Cost-effective process for preparation of manufacture of iron sucrose
Inventors
Gharpure, Milind Moreshwar • Bhawal, Baburao Manikrao • Sutar, Rajiv Pandurag • Mehta, Satish Ramanlal
Assignees
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Publication Number
US-8030480-B2
Publication Date
2011-10-04
Expiration Date
Abstract
The present invention relates to a cost-effective process for manufacture of iron sucrose complex.
Core Innovation
The invention relates to a cost-effective process of preparing an iron sucrose complex having a molecular weight between 34,000 and 60,000 daltons. A key aspect is formation of ferric oxyhydroxide from a selected ferric salt by reacting the ferric salt with a base in a solvent at acidic pH conditions, with the ferric oxyhydroxide isolated as a slurry.
The ferric oxyhydroxide slurry is added to an aqueous solution of sucrose, and the reaction mixture is adjusted to a highly basic pH using an aqueous solution of an inorganic base in an aqueous medium comprising sodium ions. The process then heats the reaction mixture, adjusts pH to a narrower basic range, and stirs to form the iron sucrose complex.
The iron sucrose complex is isolated by adjusting the pH to a higher basic range, concentrating the reaction mixture, and treating it with an organic solvent followed by filtration. Organic solvents are described as including methanol and other organic solvents, with solvent reprocessing steps emphasized, and the process is presented as addressing prior-art shortcomings such as expensive freeze-drying and regulatory molecular-weight mismatch.
Claims Coverage
The independent claims provide claim coverage for a process for preparing an iron sucrose complex with a molecular weight between 34,000 and 60,000 daltons. Across the independent claims, the inventive features are organized into three stages: ferric oxyhydroxide formation under acidic pH, reaction with sucrose under highly basic pH followed by heating and stirring, and isolation by additional pH adjustment, concentration, organic solvent treatment, and filtration.
Acidic ferric oxyhydroxide formation and slurry isolation
Reacting a ferric salt with a base in a solvent at a pH between 4.0 and 6.0 to form ferric oxyhydroxide and isolating the ferric oxyhydroxide as a slurry.
Sucrose reaction with controlled high pH and heating/stirring
Adding the ferric oxyhydroxide slurry to an aqueous solution of sucrose and adjusting the pH of the reaction mixture to between 11.3 and 12.0 with an aqueous solution of an inorganic base at a temperature between 15° C. and 40° C. to form a reaction mixture; heating the reaction mixture to a temperature between 85° C. and 100° C., adjusting the pH of the reaction mixture to between 9.75 and 10.0 and stirring the reaction mixture for a period of time from 2 to 3 hours to form the iron sucrose complex.
Isolation by pH adjustment, concentrating, organic solvent treatment, and filtration
Isolating the iron sucrose complex from the reaction mixture by adjusting the pH of the reaction mixture between 12.0 and 12.5, concentrating the reaction mixture, adding the concentrated reaction mixture to an organic solvent or adding an organic solvent to the concentrated reaction mixture, and filtering.
Iron sucrose complex preparation in a sodium-ion aqueous medium
Reacting sucrose and ferric oxyhydroxide in an aqueous medium comprising sodium ions, initially at a pH between 11.3 and 12.0 at an initial temperature between 15° C. and 40° C., followed by heating to a temperature between 85° C. and 100° C. and adjusting pH between 9.75 and 10.00.
Isolation in sucrose by further pH adjustment, concentrating, organic solvent addition order, and filtration
Isolating iron sucrose complex in sucrose from the reaction mixture by adjusting pH between 12.0 and 12.5, concentrating and adding to it an organic solvent or reversely adding the organic solvent to the concentrated reaction mixture and filtering.
Across the independent claims, the core claim coverage is for producing an iron sucrose complex of 34,000–60,000 daltons by: forming ferric oxyhydroxide under acidic pH and isolating it as a slurry; reacting with sucrose under highly basic pH followed by heating, pH adjustment, and stirring; and then isolating the complex through additional basic pH adjustment, concentration, organic solvent addition, and filtration in a sucrose/sodium-ion aqueous medium.
Stated Advantages
Cost-effective and industrially suitable process to manufacture iron(III)-sucrose complexes.
Addresses prior-art shortcomings, including expensive freeze-drying and regulatory molecular weight mismatch.
Improved purity and robustness to multiple pH adjustments.
Documented Applications
Manufacture and preparation of iron(III)-sucrose complexes, including downstream isolation suitable for pharmaceutically acceptable formulations.
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