REVERSED PHASE CHROMATOGRAPHIC PROCESS

Abstract: A process for the reversed phase chromatographic decolorisation, separation and purification of water-soluble nonionic contrast media compounds from solutions containing nonionic compound impurities is described. A solution containing the contrast media compound and impurities is passed through a chromatographic column, the column is eluted to produce primary eluate, and a solvent is passed through the column. The solvent is removed from the mixture thus formed leaving an aqueous solution which concentrated and nonionic constrast media compound is recovered from the aqueous solution.

Description: "Reversed Phase Chromatographic Process" Background of the Invention This invention relates to a process for the reversed phase chromatographic decolorisation, separationandpurification of water-soluble nonionic contrast media compounds from solutions containing nonionic compound impurities. A process of this type is described in WO 91/12868A. While this process is very successful for maximum manufacturing efficiency, there is a need to optimise the yield of the nonionic contrast media compound. Summary of the Invention The object of the invention, therefore, is to provide an improved factory scale process for the decolorization, reversed phase chromatographic separation and purification of water-soluble, nonionic contrast media compounds inwhich the yield of the desired contrast media compound is maximised. According to the invention there is provided a process for the reversedphase chromatographic decolorisation, separation and purification of water-soluble nonionic contrast media compounds from solutions containing nonionic compound impurities comprising the steps of:- passing a solution containing a water-soluble, nonionic contrast media compound and nonionic compounds as impurities through a chromatographic packing material in a chromatographic column; and eluting said column to produce primary eluate containing substantiallypure, water-soluble, nonionic contrastmedia compound; passing a solvent through said column to wash the chromatographic packing material and form a mixture comprising solvent, nonionic contrast media compound and, as impurities, nonionic compounds; removing the solvent from the mixture to leave an aqueous solution containing contrast media compound and impurities; concentrating the aqueous solution to increase the concentration of the nonionic contrast media compound; removing at least some of the nonionic compound impurities from the concentrated aqueous solution; and recovering the nonionic contrast media compound from the concentrated aqueous solution. In a preferred embodiment of the invention, the solvent which has passed through said column is removed by:- distilling said mixture to provide a distillate of substantially pure solvent and a bottoms product comprising the aqueous solution containing the nonionic contrast media compound and nonionic compounds as impurities. In this case preferably at least some of the nonionic compound impurities are removed from the said bottoms product by:- concentrating the bottoms product; crystallising said impurities; and filtering said bottoms product containing impurities to remove the crystallised impurities as a filter cake and to provide a filtrate containing the nonionic contrast media compound. Advantageously, the nonionic contrast media compound is recovered from the filtrate by:- passing the filtrate through a chromatographic column to form a tertiaryeluate containing nonionic contrast media compound. Typically, said tertiary eluate is concentrated by evaporation to form a concentrated tertiary eluate. Preferably, the tertiary eluate is concentrated undervacuum in order to minimise any potential for thermal degradation. In a preferred embodiment of the invention, said concentrated tertiary eluate is mixed with primary and/or secondary eluate from the main process and the combined eluate is purified and dried to produce a nonionic contrast media compound. Preferably, the solvent is a lower alkanol, especially methanol. The novel process of the present invention is applicable to the general decolorization and separation of nonionic compound impurities from water-soluble, nonionic contrast media compounds, nonionic nuclear diagnostic imaging compounds or alternatively, MRI agents. The nonionic contract media compounds include x-ray contract media compounds such as N,N'-bis(2, 3-dihydroxypropyl ) -5-(N- (2- hydroxyethyl ) glycol amido] -2 , 4 , 6-triiodo-isophthala- mide(ioversol) , N,N' -bis ( 2 , 3 -dihydroxypropyl ) -5- [N-( 2 , 3- di hydroxypropyl )acetamido]-2,4 , 6-triiodoisophthal- amide ( iohexol ) , N,N' -bis ( 1 , 3-dihydroxypropyl ) -5-lactylamido- 2,4, 6-triiodoisophthalamide( iopamidol ) , 2 [ 3-acetamido-2 ,4,6- triiodo-5- (N-methylacetamido) benzamido]-2-deoxy-D- glucose (metrazamide) , N,N'-bis(2,3-hydroxy- propyl ) -2,4, 6- triiodo-5-(2-keto-L-gulonamido) isophthalimide( iogulamide) , 5, 5 '-[malonylbis[ ( 2-hydroxy-ethyl) imino] ]bis[N,N'-bis[2- hydroxy-l- ( hydroxymethylethyl ] -2 , 4 , 6- triiodoisophthalamide ( iodecimol ) 5 , 5 ' - [ ( 2 - hydro xytrimethylene) bis (acetyl imino) ]bis [N,N'-bis (2,3- di hydroxypropyl ) -2 , 4 , 6-triiodoisophthalamide ( iodixanol ) , 3- [ N- ( 2-hydroxyethyl ) acetamido ] -2 , 4 , 6-triiodo-5- {methylcarbamoyl ) -D-glucoanil ide ( ioglucol ) , N , N ' -bis (2,3- dihydroxypropyl ) -2 , 4 , 6-triiodo-5- ( N-methylglycolamido ) isophthalamide(iomeprol) , N,N'-bis(2,3-dihydroxypropyl)-5- [N-( 2-hydroxy-3-methoxypropyl)acetamido]-2,4 ,6- triiodoisophthalamide ( iopentol ) , N, N ' -bis ( 2 , 3-dihydroxy- propyl ) 2 , 4 , 6-triiodo-5- ( 2 -methoxyacetamido ) -N- methylisophthal-amide(iopromide) , 3,5-diacetamido-2,4 , 6- triiodo-N-methyl-Nt [methyl (D-gluco2, 3,4-5,6- pentahydroxyhexyl ) carbamoyl ] methyl ] benzamide ( iosarcol ) , , N , N ' , N ' , N " , N " -hexakis ( 2 -hydroxyethyl ) -2 , 4 , 6-triiodo-l , 3 , 5- benzenetricarboxamide(iosimide, 5,5' [thi- obis ( ethylenecarbonyl imino ) ] bis [ N , N-bis ( 2 , 3-dihydroxypropyl ) - 2 ,4 ,6-triiodo-N,N'-dimethylisophthalamide (iotasul), and 5,5' - (malonylbis ( methyl imino ) ] bis [ N , N ' -bis [ 2 , 3-dihydroxy- 1 (hydroxy-methyl ) propyl ]-2 , 4 , 6 -triiodoi soph thai am ide ( iotrolan) . As used herein, the term "nonionic contrast media compounds" includes, and the present invention is applicable to, nonionic magnetic resonance imaging (MRI) agent ligands and neutral (or nonionic) metal complexes of their ligands with suitable metals from the first, second, or third row transition elements or the lanthanide or actinide series. Typical ligands include N, N" -bis [ N- ( 2 , 3- dihydroxypropyl)carbamoylmethyl]diethylenetriamine- ,N' ,N"- triacetic acid, N,N'-bis[N-(2, 3-dihydroxypropyl) carbamoylmethyl]ethylene-diamine-N,N'-diacetic acid, N,N'"- bis[N-(2-hydroxyethyl)carbamoylmethyl] triethylenetetraamine- N,N' ,N",N' "-tetraaceticacid, N,N"-bis[N-(1-hydroxymethyl- 2,3-dihydroxypropyl) car-bamoylmethyl]diethylenetriamine- N,N' ,N"-triaacetic acid and N,N' -bis [N- ( 2- hydroxyethyl)carbamoylmethyl] ethylenediamine-N,N'-diacetic acid. Examples of various other complexes, nonionic contrast media compounds and MRI agents which may be purified through the process of the invention are known to those skilled in the art. In one particular embodiment of the invention, the contrast media compound is the nonionic X-ray contrast media compound N , N ' -bis ( 2 , 3-dihydroxypropyl ) -5- [ N- ( 2- hydroxyethyl)glycolamido]-2,4,6-triiodoisophthaiamide (loversol) described in US 4,396,598. Description of the Drawings The invention will be more clearly understood from the following description thereof, given byway of example only, in which:- Fig.1 is a schematic flow diagram of an improved recovery process according to the invention; and Fig . 2 is a flowchart of some details of the process Description of Preferred Embodiment It has been found that the process described in WO 91/12868A may be further improved by extracting the relatively small but significant amount of nonionic contrast medium compound remaining on the column packing and recovering the nonionic contrast medium compound. In the improved factory scale process of the invention illustrated in Fig. 1, the first step is decolorisation 1 followed by deionisation 2 and evaporation 3. After evaporation, the nonionic contrast medium compound is purified in step 4, concentrated by evaporation in step 5 and dried in step 6 to provide a finished nonionic contrast medium product 7. In the purification process, methanol delivered along line 10 is used to wash the chromatographic purification columns and the mixture containing methanol and nonionic contrast media compound from the column packing is delivered along a line 11 to a solvent recovery still 12. The substantially pure methanol distillate from the recovery still 12 is recycled along line 13 to the main methanol intake 10 and bottoms product 14 from the methanol recovery still 12 is delivered to a nonionic contrast medium recovery process 15 which is described in more detail below. Waste material from the recovery process may be deiodinated at 40 prior to waste treatment 41. Nonionic contrast medium recovered in the recovery process 15 is recycled along line 16 for combining with a primary and/or secondary eluate stream either after deionisation as illustrated or before deionisation. The bottoms product 14 is an aqueous solution containing the nonionic contrast media compound and nonionic compounds as impurities. In more detail, and referring to Fig. 2, the bottoms product 14 from the methanol still 12 is pumped by a pump 20 to a vessel 21 in which the bottoms are concentrated and impurities are crystallised. Tops product 17 from the still 12 is condensed in a condenser 18, the condensate being collected in a receiver 19 and gases being discharged to vent V. A stream 25 containing concentrated bottoms product and crystallised impurities is then pumped to a filter 27 in which the solids impurities are filtered out in the form of a filter cake 28A, with the filtrate 28B containing the nonionic contrast medium passing into a holding tank 29. From the holding tank 29, the filtrate is delivered by a pump 32 for purification by reverse phase chromatography in a chromatographic column 30 using the techniques described in WO 91/12868A. Tertiary eluent from the column 30 is delivered into a holding tank 33 and then pumped by a pump 34 to an evaporator 35 in which the tertiary eluent is concentrated under vacuum to form a concentrate 36 which may be combined in a tank 37 with primary and secondary eluent 38 from the primary process described above. Alternatively, as illustrated by the interrupted line 38a in Fig. 1, the tertiary eluate may be combined with the secondary eluent prior to evaporation 35. We have found that using the improved process of the invention has increased the yield of nonionic contrast medium by up to 3% per batch resulting in very significant improvements in productivity while minimising waste. EXAMPLE 1 The process outlined in Example 3 of WO 91/12868 was carried out. When the last purification column regeneration operation from the process described in WO 91/12868 was completed, the methanol recovery operation was continued until the methanol levels in the still bottoms were <3% w/v. The still bottoms solution was then tested for density, transferred to a 630 lt glass lined reactor, agitated and maintained at 40°C. The reactor was then placed under a vacuum of ca. 0.15 barA and the temperature of the reactor contents were then brought up slowly to the solution boiling point of ca. 55-70°C As water was evaporated from the solution, the solubility of impurity A decreased resulting in precipitation or crystallisation of the impurity. This concentration/crystallisation step was continued until the final required concentration of ca.50-70% w/w was achieved, as estimated from the solution density. Once the correct concentration was achieved, the reactor contents were cooled to <40°C. At this temperature vacuum was removed and cooling continued until the temperature was <20°C. The contents of the reactor were then agitated for 1 hour to enhance the crystallisation of impurity A. After this holding period the contents were pumped through a horizontal plate filter and the filtrate was collected in a hold tank. Impurity A, crystallised in the glass lined reactor, was removed on the filter plates resulting in a clear filtrate, with a much reduced impurity level passing to the next step. The filter cake was washed and the wash recycled to the glass lined concentration/crystallisation vessel for addition to the next batch. The filter was then blown dry with compressed air and the filter split to remove the filter cake. The plates were then cleaned and the filter unit made ready for the next batch. The filtrate from the above stepwas then purified by reverse phase chromatographic separation in a stainless steel column (610mm internal diameter x 996mm length) packed with approximately 155kgs of dry silanized chromatographic packing material, consisting of octadecylsilane bonded to solid silica particles ( 'ODS-Si' ) . The column bed was prepared by filling the column initiallywith ca. 150kgs of dry packing, while vibrating the column to ensure a uniform column bed. Approximately 790 Its of Methanol were then pumped through the column, followed by ca. 833 Its of Process Water. This process forces air from the packing material, compacting it to leave an empty space at the top of the column, which was then filled with additional fresh resin. The flushing procedure was then repeated and the column 'topped off again with this process repeated until there was no further compression of the packing material. The column holds a total of ca. 155 kgs of packing material when completely packed. The filtrate from the earlier filtration step was sampled for density and a calculation then performed using the volume of filtrate (based on tank level), the solution density and the purification loading ratio to determine the optimum number of runs required to effect separation of nonionic impurities A, B, C and D in the feed stream. The required volume of solution, containing approximately 30 kgs of Ioversol and containing nonionic impurities A, B, C - li ¬ ft D was pumped through a 0.2 micron filter onto the chromatographic column. The loading ratio of packaging material/total wt. nonionic compounds was approximately 7:1. Process water was then pumped through the column to elute the product. The first ca. 300 Its of effluent, or eluate, from the chromatographic column was directed to drain. On detection of product (density at the outlet of the column exceeds 1.005 for > 3 seconds or a maximum of 300 Its eluate is reached) the eluate is then redirected to a holding tank for collection. This fraction, which will be termed the Ioversol 3rd Crop, to differentiate it from the 1st and 2nd cuts already generated in the standard process described in W091/12868 contains ca. 85-95% of the purified Ioversol. The chromatographic column was then flushed with a mixture of methyl alcohol and water which contained at least 50% methyl alcohol to remove non ionic compound impurities from the column and regenerate the column packing for reuse. The column was then reequilibrated with process water before reuse in purifying subsequent batches containing Ioversol and nonionic impurities A, B, C and D. The 3rd crop chromatography fraction containing purified Ioversol was then concentrated on a single pass through a wiped film evaporator under a vacuum of ca. 0.28 barA to obtain a solution of ca. 3-6% concentration. This concentrated 3rd crop solution was then mixed with normal concentrated second cut material, with the composite material sampled to evaluate quality. On satisfactory review of the levels of nonionic impurities A, B, C and D in the 3rd crop and composite 3rd crop/2nd cut materials described above, the composite solution may then be recycled to a subsequent batch of crude, deionised Ioversol solution, for purification by reverse phase chromatographic separation as described in WO 91/12868. This process illustrates that the combined 3rd crop and second fraction materials may be further reprocessed by recycling into the original column feed provided sufficient overall quality is maintained. The process of the invention is applicable not only to Ioversol but also to the general decolorisation and separation of nonionic compound impurities from water¬ soluble, nonionic contrast media compounds in general, or MRI agents. Examples of such compounds and agents are given in WO 91/12868A. The invention is not limited to the embodiments hereinbefore described which may be varied in detail.

Claims: CLAIMS 1. A process for the reversed phase chromatographic decolorisation, separation and purification of water¬ soluble nonionic contrast media compounds from solutions containing nonionic compound impurities comprising the steps of:- passing a solution containing a water-soluble, nonionic contrast media compound and nonionic compounds as impurities through a chromatographic packing material in a chromatographic column; and eluting said column to produce primary eluate containing substantially pure, water-soluble, nonionic contrast media compound; passing a solvent through said column to wash the chromatographic packing material and form a mixture comprising solvent, nonionic contrast media compound and, as impurities, nonionic compounds; removing the solvent from the mixture to leave an aqueous solution containing contrast media compound and impurities; concentrating the aqueous solution to increase the concentration of the nonionic contrast media compound; removing at least some of the nonionic compound impurities from the concentrated aqueous solution; and recovering the nonionic contrast media compound from the concentrated aqueous solution. 2. A process as claimed in claim 1 wherein the solvent which has passed through said column is removed by:- distilling said mixture to provide a distillate of substantially pure solvent and a bottoms product comprising the aqueous solution containing the nonionic contrast media compound and nonionic compounds as impurities. 3. A process as claimed in claim 2 wherein at least some of the nonionic compound impurities are removed from the said bottoms product by:- concentrating the bottoms product; crystallising said impurities; and filtering said bottoms product containing impurities to remove the crystallised impurities as a filter cake and to provide a filtrate containing the nonionic contrast media compound. 4. A process as claimed in claim 3 wherein the nonionic contrast media compound is recovered from the filtrate by:- passing the filtrate through a chromatographic column to form a tertiary eluate containing nonionic contrast media compound. 5. A process as claimed in claim 4 wherein said tertiary eluate is concentrated by evaporation to form a concentrated tertiary eluate. 6. A process as claimed in claim 5 wherein said tertiary eluate is concentrated under vacuum. 7. A process as claimed in claim 5 or 6 wherein said concentrated eluate is mixed with primary and/or secondary eluate and the combined eluate is purified and dried to produce a nonionic contrast media compound. 8. A process as claimed in any preceding claim wherein the solvent is a lower alkanol. 9. A process as claimed in claim 8 wherein the solvent is methanol. 10. A process as claimed in any preceding claim wherein the contrast media compound is the nonionic X-ray contrast mediacompoundN, '-bis(2,3-dihydroxypropyl)-5-[N-(2- hydroxyethyl)glycolamido]-2,4,6-triiodoisophthalamide. 11. A process substantially as hereinbefore described with reference to the example and drawings. 12. Nonionic contrast media compounds whenever prepared by a process as claimed in any preceding claim.

Inventors: CAROLAN DOMINIC, COLLINS ELIZABETH, MULDOON STEPHEN, O'CALLAGHAN BRENDAN, CAROLAN, DOMINIC, COLLINS, ELIZABETH, MULDOON, STEPHEN, O'CALLAGHAN, BRENDAN
Applicants: CALLAGHAN BRENDAN O, CAROLAN DOMINIC, COLLINS ELIZABETH, MALLINCKRODT MED IMAGING IE, MULDOON STEPHEN, CAROLAN, DOMINIC, COLLINS, ELIZABETH, MALLINCKRODT MEDICAL IMAGING-IRELAND, MULDOON, STEPHEN, O'CALLAGHAN, BRENDAN
Application year: 1996
Main classification: B01D15
IPC codes: B01D15, C07C231, C07C237