Contrast agent preparation

Details Contrast agent preparation Contrast agent preparation

1999-10-15

2001-02-20

Dudash, Diana (Department: 1619)

Organic compounds -- part of the class 532-570 series

Organic compounds

Rare earth containing

C534S010000, C534S013000, C534S015000, C423S263000

Reexamination Certificate

active

06191262

ABSTRACT:

This invention relates to a process for the metallation of complexing agents with lanthanides, e.g. gadolinium, and in particular to the preparation of lanthanide chelates such as those suitable for use as contrast agents in diagnostic imaging modalities such as magnetic resonance (MR) imaging.
In MR imaging, the use of lanthanide chelates as contrast agents has become well established. Several such agents (eg. Gd DTPA, Gd DTPA-BMA and Gd HP-DO
3
A, available under the trade marks Magnevist, Omniscan and Pro-Hance) are already commercially available, while still others are in early, middle and late stages of development. Such contrast agents are complexes of lanthanide ions with various different complexing agents (ligands) and a key stage of their production is the metallation of the ligand with a lanthanide. In general this is the last stage of primary production, ie. the production of the chemical drug substance that is subsequently formulated into the drug product in the secondary production phase.
Between metallation and secondary production the lanthanide complex must be thoroughly purified to remove unwanted impurities. As with any commercial drug synthesis, it is important to optimize yield of the desired product, reduce the levels of impurities produced during the various synthetic steps, and reduce process duration (and so. optimize the efficiency of reactor usage).
Metallation with lanthanides is normally performed by reacting the ligand with a lanthanide oxide (e.g. Gd
2
O
3
) in a heated aqueous medium. If this reaction takes too long, decomposition of the ligand can occur, resulting in reduction in yield and increased levels of impurities in the end product.
Thus for example in the metallation of DTPA-BMA (diethylene-triaminepentaacetic acid-N,N′-bis(methylamide) with gadolinium oxide, where the metallation proceeds too slowly some breakdown of the ligand to the mono-methylamide DTPA-MMA occurs. The reaction product then includes both Gd DTPA-BMA and a salt, eg. the sodium salt, of Gd DTPA-MMA. As a result NaGd DTPA-MMA must be removed by a recrystallization procedure.
The lanthanide oxide used in the metallation process is produced commercially by thermal decomposition of a lanthanide oxalate.
It has now surprisingly been found that the rate of the ligand metallation reaction is increased if the reaction medium includes oxalic acid or derivatives (eg. salts thereof).
Thus viewed from one aspect the invention provides a process for the preparation of a lanthanide complex by reaction of a lanthanide oxide with a complexing agent in an aqueous reaction medium, characterised in that oxalic acid or a salt or derivative thereof is used as a reaction accelerator.
When the ligand is subject to thermal decay, the process of the invention will represent an improvement in terms of speed of reaction as well as reduction in by-product formation; however, even where the ligand is thermally stable an improvement in speed of reaction will still be achieved.
The lanthanide used according to the invention may be any lanthanide but preferably is Eu, Th, Tm, Yb, Er or Ho, more preferably Dy, and most preferably Gd.
In this process where oxalic acid or a salt or derivative thereof is used as a reaction accelerator, this relates to further oxalic acid and not simply to the oxalate residue in the lanthanide oxide, even though this residue will of course contribute to the acceleration of the reaction.
The total amount of oxalic acid (or salt or derivative) added as a reaction accelerator is conveniently at least 10 &mgr;g oxalic acid/g L
2
O
3
(where L is the lanthanide, e.g. Gd), preferably at least 50 &mgr;g/g, especially at least 100 &mgr;g/g, particularly at least 200 &mgr;g/g and more particularly at least 400 &mgr;g/g, eg. about 500 &mgr;g/g. The amount added will preferably be less than 2000 &mgr;g/g, particularly less than 1000 &mgr;g/g, preferably less than 800 &mgr;g/g.
The oxalic acid reaction accelerator can be added to the metallation reaction mixture as a separate reagent. However in alternative aspects of the invention some or all of the oxalic acid/oxalate may derive from oxalate impurity in the lanthanide oxide.
Thus viewed from a further aspect the invention provides a process for the preparation of a lanthanide complex by reaction of lanthanide oxide with a complexing agent in an aqueous reaction medium, characterised in that said process comprises the steps of: (a) determining the level of impurity in the lanthanide oxide; and (b) mixing lanthanide oxide from batches with different determined levels of impurity and/or including in the reaction medium a predetermined quantity of oxalic acid or a salt or derivative thereof; whereby by virtue of step (b) the reagents used in the metallation reaction contain oxalic acid (or salt or derivative) or oxalate at a total level of at least 50 &mgr;g oxalic acid per gram L
2
O
3
, preferably at least 100 &mgr;g/g, more preferably at least 200 &mgr;g/g, especially at least 250 &mgr;g/g and particularly preferably at least 400 &mgr;g/g, eg. up to 1750 &mgr;g/g, particularly 700 to 900 &mgr;g/g.
Viewed from a yet further aspect the invention provides a process for the preparation of a lanthanide complex by reaction of a lanthanide oxide with a complexing agent in an aqueous reaction medium, characterised in that for use as said lanthanide oxide is selected a lanthanide oxide having (eg. pre-analysed to contain) an oxalate impurity level of at least 100 &mgr;g oxalic acid/g lanthanide oxide, preferably at least 200 &mgr;g/, more preferably at least 250 &mgr;g/g, especially preferably at least 400 &mgr;g/g, more especially at least 700 &mgr;g/g.
The oxalate impurity level of the L
2
O
3
may be inferred from its residue on ignition—the higher the residue the higher the oxalate content. Alternatively it can be determined by suitable analytical methods.
Where oxalic acid is added to the reaction medium, with or without predetermination of oxalate impurity levels of the lanthanide oxide, it may be added as a salt (eg. an alkali metal or alkaline earth metal salt), an ester or an amide or as the free acid. Lanthanide oxalates themselves may be used. However, preferably the free acids are used.
The use of oxalic acid (or salts or derivatives thereof) can reduce the metallation reaction time by a factor of two or more, eg. by a factor of up to 6.
The ligand which is metallated may be any ligand capable of producing a highly stable lanthanide complex, eg. one with a dissociation content of at least 10
12
. Preferably it will be a linear, cyclic or branched chelating agent, eg. a linear mono- or polychelant, a macrocyclic chelant or a branched polychelant (eg. a dendrimeric polychelant). Preferably the ligand will be a polyaminopolyoxyacid (eg. polyaminopolycarboxylic acid), such as one of the mono and polychelants suggested for lanthanide chelation in the patent literature relating to MR contrast agents, eg. the patent publications of Nycomed (including Nycomed Imaging and Nycomed Salutar), Sterling Winthrop, Schering, Bracco, Squibb, Mallinckrodt, Guerbet and Metasyn, eg. US-A-4647447, EP-A-71564, WO96/03154, WO96/01655, EP-A-430863, WO96/41830, and WO93/10824. Thus by way of example the ligand may be of formula
(
Y
) (
X
)
N
(
CHR
)
n
(
N
(
X
) (
CHR
)
n
)
m
N
(
X
) (
Y
)
where m is 0, 1, 2, or 3; n is 2 or 3; y; each X is a hydrogen or a substituted C
1-6
alkyl group; each Y is a group X or the two Y groups together represent a (CHR)
n
bridge; and each R is hydrogen or a substituted C
1-6
alkyl group or a CHR-N(X)-CHR moiety may represent an optionally substituted, saturated or unsaturated 5 to 7 membered heterocyclic ring or a CHRCHR moiety may represent an optionally substituted, saturated or unsaturated 5 to 7 membered homo- or heterocyclic ring; where at least two X groups are alkyl groups substituted by sulphur, phosphorus or carbon oxyacid groups or amides or esters thereof, and where alkyl group substitution is preferably by oxyacid or oxyacid derivative groups, by hydroxyl groups, by optionally substituted phenyl

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