Method for preparing an Fe-tCDTA contrast agent and product obtainable by the method

Abstract

A process is provided in which the resulting Fe-tCDTA contrast agent has a reduced osmolality. The process according to the invention comprises the following steps: a) preparing an aqueous solution of tCDTA and FeO(OH), tCDTA and FeO(OH) being present in a molar ratio of from 1:1 to 1:1.4; b) b.1) adjusting a pH of the aqueous solution to between pH 2.5 and pH 4.5 by adding a base, preferably meglumine, and separating the precipitate; or b.2) precipitating the Fe-tCDTA contrast agent from the aqueous solution by adding acetone, separating the precipitate, and preparing an aqueous solution from the precipitate; and c) adjusting a pH of the aqueous solution to between pH 6.5 and pH 8.0 by adding a base, preferably meglumine, and separating the precipitated FeO(OH).

Claims

1. A process for preparing an Fe-tCDTA contrast agent comprising: a) preparing an aqueous solution of tCDTA and FeO(OH), wherein tCDTA and FeO(OH) are present in a molar ratio of from 1:1 to 1:1.4 and the pH of the aqueous solution is adjusted to between pH 0.1 and pH 2 to dissolve the FeO(OH); b) b1) adjusting a pH of the aqueous solution of tCDTA and FeO(OH) to between pH 2.5 and pH 4.5 by adding a base and separating any precipitate that is formed; or b2) precipitating Fe-tCDTA from the aqueous solution by adding a water-miscible organic solvent, separating the Fe-tCDTA precipitate, and preparing an aqueous solution from the Fe-tCDTA precipitate; and c) adjusting a pH of the aqueous solution to between pH 6.5 and pH 8.0 by adding a base, separating the precipitated FeO(OH) and isolating Fe-tCDTA from the remaining aqueous solution.

2. The process according to claim 1, in which the FeO(OH) in a) is prepared in advance by precipitation i) from an aqueous Fe(NO.sub.3).sub.3 solution with addition of an NH.sub.4OH solution or ii) from an aqueous FeCl.sub.3 solution with addition of an NaOH solution.

3. The process according to claim 1, in which the aqueous solution of tCDTA solution and FeO(OH) in a) is heated to between 70 and 100° C. for 1 to 3 h after the addition of tCDTA and FeO(OH).

4. The process according to claim 1, in which the aqueous solution of tCDTA solution and FeO(OH) in a) is stirred at room temperature for 0.5 h or more after adjusting the pH.

5. The process according to claim 1, wherein the base in b1) is meglumine.

6. The process according to claim 1, wherein the base in c) is meglumine.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The preparation of an Fe-tCDTA contrast agent will be explained in further detail below in two examples.

(2) A. Synthesis from a Solution of Ferric Nitrate

(3) 20 g of ferric nitrate hexahydrate (Fe(NO.sub.3).sub.3.6H.sub.2O) were dissolved in 100 ml of water (dist.) and filtered. A mixture of 50 ml ammonium hydroxide solution (ammonia water, 28 to 30% by weight in water) and 50 ml water (dist.) was added dropwise to the Fe(NO.sub.3).sub.3 solution at room temperature and with stirring. The resulting insoluble iron(III) hydroxide oxide FeO(OH) was collected by filtration (Büchner funnel) and washed several times with water.

(4) 17.1 g tCDTA were dissolved in 40 ml water (dist.). The FeO(OH) was added and the volume of the solution was made up to 100 ml with water (dist.). The solution was heated at 95° C. for about 2 h and stirred. The solution was then cooled, filtered, and the volume was reduced to 20 ml by heating. The iron complexes were precipitated from the reduced solution by adding acetone (approx. 300 ml), and the precipitate was centrifuged and dried.

(5) The precipitate of Fe-tCDTA was dissolved again in water (dist.) and the pH was adjusted to between 7.3 and 7.4 using meglumine, with a relative iron concentration of the solution of 38 mg/ml.

(6) B. Synthesis from a Solution of Ferric Chloride

(7) A solution of 14 g NaOH in 70 ml water (dist.) was added dropwise to a solution of 18.92 g ferric chloride hexahydrate (FeCl.sub.3.6H.sub.2O) in 70 ml water (dist.), while stirring. The precipitated iron(III) hydroxide oxide FeO(OH) was separated (centrifugation 3 min at 1000×g) and washed 3 times with water (dist.).

(8) 18.22 g tCDTA was suspended in 50 ml water (dist.) and added to the FeO(OH). The mixture was heated to 95° C. for 2 h, with stirring, and after cooling was centrifuged (3 min at 1000×g) and filtered through a 0.45 μm syringe filter.

(9) The pH of the solution obtained was adjusted to 4 using meglumine and stirred for 1 h at room temperature. Any precipitates formed were separated by filtration.

(10) After 1 hour, the pH was adjusted to 7.4 using meglumine and the corresponding precipitate was centrifuged off and filtered.

(11) Within the first 1 to 3 days, FeO(OH) precipitate formed. The solution was left to stand at room temperature for another 12 h. The tCDTA solution was centrifuged (3 min at 1000×g), then removed from the iron(III) hydroxide precipitate and filtered with a 0.2 μm syringe filter. The solution was centrifuged again after 3 days (3 min at 1000×g) to remove remaining traces of iron(III) hydroxide.

(12) Determination of Osmolality

(13) The osmolality indicates the molality of the osmotically active particles in a solution:

(14) $b_{\mathrm{osm}}=\frac{n_{\mathrm{osm}}}{m_{\mathrm{sol}}}$
with
n.sub.osm: amount of osmotically active particles
m.sub.sol: mass of the solvent, here water

(15) The osmolality here therefore indicates the number of particles of osmotically active substances per kilogram of water and was determined as follows:

(16) For the osmolality measurements, the freezing point measuring instrument OSMOMAT 030 from Gonotec GmbH was used. To determine the total osmolality in aqueous solutions, comparative measurements of the freezing points of pure water and solutions were carried out. While water has a freezing point of 0° C., a solution with a salt concentration of 1 osmol/kg shows a freezing point of −1.858° C. This means that one mole of a given non-dissociated substance (6.023×1023 parts diluted in one kilogram of water) lowers the freezing point of a solution by 1.858° C. The device uses the following definitions to calculate the osmolality: C.sub.osm=ΔT/K with C.sub.osm=osmolality [osmol/kg], T=freezing point decrease [° C.], K=1,858° C. kg/osmol freezing point constant.

(17) Table 1 below shows the osmolality of the two products of the practical examples determined by this method. For comparison, the osmolality of the common gadolinium contrast agent Magnevist was determined in the same way. Furthermore, Fe-tCDTA was synthesised according to the specification described in U.S. Pat. No. 5,362,475 A and the osmolality was determined.

(18) TABLE-US-00001 TABLE 1 Osmolality [mOsm/kg] at 0.25 mmol/l in water (c in relation to Fe or Gd) Magnevist (gadopentetate dimeglumine, Gd-DTPA) 815 Synthesis Fe-tCDTA according to U.S. Pat. No. 5,362,475 3030 Fe-tCDTA contrast agent according to synthesis pathway A 517 Fe-tCDTA contrast agent according to synthesis pathway B 398

(19) As can be seen, the osmolality of the Fe-tCDTA contrast agents obtainable in accordance with the invention is greatly reduced, making them particularly suitable for intravenous injection.

(20) Orienting Toxicity Determinations

(21) In first orienting studies with Fe-tCDTA contrast agent according to synthesis pathway A, which was administered intravenously to rats, the animals tolerated doses of 2 mmol per kg body weight (10 times the typical application dose of 0.2 mmol per kg) very well. The urine values were largely normal. The Fe-tCDTA contrast agent according to synthetic pathway B was even administered at 4 mmol per kg body weight (20 times the typical application dose), which corresponds to about 11 g iron in a person weighing 50 kg. The rats tolerated this dose well and only showed increased protein levels in urine after one and two days. At the follow-up after 14 days, all values were normal.