U.S. patent application number 13/846784 was filed with the patent office on 2013-08-22 for process for the crystallisation of cefadroxil monohydrate.
This patent application is currently assigned to DSM SINOCHEM PHARMACEUTICALS NETHERLANDS B.V.. The applicant listed for this patent is Carlos Enrique LENHARD, Harold Monro MOODY, Theodorus Johannes Godfried Maria VAN DOOREN. Invention is credited to Carlos Enrique LENHARD, Harold Monro MOODY, Theodorus Johannes Godfried Maria VAN DOOREN.
Application Number | 20130217659 13/846784 |
Document ID | / |
Family ID | 37309255 |
Filed Date | 2013-08-22 |
United States Patent
Application |
20130217659 |
Kind Code |
A1 |
LENHARD; Carlos Enrique ; et
al. |
August 22, 2013 |
PROCESS FOR THE CRYSTALLISATION OF CEFADROXIL MONOHYDRATE
Abstract
Cefodroxil monohydrate is formed by a processing which includes
a) bringing an aqueous solution of cefadroxil monohydrate to a pH
of between 7 to 9 with a suitable titrant; b) lowering the pH to a
value of between 5 and 6.5 to obtain a suspension of cefadroxil
monohydrate in crystal form; and c) isolating the cefadroxil
monohydrate in crystal form from the suspension obtained in step
b). The cefadroxil monohydrate thereby obtained exhibits a CIE b
value of below 6, and advantageously a CIE b value of below 12 when
stored at a temperature of 25.degree. C. for at least 1 month.
Inventors: |
LENHARD; Carlos Enrique;
(Alella Barcelona, ES) ; MOODY; Harold Monro;
(Gulpen, NL) ; VAN DOOREN; Theodorus Johannes Godfried
Maria; (Roermond, NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LENHARD; Carlos Enrique
MOODY; Harold Monro
VAN DOOREN; Theodorus Johannes Godfried Maria |
Alella Barcelona
Gulpen
Roermond |
|
ES
NL
NL |
|
|
Assignee: |
DSM SINOCHEM PHARMACEUTICALS
NETHERLANDS B.V.
Delft
NL
|
Family ID: |
37309255 |
Appl. No.: |
13/846784 |
Filed: |
March 18, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12300046 |
Sep 30, 2009 |
8420806 |
|
|
PCT/EP2007/054572 |
May 11, 2007 |
|
|
|
13846784 |
|
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|
Current U.S.
Class: |
514/209 ;
540/230 |
Current CPC
Class: |
A61P 31/04 20180101;
C07D 501/12 20130101; C07D 501/22 20130101; C07D 501/20
20130101 |
Class at
Publication: |
514/209 ;
540/230 |
International
Class: |
C07D 501/20 20060101
C07D501/20 |
Foreign Application Data
Date |
Code |
Application Number |
May 19, 2006 |
EP |
06114240.2 |
Claims
1. Cefadroxil monohydrate in crystal form obtained by a process
comprising: a) bringing an aqueous solution of cefadroxil
monohydrate to a pH of between 7 to 9 with a suitable titrant; b)
lowering the pH to a value of between 5 and 6.5 to obtain a
suspension of cefadroxil monohydrate in crystal form; and c)
isolating the cefadroxil monohydrate in crystal form from the
suspension obtained in step b).
2. Cefadroxil monohydrate according to claim 1, wherein step a) and
step b) are carried out at a temperature of between 5 and
25.degree. C.
3. Cefadroxil monohydrate according to claim 1, wherein lowering
the pH in step b) is carried out within a period of time of between
20 to 60 min.
4. Cefadroxil monohydrate according to claim 1, wherein the
suspension of the cefadroxil monohydrate in crystal form obtained
in step b) is stirred for 10 to 120 min.
5. Cefadroxil monohydrate according to claim 1, wherein the
cefadroxil in crystal form is isolated from the suspension obtained
in step b).
6. Cefadroxil monohydrate in crystal form with a CIE b value of
below 6.
7. Cefadroxil monohydrate in crystal form with a CIE b value of
below 12 when stored at a temperature of 25t for at least 1
month.
8. A pharmaceutical composition comprising cefadroxil monohydrate
as defined in claim 6, and a pharmaceutically acceptable carrier.
Description
[0001] This application is a continuation of commonly owned
co-pending U.S. patent application Ser. No. 12/300,046, filed Sep.
30, 2009 (now U.S. Pat. No. ______), which in turn is the national
phase application under 35 USC .sctn.371 of PCT/EP2007/054572,
filed May 11, 2007 which designated the US and claims priority to
EP Application No. 06114240.2, filed May 19, 2006, the entire
contents of each of which are hereby incorporated by reference.
[0002] The present invention relates to a process for the
crystallisation of cefadroxil monohydrate and cefadroxil
monohydrate in crystal form.
[0003] Cefadroxil is the name for the chemical compound
7-[D-.alpha.-amino-.alpha.-(p-hydroxyphenyl)-acetamido]
desacetoxycephalosporanic acid. A process for the crystallisation
of a .beta.-lactam compound, such as cefadroxil, is for instance
known from WO99/24441. WO 99/24441 discloses a process for the
crystallisation of a .beta.-lactam compound wherein a solution of
said .beta.-lactam compound and a corresponding titrant are
simultaneously added to a crystallisation vessel to form a
crystallisation mixture. In the process disclosed in WO99/55710 a
crystalline .beta.-lactam compound, for instance cefadroxil is
prepared from a nitric acid solution by the addition of an alkaline
solution to the nitric acid solution.
[0004] It was found that crystallisation of cefadroxil monohydrate
by a crystallisation process known in the art resulted in
agglomerates of cefadroxil monohydrate with a large particle size
distribution, much colour and low colour stability. The aim of the
present invention is to provide an alternative process for the
crystallisation of cefadroxil monohydrate, which results in
crystalline cefadroxil monohydrate with a small particle size
distribution, little colour, and a high colour stability. The aim
is achieved according to the invention by a process for the
preparation of cefadroxil monohydrate in crystal form,
comprising
[0005] a) bringing an aqueous solution of cefadroxil monohydrate at
a pH of between 7 to 9 with a suitable titrant; and
[0006] b) lowering the pH to a value of between 5 and 6.5 to obtain
a suspension of cefadroxil monohydrate in crystal form.
[0007] It was found that by keeping the pH of the aqueous solution
at the desired value in step a) an explosion of cefadroxil
monohydrate crystals was prevented which resulted in cefadroxil
monohydrate crystals with a small particle size distribution,
little colour, and a high colour stability.
[0008] As used herein cefadroxil monohydrate in crystal form with a
small particle size distribution (psd) is defined as a psd of
between 10 and 150 .mu.m. The psd of the cefadroxil monohydrate in
crystal form is preferably between 10 and 100 .mu.m, more
preferably between 20 and 80 .mu.m, more preferably between 25 and
60 .mu.m, most preferably between 30 and 50 .mu.M.
[0009] As used herein, cefadroxil monohydrate in crystal form with
little colour means that the cefadroxil crystals have a CIE b value
of preferably below 6, preferably below 5.5, more preferably below
5, more preferably below 4.5, more preferably below 4, more
preferably below 3 and usually above 1.
[0010] High colour stability means that the cefadroxil crystals
have a CIE b value of below 12, more preferably below 11, more
preferably below 10, more preferably below 9, more preferably below
8, more preferably below 7, more preferably below 6, more
preferably below 5 and usually above 1, preferably when stored at a
temperature of 25.degree. C. for at least 1 month, more preferably
for at least 2 months, more preferably for at least 3 months, more
preferably for at least 4 months, more preferably for at least 5
months, more preferably for at least 6 months, more preferably for
at least 7 months, more preferably for at least 8 months, more
preferably for at least 9 months, more preferably for at least 10
months, more preferably for at least 11 months, more preferably for
at least 12 months.
[0011] The aqueous solution of cefadroxil monohydrate used in step
a) of the process of the present invention may be alkaline, for
instance having a pH of between 8 and 9.5, for instance between 8.5
and 9, for instance between 8.6 and 8.9. Alternatively, the aqueous
solution of cefadroxil monohydrate may be acidic, for instance
having a pH of between 1 and 4, for instance between 1.5 and 3, for
instance between 1.5 and 2.5.
[0012] The pH in step a) in the process according to the present
invention is preferably brought to a pH of between 7 and 9,
preferably between 7.1 and 8.9, preferably between 7.2 and 8.8,
preferably between 7.3 and 8.7, more preferably between 7.4 and
8.6, more preferably between 7.5 and 8.5, more preferably between
7.6 and 8.4, more preferably between 7.7 and 8.3, more preferably
between 7.8 and 8.2, more preferably between 7.9 and 8.1. A
suitable titrant to bring the pH in step a) at a pH of between 7
and 9 may be any suitable acidic titrant such as formic acid,
citric acid, acetic acid, sulphuric acid or hydrochloric acid. A
suitable titrant is preferably formic acid. Alternatively a
suitable titrant to bring the pH at a value of between 7 and 9 may
be any suitable alkaline titrant such as sodium hydroxide,
potassium hydroxide, ammonium hydroxide, or an amine, for instance
a monoamine, such as tertiary butylamine, tertiary octylamine,
benzhydrylamine or a diamine, for instance
N,N'-diisopropylethylenediamine,
N,N,N',N'-tetramethyl-1,2-diaminoethane or
bis(2-(dimethylamino)ethyl)ether. The skilled man understands that
depending on the pH of the aqueous solution of cefadroxil
monohydrate used in step a) of the process of the present invention
an acidic or alkaline titrant may be needed to arrive at the
desired pH value.
[0013] When adding the aqueous solution of cefadroxil monohydrate
to the crystallisation vessel, the crystallisation vessel may
comprise a small amount of water. The crystallisation may also
comprise a small amount of cefadroxil monohydrate in crystal form,
serving as a seed for the cefadroxil monohydrate in the aqueous
solution.
[0014] The pH in step b) in the process according to the present
invention is preferably lowered to a pH value between 5.2 and 6.4,
preferably between 5.4 and 6.3, preferably between 5.6 and 6.2,
more preferably between 5.8 and 6.1.
[0015] During step b), the pH may be lowered using any suitable
titrant, for instance, formic acid, citric acid, acetic acid,
sulphuric acid or hydrochloric acid. Preferably, formic acid is
used for decreasing the pH in step b).
[0016] Lowering the pH in step b) of the process according to the
present invention may be carried out within any suitable period of
time. Preferably, lowering the pH in step b) may occur within a
period of time of between 5 min and 4 hrs, preferably between 10
min and 3 hrs, preferably between 15 min and 2 hrs, preferably
between 20 min and 60 min.
[0017] The aqueous solution of cefadroxil monohydrate in the step
a) in the process according to the present invention may be
obtained from any suitable chemical or enzymatic acylation process
for the synthesis of cefadroxil. A chemical acylation process for
the synthesis of cefadroxil is for instance disclosed in EP 0 295
333. Preferably, the aqueous solution of cefadroxil is obtained
from an enzymatic process for the synthesis of cefadroxil, wherein
7-amino-3-desacetoxycephalosporanic acid (7-ADCA) is acylated with
a D-p-hydroxyphenylglycine (HPG) in activated form in the presence
of a suitable acylase in free or immobilised form. HPG in activated
form may for instance be an amide or an ester of HPG, for instance
methylester. Processes for the enzymatic synthesis of cefadroxil
are described in EP 0 865 443 B1, EP 0771 357 B1, EP 537 255 and WO
99/20786, which are herein incorporated by reference.
[0018] Adding the aqueous solution of cefadroxil monohydrate to a
crystallisation vessel in step a) of the process according to the
invention may be carried out during any suitable period of time,
depending for instance on the total volume of aqueous solution to
be added. A suitable period of time may range between 5 min and 4
hrs, for instance between 10 min and 3 h, for instance between 15
min and 2 hrs, for instance between 20 min and 1.5 hrs.
[0019] Adding the aqueous solution of cefadroxil monohydrate to a
crystallisation vessel in step a) and lowering the pH in step b) in
the process according to the present invention may be carried out
at any suitable temperature. Preferably, the temperature in step a)
is carried out at a temperature of between 5 and 25.degree. C.,
more preferably between 10 and 20.degree. C. Preferably, the
temperature in step b) is carried out at a temperature of between 5
and 25.degree. C., more preferably between 10 and 20.degree. C. In
the process according to the present invention, cefadroxil
monohydrate crystals may be formed from the aqueous solution during
each step. Depending for instance on the temperature and pH value,
the amount of cefadroxil monohydrate in crystal form prepared may
be higher or lower during any of the steps a) or b). Usually, a
major amount of cefadroxil monohydrate in crystal form is prepared
from the aqueous solution during step b).
[0020] The suspension of cefadroxil monohydrate in crystal form
obtained in step b) in the process according to the invention may
be stirred during a suitable period of time, for instance during 10
to 120 min, preferably during 15 to 90 min, preferably during 20 to
60 min, preferably during 25 to 50 min. It was found that stirring
the suspension of cefadroxil monohydrate in crystal form resulted
in an increased yield of the cefadroxil monohydrate in crystal
form. Cefadroxil monohydrate in crystal form may be isolated from
the suspension by any suitable method known in the art. Cefadroxil
monohydrate in crystal form may for instance be isolated from the
suspension by filtration or centrifugation. Usually the cefadroxil
monohydrate crystals are washed with water to remove
impurities.
[0021] Isolation of the cefadroxil monohydrate crystals may further
comprise drying the crystals at a temperature of, for instance
between 40 and 50.degree. C. Preferably, the .beta.-lactam crystals
are washed with acetone to remove a major amount of water, prior to
drying.
[0022] The present invention also relates to cefadroxil monohydrate
in crystal form obtainable by the process according to the present
invention. It was surprisingly found that the cefadroxil
monohydrate in crystal form obtainable by the process according to
the present invention has a CIE b value of below 6, preferably
below 5.5, more preferably below 5, more preferably below 4.5, more
preferably below 4, more preferably below 3 and usually above
1.
[0023] It was also surprisingly found that the cefadroxil
monohydrate crystals were very stable in the colour stability test.
It was found that the cefadroxil monohydrate crystals obtainable by
the process according to the present invention have a CIE b value
of below 12, more preferably below 11, more preferably below 10,
more preferably below 9, more preferably below 8, more preferably
below 7, more preferably below 6, more preferably below 5 and
usually above 1, preferably when stored at a temperature of
25.degree. C. for at least 1 month, more preferably for at least 2
months, more preferably for at least 3 months, more preferably for
at least 4 months, more preferably for at least 5 months, more
preferably for at least 6 months, more preferably for at least 7
months, more preferably for at least 8 months, more preferably for
at least 9 months, more preferably for at least 10 months, more
preferably for at least 11 months, more preferably for at least 12
months.
[0024] In addition, the cefadroxil monohydrate in crystal form
according to the present invention has a particle size distribution
of below 150 .mu.m, preferably below 100 .mu.m and preferably above
10 .mu.m. The psd of the cefadroxil monohydrate in crystal form is
preferably between 10 and 150 .mu.m, more preferably 10 and 100
.mu.m, more preferably between 20 and 80 .mu.m, more preferably
between 25 and 60 .mu.m, most preferably between 30 and 50
.mu.M.
MATERIALS AND METHODS
Determination of the CIE b Value
[0025] CIE is an abbreviation for the French title of the
International Commission on Illumination: "Commission International
de l'Eclairage". The CIE b is a measure to determine the colour of
crystals, which is a known technology for the skilled man in the
art. An overview of the fundamentals of the CIE colorimetry system
is given in Ohno, Y., Paper for IS&T NIO16 Conference,
Vancouver, Canada, Oct. 16-20, 2000, p. 1-5.
[0026] The CIE b value was determined using a X-Rite.RTM. 918
apparatus (X-Rite Incorporated, 4300 44th St. SE, Grand Rapids,
Mich. 49512 USA). A sample of 2 g of cefadroxil crystals was placed
at the appropriate place of the apparatus and the CIE b value was
read. The average of two separate readings was calculated.
EXAMPLES
Preparation of a Cefadroxil Monohydrate Solution
[0027] Cefadroxil monohydrate was obtained by an enzymatic process
for the synthesis of cefadroxil, wherein
7-amino-3-desacetoxycephalosporanic acid (7-ADCA) was acylated with
D-p-hydroxyphenylglycinemethyl ester in the presence of immobilised
Pen G acylase as described in WO 99/20786.
[0028] A sample of 500 g of mother liquor and water washings was
taken from the enzymatic reactor at the end of the condensation
step. The sample contained 16.34% (w/w) of dissolved cefadroxil
monohydrate. The pH was 8.7-8.8
Reference Experiment A: One-Step Crystallisation
[0029] A 500 g sample of the cefadroxil monohydrate solution
prepared as described above was dosed into a crystallisation
reactor within 25 to 70 minutes. The crystallisation reactor
contained a small amount of water to allow stirring. The pH was
kept at a value of between 7.10 and 7.30 with formic acid at a
temperature of between 7 to 10.degree. C. The suspension of
cefadroxil monohydrate was stirred for 30 min. The cefadroxil
monohydrate suspension was centrifuged and dried. The colour of the
cefadroxil monohydrate agglomerates at t=0 was determined as
described below. The CIE b value was 6.2.
Example 1
Two-Step Crystallisation of Cefadroxil Monohydrate
Step a)
[0030] 5 g of cefadroxil monohydrate (used as a seed) and 60 ml of
fresh water (pH=5.50-5.70) were loaded into a crystallisation
vessel and the temperature was adjusted to 15.degree. C. A 500 g
sample of the cefadroxil monohydrate solution prepared as described
above was dosed into the crystallisation vessel within 45 minutes.
The pH was kept at 7.9 by titration with 6.9 ml of formic acid (85%
v/v).
Step b)
[0031] 2.5 ml of formic acid was added to the suspension obtained
in step (a) in such a way that the pH decreased to 6.0 in 30
minutes. The cefadroxil monohydrate suspension thus obtained was
stirred for 30 min. The suspension was filtered and the cake was
washed with 50 ml of water followed by 34 ml acetone. After drying,
76.4 g of cefadroxil monohydrate was obtained (84.0 w/w %
yield).
[0032] The CIE b value of the cefadroxil monohydrate crystals was
4.68.
Example 2
Two-Step Crystallisation of Cefadroxil Monohydrate
Step a)
[0033] 33 ml of a 500 g sample of the cefadroxil monohydrate
solution prepared as described above, and 27 ml of fresh water,
were added to a crystallisation reactor. The temperature was
adjusted to 15.degree. C. Subsequently the remaining part of the
500 g sample of cefadroxil monohydrate solution was dosed into the
crystallisation reactor in 35 minutes. The pH was kept at 7.9 by
titration with 4.5 ml of formic acid (85% v/v).
Step b)
[0034] 8.4 ml of formic acid (85% v/v) were added to the cefadroxil
monohydrate solution obtained in step (a) in such a way that the pH
decreased to 6.0 in 30 minutes. The obtained cefadroxil monohydrate
suspension was stirred for 30 min. The suspension was filtered and
the cake was washed with 50 ml of water followed by 34 ml acetone.
After drying, 72.8 g of cefadroxil was obtained (84.7% (w/w)
yield). The CIE b value of the cefadroxil monohydrate crystals was
4.52.
Example 3
Colour Stability Test
4.1 Stress Conditions: Storage at 40.degree. C.
[0035] Cefadroxil (CDX) monohydrate crystals obtained by the
one-step crystallisation process of the Reference Experiment A and
the two-step crystallisation process according to the present
invention were stored at a temperature of 40.degree. C. The CIE b
values of the different cefadroxil monohydrate crystals were
determined at different time intervals as indicated in Table 1. CDX
(1)-(3) were obtained from 3 different crystallisation
processes.
TABLE-US-00001 TABLE 1 CIE b of CDX CIE b of CDX monohydrate
crystals monohydrate crystals obtained by the two-step obtained by
the one-step crystallisation process Weeks crystallisation process
CDX (1) CDX (2) CDX (3) 0 6.2 4.8 4.4 3.1 2 10.0 -- 4.8 3.0 4 13.2
6.6 5.1 4.6 6 15.6 -- -- -- 8 17.0 9.1 -- -- 12 14.2 10.4 -- -- 14
18.2 -- -- -- 18 18.6 -- -- -- 20 19.1 12.4 -- -- 24 20.0 12.9 --
-- --: not determined
4.2 Storage at 25.degree. C.
[0036] The cefadroxil monohydrate crystals obtained with the
one-step crystallisation process of Reference experiment A and a
two-step crystallisation process according to the present invention
were stored at 25.degree. C. The CIE b value was determined at
different time intervals as indicated in Table 2.
TABLE-US-00002 TABLE 2 Comparison colour stability at 25.degree. C.
CIE b CIE b one-step two-step Months crystallization process
crystallization process 0 6.2 4.8 3 14.0 5.8 6 14.7 6.0 9 15.1 6.3
12 15.5 -- 18 17.7 -- --: not determined
[0037] The results in table 1 and 2 show that the CIE b values of
the cefadroxil monohydrate crystals obtained with the two-step
crystallisation process according to the present invention remained
lower than the CIE b values of cefadroxil monohydrate crystals
obtained with the one-step crystallisation process when the
cefadroxil monohydrate crystals were stored at 25.degree. C. and
40.degree. C. Therefore, colour stability of the cefadroxil
monohydrate crystals prepared with the process according to the
present invention was higher than prepared with the one-step
crystallisation process of Reference experiment A.
* * * * *