U.S. patent application number 11/290185 was filed with the patent office on 2006-04-13 for agglomerates by crystallisation.
Invention is credited to Johannes Booij, Geertruida Ageeth Lefferts.
Application Number | 20060079496 11/290185 |
Document ID | / |
Family ID | 8240058 |
Filed Date | 2006-04-13 |
United States Patent
Application |
20060079496 |
Kind Code |
A1 |
Booij; Johannes ; et
al. |
April 13, 2006 |
Agglomerates by crystallisation
Abstract
The present invention describes novel agglomerates in
crystalline form of .beta.-lactum compounds, Furthermore, a process
for the preparation of said agglomerates, wherein a solution or
suspension of at least one .beta.-lactum compound in a solvent is
mixed with one or more anti-solvents has been described.
Inventors: |
Booij; Johannes;
(Bloemendaal, NL) ; Lefferts; Geertruida Ageeth;
(Breda, NL) |
Correspondence
Address: |
MORRISON & FOERSTER LLP
12531 HIGH BLUFF DRIVE
SUITE 100
SAN DIEGO
CA
92130-2040
US
|
Family ID: |
8240058 |
Appl. No.: |
11/290185 |
Filed: |
November 30, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09937834 |
Feb 13, 2002 |
6979735 |
|
|
PCT/EP00/02917 |
Apr 3, 2000 |
|
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11290185 |
Nov 30, 2005 |
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Current U.S.
Class: |
514/192 ;
514/210.09; 540/349 |
Current CPC
Class: |
A61K 9/1688 20130101;
A61K 31/43 20130101; A61K 31/43 20130101; C07D 503/00 20130101;
A61K 2300/00 20130101; A61K 31/424 20130101; A61K 31/42 20130101;
A61K 31/43 20130101; Y10T 428/2982 20150115; C07D 499/00 20130101;
A61P 31/04 20180101 |
Class at
Publication: |
514/192 ;
540/349; 514/210.09 |
International
Class: |
A61K 31/43 20060101
A61K031/43; A61K 31/407 20060101 A61K031/407; C07D 487/08 20060101
C07D487/08 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 1, 1999 |
EP |
99201034.8 |
Claims
1. An agglomerate of potassium clavulanate crystals, wherein said
agglomerate has a loose bulk density between about 0.20 and 0.60
g/mL, a tapped bulk density between about 0.50 and 0.90 g/mL, and a
compressibility between about 10 and 40%, wherein said
compressibility is calculated as 100 times the ratio of the
difference between tapped bulk density and loose bulk density to
the tapped bulk density, and said agglomerate has a weight
percentage of between 0% and 10% potassium clavulanate crystals in
the needle form, with the proviso that the rosette-like crystalline
form of potassium clavulanate is excluded.
2. The agglomerate of claim 1, wherein said agglomerate contains no
potassium clavaulate crystals in the needle form.
3. The agglomerate of claim 1, further comprising amoxicillin.
4. The agglomerate of claim 1, further comprising one or more
excipients.
5. The agglomerate of claim 4, wherein said one or more excipients
is selected from the group consisting of microcrystalline cellulose
and silica.
6. The agglomerate of claim 1, wherein said agglomerate has an
average particle size between about 1 .mu.m and 1500 .mu.m.
7. The agglomerate of claim 6, wherein said agglomerate has an
average particle size of about 100 .mu.m.
8. The agglomerate of claim 6, wherein said agglomerate has an
average particle size of about 1000 .mu.m.
9. A pharmaceutical formulation comprising the agglomerate of claim
1 and one or more pharmaceutically acceptable excipients.
10. The pharmaceutical formulation of claim 9, further comprising
amoxicillin.
11. The pharmaceutical formulation of claim 9, wherein said one or
more pharmaceutically acceptable inert excipients is selected from
the group consisting of microcrystalline cellulose and silica.
12. A pharmaceutical dosage form comprising a pharmaceutical
formulation of claim 9.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 09/937,834 filed Feb. 13, 2002, which is a 371
application of PCT/EP00/02917 filed Apr. 3, 2000, which claims
priority to European application no. EP99201034.8 filed Apr. 1,
1999. The contents of these applications are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention describes agglomerates of
.beta.-lactam compounds in crystalline form and a process to
prepare the same.
BACKGROUND OF THE INVENTION
[0003] .beta.-Lactam antibiotics constitute the most important
group of antibiotic compounds, with a long history of clinical use.
Among this group, the prominent ones are the penicillins and
cephalosporins.
[0004] Presently, most of the P-lactam antibiotics used are
prepared by semi-synthetic methods. These .beta.-lactam antibiotics
are obtained by modifying a .beta.-lactam product obtained by
fermentation by one or more reactions.
[0005] Clavulanic acid and its alkaline metal salts and esters,
another type of .beta.-lactam compound than the penicillin and
cephalosporin, act as .beta.-lactamase inhibitors, able to enhance
the effectiveness of penicillins and cephalosporins. Clavulanic
acid has been applied therefore in pharmaceutical compositions to
prevent inactivation of .beta.-lactam antibiotics. For example, the
antibacterial activity profile of amoxicillin is enhanced by the
use of potassium clavulanate as .beta.-lactamase inhibitor. A
combination preparation of amoxicillin trihydrate with potassium
clavulanate (Augmentin.RTM.) is well known.
[0006] It is generally known that antibiotic compounds in powder
form are not suitable for formulation purposes, because generally
these powders perform badly as far as flowability is concerned
which causes problems in the manufacturing of final dosage forms,
such as tablets. Accurate dosing of the several ingredients is
needed to ensure constant end product quality. In case of poor
flowabilities, such accurate dosing is difficult to guarantee.
Also, the needle shaped crystals, such as of potassium clavulanate,
often show a low bulk density. Thus, the contribution of such
crystals to the overall volume of the final dosage form is
relatively high.
[0007] To overcome these problems, often granules of compounds, for
example potassium clavulanate with excipients (such as
microcrystalline cellulose like Avicel.RTM. or silica like
Syloid.RTM. or Aerosil.RTM.) or granules of composition, for
example potassium clavulanate with other active ingredients like
amoxicillin trihydrate are made before producing the final
formulation. Several processes are known to form such granules. For
example, in case of wet granulation, potassium clavulanate can be
mixed with, for instance, amoxicillin and a binding agent after
which the mixture is moistened by a solvent, granulated and
bounded. Before tabletting the granules with excipients, the
granulates might be sieved. This wet granulation process is
economically unattractive, as it uses solvents which must be
recovered and/or recycled. It is labour intensive, expensive and
time consuming due to the large number of processing steps such as
mixing, granulating, sieving, drying etc. Moreover, in case of
unstable .beta.-lactam compounds such as potassium clavulanate, wet
granulation is problematic due to the use of a solvent and high
temperature during the drying step of the process.
[0008] Another method to granulate poor flowing powders is dry
granulation As an example, the slugging process can be mentioned as
described in International patent applications WO 9116893 and WO
9219227. Here, tablets of the poor flowing material with excipients
are made and subsequently broken again and sieved to produce
granules. Another example of dry granulation is the compaction
process as described in International patent application WO
9528927. In this application, a process has been mentioned wherein
compacted granules of a .beta.-lactam antibiotic, for example
amoxicillin, and a mixture of an active .beta.-lactam antibiotic
and a secondary pharmaceutically active agent, for example
potassium clavulanate with excipients are made using roller
compacting. Subsequently, the roller compacted flakes are milled,
resulting in granules which can be mixed with excipients to press
the final tablets. An advantage compared to the wet granulation is
the absence of solvents. However, the dry granulation is relatively
time consuming due to a large number of processing steps. Also, in
case of unstable products, a quality risk exists due to locally
high temperatures in the process, e.g. due to abrasion. In case the
material is hygroscopic, such as potassium clavulanate, another
disadvantage is the handling of the dried crystals before and
during the granulation process. During this handling, the product
might attract water leading to unwanted degradation reactions. Also
a major disadvantage of roller compacted products is the relatively
large amount of fines which should be removed using sieving
techniques to improve the flowability of such products.
[0009] Furthermore, difficulties one may encounter by using dry
granulation are: [0010] a lot of dust is produced during the
slugging or roller compaction process and in some cases, for
example such as amoxicillin, this dust sticks to the coarser
particles and can not be separated by currently applied vibrating
sieves, [0011] dust may deteriorate the flow properties of
agglomerates, [0012] dust is also responsible for air born
.beta.-lactam antibiotics particles which can cause allergic
reaction.
[0013] Granules of the active ingredient in the presence of
excipients are produced by the process mentioned above. It would be
advantageous to have the possibility to produce granules of the
pure active ingredient. In that case, the production process can be
more flexible and possibly overall less excipients are necessary.
Also the production of final dosage forms will be more flexible. In
case of hygroscopic substances such as potassium clavulanate,
however, it will be difficult to granulate using one of the above
processes without the presence of excipients like microcrystalline
cellulose or silica, as the latter are known to protect the
hygroscopic potassium clavulanate by removing the free water from
it and, thus, keeping the water activity of such compositions low.
However, in the International patent application WO 9733564 a
method has been mentioned in which granules of a pure active
ingredient, without the presence of excipients, are made by
extrusion. Here, a paste is made of the crystalline powder by
adding a liquid wherein the powder is insoluble or slightly
soluble. The paste is needed then and extruded in a double screwed
extruder, after which the granules are dried. The process again is
not suitable for unstable products, as locally the temperature in
the extruder is high (up to 80.degree. C.). Also, this wet material
should be dried at elevated temperatures.
[0014] Another method to improve the flowability of needle shaped
crystals, especially in the case of potassium clavulanate, is to
agglomerate them during crystallisation to the so-called rosette
form as described in European patent EP 277008 B1. In this case, a
plurality of needle crystals radiate out from a common nucleation
point. The rosettes show an increased flowability compared to the
needles. However, a large disadvantage of these types of granules
is the inclusion of impurities, leading to a decreased chemical
quality of the product. Also, the included impurities probably
increase the degradation rate of the .beta.-lactam compound, thus
resulting in an even worse chemical quality during storage.
[0015] The object of the invention is to provide a valuable form of
a .beta.-lactam antibiotic compound and a process to prepare such a
compound that overcomes most of the above mentioned
disadvantages.
[0016] Surprisingly, it has been found that novel agglomerates in
crystalline form of .beta.-lactam antibiotics in a liquid phase are
produced through a crystallisation process when a solution of at
least one .beta.-lactam compound in a solvent or in a mixture of
solvents under stirring is mixed together with one or more
anti-solvents. Preferably, one or both solutions contain water.
DESCRIPTION OF THE FIGURE
[0017] An Electron-microscope photo of potassium clavulanate
agglomerates as prepared according to Example 9 is shown in the
FIGURE.
SUMMARY OF THE INVENTION
[0018] The present invention provides agglomerates in crystalline
form comprising one or more .beta.-lactam compounds having at least
one .beta.-lactam compound of a high water affinity, and optionally
contain one or more excipients. Preferably, said agglomerates
comprise clavulanic acid or a pharmaceutically acceptable salt
thereof like potassium clavulanate. Further, the agglomerates
comprising potassium clavulanate may contain amoxicillin as the
active .beta.-lactam antibiotic compound. The term agglomerate
refers to clustering of the crystals of a compound.
[0019] The excipients are microcrystalline cellulose, preferably
Avicel.RTM. or silica, preferably Syloid.RTM. or Aerosil.RTM..
[0020] The said agglomerates can also be of sterile form.
[0021] The new agglomerates are of an average particle size between
about 1 .mu.m and 1500 .mu.m, preferably between about 500 .mu.m
and 1500 .mu.m, more preferably between 800 .mu.m and 1200 .mu.m,
or between 1 .mu.m and 300 .mu.m, preferably between 1 .mu.m and
200 .mu.m.
[0022] Moreover, the agglomerates of the present invention are
substantially free from non-agglomerated .beta.-lactam crystals,
for instance, non-agglomerated crystals having a weight percentage
between 0-10%.
[0023] Furthermore, a process to prepare said agglomerates has been
provided for. The agglomerates are produced in a liquid phase
medium, which process involves mixing together a solution or
suspension of at least one .beta.-lactam compound corresponding to
the .beta.-lactam compound to be prepared in agglomerate form in a
solvent or in a mixture of solvents under stirring with one or more
anti-solvents, whereby at least one of both solvents and co-solvent
contains water. The overall weight ratio of the solution containing
the .beta.-lactam compound to anti-solvent is about 0.05 to 10%.
The solvent is for instance water or ethanol and the anti-solvent a
ketone, like acetone, methylethylketone, methylisobutylketone or an
ester, like methyl acetate, ethyl acetate, isopropyl acetate, butyl
acetate or an alcohol, like 1-propanol, 1-butanol, 2-butanol,
2-methyl-1-propanol or a mixture of these solvents. The pH of the
solution of the .beta.-lactam compound may be adjusted to neutral.
Preferably, the solvent is water or ethanol and the anti-solvent is
acetone or ethyl acetate with some water present in at least the
solvent or the anti-solvent. It is possible also to add other
ingredients in one of the streams (solvent, anti-solvent or mixture
thereof), either suspended or dissolved.
[0024] During the preparation of the agglomerates, one or more
stirring devices are used to crystallise, agglomerate and
deagglomerate, or to crystallise and agglomerate, or to crystallise
and deagglomerate the .beta.-lactam compound and optionally
classification and blending with excipients and/or another
.beta.-lactam compound in a batch or continuous operation in one or
more reaction vessels or in one integrated step. Furthermore, the
operation is performed by applying stirring devices in one or more
vessels, in-line mixers or a combination thereof. Furthermore, it
is possible to use a high shear mixer during the preparation of
these agglomerates. Also, agglomerates with various particle sizes
can be prepared by using a nozzle-sprayer for the .beta.-lactam
containing solution.
[0025] The agglomerates of various particle sizes are regulated by
further using a combination and permutation of different stirring
devices and their speed, the type and amount of the solvents used
and the way of mixing of the solvents.
[0026] Agglomerates of potassium clavulanate of the present
invention show a good level of stability and hygroscopicity.
[0027] The agglomerates, prepared according to the present
invention, with one or more pharmaceutical acceptable excipients
are suitable for pharmaceutical formulations.
[0028] Pharmaceutical formulations comprising amoxicillin,
preferably amoxicillin trihydrate and the crystalline agglomerates
of potassium clavulanate of the present invention and optionally
one or more pharmaceutically acceptable inert excipients form
another aspect of the present invention.
[0029] Also, a pharmaceutical formulation, comprising crystalline
agglomerates of amoxicillin trihydrate and potassium clavulanate
and one or more pharmaceutically acceptable inert excipients can be
made.
[0030] The agglomerates, prepared according to the present
invention, are suitable to prepare oral dosage forms such as
tablets, capsules, syrups or sachets, dry instant or ready to use
in multiple or single dose form. According to another embodiment of
the invention, the oral dosage form, comprising agglomerates or
granules of amoxicillin with or without one or more excipients can
also contain a .beta.-lactamase inhibitor such as potassium
clavulanate, preferably in the agglomerated form. Said agglomerates
can also be used in Dose Sipping devices.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The present invention provides economically interesting
agglomerates in crystalline form of a .beta.-lactam compound. The
.beta.-lactam compounds are for instance clavulanic acid but one
can also think of amoxicillin or ampicillin. The compound can be in
the salt form, such as amine or alkaline metal salt. Preferably,
agglomerates of potassium clavulanate are produced.
[0032] The agglomerates of said invention have an average particle
size between about 1 .mu.m and 1500 .mu.m, preferably between about
500 .mu.m and 1500 .mu.m, more preferably between 800 .mu.m and
1200 .mu.m, or between 1 .mu.m and 300 .mu.m, preferably between 1
.mu.m and 200 .mu.m.
[0033] Furthermore, said agglomerates are preferably substantially
free from non-agglomerated .beta.-lactam crystals, as for instance
in the needle form. By substantially free from non-agglomerated
crystals is meant that the agglomerates have a weight percentage
between 0-10% of non-agglomerates.
[0034] A process for the preparation of the agglomerates, wherein
one or more .beta.-lactam compounds with or without excipients are
used, consists of a crystallisation procedure to build up
agglomerates. The process comprises mixing together a solution or
suspension of one or more .beta.-lactam compounds corresponding to
the agglomerates to be produced in a solvent or in a mixture of
solvents with one or more anti-solvents under stirring. The
combination of solvent and anti-solvent can result in an emulsion.
In the solvent or anti-solvent an amount of water should be
present, for instance in an amount of 0.05 to 10%. Thereafter, the
agglomerates are filtered off, washed and dried. The agglomerates,
thus produced in high yield, maintain the quality criteria set and
are highly suitable for further processing. For the present
application, a anti-solvent is defined as a liquid in which the
.beta.-lactam compound does not dissolve or dissolves only
poorly.
[0035] More in detail, the .beta.-lactam compound, for instance
potassium clavulanate, is dissolved or suspended in an appropriate
solvent or a mixture of (partly) miscible solvents, such as water,
alcohols, like ethanol, methanol, 1-propanol, 2-butanol,
2-methyl-propanol, ketones, like acetone, methylethylketone,
methylisobutylketone, or an ester, like methyl acetate, ethyl
acetate, butyl acetate, with at least a small amount of water
present. Sometimes an emulsion is formed during the agglomeration
process. Optionally, the pH of the solution is adjusted to about
neutral, namely to pH 5.0-7.5 by adding an acid, as for instance
acetic acid or ethylhexanoic acid. The way of dissolution will be
known to those skilled in the art and will depend on the stability
of the .beta.-lactam compound in the solvent or in a mixture of
solvents. In case water is used as the only solvent for the
dissolution of potassium clavulanate, residence time and
temperature should be as low as possible and a technique such as
in-line mixing, for example a static mixer, can be attractive. If
for example acetone is present, a residence time of several hours
might be acceptable.
[0036] The .beta.-lactam compound, for example potassium
clavulanate, present in the solvent dissolved or in suspension or
in both forms, is contacted with a anti-solvent such as ketone,
like acetone, methylethylketone, methylisobutylketone, or an ester,
such as methyl acetate, ethyl acetate, butyl acetate or a mixture
thereof, or an alcohol such as 1-propanol, 2-butanol,
2-methyl-propanol optionally containing a solvent for the
.beta.-lactam compound, such as water or an alcohol, like methanol
or ethanol for potassium clavulanate. The overall weight ratio of
the solution containing the .beta.-lactam compound to the
anti-solvent depends on the combination of solvents and on the
desired agglomerate diameter, but generally lies within 0.05-10%.
Also, it is possible to adjust this ratio by adding some solvent to
the crystalliser before or during the process. This ratio will
influence the average diameter of the agglomerates: the higher the
relative volume of the solvent, the larger the agglomerates will
be.
[0037] Several methods of mixing can be applied and will be known
to those skilled in the art. For example, the solution of the
.beta.-lactam compound, for instance a potassium clavulanate
solution and the anti-solvent can be added simultaneously to the
crystalliser or the solution of the .beta.-lactam compound, for
instance a potassium clavulanate solution can be added to the
anti-solvent or the anti-solvent can be added to the solution of
the .beta.-lactam compound, for instance a potassium clavulanate
solution. The temperature should be kept below 50.degree. C. The
use of seeding material can also be advantageous to enhance the
agglomeration process.
[0038] The method of contacting the potassium clavulanate
containing solution and the anti-solvent can be controlled via
specific equipment, such as spray nozzles or capillaries. This
contacting can occur in a vessel or in line or in a recycling loop
over the vessel. It is also possible to first form droplets of
solution of a certain diameter, after which the droplets are
contacted with the anti-solvent.
[0039] Parameters such as the amount of nozzles, their diameter,
the flow through the nozzles and the rotational speed of the mixer
can be used to control the average particle size and density. In
this way, several grades of agglomerates can be produced, with
different physical properties.
[0040] The method of agitation is determined by the desired
agglomeration size of the .beta.-lactam compound. In case of
relatively large agglomerates (order of magnitude of 1000 .mu.m),
the agitation should be moderate. For example a common turbine
agitator or pitched blade agitator can be used. Here, the general
scales up parameters for agitation apply: the diameter of the
blades versus the diameter of the vessel should be between 0.2-0.9,
preferably between 0.2-0.5, depending on the type of agitator used.
The rotational speed (and thus shear), tip velocity, the size of
the nozzle sprayer and power input determine the agglomerate size
and density and can be used as control parameters. In case the
desired agglomerate diameter is small, for example 50-100 .mu.m,
high speed agitators, such as toothed disks or rotor-stator mixers
with multiple stage mixing/shearing action can be used. It is also
possible to use in-line high shear mixers, with the advantage of
short residence times. If needed, a recycle loop can be applied
over such an in-line system. Another possibility is to combine a
moderate shear mixer with a high shear mixer or a mill. For
example, agglomerates with a diameter of the order of a magnitude
of 1000 .mu.m can be deagglomerated during the crystallisation
using a high shear mixer, which is situated in the same
crystalliser (such as mounted in the bottom) or as a separate unit
after the crystalliser. Also, for example a colloid mill can be
placed after the crystalliser for the same purpose. Moreover, the
simultaneous crystallisation/agglomeration technique can be
combined using ultrasonic crystallisation. This technique has been
described for instance in i Pharmaceutical Technology Europe, 9(9),
78 (1997). In this way different grades concerning particle size
distribution, density, porosity and flowability can be easily
achieved.
[0041] Generally, the residence time in the crystalliser and/or
deagglomerator is determined by the desired average diameter of the
agglomerates. For purposes of precipitation/crystallisation, long
ageing times are not needed, as the crystals are formed immediately
after contact with the anti-solvent. For agglomeration and
deagglomeration, however, a certain minimum and maximum residence
time will be valid, depending on parameters such as mixing time and
volume of the vessel.
[0042] One of the embodiments of the invention is to have the
excipients included in the agglomerates by addition of the same
before, after or during the precipitation and/or agglomeration,
such as cellulose, preferably microcrystalline cellulose, more
preferably with a water activity <0.2 at 25.degree. C., most
preferably Avicel.RTM. PH112. Also, amorphous silica (Syloid.RTM.)
or colloidal silicon dioxide (Aerosil.RTM.) can be used as
excipient. All methods of mixing are possible: for example the
excipient can be added before, simultaneously or after the addition
of the .beta.-lactam compound solution or (partly) suspension to
the crystalliser. The excipients can be added as dry matter,
suspended or dissolved in a solvent, preferably one of the solvents
(or a mixture thereof) which is already used in the agglomeration
process. An extra advantage of the addition of such excipients is
the positive influence on the agglomeration formation, as they can
act as some kind of seeding material.
[0043] Another embodiment of the present invention is that the
crystallisation and agglomeration can occur in the presence of
another active .beta.-lactam ingredient, for example amoxicillin
trihydrate besides potassium clavulanate. The amoxicillin can
either be added as a solution or suspension leading to
co-crystallisation, similar to the agglomeration in the presence of
excipients.
[0044] The agglomerates of the present invention are not of the
rosette type: they consist of small crystals clustered together in
a random order (see the FIGURE). Depending on the method of
agitation, method of addition and amount of water, the agglomerate
size can easily be adjusted between about 1 and 1500 .mu.m and also
relatively small particles as with an average size of 100 .mu.m or
relatively large particles with an average size of 1000 .mu.m may
be prepared. Compared to, for example, dry compaction, the amount
of fines that either must be discharged of or that must be
recycled, is small. The agglomerates can easily be separated by for
example, filtration or centrifugation and subsequently dried using
conventional methods such as tumbling drying. It is also possible
to include a classification process. For example, agglomerates of
the desired size can be selectively removed from the crystalliser
using gravity and/or a sieve. Fines or large particles which can be
removed by sieving as well, can be recycled, either by addition in
suspension or solution to the next batch.
[0045] If necessary, pH-adjustment in order to adapt the pH of the
end product can be achieved by adding an acid or base to the
solution or the anti-solvent before contacting the streams of
solvents containing the .beta.-lactam compound and the
anti-solvent. Also, acid or base can be added during the
precipitation/crystallisation/agglomeration process or even after
the process.
[0046] Surprisingly, the process of the present invention produces
agglomerates with a high bulk density, an improved flowability and
less compressibility, which can be regulated. For example,
potassium clavulanate agglomerates produced can have a loose bulk
density between about 0.20 and 0.60 and a tapped bulk density
between about 0.50 and 0.90 g/ml and a compressibility between
about 10 and 40%.
[0047] Due to the excellent flowability of the agglomerates
prepared using the above method, they can be used for, for example,
direct compression of tablets without the need for further
pre-granulation. Moreover, due to the decreased surface area of the
agglomerates, the degradation caused by chemical reactions on the
surface (e.g. with water) may be reduced. The level of impurities
in the agglomerates is also equal to or even lower than in case of
conventional needles type crystals. As the bulk density increases
significantly, large advantages can be achieved in the
transportation as well as in the tabletting process: the final
tablet volume can decrease significantly when using agglomerates
compared to using needles.
[0048] The energy consumption of the present process is low, as the
crystallisation process which is commonly present in the down
stream process of pharmaceuticals can be combined with the
agglomeration process. Moreover, it is possible to combine the
usual operations comprising purification and separation by
precipitation or crystallisation, agglomeration and
deagglomeration, classification and blending with e.g. excipients
in one unit. The temperatures can be kept below 50.degree. C.
during the complete agglomeration process, excipients-free
agglomerates can be produced and handling of dry solids before the
granulation does not occur, which is an important advantage in case
of hygroscopic materials. The solvents needed for the agglomeration
can easily be recycled, possibly without the need for purification.
Moreover, the possibility to make pure agglomerates of an unstable
and hygroscopic product such as potassium clavulanate is highly
attractive.
[0049] The agglomerates of the present invention can be used for
all formulations to produce chew, swallow, disperse, effervescent
or normal tablets of all sizes, forms and weights, also to fill
hard gelatine capsules and to formulate dry syrups and for
administering drugs with the help of a dose sipping device. These
agglomerates can also be used, for instance, in a pharmaceutical
composition as a tablet of amoxicillin trihydrate produced from
agglomerates of amoxicillin trihydrate and potassium clavulanate.
For the preparation of sterile agglomerates, the solution of the
.beta.-lactam compounds, solvent and anti-solvent are sterilely
filtered prior to crystallisation/agglomeration. Also, the sterile
agglomerates substantially free of non-agglomerates, form another
aspect of the present invention.
[0050] The invention will now be described with reference to the
following Examples, which are not to be constructed as being
limiting on the invention, and are provided purely for illustrative
purposes.
EXAMPLE 1
Preparation of Agglomerates of Potassium Clavulanate (Batch
Process)
[0051] In a 5-litre flask equipped with a mechanical stirrer, a
thermometer and inlet for nitrogen, 4 litres of acetone were
placed. A solution of potassium clavulanate (60 g.) in a mixture of
water/acetone (120 g, 1:1 w/w) was added in 30 min at 20.degree. C.
under stirring.
[0052] The solid material was filtered off and dried in vacuum at
30.degree. C. during 2-3 hours to give agglomerates of potassium
clavulanate with an average diameter in the range of 100-1000 .mu.m
and a yield of 98%.
EXAMPLE 2
Preparation of Agglomerates of Potassium Clavulanate
(Semi-Continuous Process)
[0053] In a 2-litre flask equipped with a mechanical stirrer, a
thermometer and inlet for nitrogen, acetone (1000 ml) and water (10
ml) were placed. Simultaneously a solution of potassium clavulanate
(60 g) in a mixture of water/acetone (120 g, 1:1 w/w) and acetone
(4000 ml) was added in about one hour, while agitating.
[0054] During the addition the content of the vessel was kept at
about 1800 ml by periodically removing suspension through an
outlet. Thereafter, the solid material was filtered off, washed
with dry acetone and dried in vacuum at 30.degree. C. during 2-3
hours to yield potassium clavulanate agglomerates with an average
diameter in the range of 500-1500 .mu.m.
EXAMPLE 3
Preparation of Agglomerates of Potassium Clavulanate by Using a
Turbine Stirrer Without Baffles in the Reaction Vessel
[0055] Acetone (300 ml) and water (3 ml) were placed in a glass
cylinder (100 mm in diameter, 150 mm height) equipped with a
turbine stirrer (40 mm diameter), a two dropping funnel and a
nitrogen inlet tube. Under stirring (900 rpm) simultaneously a
solution of potassium clavulanate (30 g) in a water/acetone mixture
(60 g, 1:1 w/w) and acetone (2000 ml) were added.
[0056] During the addition, the contents of the vessel were kept at
about 900 ml by removing a part of the contents with the help of an
outlet. After the completion of the additions, the solid material
was filtered off, washed with dry acetone and dried in vacuum at
30.degree. C. Agglomerates of potassium clavulanate with an average
particle diameter of 1000 .mu.m were obtained in 98% yield.
EXAMPLE 4
Preparation of Agglomerates of Potassium Clavulanate by Using
Turbine Stirrer With Baffles in the Reaction Vessel
[0057] The experiment was repeated as described in Example 3, but
using a vessel with four baffles with a width of 10 mm. Potassium
clavulanate agglomerates with an average diameter in the range of
500-1000 .mu.m were obtained.
EXAMPLE 5
Preparation of Agglomerates of Potassium Clavulanate by Using a
Ultra-Turrax Mixer
[0058] Acetone (500 ml) and water (5 ml) were placed in an one
litre 4-necked round-bottom flask equipped with a thermometer,
Ultra-Turrax mixer (type T25 and shaft S25N-18G), two dropping
funnels and a nitrogen inlet tube.
[0059] Under mixing (8000 rev/min) simultaneously a solution of
potassium clavulanate (30 g.) in a water/acetone mixture (60 g. 1:1
w/w) and acetone (2000 ml) was added in one hour at 15-20.degree.
C. During the addition, the contents of the vessel were kept
between 700 and 800 ml by removing a part of the content with the
help of an outlet.
[0060] After the completion of the additions, the solid material
was filtered off, washed with acetone and dried in vacuum at
30.degree. C. Agglomerates of potassium clavulanate with an average
diameter in range of 50-250 .mu.m were obtained.
EXAMPLE 6
Preparation of Agglomerates of Potassium Clavulanate by Using
Silverson L4RT Mixer
[0061] The experiment was repeated as described in Example 5, but
using a rotor-stator type high shear mixer (Silverson mixer with
emulsion screen, i.e. a screen with spherical pores of about 1.5
mm) at 3000 rev/min.
[0062] Agglomerates of potassium clavulanate with an average
diameter in the range of 10-200 .mu.m were obtained.
EXAMPLE 7
Preparation of Agglomerates of Potassium Clavulanate in Ethyl
Acetate
[0063] Ethylacetate (400 ml) and water (1 ml) were placed in a
glass cylinder (100 mm in diameter, 150 mm height) equipped with a
turbine stirrer (40 mm diameter), a two dropping funnel and a
nitrogen inlet tube. Under stirring (900 rpm) at the same time a
solution of potassium clavulanate (10 g) in water (10 ml) and ethyl
acetate (600 ml) were added.
[0064] After the completion of the additions the solid was filtered
off, washed with dry ethyl acetate and dried in vacuum at
30.degree. C. to give agglomerates with an average diameter in the
range of 500-1500 .mu.m.
EXAMPLE 8
Comparison of Agglomerates and Needles of Potassium Clavulanate,
Optionally Mixed With Avicel PH112
[0065] The agglomerates of potassium clavulanate were prepared as
described in Example 6, but using a Silverson mixer with general
purpose disintegrating screen, i.e. a screen with square holes with
a diameter of about 2.5 mm. In a 2-litre flask equipped with the
Silverson mixer, a thermometer and inlet for nitrogen acetone (1000
ml) and water (10 ml) were placed. Under mixing (3400 rev/min)
simultaneously a solution of potassium clavulanate (120 g) in a
mixture of water/acetone (240 g, 1:1 w/w) and acetone (8000 ml)
were added at 15-20.degree. C. During the addition the contents of
the vessel was kept at about 1800 ml with an outlet. After
completion of the additions the solid was filtered off, washed with
acetone and dried in vacuum at 30.degree. C. during 2-3 hours to
give agglomerates with an average diameter in the range of 40-200
.mu.M.
[0066] Needles of potassium clavulanate were prepared by suspending
diclavulanate salt of bis(2-dimethylaminoethyl) ether (100 g) in
acetone (3350 ml) and water (50 ml). Under stirring a solution of
potassium 2-ethylhexanoate (1450 ml, 0.34 M) in acetone at
5-10.degree. C. was added. After 1 hour stirring the mixture was
filtered off, washed with dry acetone and dried in vacuum during 18
hours at room temperature to give 81.2 g of potassium clavulanate
needles.
[0067] A comparison of physical properties of potassium clavulanate
in agglomerated and needle form, optionally mixed with Avicel PH
112 in a ratio of 70:30 w/w % have been described in Table 1.
TABLE-US-00001 TABLE 1 Comparison of physical properties of
potassium clavulanate in agglomerated and needle form, optionally
mixed with Avicel PH112 Loose bulk Tapped bulk Compress- Particle
size Material density density ibility distribution Agglomerates
0.49 g/ml 0.68 g/ml 28% between 1 of potassium and 200 .mu.m
clavulanate Needles of 0.18 g/ml 0.36 g/ml 50% between 5 Potassium
and 75 .mu.m clavulanate Agglomerates 0.43 g/ml 0.61 g/ml 29% Not
of potassium determined clavulanate mixed with Avicel PH112 Needles
of 0.20 g/ml 0.40 g/ml 50% Not potassium determined clavulanate
mixed with Avicel PH112
EXAMPLE 9
Preparation of Agglomerates of Potassium Clavulanate in
Acetone/Water at a Speed of the Agitator of 3000 RPM
[0068] A solution of potassium clavulanate was made by dissolving
circa 5 kg of potassium clavulanate in 10 l aqueous acetone
(acetone:water=50:50 w/w). This solution, which was kept at
5.degree. C. was pumped through a 0.9 mm nozzle to a crystalliser
equipped with a high shear mixer and containing 50 l of acetone.
Simultaneously, acetone was added to the crystalliser with a volume
ratio compared to the solution of circa 21. During the process, the
rotational speed of the agitator was 3000 RPM and the temperature
was circa 15.degree. C. The agglomerated suspension was removed
continuously from the crystalliser, centrifuged, washed with dry
acetone and dried in vacuum at 30.degree. C. In this way,
agglomerates such as shown on the FIGURE were produced with a loose
bulk density of 0.22 g/ml, a tapped bulk density of 0.30 g/ml and a
compressibility of 27%. The particle size distribution is given in
Table 2 and a photo made by an Electron-microscope of potassium
clavulanate is shown in the FIGURE. TABLE-US-00002 TABLE 2 Particle
size distribution [volume %] <75 75-150 150-250 250-500 500-710
>710 .mu.m .mu.m .mu.m .mu.m .mu.m .mu.m 46.3 43.3 8 1 0.2
0.1
EXAMPLE 10
Influence of the Agitator Speed During Agglomeration on the
Physical Properties of the Agglomerates
[0069] A solution of potassium clavulanate was made by dissolving
circa 10 kg of potassium clavulanate in 20 l aqueous acetone
(acetone:water=50:50 w/w). This solution, which was kept at
5.degree. C. was pumped through a 2.5 mm nozzle to a crystalliser
equipped with a high shear mixer and containing 40 l of acetone.
Simultaneously, acetone was added to the crystalliser with a volume
ratio compared to the solution of circa 22. During the process, the
rotational speed of the agitator was increased from 1000 RPM to
2000 RPM and the temperature was circa 15.degree. C. Continuously,
the suspension was removed from the crystalliser using a pump. The
two agglomerated suspensions made were centrifuged, washed with dry
acetone and dried in vacuum at 30.degree. C. The physical
properties can be seen in Table 3. TABLE-US-00003 TABLE 3 Physical
properties: particle size distribution [volume %] Loose bulk Tapped
bulk density [g/ml] density [g/ml] Compressibility [%] <75 .mu.m
75-150 .mu.m 150-250 .mu.m 250-500 .mu.m 500-710 .mu.m >710
.mu.m 1000 RPM 0.39 0.44 11 5.1 6.5 20.7 60.8 6.1 0.2 2000 RPM 0.42
0.47 11 1.8 2.4 9.5 57.3 27 1.5
EXAMPLE 11
Influence of the Flow Upon Addition to Crystalliser on the Physical
Properties of the Agglomerates
[0070] Two experiments were performed in which all parameters were
kept constant, except the flows of the solution and acetone to the
crystalliser. In both experiments, a solution of potassium
clavulanate was made by dissolving circa 5 kg of potassium
clavulanate in 10 l aqueous acetone (acetone:water=50:50 w/w). This
solution, which was kept at 5.degree. C. was pumped through a 0.9
mm nozzle to a crystalliser equipped with a high shear mixer and
containing 30 l of acetone. Simultaneously, acetone was added to
the crystalliser with a volume ratio compared to the solution of
circa 21. During the process, the rotational speed of the agitator
was 3000 and the temperature was circa 15.degree. C. In the first
experiment, the solution flow was 15 l/h and the acetone flow was
312 l/h. In the second experiment, the flows were decreased by a
factor 2. Continuously, the suspension was removed form the
crystalliser using a pump. The two agglomerated suspensions made
were centrifuged, washed with dry acetone and dried in vacuum at
30.degree. C. The physical properties can be seen in Table 4.
TABLE-US-00004 TABLE 4 Physical properties: Particle size
distribution [volume %] Loose bulk Tapped bulk density [g/ml]
density [g/ml] Compressibility [%] <75 .mu.m 75-150 .mu.m
150-250 .mu.m 250-500 .mu.m 500-710 .mu.m >710 .mu.m High flow
0.27 0.36 25 48.7 41.2 9.3 0.3 0 0 Low flow 0.35 0.44 20 48.8 50.4
1.1 0.6 0.4 0
EXAMPLE 12
Influence of the Nozzle Diameter Through Which the Potassium
Clavulanate Solution is Pumped on the Physical Properties of the
Agglomerates
[0071] Two experiments were performed in which all parameters were
kept constant, except the diameter of the nozzle through which the
potassium clavulanate solution is added to the crystalliser. In
both experiments, a solution of potassium clavulanate was made by
dissolving circa 5 kg of potassium clavulanate in 10 l aqueous
acetone (acetone:water=50:50 w/w). This solution, which was kept at
5.degree. C., was pumped through either a 0.9 mm or 1.2 mm nozzle
to a crystalliser equipped with a high shear mixer and containing
50 l of acetone. Simultaneously, acetone was added to the
crystalliser with a volume ratio compared to the solution of circa
21. During the process, the rotational speed of the agitator was
3000 and the temperature was circa 15.degree. C. Continuously, the
suspension was removed from the crystalliser using a pump. The two
agglomerated suspensions made were centrifuged, washed with dry
acetone and dried in vacuum at 30.degree. C. The physical
properties can be seen in Table 5. TABLE-US-00005 TABLE 5 Physical
properties: particle size distribution [volume %] Nozzle Loose bulk
Tapped bulk diameter density [g/ml] density [g/ml] Compressibility
[%] <75 .mu.m 75-150 .mu.m 150-250 .mu.m 250-500 .mu.m 500-710
.mu.m >710 .mu.m 0.9 mm 0.22 0.3 0.27 46.3 43.3 8 1 0.2 0.1 1.2
mm 0.36 0.44 0.18 15.9 50.6 31.3 1.9 0 0.3
* * * * *