Synthesis methods and compositions of low intermediate and low dichelate intermediate contrast agents
Macrocyclic gadolinium-based contrast agents (GCA) are synthesized by pathways characterized by the formation of a sequence of metastable complexes before obtaining the final stable complex. Commercial macrocyclic GCAs contain unstable metastable complexes. These metastable species quickly release free Gd3+ ions upon delivery into the body. Aqueous or dry/solid GCA with near zero metastable species content and methods of synthesizing the same are disclosed.
1 . A method of making a lanthanide series contrast agent, wherein the lanthanide series contrast agent comprises at least one atom of lanthanide series metal and at least one macrocyclic chelate, said method comprising:
(a) reacting a macrocyclic chelate with a lanthanide series metal oxide in water at a temperature and reaction time sufficient to provide a lanthanide series metal ion:macrocyclic chelate complex, wherein the macrocyclic chelate is 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and has <10 ppm impurities containing a cyclen ring, and wherein the lanthanide series metal is gadolinium;
(b) monitoring the reaction of the macrocyclic chelate with the lanthanide series metal oxide to determine a content of metastable intermediates, wherein the metastable intermediates are partially chelated complexes of the lanthanide series metal ion:macrocyclic chelate complex;
(c) returning to (a) if the content of metastable intermediates determined by (b) exceeds 500 parts per million relative to a total amount of the lanthanide series metal ion:macrocyclic chelate complexes present; and
(d) reacting the lanthanide series metal ion:macrocyclic chelate complex with a base at a temperature and reaction time sufficient to provide a complex of lanthanide series metal ion, macrocyclic chelate, and base in an aqueous formulation, wherein the aqueous formulation comprises less than about 500 parts per million of metastable intermediates relative to a total amount of the lanthanide series metal ion:macrocyclic chelate complexes present in the aqueous formulation,
wherein the method is performed without use of solvents.
2 . The method of claim 1 , wherein the monitoring is performed in situ.
3 . The method of claim 1 , further comprising: after (d),
(e) monitoring the reaction of the lanthanide series metal ion:macrocyclic chelate complex with a base to determine the content of metastable intermediates and
(f) returning to (d) if a content of metastable intermediates determined by (e) exceeds 500 parts per million.
4 . The method of claim 1 , wherein the (c) returning to (a) is performed if the content of metastable intermediates determined by (b) exceeds 100 parts per million.
5 . The method of claim 1 , wherein the (f) returning to (d) is performed if the content of metastable intermediates determined by (e) exceeds 100 parts per million.
6 . The method of claim 1 , wherein the content of metastable intermediates is determined at least by one technique selected from the group consisting of: Fourier Transform Infrared Spectroscopy, High Performance Liquid Chromatography, Ultra High Performance Liquid Chromatography, and Trans-metalation reaction.
7 . The method of claim 1 , wherein the metastable intermediates are metal ion-ligand complexes with a coordination complex that is not the minimal energy coordination complex.
8 . The method of claim 1 , wherein the metastable intermediates are metal ion-ligand complexes with minimally hydrated ligand coordination groups.
9 . The method of claim 1 , wherein the macrocyclic chelate is reacted with the lanthanide series metal oxide in water at a temperature from about 60° C. to about 120° C., and for a reaction time from about 12 hours to about 48 hours.
10 . The method of claim 1 , wherein the aqueous formulation has a free macrocyclic chelate concentration from about 0.0001 to about 0.0600 weight percent.
11 . The method of claim 1 , wherein the macrocyclic chelate and the lanthanide series metal oxide are reacted in essentially stoichiometric amounts.
12 . The method of claim 1 , wherein the aqueous formulation comprises less than about 50 parts per million of metastable intermediates.
13 . The method of claim 1 , wherein the aqueous formulation comprises less than about 50 parts per million of a non-aqueous solvent.
14 . The method of claim 1 , wherein the lanthanide series metal ion:macrocyclic chelate complex is reacted with the base at a temperature and time until the complex is buffered to a pH of about 7.1 to about 7.6.
15 . The method of claim 1 , wherein step (a) is accelerated by light at a wavelength of 400 nm to 800 nm wavelength light, a catalyst, ultrasonic sound, or combinations thereof.
16 . The method of claim 1 , wherein the base is selected from the group consisting of: meglumine, sodium hydroxide, protonated amines, water, alkynes, amines, and alkanes.
17 . The method of claim 1 , further comprising: removing metastable intermediates from the reaction by an acid-phosphate precipitation method, a negative ionic resin precipitation method, a diethylenetriaminepentacetate (DTPA) addition method, or a cage formation method.
18 . The method of claim 17 , wherein the cage formation method comprises providing a cyclen molecule and lanthanide series metal ion, capturing the lanthanide series metal ion within the cyclen molecule, and adding carboxylic acid arms sequentially to complex with the lanthanide series metal ion, thereby forming a cage around the lanthanide series metal ion.
19 . The method of claim 1 , further comprising: controlling the content of metastable intermediates by forming bi-chelate metastable-free lanthanide series metal ion:macrocyclic chelate complexes, wherein the lanthanide series contrast agent has less than about 500 parts per million of the bi-chelate metastable-free lanthanide series metal ion:macrocyclic chelate complexes.
20 . The method of claim 19 , wherein the bi-chelate metastable-free lanthanide series metal oxide:macrocyclic chelate complexes comprise DOTA-Gd-DOTA complexes.
21 . The method of claim 19 , wherein the bi-chelate metastable-free lanthanide series metal oxide:macrocyclic chelate complexes are biocompatible contaminants, and not metastable intermediates.
22 . The method of claim 19 , wherein the DOTA-Gd-DOTA complexes are formed by Gd 3+ associating with two DOTA molecules, with neither DOTA molecule fully entering the coordination sphere of Gd 3+ .