WO2012060675A1

WO2012060675A1 - Process for the preparation of amorphous rifaximin

Info

Publication number: WO2012060675A1
Application number: PCT/MX2010/000123
Authority: WO
Inventors: Umberto Bruno Casazza; Aaron RODRÍGUEZ WELTON
Original assignee: Interquim, S.A. De C.V.
Priority date: 2010-11-05
Filing date: 2010-11-05
Publication date: 2012-05-10

Abstract

The present invention discloses a process for the obtainment of Rifaximin in the amorphous form thereof through managing the original basic pH of the reaction between Rifamycin O and 2-amino-4-methylpyridine and the purification thereof with ethanol. It is thus demonstrated that Rifaximin obtained in this manner does not depend on moisture content to determine the crystalline form thereof, but that it is a function of pH. Furthermore, conversion of the α, β or γ crystalline form to the amorphous form is realized through changing the pH from acidic to basic, confirming that the form of the crystal does not depend on moisture content.

Description

PROCESS FOR THE PREPARATION OF RIFAXIMINE AMORFA

FIELD OF THE INVENTION

This invention relates to a process of preparing rifaximin in a stable amorphous form.

BACKGROUND

Rifaximin is a bactericidal antibiotic molecule, with a broad spectrum of action on Gram-positive and Gram-negative bacteria, both aerobic and anaerobic. Its absorption in the gastrointestinal tract is practically nil (less than 1%), which favors the concentration of the drug in the intestinal lumen and, especially, in the feces in active form.

Rifaximin is a semi-synthetic antibiotic, derived from rifamycin. The introduction of a pyridoimidazole group in the basic structure of rifamycins makes this antibiotic practically not absorbed through the digestive tract.

GB 2,079,270 discloses imidazo-rifamycin derivatives that have antibacterial activity, prepared from 3S-halo-rifamycin. US Patent No. 4,341,785 and EP 0.161,534 describe the processes for preparing rifaximin from pyridoimidazole rifamycin O. The above patents detail a generic method for purification of rifaximin in convenient solvent systems such as chloride of methylene, chloroform, methanol, ethanol, isopropanol. Water is generally used as an anti-solvent. The polymorphic form of rifaximin obtained by these methods was not disclosed. Recently, three polymorphic forms of Rifaximin were described in Ü.SA Patent No. 7,045,620, identified as α, β, and y. The point of differentiation between these forms is their water content and respective diffraction X-ray diffraction (dust) {PXRD). These forms are interchangeable and, therefore, obtaining a specific polymorphic form is dependent on the drying conditions. The form and mentioned in US Patent No. 7,045,620 is described as a non-crystalline form with a high content of the amorphous component. It is characterized by having a water content between 1.0% and 2.0% and having a PXRD diffractometer with some significant peaks at 5.0, 7.1 and 8.4 (two-theta). Particularly, this form is prepared by dissolving in ethanol followed by the addition of water. It is also significant that this form is prone to conversion to other polymorphic forms in contact with, for example, moisture. This is a disadvantage since it is highly desirable to have an active pharmaceutical ingredient that is polymorphically stable and suitable for pharmaceutical uses (see Konne,., Chem. Pharma. Bulletin, 38, P. 2003, (1990)). EP 1,698,630 teaches two new polymorphic forms (δ and ε.). These forms are also obtained with the same method described above and their specific crystalline structures are again dependent on the water content.

Clearly, in the state of the art it is accepted that the crystalline and amorphous forms of rifaximin are dependent on the degree of existing moisture. In the Mexican application 2007/001070, called "PROCESS OF SYNTHESIS OF RIFAXIMIN, COMPOSITIONS AND USE OF THE SAME" IN ERQOÍM, SA DE CV describes a process of synthesis of rifaximin by the reaction of rifamycin O with 2-amino-4- methylpyridine in the presence of ascorbic acid, extracting the resulting product by ethanol.

In Mexican patent application / 2009/002445, ALFA WASSERMANN SPA; called "USE OF POLYOLS TO OBTAIN STABLE POLYMORPH FORMS OF RIFAXYMIN" describes polyols that stabilize the polymorphic form of rifaximin, in particular the form &; when polyols with at least two hydroxy groups are added to the rifaximin powder, the β polymorph is stable and remains stable over time, regardless of ambient humidity; A method for preparing formulations consisting of pure and stable polymorphic forms capable of giving a pharmaceutical product is also described. Mexican Patent No. 260156; VISCOMI, Giuseppe C. et al-, referred to as "RIFAXYMIN POLYMORPHIC FORMS AS ANTIBIOTICS", polymorphic crystalline forms of the antibiotic rifaximin (INN) called rifaximin α and rifaximin β are disclosed, a poorly crystalline form called rifaximin and. In Mexican patent application number 2007/010742; ALFA WASSERMANN SPA, called "NEW RIFAXIMIN POLYMORPHIC FORMS, PROCEDURES FOR THEIR PRODUCTION AND USE OF THE SAME IN MEDICINAL PREPARATIONS" crystalline polymorphic forms of rifaximin antibiotic (INN) known as rifaximin δ and rifaximin ε useful in the preparation of medicinal preparations are disclosed containing rifaximin for oral and topical use and obtained by means of a crystallization procedure that is carried out by hot dissolving the raw rifaximin in ethyl alcohol and by causing the crystallization of the product by adding water at a certain temperature and during a determined period, followed by a drying that is carried out under controlled conditions until reaching a fixed water content in the final product, are the object of the invention.

US Patent 7, 709, 634 published on May 4, 2010, called "Stable form of rifaximin and process for its preparation"; a chemically and polymorphically stable form is disclosed, which can be prepared by dissolving rifaximin in a solvent to form a solution, which is precipitated by adding an anti-solvent and isolating precipitated amorphous rifaximin as the final product. In the US patent application publication number 2010/0137580, June 3, 2010, "Process for the preparation of amorphous rifaximin and the 'amorphous rifaximin obtained" describes a process capable of obtaining Rifaximin in a totally amorphous form. The process comprises dissolving raw Rifaximin in hot absolute ethanol and collecting the amorphous rifaximin by cooling the mixture.

Therefore, it is an object of the present invention to provide a pure and stable amorphous form of rifaximin, prepared using an acceptable industrial process, that overcomes the deficiencies of the prior art. 3

OBJECT OF THE INVENTION

The present invention aims to prepare Rifaximin in its amorphous form by handling the original basic pH of the reaction between Rifamycin O and 2-Amino-4-methylpyridine and its purification with Ethanol.

It also aims to demonstrate that Rifaximin obtained in this way does not depend on the moisture content to determine its crystalline form, but that it is a function of pH.

Still another object of the present invention is to effect the conversion of the crystalline form α, β or γ to the amorphous form by the change of acidic to basic pH confirming that the crystal form does not depend on the moisture content.

Moreover, it is the object of the present invention to disclose a stable amorphous form of rifaximin. Preferably, the stable amorphous form of rifaximin is characterized by having peaks of the X-ray powder diffraction pattern, as illustrated in fig. 1, expressed in Intensity vs 28 / degree.

Additional objects of the invention will become apparent to those skilled in the art in view of the following detailed description of the invention, as well as its different modalities. SUMMARY OF THE INVENTION

The present invention demonstrates that amorphous Rifaximin can be obtained independently of the moisture content, and that said form depends on the basic pH. As well as the fact that it is possible to convert the crystalline form α, β or γ to the form amorphous by the change of acidic pH to basic confirming that the shape of the crystal does not depend on the moisture content.

Surprisingly, this form is chemically and polymorphically stable and is relatively unaffected by external parameters such as; Ambient humidity For example, exposure of the amorphous form of the present invention to ambient humidity for a period of 10 days did not change the polymorphic form as indicated by the PXRD analyzes. The high production of the amorphous form of rifaximin is obtained with the processes of the present invention and has high chemical purity.

The present invention provides a process for the preparation of the stable amorphous form of rifaximin comprising:

a) obtain Rifaximin in its different crystalline forms (α, β and), reacting Rifamycin O (1 molar equivalent) with 2-Amino-4-methylpyridine (2.5 to 3.5 molar equivalent), in a system of protic solvents and aprotic

b) adjust the pH from 2.0 to 3.0 with hydrochloric acid / ascorbic acid, and

c) purify with Ethanol / Water.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 illustrates the X-ray diffractometer

(powders) of Rifaximin in the polymorphic form α

Fig. 2 and 3 illustrate the X-ray diffractometers (powders) of Rifaximins with the amorphous form

Fig. 4 and 5 illustrate the X-ray diffractogram (powders) of Rifaximins in the amorphous form of pilot batches. Fig. 6 illustrates the X-ray diffractogram (powders) of Rifaximin in the amorphous form of a recovery lot.

Fig. 7 and 8 illustrate the Dif X-ray actomegrams (powders) of Rifaximin with the amorphous form (to these Rifaximins the conversion of α crystal to amorphous form was performed).

DETAILED DESCRIPTION OF THE INVENTION

Obtaining Rfa imina amorphous.

Amorphous rifaximin is obtained by adding a mixture of demineralized water, potable ethanol and acetone, rifamycin O and 2-Amino-4-methylpyridine, at pH 9.0 to 9.5, stir at a temperature of 23-27 ° C for 22 hours. Cool the reaction mixture to 5-10 ° C and keep at this temperature for 30 minutes.

Filter and wash with a mixture of potable ethanol / demineralized water (1: 1) and then 2 washes with demineralized water. It is dried under vacuum at 70 ° C, to a humidity below 4.5%.

Raw amorphous rifaximin is purified by adding a mixture of anhydrous ethanol and potable ethanol, 1: 1, raw amorphous Rifaximin. This suspension is heated at 40 +/- 2 ° C, with stirring and maintained at this temperature for 3 hours. It is cooled to 10 + 1 ° C and maintained for 30 minutes at this temperature. Filter and wash with a drinkable Ethanol / Demineralized Water (1: 1) mixture.

It is dried under vacuum at 70 ° C, to a humidity below 4.5%. The overall yield is 75 to 78% w / w, compared to Rifamycin O. Pure amorphous Rifaximin obtained meets the specifications established in the European Pharmacopoeia, sixth edition, supplement 6.5 (2009).

Conversion of the crystalline form of Rifax mine α, β or γ to the amorphous form.

For the conversion of α, β or γ crystal to amorphous crystal, Rifaximin was dissolved in any of its crystalline forms in Acetone, and subsequent addition of demineralized Water, using the pH at 9.5 with an alkaline Hydroxide solution sodium, potassium hydroxide, sodium carbonate, ammonium hydroxide or similar base.

With subsequent distillation of the solvent, obtaining the raw amorphous Rifaximin, its purification was carried out according to the established procedure.

This amorphous Rifaximin was also identified and characterized by the X-ray diffraction technique.

Two different devices were used for the identification and characterization of the Rifaximin samples, using X-ray Diffraction analysis (powders). DRIFA-570908 C2 samples; DRIFA-720910 RIFA- 50022002 and RIFA- 002100: 6 (Figures 2, 3, 6 and 8) were analyzed at the Institute of Physics, ÜNAM, Crystal Structures Refining Laboratory, on a BRüJKER D8 ADVANCE diffractometer, using Ka radiation Cu; at 40kV, 30mA; under the following conditions: from 2 to 40 ° 2Θ, at 0.01945 ° (2θ) / 81 seconds in 16:21 minutes. RIFA-011002 samples; RIFA-40011003 and DRIFA-20031005 Figures 4, 5 and 7 were analyzed in the USAI, Faculty of Chemistry, DNAM, on a SIEMENS D5000 diffractometer, using Cu radiation Ka (λ = 1.05406 A); at 35 kV, 30 mA; under the following conditions: from 2 to 60 ° 2θ, at I ^or (2θ) / minute in 57 minutes. Results

Amorphous Rifaximin was identified and characterized by the X-ray diffraction technique (powders).

It was found that the formation of amorphous Rifaximin depends on the pH value (7.5-10.5) in the reaction solution and that it does not depend on the humidity (KF) at which it is found, for this work was carried out in a humidity range (KF) from 0.5 to 5.0%.

These results highlight a relevant importance for the manufacturing conditions of the amorphous Rifaximin, whose manufacturing and drying stages are not considered critical for obtaining the amorphous product, as well as its handling and storage conditions. Lot% Humidity (KF)

DRIFA-570908 C2 3.38

DRIFA-720910 3.27

RIFA-011002 3.26

RIFA-40011003 0.70

RIFA-50011002 2.5

The following examples illustrate the best way to put the present invention into practice, without necessarily being limiting, since since a technician with average knowledge in the field will be able to deduce other modalities which are also part of the present invention: Example 1.

Preparation of raw amorphous Rifaximin.

In a 3-mouth glass ball flask equipped with mechanical agitation and thermometer, 200 mL of demineralized water, 150 mL of potable ethanol, 50 mL of acetone, 100 grams of Rifamycin O and 43.03 g are added at room temperature. of 2-Amino-4-methylpyridine, pH = 9.3, are stirred at a temperature of 23-27 ° C for 22 hours. It is cooled to 5-10 ° C and maintained at this temperature for 30 minutes.

Filter and wash with 10 mL of drinkable Ethanol / Demineralized Water (1: 1) mixture and then 2 washes with 100 mL each of Demineralized Water.

It is dried under vacuum at 70 ° C, to a humidity below 4.5%. 85 to 90 grams of raw amorphous Rifaximin are obtained.

Preparation of pure amorphous Rifaxim na

In a 3-mouth ball flask equipped with mechanical stirring, condenser and thermometer, 135 mL of anhydrous ethanol are added at room temperature; 135 mL of drinking ethanol and 90 ^; grams of raw amorphous rifaximin. The suspension is heated at 40 +/- 2 ° C, with stirring and maintained at this temperature for hours.

It is cooled to 10 + 1 ° C and maintained for 30 minutes at this temperature.

Filter and wash with 90 mL of potable ethanol / demineralized water (1: 1) mixture.

It is dried under vacuum at 70 ° C, to a humidity below 4.5%.

75 to 78 g are obtained. of pure amorphous Rifaximin, which meets the specifications established in the European Pharmacopoeia, sixth edition, supplement 6.5 (2009). Overall yield 75 to 78% w / w, compared to Rifamycin O

EXAMPLE 2

Obtaining Rifax mine, β or γ.

Rifaximin α, β and γ crude is obtained according to the technique described in the patent DS 2008/0262024 Al and is purified according to the procedure established therein.

This Rifaximin was identified and characterized by the X-ray diffraction technique (powder), obtaining a crystal defined as seen in the diffractometer of Figure 1. EXAMPLE 3

Obtaining amorphous Rifaximin from Ri aximin a, β or γ.

In a 3-mouth ball flask equipped with mechanical stirring, condenser and thermometer, 150 mL of Acetone and 50 grams of Rifaximin α, β or y are added at room temperature.

With stirring, 100 mL of demineralized water are added, over a period of 30 minutes.

Leave with stirring for 1 to 15 minutes.

The pH is adjusted to 9.4-9.6 with concentrated ammonium hydroxide.

50 mL of demineralized water are added over a period of 10 to 15 minutes.

It is heated to 50-55 ° C and 70-80% of the solvent is distilled off.

It is cooled to 10 + 1 ° C and maintained at this temperature for SO minutes.

Filter and wash with 5 mL of drinkable Ethanol / Demineralized Water (1: 1) mixture and then 2 washes with 100 mL each of Demineralized Water.

It is dried under vacuum at 70 ° C, to a humidity below 4.5%.

45 to 48 grams of raw amorphous Rifaximin are obtained.

It is purified according to the procedure established in example 1.

41 to 42 g are obtained. of pure amorphous Rifaximin, which meets the specifications established in the European Pharmacopoeia, sixth edition, supplement 6.5 (2009).

Claims

Process for the preparation of rifaximin characterized in that it comprises the following add to a mixture of demineralized water, potable ethanol and acetone,

2: 1.5: 0.5, Rifamycin O and 2-Amino-4-methylpyridine,

stir at a temperature between 20 to 40 ° C for 22 hours, maintaining the pH from 9.0 to 9.5, preferably at pH 9.

3;

cool to 5-10 ° C and keep the temperature for 30 minutes;

filter and wash with a mixture of potable ethanol / demineralized water (1: 1) and then 2 washes with demineralized water; and dry under vacuum at 70 ° C, to a humidity below 4.5% 2.- The process according to claim 1, characterized in that the ratio of Rifamycin O to 2- Amino-4-methylpyridine is between 1: 1.5 to 4.0, preferably 1: 2.0 to 3.0 3. The process according to claim 1, characterized in that the reaction temperature is preferably 20 to 40 ° C, more preferably 20-30 ° C.

4.- Process for the preparation of amorphous rifaximin, characterized in that it comprises the following stages:

to. dissolve crystalline Rifaximin α, β or y, in acetone at room temperature;

b. stir with demineralized water, in a period of 30 minutes and stir the mixture for 10 to 15 minutes;

C. adjust the pH from 9.4 to 9.6 with a concentrated hydroxide;

d. add demineralized water in a period of 10 to 15 minutes;

and. heat at 50-55 ° C and distill 70-80% of the solvent;

f. cool to approximately 10 + 1 ° C and keep at this temperature for 30 minutes;

g. filter and wash with a mixture of potable ethanol / demineralized water (1: 1) and then wash twice with demineralized water;

h. dry under vacuum at 70 ° C, to a humidity below 4.5%; and purify.

5. The process according to claim 4, characterized in that the hydroxide is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide or similar bases.

6. The process according to claim 1 or 4, characterized in that the amorphous rifaximin is purified by the following process: to. suspend raw amorphous Rifaximin in anhydrous ethanol and potable ethanol at room temperature;

b. heat to approximately 40 +/- 2 ° C, with stirring and keep the temperature for 3 hours; C. cool to 104 / - 1 ° C and keep the temperature for 30 minutes; Y

d. filter and wash

7. The amorphous rifaximin obtained according to the process of claim 1, characterized in that it is stable for up to 10 days under conditions of ambient humidity.