U.S. patent application number 12/452152 was filed with the patent office on 2010-06-03 for process for preparing amorphous rifaximin and the amorphous rifaximin thus obtained.
Invention is credited to Roberta Pizzocaro, Emilio Vecchio.
Application Number | 20100137580 12/452152 |
Document ID | / |
Family ID | 39828461 |
Filed Date | 2010-06-03 |
United States Patent
Application |
20100137580 |
Kind Code |
A1 |
Vecchio; Emilio ; et
al. |
June 3, 2010 |
Process for preparing amorphous rifaximin and the amorphous
rifaximin thus obtained
Abstract
A process is described which 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.
Inventors: |
Vecchio; Emilio; (Cernusco
Sul Naviglio, IT) ; Pizzocaro; Roberta; (Milano,
IL) |
Correspondence
Address: |
ABELMAN, FRAYNE & SCHWAB
666 THIRD AVENUE, 10TH FLOOR
NEW YORK
NY
10017
US
|
Family ID: |
39828461 |
Appl. No.: |
12/452152 |
Filed: |
June 18, 2008 |
PCT Filed: |
June 18, 2008 |
PCT NO: |
PCT/IB2008/052396 |
371 Date: |
December 15, 2009 |
Current U.S.
Class: |
540/457 |
Current CPC
Class: |
C07D 491/22 20130101;
C07D 498/22 20130101 |
Class at
Publication: |
540/457 |
International
Class: |
C07D 498/22 20060101
C07D498/22 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 20, 2007 |
IT |
M12007A001241 |
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.degree. C. with stirring
until completely dissolved. The solution was allowed to cool to
25.degree. 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.degree. 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.degree.
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.degree. C. with stirring until
completely dissolved. The solution was allowed to cool to
18.degree. 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.degree. 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.degree.
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.degree.
C..+-.0.5.degree. 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
.mu.m 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.
* * * * *