Formulation of contrast media and process of preparation thereof

A process for preparing a liquid pharmaceutical formulation, the process comprising the following steps:

• providing a pharmaceutically acceptable solvent;
• dissolving a DO3A-derived tetra-chelate of formula (I):
• wherein
• R1 represents a group selected from:
• wherein group * indicates the point of attachment of the group with the rest of the molecule,
• R2, R3, and R4 independently of each other represents a hydrogen atom or a group selected from:
• C1-C6-alkyl, C3-C6-cycloalkyl, (C1-C2-alkoxy)-(C2-C3-alkyl)-, and phenyl,
• wherein the C1-C6-alkyl group is optionally substituted, identically or differently, with a phenyl substituent, wherein the phenyl substituent is optionally substituted, one, two or three times, identically or differently, with a group selected from a halogen atom, C1-C3-alkyl, C1-C3-haloalkyl, and C1-C3-alkoxy, and
• wherein the phenyl group is optionally substituted, one, two or three times, identically or differently, with a group selected from a halogen atom, C1-C3-alkyl, C1-C3-haloalkyl, and C1-C3-alkoxy,
• R5 represents a group selected from:
• C1-C6-alkyl, C3-C6-cycloalkyl, (C1-C2-alkoxy)-(C2-C3-alkyl)- and phenyl,
• wherein the C1-C6-alkyl group is optionally substituted, identically or differently, with a phenyl substituent, wherein the phenyl substituent is optionally substituted, one, two or three times, identically or differently, with a group selected from a halogen atom, C1-C3-alkyl, C1-C3-haloalkyl, and C1-C3-alkoxy, and
• wherein the phenyl group is optionally substituted, one, two, or three times, identically or differently, with a group selected from a halogen atom, C1-C3-alkyl, C1-C3-haloalkyl, and C1-C3-alkoxy,
• X represents a group C(═O)OH or C(═O) O31, and
• M represents Gd3+;
• or a stereoisomer, a tautomer or a salt thereof, or a mixture of same, in the pharmaceutically acceptable solvent in in sufficient amount to produce a solution of the formulation having a concentration of DO3A-derived tetra-chelate of formula (I) in a range of 60 to 750 mmol paramagnetic Gd3− ion/L (inclusive), and
• dissolving at least one compound capable of forming a chelate with Gd3+ in sufficient amount to produce a solution having a concentration in a range of 0.002% to 5% mol/mol (inclusive) with reference to the total concentration of the Gd3+ ion , wherein the compound capable of forming a chelate with Gd3+ is Ca-BT-DO3A (Calcobutrol).

A process for preparing a liquid pharmaceutical formulation, the process comprising the following steps:

• providing a pharmaceutically acceptable solvent;
• dissolving Ca-BT-DO3A (Calcobutrol) in the pharmaceutically acceptable solvent;
• and
• dissolving a DO3A-derived tetra-chelate of formula (I):
• wherein
• R1 represents a group selected from:
• wherein group * indicates the point of attachment of the group with the rest of the molecule,
• R2, R3, and R4 independently of each other represents a hydrogen atom or a group selected from:
• C1-C6-alkyl, C3-C6-cycloalkyl, (C1-C2-alkoxy)-(C2-C3-alkyl)-, and phenyl,
• wherein the C1-C6-alkyl group is optionally substituted, identically or differently, with a phenyl substituent, wherein the phenyl substituent is optionally substituted, one, two or three times, identically or differently, with a group selected from a halogen atom, C1-C3-alkyl, C1-C3-haloalkyl, and C1-C3-alkoxy, and
• wherein the phenyl group is optionally substituted, one, two or three times, identically or differently, with a group selected from a halogen atom, C1-C3-alkyl, C1-C3-haloalkyl, and C1-C3-alkoxy,
• R5 represents a group selected from:
• C1-C6-alkyl, C3-C6-cycloalkyl, (C1-C2-alkoxy)-(C2-C3-alkyl)- and phenyl,
• wherein the C1-C6-alkyl group is optionally substituted, identically or differently, with a phenyl substituent, wherein the phenyl substituent is optionally substituted, one, two or three times, identically or differently, with a group selected from a halogen atom, C1-C3-alkyl, C1-C3-haloalkyl, and C1-C3-alkoxy, and
• wherein the phenyl group is optionally substituted, one, two, or three times, identically or differently, with a group selected from a halogen atom, C1-C3-alkyl, C1-C3-haloalkyl, and C1-C3-alkoxy,
• X represents a group C(═O)OH or C(═O)O−, and
• M represents Gd3+;
• or a stereoisomer, a tautomer or a salt thereof, or a mixture of same, in the pharmaceutically acceptable solvent in sufficient amount to produce a final solution having a formulation having a concentration of the DO3A-derived tetra-chelate of formula (I) in a range of 1 to 1000 mmol Gd3+/L (inclusive), and
• wherein the Ca-BT-DO3A is dissolved in the pharmaceutically acceptable solvent in sufficient amount to produce a solution having a concentration in a range of 0.002% to 5% mol/mol (inclusive) with reference to the total concentration of the Gd3+ ion.