GADOLINIUM COMPLEX AND A DIASTEREOISOMERICALLY ENRICHED PCTA-DERIVED CHELATING LIGAND AND METHOD OF PREPARATION AND PURIFICATION

Abstract

The present invention relates to a complex of formula (II) consisting of at least 90% of a diastereomeric excess comprising a mixture of II-RRR and II-SSS isomers of formulas: (see Formulas) (II-SSS) (II-RRR) The present invention also relates to a process for the preparation and purification of said complex of formula (II), as well as a composition comprising said complex.

Description

GADOLINIUM COMPLEX AND A DIASTEREOISOMERICALLY ENRICHED PCTA-DERIVED OULATING LIGAND AND METHOD OF PREPARATION AND PURIFICATION The present invention relates to a novel process for preparing and purifying a gadolinium complex and a PCTA-derived chelating ligand, preferably yielding stereoisomers of said complex with physicochemical properties particularly advantageous for applications as a contrast agent in medical imaging, especially magnetic resonance imaging. The present invention also relates to the diastereomerically enriched complex, a composition comprising said complex, a process for preparing the corresponding chelating ligand by decomplexing said complex, and the ligand itself. Numerous contrast agents based on lanthanide chelates (paramagnetic metals), particularly gadolinium (Gd), are known, as described, for example, in U.S. Patent No. 4,647,447. These products are often grouped under the term GBCA (Gadolinium-based contrast agent, gadolinium-based contrast products). Various products are marketed, including macrocyclic chelates such as DOTA-based gadoterate meglumine (1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid), DO3A-based gadobutrol, and HPDO3A-based gadoteridol, as well as linear chelates, particularly those based on DTPA (diethylenetriaminepentaacetic acid) or DTPA-BMA (gadodiamide ligand). Other products, some of which are under development, represent a new generation of GBCAs. They are essentially macrocyclic chelate complexes, such as bicyclopolyazamacrocyclocarboxylic acid (EP 0 438 206) or PCTA derivatives (i.e., comprising at least the chemical structure of 3,6,9,15-tetraazabichloro[9,3,1]pentadeca-1(15),11,13-triene3,6,9-triacetic acid), as described in EP 1 931 673. The PCTA-derived chelating ligand complexes described in EP 1 931 673 have the particular advantage of being relatively easy to synthesize chemically, and, in addition, exhibit a greater relaxation capacity than the other GBCAs (relaxation capacity n that can increase up to 11-12 mM'Ls'1 in water) currently on the market; this relaxation capacity corresponds to the effectiveness of these products and, therefore, to their contrasting power. In the body, lanthanide chelates (or complexes) (and in particular gadolinium) are in a state of chemical equilibrium (characterized by their constant Lcoonn / Lznz / E / YiAi thermodynamic Kterm), which can lead to an unwanted release of said lanthanide (see equation 1 below): [Chem. 1] Gh ' l π ___ί Ch-Lri (equation 1) Chemical equilibrium of complexation between the cheyate or ligand (Ch) and the lanthanide (Ln) to lead to the Ch-Ln complex. Since 2006, a condition called NSF (nephrogenic systemic fibrosis, also known as fibrogenic dermopathy) has been linked, at least in part, to the release of free gadolinium in the body. This condition has led to a warning from health authorities regarding gadolinium-based contrast agents marketed to certain patient groups. Therefore, strategies have been implemented to address the complex issue of patient tolerance in a completely safe manner and to limit, or even eliminate, the risk of unwanted lanthanide release after administration. This problem is further complicated by the fact that contrast agents are often administered repeatedly, either during diagnostic examinations or to adjust dosages and monitor the effectiveness of therapeutic treatments. Furthermore, since 2014, there have been reports of possible brain deposition of gadolinium following repeated administrations of gadolinium products, particularly linear gadolinium chelates. Such deposition has not been reported, or only slightly so, with macrocyclic gadolinium chelates, such as Dotarem®. Consequently, several countries have decided to withdraw most linear chelates from the market or drastically limit their indications for use, given their perceived insufficient stability. A primary strategy for limiting the risk of lanthanide release in the body is therefore to choose complexes that exhibit the greatest possible thermodynamic and / or kinetic stability. In fact, the more stable the complex, the greater the amount of lanthanides released over time. The prior art describes other areas for improving the tolerability of lanthanide chelates (especially gadolinium). US patent 5,876,695, dating back more than thirty years, reports, for example, formulations comprising, in addition to lanthanide chelate, an additional complexing agent intended to prevent unwanted in vivo release. Lcoonn / Lznz / E / YiAi of the lanthanide, forming a released lanthanide complex (Gd3+ metal ion). The additional chelating agent can be introduced into the formulation in free form or as a weak complex, typically with calcium, sodium, zinc, or magnesium. While it may be different from the ligand that constitutes the active complex, it is important that the complex formed with the released lanthanide be less stable than the active complex to avoid a transligation reaction between the active complex and the additional chelate. Such a transligation reaction would completely consume the additional ligand, preventing it from trapping the released lanthanide. This risk of consumption of the additional chelating agent by transligation is, for example, more pronounced when it is added in free form than as a calcium complex. Therefore, in the two strategies described above, it is important that the active complex be as stable as possible. Now, POTA-derived chelating ligand complexes comprising a piclene-type structure described in EP 1 931 673, although having good kinetic stability, generally have a lower thermodynamic constant than complexes of other cyclone-derived macrocycles. This is particularly the case of the complex of formula (II) represented below: [Chem. 2] Gil Lcoonn / ίζηζ / E / γίΛΐ HN r' H OF In fact, as described in particular in WO 2014 / 174120, the thermodynamic equilibrium constant corresponding to the reaction for the formation of the complex of formula (II), also called the stability constant, is 1014·9 (i.e., log(Kterm) = 14.9). By way of comparison, the stability constant of the gadolinium complex of 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA-Gd) is 10256 (i.e., log(Kterm) = 25.6). However, it should be noted that the complex of formula (II) corresponds to several stereoisomers, particularly due to the presence of the three asymmetric carbon atoms located in the α position of the complex's side chains, relative to the nitrogen atoms of the macrocycle to which these side chains are attached. These three asymmetric carbons are marked with an asterisk (*) in formula (II) shown above. Thus, the synthesis of the complex of formula (II) as described in document EP 1 931 673 results in obtaining a mixture of stereoisomers. The aminopropanediol groups of the side chains of the complex of formula (II) also contain an asymmetric carbon. Thus, the complex of formula (II) comprises a total of 6 asymmetric carbons, and therefore exists in the form of 64 stereoisomers of configuration. However, in the following description, the only source of stereoisomerism considered for a given side chain will be, for the sake of simplification, that corresponding to the asymmetric carbon bearing the carboxylate group, marked with an asterisk (*) in formula (II) shown above. Since each of these three asymmetric carbons can have either an absolute R or S configuration, the complex of formula (II) exists as eight families of stereoisomers, hereafter designated II-RRR, II-SSS, II-RRS, II-SSR, II-RSS, II-SRR, II-RSR, and II-SRS. More precisely, according to standard stereochemical nomenclature, the complex of formula (II) exists as eight families of diastereomers. The use of the term family is justified because each of these families includes several stereoisomers, particularly due to the presence of an asymmetric carbon within the aminopropanediol group, as mentioned above. However, insofar as the stereoisomerism linked to the asymmetric carbon of a given aminopropanediol group will not be considered in the following description, the isomers, stereoisomers, or diastereomers II-RRR, II-SSS, II-RRS, II-SSR, II-RSS, II-SRR, II-RSR, and II-SRS will be spoken of interchangeably, without specifying that each corresponds to a family of stereoisomers. The inventors succeeded in separating and identifying, by high-performance liquid chromatography (HPLC) and ultra-high-performance liquid chromatography (UHPLC), four groups of isomers of the complex of formula (II) obtained according to the process of the prior art, corresponding to four different elution peaks characterized by their retention time in the chromatogram, which will be referred to as isosol, iso2, iso3, and iso4 in the remainder of the description. By implementing the process described in EP 1 931 673, the respective contents of the isosol, iso2, iso3, and iso4 groups in the resulting mixture are as follows: 20%, 20%, 40%, and 20%. It was later discovered that these different groups of isomers had distinct physicochemical properties, and it was determined that the group of isomers called iso4, comprising a mixture of the II-RRR and II-SSS isomers (II-RRR) and (II-SSS) with formulas that are Lcoonn / Lznz / E / YiAi, shown below, turn out to be the most interesting as a contrast agent for medical imaging. [Chem. 3] OH (II-RRR) 0 Thus, iso4 is surprisingly distinguished by a markedly superior thermodynamic stability to that of the diastereomer mixture in the form in which the complex of formula (II) is obtained by implementing the process described in document EP 1 931 673. In fact, its thermodynamic equilibrium constant Kterm iso4 is equal to 10187 (i.e., log (Kterm iso4) = 18.7), this value having been determined by implementing the method in Pierrard et al. Contrast 5 Half Mol. Imaging, 2008, 3, 243-252 and Moreau et al., Dalton Trans., 2007,1611-1620. Furthermore, iso4 is the isomer group with the best kinetic inertness (also called kinetic stability) among the four groups isolated by the inventors. In fact, the inventors evaluated the kinetic inertness of the four isomer groups by studying their decomplexation kinetics in acidic aqueous solution (pH = 1.2) at 37°C. The half-life (T1 / 2) values ​​determined for each isomer group are shown in Table 1 below, with the half-life corresponding to the time after which 50% of the initially present complex has dissociated, according to the following decomplexation reaction (Equation 2): Lcoonn / Lznz / E / YiAi [Chem. 5] Table 1: Decomplexation kinetics of isomer groups from iso to iso4 Isomer groups T1 / 2 (pH 1.2 - 37°C) Isol 18 hours Iso2 6 hours Iso3 8 days Iso4 27 days By way of comparison, gadobutrol or gadoterate, the macrocyclic gadolinium complexes, have a kinetic inertia of 18 hours and 4 days respectively under the same conditions, while linear gadolinium complexes such as gadodiamide or gadopentetate dissociate instantly. Furthermore, iso4 is chemically more stable than iso3. In fact, the amide functional groups of the complex of formula (II) can be hydrolyzed. The hydrolysis reaction of an amide functional group (equation 3) results in the formation of an uncoupled impurity, accompanied by the release of 3-amino-1,2-propanediol. The inventors studied the kinetics of the hydrolysis reaction of the complex of formula (II) in aqueous solution at pH 13 and observed that the amide functional groups of iso4 are more stable with respect to hydrolysis than those of iso3. Lcoonn / Lznz / E / YiAi [Chem. 6] (equation 3) Regarding the relaxation capacity of the various isomer groups, i.e., their effectiveness as a contrast agent, the measurements carried out demonstrate a relatively equivalent contrast power for the isosol, iso2 and iso4 groups, and lower efficiency for iso3 (see Table 2). Table 2: Relaxation capacity of isomer groups to iso4 at 37°C Isomer groups n 20 MHz (mM'Ls'1) n 60 MHz (mM'Ls4) Isol 12.6 12.5 Iso2 13.3 12.9 Iso3 8.0 8.1 Iso4 12.9 13.0 The inventors have developed a new process for the preparation and purification of the complex of formula (II) that preferentially yields the diastereomers II-RRR and II-SSS of said complex, which have particularly advantageous physicochemical properties. The method according to the invention comprises an isomeric enrichment step, by converting the less stable stereoisomers into the more stable stereoisomers, which, surprisingly, while carried out in the intermediate hexaacid complex and not in the final complex, makes it possible to obtain most of the more stable isomers of the complex of formula (II). Implementing a process that allows for the predominant extraction of the desired diastereomers is undoubtedly advantageous compared to the alternative of preparing the stereoisomer mixture, then attempting to separate the diastereomers using conventional techniques, and finally isolating the isomers of interest using any well-known separation method. In fact, besides the ease of implementing a process without a diastereomer separation step on an industrial scale, the absence of this step allows for considerable time savings and improves the overall process yield by minimizing the production of unwanted diastereomers that would otherwise be discarded. Furthermore, conventional separation techniques generally involve the use of large quantities of solvents, which, beyond the financial cost, is undesirable for environmental reasons.In addition, chromatography on silica in particular should be avoided, given the health risks inherent in occupational exposure to silica, which is classified as carcinogenic to humans (group 1) by the International Agency for Research on Cancer. As indicated above, the process for preparing the complex of formula (II) developed by the inventors is based on an isomeric enrichment step of the intermediate hexaacid gadolinium complex of formula (I) depicted below: Lcoonn / Lznz / E / YiAi [Chem. 7] The complex of formula (I) corresponds to several stereoisomers, due to the presence of three asymmetric carbon atoms located in the α position of the complex's side chains, relative to the nitrogen atoms of the macrocycle to which these side chains are attached. These three asymmetric carbons are marked with an asterisk (*) in formula (I) shown above. Since each of the three asymmetric carbons bearing a carboxylate function can have an absolute R or S configuration, the complex of formula (I) exists as eight stereoisomers, hereafter designated I-RRR, I-SSS, I-RRS, I-SSR, I-RSS, I-SRR, I-RSR, and I-SRS. More precisely, according to standard stereochemical nomenclature, the complex of formula (I) exists as four pairs of enantiomers, which are diastereomers of each other. The inventors succeeded in separating and identifying by high-performance liquid chromatography (HPLC) and by ultra-high-performance liquid chromatography (UHPLC) 4 groups or groups of isomers of the complex of formula (I) obtained according to the method described in document EP 1 931 673, corresponding to 4 different elution peaks characterized by their retention time in the chromatogram, which will be called isoA, isoB, isoC and isoD in the rest of the description. IsoD crystallizes in water. X-ray diffraction analyses have allowed the inventors to determine the crystal structure of this group of isomers, and thus discover that it comprises the diastereomers I-RRR and I-SSS of the complex of formula (I), of formulas (I-RRR) and (I-SSS) shown below. Lcoonn / Lznz / E / YiAi [Chem. 8] [Chem. 9] (I-RRR) It should be noted that the diastereomers I-RRR and I-SSS of the complex of formula (I) are enantiomers of each other. The isomeric enrichment step of the process of the invention aims to enrich the intermediate hexaacid gadolinium complex of formula (I) in isoD. The synthesis of the complex of formula (II) notably involves a conversion of the carboxylic acid functions of the intermediate hexaacid complex of formula (I) into an amide function. This amidation reaction does not change the absolute configuration of the three asymmetric carbon atoms of the complex of formula (I). Thus, when the amidation reaction is carried out on the hexaacid complex of formula (I) enriched in isoD obtained previously, it makes it possible to obtain the complex of formula (II) enriched in iso4. Furthermore, the purification process developed by the inventors, when implemented following the process for the preparation of the formula (II) complex above, allows obtaining the formula (II) complex with an optimized isomeric profile, but also a significantly improved impurity profile. Therefore, this diastereomerically enriched and purified complex with improved stability can be formulated with a free macrocyclic ligand, such as free DOTA, instead of a DOTA calcium complex, the use of which was recommended in WO 2014 / 174120. The use of free DOTA has a particular advantage from an industrial point of view, as it allows omitting a step in the process for synthesizing the formulation as described in WO 2014 / 174120, namely the addition of CaCb. Formula complex (ID Therefore, the present invention relates firstly to a complex of formula (II): consisting of at least 80% of a diastereomeric excess comprising a mixture of II-RRR and II-SSS isomers of the following formulas: [Chem. 11] Lcoonn / Lznz / E / YiA I ¡N (II-SSS) [Chem. 12] I ¡N.. (II-RRR) In the context of the present invention, and with respect to the complex of formula (II), "diastereoisomeric excess" means that the complex is predominantly present as an isomer or group of isomers selected from the diastereoisomers II-RRR, II-SSS, II-RRS, II-SSR, II-RSS, II-SRR, II-RSR, and II-SRS. This diastereoisomeric excess is expressed as a percentage and corresponds to the amount represented by the majority of the isomer or group of isomers relative to the total amount of the complex of formula (II). This percentage may be either molar or mass, since the isomers, by definition, have the same molar mass. In one particular embodiment, the formula complex (II) according to the invention has at least 85%, in particular at least 90%, in particular at least 92%, preferably at least 94%, advantageously at least 97%, more advantageously at least 99% of the diastereomeric excess comprising the mixture of II-RRR and II-SSS isomers. Preferably, said diastereoisomeric excess consists of at least 70%, in particular at least 80%, advantageously at least 90%, preferably at least 95% of the mixture of II-RRR and II-SSS isomers. Advantageously, this diastereomeric excess consists of a mixture of II-RRR and II-SSS isomers. The term II-RRR and II-SSS isomer mixture also covers, by extension, the case where only one of the isomers, either II-RRR or II-SSS, is present. However, the term II-RRR and II-SSS isomer mixture preferably designates all cases where each of the II-RRR and II-SSS isomers is present in a variable but not zero amount. In a preferred embodiment, the II-RRR and II-SSS isomers are present within said mixture in a ratio between 65 / 35 and 35 / 65, in particular between 60 / 40 and 40 / 60, and in particular between 55 / 45 and 45 / 55. Advantageously, the II-RRR and II-SSS isomers are present in the mixture in a 50 / 50 ratio. More specifically, the diastereoisomeric excess as defined above corresponds to peak 4 of the UHPLC graph (i.e., the fourth mass of isomers in the elution order and corresponding to iso4), characterized by a retention time of between 6.0 and 6.6 minutes, typically around 6.3 minutes, with said graph being obtained by implementing the UHPLC method described below. In the sense of the present invention, a UHPLC graph is understood to be the profile of the concentrations measured by the detector after the passage and separation of a mixture of compounds (in this case, isomers of a compound) on a stationary phase as a function of time for a given composition and eluent flow rate. The UHPLC graph consists of different peaks or peaks characteristic of the compound or mixture of compounds being analyzed. UHPLC method: - CORTECS® UPLC T3 150 x 2.1 mm -1.6 pm column from Waters. It is a reversed-phase UPLC column with spherical particles consisting of a core, preferably very hard, made of silica surrounded by porous silica with a C18 (octadecyl) trifunctional graft, and silanols of which have been treated with protective agents (end-coated). It is further characterized by a length of 150 mm, an internal diameter of 2.1 mm, a particle size of 1.6 pm, a porosity of 120 Å, and a carbon content of 4.7%. Lcoonn / Lznz / E / YiAi Preferably, the stationary phase used should be compatible with the aqueous mobile phases. - conditions of analysis: Lcoonn / Lznz / E / YiAi Table 3 Sample Aqueous solution of the complex of formula (II) at 2.0 mg / mL Column temperature 40°C Sample temperature Room temperature (20-25°C) Flow rate 0.3 mL / min Injection volume IpL UV detection 200 - mobile phase gradient (% v / v): Table 4 Time (min) Acetonitrile (100%) H2SO4 (0.0005% v / v aqueous solution) 0 1 99 3 5 95 12 10 90 Composition that comprises the complete CID formula The present invention relates secondly to a composition comprising: - the complex of formula (II) consisting of at least 80% of a diastereomeric excess comprising a mixture of II-RRR and II-SSS isomers, and - a free macrocidic ligand. In this description, the terms macrocidic ligand or macrocidic chelate may be used interchangeably. In the context of the present invention, the term macrocycle designates a ring that typically comprises at least 9 atoms, whether carbon atoms or heteroatoms, and the macrocidic ligand or macrocidic chelate is a polydentate ligand, at least bidentate. For the purposes of this invention, "free macrocidic ligand" means the macrocidic ligand in its free, i.e., non-complexed form, particularly with metals—including lanthanides and actinides—or with alkali earth cations such as calcium or magnesium. Specifically, the free macrocidic ligand is not in the form of a complex with gadolinium and is not introduced into the composition as a weak complex, typically with calcium, sodium, zinc, or magnesium, as described in US patent 5,876,695. However, the presence of such cations in a trace state in the composition, and therefore of the corresponding complexes, is not excluded. As discussed previously, the formulation of the complex of formula (II) with a free macrocyclic ligand, and not a weak complex of said macrocyclic ligand as recommended in EP 1 931 673, is made possible by the improved stability of the diastereoisomerically enriched complex of formula (II) according to the invention. In a preferred embodiment, the complex of formula (II) present in the composition of the invention has at least 85%, in particular at least 90%, in particular at least 92%, more particularly at least 94%, preferably at least 97%, advantageously at least 99%, of the diastereomeric excess comprising the mixture of isomers II-RRR and II-SSS. Preferably, said diastereoisomeric excess consists of at least 70%, in particular at least 80%, advantageously at least 90%, preferably at least 95% of the mixture of II-RRR and II-SSS isomers. Advantageously, this diastereomeric excess consists of a mixture of II-RRR and II-SSS isomers. The term II-RRR and II-SSS isomer mixture also covers, by extension, the case where only one of the isomers, either II-RRR or II-SSS, is present. However, the term II-RRR and II-SSS isomer mixture preferably designates all cases where each of the II-RRR and II-SSS isomers is present in a variable but not zero amount. In a preferred embodiment, the II-RRR and II-SSS isomers are present within said mixture in a ratio between 65 / 35 and 35 / 65, in particular between 60 / 40 and 40 / 60, and in particular between 55 / 45 and 45 / 55. Advantageously, the II-RRR and II-SSS isomers are present in the mixture in a 50 / 50 ratio. In an advantageous embodiment, the composition according to the invention has a free gadolinium concentration of less than 1 ppm (w / v), preferably less than 0.5 ppm (w / v). In this description, unless otherwise stated, the terms Gd, gadolinium, and Gd3+ are used interchangeably to refer to the Gd3+ ion. By extension, it can also refer to a source of free gadolinium, such as gadolinium chloride (GdCh) or gadolinium oxide (Gd2O3). In the present invention, the term free Gd denotes the non-complexed forms of gadolinium, preferably available for complex formation. It is typically the Gd3+ ion dissolved in water. By extension, it can also be a source of free gadolinium, such as gadolinium chloride (GdCb) or gadolinium oxide (Gd2O3). Free gadolinium is generally measured by colorimetric dosage, usually with xylenol orange or Arsenazo(III). In the absence of a metal ion (such as gadolinium), These indicators (Lcoonn / Lznz / E / YiAi) have a specific color: at acidic pH, xylenol orange is yellow, while arsenazo is pink. In the presence of gadolinium, their color turns purple. Visual determination of the color change in the solution allows verification of the presence or absence of gadolinium in the solution. Furthermore, it is possible to quantitatively measure the free gadolinium present in the solution using a return assay, employing, for example, EDTA as the weak gadolinium chelate. In such an assay, the colored indicator is added until a purple color is obtained. Then, EDTA, a gadolinium ligand, is added to the mixture dropwise. Since EDTA is a stronger complexing agent than the colored indicator, the gadolinium will shift to the ligand, allowing the colored indicator to form a preferential complex with the EDTA. Therefore, the colored indicator will gradually revert to its non-complexed form. When the amount of EDTA added equals the initial amount of free Gd, the colored indicator is completely in its free form and the solution turns yellow. Knowing the amount of EDTA added allows us to determine the initial amount of free Gd in the solution being analyzed. These methods are well known to experts in the field, and are described in particular by the paper Barge et al. (Contrast Media and Molecular Imaging 1, 2006, 184-188). Therefore, these colorimetric methods are generally implemented in a solution whose pH is between 4 and 8. In fact, outside of these pH ranges, the accuracy of the measurement can be affected due to a modification (or even a deletion) of the color curve. Therefore, if necessary, the pH of the sample to be analyzed is adjusted between 4 and 8. In particular, if the pH of the sample is acidic and, in particular, less than 4, the pH is advantageously adjusted by adding a base, then the measurement of free Gd is carried out on the sample at the adjusted pH. The composition according to the invention thus exhibits long-term stability, meaning that its composition remains in accordance with specifications in terms of free gadolinium concentration (in particular, its free Gd concentration remains below 1 ppm (m / v)) for a period of at least 3 years, preferably at least 4 years, or even more preferably at least 5 years, particularly in terms of free paramagnetic metal content. According to ICH guidelines, observing this stability for 6 months at 40°C is considered a good indication of 3 years of stability at 25°C. In one particular embodiment, the composition according to the invention has a concentration of between 0.01 and 1.5 mol.L-1, preferably between 0.2 and 0.7 mol.L-1, more preferably between 0.3 and 0.6 mol.L-1 in the complex of formula (II) described above. Lcoonn / Lznz / E / YiAi The complex of formula (II) is determined by methods known to an expert in the field. In particular, it can be determined after mineralization and a determination of the total gadolinium present in the composition, by optical emission spectrometry (also called ICP-AES or ICP Atomic Emission Spectrometry). The composition of the complex described in formula (II) allows this formulation to have optimal contrast power while maintaining a satisfactory viscosity. In fact, below 0.01 mol / L⁴ of the aforementioned complex (II), its performance as a contrast agent is less satisfactory, and at concentrations above 1.5 mol / L⁴, the viscosity of this formulation becomes too high for easy handling. In one particular embodiment, the composition according to the invention comprises between 0.002 and 0.4% mol / mol, in particular between 0.01 and 0.3% mol / mol, preferably between 0.02 and 0.2% mol / mol, more preferably between 0.05 and 0.15% mol / mol of free macrocyclic ligand with respect to the complex of formula (II). Advantageously, the macrocyclic ligand is selected from the group consisting of DOTA, NOTA, DO3A, BT-DO3A, HP-DO3A, POTA, DOTA-GA and their derivatives. Preferably, it is DOTA (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid). The concentration of free DOTA in the composition is typically measured by a copper return assay, using, for example, copper sulfate as a source of copper ions. In this method, well known to those skilled in the technique, a solution containing a known initial concentration Qo of copper sulfate is preferably used, this concentration being greater than the amount of free ligand in the solution. The dosage solution, containing free DOTA in the amount Qi to be determined, is added to this copper sulfate solution. DOTA is a very good copper complexing agent; therefore, the formation of a DOTA-copper complex is observed. A return dosage of the free copper remaining in the solution is advantageously carried out by potentiometry. To do this, EDTA is added to the mixture drop by drop, for example. The EDTA will form complexes with free copper in solution without decomplexing the copper-DOTA, because DOTA is a stronger complexing agent than EDTA. When the amount of EDTA added (Q2) equals the amount of free copper in the solution, there is a sharp drop in the solution potential. Knowing the initial amount Qo of copper and the amount of EDTA added Q2, subtracting these two values ​​Qo - Q2 gives the amount of free EDTA in the dosage solution Qi. Alternatively, HPLC methods can be used, in particular the method HILIC LC-UV. These measurement methods (particularly potentiometric methods) are implemented in solutions whose pH is advantageously between 4 and 8. Therefore, if necessary, the pH of the sample to be analyzed is adjusted between 4 and 8. In particular, if the pH of the sample is acidic, and especially below 4, the pH is advantageously adjusted by adding a base such as meglumine; then the measurement of free DOTA is performed on the sample at the adjusted pH. Preferably, the proportions specified in the present invention and in particular above are proportions before sterilization of the composition. Advantageously, the pH of the composition is between 4.5 and 8.5, preferably between 5 and 8, advantageously between 6 and 8, especially between 6.5 and 8. These pH ranges make it possible in particular to limit the appearance of certain impurities and favor the complexation of the paramagnetic metal ion M. In particular, the composition according to the invention can be buffered, i.e., it can also comprise a buffer selected from established buffers for the pH range of 5 to 8 and preferably from lactate, tartrate, malate, maleate, succinate, ascorbate, carbonate, Tris (Tris(hydroxymethyl)aminomethane), HEPES (2-[4-(2-hydroxyethyl)-1-piperazine]ethanesulfonic acid), MES (2-morpholinoethanesulfonic acid) buffers and mixtures thereof, and preferably a buffer selected from the Tris, lactate, tartrate, carbonate, MES buffers and mixtures thereof. Advantageously, the composition according to the invention comprises the Tris buffer. The composition that is the subject of the invention is preferably sterile. Process for preparing the formula complex (II) The present invention further relates to a process for preparing the complex of formula (II) comprising the following successive steps: a) Complexation of the following hexaacid of formula (III): Lcoonn / Lznz / E / YiAi [Chem. 13] Ό L 'COQH (III) with gadolinium to obtain the hexaacid gadolinium complex of formula (I) as defined above, b) Heating isomerization of the hexaacid gadolinium complex of formula (I) in an aqueous solution at pH between 2 and 4, to obtain a diastereomerically enriched complex consisting of at least 80% of a diastereomeric excess comprising a mixture of I-RRR and I-SSS isomers of said hexaacid gadolinium complex of formula (I), and c) Formation, from the diastereomericly enriched complex obtained in step b), of the complex of formula (II), by reaction with 3-amino-l,2-propanediol. In this description, unless otherwise stated, the terms Gd, gadolinium, and Gd3+ are used interchangeably to refer to the Gd3+ ion. By extension, it can also refer to a source of free gadolinium, such as gadolinium chloride (GdCb) or gadolinium oxide (Gd2O3). In the present invention, the term free Gd denotes the non-complexed forms of gadolinium, preferably those available for complexing. It typically refers to the Gd3+ ion dissolved in water. By extension, it can also refer to a source of free gadolinium, such as gadolinium chloride (GdCb) or gadolinium oxide. Stage a) During this stage, a complexation reaction occurs between the hexaacid of formula (III) and gadolinium, which allows obtaining the gadolinium hexaacid complex of formula (I) as defined above. According to a particular embodiment, step a) comprises the reaction between the hexaacid of formula (III) and a source of free Gd in water. In a preferred embodiment, the source of free Gd is GdCb or GdOa, preferably Gd2O3. Preferably, the reagents used in step a), i.e. the gadolinium source (typically gadolinium oxide), the hexaacid of formula (III) and water, are as pure as possible, especially with regard to metallic impurities. Therefore, the gadolinium source will advantageously be gadolinium oxide, preferably with a purity greater than 99.99%, and more preferably greater than 99.999%. The water used in the process preferably comprises less than 50 ppm of calcium, more preferably less than 20 ppm, and most preferably less than 15 ppm of calcium. In general, the water used in the process is deionized water, injection water (ppi water), or purified water. Lcoonn / Lznz / E / YiAi Advantageously, the amounts of the reagents (the hexaacid of formula (III) and gadolinium) used in this step a) correspond to or are close to the stoichiometric proportions, as dictated by the equilibrium equation of the complexation reaction that takes place during this step. By close to stoichiometric proportions, it is understood that the difference between the molar proportions in which the reagents are introduced and the stoichiometric proportions is less than 15%, in particular less than 10%, preferably less than 8%. Gadolinium can be introduced in a slight excess relative to the stoichiometric proportions. The ratio of the amount of gadolinium introduced to the amount of hexaacid (III) introduced is then greater than 1, but typically less than 1.15, particularly less than 1.10, and advantageously less than 1.08. In other words, the amount of gadolinium introduced is greater than 1 equivalent (eq.), but typically less than 1.15 eq., particularly less than 1.10 eq., and advantageously less than 1.08 eq., with respect to the amount of hexaacid (III) introduced, which in turn corresponds to 1 equivalent. In the preferred embodiment according to which the source of free gadolinium is Gd2O3, the amount of Gd2O3 introduced is typically greater than 0.5 eq., but less than 0.575 eq., in particular less than 0.55 eq., advantageously less than 0.54 eq., relative to the amount of hexaacid of formula (III) introduced (1 eq.). According to a particular embodiment, stage a) comprises the following successive stages: a1) Preparation of an aqueous solution of hexaacid of formula (III), and a2) Addition, to the aqueous solution obtained in step a1), of a source of free gadolinium. In this embodiment, the content of hexaacid of formula (III) in the aqueous solution prepared during step a1) is typically between 10% and 60%, especially between 15% and 45%, preferably between 20% and 35%, advantageously between 25% and 35%, even more advantageously between 25% and 30% by weight with respect to the total weight of the aqueous solution. Preferably, steps a) and b) are carried out according to a one-pot embodiment, i.e., in the same reactor and without intermediate isolation or purification. Therefore, in this preferred embodiment, the hexaacid gadolinium complex of formula (I) formed during step a) is subjected directly to step b) of isomerization, without being isolated or purified, and in the same reactor as that used for step a). Lcoonn / Lznz / E / YiAi Stage b) The hexaacid gadolinium complex of formula (I) formed by the complexing reaction between the hexaacid of formula (III) and gadolinium during step a) is initially obtained in the form of a mixture of diastereomers. Step b) aims to enrich the diastereomeric mixture with the isomers I-RRR and I-SSS, to obtain the diastereomerically enriched hexaacid gadolinium complex of formula (I) consisting of at least 85%, in particular at least 90%, in particular at least 95%, preferably at least 97%, advantageously at least 98%, more advantageously at least 99% of the diastereomeric excess comprising the mixture of the isomers I-RRR and I-SSS. In the context of the present invention, and with respect to the hexaacid gadolinium complex of formula (I), the term "diastereoisomeric excess" refers to the fact that said complex is present mainly in the form of an isomer or group of isomers selected from the diastereoisomers I-RRR, I-SSS, I-RRS, I-SSR, I-RSS, I-SRR, I-RSR, and I-SRS. This diastereoisomeric excess is expressed as a percentage and corresponds to the amount represented by the major isomer or group of isomers relative to the total amount of the hexaacid gadolinium complex of formula (I). This percentage may be either molar or mass, insofar as the isomers, by definition, have the same molar mass. Preferably, said diastereoisomeric excess consists of at least 70%, in particular at least 80%, advantageously at least 90%, preferably at least 95% of the mixture of I-RRR and I-SSS isomers. Advantageously, this diastereomeric excess consists of a mixture of I-RRR and I-SSS isomers. In fact, the inventors have discovered that factors such as the pH and temperature of the solution of formula (I) of the hexaacid gadolinium complex obtained at the end of step a) influence the ratio in which the various isomers of the complex of formula (I) are present in the diastereomer mixture. Over time, the mixture tends to become enriched in a group of isomers comprising those that are, surprisingly, the most thermodynamically stable but also chemically stable—in this case, the I-RRR and I-SSS isomers. The term mixture of I-RRR and I-SSS isomers also covers, by extension, the case where only one of the isomers, either I-RRR or I-SSS, is present. However, in a preferred embodiment, the I-RRR and I-SSS isomers are present within said mixture in a ratio of between 65 / 35 and 35 / 65, in particular between 60 / 40 and 40 / 60, and in particular between 55 / 45 and 45 / 55. Advantageously, the mixture of I-RRR / I-SSS isomers is a racemic mixture (50 / 50). Lcoonn / Lznz / E / YiA Step b) of isomerization of the hexaacid gadolinium complex of formula (I) in an aqueous solution is typically carried out at a pH between 2 and 4, particularly between 2 and 3, advantageously between 2.2 and 2.8. The pH is preferably adjusted with an acid, preferably an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, for example with hydrochloric acid. It is quite surprising that under such pH conditions, the mixture would be enriched with particular isomers, in this case the I-RRR and I-SSS isomers, given that gadolinium chelates are known in the art to exhibit low kinetic inertia in an acidic medium. Indeed, the higher the concentration of H+ ions in the medium, the greater the probability that a proton will be transferred to one of the ligand donor atoms, leading to dissociation of the complex. Consequently, experts in the field would have expected that placing the gadolinium hexaacid complex of formula (I) in an aqueous solution at a pH between 2 and 4 would cause dissociation of the complex, and not its isomerization into I-RRR and I-SSS. It should be noted that the pH range recommended by document EP 1 931 673 for the complexation of the hexaacid of formula (III), i.e., 5.0-6.5, does not allow obtaining the complex of formula (I) enriched in its isomers I-RRR and I-SSS. Step b) is typically carried out at a temperature between 80°C and 130°C, particularly between 90°C and 125°C, preferably between 98°C and 122°C, advantageously between 100°C and 120°C, typically for a period of between 10 and 72 h, especially between 10 and 60 h, advantageously between 12 and 48 h. Contrary to all expectations, such temperature conditions, which, together with the pH conditions mentioned above, should promote the instability of the gadolinium chelate, do not lead to its decomplexation or the formation of any other impurity, but to its isomerization into I-RRR and I-SSS. In one particular embodiment, the aqueous solution of step b) comprises acetic acid. Step b) is advantageously carried out at a temperature between 100°C and 120°C, particularly between 110°C and 118°C, typically for a period between 12 and 48 h, particularly between 20 and 30 h, and particularly between 24 and 26 h. Acetic acid is preferably added before heating the solution of the hexaacid gadolinium complex of formula (I) obtained during step a) in an amount such that the acetic acid content is between 25% and 75%, in particular between 40% and 50% by mass with respect to the mass of hexaacid of formula (III) used during step a). Lcoonn / Lznz / E / YiAi When the aqueous solution is heated to a temperature advantageously between 100°C and 120°C, typically between 110°C and 118°C, acetic acid is added as the water evaporates, to maintain a constant volume of solution. According to a preferred embodiment, at the end of step b), the diastereomericly enriched complex is isolated by crystallization, preferably by seed crystallization. In this embodiment, stage b) comprises the following successive stages: b1) Heating isomerization of the hexaacid gadolinium complex of formula (I) in an aqueous solution at pH between 2 and 4, to obtain a diastereomerically enriched complex consisting of at least 80% of the diastereomeric excess comprising the mixture of I-RRR and I-SSS isomers of said hexaacid gadolinium complex of formula (I), and b2) Isolation by crystallization of said diastereomerically enriched complex preferably by seed crystallization. Step b2) of crystallization aims, on the one hand, to remove any impurities possibly present in the aqueous solution, which may result from the previous steps, in order to obtain a purer, decolorized product in crystalline form, and on the other hand, to continue the diastereomeric enrichment of the gadolinium hexaacid complex of formula (I), to obtain a diastereomeric excess comprising the mixture of the I-RRR and ISSS isomers of said complex that is greater than that obtained as a result of step b1). In fact, the I-RRR and I-SSS isomers of the hexaacid complex of formula (I) crystallize in water. On the other hand, the gadolinium hexaacid complex of formula (I) not enriched in these isomers does not crystallize. The fact that the I-RRR and I-SSS isomers, in which the complex tends to become enriched during step b) (contrary to all expectations, given the conditions under which it is carried out), are the only isomers of the complex that will crystallize in water is a completely unexpected result. Isomerization and crystallization thus contribute synergistically to the enrichment in the I-RRR and I-SSS isomers and, therefore, to the overall efficiency of the process according to the invention. Furthermore, it should be noted that crystallization in water of the isomers of interest of the hexaacid gadolinium complex of formula (I) allows avoiding the addition of solvent as described in Example 7 of EP 1,931,673, which involves a precipitation step in ethanol of the trisodium salt of said complex. Step b2) is advantageously carried out at a temperature between 10°C and 70°C, in particular between 30°C and 65°C, and especially between 35°C and 60°C. Alternatively, after lowering the temperature of the aqueous solution so that it is within the ranges indicated above, the crystallization process is induced by Lcoonn / Lznz / E / YiAi inoculation. Inoculation crystallization, also called initiation crystallization, involves introducing a known quantity of crystals, called a seed or initiator, into the reactor in which the crystallization takes place (also called a crystallizer). This reduces the crystallization time. Seed crystallization is well known to those skilled in the art. In the method according to the invention, seeding by using an initiator, in this case diastereomerically enriched gadolinium hexaacid complex crystals of formula (I) added to the previously lowered aqueous solution of the diastereomerically enriched complex, allows nucleation to occur and thus initiates crystallization. The duration of seed crystallization is advantageously between 2 and 20 hours, preferably between 6 and 18 hours, and typically 16 hours. Diastereomericly enriched hexaacid gadolinium complex crystals of formula (I) are typically isolated by filtration and drying, using any technique well known to experts in the field. Advantageously, the degree of purity of the diastereomerically enriched hexaacid gadolinium complex of formula (I) isolated at the end of step b2) is greater than 95%, in particular greater than 98%, advantageously greater than 99%, said degree of purity being expressed as a mass percentage of the complex of formula (I) in relation to the total mass obtained at the end of step b2). In one particular embodiment, the diastereomerically enriched complex from step b) isolated by crystallization is purified again by recrystallization, to obtain a diastereomerically enriched and purified complex. In this embodiment, step b) comprises, in addition to the successive steps bl) and b2) described above, a step b3) of purification by recrystallization of the diastereomerically isolated enriched hexaacid gadolinium complex of formula (I). The recrystallization step b3) aims, like the crystallization step b2), to obtain a higher purity product and to continue the diastereomeric enrichment of the gadolinium hexaacid complex of formula (I), to obtain a diastereomeric excess comprising the mixture of the I-RRR and I-SSS isomers of said complex greater than that obtained at the end of step b2). Stage b3) generally includes the following successive substages: • suspension of the diastereomerically enriched gadolinium hexaacid complex of formula (I) isolated during step b2) in aqueous solution, preferably in water, • solubilization of said complex by heating to a temperature advantageously between 80°C and 120°C, for example to 100°C, Lcoonn / Lznz / E / YiAi • recrystallization, preferably by seeding, at a temperature advantageously between 10°C and 90°C, particularly between 20°C and 87°C, particularly between 55°C and 85°C, typically for a period of between 2 hours and 20 hours, especially between 6 hours and 18 hours, and • isolation of diastereomerically enriched and purified hexaacid gadolinium complex crystals of formula (I), for example by filtration and drying. The degree of purity of the purified, enriched, diastereoisomerically isolated hexaacid gadolinium complex of formula (I) at the end of step b3) is typically greater than 98%, in particular greater than 99%, advantageously greater than 99.5%, said degree of purity being expressed as a mass percentage of the complex of formula (I) in relation to the total mass obtained at the end of step b2). In another embodiment, the diastereomericly enriched complex of step b) is further enriched by selective decomplexation of the diastereomers of the complex of formula (I) other than the diastereomers I-RRR and I-SSS, i.e., by selective decomplexation of the diastereomers I-RSS, I-SRR, I-RSR, I-SRS, I-RRS, and I-SSR. In this embodiment, step b) comprises, in addition to the successive steps b1) and b2) described above, a step b4) of selective decomplexation of the diastereomers of the complex of formula (I) other than the diastereomers I-RRR and I-SSS. In this variant, step b) may also include the step b3) described above, implementing said step b3) between steps b2) and b4), or after step b4). The selective decomplexation step b4) aims to continue the diastereomeric enrichment of the hexaacid gadolinium complex of formula (I), to obtain a diastereomeric excess comprising the mixture of the I-RRR and I-SSS isomers of said complex, greater than that obtained at the end of step b2) or at the end of step b3), when the latter is implemented before step b4). Stage b4) generally includes the following successive substages: • Suspend the diastereomerically isolated enriched hexaacid gadolinium complex of formula (I) from step b2) or step b3) in water, • Add a base, for example soda ash, • Heat to a temperature advantageously between 30°C and 60°C, particularly between 35°C and 55°C, for example at 40°C, typically for a period between 2 and 20 h, especially between 10 and 18 h, • Cool to a temperature advantageously between 10°C and 30°C, for example at Lcoonn / Lznz / E / YiAi 30°C, and • isolate from the diastereomerically enriched and purified hexaacid gadolinium complex of formula (I), for example by filtration and drying. Step b4) is possible because the I-RRR and I-SSS isomers are the most stable in a basic medium. Such basic conditions favor the formation of gadolinium hydroxide and, therefore, the decomplexation of the less stable isomers. It should be noted, therefore, that surprisingly, the I-RRR and I-SSS isomers are more stable both in an acidic medium, which allows step b) of isomerization, and in a basic medium, which allows step b4) of selective decomplexation. In a preferred embodiment, the diastereoisomerically enriched complex obtained at the end of step b) according to any of the variants described above has at least 85%, in particular at least 90%, in particular at least 95%, preferably at least 97%, advantageously at least 98%, more advantageously at least 99% of the diastereomeric excess comprising the mixture of the I-RRR and I-SSS isomers. Preferably, said diastereoisomeric excess consists of at least 70%, in particular at least 80%, advantageously at least 90%, preferably at least 95% of the mixture of I-RRR and I-SSS isomers. Advantageously, this diastereomeric excess consists of a mixture of I-RRR and I-SSS isomers. The term "mixture of I-RRR and I-SSS isomers" also covers, by extension, the case where only one of the isomers, either I-RRR or I-SSS, is present. However, the term "mixture of I-RRR and I-SSS isomers" preferably designates all cases where each of the I-RRR and I-SSS isomers is present in a variable but not zero amount. In a preferred embodiment, the I-RRR and I-SSS isomers are present within said mixture in a ratio of between 65 / 35 and 35 / 65, in particular between 60 / 40 and 40 / 60, and in particular between 55 / 45 and 45 / 55. Advantageously, the mixture of I-RRR / I-SSS isomers is a racemic mixture (50 / 50). Stage c) Step c) aims to form the complex of formula (II) from its precursor, the diastereomerically enriched hexaacid gadolinium complex of formula (I) obtained during step b). During this stage, the three carboxylic acid functional groups of the hexaacid complex of formula (I) are transported by the carbon atoms located in the position and in the side chains of the complex, in relation to the nitrogen atoms of the macrocycle into which they are grafted Lcoonn / Lznz / E / YiAi said side chains are converted into amide functions, by amidation reaction with 3-amino1,2-propanediol, in racemic or enantiomerically pure form, preferably in racemic form. This amidation reaction does not modify the absolute configuration of the three asymmetric carbon atoms located in the position or in the side chains, with respect to the nitrogen atoms of the macrocycle to which said side chains are grafted. Consequently, step c) makes it possible to obtain the complex of formula (II) with a diastereomeric excess comprising a mixture of the II-RRR and II-SSS isomers identical to the diastereomeric excess comprising a mixture of the I-RRR and I-SSS isomers with which the diastereomerically enriched gadolinium hexaacid complex of formula (I) obtained at the end of step b) is obtained, which is at least 80%. In a preferred embodiment, the complex of formula (II) obtained at the end of step c) has at least 85%, in particular at least 90%, in particular at least 92%, preferably at least 94%, advantageously at least 97%, more advantageously at least 99% of the diastereomeric excess comprising the mixture of isomers II-RRR and II-SSS. Preferably, said diastereoisomeric excess consists of at least 70%, in particular at least 80%, advantageously at least 90%, preferably at least 95% of the mixture of II-RRR and II-SSS isomers. Advantageously, this diastereomeric excess consists of a mixture of II-RRR and II-SSS isomers. The term II-RRR and II-SSS isomer mixture also covers, by extension, the case where only one of the isomers, either II-RRR or II-SSS, is present. However, the term II-RRR and II-SSS isomer mixture preferably designates all cases where each of the II-RRR and II-SSS isomers is present in a variable but not zero amount. In a preferred embodiment, the II-RRR and II-SSS isomers are present within said mixture in a ratio between 65 / 35 and 35 / 65, in particular between 60 / 40 and 40 / 60, and in particular between 55 / 45 and 45 / 55. Advantageously, the II-RRR and II-SSS isomers are present in the mixture in a 50 / 50 ratio. The amidation reaction can be carried out according to all methods well known to experts in the field, particularly in the presence of an agent that activates the carboxylic acid functions and / or in acid catalysis. In particular, it can be carried out in accordance with the methods described in patent EP 1,931,673, in particular in paragraph

[0027] of this patent. In a particular embodiment, step c) comprises the activation of the carboxylic acid (-COOH) functional groups of the hexaacid complex of formula (I) carried by the carbon atoms located at position and in the side chains of the complex, by relation to the atoms The nitrogen atoms of the macrocycle into which these side chains are grafted are derived functional groups comprising a carbonyl group (C=O), such that the carbon atom of the carbonyl group is more electrophilic than the carbon atom of the carbonyl group of the carboxylic acid functional groups. Therefore, according to this particular embodiment, these carboxylic acid functional groups can be activated, in particular, as ester, acyl chloride, acid anhydride, or any activated form capable of leading to an amide bond. Activated forms capable of leading to an amide bond are well known to those skilled in the art and, for example, can be obtained by all methods known in peptide chemistry for creating a peptide bond. Examples of such methods are given in the publication *Synthesis of peptides and peptidomimetics*, vol. E22a, pp. 425–588, by Houben-Weyl et al.Goodman Editor, Thieme-Stuttgart-New York (2004), and, among these examples, one can mention in particular the methods of activation of carboxylic acids through an azide (acyl azide), for example, by the action of a reagent such as diphenylphosphorylazide (commonly known by the acronym DPPA), the use of carbodiimides alone or in the presence of catalysts (for example, N-hydroxysuccinimide and its derivatives), the use of a carbonyldiimidazole (I,G-carbonyldiimidazole, CDI), the use of phosphonium salts such as benzotriazol-I-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (commonly known by the acronym BOP) or even uraniums such as 2-(IH-benzotriazol-I-yl)-I,3,3-tetramethyluronium hexafluorophosphate (commonly known by the acronym HBTU). Preferably, step c) comprises the activation of the carboxylic acid (-COOH) functions mentioned above in the form of ester functions, acyl chlorides or acid anhydrides. This embodiment is preferred to coupling peptides by activating the carboxylic acid function using a coupling agent such as EDCI / HOBT, as described in EP 1 931 673. In fact, such coupling results in the formation of an equivalent of 1-ethyl-3-[3-(dimethylamino)propyl]urea, which must be removed, particularly by silica chromatography or liquid / liquid extraction with the addition of a solvent. Regardless of the process complexity generated by this additional step, implementing such purification methods is undesirable, as discussed above. Furthermore, the use of HOBT is itself problematic, as it is an explosive product. For the purposes of the present invention, the ester function is understood to be a C(O)O- group. In particular, it may be a -C(O)O-Ri group, in which Ri corresponds to an alkyl group (Ci-C6). In the sense of the present invention, an alkyl group (Ci-Cs) means a saturated hydrocarbon chain, linear or branched, comprising 1 to 6, preferably 1 to 4, Lcoonn / Lznz / E / YiAi carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or even hexyl groups can be mentioned. The acyl chloride function, also called the acid chloride function, is understood in the sense of the present invention to be a -CO-CI group. For the purposes of this invention, the acid anhydride functional group is understood to be a -CO-O-CO- group. In particular, it may be a -CO-O-CO-R2 group, wherein R2 corresponds to an alkyl group (Ci-Ce). The reactions to convert a carboxylic acid functional group into an ester, acyl chloride, or acid anhydride functional group are well known to experts in the field, who can implement them according to any usual method with which they are familiar. The complex of formula (II) is then obtained by aminolysis of the activated carboxylic acid functions in the form of ester functions, acyl chlorides or acid anhydrides, in particular esters or acid anhydrides, preferably esters, by reaction with 3-amino-l,2-propanediol, in racemic or enantiomerically pure form, preferably in racemic form. Preferably, the activation steps of the carboxylic acid functions and the aminolysis steps are carried out according to a one-pot embodiment, i.e., in the same reactor and without an intermediate isolation or purification step of the intermediate comprising the activated carboxylic acid functions in the form of ester functions, acyl chlorides or acid anhydrides, in particular esters or acid anhydrides, preferably esters. According to a particular embodiment, stage c) comprises the following successive stages: the) formation of an activated complex of formula (VII), [Chem. 14] AND Lcoonn / Lznz / E / YiAi (VII) wherein Y represents a chlorine atom, an -ORi or -OC(O)-R2 group, preferably Y represents an -ORi or -OC(O)-R2 group, with Ri and R2 corresponding, independently of each other, to an alkyl group (Ci-Ce), and c2) aminolysis of the activated complex of formula (VII) with 3-amino-l,2-propanediol. As will be clear to someone skilled in the art, the reaction for the formation of the activated complex of formula (VII) does not alter the absolute configuration of the three asymmetric carbon atoms located at the α position in the side chains, relative to the nitrogen atoms of the macrocycle to which these side chains are grafted. Consequently, step (1) allows obtaining the activated complex of formula (VII) with a diastereomeric excess comprising a mixture of the VII-RRR and VII-SSS isomers, of formulas (VII-RRR) and (VII-SSS) shown below, identical to the diastereomeric excess comprising a mixture of the I-RRR and I-SSS isomers with which the diastereomerically enriched hexaacid gadolinium complex of formula (I) obtained at the end of step (b) is obtained, which is at least 80%. Lcoonn / Lznz / E / YiAi [Chem. 15] (VII-RRR). In the case where Y represents a chlorine atom, step (1) is typically carried out by reaction between the diastereomerically enriched hexaacid gadolinium complex of formula (I) obtained during step (b) and thionyl chloride (SOCb). In the case where Y represents a -OC(O)-CH3 group, step (11) is typically carried out by reaction between the diastereomerically enriched hexaacid gadolinium complex of formula (I) obtained during step (b) and acetyl chloride. In an advantageous embodiment, step c) comprises the activation of the aforementioned carboxylic acid (-COOH) functionalities in the form of ester functionalities. According to this realization, stage c) may more particularly comprise the following successive stages: the) formation of a triester of formula (VIII), [Chem. 17] Lcoonn / Lznz / E / YiAi (HIV) in which Ri represents an alkyl group (Ci-Ce), and c2) aminolysis of the triester of formula (VIII) with 3-amino-l,2-propanediol. The step (e) is typically carried out in the alcohol of formula RioH, which plays both the role of solvent and reagent, in the presence of an acid such as hydrochloric acid. Step c2) is also typically carried out in the alcohol of formula RioH, in the presence of an acid such as hydrochloric acid. Initially, the gadolinium hexaacid complex of formula (I) and the alcohol RiOH are charged into the reactor. The reaction medium is then cooled to a temperature below 10°C, specifically below 5°C, typically to 0°C, and an acidic solution of the alcohol RiOH, typically hydrochloric acid in RiOH, is gradually added. The reaction medium is kept under stirring at room temperature (i.e., between 20 and 25°C) for a period typically longer than 5 h, preferably between 10 and 20 h. The reaction medium is cooled to a temperature below 10°C, specifically between 0°C and 5°C, before step c2). Therefore, steps 11) and c2) can be easily implemented according to a one-pot embodiment. Advantageously, the triester of formula (VII) is not isolated between steps 11) and c2). However, to promote the aminolysis reaction, during step c2), the alcohol of formula RioOH is preferably removed by vacuum distillation. Vacuum distillation, in the sense of the present invention, means the distillation of a mixture carried out at a pressure between 10 and 500 mbar, in particular between 10 and 350 mbar, preferably between 10 and 150 mbar, and especially between 50 and 100 mbar. Similarly, to promote the aminolysis reaction, 3-amino-1,2-propanediol is introduced in large excess during step c2). Typically, the amount of 3-amino-1,2-propanediol introduced is greater than 4 eq., particularly greater than 7 eq., and advantageously greater than 10 eq., relative to the amount of diastereomerically enriched hexaacid gadolinium complex material of formula (I) initially introduced during step c), which corresponds to 1 equivalent. Surprisingly, despite the acidic conditions typically employed during steps (11) and (c2), which should increase the kinetic instability of the gadolinium complexes, no decomplexation or isomerization of the triester of formula (VIII) is observed. The desired triamide is obtained with a very good conversion rate, and the absolute configuration of the three asymmetric carbon atoms located in the α position of the side chains, relative to the nitrogen atoms of the macrocycle, is preserved. Furthermore, it should be noted that, in general, amidation reactions by direct reaction between an ester and an amine are very poorly described in the literature (see on this subject KC Nadimpally et al., Tetrahedron Letters, 2011, 52,2579-2582). In a preferred embodiment, step c) comprises the following successive steps: 1) formation of a methyl triester of formula (IV), Lcoonn / Lznz / E / YiAi [Chem. 18] Lcoonn / Lznz / E / YiA OIW (IV) in particular by reaction in methanol in the presence of an acid such as hydrochloric acid, and c2) aminolysis of the methyl triester of formula (IV) with 3-amino-l,2-propanediol, in particular in methanol in the presence of an acid such as hydrochloric acid. Advantageously, the methyl triester of formula (IV) is not isolated between steps 11) and c2). In a preferred embodiment, during step c2), the methanol is removed by vacuum distillation, until a temperature typically above 55°C is reached, in particular between 60°C and 65°C, and the reaction medium is maintained at this temperature under vacuum for a duration typically above 5 h, in particular between 10 and 20 h, before being cooled to room temperature and diluted with water. The present invention encompasses all combinations of the particular, advantageous, or preferred embodiments described above in relation to each stage of the process. Preparation of the hexaacid of formula (III) The hexaacid of formula (III), which is produced during step a) of the process for preparing the complex of formula (II) according to the invention, can be prepared according to all known methods and in particular according to the methods described in patent EP 1 931 673. However, according to a preferred embodiment, the hexaacid of formula (III) is obtained by alkylation of the pidene of formula (V): [Chem. 19] ÑH HR í N '' (V) with a compound of formula R3OOC-CHGP-(CH2)2-COOR4 (IX), in which: - R3 and R4 represent, independently of each other, an alkyl group (C3-C6), in particular an alkyl group (C4-C6) such as a butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl group, and - GP represents a leaving group such as a tosylate, a triflate group or a halogen atom, preferably a bromine atom, to obtain the hexaester of formula (X) [Chem. 20] Lcoonn / Lznz / E / YiAi0 xcoor4(X) followed by a hydrolysis step, which leads to said hexaacid of formula (III). In a preferred embodiment, R3 and R4 are identical. According to an advantageous embodiment, the hexaacid of formula (III) is obtained by alkylation of piclene of formula (V): [Chem. 21] (V) with dibutyl 2-bromoglutarate, to obtain the butyl hexaester of formula (VI): [Chem. 22] UBu J'Ni·'·,. COOBU ;-NN —( Lcoonn / Lznz / E / YiAi n -.y 'X Ν. X / '' or L COOBu (VI) followed by a hydrolysis step, which leads to said hexaacid of formula (III). The dibutyl 2-bromoglutarate used is in racemic or enantiomerically pure form, preferably in racemic form. The use of dibutyl 2-bromoglutarate is particularly advantageous compared to that of ethyl 2-bromoglutarate described in EP 1 931 673. In fact, commercial diethyl 2-bromoglutarate is a relatively unstable compound that degrades over time and under the effect of temperature. More specifically, this ester tends to hydrolyze or cyclize and thus loses its bromine atom. Attempts to purify commercial diethyl 2-bromoglutarate or to develop new synthetic routes to obtain it with improved purity, thereby preventing its degradation, have not been successful. The alkylation reaction is typically carried out in a polar solvent, preferably water, particularly deionized water, advantageously in the presence of a base such as potassium or sodium carbonate. The use of water is preferred in particular to that of acetonitrile, described in document EP 1 931 673, for obvious reasons. The reaction is advantageously carried out at a temperature between 40°C and 80°C, typically between 50°C and 70°C, particularly between 55°C and 60°C, for a period between 5 and 20 h, particularly between 8 and 15 h. The hydrolysis step is advantageously carried out in the presence of an acid or a base, advantageously a base such as sodium hydroxide. The hydrolysis solvent can be water, an alcohol such as ethanol, or a water / alcohol mixture. This step is advantageously carried out at a temperature between 40°C and 80°C, typically between 40°C and 70°C, especially between 50°C and 60°C, typically for a period between 10 and 30 hours, particularly between 15 and 25 hours. Procedure for purifying the LID formula complex The present invention further relates to a process for purifying the complex of formula (II) below: with at least 80% of a diastereomeric excess comprising a mixture of II-RRR and II-SSS isomers of formula: [Chem. 24] (II-SSS) [Chem. 25] HN Lcoonn / Lznz / E / YiA OH (II-RRR) including: 1) the combination of the following 2 stages: (b) passage over ion exchange resin(s), and (e) ultrafiltration of said complex, and 2) isolation of the purified complex thus obtained in solid form. Advantageously, said complex of formula (II) has at least 80%, preferably at least 85%, in particular at least 90%, in particular at least 95%, more particularly at least 97%, preferably at least 98%, advantageously at least 99%, of a diastereomeric excess comprising a mixture of II-RRR and II-SSS isomers previously obtained according to the preparation process described above. In a preferred embodiment, the diastereomerically enriched complex in which the purification process is implemented has at least 85%, in particular at least 90%, in particular at least 92%, preferably at least 94%, advantageously at least 97%, more advantageously at least 99% of the diastereomeric excess comprising the mixture of II-RRR and II-SSS isomers. Preferably, said diastereoisomeric excess consists of at least 70%, in particular at least 80%, advantageously at least 90%, preferably at least 95% of the mixture of II-RRR and II-SSS isomers. Advantageously, this diastereomeric excess consists of a mixture of II-RRR and II-SSS isomers. The term II-RRR and II-SSS isomer mixture also covers, by extension, the case where only one of the isomers, either II-RRR or II-SSS, is present. However, the term II-RRR and II-SSS isomer mixture preferably designates all cases where each of the II-RRR and II-SSS isomers is present in a variable but not zero amount. In a preferred embodiment, the II-RRR and II-SSS isomers are present within said mixture in a ratio between 65 / 35 and 35 / 65, in particular between 60 / 40 and 40 / 60, and in particular between 55 / 45 and 45 / 55. Advantageously, the II-RRR and II-SSS isomers are present in the mixture in a 50 / 50 ratio. Combination of steps Ib) and 1c) Steps Ib) and le) aim to purify the complex of formula (II) by removing impurities that may be present due to the process used to obtain it. These impurities may include in particular 3-amino-l,2-propanediol and / or a decoupled impurity. In fact, 3-amino-1,2-propanediol may be present in the final product obtained during the implementation of a process for the preparation of the complex of formula (II), typically when the complex of formula (II) is obtained by amidification of the complex of formula (I) and 3-amino-1,2-propanediol. This is particularly the case for the process for preparing the complex of formula (II) according to the invention. As detailed above, the amidification reaction may comprise the activation of the three carboxylic acid functional groups carried by the carbon atoms located in the γ position in the side chains of the complex of formula (I), relative to the nitrogen atoms of the macrocycle onto which said side chains are grafted, followed by aminolysis of the activated carboxylic acid functional groups by reaction with 3-amino-1,2-propanediol.3-Amino-l,2-propanediol is advantageously used in excess to ensure good conversion to amide functions of the three activated carboxylic acid functions. Decoupled impurity means a complex of formula (II-dc-a), (II-dc-b), (II-dc-c) shown below or a mixture thereof: [Chem. 26] Lcoonn / Lznz / E / YiAi (II-dc-a) Lcoonn / Lznz / E / YiA (II-dc-c) The uncoupled impurity may result, in particular, from the hydrolysis reaction of an amide functional group of the complex of formula (II). It may also result from incomplete activation of the carboxylic acid functional groups of the complex of formula (I) (activation of two of the three functional groups) or from incomplete aminolysis of the activated carboxylic acid functional groups (aminolysis of two of the three functional groups), when the process for preparing the complex of formula (II) implements such steps. This is particularly the case for the process for preparing the complex of formula (II) according to the invention. Step Ib) corresponds to the step over the ion exchange resin(s) of the complex of formula (II) enriched diastereoisomerically as described above. In the context of this invention, an ion exchange resin is understood to be a solid material, generally in the form of beads, composed of a polymer matrix onto which positively charged (anionic resin) or negatively charged (cationic resin) functional groups are grafted, enabling the trapping of anions or cations, respectively, by adsorption. The adsorption of anions or cations onto the resin is achieved through ion exchange between the counterions of the functional groups initially present to ensure the electroneutrality of the resin, and the anions or cations intended to be trapped. Step Ib) comprises contacting an aqueous solution of the complex of formula (II) enriched diastereomerically with a strong anionic resin. The water used is preferably purified water. Such a strong anionic resin typically comprises, as functional exchange groups, ammonium groups (N(RR'R)+, where R, R', and R are identical or different (Ci-Ce) alkyl groups). Amberlite® FPA900 resin, sold by Dow Chemical, advantageously available in HO' form, is a prime example. Passing through a strong anionic resin allows the removal, at least in part, of the decoupled impurities. Step Ib) may further comprise contacting an aqueous solution of the complex of formula (II) enriched diastereomerically with a weak cationic resin. The water used is preferably purified water. This weak cation resin typically comprises carboxylate (CO2') groups as cation exchange functional groups. The IMAC® HP336 resin, sold by Dow Chemical, advantageously in the H+ form, is a prime example. The step over a weak cationic resin makes it possible to remove, at least in part, the 3-amino-l,2-propanediol and possible Gd3+ residues. It should be noted that step Ib) of the step on ion exchange resin(s) is possible thanks to the improved stability of the diastereomerically enriched complex of formula (II) according to the invention, whose integrity is therefore preserved during this step. Step l1 corresponds to the ultrafiltration of the diastereomerically enriched formula (II) complex as described above. In the present invention, the term ultrafiltration is intended to denote a method of filtration through a semipermeable mesoporous membrane, the pores of which generally have a diameter of between 1 and 100 nm, particularly between 2 and 50 nm, and especially between 10 and 50 nm (mesopores), under the effect of forces such as pressure gradients, typically between 1 and 10 bar, and possibly concentration gradients. It is therefore a membrane separation process by which particles in solution or suspension whose size is larger than that of the pores are retained by the membrane and separated from the liquid mixture containing them. In the context of the purification process according to the invention, ultrafiltration is particularly advantageous for removing endotoxins. Lcoonn / Lznz / E / YiAi Advantageously, the ultrafiltration membrane used in stage l1 has a cut-off threshold of less than 100 kD, in particular less than 50 kD, in particular less than 25 kD, typically a cut-off threshold of 10 kD. Preferably, during stage l1), the transmembrane pressure is between 1 and 5 bar, particularly between 2.25 and 3.25 bar. In one particular embodiment, steps Ib) and le) are also combined with a nanofiltration step la). In the present invention, nanofiltration refers to a filtration method using a semipermeable porous membrane, the pores of which generally have a diameter between 0.1 and 100 nm, particularly between 0.1 and 20 nm, and especially between 1 and 10 nm, under the effect of forces such as pressure gradients, typically between 1 and 50 bar, and possibly concentration gradients. It is therefore a membrane separation process by which particles in solution or suspension larger than the pore size are retained by the membrane and separated from the liquid mixture containing them. The nanofiltration stage 1a) allows the removal of most of the excess 3-amino-l,2propanediol (optionally in the form of a salt, in particular hydrochloride, or derivatives, in particular the acetamide derivative) and mineral salts. In this particular embodiment, the nanofiltration step can be carried out directly on the crude diastereomerically enriched complex of formula (II) as obtained according to the preparation process described above. Specifically, it is not necessary to precipitate the previously prepared diastereomerically enriched complex of formula (II) by adding solvent. Advantageously, the nanofiltration membrane used in stage a1) has a cutoff threshold of less than 1 kD, in particular less than 500 Daltons, in particular less than 300 Daltons, typically, a cutoff threshold of 200 Daltons. Preferably, during stage 1a), the transmembrane pressure is between 10 and 40 bar, particularly between 2 and 30 bar. In particular, the temperature of the solution of the complex of formula (II) subjected to ultrafiltration during step a1) is between 20 and 40°C, in particular between 25 and 35°C. In an alternative to this particular embodiment, step Ib) does not include contacting an aqueous solution of the complex of formula (II) enriched diastereomerically with a weak cationic resin. In one particular embodiment, steps 1a) when present, 1b, and 1c are carried out in this order. This advantageous embodiment makes it possible, in particular, to minimize the quantities of resins used and, therefore, the cost of industrial manufacturing. Lcoonn / Lznz / E / YiAi Stage 2) Step 2) aims to isolate in solid form the purified complex of formula (II) obtained at the end of the combination of steps Ib) and le), and optionally further combined in step la). This solid-form isolation stage can be carried out according to any method well known to those skilled in the art, in particular by atomization, precipitation, lyophilization or centrifugation, advantageously by atomization. In a preferred embodiment, step 2) includes atomization. In fact, the isolation in solid form of the complex of formula (II) purified by atomization allows in particular the elimination of the use of precipitation solvents. The air inlet temperature in the atomizer is typically between 150°C and 180°C, particularly between 160°C and 175°C, advantageously between 165°C and 170°C. The outlet temperature is typically between 90°C and 120°C, preferably between 105°C and 110°C. Advantageously, the degree of purity of the diastereoisomerically enriched complex of formula (II) in the mixture of II-RRR and II-SSS isomers purified and isolated at the end of step 2) is greater than 95%, in particular greater than 97%, preferably greater than 97.5%, more preferably greater than 98%, advantageously greater than 99%, said degree of purity being expressed as a mass percentage of the complex of formula (II) with respect to the total mass obtained at the end of step 2). The present invention further relates to the diastereomerically enriched and purified complex of formula (II), which can be obtained according to the purification process of the invention. Preferably, the complex of formula (II) included in the composition according to the invention described above is the diastereomerically enriched and purified complex of formula (II), obtainable according to the purification process of the invention. EXAMPLES The examples given below are presented by way of illustration and without limitation of the invention. Lcoonn / Lznz / E / YiA Separation of the isomer groups isosol, iso2, iso3 and iso4 from the complex of formula (II) by UHPLC A UHPLC device is used, consisting of a pumping system, an injector, a chromatographic column, a UV detector, and a data station. The chromatographic column used is a 150 x 2.1 mm - 1.6 pm UHPLC column (Waters CORTECS® UPLC T3 column). Lcoonn / Lznz / E / YiAi - Mobile phase: Route A: 100% acetonitrile and Route B: aqueous solution of H2SO4 (96%) at 0.0005% - Preparation of test solutions: Solution of the formula complex (II) at 2 mg / ml in purified water. - Analysis conditions: Table 5 Column temperature 40°C Sample temperature Ambient temperature (20-25°C) Flow rate 0.3 ml / min Injection volume 1 μL UV detection 200 nm Analysis time 20 min Gradient: Table 6 Time % Acn % H2SO4 0.0005 % 0 1 99 3 5 95 12 10 90 15 25 75 16 1 99 20 1 99 Four main peaks are obtained. Peak 4 of the UHPLC graph, i.e., iso4, corresponds to a retention time of 6.3 minutes. Preparation of the butylhexaester of formula (VI) In a reactor, 184 kg (570 moles) of dibutyl 2-bromoglutarate and 89 kg (644 moles) of potassium carbonate are mixed and heated to 55–60°C. An aqueous solution of 29.4 kg (143 moles) of piclene in 24 kg of water is added to the mixture. The reaction mixture is maintained at 55–60°C and then heated under reflux for ten hours. After the reaction, the medium is cooled, diluted with 155 kg of toluene, and then washed with 300 liters of water. The butylhexane ester is extracted in the aqueous phase with 175 kg (1340 moles) of 75% phosphoric acid. It is then washed three times with 150 kg of toluene. Butyl hexyester is re-extracted from the toluene phase by dilution with 145 kg of toluene and 165 kg of water, followed by basification with 30% (w / w) sodium hydroxide to achieve a pH of 5–5.5. The lower aqueous phase is discarded. Butyl hexyester is obtained by dry vacuum concentration at 60°C with a yield of approximately 85%. Preparation of the hexaacid of formula (III) In a reactor, 113 kg (121 moles) of butylhexane ester and 8 kg of ethanol are charged. The medium is heated to 55 ± 5°C, and then 161 kg (1207.5 moles) of 30% (w / w) sodium hydroxide are added over 3 hours. The reaction mixture is maintained at this temperature for approximately 20 hours. The butanol is then removed from the reaction medium by decantation. The resulting hexaacid (III) as a sodium salt is diluted with water to obtain an aqueous solution of approximately 10% (w / w). This solution is treated in an acidic cation exchange resin. The aqueous hexaacid (III) solution is obtained with a yield of approximately 90% and a purity of 95%. Preparation of the hexaacid gadolinium complex of formula (I) Experimental protocol • Co-oiling and isomerization. Acetic acid free In a reactor, 418 kg (117 kg of pure hexaacid of formula (111) / 196 moles) of a 28 wt% aqueous solution of hexaacid of formula (III) are charged. The pH of the solution is adjusted to 2.7 by adding hydrochloric acid, then 37 kg (103.2 moles) of gadolinium oxide are added. The reaction medium is heated to 100–102°C for 48 hours to achieve the expected isomeric distribution of the hexaacid of formula (III). Lcoonn / Lznz / E / YiAi With acetic acid Gadolinium oxide (0.525 mol eq.) is suspended in a 28.1% by mass hexaacid solution of formula (III). Acetic acid 99-100% (50% by mass / pure hexaacid of formula (III)) is poured into the medium at room temperature. The medium is heated under reflux and then distilled at 113°C by mass, recharging the medium with acetic acid as the water is removed. Once 113°C is reached, add enough acetic acid to return to the initial volume. The environment remains at 113°C during the night. "Crystallization, recrystallization" - Crystallization The gadolinium hexaacid complex of formula (I) in solution is cooled to 40°C, the primer is added, and it is left in contact for at least 2 hours. It is then isolated by filtration at 40°C and washed with reverse osmosis water. - recrystallization 180 kg of the previously obtained hexaacid gadolinium complex of formula (I) (approximately 72% dry extract) are suspended in 390 kg of water. The medium is heated to 100°C to dissolve the product, then cooled to 80°C to initiate the reaction by adding a small amount of initiator. After cooling to room temperature, the hexaacid gadolinium complex of formula (I) is isolated by filtration and drying. • Selective decompletion The dry product is loaded into the reactor with reverse osmosis water at 20°C. The mass of water added is equal to twice the mass of the gadolinium hexaacid complex with theoretical formula (I). 30.5% (w / w) soda ash (6.5 eq) is added to the medium at 20°C. The medium is left in contact at 50°C for 16 hours after the NaOH addition. The medium is then cooled to 25°C and the product is filtered through a Clarcel bed. Content in the mixture of diastereomers I-RRR and I-SSS The proportion in which the different isomers of the complex of formula (I) are present within the mixture of diastereomers depends on the conditions under which the complexation and isomerization steps are carried out, as shown in Table 3 below. Lcoonn / Lznz / E / YiAi Table 7 p / / Temperature Content in hexaacid of formula (III) Duration Diastereoisomeric excess in the mixture of I-RRR and I-SSS 5.7 80°C 40% 3h 19% 3.5 90°C 50% 10 h 49% 3.0 101°C 40% 10 h 68% 2.7 101°C 28% 48 hours 98.04% Lcoonn / Lznz / E / YiAi Table 3: Content of the I-RRR and I-SSS mixture as a function of the complexation / isomerization conditions Additional recrystallization and selective decomplexation steps allow increasing the diastereoisomeric excess by mixing I-RRR and I-SSS (see Table 4). Table 8 After Ia re-crystallization After Ia re-crystallization After selective decomplexation Diastereoisomeric excess in the I-RRR and I-SSS mixture 98.04% 99.12% 99.75% Table 4: Content in the I-RRR and I-SSS mixture after crystallization / recrystallization / selective decomplexation Preparation of the formula complex (II) In a reactor, 90 kg (119 moles) of the hexaacid complex of formula (I) and 650 kg of methanol are charged. The mixture is cooled to approximately 0°C, and then 111 kg (252 moles) of a methanolic hydrochloric acid solution (8.25% HCl in methanol) is added while maintaining the temperature at 0°C. The reaction medium is brought to room temperature and then stirred for 16 hours. After cooling to 0–5°C, 120 kg (1319 moles) of 3-amino-1,2-propanediol are added. The reaction medium is heated by distilling the methanol under vacuum until a temperature of 60–65°C is reached. The concentrate is held at this temperature under vacuum for 16 hours. At the end of the contact, the medium is diluted with 607 kg of water while cooling to room temperature. The crude complex solution of formula (II) is neutralized with 20% (w / w) hydrochloric acid. This yields 978.6 kg of solution, with a concentration of 10.3%, representing 101 kg of material.The yield obtained is 86.5%, the purity of the complex of formula (II) is 92.3% (HPLC s / s). The amount of decoupled impurities is 6.4% (HPLC s / s). Purification of the formula complex (III • Nanofiltration The nanofiltration membrane used has a cutoff threshold of 200 Daltons (Koch Membrane System SR3D). This processing is carried out as follows: The crude complex solution of formula (II) is heated to 30°C. The nanofilter is filled with this solution. The pump is started at a low flow rate to purge the system, then the nanofilter pump flow rate is gradually increased to the desired recirculation flow rate (1.0 m³ / h for a 2.5 x 40-inch membrane). The system is fully recirculated at 30°C for at least 2 hours to establish a polarization layer. The medium is then passed through diafiltration at 30°C under 25 bar while maintaining a constant volume by adding pure water until the conductivity of the retentate is less than 1000 pS. At the end of diafiltration, the medium is concentrated to approximately 40% (w / w). • Resin treatment The complex solution of formula (II) resulting from nanofiltration is diluted with purified water under agitation to obtain a 15% (w / w) solution. This solution is sequentially eluted in 50 liters of strong anionic resins (FPA900) in the OH' form, then in 50 liters of weak cationic resins (HP336) in the H+ form at an average elution rate of 2V / V / H (2 volumes of solution per volume of resin per hour). The resins are then rinsed with approximately 450 liters of purified water until a refractive index below 1.3335 is reached. The complex solution of formula (II) is then concentrated by heating to 50-60°C under a vacuum of 20 mbar to achieve a concentration of 35% (m / m). • Ultrafiltration The ultrafiltration membrane is a Koch Spiral UF 10KD membrane. The ultrafilter is supplied with the above solution of the formula (II) complex at 35%, heated to 40°C. Ultrafiltration is applied at a flow rate of 3 m³ / h with a transmembrane pressure of 2.5–3 bar. Several system rinses are carried out with 13 liters of pyrogen-free purified water until a final dilution of the formula (II) complex of 25% (w / w) is achieved. Lcoonn / Lznz / E / YiAi • Atomization The complex of formula (II) is obtained in powder form by atomizing the above solution of the complex of formula (II) concentrated to 25%. Atomization is carried out as follows: The atomizer is balanced with pure, pyrogen-free water by adjusting the inlet temperature to 165°C - 170°C and adapting the feed rate so that the outlet temperature is between 105 and 110°C. Next, the concentrated solution of formula (II) is added and the flow rate is adjusted to maintain the above parameters. These operating conditions are maintained throughout the atomization process, ensuring the proper behavior of the powder in the atomization chamber and at the atomizer outlet. In particular, ensuring that the product does not stick together. At the end of feeding the atomizer with the solution, the container of this formula (II) complex and the atomizer are rinsed with pure pyrogenic water until maximum powder recovery. A complex of formula (II) is obtained that is 99.6% pure. This degree of purity is determined by reversed-phase liquid chromatography. Composition according to the invention and results of studies regarding it • Example of a manufacturing process according to the invention. The process for manufacturing a composition according to the invention is carried out following these steps: a) 485.1 g (or 0.5 M) of complex of formula (II) is dissolved in water (qs 1 liter) by heating the tank to a temperature between 39 and 48°C and vigorously stirring the solution until complete dissolution of this complex in water. The solution is then cooled to approximately 30°C. b) 0.404 g (i.e., 0.2% mol / mol relative to the proportion of complex added in step a)) of DOTA (Simafex, France) is added with stirring to the solution obtained in step a) through a 10% w / v DOTA solution. c) Trometamol (Tris) is added to the solution obtained in step b) with stirring. The pH is then adjusted to a value between 7.2 and 7.7 by adding a hydrochloric acid solution with stirring. d) The target concentration (0.5 mol / L) is obtained by adding ppi water in two stages until a density value between 1.198 and 1.219 g / mL is obtained. Lcoonn / Lznz / E / YiAi The liquid composition is then filtered through a polyethersulfone membrane and placed into its final container, which is then sterilized at 121°C for 15 minutes. • Example of composition according to the invention. Thanks to the process described above, the following formulation is obtained: Lcoonn / Lznz / E / YiAi Table 9 Ingredients. Proportions in composition. Formula Complex (II) 485.1 g (0.5 M) DOTA** 0.404 g (1 mM, i.e., 0.2% mol / mol vs. complex) NaOH or HCl q.s. pH 7.2 to 7.7 Trometamol 1.211 g Free Gadolinium* < 1 ppm w / v Water ppi (ready for injection) q.s. 1 L * Measurement performed by colorimetric method with orange xylenol ** expressed on an anhydrous and pure base • Formulation tests performed Different concentrations of trometamol, from 0 to 100 mM, were tested. The results of these tests showed that a content of 10 mM (0.12% w / v) was sufficient to ensure the pH stability of the formulation while limiting the formation of degrading impurities. Different concentrations of DOTA, from 0 to 2.5 mM, were tested. The results of these tests have shown that a content of 1 mM, corresponding to 0.04% w / v or 0.2% mol / mol, ensures the absence of free Gd release during the process and throughout the product's life. • Stability studies under accelerated conditions of a composition according to the invention. The formulation of the previous example is analyzed immediately after its manufacture (To) and after storage at 40°C for 6 months after its manufacture (T+6 months). ATo: - Purity assessed by chromatography*: 99.6% - Gd-DOTA concentration: 0.007% (m / V) - Gd concentration: below 0.0001% (m / V) - pH: 7.5 At T+6 months: - Purity assessed by chromatography*: 97.2% - Gd-DOTA concentration: 0.014% (m / V) - 0.25 mM - Gd concentration: below 0.0001% (m / V) - pH: 7.5 * reversed-phase liquid chromatography These results demonstrate that this formulation has good stability over time. Lcoonn / Lznz / E / YiAi • Comparative stability studies The stability of the following compositions was evaluated over time. The term PA non-optimized designates the active ingredient, namely the complex of formula (II), obtained according to the process described in document EP 1 931 673. The term PA optimized designates the diastereomerically enriched and purified complex of formula (II) obtained by the process according to the invention. Table 10 PA (0.5 M) [DOTA] % mol / mol Trometamol mM pH adjustment C1 Not optimized 0.3 - 5.0 C2 Optimized 0.2 - 7.5 C3 Optimized 0.1 - 7.5 C4 Optimized 0.2 - 7.5 C5 Optimized 0.1 - 7.5 C6 Optimized 0.2 - 5.0 C7 Optimized 0.1 - 5.0 Table 11 Free Gd in ppm m / v (xylenol) DOTA-Gd in % mol / mol (Formate LC*) T0 T 6 months 40°C T0 T 6 months 40°C C1 < LOD 0.18 0.27 0.3 C2 < LOD < LOD 0.02 0.05 C3 < LOD < LOD 0.02 0.05 C4 < LOD < LOD 0.02 0.05 C5 < LOD < LOD 0.02 0.08 C6 < LOD < LOD 0.03 0.03 C7 < LOD < LOD 0.02 0.07 * Formate LC: a chromatographic method involving fluorimetric detection. Separation is carried out on a C18 grafted chromatographic column in reversed phase with gradient elution. The results reported above indicate that the formulation of the non-optimized PA with free DOTA is not possible. In fact, the chelating excipient is completely consumed by the transligation reaction between the complex of formula (II) and DOTA, and therefore can no longer fulfill its function of trapping released Gd3+. On the other hand, the enriched and purified diastereoisomerically obtained complex of formula (II) 10, obtained by the process according to the invention, can be formulated with free DOTA. In fact, free Gd is absent from the composition after 6 months at 40°C, regardless of the formulation pH and the presence or absence of buffering species. Furthermore, the consumption of chelating excipient is very low, not exceeding 0.08 mol / mol. It is hereby stated that, as of this date, the best method known to the applicant to implement the aforementioned invention is the one that is clear from the present description of the invention.

Claims

1. - Complex of the following formula (II): consisting of at least 90% of a diastereomeric excess comprising a mixture of II-RRR and II-SSS isomers of formulas: (II-SSS), Lcoonn / Lznz / E / YiA (II-RRR).

2. - Composition comprising the complex according to claim 1 and a free macrocyclic ligand, and advantageously having a free gadolinium concentration of less than 1.5 ppm (w / v). 3.- Composition according to claim 2, characterized in that it comprises between 0.002 and 0.4% mol / mol of free macrocyclic ligand with respect to the complex of formula (II). 4.- Composition according to claim 2 or 3, characterized in that the free macrocyclic ligand is selected from the group consisting of DOTA, NOTA, DO3A, BT-DO3A, HP-DO3A, 10 PCTA, DOTA-GA and their derivatives. 5.- Composition according to claim 4, characterized in that the free macrocyclic ligand is l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid (DOTA).

6. Method for purifying the complex of the following formula (II): consisting of at least 80% of a diastereomeric excess comprising a mixture of II-RRR and II-SSS isomers of formula: comprising: 1) combining the following 2 steps: 1b) passing over ion exchange resin(s), and 1e) ultrafiltration of said complex, and 2) isolating the purified complex 10 thus obtained in solid form.

7. Method according to claim 6, characterized in that steps Ib) and le) are further combined with a nanofiltration step la).

8. Method according to claim 6 or 7, characterized in that steps 1a) when present, 1b) and 1e) are carried out in this order. 15 9.- Method according to any of claims 6 to 8, characterized in that step 2) comprises atomization.

10. - Method according to any of claims 6 to 9, characterized in that the complex of formula (II) consisting of at least 80% of a diastereomeric excess comprising a mixture of II-RRR and II-SSS isomers in which the purification process is carried out has been previously prepared by the following successive steps: a) complexation of the hexaacid of the following formula (III): O OH (WI 1 J / -NN < .N . / HQOC , „ ' ; HO Hü O .WGH (III) Lcoonn / Lznz / E / YiAi with gadolinium to obtain the hexaacid gadolinium complex of formula (I) as follows: CÜOH (η, b) heating isomerization of the hexaacid gadolinium complex of formula (I) in an aqueous solution at pH between 2 and 4, to obtain a diastereomerically enriched complex consisting of at least 80% of a diastereomeric excess comprising a mixture of I-RRR and I-SSS isomers of said hexaacid gadolinium complex of formula (I), and c) formation, from the diastereomerically enriched complex obtained in step b), of the complex of formula (II), by reaction with 3-amino-l,2-propanediol.

11. - Method according to claim 10, characterized in that: - at the end of step b), the diastereomericly enriched complex is isolated by crystallization, purified by recrystallization, and further enriched by selective decomplexation of the diastereomers of the complex of formula (I) other than the diastereomers I-RRR and I-SSS, i.e., by selective decomplexation of the diastereomers I-RSS, I-SRR, I-RSR, I-SRS, I-RRS, and I-SSR; and - step c) comprises the following successive steps: (1) formation of a triester of formula (VIII), Lcoonn / Lznz / E / YiA, wherein Ri represents an alkyl group (Ci-Ce), in particular by reaction in the alcohol of formula RiOH in the presence of an acid such as hydrochloric acid; and (2) aminolysis of the triester of formula 5 (VIII) with 3-amino-l,2-propanediol, in particular in the alcohol of formula RiOH in the presence of an acid such as hydrochloric acid,The triester of formula (VIII) is not isolated between stages 11) and c2)., 12. Complex of formula (II): r ΌH OH (Π) consisting of at least 80% of a diastereomeric excess comprising a mixture of II-RRR and II-SSS isomers of formulas: Lcoonn / Lznz / E / YiA capable of being obtained by the process according to any one of claims 6 to 11. 5 13.- Complex according to claim 12, characterized in that its degree of purity is greater than 95%.

14. A composition comprising the complex according to claim 12 or 13 and free DOTA, and advantageously having a free gadolinium concentration of less than 1 ppm (w / v).

15. A composition according to claim 14, characterized in that it comprises between 0.002 and 0.4 mol / mol of DOTA with respect to the complex of formula (II).