Note: Descriptions are shown in the official language in which they were submitted.
CA 02710107 2010-07-20
PN0966
Recovering Unreacted Intermediate From Desalinated and Desolventized
Dimerisation
Reaction Mixture By Ultrafiltration
CROSS REFERENCE TO RELATED APPLICATIONS
The present application claims benefit of priority under 35 U.S.C. 119(e) to
United
States Provisional Application number 61/227,102 filed July 21, 2009, the
entire disclosure
of which is hereby incorporated by reference.
TECHNICAL FIELD
This invention relates generally to industrial preparation of iodixanol (1,3-
bis(acetamido)-N,N'-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-
triiodophenyl]-2-
hydroxypropane), a non-ionic X-ray contrasting agent. It further relates to a
method of
recovering intermediate 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-
triiodoisophthalamide ("Compound A") from a desalinated and desolventized
dimerisation
reaction mixture. In particular, the present invention employs uitrafiltration
prior to the
crystallisation of iodixanol to recover non-crystalline Compound A where the
permeate
contains less than about 8 % of Compound A by weight relative to iodixanol.
BACKGROUND OF THE INVENTION
lodixanol is the non-proprietary name of the chemical drug substance, 1,3-
bis(acetamido)-N,N'-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4 ,6-
triiodophenyl]-2-
hydroxypropane). Marketed under the trade name Visipaque , Iodixanol is one of
the most
used agents in diagnostic X-ray procedures. It is produced in large quantities
by GE
Healthcare in Lindesnes, Norway. The manufacture of Iodixanol requires the
production of
the chemical drug substance (referred to as primary production) followed by
formulation into
the drug product (referred to as secondary production). The primary production
of Iodixanol
involves a multistep chemical synthesis and a thorough purification process.
It is important
for the primary production to be efficient and economical and to provide a
drug substance
fulfilling the regulatory specifications, such as those mandated by US
Pharmacopeia. In
addition, the cost and efficiency of the secondary production depend on the
synthesis and
purification processes in the primary production. Thus, optimization is
desired in each step
of the primary production of Iodixanol.
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The industrial synthesis of iodixanol involves dimerisation of intermediate 5-
acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide ("Compound
A") as
the final synthetic step as shown in Scheme 1 below.
CH O O OH
HO 0 3 1-amino-2,3- HO N O
CH3OH / propanediol
LNO offHO z CH30 \ NO2
HO,_ N \ I NO
0 0 NO,
O
OH OH
11
U12 HO N O HON O
~ ICI Acetic
OH OH 1 i 1 Anhydride
H
HON HO~~N
NH, NHz
0 0 1
Compound B
OH
H 01l OH
HO N O Epichloro- HO ,J,, N O O N OH
HO OH { { hydrin 1 { 1 I H 11 OH OH
NH FIO ,),, N \ N \N \ N 011
O I
O 0 1 O 011 0 1 0
Compound A
lodixanol
Scheme I
The dimerisation of Compound A to iodixanol leads to a conversion of about 55-
60 %
of the starting material. Most of the unreacted Compound A is subsequently
removed and
recovered from the reaction solution by addition of hydrochloric acid, which
allows for
precipitation of neutral Compound A from the reaction solution. See U.S.
Patent No.
6,974,882. Despite the initial removal and recovery of Compound A, a
considerable amount
of Compound A, about 14-18 % relative to iodixanol, remains in the reaction
solution. There
exists a need for a cost-effective industrial process for the recovery of this
additional
Compound A.
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SUMMARY OF THE INVENTION
The present invention provides a process for recovering a key intermediate in
the
synthesis of iodixanol. It further relates to recycling residual non-
crystalline Compound A
before the initiation of the crystallisation process for iodixanol.
Specifically, the instant
invention is directed to the sequential steps of (1) reducing the salt and
solvent content in a
dimerisation reaction mixture containing Compound A and iodixanol to
precipitate
Compound A in a non-crystalline form; (2) passing the mixture of step (1)
through an
ultrafiltration membrane; (3) recovering non-crystalline Compound A in the
retentate of step
(2) for reuse in a subsequent dimerisation reaction to prepare iodixanol; and
(4) crystallising
iodixanol from the permeate of step (2) wherein the weight content of Compound
A in the
permeate is less than about 8% relative to that of iodixanol. A suitable
ultrafiltration system
may include tubular, spiral or hollow fibre based systems.
The present procedure represents an optimal industrial process. In particular,
the
wastage of Compound A is minimized without adding excessive time or incurring
substantial
cost. In addition, the iodixanol solution before its crystallisation contains
sufficiently less
Compound A to enable the final iodixanol product to meet the regulatory
requirement.
DETAILED DESCRIPTION OF THE INVENTION
Following the acid quenching of the dimerisation reaction from Compound A to
iodixanol and the initial recovery of unreacted Compound A by precipitation,
about 14-18 %
of Compound A (relative to iodixanol by weight) is still dissolved in
solution. The dissolved
Compound A, along with the iodixanol product in solution, could be fed to the
next process
step without any discrete recovery step for Compound A. This procedure however
presents
several problems.
First, the unrecovered Compound A represents a loss of valuable intermediate
in the
primary production of iodixanol. This waste of Compound A is significant
because it is the
last intermediate in the iodixanol manufacture and because it contains iodine,
the most
expensive reagent in the chemical synthesis. Any loss of Compound A increases
the overall
cost of the primary production of iodixanol.
Second, Compound A can be reused in a subsequent dimerisation reaction to
prepare
iodixanol. In other words, the additional Compound A in solution with
iodixanol can be
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converted to iodixanol in a new dimerisation reaction. The unrecovered
Compound A thus
lowers the effective production yield of iodixanol.
Finally, we have found that a high content of Compound A in the feed to
subsequent
crystallisation steps of iodixanol makes it difficult to obtain the required
purity of the final
iodixanol product.
To address these issues, an effective and efficient method has been found to
recover
the additional soluble Compound A. Specifically, the reduction of salt content
of the
dimerisation reaction mixture causes the solubility of Compound A to decrease,
which leads
to the precipitation of Compound A. In addition, the amount of solvent is
reduced along with
the salt content, which again contributes to the precipitation of Compound A
due to its poor
solubility in water.
We have found that the precipitated Compound A during the salt and solvent
reduction process is largely non-crystalline. However, conventional filtration
techniques,
such as pressure or vacuum filtration, are not suitable for an industrial
scale recovery of
Compound A due to a variety of factors, such as the added cost and time, the
compatibility
with the existing iodixanol primary production operation, and the loss of
iodixanol.
On the other hand, the additional Compound A precipitated during desalination
and
desolventization can be efficiently removed by ultrafiltration with minimal
addition of time
and cost. Further, the ultrafiltration cake can be combined with the
precipitated Compound A
from the previous hydrochloric acid precipitation step. Pooling Compound A
from two
separate recovery steps gives a net yield increase in the process of primary
production of
iodixanol and enhances the economy of production considerably.
Another improvement of the instant process is that the content of Compound A
in the
process solution subjected to iodixanol crystallisation is reduced to a level
that the residual
Compound A in the ultrafiltration permeate does not interfere with the
subsequent
crystallisation of iodixanol. In certain embodiments, the level of compound A
in the
crystallisation feed is between about 4 and about 8 w/w % relative to
iodixanol. It has been
found that this relative small amount of Compound A left in the permeate
solution containing
iodixanol after ultrafiltration can be removed in the crystallisation process
for iodixanol
without the need for expensive and time consuming reprocessing steps.
Yet another improvement of the instant process is that the loss of the main
product
iodixanol is kept at a minimal during ultrafiltration. The solubility of
iodixanol in water has
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been found to be high enough such that it does not precipitate during the
instant process of
recovering additional Compound A.
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
described in them.
EXAMPLES
EXAMPLE 1
A reaction mixture containing about 340 kg iodixanol and substantial amounts
of
Compound A (about 14-18 w/w % relative to iodixanol) and iohexol (6-8 w/w %
relative to
iodixanol) is subjected to nanofiltration. Water is added continuously to
facilitate diafiltration
followed by volume reduction. A final salt concentration of about 0.60 w/w %
relative to
iodixanol (2.0 kg NaCI in 340 kg iodixanol) is obtained. At this stage, the
reaction medium is
aqueous with the pH between about 4 and 6. Compound A is precipitated on the
retentate
side of the nanofiltration membrane due to reduced salt and organic solvent
content. The
organic solvent is 2-methoxyethanol.
The precipitated Compound A is removed from the process solution by
ultrafiltration
using a PallsepTM PS400 vibrating membrane system at ambient temperature with
the pH
between about 5 and 7.5. At the end of the ultrafiltration step water is added
continuously to
facilitate diafiltration in order to flush out any remaining iodixanol on the
retentate side. The
diafiltration step is terminated when almost pure water flows through the
ultrafilter, detected
by a density of the permeate of less than 1.005 kg/L. The last fraction of
permeate is led to a
different stream than the main process solution for later re-use in an earlier
step to avoid
dilution of the product mixture before crystallisation. The Compound A content
in the main
filtrate is about 4 to about 7 % (w/w) relative to iodixanol content. The
filtrate is subjected to
crystallisation and subsequent purification steps to obtain the necessary
purity.
EXAMPLE 2
A reaction mixture containing about 340 kg iodixanol and substantial amounts
of
Compound A (about 14-18 w/w % relative to iodixanol) and iohexol (6-8 w/w %
relative to
iodixanol) is subjected to nanofiltration. Water is added continuously to
facilitate diafiltration
followed by volume reduction. A final salt concentration of about 0.60 w/w %
relative to
iodixanol (2.0 kg NaCl in 340 kg iodixanol) is obtained. At this stage, the
reaction medium is
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aqueous with the pH between about 4 and 6. Compound A is precipitated on the
retentate
side of the nanofiltration membrane due to reduced salt and organic solvent
content. The
organic solvent is methanol.
The precipitated Compound A is removed from the process solution by
ultrafiltration
using a PallsepT"' PS400 vibrating membrane system at ambient temperature with
the pH
between about 5 and 7.5. At the end of the ultrafiltration step water is added
continuously to
facilitate diafiltration in order to flush out any remaining iodixanol on the
retentate side. The
diafiltration step is terminated when almost pure water flows through the
ultrafilter, detected
by a density of the permeate of less than 1.005 kg/L. The last fraction of
permeate is led to a
different stream than the main process solution for later re-use in an earlier
step to avoid
dilution of the product mixture before crystallisation. The Compound A content
in the main
filtrate is about 4 to about 7 % (w/w) relative to iodixanol content. The
filtrate is subjected to
crystallisation and subsequent purification steps to obtain the necessary
purity.
All patents, journal articles, publications and other documents discussed
and/or cited
above are hereby incorporated by reference.
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