US 2013 0277221A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0277221 A1 Birkeland (43) Pub. Date: Oct. 24, 2013

(54) DESALINATION OF A COMPOSITION Publication Classification COMPRISINGA CONTRASTAGENT (51) Int. Cl. (75) Inventor: Aslaug Birkeland, Lindesnes (NO) A614.9/00 (2006.01) (52) U.S. Cl. (73) Assignee: GE HEALTHCARE AS, OSLO (NO) CPC ...... A61K 49/0002 (2013.01) USPC ...... 204/536; 204/541 (21) Appl. No.: 13/995,588 (22) PCT Filed: Dec. 20, 2011 (57) ABSTRACT (86). PCT No.: PCT/EP2011/073377 The invention relates to industrial preparation of contrast S371 (c)(1), agents, and further to an improved process for the purification (2), (4) Date: Jun. 19, 2013 of contrast agents. In particular, it relates to a process for reducing the salt content of compositions comprising an MR (30) Foreign Application Priority Data contrast agent or an X-ray contrast agent, such as a non-ionic iodinated monomeric compound or a non-ionic iodinated Dec. 21, 2010 (EP) ...... 101961 17.5 dimeric compound. US 2013/0277221 A1 Oct. 24, 2013

DESALINATION OF A COMPOSITION prepared crude composition comprising the X-ray contrast COMPRISINGA CONTRASTAGENT agent iohexol includes considerably amounts of salts. The 0001. This invention relates generally to industrial prepa Sources of chloride are 1-chloro-2,3-propanediol, used as the ration of contrast agents, and further to an improved process alkylating agent, and hydrochloric acid, which is used to for the purification of contrast agents. In particular, it relates adjust the pH. The source of sodium cations is the Sodium to a process for reducing the salt content of compositions hydroxide (NaOH). After the final reaction step of the pri comprising an X-ray contrast agent or an MR contrast agent. mary production process, iohexol has to be purified by desali 0002. In techniques such as X-ray, one approach to nating the composition, before crystallization. In order to improve the diagnostic quality factor has been to introduce crystallize iohexol in accordance with the regulatory purity contrast enhancing materials formulated as contrast media requirement, the salt content prior to a crystallization process into the body region being imaged. Thus for X-ray, early should be less than about 0.02 w/w % relative to iohexol. examples of contrast agents were insoluble inorganic barium Further, after the crystallization step, the composition is sub salts which enhanced X-ray attenuation in the body Zones into jected to further purification to obtaina composition compris which they distributed. For the last 50 years the field of X-ray ing iohexol with a salt content below about 0.01 w/w %. contrast agents has been dominated by soluble iodine con 0006. Likewise, Iodixanol is the non-proprietary name of taining compounds. Commercial available contrast media the chemical drug substance 1,3-bis(acetamido)-N,N'-bis(3, containing iodinated contrast agents are usually classified as 5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-tri ionic monomers such as diatrizoate (marketed e.g. under the iodophenyl-2-hydroxypropane). The drug product is mar trade mark GastrografenTM), ionic dimers such as ioxaglate keted under the trade name Visipaque R. The final step of the (marketed e.g. under the trade mark HexabrixTM), nonionic iodixanol primary production is the dimerisation of the inter monomers such as iohexol (marketed e.g. under the trade mediate 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6- mark OmnipaqueM), iopamidol (marketed e.g. under the triiodoisophthalamide (Compound A). Reference is made to trade mark IsoVueTM), iomeprol (marketed e.g. under the U.S. Pat. No. 6,974,882. The reaction mixture, or composi trade mark IomeronTM) and the non-ionic dimer iodixanol tion, after the dimerisation of Compound A to iodixanol also (marketed under the trade mark VisipaqueTM). The clinical includes a considerable amount of salts, mainly in the form of safety of iodinated X-ray contrast media has continuously Sodium chloride (NaCl), as an impurity. The crude composi been improved over the recent decades through development tion may comprise as much as up to 20 w/w % NaCl content of new agents; from ionic monomers (IsopaqueTM) to non relative to iodixanol, such as 10-15 w/w % relative to iodix ionic monomers (e.g. OmnipaqueTM) and non-ionic dimers anol, before the purification. The sources of chloride are (e.g. VisipaqueTM). epichlorohydrin and hydrochloric acid, which is used to 0003. The manufacture of non-ionic X-ray contrast media adjust the pH before epichlorohydrin addition and to precipi involves the production of the chemical drug, the contrast tate unreacted Compound A after the reaction. The source of agent (referred to as the primary production), followed by the sodium cations is the sodium hydroxide (NaOH) used to formulation into the drug product (referred to as the second dissolve Compound A in the reaction solvent. Iodixanol has ary production). In the preparation of an X-ray composition, to be purified by desalinating the composition before crystal i.e. the secondary production of a contrast media, the contrast lization. In order to crystallize iodixanol in accordance with agent is admixed with additives, such as salts, optionally after the regulatory purity requirement, the Salt content prior to the dispersion in a physiologically tolerable carrier. Primary pro crystallization process should be less than about 0.7 w/w % duction of the contrast agent normally involves a multi step relative to iodixanol. chemical synthesis and a thorough purification process. For a 0007. It is thus desirable to devise a cost effective proce commercial drug product, it is important for the primary dure for desalinating compositions comprising a contrast production to be efficient and economical and to provide a agent, Such as prepared in the primary production. drug Substance fulfilling the regulatory specifications, such as 0008 To achieve such low salt levels in the composition those mandated by US Pharmacopeia. In addition, the cost comprising the contrast agent as required for iohexol and and efficiency of the secondary production depend on the iodixanol, many attempts have been made to devise a process synthesis and purification processes in the primary produc to effectively and efficiently reduce large salt contents gener tion. It is therefore critical to optimize each process in the ated in primary production. Such known methods include primary production of the contrast agent. various techniques involving filtration, such as nano-filtration 0004 Iohexol is the non-proprietary name of the non-ionic and ultra-filtration, use of purification columns, ion exchange iodinated X-ray contrastagent of the chemical drug Substance 5-N-(2,3-dihydroxypropyl)-acetamido-N,N'-bis(2,3-dihy and dialysis. droxypeopyl)-2,4,6-triiodoisophtalamide. The drug product 0009 U.S. Pat. No. 5,210,300 by Mallinckrodt is directed is marketed under the trade name Omnipaque R. The manu to a method of purifying the X-ray contrast agentioVersol by facture of iohexol involves the production of the chemical removing acids and other impurities by continuous deioniza drug Substance (primary production) followed by formula tion. Crude ioVersol is passed through a mixed-bed resin and tion into the drug product (secondary production). an electrical current is applied. However, as use of traditional 0005. The final synthesis step of iohexol primary produc electrodeionization (EDI) systems are disclosed it is believed tion is an N-alkylation step in which 5-acetamido-N,N'-bis(2. that challenges such as leakage of the contrast agent from the 3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (Com feed stream is experienced. Further, poor exploitation of pound A) is reacted with an alkylating agent to introduce the energy is likely to be seen. 2,3-dihydroxypropyl group at the nitrogen of the 5-acetamido 0010 Hence, an alternative, and preferably improved pro group. The reaction mixture, or crude composition, after this cess, has been sought for reducing the Salt content of crude alkylation step, includes a considerable amount of salts, compositions comprising an X-ray contrast agent or an MR mainly in the form of sodium chloride (NaCl). Hence, the contrast agent, particularly in industrial scale. US 2013/0277221 A1 Oct. 24, 2013

0011 Thus, in a first aspect the invention provides a pro and a means for applying an electrical potential to said com cess for the preparation of a composition comprising a con partment, wherein the entities are preferably embedded in a trast agent in a carrier, the process comprising the step of thermoplastic. Such as selected from the group consisting of desalinating the composition by electrodeionization using a low linear density polyethylene, high density polyethylene, wafer based EDI device. and combinations thereof. 0012 Electrodeionization (EDI), also called electro chemical deionization, is a process that removes ionizable 0015 The electrodeionization process of the invention can species from liquids using an ionically active media and an be batch wise or continuous. The continuous electrodeioniza electrical potential to influence ionic transport. EDI devices tion (CEDI) process of the invention employs anion and cat combine the use of ion exchange resins, ion exchange mem ion permeable ion exchange membranes, with the porous ion branes and electrodes without the need for regeneration of exchange resins packed between them. The typical process chemicals. The EDI cell combines the benefits of ion includes separate diluting and concentrating compartments. exchange and electrodialysis while minimizing the problems Applying a DC electric potential causes ions to move from associated with each of these separate technologies. The EDI one compartment to another, affecting a separation. Since the cell uses the ion exchange resin to provide high ionic conduc concentration of ions is reduced in one compartment and tivity to the normally high resistance found in the dilute increased in the other, the process can be used for either compartments of an electrodialysis cell. The resin's high purification or concentration. Under the influence of the elec ionic capacity increases the residence time of the ionic con tric field, cations will migrate in the direction of the nega taminants inside the cell allowing more time for the transport tively charged cathode, through the cation-exchange resin, of these ions into the appropriate compartments. The elec cation-permeable membrane and into the concentrating trodes generate a potential gradient for ionic movement stream. An anion permeable membrane on the opposite side within the cell. At cation/anion (resin/resin and resin/mem of that stream prevents further migration, effectively trapping brane) interfaces water is dissociated into its constituentions, H+ and OH- , which regenerate the resins on-line, so there is the cations in the concentrating stream. The process for anion no down time or need for regenerative chemicals as in ion removal is analogous, but in the opposite direction, toward the exchange. Processes using electrodeionization to remove positively charged anode. Most commercially available ions have been known from the mid-1950s, and EDI has CEDI modules are plate and frame devices with multiple mainly been used in the production of pure or ultrapure water arrangements of alternating diluting and concentrating com for industrial processes. Applications have included pharma partments, hydraulically in parallel and electrically in series, ceuticals and particularly production of pure feed water for and such CEDI devices may be used in the process of the pharmaceuticals and food and beverage applications, high invention. quality rinsing water for electronics, and use in laboratories. 0016. The process of the invention addresses the specific EDI has normally not been used in chemical processing need of the current iohexol and iodixanol synthesis method because it leaked and used electricity inefficiently. We have ology, wherein large amounts of salts are generated as a result now surprisingly found the EDI may be beneficially used in of the alkylation or dimerisation steps, and wherein the the preparation of compositions comprising contrastagents to requirements to purity is high. Particularly, for iohexol the desalinate such by using a wafer based EDI device. Such EDI salt content of the crude composition, before the crystalliza devices provide an improved electrical flow over other EDI tion step, must be very low, and the process of the invention systems and have a less tendency to leak the product which is addresses this requirement. The process further applies to to be purified. similar contrast agents and compositions prepared by pro 0013 The EDI device used in the process of the invention cesses generating salts. The instant process represents a sig comprises an ion exchange resin, membranes and means for nificant improvement over the alternative of employing ion applying a DC voltage, wherein the ion exchange resin is exchange resins. For example, two ion exchange resins, one moulded into a porous wafer. In one embodiment the ion anionic and one cationic, are needed to remove the significant exchange resin comprises wafers of uniform thickness. Dif amount of salts present following the alkylating reaction ferent types of ion exchange resins may be used in the same when preparing iohexol. The requirement of two resins, both system. The ion exchange resin consists of a porous ion in large quantities, causes significant loss of intermediates exchange material or is alternatively in gel form. The patent and final product, such as of Compound Aandiohexol for the U.S. Pat. No. 6,495,014 discloses relevant wafer-based EDI iohexol process. devices and the Subject matter of this patent, particularly 0017. With the process of the invention a low leakage and regarding the EDI device, is hereby incorporated by refer a low energy consumption is seen. Hence, one improvement CCC. of the instant process is that the loss of the main product, i.e. 0014. In a particularly preferred embodiment the EDI the contrast agents such as iohexol or iodixanol, is kept at a device used in the process of the invention comprises minimal during electrodeionization. In addition, the opera a cation-exchange membrane; tion of large scale purifications using ion exchange resins an anion-exchange membrane, preferably juxtaposed co-pla includes separation time, energy consumption, cost of resin narly to said cation exchange membrane; regeneration and replacement, i.e. an equipment requirement a porous ion-exchange resin material, preferably positioned which is lengthy, complex, and expensive. With the wafer intermediate said cation-exchange membrane and said anion based EDI device the energy consumption is lower and costs exchange membrane to form a compartment, preferably are reduced. Another advantage of the wafer used in the whereby the material comprises anion-exchange entities and present invention is that a section or cell comprising ion cation exchange entities immobilized relative to each other exchange resins can easily be lifted out. With the process of via a binder which comprises said material, preferably with at the invention there is no need to use chemicals such as hydro least 20 weight percent; gen chloride and sodium hydroxide in the regeneration of the US 2013/0277221 A1 Oct. 24, 2013

ion exchange resins. Less water is further likely to be needed, 0021. The patent applications referred to, i.e. particularly and this will result in less water needed to be removed andless EP2010/050118 and WO2009/008734, are hereby incorpo strains of the contrast agent. rated by reference. 0018. The term “contrast agents' denotes agents that com 0022. In one embodiment of the invention, the contrast prise a material that can significantly attenuate incident radia agent of the composition to be desalinated is an MRI contrast tion causing a reduction of the radiation transmitted through agent. Preferred contrast generating species in MR imaging the Volume of interest. Increased radiation attenuation is spectroscopy are paramagnetic compounds such as stable interpreted as an increase in the density of the volume of free radicals, compounds comprising transition metals and interest, which creates a contrast enhancement in the Volume compounds comprising lanthanide metals. Such contrast comprising the contrast agent relative to the background tis agents are preferably transition metal chelates, transition Sue in the image. Preferably, contrast agent denotes an X-ray metal salts and lanthanide metal chelates, e.g. manganese contrast agent or a magnetic resonance imaging (MRI) con salts, gadolinium chelates or dysprosium chelates. Preferred trast agent, and most preferably an X-ray contrast agent. The contrast agents are chelators selected from the group of X-ray contrast agent of the composition prepared by the pro DTPA, DTPA-BMA, DOTA, HPDO3A, preferably chelating cess of the invention can be any type of X-ray agent. The a metal selected from the group of gadolinium (Gd), process of the invention is hence useful for compositions praseodymium (Pr), dysprosium (Dy), europium (Eu), thu comprising any X-ray agent and further comprising salts that lium (Tm) and manganese (Mn). Particularly preferred is the should be removed from the composition. The primary pro contrast agent GdDTPA-BMA which is a low molecular duction of X-ray agents typically includes a multi step chemi weight paramagnetic contrast agent used in magnetic reso cal synthesis. For Such agents there are alternative synthesis nance imaging (MRI), known as Omniscan R. In the prepa schemes and the synthesis also depend on the agents to pro ration of Such contrast agents, both in the synthesis of the duce. However, in Such synthesis there are some similarities, chelator and in the preparation of the metal chelate, salts are e.g. in that different reagents, acids and bases are used which generated, and Such salts should be removed from the gener may form salts that have to be removed from the composition, ated composition. In the preparation of GdDTPA-BMA e.g. before crystallization of the agent and/or after crystalli methylamine is used as a reagent in preparation of the chela Zation has taken place. tor and HCl is used for pH adjustment. Before addition of the 0019. The contrast agent of the produced composition is gadolinium, salts like methylamine hydrochloride should be preferably an iodinated X-ray compound. Preferably this is a removed. Other salts, like NaCl may also be removed by the non-ionic iodinated monomeric compound or a non-ionic EDI process. Further, after complexing with a metal, free iodinated dimeric compound, i.e. a compound comprising metalions, like Gd", may also be removed by the process of single triiodinated phenyl groups or a compound comprising the invention. two linked triiodinated phenyl groups. However, trimeric, 0023 For the embodiment wherein the contrast agent is an tetrameric and pentameric compounds are also included. Rel X-ray contrastagent, such as iohexoloriodixanol, the process evant monomeric and dimeric compounds are provided by the of the invention is either carried out before crystallization of applicant’s application EP2010/050118. Particularly relevant the contrast agent and/or after such crystallization. Prefer ably, the process of using EDI for desalination of the contrast contrast agents that are monomeric compounds are described agent is carried out before crystallization. However, in addi in WO97/00240 and in particular the compound BP257 of tion, or instead, the process of the invention, desalinating a example 2, and additionally the commercially available com composition comprising a contrast agent, can be used after pounds iohexol, iopamidol, iomeprol, ioversol, iopromide, crystallization for a further bulk treatment, or so called “pol iobitridol and iopentol. Most particularly preferred are the ishing step', to further purify the contrast agent before dry compounds iohexol and iopamidol. In one embodiment, ing. Such polishing step includes solving the filtered crystal ioversol is disclaimed from the process of the invention. lized contrast agent in water and desalinating Such 0020 Particularly relevant contrast agents that are dimeric composition by the EDI process of the invention. compounds are iodixanol (Visipaque) and compounds 0024. In a particularly preferred embodiment, the inven described in WO2009/008734, and particularly the com tion provides a process for the preparation of an X-ray com pound of formula (I), now called Ioforminol, position comprising the contrast agent iohexol, the process

Formula (I) H O O H O I Y OH N I O HO Null OH N NH r HO r I I I I OH

HN O O NH

HO OH

OH OH US 2013/0277221 A1 Oct. 24, 2013

comprising the step of desalinating a crude composition com 0032. The desalination process of the invention, con prising iohexol by electrodeionization using a wafer based ducted either before or after crystallization of the contrast EDI device, including the sequential steps of agent, may be combined with other methods for removing (1) reducing the salt content in a crude composition which is salts or other impurities. Such other methods are preferably the reaction mixture comprising Compound A, salts and selected from filtrations, ion exchange and electrodialysis. In iohexol, by EDI: a preferred embodiment the process comprises the step of (2) crystallizing iohexol from the composition of step (1). desalinating the composition by electrodeionization (EDI), 0025. In another preferred embodiment, the invention pro combined with an additional desalinating by electrodialysis vides a process for the preparation of an X-ray composition (ED) in a separate step before the EDI step. In such preferred comprising the contrastagentiodixanol, the process compris embodiment, a composition comprising a contrast agent and ing the step of desalinating a crude composition comprising salts to be removed, is subjected to ED first to remove the iodixanol by electrodeionization using a wafer based EDI majority of the salts, followed by a step of subjecting the device, including the sequential steps of: composition to EDI to further lower the salt content, remov (1) reducing the salt content in a crude composition which is ing the last remaining salts which are difficult to remove by the reaction mixture comprising Compound A, salts and other methods. The electrodeionization is preferably con iodixanol, by EDI; ducted using a wafer based EDI device. (2) recovering Compound A in the composition of (1) after desalination, for reuse in a Subsequent dimerisation reaction 0033. In yet another embodiment, the process of the inven to prepare iodixanol; and tion comprising the step of desalinating an X-ray composition by electrodeionization, is included in a continuous process for (3) crystallizing iodixanol from the composition of step (1). preparing an X-ray contrast agent. In a batch process, all the 0026 Compound A is 5-acetamido-N,N'-bis(2,3-dihy operations are performed Successively in the same reactor. droxypropyl)-2,4,6-triiodoisophthalamide. Thus, production capacity increase in a batch production 0027. For the process above for iodixanol, the side stream requires very large reactor Volumes and a corresponding from step (2) comprising feeding unreacted reagent Com increase in capital investments. On the other hand, a continu pound Aback for another dimerisation reaction could also be ous process has dedicated equipment for every operation, Subjected to desalinating by the process of the invention. where the mixture moves from one operation to the next 0028. The crystallized contrast agent, such as iohexol or within the production line. All the operations are performed iodixanol, may be subjected to the additional bulk treatment continuously all the time and the system is at a steady state. steps of: Consequently, a continuous production process requires a) Solving the crystallized contrast agent in water, much smaller equipment Volumes and investments for b) purifying the composition from step (a), achieving the same production capacity. In addition, a con c) drying the composition from step (b). tinuous operation allows for less varying quality of the prod 0029. The purification of the composition from step a) uct. While desirable, a continuous system is more compli includes further desalination of the contrast agent and cated to design and highly specific to one single product. We removal of other impurities, and may include the use of ion have however found that the synthesis of the contrast agent, exchange treatment, treatment with charcoal, and/or desali and the Subsequent desalination of the composition compris nation by EDI, preferably using a wafer based EDI device, ing the contrast agent, can be performed in a continuous according to the process of the invention. mode. The contrast agent is preferably an iodinated X-ray 0030. In yet another embodiment of the invention, the compound and the primary production of Such would hence composition comprising a contrast agent Subjected to the include a multi step chemical synthesis including e.g. iodina desalinating process is a side stream or waste stream from the tion and alkylation and/or dimerisation step, followed by the process of preparing a contrast agent, and this composition desalination process of the invention, performed in a continu typically comprises minor amounts of the contrastagent, Such ous mode. Alternatively, the contrast agent is an MM contrast as less than 10%, even less than 1%. By desalinating and agent. In one embodiment, some steps of the process for purifying Such side stream or waste stream this can go to preparing a contrast agent are batch wise, while other are proper waste disposal. By separating out e.g. salts from included in a continuous mode. In another embodiment. Such remains of the main product (contrastagent), intermediates or continuous process includes the process of the invention, i.e. byproducts, these can be sent to recycling of e.g. iodine. desalinating the crude composition comprising the contrast agent, and in addition including some or all of the following 0031. By using the process of the invention the salt content steps necessary to purify the contrast agent before secondary of the composition after the process has been conducted, is production. Such following steps e.g. include filtration of the less than about 1.0%, more preferably less than 0.7 weight%, contrast agent after crystallization, Solving this in water, puri or even less than 0.6 weight%, compared to the contrastagent fying by e.g. ion exchange, treatment with charcoal, ED and/ content. In a preferred embodiment, the salt content in the or EDI, and evaporation, to obtain a pure contrast agent. The composition comprising iodixanol is less than about 0.7 instant continuous process gives significant benefits in weight %, or even less than 0.6 weight %, compared to the reduced cycle times, reduced amount of equipment required iodixanol content. In another preferred embodiment, the salt in a production line, reduced headcount and a stabilized pro content in the composition comprising iohexol is less than cess with resulting consistent product quality in terms of about 0.02 weight%, or even 0.01% or less, compared to the yield, impurity profile and physical characteristics of the iohexol content. The salts generated in the preparation of product. iohexoland iodixanol are mainly NaCl, but other salts such as acetates and formiates, e.g. in the form of sodium acetates and 0034. The invention is illustrated further by the following formiates, could equally well be removed according to the examples that are not to be construed as limiting the invention process of the invention. in scope to the specific procedures described in them. US 2013/0277221 A1 Oct. 24, 2013

EXAMPLES selected from a non-ionic iodinated monomeric compound and a non-ionic iodinated dimeric compound. Example 1 3. A process as claimed in any of claims 1 to 3 wherein the contrast agent is selected from iohexol, iodixanol and Preparation and purification of iodixanol ioforminol. 0035 5-Acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4, 4. A process as claimed in any of claims 1 to 3 wherein the 6-triiodoisophthalamide (Compound A) (600 kg) is reacted electrodeionization step takes place before or after the con with epichlorohydrin (0.33 eq) in an alcoholic solvent in the trast agent is crystallized. presence of sodium hydroxide at a pH of about 11.9 at 15° C. 5. A process as claimed in any of claims 1 to 4 wherein the About 55% conversion to iodixanol is obtained. Most of contrast agent is iohexol, the process comprising the step of unreacted Compound A is precipitated from the reaction mix desalinating a crude composition comprising iohexolby elec ture by addition of hydrochloric acid followed by filtration. trodeionization using a wafer based EDI device, including the The aqueous filtrate contains about 340 kg iodixanol, 100 kg sequential steps of: Compound A and 20 kg iohexol. The pH is measured to about (1) reducing the salt content in a crude composition which 4-6. The NaCl content is about 12-14 w/w % relative to is the reaction mixture comprising Compound A, salts iodixanol. The solution is then subjected to a membrane fil and iohexol, by EDI: tration or an electro dialysis followed by electrodeionization (2) crystallizing iohexol from the composition of step (1). using a wafer based EDI, for salt removal and for separating 6. A process as claimed in any of claims 1 to 4 wherein the out Compound A, resulting in an aqueous process Solution contrast agent is iodixanol, the process comprising the step of ready for the next process including the crystallization step. desalinating a crude composition comprising iodixanol by electrodeionization using a wafer based EDI device, includ Example 2 ing the sequential steps of (1) reducing the salt content in a crude composition which Preparation and Purification of Iohexol is the reaction mixture comprising Compound A, salts 0036. After alkylation of “Compound A with 3-chloro-1, and iodixanol, by EDI; 2-propanediol in an alcoholic Solvent in the presence of (2) recovering Compound A in the composition of (1) after sodium hydroxide, and termination of the reaction with desalination, for reuse in a Subsequent dimerisation hydrochloric acid, the following crude reaction mixture is reaction to prepare iodixanol; and obtained: An about 40 w/v solution of iohexol (about 99 area (3) crystallizing iodixanol from the composition of step % purity by HPLC) in an alcoholic solvent containing about (1). 3 w/w % NaCl (3 g NaCl/100 giohexol) and traces of unre 7. A process as claimed in any of claims 4 to 6, wherein the acted 3-chloro-1,2-propanediol and traces of sodium acetate. crystallized contrast agent, is subjected to the additional bulk The solution is then subjected to ED followed by wafer based treatment steps of EDI, resulting in an aqueous process Solution ready for the a) Solving the crystallized contrast agent in water, next process including the crystallization step. b) purifying the composition from step (a), c) drying the composition from step (b). Example 3 8. A process as claimed in claim 7 wherein the purification Bulk Treatment of Crystallized Iohexol step b) includes removal of salts by electrodeionization. 9. A process as claimed in any of the claims 1 to 8 wherein 0037. After crystallization of iohexol, the crystallized the salt content in the composition after the process has been product is solved in water (ca. 40 w/v '% iohexol). The last conducted is less than about 1.0%, compared to the contrast remaining salt is removed in this bulk treatment step (polish agent content. ing step). To obtain a salt content of 0.01 w/w %, or lower 10. A process as claimed in claim 9 wherein the salt content compared to iohexol content, the Solution is Subjected to of the composition comprising iodixanol is less than about 0.7 wafer based EDI. After this bulk treatment the composition is weight 96 compared to the iodixanol content. Subjected to bulk concentrating and drying. 11. A process as claimed in claim 9 wherein the salt content of the composition comprising iohexol is less than about 0.02 Example 4 weight% compared to the iohexol content. 12. A process as claimed in any of claims 1 to 11 wherein DTPA-BMA Synthesis and Purification the process is included in a continuous process for preparing 0038. DTPA bis(anhydride) is reacted with an excess an X-ray contrast agent. methylamine (3 equivalents) to prepare DTPA-BMA and the 13. A process as claimed in any of claims 1 to 12 wherein pH is adjusted to about pH 3. Before complexing the chelator the process is combined with additional purification and/or with gadolinium, the obtained solution is subjected to elec desalinating by a method selected from filtrations, ion trodeionization by using a wafer based EDI for removal of exchange and electrodialysis (ED). methylamine hydrochloride. 14. A process as claimed in claim 13 wherein the process We claim: includes additional desalinating by ED in a separate step 1. A process for the preparation of a composition compris before or after the EDI step. ing a contrast agent in a carrier, the process comprising the 15. A process as claimed in any of claims 1 to 14 wherein step of desalinating the composition by electrodeionization the composition comprising the contrast agent Subjected to (EDI) using a wafer based EDI device. desalinating is a side stream or waste stream from a process of 2. A process as claimed in claim 1 wherein the contrast preparing the contrast agent, the composition comprising agent is an MR contrast agent or an X-ray contrast agent minor amounts of the contrast agent. US 2013/0277221 A1 Oct. 24, 2013

16. A process as claimed in any of claims 1 to 14 wherein the EDI device used comprises ion exchange resins, mem branes and means for applying a DC voltage, wherein the ion exchange resins are moulded into a porous wafer. k k k k k