Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-11-12
2002-01-08
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C424S009452
Reexamination Certificate
active
06337422
ABSTRACT:
This invention relates to the compound 5-amino-2,4,6-triiodo-N,N′-bis(2,3-dihydroxypropyl)-isophthalamide (hereinafter “compound A”) and in particular to the yellow polymorphic form of compound A and its preparation and use.
Compound A is 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 commiercially 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 WO95/35122 (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 in 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 999 cm
−1
.
Thus in one aspect the invention provides 5-amino-2,4,6-triiodo-N,N′-bis(2,3-dihydroxypropyl)-isophthalamide 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:
d (Å)
I
d (Å)
I
d (Å)
I
15.66
w
4.27
s
2.82
w
13.79
w
4.24
m
2.78
m
12.90
s
4.16
m
2.72
w
8.59
vw
4.11
m
2.69
w
8.25
m
4.00
m
2.62
vw
7.93
w
3.87
m
2.58
w
7.18
w
3.83
w
2.56
w
7.05
vw
3.58
m
2.52
vw
6.42
s
3.51
w
2.50
vw
6.30
vwd
3.44
wd
2.45
vwd
6.17
w
3.35
vwd
2.41
vw
5.84
vw
3.30
vwd
2.39
vw
5.71
vwd
3.23
vwd
2.35
w
5.53
vw
3.20
w
2.30
wd
5.25
vwd
3.18
w
2.23
w
5.01
w
3.04
vw
4.89
w
3.01
w
4.62
m
2.93
vwd
4.54
vw
2.92
w
4.45
vwd
2.85
w
(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 &mgr;m, preferably 200 to 400 &mgr;m.
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 of 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,N′-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. NaICl
2
) 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. C
1-4
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 WO95/35122 (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 WO96/09285 (Nycomed).
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.
REFERENCES:
patent: 1 548 594 (1979-07-01), None
Haavaldsen et al, Acta Pharm. Suec., 20, 219-232, 1983.
Aukrust Audun
Malthe-Sorenssen Dick
Bacon & Thomas
Kumar Shailendra
Nycomed Imaging AS
LandOfFree
Yellow polymorph of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Yellow polymorph of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Yellow polymorph of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2847769