BOPTA calcium complex

Abstract

The present invention relates to calcium complexes of (4RS)(4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecane-13-oate(5-))pentahydrogen (BOPTA) in the form of salts, methods for their preparation, and formulations containing said salts.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates generally to calcium complexes of (4RS) (4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecane-13-oate(5-))pentahydrogen (BOPTA) in the form of a salt, their preparation, and their use in the preparation of pharmaceutical compositions containing same. [Background technology]

[0002] 2. Background of the Invention Metal chelate complexes, more commonly calcium (Ca 2+ ) and zinc (Zn 2+ Complexes with ) are known in medicine for the treatment of heavy metals, including metal ions and radionuclides. For example, Wax, PM, J. Med. Toxicol. 2013, 9:303-307 reports on currently available FDA approved chelating agents as scavengers.

[0003] Examples of calcium complexes are described in documents 2 (US9447053 B2 - Bayer Intellectual Property GmbH) and 3 (EP1210353) or 4 (US5876695 - Schering AG). Summary of the Invention [Problem to be solved by the invention]

[0004] Applicants have now discovered new calcium complex compounds, namely, calcium complex compounds of (4RS)-[4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecane-13-oate(5-)]pentahydrogen chelating ligand, otherwise known as BOPTA. Applicants have also discovered new synthetic procedures that allow for the advantageous preparation and isolation of such compounds.

[0005] Indeed, the applicant has observed that known manufacturing methods for producing solid forms of gadobenate (Gd-BOPTA) dimeglumine (see, for example, document 5 (WO2016012386)) cannot be used to effectively produce Ca-BOPTA.

[0006] Applicants have unexpectedly discovered that calcium complexes of BOPTA can be obtained as salts in a solid and conveniently filterable physical form using appropriate operating conditions.

[0007] The Applicant therefore proposes for the first time a process for the preparation of Ca-BOPTA salt in solid form, suitable for pharmaceutical use. The proposed process makes it possible to obtain a solid product that can be advantageously used for the preparation of pharmaceutical solutions due to its good solubility, good flowability, good yield and high quality. [Means for solving the problem]

[0008] The present invention relates generally to calcium complexes of (4RS) (4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecane-13-oate(5-))pentahydrogen (BOPTA), and salts thereof, their preparation, and their use in the preparation of pharmaceutical compositions containing them.

[0009] In a preferred embodiment, the present invention provides a compound of formula (I): [ka] [where, X + is preferably sodium (Na + ) or potassium (K + ), and ammonium (NH4 + ), more preferably Na + represents a monovalent cation, This relates to the calcium complex of BOPTA as a salt, represented by the formula:

[0010] Another aspect of the present invention relates to a method for preparing a solid form of the compound of formula I.

[0011] In a further aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula I in admixture with one or more physiologically acceptable carriers, diluents and galenic excipients. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Detailed Description of the Invention In this specification and claims, the term BOPTA means: Formula (III): [ka] a chelating agent represented by the formula (4RS)-[4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecane-13-oate(5-)]pentahydrogen, or Formula (III'): [ka] or its anionic form, represented by Any of its partial anionic forms.

[0013] In this specification and claims, the terms chelator and ligand are used interchangeably.

[0014] As defined herein, the calcium complex of BOPTA (anionic form) is Formula (II): [ka] It is a compound represented by the formula:

[0015] The term "complex" has its conventional meaning in the chemical arts and generally refers to a metal complex that comprises a central metal atom or ion coordinated to one or more ligands, which are ions or molecules that have one or more pairs of electrons that can be shared with the metal.

[0016] The complexes of formula II of the present invention contain calcium ions (i.e., Ca 2+ ) and BOPTA as a chelating agent. Preferred in the present invention are BOPTA monocalcium complex compounds having a single calcium complexed with the BOPTA ligand. The BOPTA ligand may be in a fully or partially ionic form.

[0017] In this specification and claims, the calcium complex of BOPTA of formula II is referred to interchangeably as Ca-BOPTA, or Ca-BOPTA complex, or the calcium complex of BOPTA.

[0018] One aspect of the present invention relates to a Ca-BOPTA complex of formula II in the form of a pharma- ceutically acceptable salt. As used herein, the term "pharma- ceutically acceptable salt" refers to a salt in which at least one of the carboxyl groups of BOPTA that is not involved in the complexation of calcium ions is in ionic form (i.e., -COO - ) and interacts with the corresponding cations of physiologically compatible bases. The actual number of free carboxylic acid groups may depend, for example, on the pH of the solution containing the complex.

[0019] Examples of suitable cations that can be used to prepare salts of Ca-BOPTA are inorganic (monovalent) cations. Preferred cations include potassium (K + ) and sodium (Na + ), or the ammonium ion (NH4 + ) are included.

[0020] In a preferred embodiment, the present invention provides a compound of formula Ia: [ka] This relates to the calcium complex of BOPTA as the trisodium salt, represented by the formula:

[0021] The compound of formula Ia may also be represented as (4RS)-[4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecane-13-oate(5-)]calciate(3-) trisodium.

[0022] The expressions "calcium complex trisodium salt of formula Ia" and "compound of formula Ia" are used interchangeably in this specification and claims.

[0023] Another aspect of the invention is a process for producing a solid form of a compound of formula I, comprising the steps of: a) obtaining an aqueous solution of a compound of formula I by combining, in an aqueous solvent, a compound containing calcium ions, a ligand BOPTA and a compound containing a cation X; b) optionally adjusting the pH of the solution obtained in step a); c) adding ethanol to the resulting solution to obtain precipitation of the compound of formula I in solid form; d) recovering the resulting solid form of the calcium complex of formula I. The present invention relates to a method for producing the same.

[0024] The process of the present invention allows the isolation of crystalline solid forms of the compound of formula I which advantageously meet the quality standards set by international organizations for pharmaceutical compounds.

[0025] Step a) Step a) of the process of the invention comprises obtaining an aqueous solution of the compound of formula I by combining, in an aqueous solvent, a compound containing calcium ions, the ligand BOPTA, and a compound containing a cation X.

[0026] The aqueous solvent is preferably selected from the group of water, saline and highly polar solvents such as highly polar organic solvents, and suitable mixtures thereof. More preferably, said aqueous solvent comprises water.

[0027] As used herein, calcium ions (Ca 2+ The term "compound containing calcium ions", or "calcium compound" for short, refers to an electrically neutral (no net charge) compound in which calcium cations and anions are ionic-bonded. Suitable calcium compounds include calcium hydroxide (Ca(OH)2), calcium carbonate (CaCO3), calcium acetate (Ca(CH3COO)2), calcium oxide (CaO2) and calcium chloride (CaCl2). According to the present invention, the compound containing calcium ions is preferably calcium hydroxide or calcium carbonate.

[0028] In an embodiment of the invention, the compound comprising a cation X in step a) is a base, preferably an inorganic base, the cation of which is capable of forming a salt with the free carboxylic acid group of BOPTA.

[0029] Examples of suitable inorganic bases include, for example, alkali metal hydroxides or carbonates, such as potassium carbonate (K2CO3), potassium bicarbonate (KHCO3), potassium hydroxide (KOH), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), sodium hydroxide (NaOH), and ammonium hydroxides or carbonates, such as ammonium carbonate ((NH4)2CO3), ammonium bicarbonate ((NH4)HCO3), ammonium hydroxide (NH4OH), etc. Preferably, the base in step a) is sodium hydroxide (i.e., NaOH).

[0030] As observed by the Applicant, the addition of an organic base or an alkaline earth metal base in step a) to obtain, for example, the Ca-BOPTA complex as the meglumine or calcium salt, gave unsatisfactory results (for example the end product in the form of a sticky solid mass).

[0031] In an embodiment of the invention, in step a), a compound comprising a cation X is mixed, as an aqueous solution, with a compound comprising calcium ions and the ligand BOPTA.

[0032] In another embodiment, in step a), the compound comprising the cation X is admixed, as a solid form, with the compound comprising calcium ions and the ligand BOPTA.

[0033] In a preferred embodiment of the present invention, the molar ratio of BOPTA to the compound containing a cation X in step a) is preferably 1:1.5 to 1:3 mol / mol, more preferably 1:2.5 to 1:3 mol / mol, more preferably 1:2.5 mol / mol.

[0034] Step a) comprises mixing a compound comprising a calcium ion, a ligand BOPTA, and a compound comprising a cation X in an aqueous solvent, and stirring the resulting mixture for 0.5 to 24 hours, preferably 2 to 20 hours, more preferably 4 hours, to obtain an aqueous solution of the compound of formula I.

[0035] According to the invention, during step a), Ca 2+ A complexation reaction occurs between the ions and BOPTA. The product of this complexation reaction is the Ca-BOPTA complex shown in formula II.

[0036] In step a), Ca 2+ The theoretical stoichiometric ratio of the ion to BOPTA is 2 to 0.5, preferably 0.95 to 1.05, and more preferably 1.

[0037] In another embodiment, at the end of step a), an additional amount of calcium ion-containing compound or BOPTA can be admixed. This additional amount provides free ligand or free Ca 2+ Contains no or free Ca 2+ Alternatively, an aqueous solution of the compound of formula I can be obtained that contains a small excess of free BOPTA.

[0038] In a preferred embodiment, at the end of step a), the aqueous solution of the compound of formula I is added with an excess of free Ca 2+ This excess is less than 0.09 molar equivalents (i.e., 9% mol / mol) relative to Ca-BOPTA, more preferably less than 0.05 molar equivalents (i.e., 5% mol / mol), and a minimum of 0.9×10 -4 It is the molar equivalent (0.009% mol / mol).

[0039] As observed by the applicant, an excess of Ca of more than 10% mol / mol 2+ Using about 2% mol / mol excess of calcium ions to prepare Ca-BOPTA trisodium salt would result in an end product that is less suitable for pharmaceutical applications. Unexpectedly, the use of about 2% mol / mol excess of calcium ions resulted in a suitable solid form of Ca-BOPTA trisodium at the end of the proposed preparation process with good properties and good yield (i.e. 94.5%).

[0040] Step b) The optional step b) of the process of the invention comprises adjusting the pH of the aqueous solution of the compound of formula I obtained in step a), preferably by addition of a base.

[0041] Step b) is necessary if the pH of the solution of step a) is not in the desired range.

[0042] In a preferred embodiment of the present invention, in step b) the pH is adjusted to a value between 6.5 and 9.5, more preferably between 7.0 and 8.5, even more preferably close to 7.5.

[0043] As observed by the applicant, at low pH values ​​(e.g. pH 6.1) in aqueous solutions of compounds of formula I (particularly those of formula Ia), the final product formed as sticky masses. Similarly, at pH values ​​higher than 9.5, the final product was obtained in the form of solid masses. In both these cases, the final product obtained at the end of the proposed manufacturing process was not very suitable for pharmaceutical use.

[0044] In one embodiment of the invention, the pH in step b) is adjusted by the addition of a base, preferably an inorganic base, where the cations of the base are capable of forming a salt with the free carboxylic acid groups of BOPTA.

[0045] According to the present invention, examples of suitable inorganic bases in step b) are, for example, alkali metal hydroxides or carbonates, such as potassium carbonate (K2CO3), potassium hydrogen carbonate (KHCO3), potassium hydroxide (KOH), sodium carbonate (Na2CO3), sodium hydrogen carbonate (NaHCO3), sodium hydroxide (NaOH), and ammonium hydroxides or carbonates, such as ammonium carbonate ((NH4)2CO3), ammonium hydrogen carbonate ((NH4)HCO3) and ammonium hydroxide (NH4OH).

[0046] In a preferred embodiment of the present invention, the base in step b) is the same as the base in step a), in a further preferred embodiment the base in step b) is sodium hydroxide.

[0047] In another embodiment of the invention, the base of step b) comprises a cation different from the cation of the base of step a), in which at the end of step b) a solution of Ca-BOPTA complex of formula II in the form of a mixed salt is obtained.

[0048] As used herein, the expression "mixed salt" refers to a pharma- ceutically acceptable salt of the Ca-BOPTA complex of formula II, in which the ionic form (i.e., COO -The carboxyl groups of BOPTA, which are present at 1000 .mu.m and are not counterbalanced by the positive charge of the calcium ion, can interact with at least two different corresponding cations of physiologically compatible bases. The actual number of these free carboxylic acid groups can depend on the pH of the solution containing the complex, since, for example, depending on the pH value, they may be in protonated form.

[0049] In one embodiment of the present invention, step a) and step b) of the proposed process are carried out at a reaction temperature between 0°C and 100°C, preferably between 10°C and 80°C, more preferably between 15°C and 60°C.

[0050] In a preferred embodiment of the invention, at the end of step b), a solution of compound of formula I is obtained, in which the concentration of said compound (w / w relative to the total weight of the solution) is between 30% and 80%, preferably between 40% and 75%, more preferably between 45% and 70%.

[0051] Preferably, at the end of step b), the aqueous solution of the compound of formula I is distilled to concentrate the solution, obtaining a solution of the compound of formula I at the concentration defined above.

[0052] This distillation process is preferably carried out at a temperature of 50°C to 100°C, more preferably 50°C to 70°C, and even more preferably 50°C to 60°C.

[0053] The distillation process is preferably carried out at atmospheric pressure (i.e. 101325 Pa) or more preferably under reduced pressure, for example 0-2.0×10 4 Pa, preferably 2.5 x 10 3 ~1.5×10 4 Pa, more preferably 5.0×10 3 ~1.0×10 4 It will be carried out in Pa.

[0054] In one embodiment of the invention, the distillation process comprises distilling at a temperature of 50 to 60° C. with 5.0×10 3 ~1.0×10 4 The reaction is carried out under reduced pressure of 100 Pa.

[0055] Step c) According to the present invention, step c) of the proposed preparation process comprises adding ethanol to the obtained solution of Ca-BOPTA salt in order to precipitate the compound of formula I, preferably the compound of formula Ia, in solid form.

[0056] Applicant has tested several solvents for precipitation of Ca-BOPTA trisodium salt (e.g., acetone and several short chain alcohols, e.g., 1-propanol, 2-propanol, 1-butanol, 2-butanol), but these preliminary attempts at isolating Ca-BOPTA trisodium have yielded unsatisfactory results, such as oily products or solids with unacceptable properties (e.g., rubbery, sticky or glassy solids), and in some cases (i.e., methanol) precipitation was not even possible.

[0057] Thus, the Applicant has surprisingly found that it is possible to obtain a suitable solid form of Ca-BOPTA trisodium salt by adding ethanol to a Ca-BOPTA trisodium salt solution.

[0058] In this specification, the expression "suitable solid form" refers to a filterable solid form of Ca-BOPTA trisodium having suitable physicochemical properties such as high solubility, high dissolution rate, high purity, and high flowability, suitable for pharmaceutical use.

[0059] According to a preferred embodiment of the invention, step c) of the proposed preparation process comprises adding ethanol to an aqueous solution of Ca-BOPTA trisodium salt in order to precipitate the compound of formula Ia in solid form.

[0060] According to another embodiment of the invention, step c) of the proposed preparation method can be carried out by adding this aqueous solution to ethanol.

[0061] In one embodiment of the present invention, the weight ratio of BOPTA to ethanol is preferably 1:4 to 1:30 w / w, more preferably 1:5 to 1:15 w / w, and even more preferably 1:7 to 1:12 w / w.

[0062] In a preferred embodiment of the present invention, the precipitation of trisodium Ca-BOPTA in step c) is obtained when the concentration of the solution of calcium complex of formula Ia is between 30% and 80%, preferably between 40% and 75%, more preferably between 45% and 70%.

[0063] For example, Applicants have observed that when the concentration of the compound of Formula Ia is below 40%, no precipitation occurs, whereas when the concentration in aqueous solution is above 70%, a very thin solid forms that is very viscous and difficult to filter and dry.

[0064] Step c) is preferably carried out at a temperature between 20 and 80°C, more preferably between 40 and 70°C, even more preferably between 50 and 60°C.

[0065] According to a further embodiment of the invention, at the end of step c) of the proposed preparation process, the precipitated suspension of Ca-BOPTA trisodium salt is cooled to a temperature below 30° C., more preferably below 20° C., even more preferably below 10° C.

[0066] Step d) According to the invention, step d) of the proposed preparation process comprises recovering the obtained solid form of the calcium complex of formula I, preferably of formula Ia.

[0067] In this specification and claims, the expression "isolation procedure" has its conventional meaning in the chemical arts to denote any process intended to separate a substance from a mixture, thereby removing substances that may be considered impurities.

[0068] Examples of suitable isolation procedures are filtration and centrifugation.

[0069] In a preferred embodiment of the present invention, the solid form of Ca-BOPTA trisodium salt of formula Ia is isolated by filtration.

[0070] According to another embodiment of the present invention, after isolation, the Ca-BOPTA trisodium salt is washed with ethanol and diluted with 0.0 to 2.0×10 4 Pa, more preferably 2.5×10 3 ~1.5×10 4 Pa, and even more preferably 5.0×10 3 ~1.0×10 4 The drying is performed at a temperature of at least 30°C or higher, preferably 30°C to 100°C, more preferably 50°C to 70°C, and even more preferably 50°C to 60°C, and at a pressure of 20 Pa.

[0071] The Ca-BOPTA trisodium salt thus prepared is characterized by very high quality: the solid form of the salt is colourless, soluble in water and has a purity of more than 97.0%, and in some batches even more than 99.5%.

[0072] TG-IR, DSC, IR and elemental analyses were consistent with the proposed compound of Formula Ia.

[0073] The entire process is characterized by high reproducibility and workability, with an overall yield of approximately 94%, as detailed in the examples.

[0074] Another aspect of the present invention relates to a pharmaceutical composition comprising an effective amount of a compound of formula I, preferably a compound of formula Ia, and one or more pharma- ceutically acceptable carriers, galenic diluents and excipients, useful for use as a scavenger to limit or prevent the retention of heavy metals in biological organs or tissues.

[0075] The pharmaceutical compositions can be prepared according to methods known in the literature by dissolving the salts of the calcium complexes of the invention in an aqueous medium together with the additives commonly used in galenic preparations, optionally followed by sterilization of the solution. Suitable additives are, for example, physiological buffers, electrolytes and antioxidants.

[0076] In a further aspect, the present invention relates to the use of a compound of formula I, preferably a compound of formula Ia, or a pharmaceutical composition comprising it, as a medicament for therapeutic or diagnostic use. In one embodiment, the pharmaceutical use is as a scavenger of heavy metals, for example to prevent, remove or reduce the retention or accumulation of known or possible heavy metals in living organisms. Metals that can be treated (i.e., removed or reduced) with the calcium chelates of the present invention include divalent and trivalent metal ions that displace calcium from complexes. Suitable examples include lead; transition metals (such as chromium, iron, cadmium, manganese, mercury); and lanthanides and actinides (including paramagnetic metal ions and radionuclides typically used in MRI diagnostics and nuclear medicine, respectively).

[0077] Remarkably, the process of the present invention can be conveniently employed even on a large scale for the production of CaBOPTA (trisodium) salt, intended for use as a scavenger in the manufacture of pharmaceutical compositions to reduce or prevent metal retention.

[0078] The following examples will serve to further illustrate the invention. EXAMPLES

[0079] Example 1: Preparation of Ca-BOPTA trisodium salt by direct precipitation In a 1.5 L reactor equipped with a mechanical stirrer, calcium hydroxide (68.20 g, assay 99.1% w / w, 0.912 mol) is suspended in 750 mL of water. BOPTA (500.0 g, assay 91.39%, 0.890 mol) is charged in portions at 20° C., followed by the dropwise addition of 28% NaOH solution (317.8 g) over approximately 1 hour. The suspension is stirred for 4 hours. Finally, a clear solution is obtained and the pH is adjusted to 7.47 by adding 28% NaOH. The solution was cooled to 50-60°C and cooled under reduced pressure (50-100 mbar, i.e., 5.0 × 10 3 ~1.0×10 4 Partially distill at 1000 rpm (Pa) to a product concentration of 64.9% w / w. Ethanol (3.85 kg) is then added over 2.5 h while maintaining the temperature at 40-50 °C. The resulting suspension is stirred at the same temperature for a further 0.5 h, then cooled to 0° C. in 4 h and kept at this temperature for 11 h. Finally the solid is isolated by filtration, washed with ethanol (750 g, pre-cooled to 0° C.) and concentrated under reduced pressure (p<30 mbar, i.e. <3.0×10 3 Dry at 50°C for 36 hours. 575.8 g of Ca-BOPTA trisodium are obtained (yield 94.5%). TIFF0007603690000006.tif36142

[0080] Example 2: Preparation of trisodium Ca-BOPTA by reverse precipitation In a 2 L reactor equipped with a mechanical stirrer, pelletized NaOH (80.28 g, 2.01 mol) and BOPTA (450.0 g, assay 91.6% w / w, 0.803 mol) are dissolved in 1575 mL of water at 25° C. Then, with stirring, CaCO3 (80.36 g, 0.803 mol) is charged in portions over approximately 1 hour. The mixture is kept at 25° C. for 1 hour and then heated to 55° C. for 4 hours to remove carbonic anhydride. Finally, the pH is adjusted to 7.05 by adding 30% NaOH. The solution was cooled to 50-60°C and cooled under reduced pressure (50-100 mbar, i.e., 5.0 × 10 3~1.0×10 4 Partially distill at 1000 rpm (Pa) to a product concentration of 51.6% w / w. A 5 L reactor is charged with 4.92 kg of ethanol and the concentrated solution is added over 2.5 hours at 20° C. The resulting suspension is stirred for an additional hour and then filtered. The wet solid is concentrated under reduced pressure (p<30 mbar, i.e. <3.0×10 3 The mixture was dried at 40°C for 16 hours. 400.3 g of Ca-BOPTA trisodium are obtained (yield 80.7%).

[0081] Example 3 Preparation of Ca-BOPTA trisodium using 2-propanol An aqueous solution of trisodium Ca-BOPTA (200 g, concentration 51.8%) prepared as described in Example 2 was diluted with water at 45° C. under reduced pressure (50-100 mbar, i.e. 5.0×10 3 ~1.0×10 4 It is partially distilled at 1000 psi (Pa) to a concentration of 63%. At the same temperature, 2-propanol (655.0 g) is added dropwise over 1.5 hours. The suspension is then cooled to room temperature. An oily, sticky product is obtained.

[0082] Example 4 Preparation of Ca-BOPTA trisodium using acetone A 1.5 L reactor equipped with a mechanical stirrer is charged with 30% NaOH solution (297.4 g) and water (238.4 g). BOPTA (500.0 g, assay 91.63%, 0.890 mol) is charged in portions at 20° C. Once completely dissolved, add calcium hydroxide (66.1 g, 0.89 mol). The resulting suspension is stirred for 1 hour, heated to 55° C. and maintained under stirring for another 4 hours. Finally, the mixture is cooled to 25° C. and maintained at this temperature overnight. The pH is then adjusted to 7.01 by adding 30% NaOH. The aqueous solution of trisodium Ca-BOPTA (200 g, concentration 46.0%) was dissolved in water at 40° C. under reduced pressure (50 to 100 mbar, i.e., 5.0×10 3 ~1.0×10 4 Partially distill at 1000 psi (Pa) to a concentration of 55.1%. At the same temperature, acetone (911.6 g) is added. The suspension is then maintained overnight at 40° C. An oily, sticky product is obtained.

[0083] Example 5 Preparation of Ca-BOPTA trisodium using 1-propanol In a 1.5 L reactor equipped with a mechanical stirrer, calcium carbonate (90.93 g, 0.91 mol) is suspended in 212 mL of water. BOPTA (500.0 g, assay 91.48%, 0.89 mol) and 30% NaOH solution (317.8 g) are added alternately at 25° C. over a period of approximately 8 hours. The suspension is heated to 50° C. in 1 hour and stirred for 3 hours. The suspension is then cooled to 25° C. in 1 hour and kept at this temperature overnight. Finally, a clear solution is obtained and the pH is adjusted to 7.0 by adding 30% NaOH. A portion of this aqueous solution of trisodium Ca-BOPTA (110 g, concentration 46.7%) is heated at 40° C. At the same temperature 1-propanol (179.5 g) is added. The resulting cloudy mixture is then heated to 50° C. to obtain a complete solution and cooled to 5° C. for 4 hours. An oily product is obtained.

[0084] Example 6 Preparation of Ca-BOPTA trisodium using a solution of pH 6.1 In a 1 L reactor equipped with a mechanical stirrer, calcium hydroxide (20.26 g, assay 99.1% w / w, 271 mmol) is suspended in 150 mL of water. BOPTA (150.0 g, assay 91.8%, 268 mmol) is charged in portions at 20° C., followed by dropwise addition of 30% NaOH solution (89.37 g) over approximately 1 hour. The suspension is stirred for 16 hours, at the end of which a clear solution with a pH of 6.07 is obtained. The solution was cooled to 50-60°C and cooled under reduced pressure (50-100 mbar, i.e., 5.0 × 10 3 ~1.0×10 4 Partially distill at 1000 rpm (Pa) to a product concentration of 59.03% w / w. Ethanol (1.06 kg) is then added over 2.5 hours while maintaining the temperature at 40°C. A sticky, lumpy product is obtained.

[0085] Example 7 10% mol / mol excess Ca 2+ Production of Ca-BOPTA trisodium by In a 1.5 L reactor equipped with a mechanical stirrer, calcium hydroxide (17.64 g, assay 99.1% w / w, 236 mmol) is suspended in 135 mL of water. BOPTA (120.0 g, assay 91.8%, 215 mmol) is charged portionwise at 20° C., followed by dropwise addition of 30% NaOH solution (71.50 g) over approximately 1 hour. The suspension is stirred for 16 hours. Finally, a clear solution is obtained and the pH is adjusted to 7.06 by adding 30% NaOH. The solution was cooled to 50° C. under reduced pressure (50 to 100 mbar, i.e., 5.0×10 3 ~1.0×10 4 Partially distill at 1000 psi (Pa) to a product concentration of 65.6% w / w. Ethanol (993 g) is then added over approximately 2 hours, keeping the temperature at 40-50 °C. The resulting suspension is stirred at the same temperature for a further 0.5 h, then cooled to 0° C. over 4 h and maintained at this temperature for 16 h. The resulting solids are sticky, form large clumps or crusts on the reactor walls, and cannot be quantitatively recovered.

[0086] Example 8 Preparation of Ca-BOPTA trimeglumine In a 4 L reactor equipped with a mechanical stirrer, meglumine (174.2 g, 892 mmol) is dissolved in 500 mL of water and then BOPTA (250.0 g, assay 91.6%, 446 mmol) and calcium hydroxide (34.22 g, assay 99.1% w / w, 457 mmol) are charged portionwise at 15-20 °C. The mixture is stirred for 16 h at 20 °C. Finally, a clear solution is obtained and the pH is adjusted to 7.50 by adding meglumine. The solution was cooled to 50° C. under reduced pressure (50 to 100 mbar, i.e., 5.0×10 3 ~1.0×10 4 Partially distill at 1000 rpm (Pa) to a product concentration of 65.87% w / w. Then, ethanol (2.50 kg) is added over about 2 hours while maintaining the temperature at 40-50°C. The resulting suspension is stirred at the same temperature for a further 0.5 h, then cooled to 3° C. over 4 h and maintained at this temperature for 14 h. The resulting solid is sticky and forms large clumps.

Claims

1. Formula I 【Chemistry 1】 [In the formula, X ＋ is an alkali metal cation and ammonium (NH ４ ＋ represents a monovalent cation selected from the group consisting of A compound represented by the formula:

2. 2. The compound of claim 1, wherein X is sodium.

3. 10. A method for preparing a solid form of the compound of claim 1, comprising the steps of: a) A compound containing calcium ions, Formula III' 【Chemistry 2】 and a compound comprising a cation X in an aqueous solvent to obtain an aqueous solution of the compound of formula I; b) adjusting the pH of the solution obtained in step a) to between 6.5 and 9.5; c) adding ethanol to the resulting solution to obtain precipitation of the compound of formula I in solid form; d) recovering the resulting solid form of the calcium complex of formula I. The method of manufacturing the same.

4. The method according to claim 3, wherein the compound containing calcium ions is calcium hydroxide or calcium carbonate.

5. 5. The process according to claim 3 or 4, wherein the compound containing a cation X in step a) is a base selected from alkali metal or ammonium hydroxides or carbonates.

6. The process according to claim 5, wherein the compound containing cation X in step a) is sodium hydroxide.

7. The process according to any one of claims 3 to 6, wherein in step a) the molar ratio of the compound of formula III' to the compound containing the cation X is from 1:1.5 to 1:3 mol / mol.

8. The method of claim 7, wherein the ratio is 1:2.5 to 1:3 mol / mol.

9. At the end of step a), the aqueous solution contains an excess of free Ca relative to Ca-BOPTA. ２＋ The method according to any one of claims 3 to 8, comprising:

10. The free Ca ２＋ The method of claim 9, wherein the excess amount of is less than 0.09 molar equivalents relative to Ca-BOPTA.

11. The free Ca ２＋ The method of claim 9, wherein the excess amount of is less than 0.05 molar equivalents relative to Ca-BOPTA.

12. The process according to claim 3, wherein step b) comprises adjusting the pH of the aqueous solution of the compound of formula I obtained in step a) by adding a base.

13. 13. The process according to claim 12, wherein the base is selected from alkali metal or ammonium hydroxides or carbonates.

14. The process according to claim 13, wherein the base is sodium hydroxide.

15. The process according to claim 14, wherein the pH is adjusted to 7.0 to 8.

5.

16. The process according to any one of claims 3 to 15, wherein the ratio of the compound of formula III' to ethanol is 1:4 to 1:30 (w / w).

17. The method of claim 16, wherein the ratio is from 1:5 to 1:

15.

18. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 or claim 2 and one or more pharma- ceutically acceptable carriers, galenic diluents and excipients.

19. 10. Use of a compound according to claim 1 or claim 2 for the manufacture of a medicament.

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