Method for preparing gadoteric acid meglumine using high-purity tetraracetam (DOTA) and its application in preparing injectable galenic preparations

Abstract

The present invention relates to a method for producing gadoteric acid meglumine using high-purity tetraracetam (DOTA). This method does not require the use of organic solvents and optimizes synthesis process conditions. The synthesis process for producing gadoteric acid meglumine using tetraracetam includes at least one electrodialysis purification step. This step can produce tetraracetam and gadoteric acid meglumine with minimal impurity content.

Description

Technical Field

[0001] The present invention relates to a method for producing gadoteric acid meglumine from high-purity tetraracetam. This method does not require the use of organic solvents and allows for optimized synthesis conditions. Gadoteric acid meglumine is used as a contrast agent in diagnostic tests. Therefore, the present invention can be incorporated into the fields of pharmacology or medicinal chemistry. Background Art

[0002] Diagnostic imaging is a widely used technique in medicine for visualizing biological processes, organs, or tissues, requiring the use of contrast agents. Gadolinium-based derivatives are one such contrast agent, and these compounds are increasingly being used in magnetic resonance imaging (MRI) studies. However, due to the toxicity of linear gadolinium-based contrast agents and the deposition of free gadolinium in certain areas of the brain, existing gadolinium-based derivatives are not widely used. Macrocyclic derivatives, which deposit less free gadolinium, have become safer alternatives. Among the macrocyclic derivatives, gadoterate meglumine is the compound that produces the least gadolinium deposition in the brain, likely due to its high stability (Am. J. Neuroradiol. 2016, 37, 1192-1198).

[0003] Tetraracetam is a precursor to gadoterate meglumine. The synthetic process for producing tetraracetam involves a lengthy and expensive purification process, which typically involves the use of ion exchange resins, which require subsequent treatment with organic solvents to desorb the desired compound. US5922862 describes the purification of tetraracetam and its derivatives by elution with PVP resin. US5334729 discloses the purification of these complexes using cation exchange columns.

[0004] EP3223863 and EP2799090 describe the preparation of a final 0.5 M aqueous solution of gadoteric acid meglumine for injection from separated tetraracetam, gadolinium oxide, and meglumine. This method involves continuous and lengthy adjustments of the amounts of tetraracetam and gadolinium oxide to maintain the tetraracetam content between 0% and 0.25%. The pH is then adjusted with meglumine, and finally the concentration is adjusted to obtain a 0.5 M solution for use as a contrast agent.

[0005] WO2017 / 103258 describes a method for synthesizing DOTA, which includes the steps of crystallization and membrane filtration, but methanol is added in both steps, and the methanol content in the final product still reaches about 4% by weight.

[0006] Therefore, the tetraracetam synthesis process needs to be optimized to reduce the number of steps required to produce a high-purity final product. At the same time, to minimize environmental impact and the potential presence of impurities in the final product, the degradation of reagents and intermediates in the synthesis process must be minimized, and the use of organic solvents must be eliminated. Summary of the Invention

[0007] The present invention addresses the shortcomings of prior art methods by optimizing the synthesis process for tetraracetam by using milder reaction conditions to reduce degradation of the starting reagents. Furthermore, a combination of purification and separation techniques is employed to produce high-purity tetraracetam without the use of organic solvents (green chemistry). This tetraracetam is then used to produce gadoteric acid meglumine, an active pharmaceutical ingredient (API). This API is then prepared through a simple dissolution and concentration adjustment process into an aqueous injectable formulation for use in magnetic resonance imaging diagnostics. The present invention significantly simplifies the production process for gadoteric acid meglumine by optimizing the manufacturing process and isolating gadoteric acid meglumine into a solid that meets clear specifications. Furthermore, the use of high-purity tetraracetam eliminates the need for any additional purification steps.

[0008] Therefore, in a first aspect, the present invention relates to a method for preparing tetraracetam, comprising the following steps:

[0009] (a) Tetraracetam is prepared by the following reaction:

[0010]

[0011] wherein X is a halogen, preferably chlorine, Y is selected from hydrogen or an alkali element, preferably sodium, the base is selected from potassium hydroxide, sodium hydroxide or lithium hydroxide, preferably sodium hydroxide, the pH value is maintained between 7 and 8.5, preferably 8, the reaction temperature is maintained between 70 and 100° C., preferably 80° C., and the prepared tetraracetam is crystallized by lowering the pH value to below 3 to obtain a crude tetraracetam product;

[0012] (b) purifying the crude crystalline tetraracetam obtained in the preceding step, comprising at least one electrodialysis step;

[0013] (c) isolating the product obtained in the preceding step, preferably by spray drying.

[0014] In the present invention, tetraracetam is also referred to as DOTA.

[0015] In a preferred embodiment, the crystallization of tetraracetam produced in the reaction of step (a) is carried out at a pH below 3, preferably equal to or lower than 2, and more preferably equal to or lower than 1. The pH can be lowered by adding a common acid such as hydrochloric acid. Such pH values can achieve higher yields because they favor the conversion of all carboxylic acid groups to carboxylic acids and avoid the use of organic solvents since purification is not required. Variations in pH between ±0.2 and ±0.5 are contemplated within the scope of the present invention and can be used at such pH values.

[0016] In a preferred embodiment, the electrodialysis employs a cationic membrane, an anionic membrane, a bipolar membrane, or a combination thereof.

[0017] In another preferred embodiment, two consecutive electrodialysis steps are carried out in the purification step (b). In a first more preferred embodiment, the first electrodialysis step is carried out using:

[0018] - a combination of a cationic membrane, an anionic membrane and a bipolar membrane or

[0019] - A combination of a cationic membrane and an anionic membrane, wherein the anionic membrane is preferably a monoselective membrane.

[0020] In another more preferred step, the second electrodialysis is performed using:

[0021] - a combination of a cationic membrane, an anionic membrane and a bipolar membrane or

[0022] - Combination of cationic membrane and bipolar membrane.

[0023] Preferably, during the two electrodialysis steps of this preferred embodiment, the pH value is maintained between 2 and 6.

[0024] In another preferred embodiment, in the above-mentioned purification step (b), constant volume nanofiltration is performed before electrodialysis. In a more preferred embodiment, the electrodialysis adopts:

[0025] - a combination of a cationic membrane, an anionic membrane and a bipolar membrane or

[0026] - a combination of a cationic membrane and an anionic membrane, wherein the anionic membrane is preferably a monoselective membrane or

[0027] - Combination of cationic membrane and bipolar membrane.

[0028] Preferably, the pH value during nanofiltration is maintained between 2-8, more preferably between 3-5, even more preferably at 4.

[0029] Preferably, the pH value during the electrodialysis of this preferred embodiment is maintained between 2 and 5, more preferably maintained at 4.

[0030] In a preferred embodiment, in step (c) above, the compound is isolated by spray drying, wherein the inlet air temperature is 160-200°C. In a more preferred embodiment, the inlet air temperature is 170-190°C. In a more preferred embodiment, the inlet air temperature is 175-185°C. In an even more preferred embodiment, the inlet air temperature is 180°C. In a preferred embodiment, the outlet air temperature is 90-120°C. In a more preferred embodiment, the outlet air temperature is 105-115°C. In an even more preferred embodiment, the outlet air temperature is 110°C.

[0031] The spray drying step represents a fundamental improvement in the present method compared to other similar methods known in the art. Due to the high purity of the DOTA obtained in step (b), there is no need to use organic solvents to isolate the product, as described in the prior art. For example, in WO2017 / 103258, large amounts of methanol are used in multiple steps, and methanol still remains in the final product. Therefore, by applying the present method, the final product is free of organic solvents, which is beneficial for the manufacture of pharmaceutical products.

[0032] In another preferred embodiment, the product obtained in the above step (c) is characterized in that the maximum residual amount of alkali element (preferably sodium) is 500 ppm (0.05%) and the maximum residual amount of halide (preferably chlorine) is 500 ppm (0.05%).

[0033] Another aspect of the present invention relates to tetraracetam prepared by the above method, characterized in that: (a) the maximum residual amount of alkali element (preferably sodium) is 500 ppm (0.05%), preferably 100 ppm (0.01%), more preferably 50 ppm (0.005%), for example, as determined by inductively coupled plasma mass spectrometry (ICP-MS); (b) the maximum residual amount of halide (preferably chlorine) is 500 ppm (0.05%), preferably 100 ppm (0.01%), more preferably 50 ppm (0.005%), even more preferably 20 ppm (0.002%), for example, as determined by inductively coupled plasma mass spectrometry (ICP-MS); and (c) the maximum residual amount of solvent and volatile matter is below the detection limit.

[0034] In the present invention, "limit of detection" (LOD) or "limit of detection" is defined as the smallest amount of an analyte whose signal can be distinguished from the absence of the substance ("noise") at a given confidence level, and is generally defined as the smallest amount or lowest concentration of a substance that can be reliably detected by a given analytical method. In practice, the limit of detection is the lowest concentration obtained by analyzing a sample (containing the analyte) that can be distinguished from the concentration determined from a blank sample (i.e., a sample without the analyte). Therefore, the limit of detection for possible solvents used in the method of the present invention can be set to 10 ppm (0.001%), as determined by methods such as gas chromatography / mass spectrometry (GC-MS).

[0035] Compared to the aforementioned prior art methods, the present method can produce tetraracetam in higher yield and / or higher purity. The purity of tetraracetam produced by the present method is typically at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or higher. The purity of the produced tetraracetam can be determined by methods known to those skilled in the art, such as inductively coupled plasma mass spectrometry (ICP-MS), high performance liquid chromatography (HPLC), or gas chromatography / mass spectrometry (GC-MS), as described in the Examples.

[0036] The term "halogen" refers to chlorine (Cl), bromine (Br), and iodine (I). Their anionic forms are called halides.

[0037] The term "alkali" refers to lithium (Li), sodium (Na) and potassium (K).

[0038] The term "base" refers to a compound that releases hydroxyl ions (OH - ) and a substance that makes the medium alkaline. Preferably, it refers to an alkaline hydroxide, such as potassium hydroxide (KOH), sodium hydroxide (NaOH) and lithium hydroxide (LiOH).

[0039] The term "electrodialysis" refers to an ion exchange membrane process in which an electric field is used as the driving force to achieve ion transfer through the ion exchange membrane. The electrodialysis system consists of an electrolyte solution, a concentrated solution, and a dilute solution. In the present invention, "electrolyte solution" refers to a sulfuric acid solution or a dilute sodium sulfate solution with a pH of 1-3. In the present invention, "concentrated solution" refers to a dilute aqueous sulfuric acid solution. In the present invention, "dilute solution" refers to a tetracyclam solution. The electrodialysis step of the present invention can be scaled up industrially using different configurations. Figure 1 and Figure 2 Non-limiting examples of possible configurations are shown.

[0040] In the present invention, in order to reduce the formation of salt in the crude reaction product as far as possible, the addition of base is controlled. In addition, the crude reaction product can be treated with electrodialysis and / or nanofiltration to remove inorganic ions and other impurities in the crude reaction product, such as organic impurities.

[0041] Another aspect of the present invention relates to a method for preparing gadoteric acid meglumine, which comprises the steps of the above-mentioned method for preparing tetraracetam and the following additional steps:

[0042] (d) reacting the product obtained in step (c) above with a gadolinium derivative, preferably Gd2O3 and meglumine,

[0043] (c) isolating the product obtained in step (d) above by spray drying.

[0044] In the present invention, the high-quality DOTA produced in steps (a)-(c) can be directly separated from the reaction material in the solution of step (d) via a spray drying step, without requiring any purification steps. This improves yield compared to other existing technologies and eliminates the need for the use of organic solvents, which typically separate gadoterate meglumine slurry from solution through crystallization from organic solvents.

[0045] The corresponding gadolinium derivative (1 equivalent) is added to the tetraracetam solution purified by any of the above methods. The mixture is heated for a period of time. In step (d), meglumine and the gadolinium derivative are added, and the pH of the reaction is maintained constant throughout the reaction. This improves the reaction time by directly producing gadoterate meglumine and preventing the formation of highly water-insoluble gadolinium hydroxide.

[0046] In a preferred embodiment, the initial tetraracetam concentration is 50-250 g / L.

[0047] In the present invention, "gadolinium derivative" refers to gadolinium oxide or gadolinium salts, such as gadolinium chloride, gadolinium sulfate, etc. Preferably, the gadolinium derivative is gadolinium oxide.

[0048] In a preferred embodiment, the pH of the reaction is maintained constant. In a preferred embodiment, the pH of the reaction is maintained between 1 and 7. In a more preferred embodiment, the pH of the reaction is maintained between 2 and 5. In an even more preferred embodiment, the pH of the reaction is maintained between 3.5 and 4.5. In a preferred embodiment, the pH of the reaction is maintained by adding meglumine.

[0049] In a preferred embodiment, the solvent is water.

[0050] In a preferred embodiment, the reaction temperature is 80-100°C. In a more preferred embodiment, the reaction temperature is 85°C.

[0051] In a preferred embodiment, the final pH value of the solution is adjusted to between 6.5 and 8 by adding meglumine. In another preferred embodiment, the final pH value of the solution is adjusted to between 6.5 and 7.5 by adding meglumine.

[0052] In a preferred embodiment, the compound is isolated by spray drying in step (e) above. During this process, the inlet air temperature is between 160-200°C. In a more preferred embodiment, the inlet air temperature is between 170-190°C. In a more preferred embodiment, the inlet air temperature is between 175-185°C. In an even more preferred embodiment, the inlet air temperature is 180°C. In another preferred embodiment, the outlet air temperature is between 90-120°C. In a more preferred embodiment, the outlet air temperature is between 105-115°C. In an even more preferred embodiment, the outlet air temperature is 110°C.

[0053] In a preferred embodiment, the product obtained in the above step (d) is subjected to at least one ultrafiltration.

[0054] The gadoterate meglumine obtained in this way does not require any further purification process and can therefore be used directly for the preparation of pharmaceutical compositions.

[0055] Another aspect of the present invention relates to gadoterate meglumine prepared according to the method of claim 1, wherein the maximum amount of residual solvent and other volatile substances is below the detection limit. The detection limit for the residual solvent (which may be, for example, the aforementioned solvent) is approximately 10 ppm (0.001%). The content of other related substances, such as macrocyclic polyamines, chloroacetic acid, and glycolic acid, as determined by high performance liquid chromatography (HPLC), is approximately 0.001%.

[0056] Another aspect of the present invention relates to a pharmaceutical composition comprising the above-mentioned gadoterate meglumine. Preferably, the pharmaceutical composition is formulated as an injectable contrast agent.

[0057] The pharmaceutical composition is prepared using methods and techniques known to those skilled in the art and established in applicable pharmacopoeias. For example, for an injection, gadoterate meglumine is dissolved in water for injection at the desired concentration and processed accordingly to obtain a ready-to-use reagent. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 A process scheme for the purification of tetraracetam by two electrodialysis steps is shown.

[0059] Figure 2 A process scheme for the purification of tetraracetam by nanofiltration after electrodialysis is shown. DETAILED DESCRIPTION

[0060] Example 1. Synthesis of Tetraracetam Crude Product

[0061] Prepare a 125 g / L macrocyclic polyamine solution (1 equivalent). Then add chloroacetic acid (4.5 equivalents). Heat the mixture to 80 ° C, add sodium hydroxide using a pH controller, and adjust the pH of the reaction to 8. When the reaction is complete, raise the pH to 10 and maintain the temperature for the necessary time. Then cool the reaction mixture to 65 ° C, and add concentrated hydrochloric acid until the pH is less than 1. Finally, remove part of the solvent under reduced pressure, cool the mixture, and centrifuge to obtain a crude tetraracetam (yield 80-85%).

[0062] Example 2. Purification of Tetraracetam by a combination of nanofiltration and / or electrodialysis techniques

[0063] A. Treatment of crude tetraracetam by two electrodialysis steps:

[0064] A crude solution of tetraracetam (45 g / L) was purified by electrodialysis using monoselective anionic and cationic membranes. The pH of the dilute solution was maintained between 2 and 5. The concentrate and electrolyte solution could be sulfuric acid at a pH of 1-3 or sodium sulfate at a concentration of 5 g / L (yield 95%; Cl < 0.01%; Na < 0.5%).

[0065] The electrodialysis solution is then purified by a second electrodialysis step using a cationic membrane and a bipolar membrane. The pH of the diluted solution is maintained between 2.8 and 4.5. The concentrated solution and electrolyte solution are prepared as described above. This produces a tetraracetam solution (yield 90-95%; sodium <0.01%) that can be used directly in the next separation step.

[0066] B. Treatment of Crude Tetraracetam by Nanofiltration and Electrodialysis:

[0067] A 45 g / L solution of crude tetraracetam was prepared and the pH was adjusted to 4 by adding sodium hydroxide solution. This solution was passed through a nanofiltration membrane, resulting in two streams: a waste solution that was returned to the initial solution containing tetraracetam, and a permeate solution that was collected in a separate tank. This solution contained inorganic ions and low-molecular-weight organic impurities. The volume of the waste solution was maintained constant by adding water. The nanofiltration process was terminated when the chloride ion concentration fell below the specified value (yield 98-99%; Cl <0.01%; Na <4.1%).

[0068] The 45 g / L tetraracetam solution is then electrodialyzed through a cationic membrane and an anionic membrane, maintaining the pH of the dilute solution between 2.8 and 4.5. Alternatively, the tetraracetam solution is treated with a cationic membrane and a monoselective anionic membrane, maintaining the pH of the dilute solution between 2 and 3. Alternatively, the 45 g / L tetraracetam solution is treated with a cationic membrane and a bipolar membrane, maintaining the pH of the dilute solution at 4. The electrolyte solution and the concentrated solution are sulfuric acid or sodium sulfate solutions. The electrodialysis process ends when the sodium ion concentration falls below the specified value. This produces a tetraracetam solution (yield 90-95%; Na <0.008%) that can be directly used in the separation step.

[0069] Example 4. Isolation and Characterization of Tetraracetam

[0070] The resulting solution can be used to synthesize gadoteric acid meglumine or to isolate tetraracetam. Tetraracetam can be isolated from the aqueous solution by spray drying at an inlet air temperature of 180°C and an outlet air temperature of 110°C. The resulting product meets the following specifications (yield 97-99%; sodium <0.008%).

[0071] The obtained high purity tetracyclam meets the following specifications:

[0072] Appearance: white powder

[0073] Identification:

[0074] οInfrared spectrum: comparable to tetraracetam reference

[0075] οHPLC: retention time is consistent with the reference

[0076] Water ≤8.5%

[0077] Clear solution, color no greater than control solution Y7

[0078] Sodium ≤ 500ppm (0.05%)

[0079] Halides ≤ 500ppm (0.05%)

[0080] Residue on ignition ≤ 0.10%

[0081] Related impurities:

[0082] οDO3A≤0.05%

[0083] οAny other single impurity ≤ 0.05%

[0084] Total impurities ≤ 0.5%

[0085] Titration (acid-base): dry product 98.0-102.0%

[0086] Bacterial endotoxin ≤ 22EU / g

[0087] Total number of aerobic microorganisms ≤ 10 2 CFU / g

[0088] Total yeast and mold count ≤ 10 2 CFU / g

[0089] Escherichia coli: None / 1g

[0090] Residual solvent <10ppm (0.001%)

[0091] Example 5. Synthesis of Gadoterate Meglumine

[0092] Gd2O3 (1 equivalent) was added to a 200 g / L aqueous solution of tetraracetam. The mixture was heated to 85°C for 2-4 hours. The pH of the reaction was maintained at 4 by the addition of meglumine. The reaction was terminated when the final amount of tetraracetam and free gadolinium was less than 0.005% (w / v). The pH of the solution was then raised to between 6.5 and 8 (quantitative yield) by the addition of meglumine.

[0093] Example 6. Isolation and Characterization of Gadoterate Meglumine

[0094] The final product dissolved in water is then depyrogenated by ultrafiltration and then spray-dried for isolation. The processing conditions are as follows: inlet air temperature 175-185°C, outlet air temperature 110°C (yield 97-98%). The gadoteric acid meglumine isolated using this method meets the following specifications:

[0095] Appearance: white powder

[0096] Water ≤ 10.0%

[0097] Identification:

[0098] οHPLC: retention time is similar to that of the reference

[0099] οInfrared spectrum: similar to the reference

[0100] Clear, or the turbidity of the solution does not exceed that of the reference solution I used for clarity and turbidity tests in the European Pharmacopoeia and the United States Pharmacopoeia (USP)

[0101] Solution color ≤Y7

[0102] pH = 6.5-8

[0103] Related impurities:

[0104] οDO3A≤0.05%

[0105] Tetraracetam ≤ 0.1%

[0106] οAny other single impurity ≤ 0.05%

[0107] Total impurities ≤ 0.50%

[0108] Purity (HPLC): 97-103% anhydrous product

[0109] Methylglucamine content: 24.5-26.5% of anhydrous product

[0110] Free gadolinium content ≤ 0.01%

[0111] Total gadolinium content: 19-22%.

[0112] Impurities ≤ 100ppm (0.01%)

[0113] Bacterial endotoxin <20UE / g

[0114] Total aerobic microorganism count (TAMC) ≤ 10 2 CFU / g

[0115] Total yeast and mold count (TYMC) ≤ 10 2 CFU / g

[0116] Escherichia coli: None

[0117] Residual solvent <10ppm (0.001%)

[0118] Main impurities:

[0119] οAs≤1500ppb

[0120] οPb≤500ppb

[0121] οCd≤200ppb

[0122] οHg≤300ppb

[0123] οV≤1000ppb

[0124] οNi≤2000ppb

[0125] οCo≤500ppb

[0126] οPd≤1000ppb

[0127] οCu≤30000ppb

[0128] οLi≤25000ppb

[0129] οSb≤9000ppb

[0130] Example 7. Gadoteric acid meglumine galenic formulation.

[0131] The prepared gadoterate meglumine is used to prepare an injectable galenic preparation for magnetic resonance imaging diagnosis.

[0132] Table 1. 0.5 M aqueous solutions of gadoterate meglumine.

[0133]

[0134] *WFI: Water for Injection.

[0135] Table 2. Aqueous solutions with 0.5 M gadoterate meglumine and tetraracetam as excipients.

[0136]

[0137] Two formulations prepared using gadoterate meglumine isolated from the present invention were depyrogenated and sterilized. Both formulations met the following specifications:

[0138] A clear solution with a turbidity not exceeding that of the reference solution Y7 used for clarity and turbidity tests in the European Pharmacopoeia and the United States Pharmacopoeia (USP)

[0139] Identification:

[0140] οInfrared spectrum: similar to the control compound

[0141] oHPLC: Retention time was similar to that of the reference standard.

[0142] pH = 6.9-8.

[0143] Density = 1.1649-1.1828 g / mL

[0144] No visible particles.

[0145] Particles visible under a microscope: <6000 (particle size <10μm); <600 (particle size <25μm)

[0146] Absorbance: <0.40AU at 450nm; <0.20AU at 500nm

[0147] Determination:

[0148] Gadolinium terate: 26.53-29.33% (w / v)

[0149] Total gadolinium content: 7.63-8.10% (w / v)

[0150] Free gadolinium <0.005% (w / v)

[0151] Meglumine: 9.27-10.25% (w / v)

[0152] Related impurities:

[0153] οDO3A < 0.02% (w / v)

[0154] Tetraracetam <0.05% (w / v)

[0155] Any other impurities < 0.02% (w / v)

[0156] Total impurities <0.2% (w / v)

[0157] Main impurities:

[0158] οAs≤560ppb

[0159] οPb≤190ppb

[0160] οCd≤75ppb

[0161] οHg≤110ppb

[0162] οV≤370ppb

[0163] οNi≤750ppb

[0164] οCo≤190ppb

[0165] οPd≤370ppb

[0166] οCu≤1100ppb

[0167] οLi≤940ppb

[0168] οSb≤3400ppb

[0169] Sterile solution, free of bacterial endotoxins (<8EU / mL).

[0170] Example 8. Comparison of Tetraracetam prepared by the method of the present invention.

[0171] The impurity levels of tetraracetam samples (DOTA 001-003) prepared by the method of the present invention were compared with other commercial tetraracetam samples obtained from different suppliers (Suppliers 1-5). The data are summarized in the following table:

[0172] Table 3. Determination of alkali and halide impurities in tetracyclane by inductively coupled plasma mass spectrometry (ICP-MS)

[0173]

[0174] Table 4. Determination of residual solvents in tetraracetam by gas chromatography / mass spectrometry (GC-MS)

[0175]

[0176] Table 5. Tetraracetam purity of each sample determined by HPLC

[0177]

[0178] Table 6. Other impurities determined by HPLC

[0179]

Claims

1. A method for preparing tetracycline, comprising the following steps: (a) Tetraracetam is prepared by the following reaction: wherein X is a halogen, Y is selected from hydrogen, potassium, sodium or lithium, the base is selected from potassium hydroxide, sodium hydroxide or lithium hydroxide, the pH is maintained between 7 and 8.5, the reaction temperature is maintained between 70 and 100° C., and the prepared tetraracetam is crystallized by lowering the pH to below 3 to obtain a crude tetraracetam product; (b) purifying the crude crystalline tetraracetam obtained in the above step, wherein the purification comprises performing two consecutive electrodialysis steps, or the purification comprises at least one electrodialysis step and performing constant volume nanofiltration before performing the electrodialysis step; (c) Isolating the product obtained in the preceding step by spray drying.

2. The method according to claim 1, wherein X is chlorine and Y is sodium.

3. The method according to claim 1 or 2, wherein the base is sodium hydroxide.

4. The method according to claim 3, wherein the pH value of the reaction is maintained at 8 and / or the temperature is maintained at 80°C.

5. The method according to claim 4, wherein the pH value in the crystallization in step (a) is less than 2.

6. The method according to claim 5, wherein the pH value in the crystallization in step (a) is less than 1.

7. The method according to claim 1, wherein for the two consecutive electrodialysis in the step (b), the first of the two electrodialysis is performed by using: - Combination of cationic membranes, anionic membranes and bipolar membranes or - Combination of cationic and anionic membranes.

8. The method according to claim 7, wherein the anionic membrane is a monoselective membrane.

9. The method according to claim 1, wherein for the two consecutive electrodialysis in the step (b), the second of the two electrodialysis is performed by using: - Combination of cationic membranes, anionic membranes and bipolar membranes or - Combination of cationic and bipolar membranes.

10. The method according to any one of claims 7 to 9, wherein the pH value in the two electrodialysis steps is maintained between 2 and 6.

11. The method according to claim 1, wherein the constant volume nanofiltration is performed before the electrodialysis in step (b), and the electrodialysis is performed by using the following substances: - Combination of cationic membranes, anionic membranes and bipolar membranes or - A combination of cationic and anionic membranes or - Combination of cationic and bipolar membranes.

12. The method according to claim 11, wherein the anionic membrane is a monoselective membrane.

13. The method according to claim 11 or 12, wherein the pH value during the nanofiltration is maintained between 2 and 8.

14. The method according to claim 13, wherein the pH value during the nanofiltration is maintained between 3 and 5.

15. The method according to claim 13, wherein the pH value during the nanofiltration is maintained at 4.

16. The method according to claim 13, wherein the pH value during the electrodialysis is maintained between 2 and 5.

17. The method according to claim 16, wherein the pH value during the electrodialysis is maintained at 4.

18. A method for preparing gadoteric acid meglumine, comprising the steps of the method according to any one of claims 1-2, 4-9, 11-12, 14-17 and the following additional step: (d) reacting the product obtained in step (c) with Gd2O3 and meglumine (e) isolating the product obtained in step (d) above by spray drying.

19. The method according to claim 18, wherein the compound is separated in step (e) by spray drying, wherein the inlet air temperature of the spray drying system is 160-200°C.

20. The method according to claim 18, wherein in the step (e) the compound is separated by spray drying, wherein the outlet air temperature of the spray drying system is 90-120°C.

21. The method according to claim 19, wherein the inlet air temperature of the spray drying system is 170-190°C.

22. The method of claim 19, wherein the inlet air temperature of the spray drying system is 175-185°C.

23. The method according to claim 19, wherein the inlet air temperature of the spray drying system is 180°C.

24. The method according to claim 20, wherein the outlet air temperature of the spray drying system is 105-115°C.

25. The method according to claim 20, wherein the outlet air temperature of the spray drying system is 110°C.

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