Note: Descriptions are shown in the official language in which they were submitted.
CA 02333943 2000-11-30
WO 99/62910 PCT/US99/11991
PROCESS FOR PREPARING CRYSTALLINE SALTS OF AMOXYCILLIN
This application claims the benefit of U.S. Provisional Application No.
60/087,554,
filed June 1, 1998.
This invention relates to a process for the preparation of crystalline salts
of the beta
lactam antibiotic amoxycillin viz. 6-[[amino (4-hydroxyphenyl)acetyl]-amino]-
3,3-
dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid. In
particular this
invention relates to a process for the preparation of crystalline sodium
amoxycillin.
Crystalline sodium amoxycillin is a known substance and processes for its
preparation are disclosed in the state of the art. For example EP 013 I 147A
discloses a
process in which amoxycillin trihydrate is converted into a crystalline
solvate of sodium
amoxycillin from which the solvating solvent is removed. In one experimental
example of
this disclosure amoxycillin trihydrate is suspended in methyl acetate, then a
solution of a
mixture of triethylamine and sodium 2-ethylhexanoate is added to this
suspension. In EP
0596262A amoxycillin trihydrate is dissolved in a methyl acetate / isopropanol
/
triethylamine mixture, then this solution is added to a solution of sodium 2-
ethylhexanoate
in a methyl acetate / methanol mixture. A crystalline solvate of sodium
amoxycillin is
believed to crystallize out from the reaction mixture, from which the
solvating solvent is
removed. In WO 97/15579 amoxycillin trihydrate is added to an ethanol /
triethylamine
mixture to form a solution which is then reacted with sodium 2-ethylhexanoate
in ethanoiic
solution, and a crystalline product is obtained. In US 4737585 amoxycillin
trihydrate is
suspended in a mixture of an aprotic solvent, such as methylene chloride, and
a lower
alcohol, the amoxycillin is solubilized using a low molecular weight amine,
and to this
mixture is added the sodium salt of diethyloxalacetic acid. Sodium amoxycillin
is then
precipitated by addition of more of the aprotic solvent.
In processes used to prepare crystalline sodium amoxycillin it is desirable to
minimize the quantities of solvents used and to improve yield and purity of
the product.
Consequently there is an ongoing problem of process improvement. It is an
object of the
present invention to provide an alternative and improved process for the
preparation of
crystalline sodium amoxycillin. Other objects and advantages of the present
invention will
be apparent from the following description.
According to this invention a process for the preparation of a crystalline
alkali
metal salt of amoxycillin is provided, in which;
a suspension of an amine salt of amoxycillin is formed in a first organic
solvent,
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WO 99/62910 PCT/US99/11991
the suspension is admixed with a second organic solvent and the amine salt is
caused to enter solution in the so-formed mixture of first and second organic
solvents,
the amine salt is reacted with a salifying compound of the alkali metal,
the so-formed alkali metal salt of amoxycillin is isolated from the solution
as a
crystalline product.
In the process of the invention it is believed that the formation of the
suspension of
the amine salt in the first solvent, and rapid dissolution of the salt when
the second organic
solvent 1-5is admixed, leads to decreased breakdown of the amoxycillin, and
consequently
increased yield and purity of the crystalline product. In the process of this
invention the
reagents are formed into solution, which facilitates sterilising filtration
and consequent use
of the product as an injectible pharmaceutical product. However the process of
the present
invention may equally effectively be used without a sterile filtration step to
prepare
crystalline sodium amoxycillin which may be administered orally.
Preferably the crystalline alkali metal salt of amoxycillin prepared by the
process of
this invention is crystalline sodium amoxycillin.
Preferably the amine salt of amoxycillin is a salt of a tri- or di- (C 1-51-
5)alkyl
amine, such as triethylamine, diethylamine or diisopropylamine, especially the
triethylamine, salt of amoxycillin. A mixture of amine salts may be used such
as a mixture
of the salts of amoxycillin with triethylamine and diisopropylamine. Other
suitable amine
salts include the salt with dicyclohexylamine.
A preferred first organic solvent is a (C1-51-5)alkyl (C1-51-5)alkanoate
ester, a
preferred such ester being a (CI-51-5)alkyl acetate ester, particularly methyl
acetate. The
first organic solvent may comprise a single solvent or a mixture of solvents,
for example a
mixture of said esters or said esters and other co-solvents.
Preferably the suspension is formed by first forming a suspension of
amoxycillin,
preferably in the form of amoxycillin trihydrate, in the first organic solvent
then admixing
the amine with this suspension so that the amine reacts with the amoxycillin
to form the
amine salt. This reaction is preferably carried out at below ambient
temperature, for
example below 10°C, especially at 0-5°C. Suitably the
amoxycillin trihydrate may be
suspended in a volume of methyl acetate at a ratio weight of amoxycillin
trihydrate
volume of methyl acetate ca. 1:1 - 1:2.5, for example typically 1:1.7 - I : 2,
and this
suspension may be admixed with the triethylamine in a stoichiometric excess to
the
amoxycillin, for example at a molar ratio amoxycillin : triethylamine 1:1 - I
:2, for example
typically 1:1.3 - 1:1.5.
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A suitable second organic solvent with which the suspension of the amine salt
may
be admixed is a (C 1-51-5)alcohol, such as methyl alcohol, which is preferred,
or ethyl
alcohol, propyl alcohol e.g. isopropyl alcohol, or butyl alcohol e.g. iso-
butyl alcohol. The
second organic solvent may comprise a single solvent or a mixture of solvents,
for example
a mixture of said alcohols or said alcohols and other co-solvents.
The admixing of the second solvent and the suspension of the amine salt in the
first
solvent causes the salt to enter solution, and the volume of the second
solvent e.g. the
alcohol used may be determined experimentally as the minimum volume of the
second
solvent necessary to achieve this. Typically when the first solvent is the
above-described
ester and the second solvent is the above-described alcohol a volume ratio
ester : alcohol of
ca. 1: 0.3 - 0.6 will be found suitable, e.g. about 1 : 0.4-0.5 of methyl
acetate : methyl
alcohol. If such a volume ratio of methyl alcohol is admixed with the above-
described
suspension of the triethylamine salt of amoxycillin then the salt generally
dissolves
immediately upon stirring.
At this stage the so-formed solution of the amine salt of amoxycillin may for
example be filtered and/or treated by other standard purification steps e.g.
treatment with
dicalite or other materials which selectively absorb impurities. If the
solution is filtered the
filter medium may subsequently be washed with more of the second solvent e.g.
the
alcohol, e.g. corresponding to an amount 0.5 - 1.0 of the amount already in
admixture with
the solution of the salt.
A suitable salifying compound is a pharmaceutically acceptable salifying
compound of a suitable alkali metal, for example the sodium salt of an organic
compound,
for example an alcoholate such as of a (C1-51-5)alcohol e.g. the methoxide
and/or
ethoxide, or a salt of an organic acid e.g. a (C1-121-5) carboxylic acid such
as an alkyl
substituted- alkanoate for example a 2-ethylhexanoate. In the case of
preparation of
crystalline sodium amoxycillin sodium 2-ethylhexanoate is a preferred
salifying compound.
The reaction of the amine salt is suitably carried out by admixing the
solution of
the amine salt with a solution of the salifying compound. Suitably the
salifying compound
is in solution in a solvent mixture which comprises the abovementioned first
and second
organic solvents, e.g. the abovementioned (C1-51-5)alkyl (CI-51-5)alkanoate
ester and
(Cl-51-5)alcohol, for example a methyl acetate : methanol mixture comprising
predominantly the ester, for example a 9-12 : 1 v:v, e.g. 10-11 : 1 v:v methyl
acetate
methanol mixture. Suitably a stoichiometric excess of the salifying compound
relative to
the amoxycillin is used, e.g. a 1.5 - 2.5 : 1 molar ratio of sodium 2-ethyl
hexanoate
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WO 99/62910 PCTNS99/11991
amoxycillin. Suitably a solution of sodium 2-ethylhexanoate in the
abovementioned solvent
mixture which is of concentration around 1.8 - 2.5 M may be used. This
solution may be
filtered and/or subjected to other appropriate purification steps before the
reaction with the
amoxycillin.
Preferably the reaction between the salifying compound and the amoxycillin is
carried out at below ambient temperature, e.g. below 10°C, especially
at 0-5°C. Preferably
the solution of the amine salt is added to the solution of the salifying
compound, although
the reverse mode of addition, i.e. addition of the solution of the salifying
compound to the
solution of the amine salt, or concurrent admixing, may be used. Preferably
the mixing of
the two solutions is carried out as fast as possible, with rapid stirring.
Spontaneous crystallization of the reaction product may occur, but it is
preferred to
induce crystallization by the addition of seed crystals, e.g. of crystalline
sodium
amoxycillin or some crystallographically equivalent material e.g. a solvate of
crystalline
sodium amoxycillin, to the reaction mixture immediately after the mixing of
the solutions.
To further encourage crystallization further of the abovementioned first
organic solvent e.g.
the (C1-51-5)alkyl (C1-51-5}alkanoate ester, e.g. methyl acetate, may be
admixed with the
reaction mixture, preferably in excess of the reaction medium volume e.g. in a
1.5 - 2.0 x
excess of the reaction medium volume. This admixing of the first organic
solvent may be
carried out relatively slowly, e.g. over a period of ca. 30-40 minutes. After
the admixing of
this further amount of the first solvent the mixture may be stirred for a
time, e.g. ca. 1 hour
preferably below ambient temperature, e.g. below 10°C, especially at 0-
5°C.
After this stage the crystalline product may be separated off from the
reaction
medium using standard procedures, e.g. filtered off, and washed with a
suitable wash
liquid, preferably the first organic solvent.
The crystalline product obtained in this way is believed to be a crystalline
solvate
of sodium amoxycillin, e.g. the methyl acetate solvate from which the
solvating solvent
may be removed by a drying process, e.g. the process disclosed in EP 0131147A,
the
contents of which are incorporated herein by reference. This drying process
may be in
vacuum preferably at an elevated temperature such as 50-65°C, for
example 60-65°C to
remove residual reaction medium solvents, wash liquids and solvating solvents,
to yield the
crystalline alkali metal salt of amoxycillin.
Crystalline sodium amoxycillin prepared by the process of this invention may
be
used as a pharmaceutical antibiotic product e.g. in injectible form. For this
purpose it may
be provided contained in sealed sterile vials. Alternatively the sodium
amoxycillin prepared
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by the process of this invention may be used in formulations for oral
administration e.g. in
tablet, granule, syrup etc formulations and for oral administration sterile
formulation is not
necessarily required. Preferably for use as an antibiotic product the product
crystalline
alkali metal salt of amoxycillin is administered in combination with a
pharmaceutically
acceptable beta-lactamase inhibitor such as a salt of clavulanic acid,
particularly potassium
clavulanate.
The invention will now be illustrated by way of non-limiting example.
Example I: Laboratory Scale.
1.1 Dissolution of sodium 2-ethyl hexanoate.
Sodium 2-ethyl hexanoate (160g) was dissolved in a mixture of methyl acetate
(310m1) and methanol (30m1). The mixture was stirred at room temperature until
dissolution was complete and the solution was filtered through Whatman No. 1
filter paper
to remove cloudiness. The solution was transferred to a crystallization
vessel, followed by a
wash of methyl acetate (210m1} and stirred at 0-5°C. This solution was
consequently 2.15M
in Sodium 2-ethyl hexanoate.
1.2 Dissolution of amoxycillin trihydrate.
Amoxycillin trihydrate (250g) was slurried in methyl acetate (450m1).
Triethylamine (120 ml) was added to the slurry creating a thick suspension.
Methanol
(200m1) was added, causing the amoxycillin triethylamine salt to dissolve
instantly. The
solution was stirred for 5 minutes before dicalite ( l Og) was added and the
mixture was
allowed to stir for a further 5 minutes. The solution was then filtered
through Whatman No.
1 filter paper followed by a wash with methanol ( 120m1) and transferred to
the
crystallization vessel containing sodium 2-ethyl hexanoate from 1.1 above.
1.3 Reaction and crystallization.
The mixture in the crystallization vessel was stirred vigorously at 0-
5°C and
crystalline sodium amoxycillin seed (lg) was added. As crystallization began
methyl
acetate (2300m1) was added over a period of 30-40 minutes. The mixture was
allowed to
stir for 1 hour at 0-5°C. The product was then filtered and washed with
methyl acetate
(750m1).
1.4 Drying
The crystalline product from 1.3 was dried under vacuum at 50-55°C
for 36 hours, or alternatively at 65°C for the shorter period of 16
hours. Product quality was
found to be unaffected by the drying temperature. The product was confirmed to
be
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crystalline sodium amoxycillin by chemical analysis, infrared spectroscopy and
X-ray
powder diffractometry.
The product obtained had an amoxycillin content of 91.0%, with a total content
of
impurities of 2.13 - 2.16%.
Example 2: Scale up.
2.1 Dissolution of sodium 2-ethyl hexanoate.
Methyl acetate ( 124L) was added to sodium 2-ethyl hexanoate (64kg), and
methanol (12L) was added with stirring until the sodium 2-ethyl hexanoate
dissolved. The
solution was filtered and transferred to a crystallization vessel, washing in
with methyl
acetate (84L).
2.2 Dissolution of amoxycillin trihydrate.
Methyl acetate (124L) was added to amoxycillin trihydrate (87.1kg) and the
resulting suspension was cooled to 0-5°C. Triethylamine (48.1L) was
added to the slurry
and the slurry was stirred for 5 minutes. Methanol (80L) was added causing the
amoxycillin
triethylamine salt to dissolve and the solution was stirred for 5 minutes.
Dicalite (2kg) was
added and the mixture was stirred for a further S minutes. The solution was
then filtered
and the cake was washed through with methanol (48L).
2.3 Reaction and crystallization.
The solution of amoxycillin triethylamine salt from 2.2 was added to the
sodium 2-
ethyl hexanoate solution from 2.1 as fast as possible and the mixture was
cooled to 0-5°C.
Crystalline sodium amoxycillin seed (400g) was added. Methyl acetate (921L)
was added at
a rate of 27 litres per minute. The mixture was stirred for 1 hour at 0-
S°C. The slurry was
then transferred to a NutrexTM mixer and the mother liquor was filtered. The
product was
then washed with methyl acetate (84L).
2.4 Drying
The crystalline product from 2.3 was blow dried with nitrogen, and then dried
in
vacuum at 60-65°C.
The product obtained had an amoxycillin content of 89.7 - 93.6°l0, with
a total
content of impurities of 1.72 - I .42% over three batches.
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