Process for the crystallisation of cefadroxil monohydrate
Inventors
Lenhard, Carlos Enrique • Moody, Harold Monro • Dooren, Theodorus Johannes Godfried Maria Van
Assignees
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Publication Number
US-8420806-B2
Publication Date
2013-04-16
Expiration Date
Abstract
The present invention relates to a process for the preparation of cefadroxil in crystal form, comprising a) adding an aqueous solution of cefadroxil to a crystallization vessel and a titrant to keep a pH in the crystallization vessel of between 7 to 9; and b) lowering the pH in the crystallization vessel to a value of between 5 and 6.5 to obtain a suspension of the β-lactam compound in crystal form. The invention further relates to cefadroxil in crystal form obtainable by the process according to the present invention. The invention also relates to cefadroxil in crystal form with a CIE b value of below 12 when stored at a temperature of 25° C. for at least 1 month.
Core Innovation
The invention relates to a process for the preparation of cefadroxil monohydrate in crystal form. The process comprises bringing an aqueous solution of cefadroxil monohydrate to a pH between 7 and 9 with a suitable titrant, and then lowering the pH to a value between 5 and 6.5 to obtain a suspension of cefadroxil monohydrate in crystal form. The cefadroxil monohydrate in crystal form is then isolated from the suspension obtained in the pH-lowering step.
The process is described as a two-step pH-controlled crystallization in which the first pH adjustment establishes a pH of 7 to 9 and the second step lowers the pH into 5 to 6.5 to form a crystalline suspension. The document also states that the process targets improved solid properties compared to prior art, including less agglomeration and particle size distribution improvements.
The document further defines a particle size distribution and uses CIE b as a color metric, together with thresholds and storage-related color stability. Reported outcomes include little colour characterized by CIE b value thresholds and improved color stability over storage, with CIE b measured after storage and stress storage tables presented.
Claims Coverage
The patent provides one independent claim directed to a two-step pH-controlled process that produces and isolates cefadroxil monohydrate in crystal form. Dependent claims refine the independent claim by adding temperature constraints, time constraints for the pH-lowering step, and stirring constraints for the crystalline suspension.
Two-step pH-controlled crystallization and isolation
A process for the preparation of cefadroxil monohydrate in crystal form, comprising bringing an aqueous solution of cefadroxil monohydrate to a pH of between 7 to 9 with a suitable titrant; lowering the pH to a value of between 5 and 6.5 to obtain a suspension of cefadroxil monohydrate in crystal form; and isolating the cefadroxil monohydrate in crystal form from the suspension obtained in step b.
Temperature-constrained pH adjustment and pH-lowering
The process of claim 1 wherein steps a) and b) are performed at a temperature between 5 and 25°C.
Timed pH decrease within a defined window
The process of claim 1 wherein lowering the pH in step b) is performed within 20 to 60 minutes.
Stirring the crystalline suspension for a defined duration
The process of claim 1 wherein the suspension of the cefadroxil monohydrate in crystal form obtained in step b) is stirred for 10 to 120 minutes.
Overall, the claims cover a two-step pH control process that produces cefadroxil monohydrate in crystal form followed by isolation, with additional dependent claim features specifying temperature for steps a) and b), a defined duration for the pH lowering in step b), and a defined stirring time for the resulting crystalline suspension.
Stated Advantages
Improved solid properties compared with prior art, including less agglomeration and smaller particle size distribution.
Little colour characterized by CIE b value thresholds.
Improved color stability over storage, including reported CIE b values below 12 over storage at 25°C.
Documented Applications
Use as a crystallization process to prepare cefadroxil monohydrate in crystal form, with reported measurements including X-Rite color measurement (CIE b) and storage/stress storage color stability.
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