Note: Descriptions are shown in the official language in which they were submitted.
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Crystallization of iodixanol using milling
TECHNICAL FIELD
This invention relates to the manufacture of iodixanol (1,3-bis(acetamido)-
N,N'-bis[3,5-
bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane),
more
specifically to the purification of iodixanol by crystallization.
BACKGROUND OF THE INVENTION
lodixanol is the non-proprietory name of the chemical drug substance of a non-
ionic X-ray
contrast agent marketed under the trade name VisipaqueTM. VisipaqueTM is one
of the most
used agents in diagnostic X-ray procedures and is manufactured in large
quantities.
The manufacture of such non-ionic X-ray contrast agents involves the
production of the
chemical drug substance (referred to as primary production) followed by
formulation into the
drug product (referred to as secondary production). Primary production of
iodixanol involves
a multi step chemical synthesis and a thorough purification process. For a
commercial drug
product it is important for the primary production to be efficient and
economical and to
provide a drug substance fulfilling the specifications, e.g. as expressed in
the US
Pharmacopeia.
A .number of methods are known for the preparation of iodixanol. These are all
multi step
chemical synthetic processes and the cost of the final formulated product thus
mainly
depends on these processes. It is therefore important to optimize the
processes both Jor
economic and environmental reasons.
Three main chemical synthetic processes are known for the preparation of
iodixanol, all of
which start with 5-nitroisophthalic acid. In the first process described in EP
108638,
the final intermediate 5-acetamido-N,N'-
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bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide (hereinafter "Compound
A") is reacted
with a dimerisation agent such as epichlorohydrin to yield the drug substance,
see Scheme I.
HO O CH30 O OH
I-amino-2,3- HO L NH O
LNO CH3O H CH 0 propanediol OH
HO 0H I 3 NOz NH O N02
O
OH OH
HO. ) NH 0 HO, J NH O
H Acetic
? OH 1 CI 1 / J anhydride
HO ,,I, NH OH
NHI HO ),_i NH NH2
0 O 1
OH OH
140 NH O HO NH 0 0 NH OH
13pichloro- OH
OH 1 / I 1 hYdon on
1 / 1 I / t
HO
NH
\ 1 11 HO NH OH
NN NH~~OH
0
0 p l 0 OHO 1 O
Compound A lodixonol
Scheme I
The overall yield in this process is relatively low and the purification of
the end product
iodixanol is expensive and time consuming. The purification process described
in EP patent
108638 involves purification by preparative liquid chromatography. The use of
preparative
liquid chromatography is a serious disadvantage in industrial processes in
particular due to
the high costs involved.
Several attempts have been made to find alternative manufacturing processes.
Attempts to
increase the yield of the chemical synthesis is published by Priebe et.al.
(Acta Radiol. 36
(1995), Suppl. 399, 21-31). This publication describes another route which
avoids the difficult
last step of the process of Scheme I. However, the route involves eight
reaction steps from
5-nitroisophthalic acid, which is undesirable, and one of the steps includes
chlorination with
thionyl chloride, which is extremely corrosive. Also, the introduction of the
iodine atoms
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takes place very early in the sequence, which is disadvantageous as iodine is
the most
expensive reagent in the process. The yield and final purification method for
this route have
not been reported.
The third route to iodixanol involves the synthesis of 5-amino-2,4,6-
triiodoisophthalic acid
(WO 96/37458) and then its dichloride (WO 96/37459), followed by conversion
into
Compound A (US 5705692) and finally dimerisation as in the process of Scheme
I. This
method thus has the same disadvantages as the first process, and also uses an
undesirable
acid chlorination step.
A common system for purification of the crude product in the final step of the
primary
production process, avoiding the liquid chromatography method, has been
purification by
crystallization. To achieve the desired purity, the crude iodixanol produced
by the synthetic
chemical process is crystallized twice. The process is time consuming and
takes about 3
days for the first crystallization and about 2 days for the second one. Hence,
the
crystallization process is very demanding in terms of time and equipment size,
it will take
several days to perform and is often a bottleneck in industrial scale
processes.
WO 99/18054 describes a process for the crystallization of i.a. iodixanol
where the
crystallization is effected with high thermal energy, specifically under
elevated pressure and
at a temperature above the boiling point of the solution at atmospheric
pressure.
WO 00/47549 describes a process for the preparation of iodixanol where
unreacted
Compound A is precipitated from the reaction mixture and recovered for reuse
in a later
batch.
It is hence a desire to shorten the crystallization time and also improve the
crystallization
step in order to increase the purity of the final product.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. I shows agglomerates of iodixanol produced in a crystallization step
according to prior
art. Scale: 1 unit = 120 pm.
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FIG. 2 shows iodixanol particles produced in a crystallization step according
to the
present invention. Scale: I unit = 30 pm.
FIG. 3A and 3B show iodixanol particles produced in a crystallization step
according
to the present invention. Scale: 1 unit = 30 pm
SUMMARY OF THE INVENTON
The present invention provides improvements to the crystallization of
iodixanol.
Thus viewed from one aspect the invention provides a process for the
purification of a
crude product comprising iodixanol by crystallization, wherein the
crystallization
involves wet milling.
The process according to the present invention reduces the process time for
the
crystallization steps and improves the washing and hence the purity of the
final
product.
In one aspect, the invention relates to an improved process for the
purification of a
crude reaction mixture resulting from the dimerization of 5-acetamido-N,N'-
bis(2,3-
- dihydroxypropyl)-2,4,6-triiodo-isophthalamide (compound A) comprising
iodixanol,
5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide
(compound
A), iohexol and impurities having longer retention times than iodixanol in
reversed
phase HPLC, comprising the step of wet milling said crude reaction mixture
during
the crystallization process of said crude reaction mixture.
DETAILED DESCRIPTION OF THE INVENTION
The processing time for the first crystallization is substantially longer than
for the
second one because of the higher concentration of impurities at this stage of
the
process. Due to the slow kinetics, both crystallizations are run at high
initial
supersaturation and during the crystallization process it is formed large
agglomerates, often of more than 100 pm in diameter. These agglomerates are
shown in Figure 1. Agglomeration significantly reduces the available total
surface
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area for crystal growth and therefore prolongs the process time to achieve the
desired yield.
It has now surprisingly been found that it is possible to perform
deagglomeration
during the crystallization process by using wet milling.
Thus viewed from one aspect, the invention provides a process for the
purification of
a crude product comprising iodixanol by crystallization, wherein the
crystallization
solution is deagglomerated by wet milling.
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The use of wet milling will significantly reduce the agglomeration of
iodixanol crystals and by
this reduce the process time for the crystallization steps. In cases where two
crystallization
steps are performed, the use of wet milling will be able to reduce the process
time from
about three days to less than two days for the first crystallization and from
about two days to
less than 1 day for the second crystallization.
Further, the use of wet milling in the crystallization step will also improve
the purity of the
final product. The purification process is finalized by filtering the
precipitated iodixanol,
preferably as unagglomerated crystals, from the solvents and finally washing
the crystals
with an alcohol such as methanol. The agglomerates of iodixanol crystals will
also entrap
mother liquor that needs to be removed by washing. By significantly reducing
the
agglomeration and hence the inclusion of mother liquor, a more effective
washing of the
crystals is achieved and also improved purity of the final product.
Figure 1 shows agglomerates produced during a crystallization process
according to prior
art. It can be seen that the agglomerates have a mean size in the area of
about 120 pm.
Figure 2 on the other hand shows particles produced under a process according
to the
present invention, and it can be seen that the particles are single crystals
or very small
agglomerates. The size of these particles is less then about 30 pm.
According to the present invention wet milling can be performed using any kind
of mill, e.g.
disc mills, colloid mills and other shear mixers.
Depending on the type of mill used, the mill can be mounted either into the
crystallizer or in-
line to the crystallizer. When mounted in-line to the crystallizer the
crystallization solution is
circulated between the crystallizer and the mill.
The mill can be used continuously throughout the crystallization, but normally
a certain
period at the start of the crystallization is sufficient to achieve the
desired results.
The crude product referred to in the present invention can be obtained from
the processes
known from the state of the art, e.g. from the dimerisation process
illustrated in Scheme I
above. The dimerisation step itself may be carried out as described in
European patent
108638 and WO 98/23296, for example using epichlorohydrin, 1,3-dichloro-2-
hydroxypropane or 1,3-dibromo - 2-hydroxypropane as the dimerisation agent,
with
epichlorohydrin being most preferred. The reaction is usually carried out in a
solvent such as
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2-methoxyethanol, methanol, 1-methoxy-2-propanol or a mixture of 2-
methoxyethanol or 1-
methoxy-2-propanol and water, and generally results in the conversion of 40 to
60% of
Compound A to iodixanol.
Hence, in a second aspect of the invention it is provided a process for the
manufacture of
iodixanol comprising the steps of:
a) reacting 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-
isophthalamide
with a dimerisation agent in the presence of a solvent
b) purifying the reaction product from step a) in a crystallization procedure
c) deagglomerating the crystallization solution in the crystallization
procedure by wet
milling
d) filtering and washing the product from step c)
The crude product from the dimerisation and following work-up steps is
preferably in
aqueous solution with small traces of organic solvent. The crude product
normally contains
about 75-90 weight% iodixanol, 3-10 weight% iohexol, 0-7 weight% Compound A,
and also
minor amounts of other impurities. The most important impurities in the
reaction with regard
to work-up consequences are the so-called backpeaks. This term refers to
retention times in
reversed phase HPLC, where the backpeaks have slightly longer retention times
than
iodixanol itself. Most of the backpeaks are either trimers or O-alkylated
dimers. This crude
product is preferably the starting material for the further purification by
crystallization
according to the present invention.
The invention is illustrated further by the following examples that are not to
be construed as
limiting the invention in scope to the specific procedures or products
described in them.
Example 1 shows a conventional crystallization process according to prior art
without the
use of wet milling. Figure 1 shows agglomerates of iodixanol produced (1 unit
= 120 pm).
The process reaches a yield of 80% after 54 hours. From the comparative
example 2
showing the same process with the use of wet milling, it can be seen that a
yield of 80% is
reached as early as after 32 hours. In addition it can be seen that the purity
of the final
product is increased. Figure 2 shows iodixanol particles produced (1 unit = 30
pm).
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In example 3 an optimized process with wet milling is described. Because of
the shorter
crystallization times involved, solvent can be added at an earlier stage than
in a process
according to prior art. In this process it can be seen that a yield of more
than 80% is reached
after only 23 hours.
Example 4 describes the process according to the present invention in a larger
scale and
with the use of a colloid mill. The crude product contained about 60% more
backpeaks than
in a comparable prior art process. However, by reducing the agglomeration by
milling, the
backpeak content after the first crystallization was similar to the backpeak
content after the
first crystallization in the prior art process. As for the prior art process,
the product
specification was met first after a further recrystallization not described in
the example.
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EXAMPLES
EXAMPLE I
305 g of crude product containing 253 g iodixanol, 17.8 g Compound A, 22.5 g
iohexol and
5.1 g backpeaks was dissolved in a mixture of water and 1-methoxy-2-propanol
(PM) in a I
liter vessel equipped with the a stirrer (with a magnet driven shaft),
condenser and heating
jacket. The amount of water and PM in the solution was 105 g and 442 g
respectively. The
solution was heated to reflux at atmospheric pressure and seeded with 2.4 g
seed particles
of iodixanol. Further addition of PM was done as follows:
Start addition
of PM (hrs Amount of PM (g) Addition time (hrs)
after seeding)
12 111 13
25 276 8
The yield of iodixanol was as follows:
Time (hrs after Yield of iodixanol
seeding) (%)
12 2
24 18
32 50
48 79
54 80
The product at the end of the crystallization was filtered and washed with
methanol. The
purity of the product is given below (HPLC):
Substance (%)
lodixanol 98.56
Compound A 0.10
lohexol 0.21
Backpeaks 1.07
Figure 1 shows iodixanol agglomerates produced.
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EXAMPLE 2
305 g of crude product containing 253 g iodixanol, 17.8 g Compound A, 22.5 g
iohexol and
5.1 g backpeaks was dissolved in a mixture of water and 1-methoxy-2-propanol
(PM) in a 1
liter vessel equipped with the a stirrer (with a magnet driven shaft), disc
mill, condenser and
heating jacket. The amount of water and PM in the solution was 105 g and 442 g
respectively. The solution was heated to reflux at atmospheric pressure and
seeded with 2.4
g seed particles of iodixanol. Further addition of PM was done as follows:
Start addition
of PM (hrs Amount of PM (g) Addition time (hrs)
after seeding)
12 111 13
25 276 8
The yield of iodixanol was as follows:
Time (hrs after Yield of iodixanol
seeding) (%)
12 57
24 71
32 80
48 83
54 83
The product at the end of the crystallization was filtered and washed with
methanol. The
purity of the product is given below (HPLC):
Substance (%)
iodixanol 99.00
Compound A 0.05
lohexol 0.05
Backpeaks 0.86
Figure 2 shows iodixanol particles produced.
EXAMPLE 3
305 g of crude product containing 253 g iodixanol, 17.8 g Compound A, 22.5 g
iohexol and
5.1 g backpeaks was dissolved in a mixture of water and 1-methoxy-2-propanol
(PM) in a 1
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liter vessel equipped with the a stirrer (with a magnet driven shaft), disc
mill, condenser and
heating jacket. The amount of water and PM in the solution was 105 g and 442 g
respectively. The solution was heated to reflux at atmospheric pressure and
seeded with 2.4
g seed particles of iodixanol. Further addition of PM was done as follows:
Start addition
of PM (hrs Amount of PM (g) Addition time (hrs)
after seeding)
111 4
14 276 4
The yield of iodixanol was as follows:
Time (hrs after Yield of iodixanol
seeding) (%)
10 51
14 65
18 78
23 81
35 82
10 The product at the end of the crystallization was filtered and washed with
methanol. The
purity of the product is given below (HPLC):
Substance (%)
lodixanol 99.0
Compound A 0.05
lohexol 0.05
Backpeaks 0.86
EXAMPLE 4
An aqueous solution of crude iodixanol product was concentrated in a vessel
and 1-
methoxy-2-propanol (PM) was added. The content of water was then adjusted to
the desired
level. The solution contained about 60 kg iodixanol, 4 kg Compound A, 4 kg
iohexol and 2 kg
backpeaks. The vessel was equipped with a stirrer, condenser, colloid mill
(MK2000/4 from
IKATM) in loop to the vessel and heating jacket. The crude product contained
about 60%
more backpeaks than in a comparable prior art process. The amount of water and
PM in the
solution was 19 kg and 58 kg respectively. The solution was heated to reflux
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pressure and seeded with 0.56 kg seed particles of iodixanol. Further addition
of PM was
done as given in the table below. The water content was reduced by 14 % by
distillation
during the crystallization.
Start addition Amount of PM
of PM (hrs (kg) Addition time (hrs)
after seeding)
19 6
16 38 6
5
The yield of iodixanol was as follows:
Time (hrs after Yield of lodixanol
seeding) (%)
11 61
14 68
37 88
The product at the end of the crystallization was filtered and washed with
methanol. The
10 purity of the product is given below (HPLC):
Substance (%)
lodixanol 98,7
Compound A 0.07
lohexol 0.04
Backpeaks 1.09
The lodixanol particles produced using the mill during for the first 11 hours
of a total
crystallization time of 37 hours, are shown in Figures 3A and 3B. Figure 3A
shows the
particles 13 hours after seeding and the Figure 3B shows the particles 37
hours after
seeding.
