PROCEDURE FOR OBTAINING GADOTERATE MEGLUMINE FROM HIGH-PURITY TETRAXETAN (DOTA) AND ITS USE IN THE PREPARATION OF INJECTABLE GALENICAL FORMULATIONS

Abstract

The present invention refers to a process for obtaining gadoterate meglumine from high purity tetraxetan (DOTA) which does not require the use of organic solvents and optimizes the conditions of the synthetic process. The tetraxetan from which the gadoterate meglumine is obtained by a synthetic process that includes a purification step in which at least one electrodialysis is performed. This procedure makes it possible to obtain a tetraxetan and a gadoterate meglumine with minimal amounts of impurities.

Claims

1. A process to obtain tetraxetan that comprises the following steps: (a) obtention of tetraxetan by the following reaction: ##STR00002## where X is a halogen, Y is selected from hydrogen or an alkaline element, the base is selected from potassium, sodium or lithium hydroxide, the pH is maintained between 7 and 8.5 and the reaction temperature is maintained between 70 and 100° C., and crystallization of the obtained tetraxetan by lowering the pH below 3 to obtain a tetraxetan crude; (b) purification of the crystallized tetraxetan crude obtained in the previous step, involving at least one electrodialysis; (c) isolation of the product obtained in the previous step by spray drying.

2. The process according to claim 1, where X is chlorine and/or Y is sodium.

3. The process according to any one of the claim 1 or 2, where the base is sodium hydroxide.

4. The process according to any one of the claims 1 to 3, where the pH of the reaction is maintained at 8 and/or the temperature is maintained at 80° C.

5. The process according to any one of the claims 1 to 4, where the pH in the crystallization of step (a) is below 2.

6. The process according to claim 5, where the pH in the crystallization of step (a) is below 1.

7. The process according to any one of claims 1 to 6, where cationic, anionic, bipolar membranes or combinations thereof are used in electrodialysis.

8. The process according to any of the claims 1 to 7, where in the step (b) of purification two consecutive electrodialysis are performed.

9. The process according to claim 8, where the first of the two electrodialysis is carried out using: a combination of cationic, anionic and bipolar membranes or a combination of cationic and anionic membranes, where preferably the anionic membranes are monoselective.

10. The process according to any of the claim 8 or 9, where the second electrodialysis is carried out using: a combination of cationic, anionic and bipolar membranes or a combination of cationic and bipolar membranes.

11. The process according to any of the claims 8 to 10, where in both electrodialysis the pH is maintained between 2 and 6.

12. The process according to any of the claims 1 to 7, where in the step (b) of purification a nanofiltration at constant volume is performed prior to electrodialysis.

13. The process according to claim 12, where electrodialysis is carried out using: a combination of cationic, anionic and bipolar membranes or a combination of cationic and anionic membranes, where preferably the anionic membranes are monoselective or a combination of cationic and bipolar membranes.

14. The process according to any of the claim 12 or 13, where the pH during nanofiltration is kept between 2 and 8.

15. The process according to claim 14, where the pH during nanofiltration is kept between 3 and 5.

16. The process according to claim 15, where the pH during nanofiltration is kept at 4.

17. The process according to any of the claims 12 to 16, where the pH during electrodialysis is kept between 2 and 5.

18. The process according to claim 17, where the pH during electrodialysis is kept at 4.

19. Tetraxetan obtained by the process of any of the claims 1 to 18, characterized by a maximum residual amount of the alkali element, preferably sodium, of 500 ppm (0.05%), a maximum residual amount of halide, preferably chloride, of 500 ppm (0.05%) and a maximum residual amount of solvents and volatile substances below the detection limit.

20. A process to obtain gadoterate meglumine comprising the steps of the process according to claims 1 to 18 and the following additional steps: (d) reaction of the product obtained in step (c) with Gd.sub.2O.sub.3 and meglumine (e) isolation of the product obtained in step (d) by spray drying.

21. The process according to claim 20, in which in step (e) the isolation of the compound is carried out by spray drying in which the temperature of the inlet air to the spray drying system is 160-200° C., and/or the temperature of the outlet air is 90-120° C., preferably

22. The process according to claim 21, in which the temperature of the inlet air to the spray drying system is 170-190° C., preferably 175-185° C., more preferably 180° C., and/or the temperature of the outlet air is 105-115° C., preferably 110° C.

23. Gadoterate meglumine obtained by the process of either claims 20 to 22, characterized by a maximum amount of residual solvents and other volatile substances below the detection limit.

24. Pharmaceutical composition comprising gadoterate meglumine according to claim 23.

25. Pharmaceutical composition according to claim 24, which is a contrast agent formulated as injectable.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0057] FIG. 1.—Shows the scheme of the tetraxetan purification process by means of two electrodialysis.

[0058] FIG. 2.—Shows the scheme of the tetraxetan purification process by means of nanofiltration followed by electrodialysis.

EXAMPLES OF THE INVENTION

Example 1. Synthesis of Raw Tetraxetan

[0059] A 125 g/L solution of cyclen (1 eq.) in water is prepared. Then chloroacetic acid (4.5 eq.) is added. The mixture is heated to 80° C. and the pH of the reaction is adjusted to 8, adding sodium hydroxide using a pH controller. When the reaction is completed, the pH is raised to 10 maintaining the temperature for the necessary time. The reaction mixture is then cooled to 65° C. and then concentrated HCl is added until pH<1. Finally, the solvent is partially removed under reduced pressure, the mixture is cooled and the tetraxetan crude obtained is centrifuged (80-85% yield).

Example 2. Tetraxetan Purification by a Combination of Nanofiltration and/or Electrodialysis Techniques

[0060] A. Treatment of Raw Tetraxetan by Means of Two Electrodialysis:

[0061] A solution of raw tetraxetan (45 g/L) is purified by a first electrodialysis containing monoselective anionic membranes and cationic membranes. The pH of the diluate solution is maintained between 2-5. The concentrate and electrolyte solutions can be sulfuric acid at pH=1−3 or sodium sulfate ata concentration of 5 g/L (95% yield; Cl<0.01%; Na<0.5%).

[0062] This electrodialysed solution is then purified by a second electrodialysis containing cationic and bipolar membranes. The pH of the diluate solution is maintained between pH=2.8-4.5. The concentrate and electrolyte solutions are as described above. In this way, a tetraxetan solution is obtained which is directly used in the next isolation step (90-95% yield; Na<0.01%).

[0063] B. Treatment of Raw Tetraxetan by Means of Nanofiltration and Electrodialysis:

[0064] A 45 g/L solution of raw tetraxetan is prepared and the pH is adjusted to 4 by adding sodium hydroxide solution. This solution is passed through the nanofiltration membrane, resulting in two streams, the rejection solution, which returns to the initial solution containing tetraxetan, and the permeate solution, which is collected in a different tank. This last solution contains inorganic ions and low molecular weight organic impurities. The volume of the rejected solution is kept constant by the addition of water. The nanofiltration process ends when the concentration of chloride anions is below the value of the specification (98-99% yield; Cl<0.01%; Na<4.1%)

[0065] This tetraxetan solution at a concentration of 45 g/L is then subjected to an electrodialysis process in which cationic and anionic membranes are used, and the pH of the diluate solution is maintained between pH=2.8-4.5. Or, a tetraxetan solution is treated with cationic membranes and monoselective anionic membranes, and the pH of the diluate solution is maintained between pH=2-3. Or, a tetraxetan solution at a concentration of 45 g/L is treated with cationic and bipolar membranes, and the pH of the diluate solution is maintained at pH=4. The electrolyte and concentrate solutions are a sulfuric acid or sodium sulfate solution. The electrodialysis process ends when the concentration of sodium cations is less than the specification value. In this way, a tetraxetan solution is obtained which goes directly to the isolation step (90-95% yield; Na<0.008%).

Example 4. Isolation and Characterization of Tetraxetan

[0066] The solution from the purification process can be used in the synthesis of gadoterate meglumine or, alternatively, tetraxetan can be isolated. Tetraxetan 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 result is a product that meets the specifications described below (97-99% yield; Na<0.008%).

[0067] The high purity tetraxetan obtained meets the following specifications: [0068] Appearance: white powder [0069] Identification: [0070] IR spectrum: comparable with the reference tetraxetan [0071] HPLC: retention time matching that of the reference [0072] Water≤8.5% [0073] Clear solution, no more coloured than reference solution Y7 [0074] Sodium≤500 ppm (0.05%) [0075] Halides≤500 ppm (0.05%) [0076] Residue on ignition≤0.10% [0077] Related impurities: [0078] DO3A≤0.05% [0079] Any other individual impurity 0.05% [0080] Total impurities 0.5% [0081] Titration (acid-base): 98.0-102.0% on dry product [0082] Bacterial Endotoxin≤22 EU/g [0083] Total aerobic microbial count≤10.sup.2 CFU/g [0084] Total combined yeast and mould count≤10.sup.2 CFU/g [0085] Escherichia coli: absence/1 g [0086] Residual solvents<10 ppm (0.001%)

Example 5. Gadoterate Meglumine Synthesis

[0087] To a solution of tetraxetan in water (200 g/L), Gd.sub.2O.sub.3 (1 eq.) is added. The mixture is heated 25 to 85° C. for 2-4 h. The pH of the reaction is maintained at pH=4 by adding meglumine. The reaction ends when the final amount of tetraxetan and free gadolinium is less than 0.005% (w/v). The pH of the solution is then raised between pH=6.5−8 by the addition of meglumine (quantitative yield)

Example 6. Isolation and Characterization of Gadoterate Meglumine

[0088] The final product dissolved in water is subjected to depyrogenizing ultrafiltration and then isolated by spray drying. The working conditions are as follows, inlet air temperature between 175-185° C. and outlet air temperature 110° C. (97-98% yield). The gadoterate meglumine isolated by this procedure has the following specifications: [0089] Appearance: white powder [0090] Water≤10.0% [0091] Identification: [0092] HPLC: retention time similar to that of the reference [0093] IR spectrum: similar to the reference [0094] Clear or no more opalescent solution than European Pharmacopoeia and American Pharmacopoeia (USP) reference solution I for the clarity and opalescence test of solutions [0095] Colour of the solution≤Y7 [0096] pH=6.5−8 [0097] Related impurities: [0098] DO3A≤0.05% [0099] Tetraxetan≤0.1% [0100] Any other individual impurity≤0.05% [0101] Total impurities≤0.50% [0102] Purity (HPLC): 97-103% on anhydrous product [0103] Meglumine content: 24.5-26.5% on anhydrous product [0104] Free Gd content≤0.01% [0105] Total Gd content: 19-22%. [0106] Foreign matter≤100 ppm (0.01%) [0107] Bacterial endotoxin<20UE/g [0108] Total aerobic microbial count (TAMC)≤10.sup.2 CFU/g [0109] Total combined yeast and mould count (TYMC)≤10.sup.2 CFU/g [0110] Escherichia coli: absence [0111] Residual solvents<10 ppm (0.001%) [0112] Elemental impurities: [0113] As≤1500 ppb [0114] Pb≤500 ppb [0115] Cd≤200 ppb [0116] Hg≤300 ppb [0117] V≤1000 ppb [0118] Ni≤2000 ppb [0119] Co≤500 ppb [0120] Pd≤1000 ppb [0121] Cu≤30000 ppb [0122] Li≤25000 ppb [0123] Sb≤9000 ppb

Example 7. Galenic Formulation of Gadoterate Meglumine

[0124] With the obtained gadoterate meglumine, injectable galenic formulations were prepared to be used in magnetic resonance imaging diagnosis.

TABLE-US-00001 TABLE 1 Solution of gadoterate meglumine in water at a concentration of 0.5M. Gadoterate meglumine 1 g 0.5M WFI* up to a total volume of 2.65 mL  *WFI, water for injection.

TABLE-US-00002 TABLE 2 Solution of 0.5M gadoterate meglumine and tetraxetan as excipient in water. Gadoterate meglumine 1 g 0.5M WFI up to a volume of 2.65 mL Tetraxetan (excipient) 0.133-1.33 mg 0.025-0.25% (mol/mol)

[0125] These two prepared formulations with the gadoterate meglumine isolated from the present invention are depyrogenized and sterilized. These two formulations meet the following specifications: [0126] Clear solution, no more coloured than the reference solution Y7 of the European pharmacopoeia and the American pharmacopoeia (USP) for the test of clarity and opalescence of solutions [0127] Identification: [0128] IR spectrum: similar to the reference compound [0129] HPLC: retention time similar to the reference standard. [0130] pH=6.9-8. [0131] Density=1.1649−1.1828 g/mL [0132] Free of visible particles. [0133] Subvisible particles<6000 (particle size<10 μm); <600 (particle size<25 μm) [0134] Absorbance: at 450 nm<0.40AU; at 500 nm<0.20AU [0135] Assay: [0136] Gadoterate: 26.53-29.33% (w/v) [0137] Total gadolinium: 7.63-8.10% (w/v) [0138] Free gadolinium<0.005% (w/v) [0139] Meglumine: 9.27-10.25% (w/v) [0140] Related impurities: [0141] DO3A<0.02% (w/v) [0142] Tetraxetan<0.05% (w/v) [0143] Any other impurity<0.02% (w/v) [0144] Total impurities<0.2% (w/v) [0145] Elemental impurities: [0146] As≤560 ppb [0147] Pb≤190 ppb [0148] Cd≤75 ppb [0149] Hg≤110 ppb [0150] V≤370 ppb [0151] Ni≤750 ppb [0152] Co≤190 ppb [0153] Pd≤370 ppb [0154] Cu≤1100 ppb [0155] Li≤940 ppb [0156] Sb≤3400 ppb [0157] Sterile solution, free of bacterial endotoxins (<8EU/mL).

Example 8. Comparison of Tetraxetan Obtained by the Process of the Invention

[0158] A comparison between the levels of present impurities in tetraxetan samples obtained by the process of the invention (DOTA 001-003) and other commercially available tetraxetan samples from different suppliers (Supplier 1-5) was made. The data are summarized in the following tables:

TABLE-US-00003 TABLE 3 Determination of elemental alkaline and halide impurities in tetraxetan by inductively coupled plasma mass spectrometry (ICP-MS) Na K Cl Br (ppm) (ppm) (ppm) (ppm) (LOD (LOD (LOD (LOD SAMPLE 1 ppm) 1 ppm) 2 ppm) 10 ppm) Supplier 1 62  7 60 n.d. Supplier 2 68 n.d. 68 n.d. Supplier 3 82 n.d. 121 n.d. Supplier 4 20550 500 8500 49000 Supplier 5 1500 150 50 n.d. DOTA-001 45 n.d. 2 n.d. DOTA-002 59 n.d. 12 n.d. DOTA-003 47 n.d. 13 n.d.

TABLE-US-00004 TABLE 4 Determination of residual solvents in tetraxetan by gas chromatography/massspectrometry (GC-MS) Ethyl Iso- Ethanol acetate Acetone Ammonia Methanol propanol (ppm) (ppm) (ppm) (ppm) (ppm) (ppm) (LOD10 (LOD10 (LOD10 (LOD10 (LOD10 (LOD10 SAMPLE ppm) ppm) ppm) ppm) ppm) ppm) Supplier 1  395 n.d. 20 n.d. Supplier 2 n.d. 2 44 n.d. Supplier 3 n.d. n.d. 10 25 n.d. Supplier 4 75 n.d. n.d. n.d. Supplier 5 1500 n.d. n.d. 67000 160 DOTA-001 n.d. n.d. n.d. n.d. n.d. n.d. DOTA-002 n.d. n.d. n.d. n.d. n.d. n.d. DOTA-003 n.d n.d. n.d n.d. n.d. n.d.

TABLE-US-00005 TABLE 5 Tetraxetan purity determined by HPLC for each sample SAMPLE DOTA (%) Supplier 1 99.88 Supplier 2 99.85 Supplier 3 99.86 Supplier 4 90.81 Supplier 5 96.30 DOTA-001 99.99 DOTA-002 99.99 DOTA-003 99.99

TABLE-US-00006 TABLE 6 Determination of other impurities by high performance liquid chromatography (HPLC) Chloroacetic Any other CYCLEN DO3A acid Glycolic acid individual Total (%) (%) (%) (%) impurity (%) impurities (LOD (LOD (LOD (LOD (LOD (%) (LOD SAMPLE 0.001%) 0.001%) 0.001%) 0.001%) 0.001%) 0.001%) Supplier 1 0.006 n.d. 0.083 0.005 0.035 0.117 Supplier 2 0.006 0.009 0.080 n.d. 0.057 0.152 Supplier 3 0.009 n.d. 0.084 0.011 0.016 0.100 Supplier 4 n.d. 0.003 n.d. n.d. 0.041 0.190 Supplier 5 n.d. 0.260 n.d. n.d. n.d. 0.420 DOTA-001 n.d. 0.004 n.d. n.d. 0.004 0.008 DOTA-002 n.d. 0.006 n.d. n.d. 0.003 0.009 DOTA-003 n.d. n.d. n.d. n.d. 0.009 0.009