Background of the invention
Gadoteric acid (Gd-DOTA) is a drug that is approved as a contrast agent for magnetic resonance imaging. The chemical name of Gadoteric acid is 2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]acetate. The compound has the following structure:
Gadoterate Meglumine is marketed by Guerbet under the brand name DOTAREM®.
Each molecule of Gadoteric acid contains one gadolinium ion, which is complexed by 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Compared with other Gadolinium complexes such as Gadopentetic acid, Gadobenic acid, Gadoxetic acid, Gadoteridol or Gadobutrol, Gadoteric acid is the most stable gadolinium complex.
WO 2013/076743 to Jagadeesh et al., discloses process for the synthesis and purification of DOTA.
European patent No. EP 0270483 to Heinz et al., describes pharmaceutical metal-containing complex compounds and processes for their preparation
Free ions of Gadolinium, i.e. non-complexed Gadolinium, are very toxic. Hence it is essential to select a proper chelating agent to form a complex with the Gadolinium. Amongst several related compounds that are used to complex Gadolinium, DOTA is

believed to form the most thermodynamically and kinetically stable complexes with Gadolinium. However, even very stable complexes such as Gd-DOTA tend to release Gadolinium. In order to prevent the undesired release of Gadolinium, it is common practice to use an excess of DOTA. Since free DOTA is also toxic, the excess quantity has to be kept within a certain range.
Prior art disclosures suggest that it is not possible to obtain Gadoteric acid solutions with an excess of DOTA in the desired target range by simply weighing and mixing together Gadolinium oxide, DOTA and Meglumine in water for injection.
To overcome this obstacle, WO 2009/103744 to Meyer et al., suggests measuring the concentration of free macrocyclic chelate and/or free Gadolinium oxide in the liquid pharmaceutical formulation after mixing of initial amounts of Gadolinium oxide and DOTA, and then adjusting the concentrations of free DOTA and/or free Gadolinium ions in order to obtain free chelate within the desired concentration range.
WO 2014/161925 to Diederik et al., describes a process for producing a complex of a lanthanide or similar compound with a macrocyclic ligand, based on the measurement of the moisture content of the material comprising a macrocyclic ligand.
In order to obtain a final composition with the concentration of free DOTA within the specifications, both processes known in the art require several additional process steps such as the measurement of free Gadolinium oxide and the moisture content in the DOTA.
It is thus desirable to obtain an accurate, but simpler process for the manufacture of liquid formulations of Gadoteric acid for the pharmaceutical use on an industrial scale.
Summary of the invention
The present invention relates to a process of preparing a liquid parenteral pharmaceutical formulation containing Gadoterate meglumine.

The invention further provides a process for preparing a liquid parenteral pharmaceutical formulation containing Gadoterate meglumine comprising of the following steps:
a) mixing a pre-determined amount of Gadolinium oxide, DOTA and Meglumine in water.
b) adjusting the pH-value of the mixture in the range of about 6.5 to 8.2, by adding DOTA or any suitable acidifying agent,
wherein the amount of DOTA present in the free form is in the range of 0.002% to 0.5% and the content of free Gadolinium is 0.02% or less.
Detailed description of the invention
The inventors of the present invention have found that an accurate level of free DOTA in the finished dosage form may be easily obtained by titrating up a solution of Gadoterate Meglumine with DOTA or an acidifying agent until a desired pH-value is reached. This process is simple unlike the prior art time consuming in-process measurements of Gadolinium and/or free DOTA.
In the context of the present invention the term "free DOTA" means any DOTA not complexed with Gadolinium or with other metal ions.
In the context of the present invention the term "free Gadolinium" means any Gadolinium not complexed with chelate DOTA.
In the context of the present invention the term "Gadoterate meglumine” comprises of complex of Gadolinium oxide (Gd2O3) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) used in form of the meglumine salt i.e., DOTA-Gd meglumine.
According to the present invention, the process of preparing a liquid pharmaceutical formulation of Gadoterate meglumine encompasses the following steps:

a) mixing a pre-determined amount of Gadolinium oxide, DOTA and Meglumine in water.
b) adjusting the pH-value of the mixture in the range of about 6.5 to 8.2, by adding DOTA or any suitable acidifying agent,
wherein, the amount of free DOTA present is in the range of 0.002% to 0.5% and the content of free Gadolinium is 0.02% or less.
Thus, in one advantageous embodiment, the amounts of free DOTA and Gd2O3 added are such that not all the DOTA is complexed with the Gd2O3 or such that not all the Gd2O3 is complexed with the DOTA. Consequently, after the step b), the pharmaceutical formulation will typically comprise DOTA-gadolinium complex and either free DOTA, or free gadolinium.
Advantageously, the pharmaceutical formulation according to the present invention is characterized in that the formulation contains from about 0.002 to 0.5% of free DOTA and 0.02% or less of free Gadolinium.
Formulations of the present invention have a pH value of about 6.5 to 8.2. The pH of the formulation is adjusted to desired range using DOTA or any suitable acidifying agent such as mineral acids, organic carboxylic acids, sulfonic acids and the like. Suitable acidifying agents include, but not limited to hydrochloric acid, sulfuric acid, boric acid, silica acid, acetic acid, phosphoric acid, formic acid, maleic acid, citric acid, tri-chloroacetic acid, trifluoroacetic acid, benzoic acid, fumaric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
The manufacturing process for preparing liquid parenteral pharmaceutical formulation of Gadoterate meglumine according to the present invention comprises of the following steps:
i. Water for injection is heated in a manufacturing vessel to about 80±5°C.
ii. DOTA is added to the above solution and stirred well.
iii. Gadolinium oxide (Gd2O3) is added to the above solution and stirred till it
dissolves completely, maintaining the temperature of solution at 80±5°C.

iv. The solution is cooled to 25±2°C and meglumine is added to the solution and
stirred.
v. The pH of the solution is adjusted to around 6.5 to 8.2, by the addition of DOTA
or acidifying agent.
vi. The solution is filtered and filled into suitable containers or vials, stoppered and
sealed followed by terminal sterilization.
Experiments were carried out in order to limit the amount of free DOTA and free gadolinium (Gd), and thus to reduce the toxicity of the product. Formulations prepared according to the invention are tested for various parameters such as pH, Assay, free Gd and free DOTA content and the results are tabulated in table 1. The amount of free Gd present in the formulation is analysed by Agilent Fluorescence detector. The amount of free DOTA in the formulation is analysed by HPLC method.
From the above results it can be concluded that the manufacturing process by the pH-adjustment method is suitable and meets the specifications for gadoterate meglumine injection.
The formulation prepared according to the invention is compared with commercially available Gadoterate meglumine injection i.e., Dotarem Injection (Batch No: 12GD100A, 11GD089A), the results are tabulated in table 2.

From table 2 it is evident that the product prepared according to the invention is comparable to that of the commercially available product.
The following examples further describe certain specific aspects and embodiments of the present invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.
Manufacturing process
Water for injection was taken in a manufacturing vessel and heated to 80±50C. DOTA was added and stirred, followed by the addition of Gadolinium oxide while maintaining the temperature at 80±50C. The solution was cooled to 25±2°C, then meglumine was added and stirred till a homogenous solution was obtained. The pH of the solution was adjusted to around 7.5 to 8.0 with hydrochloric acid. The final pH of the solution was adjusted using DOTA to around 7.3±0.2. The obtained solution was filtered followed by filling into the vials.
Manufacturing process
Water for injection was taken in a manufacturing vessel and heated to 80±50C. DOTA was added and stirred, followed by the addition of Gadolinium oxide while maintaining the temperature at 80±50C. The solution was cooled to 25±2°C, then meglumine was added and stirred till a homogenous solution was obtained. The pH of the solution was adjusted using DOTA to around 7.3±0.2. The obtained solution was filtered followed by filling into the vials.
Manufacturing process
Water for injection was taken in a manufacturing vessel and heated to 80±50C. DOTA was added and stirred, followed by the addition of Gadolinium oxide while maintaining the temperature at 80±50C. The solution was cooled to 25±2°C, then meglumine was added and stirred till a homogenous solution was obtained. The pH of the solution was adjusted using DOTA to around 7.3±0.2. The obtained solution was filtered followed by filling into the vials.

Manufacturing process
Water for injection was taken in a manufacturing vessel and heated to 80±50C. DOTA was added and stirred, followed by the addition of Gadolinium oxide while maintaining the temperature at 80±50C. The solution was cooled to 25±2°C, then meglumine was added and stirred till a homogenous solution was obtained. The pH of the solution was adjusted to around 7.4 using acetic acid. The obtained solution was filtered followed by filling into the vials.
Manufacturing process
Water for injection was taken in a manufacturing vessel and heated to 80±50C. DOTA was added and stirred, followed by the addition of Gadolinium oxide while maintaining the temperature at 80±50C. The solution was cooled to 25±2°C, then meglumine was added and stirred till a homogenous solution was obtained. The pH of the solution was adjusted to around 7.4 using phosphoric acid and/or DOTA. The obtained solution was filtered followed by filling into the vials.

Claim 1: Process for preparing a liquid parenteral pharmaceutical formulation of Gadoterate meglumine comprising of the following steps:
a) mixing a pre-determined amount of gadolinium oxide, DOTA and meglumine in water.
b) adjusting the pH-value of the mixture in the range of about 6.5 to 8.2, by adding DOTA or any suitable acidifying agent.
Claim 2: Process for preparing a liquid parenteral pharmaceutical formulation containing Gadoterate meglumine of claim 1, wherein the amount of free DOTA in the formulation ranges from about 0.002% to 0.5% and the content of free Gadolinium is 0.02% or less.
Claim 3: A process for preparing formulation according to claim 1, wherein the pH of the formulation ranges from about 7.0 and 8.0.
Claim 4: The parenteral pharmaceutical formulation of Gadoterate meglumine of claim1, wherein the acidifying agent is selected from the group comprising of hydrochloric acid, sulfuric acid, boric acid, silica acid, acetic acid, phosphoric acid, formic acid, maleic acid, citric acid, tri-chloroacetic acid, trifluoroacetic acid, benzoic acid, fumaric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.