Link: Pharm/Biotech Resources
Title: Macrolide solvates
United States Patent: 6,949,519
Issued: September 27, 2005
Inventors: Centellas; Victor (Cardedeu/Barcelona, ES); Diago; José (Granollers/Barcelona, ES); Garcia; Rafael (Sant Celoni/Barcelona, ES); Ludescher; Johannes (Breitenbach, AT)
Assignee: Sandoz AG (Basel, CH)
Appl. No.: 432545
Filed: November 26, 2001
PCT Filed: November 26, 2001
PCT NO: PCT/EP01/13760
371 Date: October 10, 2003
102(e) Date: October 10, 2003
PCT PUB.NO.: WO02/42315
PCT PUB. Date: May 30, 2002
Abstract
Azithromycin in the form of a monohydrate comprising from 4.0% to 6.5% of water, a process for its preparation and its use in pharmaceutical compositions.
Description of the Invention
The present invention relates to macrolide solvates, i.e. solvates of
azithromycin and similar compounds. Azithromycin
(9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A) is a well-known
antibacterial agent, described e.g. Ib. The Merck Index, 12th
edition (1996), page 157 (item 946) and may be produced according to a known
process. Azithromycin may be obtained in the form of a solvate, e.g. in the
form of a hydrate, such as a monohydrate or e.g. in the form of a dihydrate.
It is known that azithromycin in the form of a monohydrate may be unstable
and may contain degradation products, when set out to normal air humidity
conditions and azithromycin in the form of a monohydrate produced according
to known methods, e.g. by precipitation with water from an ethanolic
solution, may beside its instability contain a high content of residual
solvents. Thus, azithromycin currently on the market is in the form of a
dehydrate which is known to be stable under normal air humidity conditions.
We have now surprisingly found that azithromycin may be obtained in the form
of a, e.g. crystalline, monohydrate which is stable.
In one aspect the present invention provides azithromycin in the form of a
monohydrate comprising from 4.0% to 6.5% w/w of water.
Azithromycin in the form of a monohydrate comprising from 4.0% to 6.5% w/w
of water is hereinafter designated as "azithromycin according to the present
invention".
Azithromycin according to the present invention contains water from 4.0% to
6.5%. The calculated amount of water in azithromycin in the form of a
composition consisting of 1 mol of azithromycin and 1 mol of water is around
2.35% w/w, but an azithromycin/water composition wherein the water content
is different from 2.35% w/w, does not necessarily mean that the
crystallisation form of azithromycin is different from the crystallisation
form of azithromycin in the form of a monohydrate. We have found that the
X-ray powder diffraction pattern of azithromycin according to the present
invention is corresponding to the X-ray powder diffraction pattern which is
disclosed for azithromycin in the form of a monohydrate as disclosed in EP
941 999, and EP 984 020, and is substantially different from the X-ray
powder diffraction pattern of azithromycin in the form of a dihydrate as
disclosed in EP 941 999, and in EP 984 020.. Azithromycin according to the
present invention is substantially crystalline and maintains its X-ray
powder diffraction pattern, i.e. it maintains its crystalline structure,
within at least 2 weeks, e.g. up to 6 weeks and more, such as 2 to 6 weeks,
under normal, e.g. normal air, humidity conditions, e.g. even at elevated
temperatures.
Azithromycin according to the present Invention may be further defined by
Its low content of azithromycin degradation products. E.g. we have found
that in a sample of azithromycin according to the present invention
practically no azithromycin degradation occurs, when setting out said sample
to normal, e.g. normal air, humidity conditions, such as 70% to 80%, e.g.
75% humidity, within 2 to 6 weeks, e.g. within 6 weeks, and even longer,
e.g. at elevated temperatures, such as temperatures above room temperatures,
e.g. 35° C. to 45° C., such as 40° C.; e.g. we have found that the
degradation of azithromycin according to the present invention under a
temperature of 40° C. in an environment of 75% humidity within 6 weeks is
less than 2.0%, even less than 1.0% and even less than 0.5%, namely (around)
0.1%, whereas azithromycin in the form of a monohydrate having a water
content of 2.8% to 3.6% shows a degradation of 2.5% already within 2 weeks,
which degradation is increasing within 4 weeks, and is of almost 7% within 6
weeks under the same conditions.
In another aspect the present invention provides azithromycin in the form of
a monohydrate, characterized in that in a sample thereof the degradation of
azithromycin is less than 2%, even less than 1.5%, such as 0.05% to 1.0%,
e.g. 0.05 to 0.5%, when setting out said sample to normal, e.g. normal air,
humidity conditions, such as 75% envionmental humidity, e.g. at elevated
temperatures, such as of 40° C., within at least 2 weeks, e.g. within 2,
e.g. 4, and e.g. even 6 weeks.
Azithromycin degradation which occurs under the above described conditions
in a sample of azithromycin according to the present invention is within the
percentage range of degradation products allowed by Pharmacopeiias in
commercial azithromycin forms.
Azithromycin according to the present invention may be further defined by
its stable water content. E.g. we have found that in a sample of
azithromycin according to the present invention the water content
practically does not increase, e.g. the water content remains essentially
the same, when setting out said sample to normal, e.g. normal air, humidity
conditions, such as 70% to 80%, e.g. 75% humidity, within 6 weeks, e.g.
within 4 to 6 weeks, and even longer, e.g. at elevated temperatures, such as
temperatures above room temperatures, e.g. 35° C. to 45° C., such as 40° C.;
e.g. we have found that the water content of azithromycin according to the
present invention at a temperature of 40° C., in an environment of 75%
humidity remains substantially the same as in week 0 within 4 weeks and even
6 weeks.
In another aspect the present invention provides azithromycin in the form of
a monohydrate, characterized in that in a sample thereof the water content
remains substantially the same as in week 0, when setting out said sample to
normal, e.g. normal air, humidity conditions, such as 75% envionmental
humidity, e.g. at elevated temperatures, such as temperatures above room
temperatures, e.g. 35° C. to 45° C., e.g. 40° C., for a period of 4 weeks,
e.g. 4 to 6 weeks.
Azithromycin according to the present invention may be obtained e.g. as
follows: Azithromycin in any form, e.g. in free base form; and in the form
of a salt, e.g. in the form of a hydrochloride, e.g. a dihydrochloride,
acetate; and/or in the form of a solvate, e.g. in the form of a monohydrate,
having a water content which is different from 4.0% to 6.5%, in anhydrous
form, or in the form of a dihydrate, preferably in the form of a salt, may
be e.g. used as a starting material. A solution of azithromycin in the form
of a salt in a solvent may be produced, e.g. either by dissolving
azithromycin in the form of a salt in a solvent; or by conversion of
azithromycin in free form in a solvent into azithromycin in the form of a
salt; e.g. by addition of an acid to azithromycin in solvent. A "solution"
includes a suspension, In which at least a part of azithromycin (e.g. in the
form of a salt) is dissolved. Appropriate acids include organic acids, for
example formic acid or acetic acid, and inorganic acids, for example
hydrochloric, hydrobromic, nitric or sulphuric acid, preferably hydrochloric
acid or sulphuric acid. Solvent includes solvent which is appropriate to
dissolve azithromycin in the form of a salt, e.g. including aqueous solvent.
Aqueous solvent includes water or a mixture of water with organic solvent,
e.g. one or more organic solvents, for example water miscible and water
immiscibl organic solvent, such as alcohols, e.g. methanol, ethanol,
isopropanol; ketones such as acetone, methyl isobutyl ketone; alkyl
carboxylic acid esters, e.g. (C1-4)alkyl carboxylic acid esters,
of formic or acetic acid, e.g. methyl acetate, ethyl acetate, isopropyl
acetate, butyl acetate; aromatic hydrocarbons such as toluene, xylenes;
ethers, such as tetrahydrofuran, methyl t.butyl ether; chlorinated
hydrocarbons such as methylene chloride; and amides such as monoalkyl and
dialkyl amides, e.g. N-methyl formamide, N,N-dimethylacetamide,
N,N-dimethylformamide; preferably water or a mixture of water with one or
more alcohols, ketones, alkyl acetates; e.g. water, or aqueous solvent, such
as water or water containing 0.5% to 20% v/v; such as 1% to 15% v/v of
organic solvent. It is one advantage of the present invention that water in
the absence of organic solvent may be used.
Appropriate reaction conditions for the production of a solution of
azithromycin in the form of a salt according to the process of the present
invention include, e.g.
A resulting solution of azithromycin In the form of a salt in a solvent may be optionally purified as appropriate, e.g. by filtration, charcoal treatment; In order to remove impurities. The pH of an, e.g. purified, solution of azithromycin in the form of a salt may be adjusted to an pH where azithromycin is present in free form, including e.g. a pH of, e.g. ca., 8.0 to 13.0, such as 9.0 to 12.0, e.g. 10.0 to 11.0; e.g. by addition of a base to a solution of azithromycin in the form of a salt in a solvent. A "solution" of azithromycin in free form includes a suspension, in which at least a part of azithromycin is dissolved. Appropriate bases include bases which are suitable for pH adjustment, e.g. inorganic bases, such as ammonia or alkali-, e.g. sodium, potassium; earth alkali-, e.g. calcium-, magnesium-; and ammonium-hydroxide, -carbonate, -hydrogencarbonate; and organic bases, such as amines, e.g. alkyl amines; and a mixture of individual bases, e.g. individual bases as described above. A base is preferably a hydroxide, e.g. sodium, or ammonia; preferably in aqueous solution. Azithromycin in free form and in the form of a stable crystalline monohydrate may precipitate from the solution and may be isolated, e.g. analogously to a method as conventional, e.g. by centrifugation or filtration; and may be dried at appropriate temperatures, e.g. including a temperature range of 20° C. to 80° C., e.g. under atmospheric pressure or under vacuum; until a water content of 4.0% to 6.5% is achieved. Crystalline azithromycin in the form of a monohydrate may be obtained comprising from 4.0% to 6.5% of water.
In another aspect the present invention provides a process for the production of azithromycin in the form of a monohydrate comprising from 4.0% to 6.5% of water, said process comprising the steps
When solely water is used as a solvent azithromycin according to the present invention may be obtained, substantially free of organic solvent. Substantially free includes an analytically undetectable amount up to an analytically detectable amount of 0.5% w/w of organic solvent; which is an amount of organic solvents; which is within the range which European Pharmacopoellas define as appropriate for pharmaceutical ingredients, e.g. for solvents with low toxic potential (Class 3 solvents).
In another aspect the present invention provides azithromycin in the form of a crystalline monohydrate, which is substantially free of organic solvent.
Azithromycin according to the present invention, is useful in the production of a pharmaceutical composition comprising azithromycin as an active ingredient.
In another aspect the present invention provides a pharmaceutical composition, comprising, e.g. essentially consisting of, azithromycin according to the present invention in association with at least one pharmaceutical carrier or diluent.
A pharmaceutical composition according to the present invention may contain the same concentrations of azithromycin and may be used for the same indications in the same dosage ranges as a known pharmaceutical composition comprising azithromycin in the form of a dihydrate, e.g. as is currently on the market
Claim 1 of 7 Claims
1. Azithromycin in the form of a monohydrate comprising from 4.0% to 6.5%
w/w of water.
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