UA111157C2 - NEW FORMS OF RIFAXIMINE AND THEIR APPLICATIONS - Google Patents

Abstract

The present invention relates to novel forms of rifaximin kappa, theta, co-crystal 1 of rifaximin: piperazine and co-crystal 2 of rifaximin: piperazine, methods for their preparation and their use in pharmaceuticals and therapeutic methods.

Description

description

Related application

This application claims priority О55М 61/416593, submitted on November 23, 2010; О5BM 61/351281, submitted on June 3, 2010; О55М 61/357505, submitted on June 22, 2010; О55М 61/363241, submitted on July 10, 2010; OSH55M 61/363511; submitted on July 12, 2010; No. О55М 61/367185, filed on July 23, 2010, the entire content of which is hereby incorporated by reference in its entirety.

Technical level

Rifaximin (IMM; see Te MegskK Ipdeh, HIPI Eia., 8304) is an antibiotic that belongs to the rifamycin group of antibiotics, for example, is pyrido-imidazo-rifamycin. Rifaximin exhibits 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 was reported that rifaximin is characterized by too low systemic absorption due to its chemical and physical properties (YuOezsotre ..). her aI. Rnaptasokipeiis vitsau oi hyahitip apyeg oga! adtipivigayop ip peaynu myImpieegv. Ipi / Siip

Rpagtasoi Nez, M (2), 51-56, (1994)).

Rifaximin is described in Italian patent IT 1154655 and EP 0161534, which are fully incorporated into this application by reference. EP 0161534 discloses a method of obtaining rifaximin using rifamycin O as a starting substance (Te Megsk Ipaeh, XII Ed., 8301). Polymorphic forms of rifaximin are disclosed in US patent 7045620 B1 and publication PCT UMO 2006/094662 A1.

The essence of the invention

This application describes polymorphic forms of rifaximin kappa (k), theta (8) and co-crystals of rifaximin:piperazine (co-crystal 1 and co-crystal 2), which have not been described before.

According to one aspect, the polymorphs and cocrystals described in this application exhibit an X-ray powder diffraction pattern containing characteristic peaks at diffraction angle values of 2 8 (47/-0.20 degrees 8 or -/ 0.1 degrees 6, if described) , as described in this application in figures and tables. These polymorphs and co-crystals can also be characterized by the volume of the unit cell, as described in this application. A specialist in this field of technology will know

To determine the main peaks and specific characteristic distinctive peaks of co-crystals of rifaximin:piperazine and polymorphs of rifaximin using the information given in this application, as well as lists of peaks, HRKO radiographs and data.

In one aspect, the present application provides a kappa form of rifaximin, a theta form of rifaximin, a rifaximin:piperazine co-crystal 1, or a rifaximin:piperazine co-crystal 2.

In one embodiment, kappa is characterized by a HCRO, essentially similar to the HCRO in fig. 1,2, 3,101 16.

In one embodiment, the kappa form of rifaximin is characterized by a DSC or TGA thermogram substantially similar to FIG. 6, 7, 11, 12 and 13.

In one embodiment, the kappa form of rifaximin is characterized by the peaks listed in Table 3.

In one embodiment, the kappa form of rifaximin is characterized by the peaks listed in Table 4.

In one embodiment, the kappa form of rifaximin exhibits a powder X-ray diffraction pattern containing characteristic peaks at diffraction angle values of 2 89 (i/-0.10 degrees 8) at (6.45-6.67):0.20, (6, 83-6.94)-0.20 and (7.68-7.78)-0.20; (6.45-6.67)50.20, (6.83-6.94):0.20 and (18.46-18.61)240.20; (6.45-6.67)-0.20, (6.83-6.94):0.20 and (7.52-7.56)20.20; (6.83-6.94):0.20, (7.68-7.78)-40.20 and (18.46-18.61)-40.20; (6.45-6.67)-0.20, (6.83-6.94)-40.20, (7.68-7.18)-0.20 and (18.46-18.61 )-0.20; (6.83-6.94)240.20, (7.52-7.56)-0.20, (7.68-7.78)-0.20 and (18.46-18.61) -0.20; (6.45-6.67)-0.20, (6.83-6.94)-0.20, (7.52-7.56)-0.20, (7.68-7.78 )-0.20 and (18.46-18.61)-0.20; (6.45-6.67)-0.20, (6.83-6.94):0.20, (7.52-7.56)20.20, (7.68-7.78) 20.20, (8.30-8.34)-0.20 and (18.46-18.61):0.20; or (5.41-5.65)-0.20, (6.45-6.67):0.20, (6.83-6.94):0.20 and (7.52-7, 56)50.20, (7.68-7.78)50.20, (8.30-8.34):0.20 and (18.46-18.61)20.20.

In one embodiment, rifaximin:piperazine co-crystal 1 is characterized

HERO, substantially similar to one or more of FIG. 17, 18, 19, 20, 23, 30 and/or 48.

In one embodiment, rifaximin:piperazine co-crystal 1 is characterized by IR spectra essentially similar to fig. 21 and/or fig. 33.

In one embodiment, rifaximin:piperazine co-crystal 1 is characterized by Raman spectra essentially similar to those of FIG. 22, fig. 35 and/or one or more peaks in FIG. 36.

In one embodiment, rifaximin:piperazine co-crystal 1 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 289 (w/-0.10 degrees 6) that include one or more peaks listed in FIG. 26.

In one embodiment, rifaximin:piperazine co-crystal 1 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 289 (w/-0.10 degrees 6) that include one or more peaks listed in FIG. 27.

In one embodiment, rifaximin:piperazine co-crystal 1 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 289 (w/-0.10 degrees 8), at 5.7450.10; 6.58:0.10; 7.49-40.10; 8.21:0.10 and 9.83:5-0.10.

In one embodiment, rifaximin:piperazine co-crystal 1 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 28 (w/-0.10 degrees 8) at 5.7450.10; 7.49:30.10; 8.21-0.10 and 9.83:5-0.10.

In one embodiment, rifaximin:piperazine co-crystal 1 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 28 (/-0.10 degrees 9) at 5.7420.10; 6.58:20.10; 8.21:0.10 and 9.83:2-0.10.

In one embodiment, rifaximin:piperazine co-crystal 1 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 28 (/-0.10 degrees 8) at 5.7450.10; 6.58:0.10; 7.49:-0.10 and 9.83:5-0.10.

In one embodiment, rifaximin:piperazine co-crystal 1 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 29 (u/-0.10 degrees 8) at 5.7450.10; 6.58:0.10; 7.4950.10 and 8.21:-0.10.

In one embodiment, co-crystal 1 of rifaximin:piperazine is characterized by DSC and TGA curves, essentially similar to fig. 28.

In one embodiment, co-crystal 1 of rifaximin:piperazine is characterized by SPD curves essentially similar to FIG. 29.

In one embodiment, the rifaximin:piperazine co-crystal 1 is characterized by NMR spectra essentially similar to Fig.31.

In one embodiment, rifaximin:piperazine co-crystal 1 is characterized by NMR-

TT, essentially similar to fig. 32.

In one embodiment, rifaximin:piperazine co-crystal 1 exhibits IR peaks as shown in FIG. 34.

In one embodiment, the rifaximin:piperazine co-crystal comprises co-crystal 2.

In one embodiment, co-crystal 2 of rifaximin:piperazine is characterized

HERO, substantially similar to one or more of FIG. 19, 20, 37 and/or 39.

In one embodiment, rifaximin:piperazine co-crystal 2 is characterized by IR spectra essentially similar to fig. 21 and/or fig. 44.

In one embodiment, rifaximin:piperazine co-crystal 2 exhibits IR peaks as shown in FIG. 45.

In one embodiment, rifaximin:piperazine co-crystal 2 is characterized by Raman spectra essentially similar to those of FIG. 22, fig. 46, and/or one or more peaks in fig. 47.

In one embodiment, the rifaximin:piperazine co-crystal 2 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 28 (/-0.10 degrees 6), including one or more peaks listed in FIG. 40.

In one embodiment, the rifaximin:piperazine co-crystal 2 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 28 (/-0.10 degrees 6) including one or more peaks listed in FIG. 41.

In one embodiment, rifaximin:piperazine co-crystal 2 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 28 (/-0.10 degrees 9) at 3.64:20.10; 5.58:20.10; 6.45:0.10; 7.29:0.10; 7.6050.10; 8.2750.10 and 9.010.10.

In one embodiment, rifaximin:piperazine co-crystal 2 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 28 (w/-0.10 degrees 8), at 5.58:-0.10; 6.45:0.10; 7.2950.10; 7.6050.10; 8,2730,1019,010,10.

In one embodiment, rifaximin:piperazine co-crystal 2 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 29 (w/-0.10 degrees 8) at 3.6450.10; 6.45:0.10; 7.2950.10; 7.6050.10; 8.27530.1019.010.10.

In one embodiment, rifaximin:piperazine co-crystal 2 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 289 (w/-0.10 degrees 8), at 3.64:50.10; 5.58:0.10; 7.2950.10; 7.6050.10; 8.27530.1019.010.10.

In one embodiment, rifaximin:piperazine co-crystal 2 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 29 (w/-0.10 degrees 8) at 3.64:50.10; 5.58:0.10; 6.45:-0.10; 7.6050.10; 8.27530.1019.010.10.

In one embodiment, rifaximin:piperazine co-crystal 2 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 289 (w/-0.10 degrees 8), at 3.64:50.10; 5.58:0.10; 6.45:0.10; 7.29:50.10; 7.60530.10119.010.10.

In one embodiment, rifaximin:piperazine co-crystal 2 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 28 (u/-0.10 degrees 8), at 3.64:50.10; 5.58:0.10; 6.45:0.10; 7.29:50.10; 7.60530.10 and 8.270.10.

In one embodiment, the rifaximin:piperazine co-crystal 2 exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 28 (i/-0.10 degrees 8), at 3.64:-0.10; 5.58:0.10; 6.45:-0.10; 7.29:50.10 and 7.6050.10.

In one embodiment, co-crystal 2 of rifaximin:piperazine is characterized by DSC and TGA curves, essentially similar to fig. 42.

In one embodiment, rifaximin:piperazine co-crystal 2 is characterized by NMR spectra essentially similar to those of FIG. 43.

In one embodiment, the kappa form of rifaximin, theta form, rifaximin:piperazine co-crystal 1 and/or rifaximin:piperazine co-crystal 2 contain less than 595 impurities by total weight.

In one embodiment, the kappa form of rifaximin, theta form of rifaximin, rifaximin:piperazine co-crystal 1 and/or rifaximin:piperazine co-crystal 2 are at least 50 95 pure or at least 75 95 pure or at least 80 95 pure or at least 9095 pure , or at least 9595 pure, or at least 98 95 pure.

In one embodiment, the kappa form of rifaximin, theta form of rifaximin, rifaximin:piperazine co-crystal 1 and/or rifaximin:piperazine co-crystal 2 further comprise a pharmaceutically acceptable carrier.

In one embodiment, the kappa form of rifaximin, theta form of rifaximin, rifaximin:piperazine co-crystal 1 and/or rifaximin:piperazine co-crystal 2 are prepared in

In the form of coated or uncoated tablets, hard or soft gelatin capsules, sugar-coated pills, lozenges, wafers, granules or powders in sealed packages.

This application proposes methods of obtaining the kappa form of rifaximin, including one or more methods listed in Table 1 or Table 2.

In one embodiment, a method of obtaining the kappa form of rifaximin is proposed, which includes the steps of mixing the a-form of rifaximin at a temperature below 609C before the formation of a precipitate and filtering the indicated precipitate. In one embodiment, the mixing is stirring. In one embodiment, the mixing is sonicated. In one embodiment, the temperature is room temperature. In one embodiment, the mixing is stirring and the temperature is above room temperature but below 60°C. In one embodiment, the mixing is sonicated and the temperature is room temperature. In one embodiment, the filtered sediment is additionally subjected to drying (for example, over PgO5).

This application proposes methods of obtaining rifaximin:piperazine co-crystals, which include one or more methods listed in Table 10.

In one embodiment, the composition further includes one or more pharmaceutically acceptable excipients. Excipients may be one or more diluents, binders, glidants, leavening agents, coloring agents, flavoring agents, or sweeteners.

According to one embodiment, the pharmaceutical composition can be prepared in the form of tablets with or without a shell, hard or soft gelatin capsules, pills with a sugar coating, lollipops, wafers, granules or powders in a hermetically sealed package. In a related embodiment, the pharmaceutical composition may also be prepared in a topical form.

In another aspect, the present application provides methods of treating, preventing, or reducing the severity of intestinal disease, comprising administering to a subject in need thereof an effective amount of one or more of rifaximin kappa form, rifaximin cocrystal 1:piperazine, and/or co-crystal 2 of rifaximin:piperazine rifaximin.

In another aspect, the present application provides methods of treating, preventing, or reducing the intensity of intestinal disease, comprising administering to a subject in need thereof an effective amount of one or more of rifaximin kappa form, rifaximin co-crystal 1:piperazine and/ or co-crystal 2 of rifaximin:piperazine.

In one embodiment, the subject suffers from at least one bowel disease selected from the group consisting of irritable bowel syndrome, traveler's diarrhea, small intestinal bacterial overgrowth, Crohn's disease, chronic pancreatitis, pancreatic insufficiency, hepatic encephalopathy, minimal hepatic encephalopathy, diverticulosis, enteritis and colitis.

This application provides, according to one aspect, methods of obtaining the kappa form of rifaximin, theta form of rifaximin, or co-crystals 1 and/or 2 of rifaximin:piperazine.

The methods are given in the examples and in the tables below.

The present application provides, in one aspect, kits for the treatment of intestinal disease in a subject, comprising one or more of rifaximin kappa form, rifaximin theta form, rifaximin:piperazine co-crystal 1 or rifaximin:piperazine co-crystal 2 rifaximin and instructions for use .

The present application provides, in one aspect, packaged compositions comprising a therapeutically effective amount of one or more of rifaximin kappa form, rifaximin theta form, rifaximin:piperazine co-crystal 1, or rifaximin:piperazine co-crystal 2 rifaximin, and a pharmaceutically acceptable carrier or diluent, wherein the composition is formulated to treat a subject suffering from or susceptible to intestinal disease and packaged with instructions for treating a subject suffering from or susceptible to intestinal disease.

In one aspect, a pharmaceutical composition is provided that includes one or more of rifaximin kappa form, rifaximin theta form, rifaximin co-crystal 1:piperazine and/or rifaximin co-crystal 2:piperazine rifaximin, and a pharmaceutically acceptable carrier.

In one embodiment, the pharmaceutical composition additionally includes excipients.

According to another embodiment, the excipients are one or more diluents, binders, glidants, leavening agents, coloring agents, flavoring agents, or sweeteners.

In another embodiment, the composition is prepared in the form of selected coated and uncoated tablets, hard and soft gelatin capsules, sugar-coated pills, lozenges, wafers, granules and powders in sealed packages.

In one embodiment, the composition is prepared in a form for topical application.

The present application provides, in one aspect, methods of treating, preventing, or reducing the intensity of intestinal disease, comprising administering to a subject in need thereof a virus-infected cell with an effective amount of one or more forms of rifaximin.

According to another embodiment, wherein the bowel disease is one or more of irritable bowel syndrome, traveler's diarrhea, small intestinal bacterial overgrowth, Crohn's disease, chronic pancreatitis, pancreatic insufficiency, hepatic encephalopathy, minimal hepatic encephalopathy, diverticulosis, enteritis, and colitis .

Also provided herein, in one aspect, are packaged compositions comprising a therapeutically effective amount of one or more of rifaximin kappa form, rifaximin theta form, rifaximin:piperazine co-crystal 1 and/or rifaximin:piperazine co-crystal 2, and a pharmaceutically acceptable carrier or diluents, wherein the compositions are formulated to treat a subject suffering from or susceptible to intestinal disease and packaged with instructions for treating a subject suffering from or susceptible to intestinal disease.

Also, this application presents the use of one or more of the kappa form of rifaximin, theta form of rifaximin, co-crystal 1 of rifaximin:piperazine and/or co-crystal 2 of rifaximin:piperazine of rifaximin as a medicinal product.

In this application, according to another aspect, a method of obtaining rifaximin:piperazine co-crystal 1 is presented, which includes dissolving rifaximin in acetonitrile with ultrasound treatment; adding the resulting solution to piperazine with stirring.

In one embodiment, the method may further include adding an additional amount of acetonitrile to the piperazine solution.

In one embodiment, the method may additionally include continuing to stir the piperazine solution for 1 hour to 3 days.

In one embodiment, mixing is carried out at ambient temperature.

In one embodiment, the method may further include collecting the solid phase by filtration.

In one embodiment, the method may further include drying the collected solid phase.

In this application, according to another aspect, a method of obtaining rifaximin:piperazine co-crystal 2 is presented, which includes contact of rifaximin:piperazine co-crystal 1 with acetonitrile vapors.

In one aspect, the present application provides a theta form of rifaximin. In one embodiment, theta is characterized by an HCRO, essentially similar to fig. 60, 67 or 72. In one embodiment, the theta form of rifaximin comprises one or more peaks identified in FIG. 68. In one embodiment, the theta form of rifaximin includes a DSC substantially similar to FIG. 70. In one embodiment, theta form of rifaximin includes TGA, substantially similar to FIG. 70. In one embodiment, theta form of rifaximin includes HCRO with moisture sorption, essentially similar to FIG. 71. In one embodiment, the form of theta rifaximin includes XERO after moisture sorption, essentially similar to FIG. 72.

In one embodiment, the theta form of rifaximin comprises one or more peaks identified in Table 24. In one embodiment, the theta form of rifaximin comprises one or more peaks identified in Table 25.

In one embodiment, the theta form of rifaximin exhibits an X-ray powder pattern containing one or more of the following characteristic peaks expressed in degrees 29 (-7-0.10 degrees 8), at 5.48:20.10, 7.00x0.10 , 7.75:0.10, 8.72:20.10, 9.09530.10 or 10.96:0.10. In one embodiment, the theta form of rifaximin exhibits a powder X-ray diffraction pattern containing characteristic peaks expressed in degrees 28 (i/-0.10 degrees 8) at 5.48:0.10, 7.0050.10, 7.7530 ,10, 8,720,10, 9,0950,10 and 10,96:0,10; or 5.48:0.10, 7.0050.10, 7.75:20.10, or 5.48:0.10, 7.75:50.10, and 8.7220.10; or 5.48:0.10, 7.00-0.10 and 8.72:50.10; or 5.48520.10, 8.725-0.10 and 9.0920.10; or 5.48:30.10, 9.0930.10 and 10.96:30.10; or 7.75:50.10, 8.72:30.10 and 9.09:20.10; or 7.00530.10, 7.75:50.10, 8.7220.10 and 10.96:0.10; or 8.72:0.10, 9.0950.10 ii

From 10.9650.10; or 7.00-0.10, 7.7530.10, 8.72x0.10 and 10.9620.10; or 7.0030.10, 8.725010 and 10.96:0.10.

In this application, in one aspect, methods of obtaining rifaximin form eta are presented.

In one aspect, this application presents methods of obtaining iota form rifaximin.

In one aspect, this application proposes methods of obtaining rifaximin form eta, which include: precipitation of rifaximin from ethanol; drying of precipitated rifaximin in a stream of nitrogen; and holding the precipitated rifaximin at an elevated temperature for 30 minutes or longer.

In one embodiment, the precipitated form comprises a zeta form.

In one embodiment, holding is carried out at about 402C for about 2 hours or longer.

In one embodiment, holding is carried out in a vacuum at about 60C for 2 hours or longer.

In one embodiment, the drying is carried out for about 10 minutes or less.

In one aspect, this application proposes methods of obtaining the iota form of rifaximin, which include: precipitation of rifaximin from ethanol; drying of precipitated rifaximin in a stream of nitrogen; and keeping rifaximin at ambient temperature.

In one embodiment, the precipitated form comprises a zeta form.

In one embodiment, holding further comprises rifaximin under vacuum for 6 or more hours.

In one embodiment, the holding further comprises rifaximin at a humidity in the range of about 22-50 9.

In one embodiment, the drying is carried out for about 10 minutes or less.

In one aspect, this application proposes methods of obtaining mixtures of the iota form and theta form, which includes precipitation of rifaximin from ethanol; drying of precipitated rifaximin in a stream of nitrogen; and maintaining the rifaximin at a relative humidity (RH) ranging from about 1095 pH to about 4695 at ambient temperature for at least one hour to about 6 hours or longer. In other embodiments, drying is performed for about 10 minutes or less.

Also in this application, methods of obtaining theta form of rifaximin are proposed, which include precipitation of the zeta form of rifaximin from ethanol and drying in a stream of nitrogen for 10 seconds to 10 minutes.

Another embodiment and aspects are disclosed below.

BRIEF DESCRIPTION OF FIGURES

In fig. 1 shows diffractograms of XKRO k-form of rifaximin. The XKRO diffraction pattern above is shown for the substance in the form in which it was obtained. Diffractogram

HERO below is shown after drying over PgO5 at room temperature.

Fig. 2 is a list of peaks observed for the k-form of rifaximin corresponding to the XRD diffraction pattern for the substance as it was obtained.

It should be noted that the peak markings in this image are for visual representation.

See tables C and 4 to obtain the exact 29 provisions.

Fig. C is a list of peaks observed for the k-form of rifaximin corresponding to the XCRO diffractogram after drying. It should be noted that the peak markings in this image are for visual representation. See tables C and 4 to obtain the exact 28 provisions.

In fig. 4 shows the preliminary indexing for the k-form of rifaximin as it was received. The lines indicate possible mappings based on the parameters of the unit cell and the established symmetry group (P21, Y4).

In fig. 5 shows the preliminary indexing for the Kc form of rifaximin after drying. The lines indicate possible mappings based on the unit cell parameters and the established symmetry group (Rg, 44).

Fig. b is a DSC thermogram of the k-form of rifaximin in the form in which it was obtained.

Fig. 7 is a TGA thermogram of k-form of rifaximin in the form in which it was obtained.

Fi. 8 is a high-temperature microscope image of the KC form of rifaximin. fig. va was obtained at 23.32C, fig. 86 was obtained at 80.19C, fig. 8c was obtained at 101.99C, fig. 8a was obtained at 109.22C, fig. there was

Zo obtained at 123.22C, fig. 87 was obtained at 150.12C, fig. wd was obtained at 203.19C and fig. 8th was obtained at 213.16.

In fig. 9 shows the moisture sorption of k-form of rifaximin.

In fig. 10 shows HCRO after sorption of moisture of k-form of rifaximin. Diffractogram

HERO above was obtained after moisture sorption. The XKRO diffraction pattern from below was obtained before moisture sorption.

Fig. 11 is a DSC thermogram of k-form rifaximin after drying.

Fig. 12 is a TGA thermogram of k-form rifaximin after drying.

Fig. 13 is a TGA thermogram of the k-form of rifaximin after drying over PgO5.

Fig. 14 is a XRD diffraction pattern of the dried k-form after stress at 84 95 ВН.

The XKRO diffractogram from above was obtained after stress. The XKRO diffractogram below was made for the original substance.

In fig. 15 shows the moisture sorption of k-form rifaximin after drying.

In fig. 16 shows the HCRO after moisture sorption for k-form of rifaximin, after drying.

The diffractogram of HAKRO from above was made after moisture sorption. The diffractogram of ХКРО from below was made before moisture sorption.

In fig. 17 shows an exemplary overlay of the HCRO co-crystal of rifaximin: piperazine, after

chipboard The XKRO diffraction pattern from above corresponds to the 1T co-crystal to the chipboard. The XKRO diffractogram from below was made after chipboard, broad peaks similar to co-crystal 1 "t peaks at "5 and 1790.

Fig. 18 is an overlay of the XKRO co-crystal of rifaximin:piperazine after KN stress. From top to bottom: co-crystal 1, no stress; broad peaks similar to co-crystal 1 "same peak at -5928, C bottom at KN --75 95; broad peaks similar to co-crystal 1 their peak at 52268, 1 week at

VN "75 95; broad peaks similar to co-crystal 1 "t peak at 5228, 2 weeks at KN --75 Ob.

In fig. 19 shows the overlay of HCRO co-crystals of rifaximin: piperazine. From top to bottom: co-crystal 1, co-crystal 2, rifaximin, dry a-form, piperazine.

In fig. 20 shows the superimposition of XKRO co-crystal 2 of rifaximin:piperazine, before and after drying in a vacuum. From top to bottom: co-crystal 2, before drying in vacuum; similar to co-crystal 1 peak at "17268, after drying in vacuum, co-crystal 1 (diffraction pattern of Ipei for comparison).

In fig. 21 shows an overlay of IR spectra for rifaximin, piperazine and co-crystals.

From top to bottom: as-received rifaximin, as-received piperazine, co-crystal 1 of rifaximin:piperazine, predicted co-crystal 2 of rifaximin:piperazine.

In fig. 22 shows the overlay of Raman spectra for rifaximin, piperazine and co-crystals. From top to bottom: rifaximin as obtained, piperazine as obtained from bidta-

Aiagisii, rifaximin:piperazine co-crystal 1, predicted rifaximin:piperazine co-crystal 2.

In fig. 23 shows an exemplary HCR of rifaximin:piperazine co-crystal 1.

Fig. 24 is indexing for rifaximin:piperazine co-crystal 1. The lines indicate possible mappings based on the unit cell parameters and the established symmetry group (P212111, Zh19).

In fig. 25 shows the markings of the XKRO peaks of rifaximin:piperazine co-crystal 1. It should be noted that the peak markings on this image are for visual representation. See fig. 26 to get the exact 298 positions.

Fig. 26 is a list of peaks observed by XCR for rifaximin:piperazine co-crystal 1.

Fi. 27 is a representative list of peaks observed by XCR for rifaximin:piperazine co-crystal 1.

In fig. 28 shows an exemplary overlay of DSC and TGA of rifaximin:piperazine co-crystal 1.

In fig. 29 shows exemplary DSP curves for rifaximin:piperazine co-crystal 1.

In fig. 30 shows the superimposition of HCRO co-crystal 1 of rifaximin: piperazine, after DSP.

From top to bottom: co-crystal 1 to chipboard; post-DSP sample, broad peaks, similar to co-crystal 1 J peak at "5 and 17226.

Fig. (31 is an exemplary proton NMR spectrum of rifaximin:piperazine co-crystal 1.

Fig. 32 is NMR-TT of rifaximin:piperazine co-crystal 1.

In fig. 33 shows the IR spectrum of rifaximin:piperazine co-crystal 1.

Fig. 34 is a list of IR burns observed for rifaximin:piperazine co-crystal 1.

Fig. 35 is an exemplary Raman spectrum of rifaximin:piperazine co-crystal 1.

Fig. 36 is a list of Raman peaks observed for rifaximin:piperazine co-crystal 1.

From Fig. 37 is an exemplary CHERO of co-crystal 2 of rifaximin:piperazine.

Fig. 38 is indexing for co-crystal 2 of rifaximin:piperazine. The lines indicate possible mappings based on the parameters of the unit cell and the established symmetry group (P212121, Ya19).

In fig. 39 shows HCR with marked peaks for co-crystal 2 of rifaximin:piperazine.

Fig. 40 is a list of the peaks observed by XKERO for co-crystal 2 of rifaximin:piperazine.

Fig. 41 representative list of peaks observed by HCR for co-crystal 2 of rifaximin:piperazine.

Fig. 42 is an exemplary overlay of DSC and TGA of rifaximin:piperazine co-crystal 2.

In fig. 43 shows the proton NMR spectrum of co-crystal 2 of rifaximin:piperazine.

Fig. 44 is an exemplary IR spectrum of co-crystal 2 of rifaximin:piperazine.

Fig. 45 represents the characteristic IR peaks observed and for co-crystal 2 of rifaximin:piperazine.

Fig. 46 is an exemplary Raman spectrum of rifaximin:piperazine co-crystal 2.

Fig. 47 is a list of characteristic Raman peaks observed for co-crystal 2 of rifaximin:piperazine.

Fig. 48 is an exemplary superimposition of the XKRO co-crystal of rifaximin: piperazine, after

EN stress. From top to bottom: co-crystal 1, unstressed (Rapaiuisa! ХКРО); co-crystal 1 (IpeI HKROB); broad peaks, similar to co-crystal 1 same peak at 5228, C bottom at KN --75 95; broad peaks, similar to co-crystal 1 same peak at x52260, 1 week at KN "75 90; broad peaks, similar to co-crystal 1 « peak at 5226, 2 weeks at KN --75 95.

Fig. 49 is a schematic diagram showing the conversion and interconversion schemes of rifaximin:piperazine co-crystals 1 and 2.

In fig. 50 is a block diagram showing the ethanolate/hydrate system and the conversion of the E-form of rifaximin into forms n, 6 and 1.

In fig. 51 shows the conversion of the c-form of rifaximin into the p-form of rifaximin.

In fig. 52 shows the formation of p-form of rifaximin.

In fig. 53 shows the effect of stress on the p-form of rifaximin.

Fig. 54 is an exemplary XKRO diffraction pattern of p-form rifaximin before exposure to moisture, after exposure to moisture, and after drying.

In fig. 55 shows dimers of rifaximin formed as a result of the formation of hydrogen bonds.

In fig. 56 shows solvent molecules viewed along the a axis.

Fig. 58 is an approximate line of rifaximin standards in sodium acetate buffer with acetonitrile.

Fig. 59 is an approximate straight line of rifaximin standards in sodium phosphate buffer with 0.45 95 sodium dodecyl sulfate, with acetonitrile.

Fig. 60 is an exemplary XKRO diffraction pattern showing the 8-form transformation. From top to bottom: 9-form, eye shape, 1st-form.

In fig. 61 shows the indexing of rifaximin 9-form. The lines indicate possible mappings based on the unit cell parameters and the established symmetry group (P2i212ch1, 19).

In fig. 62 shows a diagram of the process of obtaining theta, eta and iota forms.

In fig. 63 shows the analysis of the unit cell of iota and the diffractogram of XKRO iota.

In fig. 64 shows the indexing of the iota.

In fig. 65 shows the analysis of the elementary cell of eta and the diffractogram of ХКРО eta.

Fig. 66 shows the indexing of eta.

In fig. 67 shows the diffractograms of ХКРО 89-form of rifaximin. From top to bottom: 9-form as received; 9-form after 8 days of storage in the environment.

Fig. 68 is a list of peaks observed for the 9-form of rifaximin. It should be noted that the peak markings on this image are for visual representation. See table 24 to obtain the exact 28 provisions.

Fig. 69 is an index for the 9-form of rifaximin. The bands indicate possible mappings based on the parameters of the unit cell and the established symmetry group (P2i212ch1,

I).

Figures 70 A and B represent exemplary DSC and TGA thermograms of the 9-form rifaximin, respectively.

Fig. 71 is an exemplary moisture sorption of the 8-form of rifaximin.

Fig. 72 is an exemplary diffractogram of XKRO 8-form rifaximin after sorption

From moisture. From top to bottom: for moisture sorption (90-form); after moisture sorption (i-form).

DETAILED DESCRIPTION

The implementation options described in this application relate to the discovery of new polymorphic and co-crystalline forms of rifaximin, and the use of such forms as antibiotics. One embodiment contemplates the use of one or more of the kappa form of rifaximin, theta form of rifaximin, rifaximin:piperazine co-crystal 1 and/or rifaximin:piperazine co-crystal 2 (Fig. 1-72) of the antibiotic known as Rifaximin (IMM) in the manufacture of medicinal products for oral or topical use. The implementation options described in this application also relate to the administration of such drugs to a subject in need of antibiotic therapy.

Rifaximin is a compound of the rifamycin group of antibiotics. Rifaximin is a compound with the structure of formula I:

And in I b d-

CH (1).

The forms "rifaximin kappa" used in this application, "kappa form", "rifaximin kappa form", "kappa polymorph" and "rifaximin kappa", as well as variations thereof, are used interchangeably to refer to the polymorphic form of rifaximin, which is described below, for example, one or more peaks of an X-ray diffractogram, differential scanning calorimetry data. The kappa form includes the peak positions of the X-ray powder diffraction patterns listed in Tables 2 and C below, as well as in the examples and figures.

As used in this application, the forms "rifaximin theta", "theta form", "theta form of rifaximin", "polymorph theta" and "rifaximin theta", as well as variations thereof, are used interchangeably to refer to the polymorph form of rifaximin, which is described below,

for example, one or more X-ray diffraction peaks, differential scanning calorimetry data shown below in the tables, examples and figures.

As used in this application, "rifaximin:piperazine co-crystal 1" and "rifaximin:piperazine co-crystal 2", as well as variations thereof, are used to denote the co-crystalline form of rifaximin described below, for example, by one or more X-ray diffractogram peaks, differential scanning calorimetry data, shown below in tables, examples and figures. In general, co-crystals may be referred to herein as rifaximin:piperazine co-crystals.

As used herein, the term polymorph is sometimes used as a general term for forms of rifaximin and includes, within the context, salt, hydrate, polymorph co-crystal and amorphous forms of rifaximin. Its use depends on the context and will be obvious to one skilled in the art.

The term "about" as used in this application, when used in relation to the peak positions of an X-ray powder diffraction pattern, refers to the natural variation of the peaks depending, for example, on the calibration of the equipment used, the process used to obtain the polymorph, the age of the crystallized material, etc. p., depending on the technical means used. In this case, the degree of variation of technical means was approximately 0.2 degrees 2-8. One skilled in the art having the benefit of this disclosure will appreciate the use of the term "about" in this context. The term "about" with respect to other certain parameters, such as water content, Stach, VOC, VOC, characteristic degrees of dissolution, temperature and time, indicates natural variation, for example, when the parameter is measured or the parameter is reached. A person skilled in the art having the benefit of this disclosure will be able to appreciate the variation of the parameter that is meant by the use of the word approximately. "Similar" as used herein, as applied to a form exhibiting characteristics similar to, e.g., X-ray, IR, Raman spectrum, DSC, TGA, NMR, NMR-TI, etc., indicates that the polymorph or co-cryst. can be identified by such a method, and may vary from similar to substantially similar, provided that the material is identified by the method with variations expected by those skilled in the art according to

With experimental variations including, for example, equipment used, time of day, humidity, season, pressure, room temperature, etc.

Polymorphism, as used in this application, refers to the existence of different crystalline forms of the same compound with different hydrate status, for example, the properties of some compounds and complexes. Thus, polymorphs are different solids that have the same molecular formula, but each polymorph can have different physical properties.

Thus, a single compound can give rise to a whole range of polymorphic forms, where each form has different and individual physical properties, such as solubility profiles, melting points, hygroscopicity, particle shape, density, flowability, compressibility and/or X-ray diffraction peak. The solubility of each polymorph can vary, so detecting the existence of pharmaceutical polymorphs is critical to producing pharmaceuticals with predictable solubility profiles. It is desirable to investigate all solid forms of the medicinal substance, including all polymorphic forms, and to determine the stability, dissolution and fluidity of each polymorphic form. Polymorphic forms of the compound can be distinguished in the laboratory using X-ray diffraction spectroscopy and other methods, such as infrared spectrometry. For a general overview of polymorphs and pharmaceutical applications of polymorphs, see S.M. Umayii, Rpapt Mapii. Z, 33 (1986); 9. K.

Naiiebiiap apa 5si., 58, 911 (1969) and U.K. NaIeriiap, U. Rpagt. Zsi., 64, 1269 (1975), which are incorporated into this application by reference. "Subject" as used herein includes organisms that may suffer from intestinal disease or other diseases amenable to treatment with rifaximin, or that may otherwise benefit from administration of rifaximin as described herein, such as animals, belonging and not belonging to a person. Preferred human animals include human subjects. The term "non-human animals" according to the invention includes all vertebrates, for example, mammals, for example, rodents, for example, mice, and non-mammals, such as non-human primates, for example, sheep, dogs, cows, chickens, amphibians, reptiles, etc. Susceptible to intestinal disease is meant to include subjects at risk of developing infectious intestinal disease, for example, subjects suffering from one or more of the immunosuppressed subjects, subjects who have been in contact with by other subjects with bacterial infection, doctors, nurses, subjects traveling to 60 remote areas known to harbor travelers' diarrhea bacteria,

subjects consuming such amounts of alcohol that damage the liver, subjects with a history of liver dysfunction, etc.

The term "prophylactically effective amount" of a compound refers to that amount of a compound of the invention of formula (I), or otherwise described in this application, which is effective, upon single or repeated administration of a dose to a subject, in the prevention or treatment of a bacterial infection.

The term "therapeutically effective amount" of a compound of the invention refers to an amount of agent that is effective, upon single or repeated administration of a dose to a subject, to provide therapeutic benefit to the subject. In one embodiment, the therapeutic benefit consists in inhibiting the virus or prolonging the ability to survive in a subject with such a viral infection. In another embodiment, the therapeutic benefit is the inhibition of a bacterial infection or prolongation of the ability to survive a subject with such a bacterial infection compared to that expected in the absence of such therapy.

Rifaximin exhibits broad antibacterial activity in the gastrointestinal tract against localized gastrointestinal bacteria that cause infectious diarrhea, including anaerobic strains. It was reported that rifaximin is characterized by insignificant systemic absorption due to its chemical and physical properties (YuOezsotre 4... ей ай.

Rpagtasokipeiis vitsau oi pahitip apyeg oga! adtipivigayop ip Neainu moYippieetgv. Ipi y) Siip Rpaptasoi

Vev, 14 (2), 51-56, (1994)).

Regarding the possible adverse events associated with the therapeutic use of rifaximin, the induction of bacterial resistance to antibiotics is of particular importance.

From this point of view, any differences found in the systemic absorption of the forms of rifaximin disclosed in this application may be significant, since at subinhibitory concentrations of rifaximin, for example in the range of 0.1 to 1 μg/ml, it has been demonstrated that відбір стійких мутантів є можливим (Магсопезе А. еї аїЇ. п міго асіїмпу ої гітахітіп, теїгопіда?оїе апа мапсотусіп адаїіпві Сіовігідіит аїнісіе апа іїйпе гаїе ої зеІєсійоп ої зропіапеоивіу гезівїапі тшапів адаіїпві гергебепіайме апаєгобіс апа аегобіс бБасієтіа, іпсійдіпд аттопіа-ргодисіпуд з5ресієв.

SpetoiNegaru, 46(4), 253-266, (2000)).

Polymorphs of rifaximin were found to have differences in bioavailability parameters

By the way Thus, the polymorphs disclosed in this application can be used in the preparation of pharmaceutical preparations with different characteristics for the treatment of infections. This may allow the creation of rifaximin preparations that have completely different adsorption levels with C values ranging from approximately 0.0 ng/ml to 5.0 μg/ml. This results in rifaximin compositions that are slightly to substantially adsorbed by subjects undergoing therapy. One embodiment of the invention is to modulate the therapeutic effect of rifaximin by selecting the desired polymorphic form or mixture of forms for the treatment of the patient. For example, in the case of invasive bacteria, the most bioavailable polymorphic forms may be selected from the polymorphic forms disclosed herein, while in the case of non-invasive pathogens, less adsorbable forms of rifaximin may be selected because they may be safer for the subject. undergoing treatment. The form of rifaximin can determine solubility, which can also determine bioavailability.

The above-mentioned forms disclosed in this application can be advantageously used in the form of pure and homogeneous products in the manufacture of medicinal preparations containing rifaximin.

With respect to the HCR analysis, the precision associated with extraneous measurements performed on independently prepared samples and on different instruments can lead to a variation greater than 50.12 29. Regarding interplanar distance lists 4, the wavelength used to calculate interplanar distances y, was 1.541874 A, the weighted average value of the wavelengths of Si-Kai and Si-Ka2. The variation associated with estimates of interplanar distance 4 was calculated according to the O5R recommendation at each interplanar distance d and reported in the appropriate data tables and peak lists.

Methods of treatment

This application provides methods of treating, preventing, or reducing the intensity of intestinal diseases, which include administering to a subject in need thereof an effective amount of one or more of the kappa form of rifaximin, rifaximin:piperazine co-crystal 1, or rifaximin:piperazine co-crystal 2. Bowel disease includes one or more of irritable bowel syndrome, diarrhea, infectious diarrhea, diarrhea associated with

Cystic hydatiditis, traveler's diarrhea, overgrowth of bacteria in the small intestine, diseases

Crohn's disease, diverticulosis, chronic pancreatitis, pancreatic insufficiency, enteritis, colitis, hepatic encephalopathy, minimal hepatic encephalopathy, or arachnoiditis.

Superficial skin infections and vaginal infections can also be treated with the forms of rifaximin described in this application.

The duration of treatment of a specific intestinal disease in most cases partly depends on the disease itself. For example, the treatment of traveler's diarrhea may require only 12 to about 72 hours, while the duration of treatment for Crohn's disease may be from about 2 days to 3 months. The dosage of rifaximin also varies depending on the condition of the disease. Appropriate dosage ranges are listed below. The polymorphs and co-crystals described in this application can also be used to treat or prevent pathology in a subject suspected of being in contact with a biological warfare agent.

Identification of subjects in need of prophylactic therapy for intestinal disease is within the skill and knowledge of a specialist skilled in the art. Some of the methods for identifying subjects at risk of developing intestinal disease that can be treated with the method under consideration are evaluated in medical skills, for example, family history, past and planned travel, the presence of risk factors associated with the development of the disease state in subject A clinician skilled in the art can easily identify such candidate subjects through, for example, clinical tests, examination and study of medical/family history and past travel history.

In yet another aspect, a method of treating a subject suffering from or susceptible to the development of an intestinal disease comprises administering to a subject in need thereof a therapeutically effective amount of one or more of the rifaximin polymorphs and cocrystals described herein, wherein way, treatment of the subject. Upon identification of a subject suffering from or susceptible to the development of an intestinal disease, e.g.

IBS, he is injected with one or more of the polymorphs and/or co-crystals of rifaximin.

Pharmaceutical drugs

Embodiments also provide pharmaceutical compositions that include an effective amount of one or more of the rifaximin polymorphs and co-crystals described in this application (eg, described in this application and a pharmaceutically acceptable carrier). In another embodiment, the effective amount is effective in the treatment of a bacterial infection, e.g., small intestinal bacterial overgrowth, Crohn's disease, hepatic

From encephalopathy, antibiotic-associated colitis, and/or diverticulosis. Embodiments also provide pharmaceutical compositions comprising an effective amount of one or more rifaximin polymorphs described herein in combination with one or more previously known rifaximin polymorphs (eg, alpha, beta, gamma, delta, epsilon, iota, zeta, eta and amorphous form).

For examples of the use of rifaximin in the treatment of traveler's diarrhea, see

Ipiapie VAM, Egiszvvop SO, 2pi-Uopud y, Ke 5, bieyep V, VioreYi Her, Zask BA, OyRopi, NI.

Epiegoaddgedaiyime EvzspPegispia soii Oiatteea ip Tgameiegv: Nezropze o Wiiahitip Pnaegaru. Siiipisai

Savzigoepiegoiodu apa Nerashiuiodu. 2004; 2: 135-138; and also Zieyep EK, M.O., Zask rA, M.O., Kiorei

G, RNY.O., 2pi-Bopa U, RA.O., Agopieg M, M.O., Egiszzop SO, M.O., Gomzhme V, M.RP., Umaiuaki R, RY.O.,

Mupye M, RY.O., YuiRopi NI, M.O. TNegaru oi Tgameiietv' Oiatnea M/y Viiakhitip op Magoiiv5

Sopiipepib5. Te Ategisap doshigpa! oi Szazigoepiegoisdu. Mau 2003, Moiishte 98, Mitreg 5, which are fully incorporated into this application by reference. For examples of treatment with rifaximin of hepatic encephalopathy, see, for example, M. Epoia. U. Mea. 2010 362 1071-1081.

Embodiments also provide pharmaceutical compositions comprising one or more of the kappa form of rifaximin, co-crystal 1 rifaximin:piperazine and/or co-crystal 2 rifaximin:piperazine, and a pharmaceutically acceptable carrier. Thus, dosage forms may contain only one polymorph or co-crystal, or may contain a mixture of more than one polymorph or co-crystal. The mixtures can be selected, for example, based on the required levels of systemic adsorption, the solubility profile, the required site of action in the digestive tract, etc. Variants of the implementation of the pharmaceutical composition additionally include excipients, for example, one or more diluents, binders, lubricants , leavening agents, dyes, flavors or sweeteners. One composition can be prepared in the form of selected coated and uncoated tablets, hard and soft gelatin capsules, sugar-coated pills, lozenges, wafers, granules and powders in hermetically sealed packages. For example, the compositions may be prepared in a form for topical application, such as ointments, pomades, creams, gels, and lotions.

In an embodiment, the rifaximin polymorph is administered to the subject using a pharmaceutically acceptable dosage form, e.g., a pharmaceutically acceptable dosage form that provides sustained delivery of the rifaximin polymorph to the subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after administration of the pharmaceutically acceptable dosage form to the subject.

In some embodiments, the specified pharmaceutical compositions are suitable for topical or oral administration to a subject. In other embodiments, as detailed below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid dosage form, including forms suitable for the following: (1) oral administration, e.g., liquid forms (aqueous or nonaqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection, such as, for example, sterile solutions or suspensions; (3) topical, for example, in the form of a cream, ointment, or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a vaginal suppository, cream, or foam; or (5) an aerosol, for example, in the form of an aqueous aerosol, liposomal preparation, or solid particles containing the compound.

The phrase "pharmaceutically acceptable" refers to such rifaximin polymorphs and co-crystals of the present invention, compositions containing such compounds, and/or dosage forms which, under careful medical evaluation, are suitable for use in contact with human and animal tissues without undue toxicity. , irritation, allergic reaction or other problem or complication, proportionate to the reasonable benefit/risk ratio.

The phrase "pharmaceutically acceptable carrier" includes a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid excipient, diluent, excipient, solvent, or encapsulating material, involved in the transfer or transport of a subject chemical from one organ or part of the body to another organ or part of the body. Each carrier is preferably "acceptable" in the sense that it is compatible with the other components of the dosage form and is not dangerous to the subject. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) gum tragacanth in the form of powder; (5) malt; (b) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil

Zo oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffer substances such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogenic water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions and (21) other non-toxic compatible substances used in pharmaceutical compositions.

Wetting agents, emulsifiers and glidants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, additives that facilitate the release of active ingredients, coating agents, sweeteners, flavors and aromas, preservatives and antioxidants may also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal-chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

Compositions containing forms of rifaximin disclosed in this application include compositions suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral use. The compositions can be conveniently presented in the form of a single dosage form and can be prepared by any methods known in the pharmaceutical industry. The amount of active ingredient that can be combined with the carrier material to obtain a unit dosage form varies depending on the recipient to be treated and the specific method of administration. The amount of active ingredient that can be combined with the carrier material to obtain a single dosage form will generally be the amount of the compound that exerts a therapeutic effect. In most cases, based on 100 95, such amount will vary from about 1 95 to about ninety-nine 95 of active ingredient, preferably from about 5 95 to about 80 95 or from about 10 95 to about 60 95.

Methods of preparation of these compositions include the step of combining the polymorph(s) and 60 co-crystals of rifaximin with a carrier and, optionally, one or more additional components. As a rule, dosage forms are prepared by homogeneously and carefully combining the rifaximin polymorph with liquid carriers or finely divided solid carriers, or with both, followed by, if necessary, the formation of the product.

Compositions suitable for oral administration may be in the form of capsules, wafers, pills, tablets, lozenges (3 using a flavored base, usually sucrose and gum arabic or tragacanth), powders, granules, or as a solution or suspension in an aqueous or a non-aqueous liquid, or in the form of an oil-in-water or water-in-oil liquid emulsion, or in the form of an elixir or syrup, or in the form of lozenges (using an inert base such as gelatin and glycerin or sucrose and gum arabic) and /or in the form of mouthwashes, etc., which contain a given amount of polymorph(s) and co-crystals of rifaximin as an active component.

The compound can also be administered as a bolus, electuary, or paste.

The forms of rifaximin disclosed in this application can be advantageously used in the production of medicinal preparations having antibiotic activity containing rifaximin, both for oral and topical use. Oral medicinal products will contain one or more forms of rifaximin together with the usual excipients such as diluents such as mannitol, lactose and sorbitol; binders such as starch, gelatin, sugars, cellulose derivatives, natural gums and polyvinylpyrrolidone; lubricants such as talc, stearates, hydrogenated vegetable oils, polyethylene glycol, and colloidal silicon dioxide; leavening agents such as starch, cellulose, alginates, gums and mesh polymers; dyes, flavorings and sweeteners.

Embodiments of the invention include solid preparations administered orally, such as coated and uncoated tablets, soft and hard gelatin capsules, sugar-coated pills, lozenges, wafers, granules, and powders in sealed packages or other containers.

Topical preparations may contain one or more forms of rifaximin along with common excipients such as white petroleum jelly, white wax, lanolin and their derivatives, stearyl alcohol, propylene glycol, sodium lauryl sulfate, polyoxyethylene fatty alcohol esters, polyoxyethylene fatty acid esters,

Contains sorbitan monostearate, glyceryl monostearate, propylene glycol monostearate, polyethylene glycols, methylcellulose, hydroxymethylpropylcellulose, sodium carboxymethylcellulose, aluminum and magnesium colloidal silicate, sodium alginate.

Variants of the invention apply to all topical preparations, for example, ointments, pomades, creams, gels and lotions.

In solid dosage forms of rifaximin for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is usually mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or dry diluents such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; (3) humectants such as glycerin; (4) leavening agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates, and sodium carbonate; (5) dissolution retarders such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as, for example, acetyl alcohol and glycerol monostearate; (8) scavengers such as kaolin and bentonite; (9) slippery substances, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and their mixtures; and (10) dyes. In the case of capsules, tablets and pills, the pharmaceutical compositions may also include buffering agents. Solid compositions of this type can also be used as fillers in gelatin capsules that are filled in a soft and hard state, using such auxiliary substances as lactose or milk sugar, as well as polyethylene glycols of high molecular weight, etc.

The tablet may be made by compression or molding, optionally with one or more additional components. Compressed tablets may be prepared using a binder (eg, gelatin or hydroxypropyl methylcellulose), a glidant, an inert diluent, a preservative, a disintegrant (eg, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant, or a dispersant. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions described herein, such as dragees, capsules, pills, and granules, may optionally be scored or may be manufactured with coatings and shells, such as enteric coatings and other coatings known in the art. pharmaceuticals. Also, they can be prepared in such a way as to provide a slow or controlled release of the active component contained in them, using, for example, hydroxypropyl methylcellulose in different proportions that provide the required release profile, other polymer matrices, liposomes and/or microspheres. They can be sterilized, for example, by filtering through a bacteria-retaining filter or by including sterilizing substances in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile medium for injection immediately before use. Such compositions may also optionally contain contrast agents and may have such a composition that they release the active component(s) only, or preferably, in a certain part of the gastrointestinal tract, optionally, with a delay. Examples of matrix compositions that may be used include polymeric substances and waxes. The active component can also be in microencapsulated form, if necessary, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of rifaximin polymorph(s) and co-crystals include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the field, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cotton, peanut, corn, germ, olive, castor and sesame oils), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and complex sorbitan esters of fatty acids and their mixtures.

In addition to inert diluents, compositions for oral use may include excipients such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, dyes, flavors and preservatives.

Suspensions, in addition to the active polymorph(s) and co-crystals of rifaximin, may contain suspending substances, such as, for example, ethoxylated isostearyl alcohols, complex sorbitol and sorbitan esters of polyoxyethylene, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and gum tragacanth , as well as their mixtures.

Pharmaceutical compositions for rectal or vaginal administration may be presented in the form of a suppository, which may be prepared by mixing one or more polymorph(s) and co-crystals of rifaximin with one or more acceptable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol , suppository wax, or salicylate, which are solid at room temperature and liquid at body temperature, and thus will melt in the rectum or vagina and release the active ingredient.

Compositions suitable for vaginal administration also include vaginal suppositories, tampons, creams, gels, pastes, foams, or aerosol forms containing such carriers as are known in the art to be acceptable.

Pharmaceutical forms for local or transdermal administration of rifaximin polymorph(s) and cocrystals include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, transdermal patches, and inhalation preparations. The active polymorph(s) and co-crystals of rifaximin may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be desired.

Ointments, pastes, creams and gels may contain, in addition to polymorph(s) and co-crystals of rifaximin, such auxiliary substances as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth gum, cellulose derivatives, polyethylene glycols, silicones, bentonites , silicic acid, talc and zinc oxide or their mixtures.

Powders and sprays may contain, in addition to polymorph(s) and co-crystals of rifaximin, such auxiliary substances as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of the listed substances. Sprays may additionally contain standard propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Polymorphs) and rifaximin co-crystals can alternatively be administered in the form of an aerosol.

This is achieved by preparing an aqueous aerosol, liposomal formulation or solid particles containing the compound. It is possible to use a non-aqueous suspension (for example, based on fluorocarbon propellant). Ultrasonic nebulizers are preferred because they minimize the effect of shear forces on the active substance that can lead to degradation of the compound.

An aqueous aerosol is prepared, for example, by mixing an aqueous solution or suspension of an active substance with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers may vary depending on the requirements of a particular compound, but typically include nonionic surfactants (Tueep, Rigopis or polyethylene glycol), non-toxic proteins such as whey albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.

Aerosols are usually prepared from isotonic solutions.

Transdermal patches have the added advantage of providing controlled delivery of rifaximin polymorph(s) and co-crystals into the body. Such dosage forms can be made by dissolving or dispersing the active substance in the required medium. Absorption enhancers can also be used to increase the flux of the active ingredient through the skin. The speed of such a flow can be regulated either by means of a membrane regulating the flow, or by means of dispersing the active component in a polymer matrix or gel.

Ophthalmic dosage forms, eye ointments, powders, solutions, etc. are also considered included in the scope of the invention.

Pharmaceutical compositions suitable for parenteral administration may include one or more polymorphs and co-crystals of rifaximin in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile solutions. or dispersions for injection immediately before administration, which may contain antioxidants, buffers, bacteriostatic agents, solutes that make the dosage form isotonic with the blood of the intended recipient, or suspending agents or thickeners.

Examples of acceptable aqueous and non-aqueous carriers that may be used in pharmaceutical compositions include water, ethanol, polyols (such as glycerin, propylene glycol, polyethylene glycol, etc.) and acceptable mixtures thereof, vegetable oils such as olive

Zo oil, and injectable organic esters such as ethyl oleate. The required fluidity or flowability can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

These compositions may also contain auxiliary substances, such as preservatives, wetting substances, emulsifying substances and dispersing substances. Prevention of the influence of microorganisms can be ensured by including various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenolsorbic acid, etc.

It may also be necessary to include isotonic substances in the composition, such as sugar, sodium chloride, etc. In addition, prolonged absorption of the dosage form for injection can be ensured by including additives that slow absorption, such as aluminum monostearate and gelatin.

In some cases, in order to prolong the action of the drug, it is preferable to change the absorption of the drug. This can be achieved using a liquid suspension of a crystalline form, a salt, or an amorphous material that has poor water solubility.

The rate of absorption of the medicinal product may depend on its dissolution rate, which, in turn, may depend on the size of the crystals and the crystalline form. Alternatively, delayed absorption of the dosage form is achieved by dissolving or suspending the drug in an oily medium.

Injectable depot forms are obtained by forming microencapsulated matrices of polymorph(s) and co-crystals of rifaximin in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the drug and polymer, as well as the nature of the specific polymer used, the rate of release of the drug can be adjusted. Examples of other biodegradable polymers include complex poly(orthoethers) and poly(anhydrides). Injectable depot forms are also obtained by encapsulating the medicinal product in liposomes or microemulsions compatible with body tissue.

When polymorph(s) and co-crystals of rifaximin are administered as pharmaceuticals to humans and animals, they can be administered in their pure form or in the form of a pharmaceutical composition containing, for example, 0.1-99.5 95 (more preferably 0 ,5-bo 90 95) of active components in combination with a pharmaceutically acceptable carrier.

Regardless of the chosen route of administration, polymorph(s) and co-crystals of rifaximin, which can be used in an acceptable hydrated form, and/or pharmaceutical compositions of this invention, prepared in the form of pharmaceutically acceptable dosage forms by methods known to those skilled in the art.

Actual dosage levels and duration of administration of active components in pharmaceutical compositions may be different to obtain such an amount of active component that is effective to achieve the required therapeutic response for a specific subject, composition and method of administration, without toxic effects on the subject. The approximate dose range is from 25 to 3000 mg per day. Other doses include, for example, 600 mg/day, 1100 mg/day, and 1650 mg/day. Other approximate doses include, for example, 1000 mg/day, 1500 mg/day, 500 mg to about 1800 mg/day, or any intermediate value.

The preferred dose of the polymorph or co-crystals of rifaximin disclosed in this application corresponds to the maximum dose that the subject can tolerate without developing severe side effects.

Preferably, the rifaximin polymorph of this invention is administered at a concentration of from about 1 mg to about 200 mg per kilogram of body weight, from about 10 to about 100 mg/kg, or from about 40 mg to about 80 mg/kg of body weight. Ranges intermediate to the above values are also considered included. For example, doses can vary from 50 mg to about 2000 mg/day.

In combination therapy, compounds of this invention and other drug(s) are administered to mammals (eg, humans, male or female) by standard methods. Medicines can be administered in one dosage form or in separate dosage forms. Effective amounts of other therapeutic agents are known to those skilled in the art. However, determining the optimal range of an effective amount of another therapeutic agent is within the competence of a specialist skilled in the art. In one embodiment, in which the other therapeutic agent is administered to the animal, the effective amount of the compound of this invention is less than its effective amount if the other therapeutic agent is not administered. In another embodiment, the effective amount of the standard agent is less than its effective amount if the compound of this invention is not administered. Thus, the undesirable side effects associated with high doses of which-

By some means, can be minimized. Other potential advantages (including, without limitation, improved dosing regimens and/or reduced drug cost) will be apparent to those skilled in the art.

In various embodiments, the therapy (eg, prophylactic or therapeutic agent) is administered at intervals of less than 5 minutes, at intervals of less than 30 minutes, at intervals of 1 hour, at intervals of about 1 hour, at intervals of about 1 to about 2 hours, with at intervals of about 2 hours to about 3 hours, at intervals of about 3 hours to about 4 hours, at intervals of about 4 hours to about 5 hours, at intervals of about 5 hours to about 6 hours, at intervals of about b hours to about 7 hours, at intervals from about 7 hours to about 8 hours, at intervals from about 8 hours to about 9 hours, at intervals from about U hours to about 10 hours, at intervals from about 10 hours to about 11 hours, at intervals from about 11 hours to about 12 hours, with an interval of about 12 hours to 18 hours, with an interval of 18 hours to 24 hours, with an interval of 24 hours to 36 hours, with an interval of 36 hours to 48 hours, with an interval of 48 hours to 52 hours, with an interval of 52 hours to 60 hours, with an interval of 60 hours to 72 hours, with an interval of 72 hours to 84 hours, with an interval of 84 hours to 96 hours, or with an interval of 96 hours to 120 hours. In preferred embodiments, two or more therapies are administered within a single visit to the subject.

In some embodiments, one or more compounds and one or more other therapies (eg, prophylactic or therapeutic agents) are administered cyclically. Cycle therapy involves administration of a first therapy (eg, a first prophylactic or therapeutic agent) for some period of time, followed by administration of a second therapy (eg, a second prophylactic or therapeutic agent) for some period of time, optionally followed by administration of a third therapy (eg, prophylactic or therapeutic agent) during a certain period of time, etc., and repeating this sequential administration, i.e., a cycle, in order to reduce the development of resistance to one of the therapies, to prevent or reduce the side effects of one of the therapies, and/or to increase the effectiveness of the therapies .

In some embodiments, the administration of the same compounds can be repeated, and the administrations can be separated from each other by at least 1 day, 2 days, 3 days, 5 60 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, Z months or at least 6 months. In other embodiments, there may be repeated administration of the same therapy (eg, prophylactic or therapeutic agent) different from the rifaximin polymorph, wherein the administration may be separated from each other by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months or at least 6 months.

Certain indications may require longer treatment periods. For example, treatment for traveler's diarrhea may last from about 12 hours to about 72 hours, while treatment for Crohn's disease may last from about 1 day to about 3 months. Treatment of hepatic encephalopathy may continue, for example, for the rest of the subject's life. Treatment of IBS may continue in courses lasting several weeks or months or for the remainder of the subject's life.

Product

Another embodiment includes articles that include, for example, a container containing a pharmaceutical composition suitable for oral or topical administration of rifaximin in combination with printed instructions describing when a particular dosage form should be taken with food and when should be taken on an empty stomach.

Approximate dosage forms and administration protocols are described below. The composition will be contained in any acceptable container that can accommodate and allows for the dosage form, and that will not significantly interact with the composition, and will be in physical relationship with the appropriate instruction. Instructions for use will correspond to the methods of treatment described above. The instruction may be associated with the container in some way that maintains their physical proximity as a non-limiting example, it may be contained in a packaging material such as a box or shrink film, or may be associated with instructions affixed to the container, for example, with an adhesive that does not cover the instructions, or with other binding or fixing means.

Another aspect is an article of manufacture that includes a container containing a pharmaceutical composition comprising rifaximin, wherein the container preferably contains the rifaximin composition in a unit dosage form and is associated with printed instructions for use that report changes in absorption when the pharmaceutical composition is administered with and without food.

Also provided are packaged compositions that may include a therapeutically effective amount of rifaximin. Rifaximin and a pharmaceutically acceptable carrier or diluent, wherein the composition is formulated to treat a subject suffering from or susceptible to intestinal disease and packaged with instructions for treating a subject suffering from or susceptible to intestinal disease.

Kits are also proposed in this application, for example, kits for the treatment of intestinal disease in a subject. Kits may contain, for example, one or more of the kappa form of rifaximin, co-crystal 1 of rifaximin: piperazine or co-crystal 2 of rifaximin: piperazine rifaximin and instructions for use. Instructions for use may contain information on reception, information on dosage, information on storage, etc.

Also provided are packaged compositions which may include a therapeutically effective amount of one or more rifaximin polymorphs and a pharmaceutically acceptable carrier or diluent, wherein the composition is formulated for the treatment of a subject suffering from or susceptible to intestinal disease and packaged with instructions for treating the sub subject suffering from or susceptible to intestinal disease.

EXAMPLES

Example 1: Form k

Form k is a variable solvate with a unit cell structure capable of expanding and/or contracting to accommodate varying amounts of IRA. The kappa form (k) was obtained by dissolving the alpha form (0) in isopropanol (IPA) at a dosage of 57-197 mg/ml, followed by mechanical stirring.

Form k has been identified as a variable system whose unit cell parameters can change when expanded or compressed to accommodate solvent. The positions of the ХКРО peaks are a direct consequence of the unit cell parameters, and therefore a single ХКРО diffractogram may not be representative of the crystalline form. Several XRD patterns obtained with different samples indicate that there was some range in the reflection peaks observed for the k form. Indexing was obtained on two representative diffractograms

ХРО of the form k, but it is not necessary that they indicated the upper and lower limits of the range. Rather, they should be considered as two separate examples of the k-form series. A theoretical calculation based on indexing indicates that the k-form can accommodate up to 4 moles

IRA per mole of rifaximin taking into account the free space inside the unit cell.

One sample contains two moles of IRA per mole of rifaximin and a small amount of water according to "H-

NMR and Karl-Fisher titration. Another sample with a smaller unit cell volume of about 75 A" contains 0.4 moles of IRA per mole of rifaximin and 0.76 95 by weight of water.

Study of obtaining and drying

Receiving

Form k can be obtained from isopropanol (IPA, see Table 1).

Table 1

Obtaining rifaximin form k

Rifaximin Result

RA tt) ХА vo

Orange solid k 108.5 0.55 Ultrasonic substance, W/E

Ultrasound/CT Orange plates, V/E

Mixture of orange and red 93.6 0.5 Ultrasound/heating solid k substance, V/E 5v 5 4 Stirring/ Orange solid k " heating substance, V/E . and Orange solid k 57.7 1 Stirring/heating substance, B /E and Yellow solid k 24237.9 130 Mixing oem, B/E "KT - room temperature; heating - electric plate set at 602C, while the actual temperature of the sample may be lower; "B - birefringent; E - extinction.

IRA was added to rifaximin form a at a dosage of 57 to 197 mg/ml. Mechanical stirring or sonication at room temperature, or magnetic stirring at a slightly elevated temperature (for example, below 6022) was used to accelerate solid dissolution. Under both conditions, form k was precipitated from a solution in isopropanol, after which it was isolated by vacuum filtration. The material, which was stored in ambient conditions, turned out to be birefringent with extinction under a polarizing microscope.

Details of each experiment are presented in Table 1. For example, one sample was prepared by adding 0.55 ml of IRA to a 7.5 ml vial containing 108.5 mg of form a. The formation of a red solution was observed, as well as the presence of some undissolved solid phase.

Then the vial was sonicated in an ultrasonic bath at room temperature. After sonication, the crushed solid particles were removed by vacuum filtration.

Drying of form k can be done by storage in a closed container over P2O5 at ambient temperature or in vacuum at ambient or elevated temperature. Representative diffractograms of XKRO samples of form k before and after drying are shown in fig. 1. Experimental conditions used in drying form k are included in Table 2.

Table 2

Experiments on drying rifaximin form K material o Red solid k

I 86"S/vacuum, 2 h. substance, V/EE Disordered ts Red solid k 340.3 mg Vacuum/KT, 78 h. substance, partially, V/E we | veins | SAME | 5 314.2 mg Vacuum /KT, 4 h. oechovina, V/E to storage

Vacuum/402С, Red solid k 610.5 mg -36 h. substance, V/E i amorphous ov | vyutedee 0 yuave | 00 4547 mg Рg2ОБ5/CT, 6 days ourec, IV

Rg2OB5/KT, 31 days to vacuum/KT, 4 days

Undissolved solid Red gel and V/E k phase in the IRA solution of particles of ad « days, hours. - hours, CT - room temperature; B - birefringent; E - extinction; "Amorphous - X-ray amorphous; "The exact weight of the sample was not obtained.

Research

The material was analyzed using X-ray powder diffractometry (XPRD) and diffractograms were indexed. In addition, the material was investigated using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DSP), Karl-Fischer titration (KE), proton ("H-") nuclear magnetic resonance (NMR) in solution and solid-state (TT), as well as broken total internal reflection IR spectroscopy (TIR) and Raman spectroscopy.

HERO indexing (not OMR)

Diffractograms of ХКРО of two samples of form k are shown in fig. 1. Since the k-form is a variable system with a flexible unit cell structure that can easily expand or contract to accommodate different amounts of solvent, it should be noted that the diffraction patterns shown represent only two separate examples of the series of peak ranges that the k-form can exhibit.

A list of peak positions for each XCRO diffractogram of form k of rifaximin, which is compared in Fig. 1, presented in fig. 2 and fig. With, respectively. Lists of observed and most intense peaks are included in Table C and Table 4.

Table C

Peaks observed for the K form of rifaximin (HERO files Fig. 2 and Fig. 3) 7 (85.3513,34)5020, | without luggage /!Y777777777777168 11111 (19.91-20.66)5020 | 445850,045-429940042../-:/ | 99

Table 4

Peaks observed for the C form of rifaximin (HERO files Fig. 2 and Fig. 3)

KHARO diffractograms of rifaximin form k were indexed using our own program 55SI and are shown in fig. 4 and fig. 5. Indexing is the process of determining the size and shape of the unit cell, taking into account the position of the peaks on the diffractogram. This term got its name from assigning Miller indices to individual peaks. In most applications, the indices are less important than the unit cell size and angular parameters, which provide a link between the unit cell properties and the diffraction pattern. Indexing was confirmed and illustrated using Speskseya! version 11/01/04.

Correspondence between the positions of the possible peaks marked by bars in fig. 4 and fig. 5, and the observed peaks indicate the correct definition of the unit cell. Successful sample indexing indicates that each sample consists predominantly of a single crystal phase.

Symmetry groups corresponding to the indicated extinction symbol, unit cell parameters, and obtained quantities are summarized in Table 5. To confirm the indexing, it is necessary to determine the types of molecular packing in crystallographic unit cells. No attempts were made at the level of molecular packing.

Table 5

Preliminary indexing and received quantities of rifaximin form k 11111 ebradd/////// Ї77777777171717179011111171Ї1111111111111901сСс21С 0 zrad)7////Ї777771111111790111111111111111190с1

M/2 (Dz/formula unit) and SazNya MgO 1 xOSzNeO SazNya MgO 1 xOSzNeo The density and weight fraction of the solvent are based on the assumed composition.

The volume of rifaximin (1027 AZ/molecule) was obtained from the preliminary structure of rifaximin hydrate. Taking into account the presence of two independent molecules of rifaximin in the asymmetric unit, there remains sufficient volume for four molecules of IRA per molecule of rifaximin based on indexing. Calculated density and solvent values are given in Table 5. Table 5 lists with a range from zero to four molecules of IRA per molecule of rifaximin. The second diffractogram of KERO form k was also indexed with a volume per formula unit of 1295 A, while up to 3 moles of IRA per mole of rifaximin may be present in the available volume. Analysis of samples of form k using KE and "H-NMR showed that a sample with a similar diffraction pattern

XERO contains a small amount of water and about 2 moles of IRA per mole of rifaximin, while a similar sample after drying contains about 0.4 moles of IRA per mole of rifaximin and 0.75 95 wt. water (table 6 and table 7), respectively.

Table 6

Study of rifaximin form k immediately after receiving the VL (ShK

DSK Endo: 1242C (tach)

Endo or base shift: 2039 23.32C: crystalline, heating 52C/min. 80.19C: no noticeable change 101.99: loss of birefringence in many particles, probable crystal destruction (no melting) at - 109.29C same as at 101.990 no microscope 150.12: trace birefringence, change by 10 "/min. 203.19: isotropy, but the initial shape is preserved 213.190: deformation is observed, the beginning of cooling: th cooling with the formation of an isotropic vitreous substance

Approximately 2 moles of IRA per mole of rifaximin are present

Loss of 7.5 95 wt. when balancing at 5 95 HV - Increase by 4.6 95 wt. from 5 to 95 95 VN

Water balance (MV) | loss of 12 95 wt. from 95 to 5 25 VN

Total mass loss - 14.9 95 (equivalent to "2 moles of IRA) and Endo - endotherm.

Table 7

Study of rifaximin form Kk after drying oneyaenium 0

Water balance (MB) Increase by 7.7 95 wt. from 5 to 95 95 VN

Loss of 11.0 95 wt. from 95 to 5 95 VN

Both of the CHARO diffraction patterns discussed above represent a single phase of rifaximin, designated as the k-form. Because the k-form is a variable solvate, the unit cell parameters can change when expanded or compressed to accommodate the solvent. The position of the XCRO peaks is a direct result of the unit cell parameters and thus a single XCRO diffractogram will not be representative of the crystalline form, but simply a snapshot of the shape at a single position, but can still be used to identify the shape. Thus, if a material is found to have the same XKRO diffraction pattern, it can be identified as the k form.

Similarly, materials that fall into the Kk form index can also be identified as k form. Peak lists are presented for the two diffractograms above and combined in Table C and Table 4 to provide ranges of peak positions. It should be noted that these ranges illustrate only the typical positions of the peaks observed for the K form, and do not necessarily establish the upper and lower limits of the positions of the peaks of the K form.

Additional research

Additional data of the study of the newly obtained k-form of rifaximin are presented in fig. 6-9 and are listed in Table 6.

DSC and TG thermograms of form k are shown in fig. 6 and 7, respectively. The absence of a melting endotherm on the DSC thermogram also indicates that form k may be a non-stoichiometric solvate. Loss of birefringence was observed from about 1022C in a high-temperature microscope, and deformation was noted above about 2132 (Fig. 8, Table 6).

Moisture sorption data for rifaximin form k are shown in fig. 9. An initial mass loss of 7.5 95 was observed during equilibration in conditions of 5 95 EN. The material showed a 4.6 95 mass gain from 5 95 KN and a 12 95 mass loss from 95 to 5 95 KN. The total mass loss was about 14.9 95, which is consistent with the loss of about 2 moles of IRA. The XERO diffractogram of the sample after moisture sorption (Fig. 10) indicates that the material is disordered, as judged visually by the presence of extended reflection peaks and an increase in the baseline.

Form k after drying

Additional data of the study of samples of rifaximin form k after drying are presented in fig. 11-14, and are given in table 7 and table 8.

Table 8

Research under stress conditions of rifaximin form k after drying

DSC and TG thermograms of form k after drying are shown in fig. 11th fig. 12. The absence of a steep melting endotherm on the DSC thermogram also indicates that the Kk form may be a non-stoichiometric solvate.

Moisture sorption data for rifaximin form k after drying are shown in fig. 15 and are given in Table 7. An initial mass loss of 0.1 95 was observed during equilibration in conditions of 595 HV.

The material showed an increase in mass by 7.7 95 from 595 KN and a loss of 11 95 mass from 95 to 5955 VN.

The total mass loss was approximately 3.3 95. The XKRO diffractogram of the sample after moisture sorption in Fig. 16 indicates that the material is disordered, as judged visually by the presence of broadened reflection peaks and increased baseline.

The kappa form (k) was obtained by dissolving the alpha form (0) in isopropanol at loadings in the range of 57-197 mg/ml, followed by mechanical mixing.

Form k was identified as a variable system, the parameters of the unit cell of which can change as a result of expansion or compression during the inclusion of solvent molecules. Several XPO diffractograms obtained on different samples allow us to predict that there was some range for the reflection peaks observed in the Kk form. Indexing was obtained on two representative diffractograms of ХКРО form Кк, but they do not necessarily indicate the upper and lower limits of the range. Rather, they should be considered as two separate examples of k-form series. A theoretical calculation based on indexing indicates that k-form can accommodate up to 4 moles of IRA per mole of rifaximin according to the free space inside the unit cell. One sample contained two moles of IRA per mole of rifaximin, as well as a small amount of water, according to H-NMR and Karl-Fischer titration. Another sample, whose unit cell volume was smaller by about 75 AZ, contained 0.4 mole IRA per mole of rifaximin and 0.76 95 wt. water.

Indexing showed that form k is indeed a variable solvate, the structure of the unit cell of which is capable of expansion and/or compression when different amounts of IRA are placed.

The absence of a steep melting endotherm on DSC also confirms the non-stoichiometric nature of the k form.

B. Computational methods 1. Identification of powder X-ray diffraction peaks

The data presented in this report include X-ray diffraction patterns with marked peaks and tables with peak lists. Usually, in a scientific report, the range of collected data is given, in which the data is presented first and does not depend on the equipment. In most cases, peaks within a range up to about 302 29 were selected. Although the peaks are marked on the diffractograms and listed in the tables, for technical reasons different algorithms were used to round each peak to the nearest 0.12 or 0.012 26 , depending on the equipment used for data acquisition , and/or the original peak resolution. Peaks identified in the tables should be used for reporting purposes. The positions of the peaks along the X-axis (7,268) in the figures and in the tables were determined automatically using our own program (RacegpomMaisy "m 3.0.4) and were rounded to one or two symbols, meaning after the decimal point based on the above criteria. Variations in the positions of the peaks are shown within x0.22 28 based on the recommendations given in O5R description of variability in powder X-ray diffraction (pied 5iage5 Rpaptasoreia,

OBR 32, ME 27, MoI. 1, ro. 392, 2009). The accuracy associated with any particular measurement given in this description has not been determined. Also, extraneous measurements made on independently prepared samples on different instruments can lead to variation greater than x0.12 289. For the lists of interplanar a distances, the wavelength used to calculate the a-intervals was 1.541874 Å , the weighted average value of the wavelengths of Sy-Kai and Sy-Cog. Variability associated with a-interval estimates was calculated according to the O5R recommendation, in each a-interval, and presented in the corresponding data tables.

For samples with only one XCRO diffractogram and no other means of assessing whether the diffractogram provides a good approximation of the average in the powder, the peak tables contain data marked only as "Notable Peaks". Such peaks represent a subset of the entire list of observed peaks. Prominent peaks were selected from the observed peaks, revealing mostly flat, non-overlapping peaks with high intensity.

If several diffractograms are available, estimates of particle statistics (P) and/or preferred orientation (PO) are possible. The reproducibility of XKRO diffractograms from a set of analyzed samples on one diffractometer indicates that the statistical data of the particles are reliable. The constancy of the relative intensity of XKRO diffractograms obtained on several diffractometers indicates

From good orientation statistics. Alternatively, the observed XKRO diffraction pattern can be compared with a theoretical XKRO diffraction pattern based on the single crystal structure, if possible. Two-dimensional scatterplots using area sensors can also be used to estimate RB/RO. If the effects of RzZ and PO are insignificant, then the XKRO diffractogram is representative of the average intensity in the powder for the sample, and prominent peaks may be marked as "Representative peaks". Generally, the more data collected to determine Representative Peaks, the more confidence one can have regarding the classification of such peaks. "Characteristic Peaks", if they exist, are a subset of the Representative Peaks and are used to distinguish one crystalline polymorph from another crystalline polymorph (polymorphs are crystalline forms having the same chemical composition).

Characteristic peaks are determined by evaluating which representative peaks, if any, are present in one crystal polymorph of a compound compared to all other known crystal polymorphs of a given compound within 50.2 29. Not all crystal polymorphs of a compound necessarily have at least one characteristic peak .

S. Instrumental methods

The following methods have not been validated for compliance with 21 SEC211.165(e). 1. Differential scanning calorimetry (DSC)

DSC was performed using a differential scanning calorimeter TA

Ipbigitepiye 22000. Temperature calibration was performed using the MİZT standard of indium metal. The sample was placed in an aluminum DSC crucible, covered with a lid, and the weight was accurately recorded. A weighted aluminum crucible, set up as a sample crucible, was placed on the comparison side of the cell. The data acquisition parameters and crucible configuration for each thermogram are shown in the image in the Data section of this report. The method code on the thermogram is an abbreviation for the initial and final temperature, as well as the heating rate; for example, 25-250-10 means "from 252С to 2509Сb in steps of 109С/min". The following table lists the abbreviations used in each image for the crucible configurations:

Abbreviations (in notes) Meaning

IR The lid is perforated with a laser, but the lid is hermetically closed

NOR The lid is hermetically closed and laser-perforated (o; The lid is crimped

Mo The lid is not crimped 2. Dynamic vapor sorption (DSP)

Vapor sorption data (SP) were automatically collected on the MTI 5BA-100 vapor sorption analyzer. Massi and

PVP were used as standards for calibration. The samples were not dried before analysis. Sorption and desorption data were collected in the range from 5 to 95 95 KN with increments of 10 95 KN in the nitrogen stream.

The equilibrium criterion used for analysis was a weight change of less than 0.0100 95 after 5 minutes with a maximum equilibration time of 3 hours. The data were not adjusted to take into account the initial moisture content of the samples. 3. High-temperature microscopy

High-temperature microscopy was performed using a Hipcat stage (ETIK 600) with a TM593 controller installed on a Heiss OM GIR microscope equipped with a 5РОТ Ipzidpi color digital camera. Temperature calibration was performed using О5Р melting temperature standards. The samples were placed on a cover glass and the sample was covered with another cover glass. When the table was heated, each sample was visually observed using a 20x0.4 M.A. long-focus lens. with crossed polarizers and a first-order red compensator. Images were obtained using the 5ROT program (m.4.5.9). 4. Infrared spectroscopy (IR)

IR spectra were obtained on a Madpa-Ii 8602 spectrophotometer with Fourier transform (IR-FP) (Tpegpto Misoie), equipped with an Emeg-Sio source of the mid- and far-IR range, an extended-range potassium bromide (KVH) beam splitter, and a detector based on deuterated triglycine sulfate (0105). The wavelength was checked using the 1921 MIZT KM (polystyrene). A prefix broken total internal reflection (PPVV) (Tpypaegdote"mMm, Trpepto Zresiga-Tesp) with a germanium (se) crystal was used for data collection. Each spectrum is 256 co-added scans collected at a spectral resolution of 4 cm". The background data set was obtained with a pure Ce crystal. The Id 1/K spectrum (K - reflection) was obtained by dividing the two specified data sets by each other.

From 5. Titration by the Karl-Fischer (KE) method

Coulometric Karl-Fisher (KE) analysis for the determination of water was carried out using the Meshsheg Toiedo 0I39 KE titrator. A blank titration was performed before the analysis. The sample was prepared in an atmosphere of dry nitrogen, in which approximately 1 gram of the sample was dissolved in 1 ml of dry reagent NuagapaI-Soshotai AO in a pre-dried vial. The entire solution was added to the KE coulometer through the membrane and stirred for 10 seconds. Then the sample was titrated with the help of a generator electrode, which gives iodine as a result of electrochemical oxidation: 21I-iI2-2e. To ensure reproducibility, two replicates were obtained. 6. Proton NMR spectroscopy a. 10 N NMR spectroscopy in solution (Z5CI)

The NMR spectra of the solutions were obtained using a Magiapum "EMmOMmA-400" spectrometer.

Samples were prepared by dissolving approximately 5-10 mg of sample in SOHC containing TMS.

The data acquisition parameters are shown on the first spectrum in the Data section of this report. r. 10'H'NMR spectroscopy in solution (505, Ips.)

One "H-NMR spectrum in solution (IM5 228228, file 389420) was obtained in Zresig! Raia

Zegmise5 (Spatraidp, I) at 252C on the Magiapum spectrometer "MOM A-400 at the Larmorov frequency "H 399.796 MHz. The samples were dissolved in SOCI. Spectra were obtained with a 1H pulse duration of 6.0 μs, with an interval between scans of 5 seconds, a spectrum width of 10 kGu with 35K data points and 40 jointly added scans. The free induction decay (FID) was processed at 64K points and with an exponential line broadening factor of 0.2 Hz to improve the signal-to-noise ratio. 7. Solid state NMR spectroscopy (NMR-TT)

Solid-phase "3 NMR spectra in the mode of cross-polarization and magic angle rotation (KP/OMK) were obtained at ambient temperature on a MapapumtIMmomA-400 spectrometer (Larmor frequencies: 3С-100.542 MHz, "Н-399.787 MHz). The sample was placed in a 4 mm rotor made of zirconium dioxide of the REMSIA! type. and rotated at 12 kHz at the magic angle. The data acquisition parameters are shown on the first spectrum in the Data section of this report. The first three RIO data points were obtained by back extrapolation using a linear predictive algorithm

MMME to obtain a flat baseline. The chemical shifts of the spectral peaks were correlated with the external standard of the resonance of the carbonyl carbon of glycine at 176.5 ppm. 8. Thermogravimetry (THA)

TGA analyzes were performed using a thermogravimetric analyzer TA Ipzigitepib 2950 or 050001. Temperature calibration was carried out using nickel and AIIshpei "M,

Each sample was placed in an aluminum crucible. The sample was hermetically closed and a hole was made in the lid (only for 205000), after which it was placed in the TG furnace. The furnace was heated under nitrogen. The data acquisition parameters for each sample are shown in the image in the Data section of this report. The method code on the thermogram is an abbreviation for the initial and final temperature, as well as the heating rate; for example, 25-350-10 means "from 252C to 3502 in steps of 102C/min." 9. X-ray powder diffraction (XPRD) a. Diffractometer VgyKeg 0-8 Oivsomeg

XKRO diffractograms were obtained using the diffractometer VgyKeg Yu8 brizsomeg and the program VgyKeg5 Sepega! Agea-YuOebsesiog Oitascnop Zuzhet (SZAOOB5, m.4.1.20). The incident microbeam of Si Ka radiation was generated using a long fine-focus tube (40

KV, 40 mA), a parabolic multilayer mirror and a collimator with a double point aperture of 0.5 mm. Before the analysis, the silicon standard (MIZT KM 640s) was analyzed to check the position of the 5 and 111 peak. The sample was placed between films with a thickness of 3 μm, obtaining a portable sample in the form of a disc. The finished sample was installed in a holder attached to a movable table. A video camera and a laser were used to establish the investigated area intersecting the incident beam in the illumination geometry. The incident beam was scanned and selectively split to optimize sampling and orientation statistics. A beam absorber was used to reduce the background from air. The diffractograms were obtained using a two-dimensional NI-5TAK "M detector, located at a distance of 15 cm from the sample, and were processed using the SAOOBZ. The intensity of the ZABOB image of the diffractogram was integrated and displayed as a function of 28.

From the Ipe Diffractometer! KhKO-3000

XKRO diffractograms were obtained using an IpeI XKO-3000 diffractometer. The incident beam of X-ray radiation was generated using a fine-focus tube and a parabolic multilayer mirror. Before analysis, a silicon standard (MIZT ZEM 640s) was analyzed to check the position of the Z 111 peak. The sample was placed in a thin-walled glass capillary and a beam absorber was used to reduce the background from air. Diffractograms were obtained in the transillumination geometry using the UMipay m.6.6 program and the position-sensitive sensor Edzipoh with the 29 range of 1209. p. RAMaiuis diffractometer! H'Regi RKO MRO

XKRO diffractograms were obtained using a diffractometer of RAMaiuis!I Khregi RKO

MRO using an incident beam of SiKa radiation generated when using a long, fine-focus Oriich source. An elliptical multilayer mirror was used to focus SiKa X-rays through the sample and onto the sensor. Before the analysis, the silicon sample (MIZT KM 640s) was analyzed to check the position of the 5 and 111 peak. The sample was placed between films with a thickness of 3 μm and analyzed in the transmittance geometry. A beam absorber was used to reduce the background created by the air.

Soller slits for incident and diffracted beams were used to minimize broadening due to axial deviation. Diffractograms were obtained using a scanning position-sensitive sensor (X'Siega(g), located at a distance of 240 mm from the sample, and the program Oaia SoiPesiog m. 2.26.

Example 2: Rifaximin:piperazine co-crystals

Both rifaximin:piperazine co-crystals were isolated only from solvent systems containing acetonitrile, and they existed in the stoichiometric ratio of rifaximin:piperazine 21 according to proton NMR (Table 9 and Table 10).

Table 9

Screening of the co-crystal with piperazine

Molar System Result

Coformer | . r y Conditions Form/description In the ratio of solvents, 1 ml of orange solids are added. -6:1 AFM d co-crystal 2

AFM particles p vacuum similar drying 3838- orange solid co-crystal 1 21-02, CT, 1 particles t peak at day -17728 grinding orange solid weak 17 AFM at 30 Hz, we particles crystalline VD in total 10 min. piperazine orange solid co-crystal 1 17 ASM ZE particles, t co-crystal birefringent 2 dark red - o. | brought into solution, sediment at the bottom; and mess; With dark orange and about refrigeration and relative to 17 acetone aggregates and very . . cabinet, 1 day g. intensive small particles, and low-angle partially peaks birefringent dry solid and substance; bright drying with and and o orange aggregates, . piperazine 17 AFM lowered - co-crystal 1 cluster and very pressure 7 min. school small particles, non-birefringent solid matter present; dark orange, morphology about MO M/АСМ, 1 | unknown and small. 2 acetone t. and co-crystal 1 day number of small plates, birefringent; aggregates, non-birefringent dry solid matter; reddish- piperazine brown color,

MO mm/ASM, 4 irregular. 2 rom m regular co-crystal 2 d particles and aggregates, birefringent (possibly single crystals) brown spherulites with very fine needles and irregular and

MO M/ASM, From plate aggregates co-crystal 1 21 rom mk ' | same co-crystal days are birefringent; 2 (single crystals may be present)

- | brown aggregates, seeded! m/rifaximin, birefringent 2 rum MO M/АСМ, Z on the edge (no co-crystal 2 - single days . crystals) drying at orange aggregates and about ASM, In r very small co-crystal 1 reduced! particle scaling, partially | (Rapaiuiisai) pressure 6 min. and birefringent and orange, very , AFM, drying at small particles and co-crystal 1 5 reduced scaling aggregates, partially | (Rapaiuiisai) pressure "8 min. . birefringent

Table 10

Study of the rifaximin:piperazine co-crystal

HARO wide endo 116, possible small exo 159 or deck B sample 1 small endo 170

Loss of 8.35 95 mass from 25 to 1909 "NYM ratio of rifaximin:piperazine 2:71, possible presence of acetonitrile

HARO sample 2 with moderate probability of crystals; size limit

P (initial assessment) | crystals

ZzoxHAor data not obtained, the size of the crystals is too small

KHARO co-crystal 1 "I co-crystal 2 sample Z zh o, . . low probability of crystals (initial assessment)

HARO (Rapauiisa! rifaximin:piperazine co-crystal 271, H-NMR solvents absent, minor presence of impurities sample 4 wide endo 108, small wide endo 173

Loss of 7.12 95 mass from 25 to 19590

Loss of 3.54 95 mass at 5 95 VN rub Increase in mass by 10.78 95 from 5 to 95 95 VN

Loss of 11.47 95 mass from 95 to 5 95 ВН sample 5, after ХВРО broad peaks, similar to co-crystal 1 « peak at «5 and ры 17726

HARO co-crystal of rifaximin: piperazine 271, solvents sample 6 "H-NMR absent, insignificant presence of impurities a. Endo - endotherm, exo - exotherm. The indicated temperatures (C) are transition maxima. Temperatures are rounded to the nearest order. r. Mass loss (95 ) at the specified temperature; grinding mass (95) is rounded to 2 decimal places; temperatures are rounded to the nearest order.

Co-crystal 1 was obtained mainly in experiments in which the solid was thoroughly dried (usually under reduced pressure in a vacuum filtration process), whereas 5 co-crystal 2 was usually observed when the materials were not dried so thoroughly. In addition, vapor stress of co-crystal 1 in acetonitrile caused transformation to co-crystal 2, and vacuum drying of co-crystal 2 resulted in material similar to co-crystal 1 (with an additional peak) according to HCR analysis (Table 11). Thus, co-crystal 1 is assumed to be unsolvated, while co-crystal 2 probably contains acetonitrile. Proton NMR data for each co-crystal were then obtained in SOCI, with both spectra showing the absence of solvents, although it is likely that the break between HCR and NMR analyzes resulted in desolvation of co-crystal 2.

Table 11

Stress of co-crystal 1 of rifaximin:piperazine

Form/description Result of HARO. orange, slightly moist hard.

M5 M/АСМ 7 days r "TR rd co-crystal 2 substance

UvmASM

From the bottom of the dry orange substance wide peaks, similar

In co-crystal 1, the same peak at 5929 has broad peaks similar to 75 96 ВН 1 week | dry orange substance. She o zhd URR R co-crystal 1 «h peak at 5929 and broad peaks, similar to 2 weeks dry orange substance. and about the co-crystal 1 "same peak at 5929 dry orange substance АРИ, form 8-1 -97 965 ВН dry orange substance АРИ, form 8-1 dry orange substance нн

The particleboard of co-crystal 1 indicates that the material is very hygroscopic. XRD of the material after PCD showed a diffraction pattern with broad peaks similar to co-crystal 1, with the presence of additional peaks at approximately 5 and 17228 (table 10, fig. 17).

Stress relative humidity experiments with co-crystal 1 at approximately 75 95 ВН also resulted in material exhibiting an XKRO diffractogram with broad peaks similar to co-crystal 1 with the presence of an additional peak at approximately 5228 (Table 11, Fig. 18). Conversion to the hydrated form of rifaximin was observed for all pools at approximately 97–95 HV.

The rifaximin:piperazine co-crystal 21 was found in two forms: the unsolvated/hydrated form, co-crystal 1, and the acetonitrile solvate form, co-crystal 2. Information regarding the preparation and study of the two co-crystals is provided in Table 12 below. The diagram below shows the relationship between co-crystals.

Table 12

Preparation of rifaximin co-crystals

Co-crystal of rifaximin: Obtaining Properties Conducted studies of piperazine deposition with AFM unsolvated/ hydrated KERO, DSK, TGA, DSP, acetone, MO with AFM - - i

And hygroscopic proton NMR, solid phase

CS with AFM, drying at - - single-crystal phase NMR, as well as IR and Raman - reduced pressure - - - - : co-crystal 1 : : : unstable in contact with spectroscopy (with release, probably desolvation : - : mA - with water, INCREASED HUMIDITY AND peaks) of co-crystal 2 under the following conditions: - - during pressing, HERO is successfully indexed (probably destroyed from the surrounding environment when the peaks are released) environment p destroyed p heating

ASM solvate (1 mol) HARO, DSK, TGA, protonic

VS with AFM single-crystal phase NMR, as well as IR and Raman co-crystal 2 rem, MO with AFM is unstable under the conditions of spectroscopy about the selection - environmental peaks)

U5 of co-crystal 1 with AFM go to - - probably destroyed during XERO successfully indexed (with peak selection on heating)

Table 13

Acronym abbreviation

Solvent

Methods

Techniques of pad |traduy///////////777777777777777771111111111111111111 endo fendotvrm//////777777777777711111111111111111111111s1s

Analysis of raw materials

After receiving rifaximin, its analysis was performed. The material was crystalline, showing, according to the KhKRO, the previously known dry a-form. The PMR spectrum of the material corresponded to the structure. Solid-state NMR, IR, and Raman spectra were also obtained for comparison.

Solid-phase NMR, IR and Raman spectra of piperazine were also obtained for comparison with the corresponding data of co-crystals of rifaximin and piperazine obtained in the screening process.

Non-automated co-crystal screening experiments were calibrated against rifaximin using piperazine (Table 14).

Table 14

Advanced Rifaximin Co-Crystal Screening Solvent Ratio 17711171 Added! mlASM| orange solid 14 ASM FE orange solid, co-crystal 1 tbsp

And birefringent co-crystal 2 - dry substance; bright drying at - orange, aggregates and very - reduced pressure and co-crystals 1 -7 min small particles, no

And birefringent solid matter is present; dark orange, unknown 21 acetone MO m/ASMY, 1 day - morphology and small co-crystal 1 number of small plates, birefringent; aggregates, non-birefringent dry substance; reddish-brown, irregular - 21 rom MO m/ASM, 4 d particles and aggregates, co-crystal 2 piperazine - - birefringent (possible single crystals) brown spherulites with very fine needles and irregular - 21 rom MO mm/ASM, From the bottom of the cup, clusters , co-crystal 1 i, co-crystal 2 is birefringent; (possibly single crystals) seeded brown aggregates, 21 rom m/rifaximin MO | birefringent along the edge co-crystal 2

U/АСМ, Z dni (no single crystals)

AFM, drying at orange aggregates and very co-crystal 1 scaling | under reduced pressure small particles, partly (Rapaiuysai)

At -6 min. birefringent

AFM, drying at orange, tiny particles and co-crystal 1 5 scaling | REDUCED pressure from congestion, partially (Rapaiuysai)

At 8 min. birefringent a. The given relationship is АРИ: coformer.

Co-crystals were prepared with piperazine. During the entire screening, two forms of this co-crystal, determined by HCR, were detected and designated as co-crystal 1 and 5 co-crystal 2 (Fig. 19).

Table 15

Study of rifaximin:piperazine co-crystals

Co-crystal Technique Analysis/Result co-crystal 2 KHARO co-crystal 2 is wide endo 116, possibly small exo 159 or small endo doc 170 possible THAS Weight loss by 8.35 95 from 25-1902C co-crystal 2 "NIAM rifaximin:piperazine ratio 2:1, possible presence of acetonitrile co-crystal 2 KHARO co-crystal 2

SHKO (initial I od, no I I possible ots) moderate probability of crystals; limitation of crystal size co-crystal 2 "shVo data not obtained due to too small size of crystals co-crystal 142 KHARO co-crystal 1 same co-crystal 2 . possible ZSHKO (initial low probability of crystals co-crystal 142 oz.)

HARO. (Rapauisa)) co-crystal 1 co-crystal of rifaximin:piperazine 2:11, solvents not 1IN-NMR! present, slight presence of impurities deke wide endo 108, small wide endo 173 co-crystal 1 TGA: mass loss 7.12 95 from 25 to 195250 mass loss 3.54 95 at 5 95 VN dsp mass increase by 10.78 95 from 5 to 95 95 AN weight loss 11.47 95 from 95 to 5 95 AN

The NMR-TT spectrum was obtained

IR spectrum obtained

Raman spectrum obtained blurred maxima, similar co-crystal 1 "from peak reaches - KHARO I maximum in 5 and 177229 co-crystal 2 KHARO co-crystal 2 possible 1IN-NMR" co-crystal of rifaximin: piperazine 2:11, solvents are not present co-crystal 1 '

HAR. . (Rapa)uisa)) minor presence of impurities co-crystal 2 co-crystal 2 1IN-NMR co-crystal of rifaximin:piperazine 2:1, 1 mol of ASM present, minor presence of impurities probably IV! spectrum obtained co-crystal 2

Mo yvinnitsi 2 Vatap" spectrum obtained - KHARO broad peaks, similar to co-crystal 1 " peak at "5 and 17229 a. Due to the natural tendency of co-crystal 2 to rapid desolvation and transition to another form when in ambient conditions, any break between HKERO and other methods of analysis adds uncertainty about the form that is actually analyzed. p. Temperatures given (C) are transition maxima. Temperatures are rounded to the nearest order. p. Mass loss (95) at a given temperature; mass change (to) rounded to 2 digits after the decimal point; temperatures are rounded to the nearest order. a. Solvent: deuterated DMSO. e. After initial single crystal evaluation, the sample was opened and placed in a vial of hexane for 2 days for vapor stress in an attempt to separate possible single crystals from the walls of the vial; however, after stress, no accepted single crystals were observed.

Her. solvent: deuterated chloroform n. solvent: deuterated chloroform. 6 days passed between the KhKRO and PMR studies. and. solvent: deuterated chloroform. ). Samples were analyzed soon after isolation.

Rifaximin:piperazine co-crystals

Obtaining and relation of co-crystals

Both rifaximin:piperazine co-crystals were isolated only from solvent systems containing acetonitrile, while they were present in a 2:1 rifaximin:piperazine stoichiometric ratio according to proton NMR data (Table 14, Table 15, Fig. 31 and Fig. 43). The HAKRO overlay of both co-crystals is shown in Fig. 19. Detailed procedures for obtaining each co-crystal are given below.

Although both co-crystals were observed from the crystallization reaction and vapor diffusion experiments with acetonitrile, co-crystal 1 was also formed by direct precipitation in acetonitrile, while the slow evaporation experiment in acetonitrile, as well as vapor diffusion in dichloromethane using acetonitrile as an antisolvent, gave mixtures of co-crystal 1 and of co-crystal 2. Scaling up the crystallization reaction experiment in acetonitrile led to co-crystal 1. It was then noted that co-crystal 1 was formed mainly by thorough drying of the solid material (usually under reduced pressure in the vacuum filtration process), while co-crystal 2 was usually observed, when the materials were not dried so thoroughly, indicating that co-crystal 2 may be an acetonitrile solvate.

The primary proton NMR spectrum of a possible co-crystal 2 (the form is not precisely determined due to the tendency of co-crystal 2 to undergo transformation into another form under environmental conditions, as described below) obtained in deuterated DMSO was inconclusive in determining the acetonitrile content due to significant overlap of peaks in the region, of interest, "2.07

An experiment in which co-crystal 2 was subjected to vacuum drying at ambient temperature for 1 day gave a material similar to co-crystal 1 with the presence of an additional peak at approximately 17229 ХКРО (Table 16, Fig. 20).

Table 16

Vacuum drying of co-crystal 2 of rifaximin:piperazine on KTtday orange taerda 000SpKNNe 0C20-LODONY co-crystal TU pZhlrys yayu

CT, 1 day 7 I I substance a. Solvent: deuterated DMSO.

Proton NMR of this sample, also obtained in deuterated DMSO (the analysis was performed before obtaining the result of the original NMR spectrum), also showed the overlap of peaks in the region where acetonitrile should have appeared, which turned out to be inconclusive with respect to the determination of the solvent content. Thus, subsequent NMR spectra were obtained in deuterated chloroform,

Zo to ensure the separation of the peaks to be able to estimate the acetonitrile content.

Proton NMR of co-crystal 1 obtained in deuterated chloroform did not reveal the presence of any solvent or water, indicating that this material is not solvated/hydrated (Fig. 31, Table 15). Based on the obtained result and previous observations, co-crystal 1 was subjected to vapor stress in acetonitrile for 7 days, which led to the transformation into co-crystal 2 (table 17).

Table 17

Peak separation of crystal 1 of rifaximin:piperazine and orange, slightly moist solid and . dark orange, a little wet. - 7 days, part of the sample co-crystal 22

KOSTI ik lava KOM Ek co-crystal 1 "with peak at 45229 co-crystal 1 "with peak at 5229 axially -- three -- oraorayuyuvarechnyuvina 000 Lo fFORMaV 9ЗН86Й С 97 95 ВН a. 65. The sample stood (closed with a lid) under ambient conditions for approximately 5-6 hours prior to HCR analysis. with. ChKRO analysis was performed quickly after sample selection.

Solvent was not present in this material according to proton NMR; however, it is likely that the break between XCR and NMR studies led to desolvation of co-crystal 2.

Repetition of this paired stress experiment in which co-crystal 1 was subjected to stress conditions for 24 days resulted in the formation of co-crystal 1 according to HCRO analysis, again probably after a gap of about 5-6 hours between solid extraction and analysis

ХКРО Based on these experiments, they concluded that co-crystal 2 quickly desolvated upon contact with ambient conditions. Upon desolvation, co-crystal 2 probably transformed into co-crystal 1 after a relatively short exposure period (e.g., 5-6 hours), while longer exposure times (e.g., 12 days) resulted in transformation into a material similar to co-crystal 1, but demonstrating broad peaks with additional peaks at approximately 5 and 17228 according to KhKRO data (table 15).

Co-crystal 1 was again subjected to stress with acetonitrile vapors for 7 days, and analyzes of HCRO and

NMR was performed after a short period of time (-1 hour) after the isolation of solid material. In co-crystal 2, the presence of 1 mole of acetonitrile was detected according to the results of XKRO and proton NMR of the sample conducted in deuterated chloroform (Fig. 30). Further analysis of co-crystal 2 was performed shortly after the isolation of the vapor-stressed samples.

Analysis of co-crystals

Data from a study of rifaximin:piperazine co-crystals are shown in Table 16. As previously discussed, co-crystal 2 was approximately the acetonitrile solvate and showed a tendency to desolvate upon exposure to ambient conditions. It should be noted that in the first column of Table 15, the co-crystal indicated as "possible co-crystal 2" could have undergone a transformation into another form during the period that passed between ХКРО and additional methods of analysis.

Similarly, "possible co-crystal 1" refers to a sample that is believed to have formed during the transition of co-crystal 2 to co-crystal 1 under ambient conditions. Finally, the designation "presumed co-crystal 2" refers to material quickly analyzed after isolation, but HERO data were not obtained to confirm the shape.

Co-crystal 1

2. High-resolution HAKRO diffractogram of co-crystal 1 is shown in Fig. 19.

The diffractogram was successfully indexed, indicating that the sample consists of a pure, single-crystal phase (Fig. 24). Peaks were selected on the XKRO diffractogram. One diffractogram of Rapaimisai was analyzed for this material! and one diffractogram of Ipeia, and therefore the predominant orientation and statistical effects of the particles could be assessed by comparing several diffractograms. Minor effects of preferred orientation were observed, although the samples appeared to show good fit. The observed peaks are shown in fig. 25 and fig. 26, and representative peaks are listed in FIG. 27.

Wide endotherms on the DSC thermogram, combined with constant mass loss according to TGA, probably indicate that the co-crystal is destroyed when heated (Fig. 28).

Analysis of chipboard indicates that the material is very hygroscopic (Fig. 29). Approximately 11 95 mass increase was observed during sorption from 5 95 to 95 95 KN, while all the indicated mass was lost in the desorption process. X-ray diffraction of the material after chipboard showed broad peaks similar to co-crystal 1, with the presence of additional peaks at approximately 5 and 17226 (Fig. 18).

The proton NMR spectrum of co-crystal 1 is shown in Fig. 31. The spectrum showed a rifaximin:piperazine stoichiometry of 2:1 and no solvents. The presence of small peaks throughout the spectrum indicates partial decomposition of the molecule in this solvent.

The solid phase NMR spectrum of the material is unique for the co-crystal, compared to the spectra of the original materials (Fig. 32). IR and Raman spectra were obtained and subjected to peak selection (Fig. 33-36). The overlay of IR and Raman spectra on the corresponding spectra of the starting materials and co-crystal 2 is shown in Fig. 21 and fig. 22.

Co-crystal 2

The high-resolution XKRO diffractogram of co-crystal 2 is shown in Fig. 37. This diffractogram, as in the case of co-crystal 1, was also successfully indexed, indicating that the sample consisted of a pure, single-crystal phase of the solvated material (Fig. 38). Peaks were selected on the XKRO diffractogram. One diffractogram of Rapaiuis was analyzed for this material! and one diffractogram of Ipeia, and therefore the predominant orientation and statistical effects of the particles could be assessed by comparing several diffractograms. The good agreement of the diffractograms indicates that the observed samples were not affected by the orientation and statistical effects of the particles. The observed peaks are shown in Fig. 39 and fig. 40, and representative peaks are listed in FIG. 41.

For material that is a possible co-crystal of 2, the constant mass loss of about 8.35 95 observed by TGA from about 25 to 1902C, combined with a very broad endotherm at about 1162C on the DSC thermogram, roughly indicates decomposition of the co-crystal (Fig . 42).

The proton NMR spectrum of co-crystal 2 indicates that the material consists of a 2:1 rifaximin:piperazine co-crystal with approximately 1 mole of acetonitrile (Fig. 43). Similar to the spectrum of co-crystal 1, the presence of small peaks throughout the spectrum indicates partial decomposition of the molecule in this solvent.

The IR spectrum of co-crystal 2, with marked peaks, is shown in Fig. 44 characteristic peaks observed are listed in fig. 45. Although most of the IR peaks were similar to those of rifaximin, the presence of two characteristic peaks unique to co-crystal 2 was observed.

Similarly, the Raman spectrum, also with marked peaks, is presented in Fig. 46, and lists of characteristic peaks and observed peaks are shown in FIG. 47. Several peaks unique to co-crystal 2 (for example, characteristic peaks) were observed in the Raman spectrum. The overlay of IR and Raman spectra on the corresponding spectra of the starting materials and co-crystal 1 is shown in Fig. 21st fig. 22.

Indexing of rifaximin:piperazine co-crystal 1

Indexing and refinement of the structure are computational studies. The indexed XERO diffractogram of rifaximin:piperazine co-crystal 1 is shown in Fig. 24. Correspondence between the positions of possible peaks marked by bars in fig. 24, and the observed peaks indicate the correctness of the determination of the unit cell. Successful indexing of the diffractogram indicates that the sample consisted mainly of a single crystal phase. Symmetry groups consistent with the specified extinction symbol, unit cell parameters, and obtained quantities are summarized in Table 18.

Table 18

Indexing and obtained quantities for co-crystal 1 of rifaximin:piperazine nie: 7 I OO To OO ped TO: Art. I PO To OO nin z nn nyshiii t dust

M/2 (Dz/formula unit) a. The density and weight fraction of the solvent are based on the assumed composition.

Indexing of co-crystal 2 of rifaximin:piperazine

Indexing and refinement of the structure are computational studies. The indexed XRD diffraction pattern of co-crystal 2 of rifaximin:piperazine (ASM solvate) is shown in Fig. 38. Correspondence between the positions of possible peaks marked by bars in fig. C8, and the observed peaks indicate the correctness of the determination of the elementary cell. Successful indexing of the diffractogram indicates that the sample consisted mainly of a single crystal phase.

Symmetry groups consistent with the indicated extinction symbol, unit cell parameters, and resulting quantities are summarized in Table 19. The indexed unit cell volume allows for up to six moles of AFM per formula unit, assuming that the stoichiometry of rifaximin:piperazine corresponds to the ratio 2:1.

Table 19

Indexing and obtained quantities for co-crystal 2 of rifaximin:piperazine. The density and weight fraction of the solvent are based on the assumed composition.

Effect of relative humidity on co-crystal 1

Co-crystal 1 was subjected to stress in conditions of approximately 75 95 and 97 95 relative humidity (RH) at ambient temperature, while pools were prepared after 3 days, 1st week and 2 weeks (Table 18). Dry orange particles were observed under each condition. The transition to the B-1 form of rifaximin according to ХКРО was observed at 97,956 KN for 3-day and 1-week pools; the solid material isolated after 2 weeks was not analyzed, but was assumed to have undergone a shape transition as well. 3-day, 1-week, and 2-week pools at 7595 ВН showed a similar diffraction pattern of ХКРО: broad peaks, similar to co-crystal 1, with the presence of an additional peak at approximately 5229 (Fig. 48). These experiments show that the co-crystal is unstable under conditions of increased KH.

Determining the suitability of co-crystal 1 for solubility studies

In order to be able to measure the solubility (equilibrium or kinetic) of a co-crystal in water, it must remain intact in contact with aqueous conditions for some period of time. If it dissociates or changes form after brief contact with water, its characteristic dissolution can be introduced as an alternative to solubility, which measures the dissolution of the co-crystal precipitate; however, the co-crystal should not change shape at

From pressing.

In the case of co-crystal 1 of rifaximin:piperazine, transformation into VD-1 form of rifaximin was observed after 5 minutes (as well as after 3 hours and 7 hours) of suspension in water; thus, the solubility of the co-crystal in water could not be measured (Table 20).

Table 20

Aqueous suspensions of co-crystal 1 of rifaximin: piperazine

Conditions Form/description Result ХКРО extraction of filtrate, filtering by | collected a small amount of solid | АРИ, form D-1 using a vacuum (nylon filter), substances; bright orange drying under reduced pressure "5 min. aggregates and very fine particles, not birefringent vacuum filtering bright orange aggregates and very | АРИ, form |Д-1 (nylon filter), drying at small particles, not reduced pressure «4 min (M was passed over a birefringent filter for «1 min.) filtration with the help of vacuum bright orange aggregates and very | АРИ, form |Д-1 (nylon filter), drying with small particles, not reduced pressure and in gaseous M2 Z birefringent

MIN.

When co-crystal 1 was pressed into a tablet, additional XERO peaks were observed at approximately and 172268, while the material had low crystallinity (table 21). Since the shape of the co-crystal changed as a result of pressing, the characteristic rate of dissolution was also impossible to measure.

Table 21

Experiment on pressing co-crystal 1 of rifaximin: piperazine

Conditions Form/description Result ХКРО 6.9 MPa, 1 min. dark orange and co-crystal 1 « peak brown solid at 5 and 17228, 1.s.

Attempts to grow single crystals

Numerous attempts were made to grow single crystals of rifaximin:piperazine co-crystals using vapor diffusion, sonication, solvent/anti-solvent, suspension and cooling methods, but all these experiments were unsuccessful due to the formation of very small and/or broken crystals (Table 14 and Table 22).

Table 22

Attempts to grow single crystals of a co-crystal of rifaximin piperazine solvent ratio 24 rem ultrasonic treatment in solution, tapes, plates, Yes destroyed added AFM, cooling birefringent 2 rem ultrasonic treatment in solution, M c) tapes, birefringent Yes destroyed

M/АСМ in several vials dissolved 24 rem treatment with ultrasound in solution, MO | tapes, unknown morphology, Yes destroyed mASM birefringent 24 rem ultrasonic processing in solution, MO tapes, plates, Yes destroyed mASM birefringent ultrasonic processing in solution, 21 rom vial covered with mineral oil, tapes, birefringent | So; destroyed

MO m/ASM a. This ratio is the ARI:coformer ratio.

B. Specimens observed at 50° and aliquots transferred to glass slides with needles, toothpicks and pipettes were poured into Ragafope-M and mineral oils. Observations of "non-birefringent" also indicate that extinction was not observed.

Both forms of the rifaximin:piperazine co-crystal were obtained only in 3 solvent systems containing acetonitrile, and they both existed in a rifaximin:piperazine stoichiometric ratio of 2:1 according to proton NMR data. Thermal data indicate that both co-crystals were destroyed upon heating.

Co-crystal 1 is unsolvated/hydrated and very hygroscopic according to particleboard. X-ray diffraction of the material after chipboard showed a transformation into a material similar to co-crystal 1, but with the presence of two additional peaks. Co-crystal stress under conditions of approximately 97 95 KN caused conversion to VD-1 form of rifaximin in 3 days. Under stress conditions of approximately 75 95 ВН, the solid transformed into a material similar to the material after chipboard, but with only one additional peak according to ХКРО.

Co-crystal 2 contains approximately 1 mol of acetonitrile according to proton NMR. The material rapidly desolvated (probably with the formation of co-crystal 1 or material similar to co-crystal 1) under the influence of environmental conditions. On the contrary, co-crystal 1 was transformed into co-crystal 2 under stress in acetonitrile vapor.

The CHARO diffractograms of both co-crystals were successfully indexed, which indicates that each co-crystal consisted mainly of a single crystal phase.

IR and Raman spectra were obtained for co-crystals and starting materials, as well as solid-phase NMR spectra for co-crystal 1 and both starting materials. Diffractograms of HERO and

The IR Raman spectra for both co-crystals were processed by peak selection.

Methods

Co-crystal 1 of rifaximin: piperazine

Rifaximin (2.0234 g) was dissolved in acetonitrile (8 ml) with ultrasound treatment. The solution was then added to the vial containing piperazine (0.0467 g) with stirring, immediately obtaining a clear red solution (rifaximin:piperazine molar ratio 5:1).

After stirring for about 1 minute, a large amount of sediment was observed to form a thick, opaque solution. An additional portion (8 mL) of acetonitrile was added for easier mixing and the mixture was allowed to stir under ambient conditions for 3 days. The solid phase was collected by vacuum filtration, air-dried under reduced pressure for approximately 8 minutes, and analyzed. This technique also provided reproducible co-crystal 1 in small-scale experiments.

Rifaximin:piperazine co-crystal 2

A portion of rifaximin:piperazine co-crystal 1 was transferred to a 3.75 ml vial, which was not

The flask was capped and placed in a 20 mL vial containing acetonitrile (2 mL). The vial with a volume of 20 ml was closed with a lid and left in ambient conditions for vapor stress. After 7 days, a portion of the solid material was extracted and quickly analyzed by XERO, confirming it as co-crystal 2. This technique also provided reproducible co-crystal 2 approximately after longer periods of stress. It should be noted, however, that co-crystal 2 was found to rapidly transform into co-crystal 1 or material similar to co-crystal 1 when exposed to environmental conditions.

Example 3: Obtaining and examining form 8

Form 8 was obtained by drying Form C under nitrogen for approximately ten minutes, Table 23. The nitrogen flow was sufficient to mix the solids in the container.

The diffractogram of HERO is shown in fig. 67 and was of sufficient quality for indexing, see table 23.

Table 23

Attempts to obtain selected forms of rifaximin for evaluation of drying and stability birefringent disordered particles dried under nitrogen, no birefringence drying with nitrogen, flow maintained orange-red opaque currents: solid material in the vial into fine particles, no suspended birefringence

Evaluation of drying and physical stability of form 8 was not formally included in the methodology.

Based on limited analysis, stability was assessed to some extent. The initial sample was obtained by drying form C with nitrogen. The initial diffractogram of ХКРО was obtained using parameters that do not agree with obtaining other data. The analyst re-analyzed the sample for several hours, while the transformation into form 1, fig. for.

Indexing and refinement of the structure are computational studies that were not performed according to the CCOMP guidelines. The diffractogram of XKRO form 89 of rifaximin was indexed using our own 55SI program. Indexing was tested and illustrated in use

Spekssey! version 11/01/04.

The indexed diffractogram of HCRO form 8 of rifaximin is shown in fig. 61. Correspondence between the positions of possible peaks marked by bars in fig. 61, and the observed peaks indicate the correctness of the determination of the unit cell. Successful indexing of the diffractogram indicates that the sample mainly consists of a single crystal phase. Symmetry groups corresponding to the specified extinction symbol, unit cell parameters, and obtained quantities are shown in Fig. 61. To confirm the previous indexing, it was necessary to determine the molecular packing motifs in the crystallographic unit cells. No attempts were made regarding molecular packing.

In fig. 62 shows a block diagram of the process of obtaining the eta form and the iota form, as well as mixtures of other forms from eta and iota. In one aspect, the method of obtaining the ether form of rifaximin includes precipitation of rifaximin from ethanol; drying of precipitated rifaximin under nitrogen; keeping precipitated rifaximin at elevated temperature for 30 minutes or more. In some embodiments, holding is carried out at about 402C for about 2 hours or more. In other embodiments, holding is carried out in a vacuum at about 602C for 2 hours or more. In other embodiments, drying is performed for about 10 minutes or less.

The method of obtaining the iota form of rifaximin includes precipitation of rifaximin from ethanol; drying the precipitated rifaximin under nitrogen and keeping the rifaximin at ambient temperature. In some embodiments, holding further comprises rifaximin under vacuum for an hour or more. In some embodiments, the holding additionally includes rifaximin at a humidity of about 2295 to 50 95. In other embodiments, the drying is carried out for about 10 minutes or less.

The method of obtaining mixtures of the iota form and theta form of rifaximin includes precipitation

From rifaximin from ethanol; drying of precipitated rifaximin under nitrogen; and holding the rifaximin at about 1095 KH to about 4695 relative humidity (KH) at ambient temperatures for at least one hour to about 6 hours or more. In other embodiments, drying is performed for about 10 minutes or less.

In fig. 62 shows an exemplary ХКРО of the iota shape and the dimensions of the elementary cell of the iota shape.

In one aspect, the present application provides an iota form of rifaximin having dimensions substantially similar to those shown for the iota form in FIG. 62. Fig. 64 shows the iota indexing in graphical format, where the peak positions are plotted depending on the cell volume. Indexing is described in more detail below.

In fig. 65 shows an exemplary CHCRO of the eta form and the dimensions of the elementary cell of the eta form. In one aspect, the present application provides a form of ether rifaximin having dimensions substantially similar to those shown for the iota form in FIG. 65. In fig. 65 shows eta indexing in graphical format, where peak positions are plotted against cell volume. Indexing is described in more detail below.

Example 4: Form 9

Receiving

A large-scale experiment

In one example, form 9 was obtained by drying form C in a vacuum at ambient temperature for about two hours. Form 9 may be the ethanolate according to "H-NMR. One sample contains two moles of ethanol per mole of rifaximin according to "H-

NMR, however, the volume estimated from the previous indexing of HCR indicates that the unit cell is capable of holding up to 4 moles of ethanol per mole of rifaximin. Diffractograms of ХКРО forms would be successfully indexed. Successful indexing of the powder diffraction pattern exhibited by this form provides confirmation that form 8 is a single crystal phase.

Form 9 of rifaximin was obtained in a large volume by vacuum drying of form E. In this example, 58.96 g of rifaximin was added to 300 ml of ethanol with stirring under ambient conditions. Rifaximin dissolved almost completely at first and gave a very dark red solution. With continuous stirring, the solution became lighter and turbidity increased until an orange/red paste was formed. At this moment, another 100 ml of ethanol was added. The total volume of ethanol was 400 ml. Then the suspension sample was filtered using a vacuum through filter paper under a nitrogen atmosphere (21 95

VN, 222C) and obtained a red-orange paste. At the end of the flow of the filtrate from the end of the funnel, the sediment on the filter was separated from the filter paper with a spatula, while the vacuum and nitrogen supply were not turned off. The total drying time of the sample on the filter paper was approximately 30 minutes.

The resulting dry substance was identified as form C according to the results

HACKRO. This solid sample was later dried under vacuum for about two hours at ambient temperature. XERO diffractogram after drying confirmed that the solid was transformed into form 9 after vacuum drying.

A small-scale experiment

In this example, 1 ml of ethanol was added to 251.5 mg of rifaximin. When treated with ultrasound, rifaximin completely dissolved almost immediately. But with continued sonication, a red/orange precipitate formed. Another 1 ml of ethanol was added (total volume of ethanol - 2 ml) and treated with ultrasound. A thick paste was obtained. The solid substance was isolated by filtration through filter paper and washed on the filter with 2 ml of ethanol.

The material was then transferred to a 20 mL vial covered with filter paper and stirred in the vial with a rapid stream of nitrogen for approximately 10 minutes. Free-flowing orange/red opaque fine particles were observed under a microscope (and identified as Form 89 by HCR analysis.

Research

Diffractograms of ХКРО form 9 from a large-scale experiment are shown in fig. 67.

The sample was reanalyzed by HCR after 8 days of storage at ambient conditions, and it remained Form 98.

A list of peak positions for one XCRO diffractogram of form 9 of rifaximin obtained from the small-scale experiment described above is shown in Fig. 68. Lists of observed peaks and notable peaks are included in Table 24 and Table 25, while lists of representative and characteristic peaks are not included.

Table 24

Peaks of form 9 of rifaximin observed at 5 AvYUMO | l1bizva0300 | 777777771717171717171118977s7sIs720 b4ooMmo | 13821340219...G | 1 7777 8657050084.../Г/ | 777/77/сб6бсссСс2ш1 lodvnomo | 77 в4биюююв! | 7777777777777777771716сссСсСсСс2шС lav Mo | here | 7777777777777. 777777 5y2450030.. | .7777777/7l.b6 С 1 lvotiaoMo | 77777 492650027.. | .І/ю/ю/7/7?6Э.8сСсСсСиСИЙ2Й 1 лввовоМо | 77777 4721560025...G | Yuk YyK 821 7 23310 Mo | 7777 z81700167|Y77777777777711111111718сССсС21 7 2vyvoMo | zmi |77777777777777771111718ССсС21 7 283о0Мо | 777777 zi5zYuyi: 7 | 7777777777777777711716ssssssssssss 7 288eyumo | 77777 call Y777777777777777771711718111111СсС21С

Table 25

Noticeable peaks of form 9 of rifaximin 5АвЖОМО | 63830300 |7777777111111118911СсС21С

Indexing was also obtained based on the XKRO diffractogram. Indexing is the process of determining the size and shape of the unit cell, taking into account the positions of the peaks on the diffractogram. The term got its name from assigning Miller index marks to individual peaks.

The diffractogram of XKRO form 9 of rifaximin was indexed using our own program

ZZSI and presented in fig. 69. Indexing was checked and illustrated using Spexsey version 11/01/04.

Correspondence between the positions of the possible peaks marked by bars in fig. 67, and the observed peaks indicates the correctness of the determination of the elementary cell. Successful indexing of the sample indicates that the sample consisted primarily of a single crystal phase. The symmetry groups corresponding to the specified extinction symbol, unit cell parameters, and the obtained quantities are summarized in Table 26.

Table 26

Indexing and received quantities

Form/diffractogram Form 8 of rifaximin

Family and symmetry group Orthorhombic P21212: (419 15,274 (А) 20277 32231 o(grad) "NNI NN

In (grad) "nn we (grad) in

Volume (Az/cell) 9982.3

M/2 (AzZ/(asym. unit) 12478

Estimated composition of SevNeteot hoNeO

Density (g/smu) and 1.05-y-1.29

Solvent weight fraction (90)2 0-2-19.0

Based on the presence of two independent rifaximin molecules in the asymmetric unit, there remains sufficient volume for four more ethanol molecules per rifaximin molecule.

Calculated values of density and solvents in Table 26 are listed with a range from zero to four molecules of ethanol per molecule of rifaximin. The H-NMR result showed that the analyzed sample of Form 89 contained approximately 2 moles of ethanol per mole of rifaximin (Table 27).

Table 27

Analyzes of form 9 of rifaximin in

HARO - - 8 (after 8 days of storage in ambient conditions)

Endo: 63, 106 and 2209С

Mass loss 10.9 95 to 1202С

Karl-Fischer 0.27 90 wt. of water 4 The chemical structure is not disturbed, 2 moles of ethanol per mole

H-NMR! rifaximin

Solid-phase SS-NMR pPvV-Ich 1111111 Raman////// /Received sample.7/////777777777711111111111111111СсСсС change -7.314 95 wt. at equilibrium at 5 95 VH

Water balance (MB) increased by 5.733 95 wt. from 5 to 95 95 VN loss 5.826 95 wt. from 95 to 5 95 VN

KhVRO after MV

Additional data on the analysis of rifaximin form 8 are presented in fig. 70-72 and are given in table 27.

Moisture sorption data for rifaximin form 9 are shown in fig. 71. An initial mass loss of 7.3 96 was observed during equilibration in conditions of 5 95 EN. The material showed a mass gain of 5.7 95 from 5 to 95 95 KN and a mass loss of 5.8 95 from 95 to 5 95 KN. The total mass loss was approximately 7.4 95. The XRD diffraction pattern of the sample after moisture sorption (Fig. 72) was assigned to form 1.

Example 5: Particle sizes

The forms of rifaximin have different particle sizes. The table below lists the particle sizes for the kappa and eta forms of rifaximin.

Table 28

Particle size distribution for rifaximin formulations (µm) and (µm)? (μm) with a. 10 95 of the total volume of particles is less than the particle size specified in μm. r. 50 95 of the total volume of particles is less than the size of the particles specified in μm. with. 90 95 of the total volume of particles is less than the particle size specified in μm.

Example 6: Experimental methods

Pressing

A weighed amount of this rifaximin:piperazine co-crystal was transferred into a mold

Wood and pressed using a Sagueg press under the given parameters. The resulting tablet was crushed and analyzed.

Computational methods

Indexing of rifaximin:piperazine co-crystal 1

The XRD diffraction pattern of rifaximin:piperazine co-crystal 1 was indexed using

H'Regi Nidp 5soge Riiz (X'Regi Nidp 5soge Riiz 2.2a (2.2.1)).

Indexing was checked and illustrated using Spekssey! version 11/01/04 (SpeskseiY 11/01/04; available at the address on the Internet m/mly.ssri4.as.iklAshogiaitar)

Indexing of co-crystal 2 of rifaximin:piperazine

The XRD diffraction pattern of co-crystal 2 of rifaximin:piperazine (АСМ solvate) was indexed using our own 55:51 program.

Indexing was checked and illustrated using SPpesxey version 11/01/04.

Isolation of IR peaks and Raman spectra

Peak selection was performed using Otpis version 7.2. Infrared and Raman spectra are presented for each of the starting materials and co-crystals, with all observed peaks noted. The observed peaks include all IR and Raman peaks for the form except for peaks with very low intensity and broad peaks with ill-defined maxima.

Characteristic peaks are a subset of observed peaks and are used to differentiate one crystal form from another crystal form. Characteristic peaks are determined by evaluating which, if any, observed peaks are present in one crystalline form of a compound as opposed to all other known crystalline forms of the compound within 4 cm". Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak Characteristic peaks were identified for co-crystal 2 of rifaximin:piperazine.

From Variations in peak positions are given within 52 cm", based on the accuracy of selected observed peaks and data acquisition using 2 cm" data point spacing (4 cm resolution). Extraneous measurements on independently prepared samples on different instruments may lead to variation that exceeds 52 cm".

The process of identification of powder X-ray diffraction peaks

The peak allocation data presented in this report include X-ray diffraction patterns with labeled peaks and peak lists. In most cases, peaks within a range up to about 309,296 were sampled. Although the peaks are marked on the diffractograms and listed in the tables, for technical reasons different algorithms were used to round each peak to the nearest 0.12 or 0.012 26 , depending on the equipment used to collect the data , and/or the original peak resolution. The position of the peaks along the X-axis (229) on the figures and in the lists was determined automatically using our own program (RatsegoMaisp m 3.0.1) and rounded to one or two symbols, meaning after the decimal point based on the above-mentioned criteria.

Variations in the position of the peaks are given within x0.12 28 based on the recommendations given in the O5R description of variability in powder X-ray diffraction (Spyeia egage5 Rpaptasoreia, OBR 32,

ME 27, Moi. 1, genus 392, 2009). Extraneous measurements made on independently prepared samples on different instruments may result in variations greater than 0.12 28. For interplanar spacing lists 4, the wavelength used to calculate the a-intervals was 1.541874 A, weighted average the value of the wavelengths of Si-

Kai and Si-Kog (Rpuz. German. AB5Bb(b) 4554-4568 (1997)). Variability associated with a-interval estimates was calculated according to the OBR recommendation, in each a-interval, and presented in the corresponding data tables.

If several diffractograms are available, estimates of particle statistics (P) and/or preferred orientation (PO) are possible. The reproducibility of XKRO diffractograms from many analyzed samples on one diffractometer indicates that the statistical data of the particles are reliable. Constancy of relative intensity of XKRO diffractograms obtained on several diffractometers indicates good orientation statistics. Alternatively, the observed XKRO diffraction pattern can be compared with a theoretical XKRO diffraction pattern based on the single crystal structure, if possible. Two-dimensional scatterplots using area sensors can also be used to estimate RB/RO. If the P and PO effects are determined to be negligible, then the HACRO diffractogram is representative of the average intensity in the powder for the sample, and prominent peaks may be labeled as "Representative Peaks". Generally, the more data collected to determine Representative Peaks, the more confidence one can have regarding the classification of such peaks. "Characteristic Peaks", if they exist, are a subset of the Representative Peaks and are used to differentiate one crystalline polymorph from another crystalline polymorph (polymorphs are crystalline forms having the same chemical composition). Characteristic peaks are determined by evaluating which representative peaks, if any, are present in one crystal polymorph of a compound compared to all other known crystal polymorphs of a given compound within 50.12 28. Not all crystal polymorphs of a compound necessarily have at least one characteristic peak .

Instrumental methods

Differential scanning calorimetry (DSC)

DSC was performed using a differential scanning calorimeter TA

Ipbigitepiye 2920 or 02000. Temperature calibration was performed using the MİZT standard of indium metal. The sample was placed in an aluminum DSC crucible, covered with a lid, and the weight was accurately recorded. A weighted aluminum crucible set up as a sample crucible,

Cells were placed on the side of the comparison. The data acquisition parameters and crucible configuration for each thermogram are shown in the image in the Data section of this report. The method code on the thermogram is an abbreviation for the initial and final temperature, as well as the heating rate; for example, 25-250-10 means "from 252Sb to 2502C in steps of 102C/min." The following table lists the abbreviations used in each figure for the crucible configurations: 2. Dynamic Vapor Sorption (DSP)

Dynamic vapor sorption data (DSP) were automatically collected on the MTI vapor sorption analyzer

ZaA-100. mass and PVP were used as standards for calibration. The samples were not dried before analysis. Sorption and desorption data were collected in the range from 5 to 95 95 EN with increments of КН 10 95 in the nitrogen flow. The equilibrium criterion used for the analysis was a weight change of less than 0.0100 95 after 5 minutes with a maximum equilibration time of 3 hours.

Infrared spectroscopy (IR)

IR spectra were obtained on a Madpa-IA 8602 spectrophotometer with Fourier transform (IR-FP) (Tpegpto Misoie), equipped with an Emeg-Sio source of the mid- and far-IR range, an extended-range potassium bromide (KVh) beam splitter, and a detector based on deuterated triglycine sulfate (0105). The wavelength was checked using the 1921 MIZT KM (polystyrene). A prefix broken total internal reflection (PPVV) (Tpypadegdote"mM, Tpepto Bresiga-Tesp) with a germanium (se) crystal was used for data collection. Each spectrum is 256 co-added scans collected at a spectral resolution of 4 cm". The set of background data was obtained with a pure Se crystal. The Id 1/K spectrum (K - reflection) was obtained by dividing the two specified data sets by each other.

Optical microscopy

The samples were observed under an optical microscope UmoiGe with crossed polarizers and 2x or 4x objectives, or under a stereomicroscope with a red compensator of the first order with crossed polarizers and 0.8x - 10x objectives.

Proton NMR spectroscopy/10 "H-NMR spectroscopy in solution

NMR spectra of the solutions were obtained using a Magiap OMITUMIMOMA-400 spectrometer.

Samples were prepared by dissolving approximately 5-10 mg of sample in DMSO-II or SOCI containing TMS. The data acquisition parameters are shown on the first spectrum in the Data section of this report. 10'H-NMR spectroscopy in solution (505, Ips.)

Two "H-NMR spectra in solution were obtained at Zresig! Baga Zegmise5 (Spatraiydp, I) at 25Sb on a Magiap OMITMIMOMA-400 spectrometer at a Larmor frequency "H 399.798 MHz.

The samples were dissolved in DMSO-4e or SO3, respectively. The spectra were obtained with a pulse duration of 6.0 μs, with an interval between scans of 5 seconds, a spectrum width of 7000 Hz with 35K data points and 40 jointly added scans. The free induction decay (FIR) was processed for 64K points and with an exponential line broadening factor of 0 ,2 Hz to improve the signal-to-noise ratio.

A residual peak from incompletely deuterated DMSO was present at approximately 2.50 ppm; incompletely deuterated chloroform appeared as a singlet at 7.26 ppm. A relatively broad peak at approximately 3.3 ppm is associated with water (only in the spectrum obtained in DMSO).

Raman spectroscopy

Raman spectra were obtained on the ET-Katap module connected to the spectrophotometer Madpa-

IV 8602 with Fourier transform (IR-FP) (Tpepto Misoie), equipped with a detector based on gallium-indium arsenide (Ipsad5). The wavelength was checked using sulfur and cyclohexane. Each sample was prepared for analysis by placing the sample in a glass tube and placing the tube in a gold-plated holder. A Ma:UuUO4 laser with a power of approximately 0.300 W (excitation wavelength 1064 nm) was used to irradiate the sample. Each spectrum represents 256 jointly added scans obtained at a spectral resolution of 4 cm".

Solid state NMR spectroscopy (NMR-TT)

Solid-phase C NMR spectra in the mode of cross-polarization and rotation under the magic angle (KP/OMK) were obtained at ambient temperature on a Magiap OMITMIMOMA-400 spectrometer (Larmor frequencies: 73С-100.542 MHz, "Н-399.789 MHz). The sample was placed in 4 mm zirconium dioxide rotor of the REMSIA type and rotated at 12 kHz at the magic angle.

The first three RIO data points were obtained by back extrapolation using the MMME linear prediction algorithm to obtain a flat baseline. The chemical shifts of the spectral peaks were correlated with the external standard of the resonance of the carbonyl carbon of glycine at 176.5 ppm.

Thermogravimetry (TGA)

TGA analyzes were performed using a thermogravimetric analyzer TA Ipzigitepib 2950 or O5000IK. Temperature calibration was carried out using nickel and aluminum.

Each sample was placed in an aluminum crucible. The sample was hermetically closed and a hole was made in the lid (only for 05000), after which it was placed in the TG furnace. The furnace was heated under nitrogen. The data acquisition parameters for each sample are shown in the image in the Data section of this report. The method code on the thermogram is an abbreviation for the initial and final temperature, as well as the heating rate; for example, 25-350-10 means "from 252C to 3502 in steps of 102C/min."

X-ray powder diffraction (XPRD)

Diffractometer IPEI KhKO-3000

XKRO diffractograms were obtained using an IpeI XKO-3000 diffractometer. The incident beam of X-ray radiation was generated using a fine-focus tube and a parabolic multilayer mirror. Prior to analysis, a silicon standard (MI5T 5EM 640s) was analyzed to check the position of the Z 111 peak. The sample was placed in a thin-walled glass capillary and a beam absorber was used to reduce the air background. The diffractograms were obtained in the transmission geometry using the M/ipaiyi m. 6.6 program and a position-sensitive Ediipoh sensor with a 2 9 range of 1207. The data acquisition parameters for each diffractogram are shown above the image in the Data section of this report.

Diffractometer RAMaiumsaI EHREKT Rgo MRO

XKRO diffractograms were obtained using a RAMaiuisI Khrepy RKO diffractometer

MRO using an incident beam of Cy radiation generated when using a long, fine-focus Oriich source. An elliptical multilayer mirror was used to focus SiKa X-rays through the sample and onto the sensor. Before the analysis, the silicon sample (MIZT ZKM 640s) was analyzed to check the position of the 5 and 111 peak. The sample was placed between films 3 μm thick and analyzed in the transmittance geometry. A beam absorber was used to reduce the background created by the air. Soller slits for incident and diffracted beams were used to minimize broadening due to axial deviation. Diffractograms were obtained using a scanning position-sensitive sensor (H'SeiIegag), located at a distance of 240 mm from the sample, and the Vaia program

SoPesiog m. 2.25. The data acquisition parameters for each diffractogram are shown above the image in the Data section of this report, including the divergence slit (05) in front of the mirror and the incident beam counterscattering slit (55).

High-temperature microscopy

High-temperature microscopy was performed using a Hipcat table (ETIK 600) with a TM593 controller installed on a Yeiss OM IR microscope equipped with a 5РОT Ipzidpi color digital camera. Temperature calibration was performed using О5Р melting point standards. The samples were placed on a coverslip and the sample was covered with a second coverslip. When the table was heated, each sample was visually observed using a 20x0.4 M.A. long-focus lens. with crossed polarizers and a first-order red compensator. Images were obtained using the 5ROT program (m.4.5.9).

Titration by the Karl-Fischer (KE) method

Coulometric Karl-Fisher (KE) analysis for the determination of water was carried out using the Meshsheg Toiedo 0I39 KE titrator. A blank titration was performed before the analysis. The sample was prepared in an atmosphere of dry nitrogen, in which approximately 1 gram of the sample was dissolved in 1 ml of dry NudgapaI-Soshotai AYU reagent in a pre-dried vial. The entire solution was added to the KE coulometer through the membrane and stirred for 10 seconds. Then the sample was titrated with the help of a generator electrode, which gives iodine as a result of electrochemical oxidation: 21I--iI2n2e. To ensure reproducibility, two replicates were obtained.

Equivalents

Those skilled in the art will know or be able to establish, using no more than standard experimentation, many equivalents of certain embodiments of the invention described herein. Such equivalents are assumed to be

Zo are covered by the following formula.

Claims (1)

FORMULA OF THE INVENTION 1. The polymorphic form of kappa rifaximin, where the polymorphic form of kappa rifaximin is characterized by the following characteristic peaks of the powder X-ray diffractogram, expressed in degrees 29: (6.45-6.67)50.20, (6.83-6.94)-0, 20 and (7.52-7.56)50.20. 2. The polymorphic form of kappa rifaximin, where the polymorphic form of kappa rifaximin is characterized by the following characteristic peaks of the powder X-ray diffractogram, expressed in degrees 29: (6.45-6.67)50.20, (6.83-6.94)-0, 20 and (8.30-8.34)0.20. C. The polymorphic form of kappa rifaximin, where the polymorphic form of kappa rifaximin is characterized by the following characteristic peaks of the powder X-ray diffractogram, expressed in degrees 26: (6.45-6.67)20.20, (6.83-6.94):0, 20, (7.52-7.56)-0.20 and (7.68-7.78)50.20. 4. The polymorphic form of kappa rifaximin, where the polymorphic form of kappa rifaximin is characterized by the following characteristic peaks of the powder X-ray diffractogram, expressed in degrees 29: (6.45-6.67)-0.20, (6.83-6.94)-0 ,20, (7.52-7.56)50.20, (7.68-7.78)50.20 and (8.30-8.34)50.20. 5. The polymorphic form of kappa rifaximin, where the polymorphic form of kappa rifaximin is characterized by the following characteristic peaks of the powder X-ray diffractogram, expressed in degrees 29: (6.83-6.94)50.20, (7.52-7.56)0.20 and (7.68-7.78)-0.20. 6. Polymorphic form of kappa rifaximin according to any one of claims 1-5, where the form of kappa rifaximin contains less than 5 95 impurities by total weight. 7. The polymorphic form of kappa rifaximin according to any one of claims 1-5, where the kappa form of rifaximin is at least 50 95 pure or at least 7595 pure or at least 80 95 pure or at least 90 95 pure or at least 95 95 pure, or at least 98 95 pure. 8. A pharmaceutical composition containing a polymorphic form of kappa rifaximin according to any one of claims 1-7 and a pharmaceutically acceptable carrier. 9. Pharmaceutical composition according to claim 8, where the composition is made in the form of coated or uncoated tablets, hard or soft gelatin capsules, sugar-coated pills, lozenges, wafers, granules or powders in sealed packages. 10. The method of obtaining the polymorphic form of kappa rifaximin according to any of claims 1-5, which includes mixing the polymorphic form of alpha rifaximin at a temperature of no more than 60°C until the formation of a precipitate, and filtering the indicated precipitate. 154 and . . and and! : : and And : : ; and ' , 1 | ! ! : and ; : : ; And And ; " ' : N i i !! : u ! i i i N ros : i i : 5 i i i ; NYA : ; : 5 Y . I: ! : ! G- zhan or punk tin VO; she ; ! | : : : : z | 4 : and She he a : ! and in SH AKA ck Mun r opr ZV VE 5 10 15 23 35 35 4 a-20(gral) Fig. 1 ! wah shk even from torod-i a | ! E - g E r Zhoovoro-i ny I g, : m i. iya 154 Ky : SHE Ka ZHK tod ZHK 2339 z5ao shi y ODN BA ryu chere o odi i sk DOM MNN KO VMO jun 5 to 15 20 75 ZO Z8 49 iM26 rad) Fig. 2 zv: i Y i zooso-i «oshya -X - ono shin i - i | ' With N o 5bodya and : - - : and | ktya - N GRY 5 i Gi ; cho 7 and Tv - PNYA vii and i V oyu | p i eiya ny De OTKVN zrvna v na Ya R doyu tet V. "Kl 257 zav vo , duh yu ya vu pn sho vo se y Z konya peni 5 for 15 20 25 for 35 40 8:50. (gradi Fig. With rr t and ts ! shh! shchy nn K ve iveV sake i. en Ko with her uv pin sedge ! KOLBU KEN M o on ony nan i sor V Fig. 4 Y she s pnnnnzhniytnia AL. m elephant mA Pe evettryusvtn PySE KV os OK nin EI i y: I NI. and I. TE OO. ! Fig. December 5, Dr. Terti, what is it? / sh es r i v nya 5 y paches « 5 "and. Vo She u M -oi mih -38: t t-t : 5 o 50 100 150 200 250 300 З50 Temperature HO Fig: 6 0607635 de 0 DOSE gi ni nn it 1001 "VINE khizbo Ko2ozrdai OK that in to58m mg) KZ from Tychyna dya EOR t I - uch i - y i V i d o i hi shchi |! Not BO ditllilltltttttiutttttutuchtt -50 0 Z 0 150 200 250 300 350 °C Temperature Fig. 7. Ko K MN KEKV OH B Kale OK EK OKO o o OO KO PAK KV Ve MENA U Ve pom iA MO OKH KOKO PO OVA A OH KE KK OK VK OK o V KK ek v km i OV i VC rig. ZA duh "in fig VI OKO o Ko U i po po MK OH MO V OO Oh MO 3 t I KT KV pe AN o pe A KO o OK x BU o OO KK i VOVK KOKS Ko VM M o KO KE me HA OO KK KK MO CHANGE KK PC KK AK KO ke POHK H KD EK Oh ZK A V son On SKK KK MO EK KK OK Ж KK Ka MIK KO i p EKO OK p AK KK TM KOKO MM KU MOH MY iti j go. ; o Phi: VS fii. 80 vom ik ee o i M M OO a OO eh Kok KVK KHE OVO V ON MN OSOeK KK VV pe VO V On o OKA KK COM M M M OCC MAO RIK KE MK MN i ros V VO OK V o OK OKO OM PEK Co OO yun A ASOAH AK KK z OH AN So KK OH U KK KK i VO OO M V -. spirit Y I Phi, VE Fig. 8: ko V V o p eUK MA KAHYA VA pi MKM KK VO OEM o MO M V M OKEAN OV M VEK KAK I POSY A M Oh M KK MOH OK OKH On OK VN i A KK KE ECO Mi OO a ES OO POM KK o Med A DV ON eye o o OO M OV OO i: i s fig. because Fig. ZY Weighing the moisture content of the water. IS ; -- nn a be i : : : : r en i : I shk Yi i i roya ; І І і NOT ND Y, an p HTD EK: A ory PON KO pek pa ih put DEDbF tin won po 300 290 309 400 B BO 700 0 901000 ZA Yang imya faikhu 405790. 258. Experiment Temi-KN Operator on PO ekhayurimensya AdIVO Name samples rifaximin pnia Zota-4o3, MB Blood and Aapyazayu from 396 lo in Te puiroktami NO No Supination Tk min OLIO0Vo mas within 5.00 h Max number uriyuh 25,5:25,15:25, 35:35, Bai am Although UpiaK. 25,85:25,95273,85:25, 5 a, BY Steps of T-KV 25,25:725, 15205, 5 ZA) hvyabo 0010045 mas Interval of data registration of Yelena Start of exlerimvot: 6103 Peonatoh work t Cooking time, Total Weight Vme Zsimoraje KN raki, XE trovatestk min mg hm grad z ta 03 9053 0055 482 Zo 178 5930-1475 24:85 483 155 ZA. 935; 7A85 Tl 157 R 9510 6495 285 KU 156 2237 vabe 0-5 Kok Zo GA 2395 9518-5420 2485 Zav 143 2584 9568-4919 2485 54:94. 118 2589 9520 7 2585 5482 13845: 783a SB -3505 28.86 755 Another 57980 2725-8403 2485 Vada 330 and OO0-2903 285 UV 1837 2486 55 я 0525 097 Лов о4а6 5 TB 11082 28) 11539 2486 3504 ка чле 8757 TAUVi шА86 2507 Май вам о 3532 заА5 1512 ча 15764 в о 2АН5 5 Fig, 9 continued ! | ! : ! ! ; : ! 4 th : ! 15 ' Hey! and | and Those din shk ra and shchi Y y and y Bo | What! ' is: SHYN shk I-I As 1 p ; 1 and ach and she | Shi shiya piky new di I from now on nn! th th MTA city center at 3 p.m. 3 p.m. 3 p.m. 0-26 p.m. (hail) Fig. 10 doc dr more Z i | M na / s ti I c. X Ka I 5 I ,/ ki kova vysy Che -5 er nya va -a 0050 100 150 200 250. 300 350 Temperature SS) Fi 1 TGA 1115 to 60 100 vofioyavv ; That between VO aso And ! zviv i d 50 -- "7 sh 80 : I che ki Luk suto utet t relezhett rt i racket kto sune -30 0 50 00 150 300 250 300 350 Temperature SGS Fig. 12 TGA As a woman, every woman has aged, she has lived in the skin of her skin, and she has left the shadows of her skin, and the skin is also clear, every eye. horses! TOJ dv 50 ta ke OOl vy pl 7-4 523935 between (VO t i A 85 "KO Zalvmei: KZ i 1 x I i X i o vkh i x i i U. -80 0 50 0 150 500 250 306 35 Temperature (WITH) Foot. IZ shi shi she shi shk pe ny she nie «oo VE. On I and shish nene shi and. sho CHE : : o: : ' Shk a in in hny NI vyfya ono ho vani 8ZI she. I : : : : shk i shi IY : I ASHAYA zv i : ! AND! guns, "Veladkal could I | : : : "Vymaznnv, nn kyu 15 20 5 30 35 45 0-29 (degrees) Fig: 14 Weight (75) depending on the travel condition Sample name: rifaximin: File name: 405792 --Dekorbation 7 Desovitsia AVK coffee cakes renny nir uchinok ntenyi zhi tr, pet I : N y ; with she essay; PI NN N E i: N how! in ! rya Al E N N r i y E , at ! i " : Koovii i i lira. 1 , - : " H from 4 in , : : : | i - I : 1 i N i U , : i : i . kou v zha i ie A a a 0 oo sn virgins same neon, min nn that | Y : k-t : and I and : : HOW | shi still rat and . ; ! ADF sen nevy - bo 100 200 300 400 500 600 ip0 800 900 nyu KA Fng. I5 File name 40579251 Hesperomens Ttemi-NN oisresov rya TO skspernkevtu lah Chezva zraz rifaxykin Zvazok, pati 3973: 525 57 Notes - v. Divgazonovil 596-tso 555 3550 I prirystam 109 Sutinya Memoye ne zarmni 180 ha May with PO Opa mas orozyagom 5.00 ha Krovy T-VN 25,85:25,95:25,85:25, 75:45, 55:25 , 55,5, 35 ZBE ov 1545, 5 Internal data registration still hundredth of my Start of the experiment. in 23 I Pochazhgak robokhiya and Chisurshyuu 0 Zmalka Vaga Bag Tempzryalka VN zrazzha, uko Ureznlilh and lam toy Z pla vo poh 2485 358. 152 153 11033 9073 2А87 5.25 MAKI Zag LAV ad vii 1483 dl 5-3 016 06 АООа 5 ВАЗОА 51 1575 1484 from Brzhe i2e5. 1282 M ZAV 4482 zva 1659 0011.374. C15 2D5 SO: 588 7145 11465 3875 3485 544 О Fuba 15 «8 А8B of pelvis GK ings О О О О О О О О О О 2485 847 1078. iamb 186 0 Lev de Ri and 6172 145 GI 1 ZOZ 11338 2593 286 55328 103.8. and pl 134 485 5Yu 5 me 85 av 3497 Z 224 40925 008 hid 25.05 ij To 10805002 2AVe LE ka Mb sia ma schi Fig. 15 continuation of the participle that: ИЙ и | : and sho and we shi K | ! in shin she! : also S same | ! ! ov i and | and ! and vn, dobi tires ey k shi tires HB 1 I N | and in these, | 19 iz 2 2 30 35 40 Я28 (cont.) Thebes 16 N Y : " , : | i ; , : Y y y, y ne nyshe shishe Or: "sh And still shi nizh ni? zi a N I: E B i 1 ii, Shk Y s KA i her Z Me u NN Mod dikynnatitsllennyn KE: ! ! 00 Towers KILLED I V i. and x And them: o51 i shchi M, ! : and ! live and. from... ZVO 2320Ya, ninnekh ZVUVEOI, 5 10 15 at 25 30 35 at 8-20 (grad) Fig. 17 1 Y IY ih t N Oh Her and I; ; 4 wait TU n- pk question Z! Shchy A ana MMA Bomyalvs| goths in Pes Sh y Y We dey hygfaxmmietu erosion VKH x | A di Sholioi feozovind avu onkknko Yan ol shi SHIA Y u, Tek ZON LIVO Z kueinksikhoi 3929: 15455. z myst p nn shin 8-29 (pred) "Fig. 18 more 5-4 , : 1) h h V i i t foni Te AL vovka Z IJ NI A i Ii . sni 2 ov VAN yaksi VOD already oniiy icon - 1 OAMD chu TAKU Alya: fonaAita lov, ZHI, okinnk and Konni Y I Y Her ren BUK, peuetm skin tt pechach Kopani MA diko dikiy KA " Ed Katya B-28. (gran) Fig. 19 that 15 her and ' Her m and I g Z not that KDKA MMA ak lykhi /Kottyatn» zvua ogi i i VI varny MORE | A or" and mA Dt vi viv zgyudeh zaz 6, "A m and Dnya sht that and MMA and destruction And dl ia at da ut V-zyailrod) Fig. 20 g vovi and I Vch, ! nen in ENN 1 yahyu Zo 00) 2553 2009 15yu ni 505 cm" o ya | u, N st chi un IY "w zo Zbyu 003500 00 20w 01506 00160005 cm" vovi yayu Z Z OM zho 150000 yuyu cm" Buckets I IA vi Sheshi Shyn DN zhh ZMyuyu be 00500 00Hyu 01509 0030 poya v shi i iposdnyuntyatnnnnya Fig. 21 k! shchi i i iya AK ZO Me ZYU zhhb kyu byu still sm r shchi Cht SAM SCHO z. set nny she zh tyu cm" 18 ih, | / ZK pnketuntnannnnynnya si / da dpyuniyatnya zdo zb M Shchy yuyu SM E | и N Y и im KA yus ssh yuyu I sm" И ; nn Chng 22 154 kih mit tt mon korenya. | also shi ; and I | , : y Y niyu ik tsi ; ! pen ZASTTYA dinnniuu whose wave ron me a zav ia neve nie vya Fig. 23 ni i I ikhjosivm Sho. FOR goes chn. Ali chiny pi: sewed and Fig. 24 ; ши І І 58 І шк ств ' щ ! | Y va shi I dk Y shi shsh sh N I g Z U | And and with | ! N Y az I ze po she Ko : ! P. Pub with I is Ii | hey |! You are still there! no is 3 DK van it yav VIV 212 oda Sl sho KCHACHNNNN nn o a p pav ia dv pln 8-26. country) Fig. 25 Po Distance "ZIA) intensity b). Я п и не MEHTEU ХНЯ КАСТУ ЕВ МАЭ ЬБЖ ВЮ | I'm 3. I'm eating lm 100 your Soybean Gezazhalo 25055005 GOM HeyUzhvyu 1 5092009 SUM vine pulp yaelozhaiy 15 Givuzzholo VO ZHOVIY 6 a zho 1 VAZ OYUA HLIBOV 0 lav zOova in how GL OYU | LZ EOOBI 5 EK E AS NI Es DAV MYNYK EL. lo olLo 7024 oi her nn parks nn u ot yn nin yn nin gaz zholo 695820.055 SE gas 5688 20051 5 - and zba zho | of Vovoy EESEN ZVO OOTV MON Y z1500yolo 5loeX0039 17 154700 000 BE ZHO0 SI pet Oct 1625800 456-003. To Sho INNI those: znenu sh ol AND YOU THEY EZ. ZY SHIK MY Gdozholju 5039009 9 pub JAVA 27 ME ESE IPM te: Z NE LYN NESASNIYA 26250024 15 pyt tr 0210-8050 EK SEU I HNN NIC HE HRYASCHI NAH k NIE IEE LIZIN ke DI NK I Gl zo zo x009 1 I Gamayazheyayu 0 Iabiy 09 forever | labvkovya 15 ZIZ 1 0 Z85ZHOVIE 10008 NRESIEZH Y Sa NIbo5 15 Pe i VMO 17 zov 1 GoBbzhol 0 ZavazhovI 1001 ESE MENE EYA I 5 hands in KU i» M M Z; WHILE YOU WERE NOT IN THE UN Fig. 26 1 234 and Distance і Go and Intensiyavo oh nedtva i s BVzhOLo 00335007 0835 udazholo 1 1604 x060 100100 82100 00102033 66 Z Z : 53 N and so on. VYN NMA "Big, 27 I" Ears uki body "he t tov mu 105 i "i 62 shana N y x Ba y 9.0- and Kom i kh all Z zi Koch sh E Fo ho Z E | kut: che she V i NYA hv e bdi U M ; day VES ep "Z 0 5 100 150 250 350 300 350 Temperature (С) Fig. 25 Weight (75) depending on moisture content Sample name: rifaksiamen File darkness; 386752 shi ve i pl p E N: I Y NY SHE du DOD inten endovy ko V: zh; : N u i Otyt M feya Avobrbitsiya o Pyty nin i M i 8 mae i A M ON o poFoy -- and now there is a nn vino r.; rlzhayishysh -AHYUV OY t . I - o, i her i : : : : I N I : Y Net den uki rak zni poemi t a pe vyu zho 100 yuyu 300 350 00 o ma 802 950 190, jan Fi. 29 shi shi still ' SZSH E SHO N ; N N I 'shi: I. Shk! Shi she she shi te shi zhd 3 ih Ki her n ya N I Tom Lee, the family i t di I UAMmdya sna szhan ; I and I E: Crab 385172! 7 In DK and . Oh, I'm here! : i : Aa v in S a o V u 15 20 75 5 35 0 8-26 (degrees) Fig. 30 xx is with o I g her not o breath and; : / more : And! I. an ny YN M yakh Pl kp child 8 olb6oY my 8 5 4 2 -y Mo Thebes 31! IN. those and she SHE N y She she she she shik shih. ko hr shi t shi. Ek o ON vany ZV i Z MNK pishnykh i I I ZM 300 050 206 153 100 500 Fig. 32 Vasya TE poh ze ev zon) zna. 5; Povai TE s S ivova her Na V schi vo TSU NI oche lo Y Ii t Ia! M g SHY re I po NYA uche iz MU KD bdzei their BI BY y 08361 their IK KI. y SCHE Schi oh y h E I her Я Я 22321 E t zhk vazi Kk ; M her She I van pe zag y that shi shin 7 Fig, 33 Observed IChepikis for co-crystal 1 refaximuv: pyiterazine Range: 20000 400.0 Absolute Threshold. 00251 Sensitivity. 930 Observer splsbk tkiv Seya emu 7015 71824 765.0 79255 8035 81957 3813 93065 9232 9477 9719 1928 10524 10524 10513 MO 115 11582 12234 12373 1497 13383 15723 146513 15027 Fig. 34 Eh yo Ok i u sh i i i | г из и | SHCI M» Her and Z re k i | y Pa theses and Ka u U I y What A pr r DY U y chich in DK M Y was you and I Fig. 35 bo Self-observed 1U-peaks from the compound crystal and rofaximin piperazine Sloktr rifaximin Fblast 35004963. Absonduty pores? 02155 Chuhliviet 50 Observed son half-grown cm uh 1565 253.4 323.8 353.7 3905 4398 467.4 489.2 5458 528.7 bavo Ba 725 7514 7979 8240 515 9234 950.3 tО5AI 1133. 3158.8 12074 137327 12984 1348.6 1329.5 14905 15323 15875 15503 RU 935.2 79888 Fig. 36 and VE M Y what what : : . and would more shk Z Z : " : she Y Ne: : : . i BUT y : : y Z Ash . : I : ! х | z i . nishche I and p : : ' stillЖ : I y y 7 y Not shk What tya Tit ni SHEShe i yi 1 NYA :4 - : Goa Ts! V yu yi NE I yi .- ! ; and Beh ZOV), en khv viv pila pod la lin re podi ip My i AV pi vk sv pi ev kl nena ei schi y 19 15 2 o z 35 0 0-28 (grad) Fig; 37 shk x p cy Yi La A Ole em Fig. 38 AI -k I I and wa! 4 And t V | I ate at 54 E Z and again from 14 g E I cha zhov de zi . xZU and PE uh Y NI t shki vu, la u E E ml more elephants 8) lm i weni mi Dn Yan Ne ! pa o B is aEsterreuttya i g MTM I AL, adrenal 45. for t5 Koi 35 claim 928 (grades Fig. 39 la Shchy V idstam. A) Tktsnsivvvia 020 (clone A Pekhnevanoi M EE NE KIT VV SHE MENA TYA EE ZM DYN EE ME: s: MEM PMM Eh a set ge annny nina bazshom 10 10962151 10. 1 835zholo | 3 ZhoYuov, GU ETALONS ZY EE KZ U HO WITH THEM, ZM VOSENY ke li nY VOMS MSEK YAN res z NV INN ZOM tob, proek pe: NYM NO KHE A ZD i: vah LYNE hv be zhatm osi 5 Sov Zhov vovi I Zo 1 adievomo 1 6 1 57606 Zoo OZ. iU 1 39400 9 zba Goa ho V! BOKU KI LIDA EKZ ALSO ZDO: ZVO AK 5 Z Za LIV MIA Z ZX t ZAVANNA: ZDMYVYTSI sezv kom vovyh 001 OVU rum upiezholo 1 u50bhooi 10721 MIV zkh 00 ih pitazzhi gazg rob gami ha saivvuaa 1 5 T pav 2150459 5 iso llovzhoviV 1 001Й I Pat vloda ХОВ i OV VVE Piazhezsta s sdei vad 15 o ev pevna Tov MANI ET Za vysh mi iiamazhoo 5 10428 . 1 VO, VAT zenith Makokt Glebvu TEKY MYR ZAKNI ECON I MSE IN USA You ZY Ex ZK ZHAN sia st; WE MNE NK Ks TYNY: NK. VE EV MES DIV NIM HE Va ZY SHE ME I ZAHO YOU IN AGAIN Willow. va koo3 Goovav zho I Zv 5 th nevy 5231 50033 KESY FAILURE ablZ side of her kivBakOlO. | ZO. nn 012.5 Zh MO, pzakaryoyut 121522 Izazhttoia 1 Bolkhaia 6 rvzhvMT z3rahovia 8 ia 19 010030 0000 021220 VO MeBARIV iloiv WHO, NI REAK OZ VEU ZD NK ZK Gru oish 1 5065 zho KE IM NMA t Fig. 40 years and 23) Distance "A Chitensient pe and nu nn sny ni neon son r-ZBAZHOLYU av OV rve JOLO o 1582502 Her vbavzhhoDO 13596025 | Mo: Pav Zhov 1 1zvebo. i horse SY Gayu Y; 12128 0168 34 1 bo olo and 15350155 | y N Pe oon i si AD NNNV NN AN Govly kolo shk 10596013 | 29 BE IN BACK MOVE PIONEER MIN Fig. 41 Der pittenntotu ukryttu t sect Engraved mez VZ Ob m zla E Fe od z "ik ZOZ ek) iy E Shk: : E i 5 02 U |y V Eh iy ih "x Pav E I eh vo von. sud v Y fllniy M E sh i ! moe Sk hi -y2 U 7. x x h i i lag No -b4 I i peneyu nia peetetttnyi VO -5a i 50 ooo 150 200 250 300 350 Temperature (201 Fig, 42 2 in Z a I sh i Y E shk i I still i still with 4 IN I tires g Mch na m i p i m p i y Fig. 43 owl E; IB vv shchi i Her so zh 1 GE 5 ooze IAE o | p ge: What 7 bl Z 5 TK She; to her I I Ogo In Her! and; in | | in what MK HER SHE Vo nom V oh what Zoo 5 o lob MO 5. dFig. 44 Observed chiroterneuieich Pp for skrystan U riifaksimneu pezeryaton Spectra rufaxkm Area 30000 4900 Absolute pores ODIMO Sensitive 90 Observed list so far So (M in Characteristic number (im schu 40 14539 7257 5 7359 PA 5036 8205 8358 92 775,801,801, two 8506 10462 10632 157 11226 1592 12 192373 13193 13377 T3705 14525 15045 134 15901 15475 17254 I 28837 29383 293705 Y iz U z Ya m | shshe she shi o - o; Ya shi ya ge zv vi: a nya ekz v; і E Tsi INNY catch pa VO; o Ve t Kk Z | Mi i a Ga i N Kaya i KN YAN y shi NI SY SKOUKNAT oon nn v vyso p NN m 3505 Ka to z і50u 1000 ho cm Fig; 46 Observed! kharyakterasuman Riman-nko plya co-crystase 2 pifaxnyayunu ptiperaznnu E Spectr rifaxnmin XZhlast 3500 3 Absolute pores FON "Whivyvit 80 Knsok peaks ia 22 om Slostrezhukka peaks Characteristic hek 156.5 9206 2526 17182 3123 202 KU 152778 035 Ole 4435 22514 45825 4913 4/5 We 6530 5530 5599 T86A 7SAC in 14 1 53205 IUN 9768 233.0 tons 759877 307 Fi. 47 1 1 she I | : и И: И И A и ! x g Y : ! ,: і " 81 p iia Shk - vakannatyat Yan M ve mkm ; Mnuk tent ivoka 7643) 222383, In Her shi tsi y R ia och zyaaiayaoU (Z і: frills, school lifaeina beer and і AKA HA: rve "MY hg zyatkvo Z | igoaa ZV79631 29750, ra M Al i U ey Mne niv y Oz i i Kk D khlodk nA ekt 0 EKrifzhetsnu PSH M peia i nnyy sv, i bend: TU KN HM M duny I 25. poh SK . sufany ZVAYASYI 227905 KA KA chok MY o i Tyayay zliven y i ' scha by ZVuVevi 228572. In the singular ntrnrtnn tvveyuvy TIV 1545 5 cha ikh 20 22 zo 35 40 v-2o (rad) "Vir. 48. Steam stress (acetochigry) wasp. (Stvkrystat y ptennnnentttttttasy chne y divkrystaya z) y vela nn PI PAN kh Vishiezlvainkh umok / Ge KN. (fmovirno nrotatom-kersukose / Bakuyemne supnnih aqueous suspension of BOB VN, iednolu time) in (CT, storage in these conditions of navkodshitsy pressing; Kk she det h m serehovya 17. lviy refekovnti form Analogous to co-crystal 1 pn tiviinn (sparse peaks, tax ki vrybloprya 5728, 172 29 or a lot! drink Fig. 49 ON and Y and Dni UYU in quickly and | Azot she ek I 9 ov and pyt sten onnnnnnnna and orezhtiisht Ho godony Fig. 50 tt nn | ! Yeh: more of these! and | H 1 H 119490 water TOmoliya EN | Tbb oxen. OH I pray IT 1 I Ta5ayu volya zbmolv IT OO) water b3 I pray IT 1 H 1 and | And Noobblody nimol KON | | They got angry bb'omolya ON E she G Condition. Time Result eV min in dzot 575 min te "ZX min is i - Y tod y i 4 6 in, eta z ogod Form A S u yod ge Kun" Vacuum, external conditions bod In your Vacuum, External conditionally (Z dod t lyudny For days 5 Vacuum; simulated conditions 73 hours 5 similar: Bakun, OS tah? ditches "bod is 2. m YN te ! -zyud " 6 cho of ttoh is yiv - Vo; : tov Vkmistvodi 36 05 YANAV oh o yik -5Z mi d g u osmanya EYUN y "Zoi is le Vacuum, external conditions o hod gya "195 Tlvzhden 5 Vnist ox ly In mi vila 1 y a 5 b okopaya Vahuum 60S vod i: ze; 7203 mola VN 2 dyi 5 tato Pedribnepvya Pressing from arod M mod dune fast Te Fig. 53 min o Penn o U SCHE IN NANN -25 Z LIN Z i i preen rya shi she: and. ЗЭ щ A a me ЧЕ шЧ A a me ЧЕ ше ча ве каА А A or Pk nknyu і і of the day: se s Before the influence of moisture that Кк ше шчі N pen yana Ж Ол MA au pom ov ey Ii OA ben ey z І s i і S і Before being exposed to humidity Higher SHE Shchy se peki shana VO that : и Y t, ШЕ I still I : і Myslia drying nin ni an mn ce 5 zo 8-79 (degrees) fig. 54 yr. Fig. 55 y she I still effect DN km pedoetnya zhi v t - y be, Z dr, y uky V Azh DOK vy m A Our ri Mesy ho ee U KA Zh - shi rek MK o V ku no o pek y feod vn en u z - SOY and di shields Ve a ia evil Ne: zh kih Sm Mu, ne ik i B I i dn ShK. Жлян ян ВХ вва я Хай ШЙ Code Ек в з ЗШ Ек ож я У жеу ши Fig. 56 ; "HOUSE x 00155 TV! uh x- 00 re: E 1. ; then 12 ty 5 1 : E B 08 , E and pera zh oh 02 B! I'm a pory pli punk 0 23 zhk 5 VO 0 150 140 01595 Konpentridiya Suptlyug Fig. 57 50 t 45:00 "m. capacity Z 40. nsh kemnost 2 I ZB , Kk capacity Z - WATER that Bo i 1, E 25.6 z . i 2900 , SEBE Chu x ma Na, tevezht BOdh figure DOD tv elrisnozhniantfriya kn aki opti inn tt tternikotkh, 0.20 40 60 OVO 100 190 140 160 180 200 Tea (henlans) Fig. 58 35 хз ух 10715х 00555 zv rai to th ho 2 as V 15 ka vi V yo 05 5 05 |! 15 2 and 3 Kanceptrapya (μg/ml) Fig. 59 1 BUT Y ireal3977551232965, 3985-55-04, and rifaximin balls, no helium, wall hanging short A nyasazha zvo File 3992811 242965, 3985-5504, I rifaximin fluff, no helium, with I ; astavaplenya short A nozzle. GI DJ nin tobob I ; ra y EY Y DAH kakaya every k hit 3975U71232856, 385-505 shi Ii 4 ball ikelekony.. RIFAXIVKS, users of carotene 55 nozzle 0 They did not use hydrogen passvvnv sand asla nu kan or sil 5 mo 35 zh 503550 иН2В (grad). Fig. 60 tons - and! and zdo i TIKH de IN, TK TE Vo petrYav Ua ET EV i I V in at vena Nana in BO / tA Ii Indexing and obtained quantities Г Fformalufractogram! Form 9 rifaximiyu Y I fall psa nik Kn pre il kinny points! Family and troupe of Orthoromibichnka symmetry Ra 21219) E and 7/B under) and 15278 Bi | 20,277 soi) | 32731; kt nn ect rn is ini nes Days t inno lived kt ioikke sk; (grad) and Zo V (og) and 90 perek tttttttyutnttnittttn pettnsttsnsktitetinnninya tet tnyu nini "7 degrees) | 50 4 wash kKrtts those Pon gave birth to ninannny Volume "Kkomiryua) | 9823 I Y ! mu (Zhasyam. odiyaniya) I T5478 | And other sha , - - Mmyvpirpyv composition" N Sabo "ON ykh«y ! Thicken X I 105khuh129 Ho trachtion of the solvent. raii Y au 0 vo p i DI VE Ve "Density and weight fraction of the solvent. full-footed looking at the battered sknad. Fig. 61 C chance: Z (bok zamin yi iononn vtolnnou o I TUysayyutsya! 0001 Bei | І ' volost | en | N Mt, zovkashn I pronunciations umptesbtadini FEI oarzhsuyunya I eyyavetya ; she and I---- set put tov niny navan nonnmi Deposition ! | Drying (| oko elek N zetanoch |i id azotakostv and sh gave them DI U ! cows n pH, pzhyanialalzhn "0 min ! zekyano I Ba pi zovaein conditions. g | prkoodti shine t "zh O 5-3. TO SAD tyny, tr or en Bod Na h Geny py va "vs TO 1 Hnavyushsna What kmozhperatura gives mzak BO g hmm " Fig. 62