Indian Patents. 230837:''A COMPOUND OF FORMULA 5-AMINO-2, 4, 6-TRIIODO-N, N'-BIS (2, 3-DIHYDROXYPROPYL)-ISOPHTHALAMIDE IN ITS YELLOW POLYMORPHIC FORM''

Title of Invention	''A COMPOUND OF FORMULA 5-AMINO-2, 4, 6-TRIIODO-N, N'-BIS (2, 3-DIHYDROXYPROPYL)-ISOPHTHALAMIDE IN ITS YELLOW POLYMORPHIC FORM''
Abstract	This yellow polymorph of 5-amino-2, 4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl)-isophthalamide is described.

Full Text	The present invention relates a compound 5-Amino-2,4,6 -triiodo-N,N' -bis(2, 3-dihydroxypropyl) isophthalamide, (hereinafter called "Compound A") and in particular to the yellow polymorphic form of compound 'A'a a key intermediate in the preparation of non-ionic X-ray contrast agents such as iohexol,iopentol, iodixanol, ioversol and iomeprol. Compound A is available commercially, in a white form for instance from Fuji Chemical Industries, Ltd. The preparation of compound A in a white form is disclosed for example in W095/35122 (Mallinckrodt), eg. on page 6 thereof. Other publications, eg. Haavaldsen et al. in Acta Pharm. Suec. 20: 219-232 (1983), describe the preparation of compound A in a way in which the white form of compound A is produced. Compound A however has now' been found to exist in two polymorphic forms, a white form and a yellow form. Polymorphism is a solid state phenomenon associated with the structure of the solid; different polymorphs of the same compound, appear to involve different packings of the molecules within the solids. We have now found that in large scale production of compound A the yellow polymorphic form has advantages over the white polymorphic form in terms of efficiency of the crystallisation, filtration and drying steps. In any large scale multistep synthetic production of a chemical drug substance, increased efficiency in any of the synthetic steps is reflected by increased efficiency of the overall process. The white and yellow polymorphs of compound A have different infrared spectra and have characteristically different powder X-ray diffraction patterns. They may also be distinguished from each other by DSC and by colour assessment. Thus in particular the white polymorph is DSC has a peak melting temperature at about 193-196°C, while the yellow polymorph has a peak melting temperature in the range of about 247 to 252°C. Moreover the white polymorph is characterised over the yellow polymorph by having a sharp peak in the ir spectrum at 999cm-1 According to the present invention there is provided a compound of formula 5-amino-2, 4, 6-triiodo-N, N1 -bis (2, 3-dihydroxypropyl)-isophthalamide in its yellow polymorphic form. Thus in one aspect the invention provides 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalaraide in its yellow polymorphic form. In another aspect the invention provides 5-amino-2,4, 6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide in a form which in differential scanning calorimetry has a peak melting temperature in the range of about 247 to 252°C. In a further aspect the invention provides 5-amino-2,4, 6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide in a form characterised by a diffuse reflectance infrared spectrum showing the following main peaks: 3330, 3244, 2929, 1641, 1564, 1402, 1277, 1228, 1115, 1032, 957, 690, 631 and 440 cm-1. Moreover this infrared spectrum has at 999 cm"1 either no peak, a shoulder, or a peak of low intensity, as compared to the characteristic high and sharp peak at 999 cm-1 found in the equivalent infrared spectrum of the white polymorph. The diffuse reflectance infrared spectrum may be measured using a sample ground with KBr. In a still further aspect the invention provides 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide in a form characterised by the following X-ray powder diffraction pattern: (Table Removed) (where w = weak, m = medium, s = strong, v = very and d = diffuse). The mean crystal size of the yellow polymorph of compound A (as measured by particle sizing) is desirably in the range 150 to 500 µm, preferably 200 to 400 µm. The yellow polymorph of compound A may be produced by cooling an aqueous solution of compound A at a rate of less than 7 C°/hour, eg. in the crystallisation step described on page 8 of GB-A-1548594 and on page 225 of Haavaldsen et al. (supra). It is the slow cooling rate that appears to result in the formation off the yellow polymorph rather than the white polymorph. Thus viewed from a further aspect the invention provides a process for the preparation of 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide in its yellow polymorphic form, said process comprising cooling a solution of 5-amino-2,4,6-triiodo-N,N1-bis(2,3-dihydroxypropyl)-isophthalamide, preferably an aqueous solution (eg. where the solvent is water or a mixture of water with a miscible cosolvent such as isopropanol), characterised in that cooling is effected at less than 7 C°/hour (preferably at less than 6 C°/hour and more preferably at less than 5 C°/hour) during the period of precipitation of the 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide. The concentration of compound A in the starting solution is preferably 18 to 30% w/v, especially 22 to 26% w/v. Generally speaking the concentration requirement is essentially that the initial concentration should be higher than the saturation concentration at the end point of the cooling process, which will generally be in the range 0 to 30°C, preferably ambient temperature, eg. 18 to 25°C. The starting temperature for the solution will in normal practice be dictated by the temperature at the end point of the triiodination process by which compound A is prepared by reaction of an iodine halide (eg. NaIClz) with the 2,4,6-unsubstituted precursor. This will generally be in the range 70-95°C. Nevertheless the yellow polymorph may be prepared by cooling a solution of compound A from a lower starting temperature, eg. in the range 40°-70°C. In the process of the invention, the precipitation medium may be seeded with crystals of the yellow polymorph of compound A. Following precipitation of compound A in its yellow polymorphic form, it will preferably be separated by filtration, washed (e.g. with alcohols (e.g. C1-4 alkanols) or water or a mixture thereof), and dried (e.g. at 20 to 90°C), before storage or further use. Further use of the yellow polymorph will normally involve N-acylation, N-alkylation or dimerisation, eg. using procedures known in the art for the preparation of a 2,4,6-triiodinated-benzene ring containing X-ray contrast agent. Viewed from a further aspect the present invention also provides the use of 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide in its yellow polymorphic form in the production of an iodinated X-ray contrast agent, eg. an agent containing a 2,4,6-triiodo- N,N'-bis(2,3-dihydroxypropyl)-isophthalamide structure with a substituted nitrogen at the 5-position, for example an agent such as iohexol, iodixanol, iopentol, ioversol or iomeprol. Such use according to the invention may simply involve the use of the yellow polymorph in synthetic procedures which previously have called for use of 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide or for its white polymorph, eg. procedures as described by W095/35122 (Mallinckrodt) for the preparation of ioversol, or by Haavaldsen et al. (supra) for the preparation of iohexol, or for the preparation of dimers as described in W096/09285 (Ny comed). For such further use, compound A may be entirely or substantially entirely in the yellow polymorph form, however some inclusion of the white polymorph and other polymorphs (e.g. with at least 50% of compound A, preferably at least 80%, more preferably at least 90%, and most preferably at least 95% by weight being in the yellow polymorphic form) is acceptable. Desirably the compound A used for such further use is at least 97% by weight pure. The invention will now be described in further detail with reference to the following non-limiting Examples and the accompanying drawings, in which: Figures 1 and 2 are infrared spectra for the yellow and white polymorphs of compound.A respectively; and Figures 3 and 4 are powder X-ray diffraction patterns for the yellow and white polymorphs of compound A respectively; Figures '5 and 6 are DSC traces for the yellow and white polymorphs of compound A respectively. EXAMPLE 1 Preparation of Yellow Polymorph of Compound A A crude solution of 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide (A) was prepared from 90g 5-amino-N,N'-bis(2,3-dihydroxypropyl)isophthalamide HC1 salt (prepared according to the method of Haavaldsen et al. in Acta. Pharm. Suec. 20: 219-232 (1983)). Iodine chloride, 3.45 equivalents to the isophthalamide, was added in 3 steps to the reaction mixture and kept at 60-85°C. pH was kept between 3-0.5 throughout the synthetic part of the reaction. To terminate the reaction 4-6.5g of sodium metabisulphite was added at 70-80°C to the crude solution of (A) and the mixture was basified to pH 3-5 with 50% caustic solution. Thereafter 2-3.5g sodium dithionite was added and the batch was treated with 0.9g seed at 78-82°C and held at 80°C for 2-3 hours to crystallize. The batch was cooled at 3°C per hour until 15-30°C and then further chilled and filtered. The filtercake was washed with up to 50 ml water and then combined with a 10 ml rinse, filtered and washed 4 times with 50 ml water and two times with isopropanol. The products was vacuum dried to yield 157g product (A) The salt concentration in the final product was 0.02% w/w. EXAMPLE _2 Infrared spectra Characteristic peaks in the infrared spectra (diffuse reflectance measurement) for the yellow and white polymorph of compound A as shown in Fig. 1 and Fig. 2: Yellow polymorph: 3330, 3244, 2929, 1641, 1564, 1402, 1277, 1228, 1115, 1032, 957, 690, 631, 440 cm-1. White polymorph: 3411, 3323, 3300, 2939, 1620, 1601, 1433, 1387, 1309, 1119, 1076, 999, 727, 631, 482 cm-1. EXAMPLE 3 Powder X-ray diffraction Samples of the yellow and white polymorphs of compound A were investigated with monochromatic CuKα radiation over the angle range of 2θ = 3-60° using a SIEMENS D50000 diffractometer. As shown in Figs. 3 and 4, the following characteristic spacings and intensities are found for the yellow and white polymorph in terms of d spacings and relative intensities (I) is as follows (s = strong, m= medium, w = weak, v = very, d = diffuse). Only d-values > 2.20 Å are shown. Yellow polymorph: (Table Removed) White polymorph: (Table Removed) EXAMPLE 4 Melting Characteristics According to DSC (Perkin Elmer DSC 7, temperature range 45°C-270°C, heating rate 10°C/minute) the yellow and white polymorphs have the following melting characteristics, as shown in Figs. 5 and 6: Yellow polymorph: Peak melting temperature in the range 247-252°C (in this test the peak was at 249.7°C) . White polymorph: Peak melting temperature at about 193-196°C. EXAMPLE 5 Manufacture of iohexol Yellow polymorphic compound A is used in the production of iohexol in a process similar to that described by Haavaldsen et al. (supra) WE CLAIM: 1. A compound of formula 5-amino-2, 4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -isophthalamide in its yellow polymorphic form. 2. A compound as claimed in claim 1, wherein said compound in differential scanning calorimetry has a peak melting temperature at about 247 to 252°C. 3. A compound as claimed in claim 1, wherein said compound having a diffuse reflectance infrared spectrum showing the following main peaks: 3330, 3244, 2929, 1641, 1564, 1402,1277,1228, 1115,1032 , 957, 690, 631 and 440 cm-1. 4. A compound as claimed in claim 1, wherein said compound having the following X-ray powder diffraction pattern: (Table Removed) (where w = weak, m = medium, s = strong, v = very and d = diffuse). 5. A compound as claimed in any one of the preceding claims 1 to 4, wherein polymorphic form of said compound has a mean particle size in the range 150 to 500µm. 6. A process for the preparation of said compound of formula 5-amino-2,4, 6-triiodo-N, N' -bis (2, 3- dihydroxypropyl) -isophthalamide in its yellow polymorphic form, said process comprising cooling a solution of 5-amino-2, 4, 6 - triiodo-N, N' - bis (2, 3- dihydroxypropyl) -isophthalamide, characterised in that cooling is effected at less than 7 C°/ hour during the period of precipitation of the 5-amino-2, 4, 6-triiodo-N, N'-bis (2, 3,- dihydroxypropyl) -isophthalamide. 7. A compound of formula 5-amino-2, 4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -isophthalamide in its yellow polymorphic form as and when used in the production of an iodinated X-ray contrast agent of the kind iohexol, iopentol, iodixanol, ioversol and iomeprol. 8. A compound of formula 5-amino-2, 4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -isophthalamide in its yellow polymorphic form, substantially as hereinbefore described with reference to the accompanying examples.

Full Text

The present invention relates a compound 5-Amino-2,4,6 -triiodo-N,N' -bis(2, 3-dihydroxypropyl) isophthalamide, (hereinafter called "Compound A") and in particular to the yellow polymorphic form of compound 'A'a a key intermediate in the preparation of non-ionic X-ray contrast agents such as iohexol,iopentol, iodixanol, ioversol and iomeprol.
Compound A is available commercially, in a white form for instance from Fuji Chemical Industries, Ltd. The preparation of compound A in a white form is disclosed for example in W095/35122 (Mallinckrodt), eg. on page 6 thereof. Other publications, eg. Haavaldsen et al. in Acta Pharm. Suec. 20: 219-232 (1983), describe the preparation of compound A in a way in which the white form of compound A is produced.
Compound A however has now' been found to exist in two polymorphic forms, a white form and a yellow form.
Polymorphism is a solid state phenomenon associated with the structure of the solid; different polymorphs of the same compound, appear to involve different packings of the molecules within the solids.
We have now found that in large scale production of compound A the yellow polymorphic form has advantages over the white polymorphic form in terms of efficiency of the crystallisation, filtration and drying steps. In any large scale multistep synthetic production of a chemical drug substance, increased efficiency in any of the synthetic steps is reflected by increased efficiency of the overall process.
The white and yellow polymorphs of compound A have different infrared spectra and have characteristically different powder X-ray diffraction patterns. They may also be distinguished from each other by DSC and by colour assessment. Thus in particular the white

polymorph is DSC has a peak melting temperature at about 193-196°C, while the yellow polymorph has a peak melting temperature in the range of about 247 to 252°C. Moreover the white polymorph is characterised over the yellow polymorph by having a sharp peak in the ir spectrum at 999cm-1
According to the present invention there is provided a compound of formula 5-amino-2, 4, 6-triiodo-N, N1 -bis (2, 3-dihydroxypropyl)-isophthalamide in its yellow polymorphic form.
Thus in one aspect the invention provides 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalaraide in its yellow polymorphic form.
In another aspect the invention provides 5-amino-2,4, 6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide in a form which in differential scanning calorimetry has a peak melting temperature in the range of about 247 to 252°C.
In a further aspect the invention provides 5-amino-2,4, 6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide in a form characterised by a diffuse reflectance infrared spectrum showing the following main peaks: 3330, 3244, 2929, 1641, 1564, 1402, 1277, 1228, 1115, 1032, 957, 690, 631 and 440 cm-1. Moreover this infrared spectrum has at 999 cm"1 either no peak, a shoulder, or a peak of low intensity, as compared to the characteristic high and sharp peak at 999 cm-1 found in the equivalent infrared spectrum of the white polymorph. The diffuse reflectance infrared spectrum may be measured using a sample ground with KBr.
In a still further aspect the invention provides 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide in a form characterised by the following X-ray powder diffraction pattern:

(Table Removed)

(where w = weak, m = medium, s = strong, v = very and d = diffuse).
The mean crystal size of the yellow polymorph of compound A (as measured by particle sizing) is desirably in the range 150 to 500 µm, preferably 200 to 400 µm.
The yellow polymorph of compound A may be produced by cooling an aqueous solution of compound A at a rate of less than 7 C°/hour, eg. in the crystallisation step described on page 8 of GB-A-1548594 and on page 225 of Haavaldsen et al. (supra). It is the slow cooling rate that appears to result in the formation off the yellow polymorph rather than the white polymorph.
Thus viewed from a further aspect the invention provides a process for the preparation of 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide in its yellow polymorphic form, said process comprising cooling a solution of 5-amino-2,4,6-triiodo-N,N1-bis(2,3-dihydroxypropyl)-isophthalamide, preferably an aqueous solution (eg. where the solvent is water or a mixture of water with a miscible cosolvent such as isopropanol), characterised in that cooling is effected at less than 7 C°/hour (preferably at less than 6 C°/hour

and more preferably at less than 5 C°/hour) during the period of precipitation of the 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide.
The concentration of compound A in the starting solution is preferably 18 to 30% w/v, especially 22 to 26% w/v. Generally speaking the concentration requirement is essentially that the initial concentration should be higher than the saturation concentration at the end point of the cooling process, which will generally be in the range 0 to 30°C, preferably ambient temperature, eg. 18 to 25°C. The starting temperature for the solution will in normal practice be dictated by the temperature at the end point of the triiodination process by which compound A is prepared by reaction of an iodine halide (eg. NaIClz) with the 2,4,6-unsubstituted precursor. This will generally be in the range 70-95°C. Nevertheless the yellow polymorph may be prepared by cooling a solution of compound A from a lower starting temperature, eg. in the range 40°-70°C.
In the process of the invention, the precipitation medium may be seeded with crystals of the yellow polymorph of compound A.
Following precipitation of compound A in its yellow polymorphic form, it will preferably be separated by filtration, washed (e.g. with alcohols (e.g. C1-4 alkanols) or water or a mixture thereof), and dried (e.g. at 20 to 90°C), before storage or further use.
Further use of the yellow polymorph will normally involve N-acylation, N-alkylation or dimerisation, eg. using procedures known in the art for the preparation of a 2,4,6-triiodinated-benzene ring containing X-ray contrast agent.
Viewed from a further aspect the present invention also provides the use of 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide in its yellow polymorphic form in the production of an iodinated X-ray contrast agent, eg. an agent containing a 2,4,6-triiodo-

N,N'-bis(2,3-dihydroxypropyl)-isophthalamide structure with a substituted nitrogen at the 5-position, for example an agent such as iohexol, iodixanol, iopentol, ioversol or iomeprol.
Such use according to the invention may simply involve the use of the yellow polymorph in synthetic procedures which previously have called for use of 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide or for its white polymorph, eg. procedures as described by W095/35122 (Mallinckrodt) for the preparation of ioversol, or by Haavaldsen et al. (supra) for the preparation of iohexol, or for the preparation of dimers as described in W096/09285 (Ny comed).
For such further use, compound A may be entirely or substantially entirely in the yellow polymorph form, however some inclusion of the white polymorph and other polymorphs (e.g. with at least 50% of compound A, preferably at least 80%, more preferably at least 90%, and most preferably at least 95% by weight being in the yellow polymorphic form) is acceptable. Desirably the compound A used for such further use is at least 97% by weight pure.
The invention will now be described in further detail with reference to the following non-limiting Examples and the accompanying drawings, in which:
Figures 1 and 2 are infrared spectra for the yellow and white polymorphs of compound.A respectively; and
Figures 3 and 4 are powder X-ray diffraction patterns for the yellow and white polymorphs of compound A respectively;
Figures '5 and 6 are DSC traces for the yellow and white polymorphs of compound A respectively.

EXAMPLE 1
Preparation of Yellow Polymorph of Compound A
A crude solution of 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide (A) was prepared from 90g 5-amino-N,N'-bis(2,3-dihydroxypropyl)isophthalamide HC1 salt (prepared according to the method of Haavaldsen et al. in Acta. Pharm. Suec. 20: 219-232 (1983)). Iodine chloride, 3.45 equivalents to the isophthalamide, was added in 3 steps to the reaction mixture and kept at 60-85°C. pH was kept between 3-0.5 throughout the synthetic part of the reaction. To terminate the reaction 4-6.5g of sodium metabisulphite was added at 70-80°C to the crude solution of (A) and the mixture was basified to pH 3-5 with 50% caustic solution. Thereafter 2-3.5g sodium dithionite was added and the batch was treated with 0.9g seed at 78-82°C and held at 80°C for 2-3 hours to crystallize. The batch was cooled at 3°C per hour until 15-30°C and then further chilled and filtered.
The filtercake was washed with up to 50 ml water and then combined with a 10 ml rinse, filtered and washed 4 times with 50 ml water and two times with isopropanol.
The products was vacuum dried to yield 157g product (A) The salt concentration in the final product was 0.02% w/w.
EXAMPLE _2 Infrared spectra
Characteristic peaks in the infrared spectra (diffuse reflectance measurement) for the yellow and white polymorph of compound A as shown in Fig. 1 and Fig. 2:

Yellow polymorph:
3330, 3244, 2929, 1641, 1564, 1402, 1277, 1228, 1115,
1032, 957, 690, 631, 440 cm-1.
White polymorph:
3411, 3323, 3300, 2939, 1620, 1601, 1433, 1387, 1309,
1119, 1076, 999, 727, 631, 482 cm-1.
EXAMPLE 3
Powder X-ray diffraction
Samples of the yellow and white polymorphs of compound A were investigated with monochromatic CuKα radiation over the angle range of 2θ = 3-60° using a SIEMENS D50000 diffractometer.
As shown in Figs. 3 and 4, the following characteristic spacings and intensities are found for the yellow and white polymorph in terms of d spacings and relative intensities (I) is as follows
(s = strong, m= medium, w = weak, v = very, d = diffuse). Only d-values > 2.20 Å are shown.
Yellow polymorph:

(Table Removed)

White polymorph:
(Table Removed)
EXAMPLE 4
Melting Characteristics
According to DSC (Perkin Elmer DSC 7, temperature range 45°C-270°C, heating rate 10°C/minute) the yellow and white polymorphs have the following melting
characteristics, as shown in Figs. 5 and 6:
Yellow polymorph:
Peak melting temperature in the range 247-252°C (in this
test the peak was at 249.7°C) .
White polymorph:
Peak melting temperature at about 193-196°C.
EXAMPLE 5
Manufacture of iohexol
Yellow polymorphic compound A is used in the production of iohexol in a process similar to that described by Haavaldsen et al. (supra)

WE CLAIM:
1. A compound of formula 5-amino-2, 4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl)
-isophthalamide in its yellow polymorphic form.
2. A compound as claimed in claim 1, wherein said compound in differential scanning
calorimetry has a peak melting temperature at about 247 to 252°C.
3. A compound as claimed in claim 1, wherein said compound having a diffuse
reflectance infrared spectrum showing the following main peaks: 3330, 3244, 2929, 1641,
1564, 1402,1277,1228, 1115,1032 , 957, 690, 631 and 440 cm-1.
4. A compound as claimed in claim 1, wherein said compound having the following
X-ray powder diffraction pattern:
(Table Removed)
(where w = weak, m = medium, s = strong, v = very and d = diffuse).
5. A compound as claimed in any one of the preceding claims 1 to 4, wherein
polymorphic form of said compound has a mean particle size in the range 150 to 500µm.
6. A process for the preparation of said compound of formula 5-amino-2,4, 6-triiodo-N,
N' -bis (2, 3- dihydroxypropyl) -isophthalamide in its yellow polymorphic form, said
process comprising cooling a solution of 5-amino-2, 4, 6 - triiodo-N, N' - bis (2, 3-
dihydroxypropyl) -isophthalamide, characterised in that cooling is effected at less than 7 C°/
hour during the period of precipitation of the 5-amino-2, 4, 6-triiodo-N, N'-bis (2, 3,-
dihydroxypropyl) -isophthalamide.
7. A compound of formula 5-amino-2, 4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl)
-isophthalamide in its yellow polymorphic form as and when used in the production of an
iodinated X-ray contrast agent of the kind iohexol, iopentol, iodixanol, ioversol and
iomeprol.
8. A compound of formula 5-amino-2, 4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl)
-isophthalamide in its yellow polymorphic form, substantially as hereinbefore described with
reference to the accompanying examples.

Documents:

1378-del-1998-abstract.pdf

1378-del-1998-claims.pdf

1378-del-1998-correspondence-others.pdf

1378-del-1998-correspondence-po.pdf

1378-del-1998-description (complete).pdf

1378-del-1998-drawings.pdf

1378-del-1998-form-1.pdf

1378-del-1998-form-13.pdf

1378-del-1998-form-18.pdf

1378-del-1998-form-2.pdf

1378-del-1998-form-3.pdf

1378-del-1998-form-4.pdf

1378-del-1998-form-6.pdf

1378-del-1998-gpa.pdf

1378-del-1998-petition-137.pdf

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Patent Number

230837

Indian Patent Application Number

1378/DEL/1998

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

28-Feb-2009

Date of Filing

22-May-1998

Name of Patentee

AMERSHAM HEALTH AS,

Applicant Address

NYCOVEIEN 1-2, P.O. BOX 4220 NYDALEN, N-0401 OSLO, NORWAY.

Inventors:

#	Inventor's Name	Inventor's Address
1	DICK MALTHE- SRENSSEN	NYCOMED IMAGING, LINDESNES PLANT, 4510 SPANGEREID, NORWAY, AND AUDUN AUKRUST OF IMAGING, NYCOVEIEN 2, 0401 OSIO, NORWAY.

PCT International Classification Number

CO7C 233/05

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	9710726.2	1998-05-23	U.K.