ITMI20110983A1 - RIFAXIMINA AMORPHOUS AND PROCESS FOR ITS PREPARATION - Google Patents

Description

Patent application for industrial invention entitled

"RIFAXIMINA AMORPHOUS AND PROCESS FOR ITS PREPARATION"

Field of the invention

The invention relates to a new amorphous form of rifaximin and a process for its preparation. The invention also relates to the pharmaceutical compositions that contain it and their therapeutic use.

State of the art

Rifaximin, whose IUPAC name is (2S, 16Z, 18E, 20S, 21S, 22R, 23R, 24R, 25S, 26S, 27S, 28E) -5,6,21,23,25-pentahydroxy-27-methoxy- 2,4,11,16,20,22,24,26-octamethyl-2,7- (epoxypentadeca- [1, 11,1 3] -trienimino) -benzofuro- [4,5-e] -pirido- [ 1,2-a] -benzimidazol-1,15 (2 / - /) - dione, 25-acetate, is the compound of formula (I):

(THE)

As known, it is a broad spectrum antibiotic belonging to the rifamycin family, devoid of systemic activity. Due to its chemical-physical properties, it is not absorbed in the gastrointestinal tract and therefore exerts its antimicrobial action within the gastrointestinal tract. Rifaximin therefore finds application in the treatment of diarrhea and microbial infections of the gastrointestinal tract typically caused by E. coli, a microorganism which, being unable to cross the mucosa of the gastrointestinal tract, remains in contact with gastrointestinal fluids. Rifaximin is also used in the treatment of irritable bowel syndrome, Crohn's disease, diverticulitis and in the prophylactic antibiotic treatment that precedes bowel surgery.

Rifaximin was described for the first time in US patent 4,341,785 together with a process for its preparation and purification. This purification is described generically as obtainable by extraction with solvents such as ethyl acetate, chloroform, methylene chloride, analogues or mixtures thereof. Alternatively, purification can be carried out by crystallization from solvents selected from water, methanol, ethanol, n-propanol, isopropanol, nesane, ethyl acetate, methylene chloride, chloroform, ethylene glycol monomethyl ether and their mixtures. This patent does not, however, mention either amorphous or polymorphic forms of rifaximin.

The amorphous or crystalline polymorphic state requires, in fact, specific characterizations of the product in the solid state and the possibility that an organic compound exhibits polymorphism is never predictable, just as the number of polymorphs of a substance, their stability cannot be predicted ( which determines the time for which it is possible to preserve the active ingredient or a pharmaceutical composition that contains it), their solubility in different solvents (which can have an impact on the processing processes necessary to formulate the compound in a medicinal composition), their bioavailability and other features relevant to pharmaceutical applications.

Numerous polymorphic forms of rifaximin, and processes for their synthesis and purification, are described in various documents of the prior art as well as amorphous forms thereof.

With regard to the amorphous forms, the patent application W02008 / 035109 describes an amorphous form of rifaximin, the method of preparation of the same and a method for the conversion of the amorphous form into crystalline and vice versa, substantially based on treating ("stripping" and subsequent dispersion of the solid obtained) a residue containing rifaximin, obtained by extraction and concentration of the raw reaction product, with water-immiscible solvents selected from n-hexane, n-heptane, diisopropyl ether, dichloromethane, dichloroethylene, chloroform and ethyl acetate and their mixtures. The obtained amorphous form has a better dissolution profile than the polymorphic a form of rifamixin.

Patent application WO2008 / 1 55728 describes a method for the preparation of a completely amorphous form of rifaximin which consists in its dissolution in absolute ethanol, in the presence of a reducing agent at 40-60 ° C, and precipitation by cooling at temperatures between 8 -12 ° C. The solid is then washed with cold absolute ethanol and dried under vacuum at 60-70 ° C for 18 hours.

More recently the application US2009 / 0082558 describes a stable amorphous form of rifaximin prepared by dissolving it in solvents selected from C3-C6alkyl esters (e.g. methyl acetate, ethyl acetate, isopropyl acetate), CrC6alkyl alcohols (e.g. ethanol, isopropanol, 2-butanol ), C3-C6alkyl ketones (e.g. acetone, methyl iso-butyl ketone) and subsequent precipitation with anti-solvents selected from C5-C10 aliphatic hydrocarbons (e.g. heptanes), C4-C8alkyl ethers (e.g. methyl and tert-butyl ether) and mixtures of the same at a temperature between -20 ° C and 55 ° C. This amorphous form does not generate polymorphs and has an XRD spectrum with peaks at angle values 2Θ at 7.2 ° and 15.0 °.

Since the amorphous form is known to be a solid form of a pharmaceutical compound with physicochemical properties that favor its dissolution and consequently improve its bioavailability, an object of the present invention is to provide a new amorphous form of rifaximin, as well as to provide a process for its preparation.

Summary

The inventors of the present patent application have now identified a new amorphous form of rifaximin.

According to a first aspect, the present invention relates to a new amorphous form of rifaximin, which has a spectrum of the X-ray powder (XRDP) with peaks at the 2Θ angle values of 7.70 ° and 14.34 °.

In a second aspect, the invention provides a process for producing the new amorphous mentioned above.

In a further aspect, the invention provides compositions comprising the new amorphous form of rifaximin in combination with at least one pharmaceutically acceptable vehicle.

According to one embodiment, the new amorphous form of rifaximin is provided for use as a medicament for the treatment of pathologies of the gastrointestinal tract.

Brief description of the figures

Figure 1. The figure shows the diffractogram of powders with indexing of the peaks which characterize the new amorphous rifaximin form of the present invention: A. amorphous rifaximin obtained in example 1; B. amorphous rifaximin obtained in example 2.

Figure 2 A-D. the figure shows photomicrographs under the scanning electron microscope at different magnifications of rifaximin amorphous powders obtained in example 1.

Figure 3 A-D. the figure shows photomicrographs under the scanning electron microscope at different magnifications of rifaximin amorphous powders obtained in Example 2.

Detailed description of the invention

According to its first aspect, the invention relates to a new amorphous form rifaximin, which, as shown in Fig. 1, at an X-ray diffraction (XRPD) analysis on powders shows peaks at angle 2Θ equal to 7.70 ° and 14.34 °.

The two XRPD spectra do not exhibit diffraction effects of a crystal structure, but rather two large humps that suggest that the samples are amorphous. The morphology of the samples observed by SEM is compatible with that expected for an amorphous sample. In fact, rifaximin amorphous powders are made up of aggregates of irregular particles of micron and submicron size. Furthermore, the aggregates appear to be made up of particles with undefined edges and the particles seem almost fused together. This sample morphology is compatible with that expected for an amorphous sample.

Furthermore, it has been verified that in a controlled environment with a relative humidity of 80% this amorphous form of rifaximin absorbs between 4 and 5% of water, values that are close to those of the dihydrate product whose theoretical content of water is 4.4%.

In a second aspect, the invention relates to the process for obtaining the new amorphous form of rifaximin described above.

In detail, the method for obtaining the amorphous form of rifaximin is characterized by the fact that it includes at least the steps of:

- solubilize rifaximin in tetrahydrofuran;

- precipitate rifaximin from this solution by treatment with n-heptane; - isolate the precipitated rifaximin by filtration and dry the isolated solid. In the first phase of solubilization in tetrahydrofuran (THF) rifaximin and the solvent are mixed together at room temperature under stirring in ratios by weight / volume of 1 of rifaximin to 2-10 (preferably 4) of THF. The solution thus prepared is subsequently filtered and washed by addition with 1 further volume of THF.

The solution thus obtained is then treated with n-heptane to obtain the precipitation of the rifaximin dissolved in THF. This treatment is carried out either by dropping the rifaximin / THF solution in n-heptane, or by the inverse addition of n-heptane to this rifaximin / THF solution. Preferably, this treatment is carried out in a nitrogen atmosphere. The w / v ratios between rifaximin and n-heptane in this precipitation phase are 1 of rifaximin to 8-10 of n-heptane. In this way a suspension is obtained, which is kept under stirring at room temperature (20-30 ° C) for at least 4 hours and which is subsequently filtered and washed with n-heptane. The solid thus obtained is then isolated and dried at a temperature of at least 60 ° C.

Therefore, as a whole, the process of preparing the amorphous rifaximin object of the invention includes the steps of:

- solubilize rifaximin in tetrahydrofuran under stirring in w / v ratios between rifaximin and tetrahydrofuran of 1 to 2-10;

- filter the solution and wash with a further volume of tetrahydrofuran;

- treat the rifaximin / THF solution with n-heptane by dropping the n-heptane solution or by inverse addition of n-heptane to the rifaximin / THF solution in w / v rifaximin: n-heptane ratios of 1 to 8-10;

- maintaining the suspension thus obtained for at least 4 hours under stirring at room temperature;

- filter the suspension obtained and wash it with n-heptane;

- isolate the rifaximin and dry the isolated solid at a temperature of at least 60 ° C.

In certain embodiments the filtration step is carried out at room temperature.

In certain embodiments the starting rifaximin can be amorphous or in any previously known form; the initial product can be purchased, or prepared immediately before the invention process, for example according to the procedure described in EP 1557421 A1.

The quantities of the solvents indicated are the minimum ones suitable for the purposes of the invention. On the other hand, there is no upper limit for the quantity of solvents per gram of rifaximin, beyond which the process of the invention cannot be reproduced; the amount of solvent is therefore limited by practical considerations, and in particular by the need to limit the volumes of solvent used to obtain an economically efficient process. High quantities of solvent entail, for example, long filtration times, high quantities of energy for heating the same, disposal problems and other disadvantages known to a person skilled in the art. In one embodiment the inventors have observed that a practical upper limit on the amount of solvent can be set to 10ml per gram of rifaximin for THF and 50ml per gram of rifaximin for n-heptane and the lower limit of solvents for gram of rifaximin is 2ml for THF and 8ml for n-heptane.

According to a third aspect of the present invention, pharmaceutical compositions are provided comprising a therapeutically effective amount of the amorph of rifaximin or its derivatives, and at least one pharmaceutically acceptable vehicle. The term "pharmaceutically acceptable carrier" includes one or more pharmaceutically acceptable materials such as fillers, excipients, diluents, solvents, encapsulating material involved in carrying or supporting a pharmaceutically active substance. The vehicle is defined pharmaceutically acceptable in the sense of being compatible with the other substances or ingredients of the pharmaceutical composition and of being physiologically acceptable or compatible with the human body.

In certain embodiments, the composition of the invention also includes one or more excipients such as diluting agents, binders, disintegrants, lubricants, buffering agents, humectants, dyes, flavoring and / or softening agents. By way of example suitable diluents include mannitol, lactose sorbitol, suitable binding agents include gelatins, starches, cellulose derivatives, sugars, natural gums and polyvinylpyrrolidone, suitable lubricating agents include stearates, talc, hydrogenated vegetable oils, PEG, suitable disintegrating agents include cellulose , alginates, starches, cross-linked polymers.

Suitable pharmaceutical compositions containing an amorphous form of rifaximin according to the invention include those suitable for oral, topical, rectal, vaginal, parenteral, nasal and aerosol administration.

Pharmaceutical compositions for oral administration can be in solid form, for example in the form of tablets, capsules, cachets, pills, granules, powder, or in liquid form, such as solutions, suspensions, syrups, gels, emulsions, each containing an effective amount of the polymorphic form κ of rifaximin.

The amount of amorphous form of rifaximin present in the pharmaceutical composition of the invention to produce a single dosage form varies according to the method of administration and will be equal to a quantity that produces the desired therapeutic or prophylactic effect. In general, this quantity may vary from 0.1 to 99% by weight. In some embodiments, said active ingredient ranges from 1 to 50% by weight, preferably from 5 to 20% by weight.

The pharmaceutical compositions according to the invention can be prepared following the standard methods of the pharmaceutical technique which provide for the mixing of the amorph of rifaximin with a vehicle and one or more excipients or additional active ingredients. In general, the pharmaceutical composition is prepared by uniformly mixing the amorphous of rifaximin with a suitable vehicle in liquid forms or a suitable finely divided solid vehicle, or both and then forming the product where necessary.

Typically, the amorphous dosage level of rifaximin incorporated in the pharmaceutical composition of the invention will vary according to the severity of the disease and the conditions and age of the subject in need of treatment.

Typically the dose of active ingredients to be administered will vary from 20 to 2500 mg per day, preferably from 50 to 1000 mg per day, more preferably from 100 to 600 mg per day.

According to a fourth aspect of the invention, methods are provided to prevent or treat diseases or diseases of the intestine including the administration to a subject in need of treatment of an effective amount of the amorph of rifaximin.

Bowel diseases or affections that can be treated include diarrhea, particularly in forms associated with microbial infections such as E. coli and / or Clostridium, traveler's diarrhea, Crohn's disease, irritable bowel syndrome, enteritis , enterculitis, diverticulitis, excessive bacterial flora of the small intestine, colitis, pancreatic insufficiency, chronic pancreatitis and / or hepatic encephalopathy.

In certain embodiments, for the therapeutic treatment or prevention of the aforementioned diseases it is possible to administer the amorph of the invention in a concentration of approx. 0.1 to approx. 100 mg per kilo of body weight, preferably from 0.5 to 30 mg / kg, more preferably from 2 to 10 mg / kg of body weight.

The present invention will now be described with reference to the following examples which are provided for illustrative purposes only and are not to be construed as limiting the present invention.

EXAMPLE 1

Preparation of amorphous rifaximin

20g of rifaximin and 80 mL of tetra-hydrofuran (THF) are loaded into the flask and the solution is stirred and then the solution obtained is filtered by washing with 20 mL of THF (total 5voi). 200 mL, corresponding to 10 volumes, of n-heptane are loaded into a flask under nitrogen flow and the previously filtered rifaximine solution is dropped. A perfectly grainy orange suspension is obtained which is left under stirring at room temperature for about 4 hours and then filtered by washing with heptane.

The isolated sample is dried in a static oven at 60 ° C to obtain 18.34g.

On the sample obtained X-ray diffraction measurements from powders (XRPD), morphological analyzes of the powders by scanning electron microscopy (SEM) and evaluation of stability after conditioning in a humid environment were performed.

EXAMPLE 2

Preparation of amorphous rifaximin

20g of rifaximin and 80 mL of tetra-hydrophurane (THF) are loaded into the flask, leaving the solution to stir and then filter the solution obtained by washing with 20 mL of THF (total 5vol). 160 mL, corresponding to 8 volumes, of n-heptane are loaded into a flask under nitrogen flow and the previously filtered rifaximine solution is dropped. A perfectly grainy orange suspension is obtained which is left under stirring at room temperature for about 4 hours and then filtered by washing with heptane, obtaining then a dry of 15.1g.

On the sample obtained X-ray diffraction measurements from powders (XRPD), morphological analyzes of the powders by scanning electron microscopy (SEM) and evaluation of stability after conditioning in a humid environment were performed.

EXAMPLE 3

X-ray diffraction measurements from powders (XRPD) On samples of rifaximin prepared in examples 1 and 2, X-ray diffraction measurements from powders (XRPD) were performed.

The diffraction spectra were collected with a Bruker D5005 powder diffractometer equipped with Θ-Θ vertical goniometer and area detector (PSD, Braun). All spectra were collected in air, at room temperature, in the 2Θ angular interval between 3 and 30 ° in 0.02 ° step mode with counting time equal to 1.25 seconds. The XRD spectrum shown in figure 1 is typical of an amorphous product (A: rifaximin of example 1; B: rifaximin of example 2).

EXAMPLE 4

Morphological analysis of the powders for scanning electron microscopy The morphological analysis of the powders for scanning electron microscopy (SEM) was performed on rifaximin samples prepared in examples 1 and 2.

The SEM photomicrographs were taken with a Zeiss EVO MAIO scanning electron microscope (Cari Zeiss, Oberkochen, Germany) on samples rendered conductive by coating with a thin layer of gold.

The morphology of the samples observed by SEM is compatible with that expected for an amorphous sample (figure 2 A-D sample of example 1; figure 3 A-D sample of example 2).

EXAMPLE 5

Stability analysis after conditioning in a humid environment

A stability test was carried out on samples of rifaximin prepared in Examples 1 and 2 following conditioning in a humid environment.

Two amorphous samples of rifaximin were kept for 24 h in an environment with relative humidity of 80%. At the end of the conditioning, a water content was recorded, measured by the weight increase, respectively of 4% for sample sample 1 and 5% for sample sample 2. The XRPD traces of the two samples , kept for 24 hours in an environment with a relative humidity of 80%, remained identical to those recorded before conditioning. Therefore the conditioning of the Rifaximin amorphous of the invention, even at high relative humidity values, does not produce any significant structural variation.

Claims (12)

Claims 1. Amorphous form of rifaximin, characterized by a spectrum of X-ray powder diffraction (XRDP) with peaks at the 2Θ angle values of 7.70 ° and 14.34 °. 2. Isolated amorphous form of rifaximin having an XRDP spectrum as shown in Figure 1. 3. Process to obtain the amorphous form of rifaximin characterized by the fact of including at least the steps of: solubilize rifamixin in tetrahydrofuran; precipitate rifamixin from this solution by treatment with neptane; dropping of the same in n-heptane; isolate the precipitated rifamixin by filtration and dry the isolated solid. 4. Process according to claim 3, in which in the solubilization step the ratios between rifamixin and tetrahydrofuran are 1 to 2-10 w / v. 5. Process according to claim 3, wherein after solubilization the obtained rifamixin solution is filtered and washed with a further volume of terahydrofuran. 6. Process according to claim 3, wherein the precipitation is obtained by dropping the rifaximin / THF solution in n-heptane or by reverse addition of n-heptane to said rifaximin / THF solution. 7. Process according to claim 3, wherein the rifaximin and n-heptane ratios in the precipitation step are 1 to 8-10 w / v. 8. Process according to claim 3, in which the suspension obtained is maintained under stirring at room temperature for at least 4 hours. 9. Process according to claim 3, wherein the suspension is filtered and washed with n-heptane and dried at at least 60 ° C. Process according to one of claims 3 to 9, comprising the steps of: solubilize rifamixin in tetrahydrofuran under stirring in w / v ratios between rifaximin and tetrahydrofuran of 1 to 2-10 filter the solution and wash with an additional volume of tetrahydrofuran; treat the rifaximin / THF solution with n-heptane by dropping the n-heptane solution or by inverse addition of n-heptane to the rifaximin / THF solution in w / v rifaximin: n-heptane ratios of 1 to 8-10; maintaining the suspension thus obtained for at least 4 hours under stirring at room temperature; filter the suspension obtained and wash it with n-heptane; isolate the rifaximin and dry the isolated solid at at least 60 ° C. 11. Pharmaceutical composition comprising a therapeutically effective amount of the amorphous form of rifaximin or derivatives thereof, in combination with at least one pharmaceutically acceptable carrier. 12. Amorphous form of rifaximin or its derivatives for use as a medicament in the prevention or treatment of a disease of the gastrointestinal tract chosen from diarrhea, irritable bowel syndrome, Crohn's disease, diverticulitis, enteritis, colitis, pancreatic insufficiency, chronic pancreatitis .