Polymorphic mixture of rifaximin and its use for preparing solid formulations

Abstract

To provide a stable Refaximin crystalline polymorphic mixture and a method for producing the same.SOLUTION: A Rifaximin polymorphic mixture of α / β form in a relative ratio of 85 / 15±3 is obtained as follows. Crude Rifaximin, which was obtained using rifamycin O as a starting material, is dissolved in ethyl alcohol at a temperature of 50°C to 60°C. By adding water to the ethyl alcohol solution and then lowering the temperature of the suspension to 28 to 33°C while stirring for 1 to 3 hours, a wet purified Rifaximin is precipitated. The crystallized mixture is cooled to 20 to 25°C while stirring the crystallized mixture for 1 to 2 hours. By cooling the crystallized mixture to 0 to 5°C for a certain period of time until the precipitation of the crystallized mixture is finally obtained, the crystallized mixture is purified by precipitation. The suspension is filtered using a filter dryer, and the resulting solid material is washed with water. Subsequently, the washed solid material is dried at a temperature in the range of 38 to 42°C under normal pressure in an inert gas flow for a certain period of time until the final moisture content of 6±2% is reached while being stirred.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the field of organic chemistry, in particular medicinal chemistry, and more particularly to the manufacture of active pharmaceutical ingredients (API). [Background technology]

[0002] Rifaximin (a compound identified by CAS Registry Number 80621-81-4) is a non-respiratory synthetic rifamycin antibiotic first disclosed in 1981 by Alfa Wasserman (BE888895); the compound is currently utilized in therapy for the treatment of traveler's diarrhea and hepatic encephalopathy. Pharmacokinetic studies performed on rifaximin confirmed that the compound is poorly absorbed from the intestine (Cellai, L.; Cerrini, S.; Brufani, M.; Marchi, E.; Mascellani, G.; Montecchi, L. Structure-activity relationships in 4-deoxypyrido(1',2'-1.2)imidazo(5.4-c)rifamycin SV derivatives. Chemioterapia (1983), 2(5. Suppl.: Mediterr. Congr. Chemother., Proc., 3rd, 1982), 53-4).

[0003] The structural formula of rifaximin is: [ka] Due to this lack of systemic absorption, rifaximin is not used outside the gastrointestinal tract and exhibits an excellent safety profile.

[0004] Literature data confirms that the substance can be identified in different crystalline forms, identified by Greek letters: α, β, and γ forms were disclosed in 2004 (EP1557421 by Alfa Wasserman), ε and δ forms in 2006 (EP1698630 by Alfa Wasserman), ζ, η, α dry, ι forms in 2009 (WO2009108730 by Salix Pharmaceuticals), and K and θ forms in 2011 (WO2011153444 by Salix Pharmaceuticals). Furthermore, it is known that rifaximin can exist in amorphous form (WO2008035109 by Cipla Limited) and amorphous halo form (WO2011080691).

[0005] Although the polymorphic form α of Rifaximin (the crystalline form sold under the trade name Xifaxan®) is considered a non-absorbed drug, the results of more recent pharmacological studies (see, for example, GC Viscomi et al. Crystal forms of Rifaximin and their effect on pharmaceutical properties Cryst Eng Comm, 2008. 10. 1074-1081) suggest that some of the crystalline forms described above, such as the γ and δ forms, may be significantly absorbed.

[0006] Furthermore, the above cited literature data shows that the known polymorphic forms of rifaximin can easily change their polymorphic form when exposed to different values ​​of relative humidity: for example, the anhydrous α and δ forms can be obtained by drying the monohydrate β form at different temperatures (30-65° C.) under reduced pressure, and the anhydrous α form can be converted into the corresponding monohydrate β form after 40 hours at 56% relative humidity (EP1557421).

[0007] The inventors have found that in particular the crystallization and drying conditions described in EP1557421 (using conventional static or dynamic dryers such as biconical dryers) have proven to be important as they not only consistently obtain the desired α or α / β mixtures, but also the undesirable γ polymorphic form or other polymorphic mixtures.

[0008] Control of the obtained solid state of rifaximin polymorphic forms is usually performed by DRX spectroscopy, since conventional differential scanning calorimetry (DSC) and infrared spectroscopy (IR) are unable to distinguish and quantify these polymorphs; also, the water content determined by Karl Fischer can only give indirect information about the solid state, since it is not possible to distinguish between absorbed water and water in the lattice. Furthermore, one or more hydrate and anhydrous forms of rifaximin are described.

[0009] Therefore, the conversion of these polymorphic forms is important and needs to be considered to ensure "consistency" of crystalline form in active pharmaceutical ingredients (APIs) and drug substances (Guidance for Industry ANDAs: Pharmaceutical Solid Polymorphism Chemistry, Manufacturing, and Controls Information. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) July 2007).

[0010] It should be pointed out that the "consistency", ie the reproducibility, of the polymorphic form is of great importance, especially in view of regulatory requirements.

[0011] Finally, the stability of the polymorphic forms of rifaximin is also essential for the manufacture of the drug substance (e.g., film-coated tablets). The inventors have presented experimental evidence that wet granulation and tableting can alter the initial solid state of this API: for example, wet granulation of rifaximin α-form (a method that involves the use of purified water as a binder) resulted in a significant amount of rifaximin β-form (<50%) as a result of the change in the solid state of this API from anhydrous (α-form) to hydrate (β-form).

[0012] These findings indicate the need for suitable manufacturing processes for consistent yields of rifaximin in suitable solid state suitable for minimizing solid state changes during manufacturing of drug substance. Summary of the Invention

[0013] Surprisingly, it has been found that a novel rifaximin form consisting of an α / β mixture in a relative ratio of 85 / 15±3 can be consistently produced and solves the problems of the prior art described above.

[0014] A method has been found for producing a consistent rifaximin α / β mixture in a relative ratio of 85 / 15±3 by crystallization and drying of a novel polymorphic form of rifaximin (hereinafter also referred to as wet purified rifaximin). Unexpectedly, this rifaximin α / β mixture of 85 / 15±3 is stable to the effects of physical processes used for dry granulation and tableting.

[0015] The preparation of this consistent mixture rifaximin α / β is obtained by drying the mixture of novel polymorphic forms under nitrogen with stirring at atmospheric pressure at 40° C. The rifaximin α / β mixture in relative ratio of 85 / 15±3 obtained by the above process can be utilized for preparing film coated tablets using dry granulation and tabletting methods without any reasonable modification of the relative ratio between the α and β polymorphic forms.

[0016] Therefore, the object of the present invention is a polymorphic mixture of rifaximin in the α / β forms in a relative ratio of 85 / 15±3.

[0017] Another object of the present invention is a process for the preparation of said polymorphic mixture of rifaximin in α / β forms in a relative ratio of 85 / 15±3.

[0018] Another object of the present invention is a pharmaceutical composition, in particular a solid dosage form, containing as active ingredient said polymorphic mixture of rifaximin.

[0019] The object of the present invention is a film-coated tablet containing said rifaximin polymorph and a process for the preparation of said film-coated tablet.

[0020] Another object of the present invention is the above polymorphic mixture of rifaximin for use as a medicine, especially in the treatment of traveler's diarrhea and hepatic encephalopathy.

[0021] Another object of the present invention is the polymorphic form of wet crude rifaximin obtained as an intermediate in the process for the preparation of said polymorphic mixture of rifaximin in α / β forms in a relative ratio of 85 / 15±3.

[0022] Another object of the present invention is the polymorphic form of wet purified rifaximin obtained as an intermediate in the process for the preparation of said polymorphic mixture of rifaximin in α / β forms in a relative ratio of 85 / 15±3.

[0023] Another object of the present invention is the use of said wet crude rifaximin and / or said wet purified rifaximin as intermediate in a process for the preparation of a polymorphic mixture of rifaximin in α / β forms in a relative ratio of 85 / 15±3.

[0024] These and other objects of the present invention are disclosed in detail below with reference to the figures and examples. [Brief description of the drawings]

[0025] [Figure 1]FIG. 1 is a calibration curve obtained using a standard mixture of alpha and beta forms. [Diagram 2] FIG. 2 is the DRX of wet rifaximin before crystallization. [Diagram 3] FIG. 3 is the DRX of the wet rifaximin product collected in the filter drier before drying. [Figure 4] FIG. 4 is the DRX of a rifaximin α / β polymorphic mixture with a relative ratio of 85 / 15±3. [Diagram 5] FIG. 5 is the DRX of Rifaximin uncoated tablets (dry granulation and compression). [Figure 6] FIG. 6 is the DRX of microcrystalline cellulose. [Figure 7] FIG. 7 shows the DRX of polyvinyl alcohol. [Figure 8] Figure 8 shows the DRX of FeO (red iron oxide). [Figure 9] FIG. 9 is the DRX of glycerol palmitostearate. [Figure 10] FIG. 10 is the DRX of sodium starch glycolate. [Figure 11] FIG. 11 is the DRX of polyethylene glycol 6000. [Figure 12] FIG. 12 is the DRX of hydrous silicon dioxide. [Figure 13] FIG. 13 is the DRX of talc. [Figure 14] FIG. 14 shows the DRX of titanium dioxide. [Figure 15] FIG. 15 is the DRX of rifaximin alfa form. [Figure 16] FIG. 16 is the DRX of rifaximin beta form. [Figure 17] FIG. 17 is a one-dimensional 1H-NMR (500 MHz) spectrum of a mixture of rifaximin polymorphs in tetratium-labeled methanol. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Within the scope of this invention we define "polymorphism" as the ability of a solid substance to exist in more than one form or crystal structure, known as polymorphism.

[0027] Within the scope of the present invention, the terms "consistent" and "consistent" are used as synonyms for "reproducibility" and "reproducible", terms that are well understood by those skilled in the art, particularly those skilled in the art of manufacturing APIs, also taking into account the requirements of regulatory authorities.

[0028] According to the invention, the process for preparing a mixture of rifaximin α / β polymorphs in a relative ratio of 85 / 15±3 is characterized by the following steps: a) reacting 1 molar equivalent of rifamycin O with 2 or 3 equivalents of 2-amino-4-methylpyridine in a solvent mixture of water and ethyl alcohol in a volume ratio of 1:2 to 1:3 at a temperature between 20°C and 30°C to obtain a reactant; b) treating the reaction mass at 20-30°C with ascorbic acid, followed by a solvent mixture of water and ethyl alcohol and concentrated hydrochloric acid solution, and adjusting the pH of the reaction mass to a final value of 6.0-6.5 to obtain a suspension; c) filtering the suspension and washing the resulting solid with a water / ethyl alcohol solvent mixture to obtain wet crude rifaximin; d) purifying wet crude rifaximin by dissolving in ethyl alcohol at a temperature of 50°C-60°C, adding water, then precipitating wet purified rifaximin by lowering the temperature of said suspension to 28-33°C under stirring for 1-3 hours, cooling the crystallization mixture to 20-25°C under stirring for 1-2 hours, and finally precipitating by cooling to 0-5°C for a certain period of time until obtaining a precipitate of said crystallization mixture; e) filtering the suspension through a filter drier and washing the resulting solid with water, followed by f) Dry with stirring at a temperature in the range of 38-42°C and atmospheric pressure under a stream of inert gas until a final moisture content of 6±2% is reached.

[0029] It is understood that all numerical values ​​and intervals disclosed in the method of the present invention should not be taken as absolute. Any numerical value or interval should be understood by those skilled in the art as "about". The term "about" means that, as intended herein, the numerical value disclosed herein does not have to be indicated precisely per se, and deviations from this value are also within the scope of the present invention, as long as the technical effect disclosed herein is achieved.

[0030] In a preferred embodiment of the method according to the invention, the concentration of Rifamycin O in step a) is comprised between 0.2 and 0.4 M, the relative ratio between water and ethyl alcohol is 1:2.3 and the reaction temperature is 23°C.

[0031] Preferably, the molar equivalent of ascorbic acid with respect to the starting amount of rifamycin O in step b) is comprised in the range of 1 / 8 to 1 / 10, the relative proportions of water and ethyl alcohol are comprised in the range of 65 / 35 to 60 / 40 and the final concentration of hydrochloric acid is comprised in the range of 2.5M to 3.5M.

[0032] Preferably, the relative ratio between the starting amount of Rifamycin O in step e) and the filter surface of the filter drier is 1 g / 0.6 cm 2 ~1g / 1.57cm 2 is included between.

[0033] Preferably, the stirring speed in step f) is about 15 rpm / min, the preferred temperature is 40° C., and the drying time can typically be maintained for a time interval ranging from 20 to 25 hours, more preferably about 21 hours. Preferably, the inert gas in step f) is nitrogen.

[0034] Step f) can, if desired, be carried out discontinuously without affecting the relative ratio of the obtained polymorphic forms of rifaximin.

[0035] The wet crude rifaximin recovered from step c) according to the present invention is characterized by an X-ray spectrum with characteristic 2-theta values ​​of (relative intensities): 4.88 (87%), 7.78 (74%), 12.76 (57%), 14.08 (59%), 14.66 (46%), 17.80 (50%), 18.34 (69%), 19.78 (80%), 21.22 (70%), 21.92 (74%), 23.18 (80%), 25.30 (100%) (Figure 2).

[0036] The wet purified rifaximin recovered from step e) according to the present invention is characterized by an X-ray spectrum with characteristic 2-theta values ​​of (relative intensities): 5.78 (15%), 7.32 (27%), 8.16 (40%), 9.20 (44%), 10.74 (50%), 17.56 (42%), 18.04 (75%), 18.70 (100%), 20.02 (54%), 21.24 (73%), 22.32 (54%), 23.62 (46%), 25.66 (61%) (Figure 3).

[0037] The rifaximin α / β polymorphic mixture 85 / 15±3 recovered from step f) according to the present invention is characterized by an X-ray spectrum with characteristic 2-theta values ​​of (relative intensities): 5.32 (11%), 5.78 (19%), 6.50 (27%), 7.24 (45%), 7.82 (61%), 8.80 (100%), 10.50 (59%), 11.02 (35%), 11.58 (32%), 13.08 (20%), 14.42 (26%), 17.32 (48%), 17.68 (93%), 18.58 (79%), 19.52 (61%), 21.04 (52%), 21.60 (30%), 21.92 (46%) (Figure 4).

[0038] Generally, in the process according to the present invention, Rifamycin O is dispersed in a mixture of demineralized water and ethyl alcohol in the proportions disclosed above under stirring at 20-30° C., followed by 2-amino-4-methylpyridine. The reaction mixture is kept under stirring for a sufficient time to allow reaction, preferably 20-25 hours at 20-25° C.

[0039] During this time, L-ascorbic acid was added to the reaction mixture and the pH was adjusted to a final value of 6.0-6.5 by adding 3M HCl in a water / ethanol solution (e.g., 62 / 38 v / v) under stirring at 20-30° C. The reaction mixture was then cooled to 8-12° C. with stirring for a sufficient time to obtain a large amount of precipitate, typically 2 hours, and the suspension was filtered through a Buchner (or other equivalent) filter. The recovered solid on the filter was washed with an ethanol / water mixture, e.g., 1 / 1 v / v, and used as such for the next step of crystallization.

[0040] The wet product recovered in the previous step is then dispersed in ethanol and heated with stirring until a solution is obtained. Conveniently, heating is at about 50-60°C. Water is then added, keeping the heating temperature, conveniently at about 50-60°C. The reaction mixture is cooled to 28-33°C to obtain a precipitate. The suspension obtained is kept at 28-33°C with stirring for 2 hours, then cooled to 20-25°C and stirred at this temperature for 1 hour, and finally cooled to 0-5°C and stirred at this temperature for the time required to obtain a large amount of precipitate, usually 1 hour. The suspension obtained is filtered and the recovered solid is washed with water.

[0041] The wet purified rifaximin recovered on the filter (a novel polymorphic form defined by a characteristic DRX (powder) spectrum; FIG. 3) is dried (e.g., for 21 hours) under stirring under a stream of inert gas at a temperature of 40° C. until a water content of 6.0±2% (as determined by the Karl Fischer method) is reached, resulting in rifaximin as an α / β polymorphic mixture in a relative ratio of 85 / 15±3.

[0042] The method according to the invention shows advantageous consistency in obtaining identical polymorphic mixtures after multiple iterations with a variation of ±3% (82 / 18 to 88 / 12 for the α / β polymorphic mixture).

[0043] Advantageously, the α / β polymorphic mixture obtained by the method of the present invention is stable when stored at room temperature for up to six months.

[0044] The rifaximin mixture disclosed in the present invention is highly useful for the preparation of pharmaceutical compositions containing it as an active ingredient.

[0045] The compositions may contain any of the conventional vehicles, excipients, and formulation ingredients and may be prepared according to general knowledge in the art. General references can be found, for example, in Remington "The Science and Practice of Pharmacy, 21st edition Pharmaceutical Press.

[0046] In a preferred embodiment of the present invention, the rifaximin mixture disclosed above is useful for the manufacture of film-coated tablets.

[0047] Said compositions can be manufactured according to general knowledge in the art. General references can be found, for example, in Pharmaceutical Manufacturing Handbook: Production and Processes, Shayne Cox Gad, John Wiley & Sons, 2008.

[0048] The compositions may contain any of the conventional vehicles, excipients, and formulation ingredients used in coating techniques for solid pharmaceutical compositions, such as talc, microcrystalline cellulose, glycerol palmitostearate, sodium starch glycolate, and hydrous silicon dioxide.

[0049] Thus, another object of the present invention is a process for the preparation of film-coated tablets, characterized in that: a') A mixture of rifaximin α / β polymorphs in a relative ratio of 85 / 15±3 is mixed with suitable excipients at room temperature to obtain a homogenous mixture; b') processing the blend from step a') by dry granulation / compression and sieving the same through a 20 mesh sieve to obtain a blend; c') compressing the mixture obtained in step b') to obtain tablets having a disintegration time in purified water at 37°C of 1'20''±15''; d') Coating the tablets obtained in step c') with suitable coating agents, plasticizers and opacifiers.

[0050] Step a') may preferably be carried out using excipients such as microcrystalline cellulose, sodium starch glycolate, glycerol palmitostearate, hydrous silicon dioxide and talc in relative proportions in the ranges 33±3%, 4±0.4%, 4.9±0.5%, 0.5±0.05% and 3.0±0.3%.

[0051] Step d') can preferably be carried out using coating agents such as polyvinyl alcohol or hydroxypropylmethylcellulose, plasticizers such as polyethylene glycol, dibutyl sebacate, citrate esters, triacetin, and opacifiers such as titanium dioxide and aluminum lacquers, more preferably polyvinyl alcohol, polyethylene glycol and titanium dioxide.

[0052] The uncoated tablets recovered from step c') according to the invention are characterized by an X-ray spectrum with characteristic 2-theta values ​​at (relative intensities): 5.28 (15%), 5.78 (23%), 6.52 (46%), 7.26 (47%), 7.88 (75%), 8.82 (42%), 10.52 (46%), 11.02 (45%), 11.58 (40%), 13.12 (37%), 14.48 (42%), 17.38 (56%), 17.72 (62%), 18.62 (93%), 19.54 (72%), 21.10 (87%), 21.64 (82%), 22.00 (100%). The following diagnostic peaks of the excipients used are also detectable in the DRX spectra (2-theta values, relative intensities of the diffraction peaks in brackets): 19.10 (50%) and 28.72 (40%) for talc; 22.36 (99%) for microcrystalline cellulose; 21.10 (87%) for glycerol palmitostearate; 45.74 (36%) for sodium starch glycolate; hydrous silicon dioxide is amorphous and has no diffraction peaks (Figure 5).

[0053] In an exemplary embodiment of the present invention, film-coated tablets containing the rifaximin alpha / beta polymorph mixture are prepared as starting material with a tableting mixture. The rifaximin alpha / beta polymorph mixture is mixed with the usual excipients known in the art of film-coated tablets, such as microcrystalline cellulose, sodium starch glycolate, glycerol palmitostearate and talc. Other excipients can be used according to the general knowledge in the art. The components are mixed in a suitable mixing device for a sufficient time to obtain a homogeneous mixture. Typically, a few minutes is sufficient. The resulting mixture is then compressed / granulated by using a conventional compactor (e.g., a WP50 N / 75 compactor). The resulting granulation is sieved with a suitable size, such as about 20 mesh. A lubricant is added, such as one or more of glycerol palmitostearate, talc, hydrous silicon dioxide. Conveniently, the excipients are also pre-passed through a sieve of the same size as the granulation. Mixing is carried out in a suitable mixer for a suitable period of time, typically several minutes, and the mixture is compressed either by a rotary tablet press or other conventional equipment.

[0054] In a preferred embodiment, the tablet according to the invention has the following technical characteristics: hardness - 18.49 ± 1.30 Kp; thickness - 5.48 ± 0.06 mm; friability - 0.058%; disintegration time in purified water at 37°C - 1'20''.

[0055] Film coating is applied by any suitable known technique, for example in a coating pan by spraying a water suspension containing a film coating agent (e.g. polyvinyl alcohol or other equivalent) and a plasticizer (e.g. polyethylene glycol or other equivalent), and optionally an opacifier (e.g. titanium dioxide) and / or a colorant (e.g. red iron oxide). Preferably, the coated tablets are produced by maintaining the tablet bed at a temperature of 40° C. or less throughout the entire coating process.

[0056] Packaging is done according to conventional manufacturing processes, for example aluminium / plastic blisters.

[0057] According to another object of the present invention, the rifaximin polymorphic mixture disclosed herein is for use as a medicine, particularly for the treatment of traveler's diarrhea and hepatic encephalopathy.

[0058] The dosage, method of administration and clinical indications can be determined by those skilled in the art on the basis of general knowledge, as shown, for example, in US7902206, US7906542, US8158644 and US7928115 for coated or uncoated tablets, hard and soft gelatin capsules and powders in sealed pouches. EXAMPLES

[0059] The following examples further illustrate the invention.

[0060] material and method X-ray diffraction spectra were recorded by a diffractometer (Rigaku-D-Max) from a starting angle [1 / 2 2-theta] of 5.000-60.000. Diffractograms were obtained with a Cu anode (Kα=1.54060 Å and Kα=1.54439 Å). The relative ratio between the alpha and beta polymorphic forms was determined by DRX (powder) using a calibration curve obtained with two samples of rifaximin prepared by mixing the pure alpha (DRX: FIG. 15) and the pure beta (DRX: FIG. 16) forms in relative proportions of 80 / 20 and 90 / 10 (these samples were prepared according to EP1557421). The diagnostic diffraction peaks considered to quantify the relative ratio between the alpha and beta forms are: Alpha form: diffraction peak at approximately 5.9 2theta Beta form: diffraction peak at about 5.3 2theta

[0061] Said calibration curve was prepared by considering the intensity of the diffraction peak at 5.2 2-theta (beta form) divided by the intensity of the diffraction peak at 5.9 2-theta (alpha form) (see FIG. 1).

[0062] Example 1 Manufacturing of wet crude rifaximin Rifamycin O (50 g) is dispersed in a mixture of demineralized water (60 ml) and ethyl alcohol (140 ml) under stirring at room temperature, followed by 2-amino-4-methylpyridine (20.8 g). The reaction mixture is maintained under stirring at 20-30°C for 20-23 hours.

[0063] After this, L-ascorbic acid (1.4 g) was added to the reaction mixture and the pH was adjusted to a final value of 6.0-6.5 by adding 3M HCl in water / ethanol 62 / 38 v / v solution under stirring at room temperature. The reaction mixture was then kept under stirring for 2 hours, cooled to 8-12°C and filtered through a Buchner filter. The solid recovered on the filter (approximately 90.2 g wet product (54% loss on drying); 30% water content) was washed with a 1 / 1 ethanol / water mixture (242 ml) and used directly for the next step of crystallization. This new polymorphic form is defined by the DRX as shown in Figure 2. Characteristic 2-theta values ​​(relative intensities) for this polymorphic form are: 4.88 (87%), 7.78 (74%), 12.76 (57%), 14.08 (59%), 14.66 (46%), 17.80 (50%), 18.34 (69%), 19.78 (80%), 21.22 (70%), 21.92 (74%), 23.18 (80%), and 25.30 (100%).

[0064] Example 2 Preparation of a rifaximin α / β polymorphic mixture in a relative ratio of 83 / 17 from wet crude rifaximin The wet crude rifaximin recovered in the previous step was dispersed in ethanol (80.5 ml) and heated with stirring at 50-60°C (to obtain a solution), followed by addition of water (16.5 ml) while maintaining the temperature at 50-60°C. The reaction mixture was cooled to 28-33°C to obtain a precipitate. The resulting suspension was maintained at 28-33°C with stirring for 2 hours, then cooled to 20-25°C and stirred at this temperature for 1 hour, and finally brought to 0-5°C and stirred at this temperature for 1 hour. The resulting suspension was filtered through a laboratory filter drier (GFD® Mod. PF00002ATEX) and the collected solid was washed on the filter with water (62.2 ml).

[0065] The wet product recovered on the filter (defined by DRX powder and identified as wet purified rifaximin; Figure 3) was stirred (15 rpm / m) at a temperature of 40 °C and dried under nitrogen flow for 21 h to reach a moisture content of 6.0% (determined by Karl Fisher). 32 g of rifaximin was obtained as an α / β polymorphic mixture in a relative ratio of 87 / 13 (determined by DRX powder as described in Figure 4). The physicochemical data of the obtained sample are in agreement with the proposed structure and published literature data (R. Stradi et al. Journal Pharmaceutical and Biomedical Analysis, 51 (2010), 858-865); one-dimensional analysis of the obtained sample in tetratium-labeled methanol was performed. 1 The H-NMR (500 MHz) spectrum is shown in FIG.

[0066] Relevant peaks in the DRX spectrum of wet purified rifaximin recovered on the filter are detected at the following 2-theta values ​​(relative intensity): 5.78 (15%), 7.32 (27%), 8.16 (40%), 9.20 (44%), 10.74 (50%), 17.56 (42%), 18.04 (75%), 18.70 (100%), 20.02 (54%), 21.24 (73%), 22.32 (54%), 23.62 (46%), 25.66 (61%) (Figure 3).

[0067] The relevant peaks in the DRX spectrum of the rifaximin α / β polymorphic mixture in a relative ratio of 87 / 13 are detected at the following 2-theta values ​​(relative intensities): 5.32 (11%), 5.78 (19%), 6.50 (27%), 7.24 (45%), 7.82 (61%), 8.80 (100%), 10.50 (59%), 11.02 (35%), 11.58 (32%), 13.08 (20%), 14.42 (26%), 17.32 (48%), 17.68 (93%), 18.58 (79%), 19.52 (61%), 21.04 (52%), 21.60 (30%), 21.92 (46%) (Figure 4).

[0068] Example 3 Consistency of polymorphic mixtures The consistency of this method was examined by repeating the method three times, which yielded identical polymorphic mixtures with ±3% variability (α / β polymorphic mixtures of 82 / 18 to 88 / 12).

[0069] Example 4 Stability of polymorphic mixtures The stability of a sample of rifaximin α / β polymorphic mixture 88 / 12 using double polyethylene bags as temporary packaging at room temperature was confirmed by repeating the DRX (powder) analysis of the same batch after time = 0, 3 months and 6 months.

[0070] Example 5 Dry granulation and tableting of rifaximin α / β polymorphic mixture with relative ratio of 85 / 15±3 Preparation of the tableting mixture Rifaximin α / β polymorph mixture in relative ratio of 85 / 15±3 (452.86 g), microcrystalline cellulose (259.90 g / Vivapur PH102), sodium starch glycolate (16.824 g), glycerol palmitostearate (20.040 g / Precirol ATO5) and talc (1.203 g) are mixed in a suitable mixing device for 5 minutes. The mixture is then compressed / granulated using a compactor WP50 N / 75.

[0071] Only a portion of these granules was used for the next step. The resulting granules (556.76 g) were sieved through a 20 mesh sieve, together with glycerol palmitostearate (14.87 g / Precirol ATO5), talc (4.68 g), hydrous silicon dioxide (2.97 g / Syloid 244) (all excipients previously sieved through a 20 mesh sieve) and mixed in a suitable mixer for 5 minutes. The composition of the tableting mixture is as follows:

[0072] Dry granulation of rifaximin tableting composition [Table 1]

[0073] Tableting results The mixture is compressed by a rotary tablet press Ronchi EA8 equipped with 22x10 mm oval punches. Tablets are obtained with the following technical characteristics: hardness - 18.49 ± 1.30 Kp; thickness - 5.48 ± 0.06 mm; friability - 0.058%; disintegration time in purified water at 37°C - 1'20''.

[0074] The formulation for coating tablets is described below: The film coating was applied in a suitable coating pan by spraying an aqueous suspension containing a film coating agent (polyvinyl alcohol) and a plasticizer (polyethylene glycol) and an opacifier (titanium dioxide) and a colorant (red iron oxide). The coated tablets were prepared by maintaining the tablet bed at a temperature of 40° C. or less throughout the entire coating process.

[0075] The rifaximin tablet composition after coating process is described below. [Table 2]

[0076] The tablets obtained before coating were lightly crushed in a mortar and tested by DRX (powder): these analyses confirm that rifaximin is present in an unchanged relative ratio between the α / β polymorphic forms of 85 / 15±3 (Figure 5); in this DRX spectrum the following diagnostic peaks are detected for the excipients used: 19.10 (50%) and 28.72 (40%) for talc; 22.36 (99%) for microcrystalline cellulose; 21.10 (87%) for glycerol palmitostearate; 45.74 (36%) for sodium starch glycolate; hydrous silicon dioxide is amorphous and has no diffraction peaks.

[0077] In Figures 6-14, DRX spectra of the excipients used were collected; the diffraction peaks of the excipients do not interfere with the diagnostic peaks used for the relative quantification of rifaximin α and β forms (see Materials and Methods).

Claims

1. A polymorphic mixture of rifaximin in the α / β forms in a relative ratio of 85 / 15±3.

2. 2. A process for preparing the rifaximin polymorphic mixture of claim 1, comprising: a) reacting 1 molar equivalent of Rifamycin O with 2 or 3 equivalents of 2-amino-4-methylpyridine in a solvent mixture of water and ethyl alcohol in a volume ratio between 1:2 and 1:3 at a temperature between 20°C and 30°C to obtain a reactant; b) treating the reaction mass at 20-30° C. with ascorbic acid, followed by a mixture of water and ethyl alcohol and concentrated hydrochloric acid solution to adjust the pH of the reaction mass to a final value of 6.0-6.5 to obtain a suspension; c) filtering the suspension and washing the resulting solid with a water / ethyl alcohol solvent mixture to obtain wet crude rifaximin; d) purifying the wet crude rifaximin by dissolving it in ethyl alcohol at a temperature of 50°C-60°C, adding water, then precipitating the wet purified rifaximin by lowering the temperature of the suspension to 28-33°C under stirring for 1-3 hours, cooling the crystallization mixture to 20-25°C under stirring for 1-2 hours, and finally precipitating by cooling to 0-5°C for a certain period of time until obtaining a precipitate of the crystallization mixture; e) filtering the suspension through a filter drier and washing the resulting solid with water, followed by f) drying with stirring at a temperature ranging from 38°C to 42°C under atmospheric pressure and inert gas flow for a period of time to reach a final moisture content of 6±2%; The method comprising:

3. 2. The rifaximin polymorphic mixture according to claim 1 for use as a medicament.

4. 2. The rifaximin polymorphic mixture of claim 1 for use in the treatment of traveller's diarrhea and hepatic encephalopathy.

5. 10. A pharmaceutical composition comprising the rifaximin polymorphic mixture of claim 1 as an active ingredient.

6. Use of the rifaximin polymorphic mixture according to claim 1 for the preparation of a solid dosage form.

7. 2. A film-coated tablet comprising the rifaximin polymorphic mixture of claim 1.

8. A method for producing a film-coated tablet according to claim 7, comprising the steps of: a') mixing the rifaximin α / β polymorph mixture according to claim 1 with suitable excipients at room temperature to obtain a homogenous mixture; b') subjecting the mixture from step a') to dry granulation / compression and sieving to obtain a mixture; c') compressing the mixture obtained in step b') to provide tablets; d') coating the tablets obtained in step c') with a suitable coating, optionally with conventional excipients. The method comprising:

9. The method according to claim 8, wherein in step d') the usual excipients are plasticizers and / or opacifiers.

10. A wet crude rifaximin polymorphic form obtained by steps a) to c) of the process according to claim 2.

11. A wet purified polymorphic form of rifaximin obtained by steps d) to e) of the process according to claim 2.

12. Use of the wet crude rifaximin according to claim 10 as an intermediate in the process for the preparation of a polymorphic mixture of rifaximin in α / β forms in a relative ratio of 85 / 15±3.

13. 12. Use of the moist purified rifaximin according to claim 11 as an intermediate in the process for the preparation of a polymorphic mixture of rifaximin in α / β forms in a relative ratio of 85 / 15±3.

Images