WO1997020610A1

WO1997020610A1 - Reversed phase chromatographic process

Info

Publication number: WO1997020610A1
Application number: PCT/IE1996/000077
Authority: WO
Inventors: Elizabeth Collins; Conor Murphy; Brendan O'callaghan
Original assignee: Mallinckrodt Medical Imaging-Ireland
Priority date: 1995-12-01
Filing date: 1996-12-02
Publication date: 1997-06-12
Also published as: GB2321860A; EP0873169A1; GB9811571D0; NO982450L; AU7707196A; NO982450D0

Abstract

A factory scale process for the reversed phase chromatographic decolorisation, separation and purification of water-soluble nonionic contrast media compounds from solutions containing nonionic compound impurities includes the steps of passing a solution through a decoloriser chromatographic column (2) and eluting the decoloriser column (2) with solvent. The packing in the decoloriser column (2) is regenerated by passing a regenerating solvent (20) through the packing, purifying the solvent (21) in a solvent recovery plant (25) and recycling the solvent. Waste solvent (33) produced on regenerating a purification column used in a recovery process may also be recovered in the solvent recovery plant (25).

Description

"Reversed Phase Chromatographic Process"

Background of the Invention

This invention relates to a process for the reversed phase chromatographic decolorisation, separation andpurification of water-soluble nonionic contrast media compounds from solutions containing nonionic compound impurities.

A factory scale process of this type is described in WO 91/12868A. While this process is very successful, a large volume of solvent containing impurities is produced which presents a waste disposal problem.

Summary of the Invention

The object of the invention, therefore, is to provide an improved process for the decolorisation, reversed phase chromatographic separation and purification of water-soluble nonionic contrast media compounds on a factory scale in which the waste disposal of solvent is minimised.

According to the invention there is provided a process for the reversedphasechromatographic 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 decoloriser chromatographic column; and eluting said decoloriser column with an eluting solvent to produce a substantially decolorised solution of nonionic contrast media compound;

regenerating the packing in the decoloriser column by passing a regenerating solvent through the decoloriser column to remove coloured impurities from the chromatographic packing material of the column;

purifying the impurity-containing decoloriser regenerating solvent; and

recycling the purified decoloriser regenerating solvent.

In a preferred embodiment of the invention, the purified decoloriser regenerating solvent is recycled to provide at least a portion of the regenerating solvent for the decoloriser column.

Preferably, the decoloriser regenerating solvent is purified by distilling the regenerating solvent containing impurities to produce a distillate of substantially pure solvent. Typically, the substantially pure solvent is mixed with further fresh solvent.

In one embodiment of the invention, the process includes the steps of:-

passing a solvent through a purification chromatographic column to wash the column and form a mixture comprising solvent, nonionic contrast media compound and impurities; 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 this case, preferably the recovered regenerating solvent is recycled to provide at least a portion of the regenerating solvent for the purification recovery column.

Preferably 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.

Typically, the substantially pure solvent is mixed with further fresh solvent.

In one embodiment of the invention, the recovered regenerating solvent is mixed with the decoloriser regenerating solvent prior to purification. 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 contrast 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 ) acet amido] -2,4, 6-triio do isophthal- 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 - hydroxytrimethylene) bis (acetyl imino) ]bis[N,N'-bis(2,3- dihydroxypropyl ) -2 , 4 , 6-triiodoisophthalamide ( iodixanol ) , 3- [ N- ( 2-hydroxyethyl ) acetamido ] -2 , 4 , 6-triiodo-5- (methylcarbamoyl)-D-glucoanilide( 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- methyl isophthalamide( iopro ide) , 3 , 5-diacetamido-2, 4 ,6- triiodo-N-methyl- [ [methyl ( D-gluco2 , 3 , 4-5 , 6 - pentahydroxyhexyl ) carbamoyl Jmethyl ]benzamide( iosarcol ) , N,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 (methylimino ) ] bis [ N , N ' -bis [ 2 , 3-dihydroxy- 1 (hydroxy-methyl ) propyl ] -2 , 4 , 6-triiodoisophthalamide

( 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 - dihydroxypropy 1 ) carbamoy Imethyl ] diethylenetr iamine-N , N ' , N " - triacetic acid, N,N'-bis[N-( 2 , 3-dihydroxypropyl ) carbamoylmethyl]ethylene-diamine-N,N'-diacetic acid, N,N'"- bis [ N- ( 2 -hydroxyethyl ) carbamoy Imethyl ] triethylenetet raamine- N,N' ,N" ,N' "-tetraacetic acid, N,N"-bis[N-( 1-hydroxymethyl- 2 , 3-dihydroxypropyl ) car-bamoy Imethyl ] diethylenetr iamine- N,N' ,N"-triaacetic acid and N , N ' -bis [ N- ( 2- hydroxyethyl ) carbamoy Imethyl ] ethylenediamine-N , N ' -diacet ic 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 by way 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 on a factory scale by purifying the decoloriser regenerating solvent, and recycling the regenerating decoloriser column solvent to provide at least a portion of the regenerating solvent for the decoloriser column.

In the improved factory scale process of the invention illustrated in Fig. 1, the first step is hydrolysis 1, followed by decolorisation 2, deionisation 3 and evaporation 4. After evaporation, the nonionic contrast media compound is purified in step 5, concentrated in a two stage evaporation process in steps 6a and 6b and dried in step 7 to provide a finished nonionic contrast medium product 8.

In the process of the invention, methanol is used as the solvent. Methanol from the purification step 5 is delivered along line 13 to a primary methanol recovery plant 12 and the recovered methanol is recycled, typically either along line 14 to the purification column 5 or along line 14a for use in regenerating the decoloriser column 2. In the factory scale process of the invention, the packing in the decoloriser column 2 is regenerated by washing with a methanol wash stream 20 and waste methanol 21 from the regeneration of the decoloriser column 2 is recovered in a methanol recovery plant 25 which will be described in more detail below. The methanol recovered in the methanol recovery plant 25 is delivered along a line 26 for use as a regenerating solvent for the decoloriser column 2.

A waste stream 30 from the primary methanol recovery plant 12 contains some nonionic contrast medium compound which is recovered in a recovery process 31 as described in our co¬ pending application filed simultaneously with this application. Waste material from the recovery plant 31 is deiodinated at 42 prior to waste treatment 45. As part of the recovery process 31, a purification column is regenerated using a methanol stream 32 and waste methanol 33 from the recovery process 31 is also passed to the methanol recovery plant 25. The purified methanol from this stream is recycled along line 34 to provide solvent for use in regenerating the purification column used in the recovery process 31.

The methanol recovery plant 25 is shown in more detail in Fig. 2. Waste methanol 21,33 from the decoloriser column 2 and/or from the recovery process 31 is delivered into a holding tank 35. From the tank 35, the methanol is pumped by a pump 36 to a continuous distillation column 37 for recovery.

The system is inerted at startup and remains under a constant blanket of nitrogen during operation. The bottom 38 of the column 37 acts as a sump to collect the still bottoms and provide a head of liquid for a still bottoms recirculation pump 39. The still bottoms are heated by forced circulation through a shell and tube heat exchanger 40. Typically, the shell and tube heat exchanger 40 uses process steam reduced to 3 to 4 Bar to heat the still bottoms.

The still bottoms are intermittently pumped out by the pump 39 to a bottoms hold tank 41. The still bottoms are transferred from the holding tank 41 to a deiodinator 42 using a bottoms transfer pump 43. After deiodination, the still bottoms may be released to waste treatment 45.

Methanol vapours generated in the distillation column 37 are condensed in an overhead condenser 50 using process cooling water supply. The condensed methanol then passes through an in-line UV detector 51 which checks for iodinated compounds in the condensed methanol. If the UV detector 51 detects the presence of iodinated compounds the distillation column 37 is put into total reflux until the distillate is clear. The condensed methanol is collected in a reflux pot 52. A forced reflux system with pump 53 and control valve (not shown) is used to ensure that the desired reflux ratio of from 1:1 to 10:1, especially 2:1 to 4:1 is maintained at all times.

The remaining distillate will overflow under gravity from the reflux pot and pass through a plate and frame heat exchanger 55 where it is subcooled using process refrigerated water supply. The subcooled distillate is then collected in the distillate receiver 56. From the distillate receiver 56 methanol is fed back to the decoloriser 2 and third crop purification column using a distillate transfer pump 57. The distillate receiver 56 also has a make-up facility to add virgin methanol 59.

Vent lines from the condenser 50, the reflux pot 52, the bottoms holding tank 41 and the distillate receiver 56 are all part of a common venting system which passes through a vent condenser prior to venting to atmosphere through a flame arrestor and conservation vent. The vent condenser uses process refrigeratedwater to condense any remainingvapours in the system to minimise emissions.

EXAMPLE 1

A mixture of waste methanol from the regeneration of the Ioversol decolorisation and 3rd crop recoverychromatographic separation columns was collected in a 23,000 It carbon steel collection tank. The coloured waste solvent contains ca 80% v/v methanol, with approximately 15% v/v water and 3- 5% w/w nonionic organic compounds, as impurities. This waste solvent stream was fed to a continuous distillation column, containing the equivalent of approximately 10 theoretical separation stages at a rate of ca 500 It/hour. The feed stream was fed to the mid-point of the column, initially collecting in a sump at the bottom of the column, from where it was pumped, under forced recirculation, through a steam heated reboiler, to raise the temperature of the stream to it's boiling point. As the temperature increased, the distillation column served to separate the methanol solvent from it's impurities by fractional distillation. The methanol was distilled overhead and condensed in a stainless steel heat exchanger fed by plant cooling water at ca 20-25 Deg C. The distillate from this condenser, containing less than 2% water, was then passed through an in-line UV analyser to monitor for iodinated compounds (impurities in the recovered solvent stream) . This distillate stream was then collected in a reflux pot, with part of the stream pumped back to the top of the fractionation column as reflux, to improve the efficiency of component separation in the column. If an undesired level of iodinated impurities were detected in the distillate stream by the in line UV detector, the entire distillate stream was refluxed back to the distillation column until the system returned to satisfactory performance. In this way, gross contamination of the recovered solvent stream was avoided. Under normal processing, the balance of the distillate simply overflowed the reflux pot to a subcooler, where it was further cooled by plant refrigerated water supply at 5-10 Deg C and collected in a holding tank, for analysis and recycle to the process. The solvent collected in this way can, on satisfactory evaluation of quality parameters, be utilised for subsequent regenerations of the chromatographic packing materials used in the plant's purification systems. Fresh methanol solvent may also be added to the recovered solvent in this tank, to supplement the volume of solvent available for such regenerations. The recovered solvent was analysed and typically contained less than 5% water and less than 100 ppm iodinated compounds as impurities.

As the distillation proceeded, the bottoms stream was continually recycled to the steam fed reboiler to provide the heat input to drive the distillation. As the degree of separation across the fractionation column increased, this bottoms stream became increasingly lean in Methanol and increasingly rich in water and coloured, nonionic organic impurities which were present in the feed stream. When the concentration of methanol in this stream had fallen below the specified level of 1.5% (approximately), a quantity of this waste stream was purged from the system and collected in a

Still Bottoms hold tank for subsequent deiodination and/or other prescribed treatment. The hold tank provides 'buffer' capacity to enable the distillation column to operate continuously, independent of other process operations. This recovery operation allows recovery of ca 95% of the waste methanol collected from the regeneration of the decoloriser and 3rd crop chromatographic packing materials as described in WO 91/12868 and significantly reduces the volume of fresh methanol required to support plant operations on a factory scale, while, advantageously, minimising the loading for waste water treatment.

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

1. A process for the reversed phase chromatographic decolorisation, separation and purification of water- soluble nonionic contrastmediacompounds 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 packingmaterial in a decoloriser chromatographic column; and

eluting said decoloriser column with an eluting solvent to produce a substantially decolorised solution of nonionic contrast media compound;

purifying the impurity-containing decoloriser regenerating solvent; and

recycling the purified decoloriser regenerating solvent.

2. A process as claimed in claim 1 wherein the purified decoloriser regenerating solvent is recycled to provide at least a portion of the regenerating solvent for the decoloriser column.

3. A process as claimed in claim 1 or 2 wherein the decoloriser regenerating solvent is purified by distilling the regenerating solvent containing impurities to produce a distillate of substantially pure solvent.

4. A process as claimed in claim 3 wherein the substantially pure solvent is mixed with further fresh solvent.

5. A process as claimed in any preceding claim including the steps of:-

passing a solvent through a purification chromatographic column to wash the column and form a mixture comprising solvent, nonionic contrast media compound and impurities;

removing the solvent from the mixture to leave an aqueous solution containing contrast media compound and impurities;

6. A process as claimed in claim 5 wherein the purified recovered regenerating solvent is recycled to provide at least a portion of the regenerating solvent for the purification recovery column.

7. A process as claimed in claim 5 or 6 wherein the solvent which has passed through said column is removed by:-

distilling saidmixture 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.

8. A process as claimed in claim 7 wherein the substantially pure solvent is mixed with further fresh solvent.

9. A process as claimed in any of claims 5 to 8 wherein the recovered regenerating solvent is mixed with the decoloriser regenerating solvent prior to purification.

10. A process as claimed in any preceding claim wherein the solvent is a lower alkanol.

11. A process as claimed in claim 10 wherein the solvent is methanol.

12. A process as claimed in any preceding claim wherein the contrast media compound is the nonionic X-ray contrast mediacompoundN,N'-bis(2,3-dihydroxypropyl)-5-[N-(2- hydroxyethyl)glycolamido]-2,4,6-triiodoisophthalamide.

13. A process substantially as hereinbefore described with reference to the example and drawings.

14. Nonionic contrast media compounds whenever prepared by a process as claimed in any preceding claim.