FORM 2THE PATENT ACT 1970(39 of 1970)&
The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
PROCESS FOR THE PREPARATION OF PURE IOVERSOL
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.(b) NATIONALITY: INDIAN(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a process for the preparation of pure iodinated
X-ray contrast agents. More particularly this invention provides a process for
the preparation of pure loversol.
The following specification particularly describes the invention and the manner
in which it is to be performed.
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4. DESCRIPTION
The present invention provides a process for the preparation of pure iodinated X-
ray contrast agents. More particularly this invention provides a process for the preparation of pure loversol.
Chemically, ioversol is N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-glycolamido]-2,4,6-triiodo isophthalamide having the structure as per formula I. loversol is commonly used as an X-ray contrast agent. The agent may be used in various radiographic procedures including those involving cardiography, coronary arteriography, aortography, cerebral and peripheral angiography, arthroglraphy, intravenous pyelography and urography as well as myelograpihy.

U.S. Patent No. 4,396,598 disclosed the loversol, as a useful nonionic x-ray contrast agent.
U.S. Patent No. 5,204,005 provided the process for the reversed phase chromatographic decolorization, separation, and purification of water-soluble, nonionic contrast media compounds from solutions containing nonionic compound impurities, said solutions having been treated for removal of ionic impurities.
U.S. Patent Nos. 5,160,437 and 5,221,485 provided a method for the purification of crude nonionic x-ray contrast agents selected from the group consisting of loversol comprising the steps of passing said crude agent into a housing cartridge.
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U.S. Patent Nos. 5,210,300 provided a method for the purification of crude loversol by passing said crude loversol through a mixed- resin bed.
U.S. patent No. 6,500,341 provided a process for the purification of water-soluble non-ionic contrast agents from water-soluble non-ionic impurities by column chromatography using non-ionic resins.
U.S. Patent Nos. 4,997,983, 5,489,708, 5,177,261, 5,371,278, 6,596,904, 5,396,003, 5,663,432, 5,648,536, 5,840,967, 6,232,499, 6,337,422, 5,866,100, US patent application 2004-082811 and US patent application 2005-036946 provides several other processes of preparation and purification of loversol.
The present inventors have developed a process for the preparation of pure ioversol. The process involves the removal of salts and lower molecular weight impurities of ioversol by the resin treatment. The salts were removed by eluting the column with water followed by removing impurities by elution with the alcohol or alcohol-water mixture, loversol obtained above is recrystallised by alcohol to improve the purity.
In one of the aspect of the present invention there is provided a process for purification of ioversol wherein the said process includes steps of,
a) passing the crude ioversol through the bed of non-ionic resin,
b) eluting the column with the solvent,
c) isolating the pure ioversol from the reaction mass thereof.
In yet another aspect of the present invention there is provided a process for purification of loversol from alcohol.
The process of present invention is related to a process of purification of ioversol. loversol is eluted initially with water followed by mixture of alcohol and water over non-ionic resin (Amberiyte XAD-16). The impurities and unreacted chloroioversol adsorbed on column is then eluted with alcohol.
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The ioversol obtained above is recrystallised by refluxing in alcohol to get the purity
99% or more when measured by HPLC with less than 0.5 N,N'-bis (2,3-dihydroxypropyl) -5-glycolamido -2,4,6-triiodoisopthalamide impurity (hereafter referred as glycolamido impurity).
The examples of alcohol include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like.
The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example-1
Purification of Ioversol
The crude ioversol (100 gm) was loaded on column packed with Amberlyte XAD-
16 resin and was eluted with water. The ioversol was eluted with 30-40%
Methanol/Water solvent mixture. The impurities and unreacted chloroioversol
adsorbed on column was eluted with methanol. The solvent was concentrated to
dryness.
The n-butanol (2 Litre) is added to the mass and refluxed for two hours. The pure
ioversol was filtered at 50°C, washed and dried.
Yield 50 gm.
Purity : 99.40 % (by HPLC)
Glycolamido impurity : 0.1%
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WE CLAIM:
1. A process for purification of ioversol wherein the said process comprising,
a) passing the crude ioversol through the bed of non-ionic resin
b) eluting the column with the solvent.
c) Isolating the pure ioversol from the reaction mass thereof.

2. A process of claim 1 wherein the non-ionic resin is Amberlyte XAD-16.
3. A process of claim 1 wherein the solvent is used for removing of salts and impurities.
4. A process of claim 3, wherein the solvent used for removing of salts is water.
5. A process of claim 3, wherein the solvent used for removing of impurities is alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like or alcohol-water mixture thereof.
6. A process for purification of loversol from alcohol.
7. A process of claim 6, wherein the alcohol used is such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like or mixture thereof.
9. The loversol having the purity of 99.0 % and more containing the glyoolamido impurity less than 0.5 %.
Dated this 26th day of Feb, 2007. For Wockhardt Limited
WHSLKU
(MandaifKodgule) Authorized Signatory
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