product is selected from dichloromethane , dichloroethylene , chloroform , n - heptane , n - hexane and diisopropyl ether . yet another aspect of present invention provides pharmaceutical composition comprising amorphous form of rifaximin in combination with a pharmaceutically acceptable carrier . in addition to active ingredient ( s ) the pharmaceutical composition of the present invention may contain one or more pharmaceutically acceptable ingredients . the composition of the present invention can be formulated into variety of dosage forms , such as tablets , capsules , pills , caplets , lozenges , dispersible granules , dry powder syrup , ready to use suspension ; parenteral dosage forms available in the art ; various inhalation formulations ; transdermal formulations , and the like . these formulations can be prepared using processes known in the art . fig1 is an x - ray powder diffractogram ( xrd ) of amorphous rifaximin made in accordance with example 1 as described below ; fig2 is an ft - ir spectrum of amorphous rifaximin , made in accordance with example 1 described below ; fig3 is a graphical representation of intrinsic dissolution of amorphous rifaximin compared with the a form of rifaximin . the present invention will now be further illustrated by the following examples , which do not limit the scope of the invention in any way . the amorphous rifaximin according to the invention may be used as a medicament or in the manufacture of a medicament for treating bowel related disorders like irritable bowel syndrome , diarrhea , traveler &# 39 ; s diarrhea , microbe associated diarrhea , crohn &# 39 ; s disease , chronic pancreatitis , pancreatic insufficiency and / or colitis . in a preferred embodiment , the invention is directed to a method of treating diarrhea , comprising administering a therapeutically effective amount of amorphous rifaximin according to the invention to a patient in need thereof . rifamycin s 100 g ( 0 . 143 moles ), dichloromethane 300 ml and 2 - amino - 4 - picoline , 46 . 4 g ( 0 . 434 moles ) were mixed at room temperature under argon atmosphere . iodine 19 g ( 0 . 074 moles ) dissolved in dichloromethane 700 ml , was added dropwise in 30 - 45 minutes at room temperature . reaction mixture was then stirred at room temperature for 15 - 18 hours . l (−) ascorbic acid 20 g ( 0 . 113 moles ) dissolved in 100 ml water was added . the mixture was stirred for 30 - 45 minutes at room temperature and then cooled to 10 to 15 ° c . the ph of the reaction mixture was adjusted to 2 using 12 . 5 % dil . hcl solution . the mass was stirred for 10 to 15 minutes , organic layer was separated and washed at first with demineralized water then with 10 % sodium thiosulfate and finally with water till neutral ph was obtained . the organic layer was charcolized , filtered through hyflo , dried over sodium sulfate and concentrated under vacuum below 50 ° c . the product was stripped out with n - heptane and crude material thus obtained was stirred with a mixture of 20 % dichloromethane and heptane [ 500 ml ] at room temperature for 30 - 45 minutes . the solid was filtered , washed with a mixture of 20 % dichloromethane and n - heptane and dried under vacuum below 40 ° c . for 10 - 12 hours to get amorphous rifaximin 100 g . amorphous rifaximin ( 100 g ) was dissolved in acetic acid ( 200 ml ) at 50 ° c ., stirred for 30 - 45 minutes and demineralized water ( 200 ml ) was added dropwise at 50 ° c . in 30 - 45 minutes . stirring was continued at 50 ° c . for 30 - 45 minutes , cooled gradually to room temperature and stirred for 2 hours . the solid obtained was filtered and washed at first with acetic acid - water 1 : 1 mixture then with 10 % acetic acid - water mixture and finally washed with water . the solid obtained was dried at 100 - 110 ° c . for 12 - 15 hours to get 62 - 65 g of rifaximin - γ - form . amorphous rifaximin ( 100 g ) was dissolved in formic acid ( 200 ml ) at 50 ° c ., stirred for 30 - 45 minutes and demineralized water ( 200 ml ) was added dropwise at 50 ° c . in 30 - 45 minutes . stirring was continued at 50 ° c . for 30 - 45 minutes , cooled gradually to room temperature and stirred for 2 hours . the solid obtained was filtered and washed at first with formic acid - water 1 : 1 mixture then with 10 % formic acid - water mixture and finally washed with water . the solid obtained was dissolved in isopropyl alcohol ( 310 ml ) at 50 ° c . and stirred at 50 ° c . for 30 minutes . demineralized water ( 310 ml ) was added dropwise at 50 ° c . in 30 - 45 minutes and stirring was continued at the same temperature for 30 - 45 minutes . the mixture was cooled gradually to room temperature and stirred for 2 hours . the solid obtained was filtered , washed with isopropyl alcohol - water 1 : 1 mixture and then with demineralized water , dried at 80 - 90 ° c . for 10 - 15 hours to get 40 - 45g of rifaximin - β - form . rifaximin γ form ( 62 g ) was dissolved in acetonitrile ( 310 ml ) at 50 ° c . and stirred at 50 ° c . for 30 minutes . demineralized water ( 310 ml ) was added dropwise at 50 ° c . in 30 - 45 minutes and stirring was continued at the same temperature for 30 - 45 minutes . the mixture was cooled gradually to room temperature and stirred for 2 hours . the solid obtained was filtered , washed with acetonitrile - water 1 : 1 mixture and then with demineralized water , dried at 80 - 90 ° c . for 10 - 15 hours to get 40 - 45g of rifaximin - β - form . crystalline rifaximin ( 40 g ) was dissolved in dichloromethane ( 10 - 15 volumes ) at room temperature , filtered through hyflo and washed with dichloromethane ( 2 volumes ). the solution was concentrated under vacuum at 50 ° c . the solid was stripped out with n - heptane and stirred in n - heptane ( 50 ml ) at room temperature for 30 minutes . finally the solid was filtered , washed with n - heptane and dried under vacuum below 40 ° c . to get 35 - 38 g of amorphous rifaximin . a solid oral pharmaceutical formulation according to the present invention can be manufactured by granulation process known in the art .
amorphous rifaximin , methods of making it , and pharmaceutical compositions containing it . also described are methods of converting amorphous rifaximin to crystalline rifaximin and vice versa .