U.S. patent application number 13/448356 was filed with the patent office on 2012-08-09 for polymorphic forms alpha, beta and gamma of rifaximin.
This patent application is currently assigned to ALFA WASSERMANN, S.P.A.. Invention is credited to Dario Braga, Manuela Campana, Vincenzo Cannata, Donatella Confortini, Paolo Righi, Goffredo Rosini, Giuseppe Claudio Viscomi.
Application Number | 20120203000 13/448356 |
Document ID | / |
Family ID | 39872912 |
Filed Date | 2012-08-09 |
United States Patent
Application |
20120203000 |
Kind Code |
A1 |
Viscomi; Giuseppe Claudio ;
et al. |
August 9, 2012 |
POLYMORPHIC FORMS ALPHA, BETA AND GAMMA OF RIFAXIMIN
Abstract
Crystalline polymorphous forms of rifaximin (INN) antibiotic
named rifaximin .alpha. and rifaximin .beta., and a poorly
crystalline form named rifaximin .gamma., useful in the production
of medicinal preparations containing rifaximin for oral and topical
use and obtained by means of a crystallization carried out by
hot-dissolving the raw rifaximin in ethyl alcohol and by causing
the crystallization of the product by addition of water at a
determinate temperature and for a determinate period of time,
followed by a drying carried out under controlled conditions until
reaching a settled water content in the end product, are the object
of the invention.
Inventors: |
Viscomi; Giuseppe Claudio;
(Bologna, IT) ; Campana; Manuela; (Bologna,
IT) ; Braga; Dario; (Bologna, IT) ;
Confortini; Donatella; (Bologna, IT) ; Cannata;
Vincenzo; (Bologna, IT) ; Righi; Paolo;
(Bologna, IT) ; Rosini; Goffredo; (Bologna,
IT) |
Assignee: |
ALFA WASSERMANN, S.P.A.
Bologna
IT
|
Family ID: |
39872912 |
Appl. No.: |
13/448356 |
Filed: |
April 16, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13041332 |
Mar 4, 2011 |
8158781 |
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13448356 |
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12119600 |
May 13, 2008 |
7902206 |
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13041332 |
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11873841 |
Oct 17, 2007 |
7915275 |
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12119600 |
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11135651 |
May 24, 2005 |
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11873841 |
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PCT/EP04/12490 |
Nov 4, 2004 |
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11135651 |
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Current U.S.
Class: |
546/40 |
Current CPC
Class: |
C07B 2200/13 20130101;
C07D 491/22 20130101; C07D 498/22 20130101 |
Class at
Publication: |
546/40 |
International
Class: |
C07D 491/22 20060101
C07D491/22 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 7, 2003 |
IT |
MI2003A002144 |
Claims
1. Rifaximin in polymorphic form .alpha..
2. Rifaximin in polymorphic form .beta..
3. Rifaximin in polymorphic form .gamma..
Description
APPLICATION PRIORITY DATA
[0001] This application is a continuation of U.S. application Ser.
No. 13/041,332, filed Mar. 4, 2011, now U.S. Pat. No. 8,158,781,
issued on Apr. 17, 2012, which in turn is a continuation of U.S.
application Ser. No. 12/119,600, filed May 13, 2008, now U.S. Pat.
No. 7,902,206, issued on Mar. 8, 2011, which in turn is a
continuation-in-part of application U.S. application Ser. No.
11/873,841, filed on Oct. 17, 2007, now U.S. Pat. No. 7,915,275,
issued on Mar. 29, 2011, which is a continuation-in part of U.S.
application Ser. No. 11/135,651, filed on May 24, 2005, now
abandoned, which is a continuation-in-part of PCT/EP04/12490, filed
on Nov. 4, 2004, which claims priority to Italian application No.
MI2003A002144 filed Nov. 7, 2003, all of which are incorporated by
reference herein in their entirety, including any drawings.
BACKGROUND AND SUMMARY OF THE INVENTION
[0002] Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an
antibiotic belonging to the rifamycin class, exactly it is a
pyrido-imidazo rifamycin described and claimed in Italian Patent IT
1154655, while European Patent EP 0161534 describes and claims a
process for its production starting from rifamycin O (The Merck
Index, XIII Ed., 8301).
[0003] Both these patents describe the purification of rifaximin in
a generic way stating that crystallization can be carried out in
suitable solvents or solvent systems and summarily showing in some
examples that the reaction product can be crystallized from the 7:3
mixture of ethyl alcohol/water and can be dried both under
atmospheric pressure and under vacuum without specifying in any way
either the experimental conditions of crystallization and drying,
or any distinctive crystallographic characteristic of the obtained
product.
[0004] The presence of different polymorphs had just not been
noticed and therefore the experimental conditions described in both
patents had been developed with the goal to get a homogeneous
product having a suitable purity from the chemical point of view,
independent from the crystallographic aspects of the product
itself.
[0005] It has now been found, unexpectedly, that there are several
polymorphous forms whose formation, besides the solvent, depends on
time and temperature conditions under which both crystallization
and drying are carried out.
[0006] In the present application, these orderly polymorphous forms
will be, later on, conventionally identified as rifaximin .alpha.
(FIG. 1) and rifaximin .beta. (FIG. 2) on the basis of their
respective specific diffractograms, while the poorly crystalline
form with a high content of amorphous component will be identified
as rifaximin .gamma. (FIG. 3).
[0007] Rifaximin polymorphous forms have been characterized through
the technique of the powder X-ray diffraction.
[0008] The identification and characterization of these
polymorphous forms and, simultaneously, the definition of the
experimental conditions for obtaining them is very important for a
compound endowed with pharmacological activity which, like
rifaximin, is marketed as medicinal preparation, both for human and
veterinary use. In fact it is known that the polymorphism of a
compound that can be used as active ingredient contained in a
medicinal preparation can influence the pharmaco-toxicologic
properties of the drug. Different polymorphous forms of an active
ingredient administered as drug under oral or topical form can
modify many properties thereof like bioavailability, solubility,
stability, colour, compressibility, flowability and workability
with consequent modification of the profiles of toxicological
safety, clinical effectiveness and productive efficiency.
[0009] What mentioned above is confirmed by the fact that the
authorities that regulate the grant of marketing authorization of
the drugs market require that the manufacturing methods of the
active ingredients are standardized and controlled in such a way
that they give homogeneous and sound results in terms of
polymorphism of production batches (CPMP/QWP/96, 2003--Note for
Guidance on Chemistry of new Active Substance;
CPMP/ICH/367/96--Note for guidance specifications: test procedures
and acceptance criteria for new drug substances and new drug
products: chemical substances; Date for coming into operation: May
2000).
[0010] The need for the above-mentioned standardization has further
been strengthened in the field of the rifamycin antibiotics by
Henwood S. Q., de Villiers M. M., Liebenberg W. and Lotter A. P.,
Drug Development and Industrial Pharmacy, 26 (4), 403-408, (2000),
who have ascertained that different production batches of the
rifampicin (INN) made from different manufacturers differ from each
other in that they show different polymorphous characteristics, and
as a consequence they show different dissolution profiles, along
with a consequent alteration of the respective pharmacological
properties.
[0011] By applying the crystallization and drying processes
generically disclosed in the previous patents IT 1154655 and EP
0161534 it has been found that under some experimental conditions a
poorly crystalline form of rifaximin is obtained, while under other
experimental conditions other polymorphic crristalline forms of
Rifaximin are obtained. Moreover it has been found that some
parameters, absolutely not disclosed in the above-mentioned
patents, like for instance preservation conditions and the relative
ambient humidity, have the surprising effect to determine the
polymorph form.
[0012] The polymorphous forms of rifaximin object of the present
patent application were never seen or hypothesized, while thinking
that, whichever method was used within the range of the described
condition, a sole homogeneous product would always have been
obtained, irrespective of crystallizing, drying and preserving
conditions.
[0013] It has now been found that the formation of .alpha., .beta.
and .gamma. forms depends both on the presence of water within the
crystallization solvent, on the temperature at which the product is
crystallized and on the amount of water present in the product at
the end of the drying phase.
[0014] Form .alpha., form .beta. and form .gamma. of rifaximin have
then been synthesized and they are the object of the invention.
[0015] Moreover it has been found that the presence of water in
rifaximin in the solid state is reversible, so that water
absorption and/or release can take place in time in presence of
suitable ambient conditions; consequently rifaximin is susceptible
of transition from one form to another, also remaining in the solid
state, without need to be again dissolved and crystallized. For
instance polymorph .alpha., getting water by hydration up to a
content higher than 4.5%, turns into polymorph .beta., which in its
turn, losing water by drying up to a content lower than 4.5%, turns
into polymorph .alpha..
[0016] These results have a remarkable importance as they determine
the conditions of industrial manufacturing of some steps of working
which could not be considered critical for the determination of the
polymorphism of a product, like for instance the washing of a
crystallized product, or the preservation conditions of the end
product, or the characteristics of the container in which the
product is preserved.
[0017] The above-mentioned .alpha., .beta. and .gamma. forms can be
advantageously used as pure and homogeneous products in the
manufacture of medicinal preparations containing rifaximin.
[0018] As already said, the process for manufacturing rifaximin
from rifamycin O disclosed and claimed in EP 0161534 is deficient
from the point of view of the purification and identification of
the product obtained; it shows some limits also from the synthetic
point of view as regards, for instance, the very long reaction
times, from 16 to 72 hours, not very suitable to an industrial use
and moreover because it does not provide for the in situ reduction
of rifaximin oxidized that may be formed within the reaction
mixture.
[0019] Therefore, a further object of the present invention is an
improved process for the industrial manufacturing of the .alpha.,
.beta. and .gamma. forms of rifaximin, herein claimed as products
and usable as defined and homogeneous active ingredients in the
manufacture of the medicinal preparations containing such active
ingredient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 is a powder X-ray diffractogram of rifaximin
polymorphic form .alpha..
[0021] FIG. 2 is a powder X-ray diffractogram of rifaximin
polymorphic form .beta..
[0022] FIG. 3 is a powder X-ray diffractogram of rifaximin
polymorphic form .gamma..
DETAILED DESCRIPTION OF THE INVENTION
[0023] As already said, form .alpha., form .beta. and form .gamma.
of the antibiotic known as rifaximin (INN), processes for their
production and the use thereof in the manufacture of medicinal
preparations for oral or topical route, are object of the present
invention.
[0024] A process object of the present invention comprises reacting
one molar equivalent of rifamycin O with an excess of
2-amino-4-methylpyridine, preferably from 2.0 to 3.5 molar
equivalents, in a solvent mixture consisting of water and ethyl
alcohol in volumetric ratios between 1:1 and 2:1, for a period of
time between 2 and 8 hours at a temperature between 40.degree. C.
and 60.degree. C.
[0025] When the reaction is over, the reaction mass is cooled at
room temperature and is added with a solution of ascorbic acid in a
mixture of water, ethyl alcohol and aqueous concentrated
hydrochloric acid, under strong stirring, in order to reduce the
small amount of oxidized rifaximin that forms during the reaction
and finally the pH is adjusted to about 2.0 by a further addition
of hydrochloric acid concentrated aqueous solution, in order to
better remove the excess of 2-amino-4-methylpyridine used in the
reaction. The suspension is filtered and the obtained solid is
washed with the same water/ethyl alcohol solvent mixture used in
the reaction. Such semi finished product is called "raw
rifaximin".
[0026] Raw rifaximin can be directly submitted to the subsequent
purification step. Alternatively, in case long times of
preservation of the semi finished product are expected, raw
rifaximin can be dried under vacuum at a temperature lower than
65.degree. C. for a period of time between 6 and 24 hours; such
semi finished product is called "dried raw rifaximin".
[0027] The so obtained raw rifaximin and/or dried raw rifaximin are
purified by dissolution in ethyl alcohol at a temperature between
45.degree. C. and 65.degree. C. and by crystallization by addition
of water, preferably in weight amounts between 15% and 70% in
respect of the amount by weight of the ethyl alcohol used for the
dissolution, and keeping the obtained suspension at a temperature
between 50.degree. C. and 0.degree. C. under stirring during a
period of time between 4 and 36 hours.
[0028] The suspension is filtered and the obtained solid is washed
with water and dried under vacuum or under normal pressure, with or
without a drying agent, at a temperature between room temperature
and 105.degree. C. for a period of time between 2 and 72 hours.
[0029] The achievement of .alpha., .beta. and .gamma. forms depends
on the conditions chosen for crystallization. In particular, the
composition of the solvent mixture from which crystallization is
carried out, the temperature at which the reaction mixture is kept
after crystallization and the period of time at which that
temperature is kept, have proven to be critical.
[0030] More precisely, rifaximin .gamma. is obtained when the
solution is taken to a temperature between 28.degree. C. and
32.degree. C. in order to start precipitation and the obtained
suspension is further cooled to 0.degree. C. and kept at this
temperature for a period of time between 6 and 24 hours.
[0031] The suspension is filtered, the solid is washed with
demineralized water and dried to a water content between 1.0% and
2.0%.
[0032] .alpha. and .beta. rifaximins are obtained when the
temperature is first taken to a value between 28.degree. C. and
32.degree. C. to start crystallization, then the suspension is
taken to a temperature between 40.degree. C. and 50.degree. C. and
kept at this value for a period of time between 6 and 24 hours,
then the suspension is quickly cooled to 0.degree. C., in a period
of time between 15 minutes and one hour, is filtered, the solid is
washed with water and then is dried.
[0033] The drying step plays an important role in obtaining the
.alpha. and .beta. polymorphous forms of rifaximin and must be
checked with a suitable method fit for the water dosage, like for
instance the Karl Fischer method, in order to check the amount of
remaining water present in the product under drying.
[0034] The obtaining of rifaximin .alpha. or of rifaximin .beta.
during drying in fact depends on the final water residual content,
higher or lower than 4.5%, and not from the experimental conditions
of pressure and temperature at which this critical limit of water
percent is achieved. The two polymorphous forms, with higher or
lower water content, can be obtained by drying under vacuum or at
atmospheric pressure, at room temperature or at high temperatures,
with or without drying agents, provided that drying is prolonged
for the time necessary so that the water percent characteristic for
each polymorphous form is achieved.
[0035] Polymorphous form .beta. is obtained when the drying of the
product crystallized and washed with water is stopped at values of
water higher than 4.5%, measured with the Karl Fisher method,
preferably between 5.0% and 6.0%, whereas if drying continues to
values lower than 4.5%, preferably between 2.0% and 3.0%,
polymorphous form .alpha. is obtained.
[0036] Both form .gamma. and forms .alpha. and .beta. of rifaximin
are hygroscopic, absorb water in a reversible way in time in the
presence of suitable conditions of pressure and humidity in the
ambient and are susceptible of transformation from one form to
another.
[0037] Polymorphous form .alpha., kept in an ambient with a
relative humidity higher than 50% for a period of time between 12
and 48 hours, turns into the polymorphous form .beta., which in its
turn, by drying until getting an amount of water lower than 4.5%,
preferably comprised between 2.0% and 3.0%, turns into the
polymorphous form .alpha..
[0038] Another type of transition takes place between form .gamma.
and forms .alpha. and .beta., depending upon the temperatures kept
during the phase of precipitation of rifaximin.
[0039] In particular form .gamma. turns into forms .alpha. or
.beta. by keeping a suspension of form .gamma. of rifaximin in a
solvent mixture ethyl alcohol/water 7:3 (V/V) at a temperature
between 38.degree. C. and 50.degree. C. under strong stifling for a
prolonged period of time, preferably comprised between 6 and 36
hours.
[0040] After filtration and washing with demineralized water,
drying up to a water content higher than 4.5%, preferably between
5.0% and 6.0%, gives the polymorphous form .beta., whereas if
drying continues up to a water content lower than 4.5%, preferably
between 2.0% and 3.0%, form .alpha. is obtained.
[0041] Rifaximins .alpha. and .beta. turn can turn into rifaximin
.gamma. by dissolution in ethyl alcohol and by treatment of the
resulting solution as previously described for the preparation of
form .gamma..
[0042] These transitions from one form to another result to be very
important in the scope of the invention, because they can be an
alternative manufacturing method to obtain the form desired for the
production of the medicinal preparations. Therefore both the
process that allows to turn rifaximin .gamma. into rifaximin
.alpha. or .beta. in a valid way from an industrial standpoint, the
process that allows to turn rifaximin .alpha. or .beta. into
rifaximin .gamma. in a valid way from an industrial standpoint, the
process that allow to turn rifaximin .alpha. into rifaximin .beta.
in a valid way from an industrial stand point or vice versa
rifaximin .beta. into rifaximin .alpha., are important part of the
invention.
[0043] The process concerning the transformation of rifaximin
.gamma. into rifaximin .alpha. or rifaximin .beta. comprises
suspending rifaximin .gamma. in a solvent mixture consisting of
ethyl alcohol/water in a 7:3 volumetric ratio, heating the
suspension up to a temperature between 38.degree. C. and 50.degree.
C. and keeping it at this temperature under strong stifling for a
period of time between 6 and 36 hours. The suspension is then
filtered, the solid is washed with water and dried getting the
polymorphous form .beta. when drying is carried on until a water
percent between 5.0% and 6.0% measured with the Karl Fischer
method, and polymorphous form .alpha. when drying is continued
until a water percent between 2.0% and 3.0% is reached.
[0044] The process for getting form .gamma. starting from rifaximin
.alpha. or .beta. comprises dissolving under stirring, at a
temperature between 50.degree. C. and 60.degree. C., .alpha. or
.beta. form in ethyl alcohol, adding demineralized water until
reaching a 7:3 ethyl alcohol/water volumetric ratio, cooling the
solution under strong stifling to 30.degree. C., cooling the
abundant precipitate to 0.degree. C. and keeping the suspension
under stirring at 0.degree. C. for a period of time between 6 and
24 hours. The suspension is then filtered, the solid is washed with
water and dried up to a water percent lower than 2.0% thus
obtaining rifaximin .gamma..
[0045] The process concerning the transformation of form .alpha.
into form .beta. consists in keeping rifaximin .alpha., in the
powder form, in an ambient having a rate of relative humidity
higher than 50% for the required amount of time, generally between
12 and 48 hours, in order to get a water content in the powder
higher than 4.5%.
[0046] The process concerning the transformation of form .beta.
into form .alpha. consists in submitting the powder of rifaximin
.beta. to a drying process under vacuum or under conditions of
normal pressure, with or without a drying agent, at a temperature
between the room temperature and 105.degree. C., for a period of
time between 2 and 72 hours, in order to get a water content in the
powder lower than 4.5%, preferably between 2.0% and 3.0%.
[0047] From what said above, it results that during the phase of
preservation of the product particular care has to be taken so that
ambient conditions do not change the water content of the product,
by preserving the product in an ambient having controlled humidity
or in closed containers that do not allow a significant exchange of
water with the exterior ambient.
[0048] The polymorph called rifaximin .alpha. is characterized by a
water content lower than 4.5%, preferably between 2.0% and 3.0% and
from a powder X-ray diffractogram (reported in FIG. 1) which shows
peaks at the values of the diffraction angles 2.theta. of
6.6.degree.; 7.4.degree.; 7.9.degree.; 8.8.degree.; 10.5.degree.;
11.1.degree.; 11.8.degree.; 12.9.degree.; 17.6.degree.;
18.5.degree.; 19.7.degree.; 21.0.degree.; 21.4.degree.;
22.1.degree.. The polymorph called rifaximin .beta. is
characterized by a water content higher than 4.5%, preferably
between 5.0% and 6.0%, and by a powder X-ray diffractogram
(reported in FIG. 2) which shows peaks at the values of the
diffraction angles 28 of 5.4.degree.; 6.4.degree.; 7.0.degree.;
7.8.degree.; 9.0.degree.; 10.4.degree.; 13.1.degree.; 14.4.degree.;
17.1.degree.; 17.9 ; 18.3.degree.; 20.9.degree..
[0049] The polymorph called rifaximin .gamma. is characterized by a
powder X-ray diffractogram much poorer because of the poor
crystallinity; the significant peaks are at the values of the
diffraction angles 2.theta. of 5.0.degree.; 7.1.degree.;
8.4.degree. as reported in FIG. 3.
[0050] The diffractograms have been carried out by means of the
Philips X'Pert instrument endowed with Bragg-Brentano geometry and
under the following working conditions:
[0051] X-ray tube: Copper
[0052] Radiation used: K(.alpha.1), K(.alpha.2)
[0053] Tension and current of the generator: KV 40, mA 40
[0054] Monocromator: Graphite
[0055] Step size: 0.02
[0056] Time per step: 1.25 seconds
[0057] Starting and final angular 2.nu. value:
3.0.degree..+-.30.0.degree.
[0058] The evaluation of the water content present in the analyzed
samples has always been carried out by means of the Karl Fischer
method.
[0059] Forms .alpha., .beta. and .gamma. can be advantageously used
in the production of medicinal preparations having antibiotic
activity, containing rifaximin, for both oral and topical use. The
medicinal preparations for oral use contain rifaximin .alpha. or
.beta. or .gamma. together with the usual excipients as diluting
agents like mannitol, lactose and sorbitol; binding agents like
starches, gelatines, sugars, cellulose derivatives, natural gums
and polyvinylpyrrolidone; lubricating agents like talc, stearates,
hydrogenated vegetable oils, polyethylenglycol and colloidal
silicon dioxide; disintegrating agents like starchs, celluloses,
alginates, gums and reticulated polymers; coloring, flavoring and
sweetening agents.
[0060] All the solid preparations administrable by oral route can
be used in the scope of the present invention, for instance coated
and uncoated tablets, capsules made of soft and hard gelatine,
sugar-coated pills, lozenges, wafer sheets, pellets and powders in
sealed packets.
[0061] The medicinal preparations for topical use contain rifaximin
.alpha. or .beta. or .gamma. together with the usual excipients
like white petrolatum, white wax, lanoline and derivatives thereof,
stearylic alcohol, propylenglycol, sodium lauryl sulfate, ethers of
the fatty polyoxyethylene alcohols, esters of the fatty
polyoxyethylene acids, sorbitan monostearate, glyceryl
monostearate, propylene glycol monostearate, polyethylene glycols,
methylcellulose, hydroxymethylpropylcellulose, sodium
carboxymethylcellulose, colloidal aluminium and magnesium silicate,
sodium alginate.
[0062] All topical preparations can be used in the scope of the
present invention, for instance ointments, pomades, creams, gels
and lotions.
[0063] The invention is herein below illustrated by some
non-limiting examples: from what described it is evident that forms
.alpha., .beta. and .gamma. can be obtained by suitably combining
between them the above mentioned conditions of crystallization and
drying.
EXAMPLE 1
Preparation of Raw Rifaximin .alpha. and of Dried Raw Rifaximin
[0064] In a three-necked flask equipped with mechanic stirrer,
thermometer and reflux condenser, 120 ml of demineralized water, 96
ml of ethyl alcohol, 63.5 g of rifamycin O and 27.2 g of
2-amino-4-methylpyridine are loaded in succession at room
temperature. After loading, the mass is heated at 47.+-.3.degree.
C., is kept under stifling at this temperature for 5 hours, then is
cooled to 20.+-.3.degree. C. and, in 30 minutes, is added with a
mixture, prepared separately, consisting of 9 ml of demineralized
water, 12.6 ml of ethyl alcohol, 1.68 g of ascorbic acid and 9.28 g
of aqueous concentrated hydrochloric acid. When the addition is
over, the mass is kept under stirring for 30 minutes at an inner
temperature of 20.+-.3.degree. C. and then, at the same
temperature, 7.72 g of concentrated hydrochloric acid are dropped
until pH 2.0.
[0065] When the addition is over, the mass is kept under stirring,
still at an inner temperature of 20.degree. C., for 30 minutes,
then the precipitate is filtered and washed with a mixture
consisting of 32 ml of demineralized water and 25 ml of ethyl
alcohol. The obtained "raw rifaximin" (89.2 g) is dried under
vacuum at room temperature for 12 hours yielding 64.4 g of "dried
raw rifaximin" having a 5.6% water content and a diffractogram
corresponding to polymorphous form .beta.. The product is further
dried under vacuum until constant weight yielding 62.2 g of dried
raw rifaximin having a 2.2% water content, whose diffractogram
corresponds to polymorphous form .alpha..
[0066] The product is hygroscopic and the obtained polymorphous
form is reversible: polymorphous form .alpha. absorbs water from
the atmospheric humidity until reaching, depending upon the
relative humidity and the time of exposure, a water content higher
than 4.5% and turning into polymorphous form .beta. which in its
turn, by drying loses part of the water turning into polymorphous
form .alpha. with a water content between 2.0% and 3.0%.
EXAMPLE 2
Preparation of Rifaximin .gamma.
[0067] 163 ml of ethyl alcohol and 62.2 g of dried raw rifaximin
are loaded at room temperature into a three-necked flask equipped
with mechanic stirrer, thermometer and reflux condenser. The
suspension is heated at 57.+-.3.degree. C. under stifling until
complete dissolution of the solid and at this temperature 70 ml of
demineralized water are added in 30 minutes. When the addition is
over the temperature is brought to 30.degree. C. in 40 minutes and
is kept at this value until abundant crystallization, then the
temperature is further lowered to 0.degree. C. during 2 hours and
kept at this value for 6 hours. The suspension is then filtered and
the solid is washed with 180 g of demineralized water.
[0068] After drying under vacuum at room temperature until constant
weight, 52.7 g of pure rifaximin .gamma. are obtained with a 1.5%
water content.
[0069] Form .gamma. is characterized by a powder X-ray
diffractogram showing significant peaks at diffraction angles
2.theta. of 5.0.degree.; 7.1.degree.; 8.4.degree..
EXAMPLE 3
Preparation of Rifaximin .alpha.
[0070] 62.2 g of dried raw rifaximin and 163 ml of ethyl alcohol
are loaded at room temperature into a three-necked flask equipped
with mechanic stirrer, thermometer and reflux condenser. The
suspension is heated at 57.+-.3.degree. C. until complete
dissolution of the solid and then 70 ml of demineralized water are
added at this temperature during 30 minutes. When addition is over
the temperature is taken to 30.degree. C. for 40 minutes and is
kept at this value until abundant crystallization. The suspension
temperature is then taken to about 40.degree. C. and kept at this
value during 20 hours under stirring; then the temperature is taken
to 0.degree. C. in 30 minutes and the suspension is immediately
filtered. The solid is washed with 180 ml of demineralized water
and dried under vacuum at room temperature until constant weight;
51.9 g of rifaximin form .alpha. with a 2.5% water content and a
powder X-ray diffractogram showing peaks at values of angles
2.theta. of 6.6.degree.; 7.4.degree.; 7.9.degree.; 8.8.degree.;
10.5.degree.; 11.1.degree.; 11.8.degree.; 12.9.degree.;
17.6.degree.; 18.5.degree.; 19.7.degree.; 21.0.degree.;
21.4.degree.; 22.1.degree..
EXAMPLE 4
Preparation of Rifaximin .alpha.
[0071] 89.2 g of raw rifaximin and 170 ml of ethyl alcohol are
loaded at room temperature into a three-necked flask equipped with
mechanic stirrer, thermometer and reflux condenser, then the
suspension is heated at 57.+-.3.degree. C. until complete
dissolution of the solid. The temperature is taken to 50.degree. C.
and then 51.7 ml of demineralized water are added at this
temperature in 30 minutes. When addition is over the temperature is
taken to 30.degree. C. in one hour and the suspension is kept for
30 minutes at this temperature obtaining a abundant
crystallization. The suspension temperature is taken to 40.degree.
C. and kept at this value for 20 hours under stifling and then
further lowered to 0.degree. C. in 30 minutes, after which the
suspension is immediately filtered. The solid is washed with 240 ml
of demineralized water and dried under vacuum at 65.degree. C.
until constant weight obtaining 46.7 g of rifaximin .alpha. with a
2.5% water content.
EXAMPLE 5
Preparation of Rifaximin .alpha.
[0072] Example 3 is repeated by increasing to 50.degree. C. the
temperature at which the suspension is kept and lowering to 7 hours
the time in which the suspension is kept at this temperature. The
obtained product is equal to that of example 3.
EXAMPLE 6
Preparation of Rifaximin .beta.
[0073] Crystallization of dried raw rifaximin is carried out
according to the method described in example 3. The drying under
vacuum at room temperature is checked by means of the Karl Fischer
method and is stopped when the water content reaches 5.0%: 52.6 g
of rifaximin .beta. are obtained characterized by a powder X-ray
diffractogram showing peaks at values of angles 2.theta. of
5.4.degree.; 6.4.degree.; 7.0.degree.; 7.8.degree.; 9.0.degree.;
10.4.degree.; 13.1.degree., 14.4.degree.; 17.1.degree.;
17.9.degree.; 18.3.degree.; 20.9.degree..
EXAMPLE 7
[0074] Preparation of Rifaximin .alpha. Starting from Rifaximin
.gamma.
[0075] 5 Grams of rifaximin .gamma. are suspended in a mixture
consisting of 13 ml of ethyl alcohol and 5.6 ml of water and the
suspension is heated at 40.degree. C. for 24 hours under stifling
in a 50 ml flask equipped with condenser, thermometer and mechanic
stirrer. The suspension is then filtered and the solid is washed
with water and then dried under vacuum at room temperature until
constant weight. 4 g of rifaximin are obtained showing a powder
X-ray diffractogram corresponding to that of the polymorphous form
.alpha. and a 2.6% water content.
EXAMPLE 8
[0076] Preparation of Rifaximin .gamma. Starting from Rifaximin
.alpha.
[0077] 15 Grams of rifaximin form .alpha. and 52.4 ml of ethyl
alcohol are loaded into a 250 ml three-necked flask equipped with
reflux condenser, thermometer and mechanical stirrer; the
suspension is heated under stirring at the temperature of
50.degree. C. until complete dissolution of the solid.
[0078] The limpid solution is added with 22.5 ml of water for 30
minutes under stirring, cooled to 30.degree. C. and kept at this
temperature for 30 minutes. The formed suspension is cooled to
0.degree. C. under strong stifling and kept at this temperature
during 6 hours. A part of the suspension is taken after this period
of time, filtered, washed with demineralized water and dried under
vacuum at 30.degree. C. until constant weight.
[0079] The obtained product, 3.7 g, shows a diffractogram
consistent with that of form .gamma. and .alpha. 1.7% water
content.
[0080] The remaining part of the suspension is kept at 0.degree. C.
for further 18 hours under strong stirring and then is filtered,
washed with demineralized water and dried at 30.degree. C. under
vacuum until constant weight. 9 g of product showing a
diffractogram consistent with that of form .gamma. and 1.6% water
content are obtained.
EXAMPLE 9
[0081] Preparation of Rifaximin .alpha. Starting from Rifaximin
.beta.
[0082] 5 Grams of rifaximin .beta. having a 5.0% water content are
dried under vacuum at +30.degree. C. for 8 hours obtaining 4.85 g
of rifaximin .alpha. having a 2.3% water content.
EXAMPLE 10
[0083] Preparation of Rifaximin .beta. Starting from Rifaximin
.alpha.
[0084] 5 g of rifaximin .alpha. having a 2.5% water content are
kept during 40 hours in an atmosphere containing a 56% relative
humidity produced by means of a saturated aqueous solution of
calcium nitrate tetrahydrate. 5.17 g of Rifaximin .beta. with a
5.9% water content are obtained after this time.
* * * * *