Patent application title: Process for preparing amorphous rifaximin and the amorphous rifaximin thus obtained
Inventors:
Emilio Vecchio (Cernusco Sul Naviglio, IT)
Roberta Pizzocaro (Milano, IL)
IPC8 Class: AC07D49822FI
USPC Class:
540457
Class name: Polycyclo ring system which contains the hetero ring as one of the cyclos two of the cyclos share at least three ring members or a ring member is shared by three of the cyclos (e.g., bridged, peri-fused, etc.) a five-membered cyclo of the polycyclo ring system consists of four ring carbons and one ring oxygen (e.g., fused rifamycins, etc.)
Publication date: 2010-06-03
Patent application number: 20100137580
ich enables Rifaximin in a completely amorphous
form to be obtained. Said process comprises the steps of dissolving crude
Rifaximin in absolute ethanol while hot and then collecting after
precipitation by cooling the title compound under amorphous form.Claims:
1. Process for preparing amorphous rifaximin in which crude rifaximin is
dissolved in absolute ethanol while hot, then collected after
precipitation by cooling of the solution.
2. Process as claimed in claim 1 wherein the crude rifaximin has a water content of between 4 and 7%.
3. Process as claimed in claim 1 wherein the crude rifaximin is dissolved in absolute ethanol in the presence of ascorbic acid.
4. Process as claimed in claim 1 wherein the crude rifaximin is dissolved with stirring at a temperature of 40-60.degree. C. and then re-precipitated by cooling the solution to 8-12.degree. C.
5. Process as claimed in claim 4 wherein the precipitated rifaximin is collected by filtration, washed with absolute ethanol and dried.
6. Process as claimed in claim 5 wherein said drying is conducted under vacuum at 60-70.degree. C.
7. Amorphous rifaximin obtained according to the process of claim 1.Description:
FIELD OF THE INVENTION
[0001]The present invention relates to the preparation of Rifaximin in amorphous form.
STATE OF THE ART
[0002]As is known Rifaximin is a non-systemic antibiotic belonging to the rifaximin-family, applied in the treatment of various pathologies including in particular diarrhea caused by E. coli or irritable bowel syndrome.
[0003]Various polymorphic forms of the product are known, for which various synthesis and purification processes have been described.
[0004]The present invention instead relates to the preparation of Rifaximin in amorphous form, by a process that comprises precipitating the desired product in absolute ethanol starting from a solution of crude Rifaximin.
[0005]Pharmaceutical active principles in amorphous form are in general more soluble than the corresponding crystalline forms, and this can present advantages in terms of improved absorption per os and consequently improved bioavailability.
BRIEF DESCRIPTION OF THE FIGURES
[0006]FIGS. 1 (a and b) and FIGS. 2 (a and b) show respectively the PXRD and IR spectra of rifaximin obtained according to the process of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0007]The process of the invention uses as starting product crude Rifaximin containing water.
[0008]The starting product is dissolved in absolute ethanol in the presence of ascorbic acid and the solution subjected to mild heating with stirring; the product precipitates by cooling the solution while stirring, and is then collected by filtration, washed with cold absolute ethanol and dried under vacuum.
[0009]The absence of significant peaks in the PXRD spectra carried out on the product obtained in this manner is evidence of the purity of the amorphous product obtained.
EXAMPLE 1
[0010]20 g of crude rifaximin (containing an average water quantity of between 4 and 7%) were placed in a reaction flask in which 0.2 g of ascorbic acid and 200 ml of absolute ethanol were added. The suspension was heated to 60° C. with stirring until completely dissolved. The solution was allowed to cool to 25° C., maintaining stirring for a further three hours.
[0011]After precipitation, the suspension was left for a further 2 hours with stirring at a temperature of 12° C., then filtered.
[0012]The product on the filter was washed with 20 ml of cold absolute ethanol and the wet solid dried under vacuum at 70° C. for 18 hours until a KF value less than 4% was attained.
[0013]15 g of pure amorphous rifaximin were obtained.
[0014]The PXRD and IR spectra of the obtained product are shown in FIGS. 1a and 2a respectively.
EXAMPLE 2
[0015]20 g of crude rifaximin (containing an average quantity of water of between 4 and 7%) were placed in a reaction flask in which 0.2 g of ascorbic acid and 200 ml of absolute ethanol were added. The suspension was heated to 40° C. with stirring until completely dissolved. The solution was allowed to cool to 18° C., maintaining stirring for a further three hours.
[0016]After precipitation the suspension was left for a further 2 hours with stirring at a temperature of 8° C., then filtered.
[0017]The product on the filter was washed with 20 ml of cold absolute ethanol and the wet solid dried under vacuum at 60° C. for 18 hours until a KF value less than 4% was attained.
[0018]14 g of pure amorphous rifaximin were obtained.
[0019]The PXRD and IR spectra of the obtained product are shown in FIGS. 1b and 2b respectively.
[0020]The dissolution profile of the substance in amorphous form was also determined, and compared with that of the substance in crystalline form.
[0021]It was found that the amorphous form easily dissolves in ethanol even without stirring, while the crystalline form is less wettable.
[0022]Moreover, with regard to water solubility, after conditioning a dissolution tester (Pharma Test Type PTW S III s/n 5390) using distilled water at a temperature of 37° C.±0.5° C. at a speed of 100 rpm, four dissolutions were carried out, in each of which the first three vessels of the dissolution tester were used for the substance in crystalline form and the last three for the substance in amorphous form.
[0023]10 ml of the solute were withdrawn from each vessel after 15 minutes of stirring; the withdrawn samples were filtered with 0.45 μm filters and subjected to spectophotometric analysis, repeating the operation after 30 and 60 minutes.
[0024]After one hour of dissolution, the substance in crystalline form has a concentration of dissolved substance equal to about 7% of that of the substance in amorphous form.
[0025]Consequently, the substance in amorphous form has a dissolved percentage which is one order of magnitude greater than that of the substance in crystalline form.
Claims:
1. Process for preparing amorphous rifaximin in which crude rifaximin is
dissolved in absolute ethanol while hot, then collected after
precipitation by cooling of the solution.
2. Process as claimed in claim 1 wherein the crude rifaximin has a water content of between 4 and 7%.
3. Process as claimed in claim 1 wherein the crude rifaximin is dissolved in absolute ethanol in the presence of ascorbic acid.
4. Process as claimed in claim 1 wherein the crude rifaximin is dissolved with stirring at a temperature of 40-60.degree. C. and then re-precipitated by cooling the solution to 8-12.degree. C.
5. Process as claimed in claim 4 wherein the precipitated rifaximin is collected by filtration, washed with absolute ethanol and dried.
6. Process as claimed in claim 5 wherein said drying is conducted under vacuum at 60-70.degree. C.
7. Amorphous rifaximin obtained according to the process of claim 1.
Description:
FIELD OF THE INVENTION
[0001]The present invention relates to the preparation of Rifaximin in amorphous form.
STATE OF THE ART
[0002]As is known Rifaximin is a non-systemic antibiotic belonging to the rifaximin-family, applied in the treatment of various pathologies including in particular diarrhea caused by E. coli or irritable bowel syndrome.
[0003]Various polymorphic forms of the product are known, for which various synthesis and purification processes have been described.
[0004]The present invention instead relates to the preparation of Rifaximin in amorphous form, by a process that comprises precipitating the desired product in absolute ethanol starting from a solution of crude Rifaximin.
[0005]Pharmaceutical active principles in amorphous form are in general more soluble than the corresponding crystalline forms, and this can present advantages in terms of improved absorption per os and consequently improved bioavailability.
BRIEF DESCRIPTION OF THE FIGURES
[0006]FIGS. 1 (a and b) and FIGS. 2 (a and b) show respectively the PXRD and IR spectra of rifaximin obtained according to the process of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0007]The process of the invention uses as starting product crude Rifaximin containing water.
[0008]The starting product is dissolved in absolute ethanol in the presence of ascorbic acid and the solution subjected to mild heating with stirring; the product precipitates by cooling the solution while stirring, and is then collected by filtration, washed with cold absolute ethanol and dried under vacuum.
[0009]The absence of significant peaks in the PXRD spectra carried out on the product obtained in this manner is evidence of the purity of the amorphous product obtained.
EXAMPLE 1
[0010]20 g of crude rifaximin (containing an average water quantity of between 4 and 7%) were placed in a reaction flask in which 0.2 g of ascorbic acid and 200 ml of absolute ethanol were added. The suspension was heated to 60° C. with stirring until completely dissolved. The solution was allowed to cool to 25° C., maintaining stirring for a further three hours.
[0011]After precipitation, the suspension was left for a further 2 hours with stirring at a temperature of 12° C., then filtered.
[0012]The product on the filter was washed with 20 ml of cold absolute ethanol and the wet solid dried under vacuum at 70° C. for 18 hours until a KF value less than 4% was attained.
[0013]15 g of pure amorphous rifaximin were obtained.
[0014]The PXRD and IR spectra of the obtained product are shown in FIGS. 1a and 2a respectively.
EXAMPLE 2
[0015]20 g of crude rifaximin (containing an average quantity of water of between 4 and 7%) were placed in a reaction flask in which 0.2 g of ascorbic acid and 200 ml of absolute ethanol were added. The suspension was heated to 40° C. with stirring until completely dissolved. The solution was allowed to cool to 18° C., maintaining stirring for a further three hours.
[0016]After precipitation the suspension was left for a further 2 hours with stirring at a temperature of 8° C., then filtered.
[0017]The product on the filter was washed with 20 ml of cold absolute ethanol and the wet solid dried under vacuum at 60° C. for 18 hours until a KF value less than 4% was attained.
[0018]14 g of pure amorphous rifaximin were obtained.
[0019]The PXRD and IR spectra of the obtained product are shown in FIGS. 1b and 2b respectively.
[0020]The dissolution profile of the substance in amorphous form was also determined, and compared with that of the substance in crystalline form.
[0021]It was found that the amorphous form easily dissolves in ethanol even without stirring, while the crystalline form is less wettable.
[0022]Moreover, with regard to water solubility, after conditioning a dissolution tester (Pharma Test Type PTW S III s/n 5390) using distilled water at a temperature of 37° C.±0.5° C. at a speed of 100 rpm, four dissolutions were carried out, in each of which the first three vessels of the dissolution tester were used for the substance in crystalline form and the last three for the substance in amorphous form.
[0023]10 ml of the solute were withdrawn from each vessel after 15 minutes of stirring; the withdrawn samples were filtered with 0.45 μm filters and subjected to spectophotometric analysis, repeating the operation after 30 and 60 minutes.
[0024]After one hour of dissolution, the substance in crystalline form has a concentration of dissolved substance equal to about 7% of that of the substance in amorphous form.
[0025]Consequently, the substance in amorphous form has a dissolved percentage which is one order of magnitude greater than that of the substance in crystalline form.
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