Process for the production of ralfinamide salts substantially free from impurities having genotoxic effects
Inventors
Giordano, Claudio • Waldvogel, Erwin
Assignees
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Publication Number
US-9856207-B2
Publication Date
2018-01-02
Expiration Date
Abstract
The invention relates to a new process for the production and/or purification of the salt of the compound (S)-2-[4-(2-fluorobenzyloxy) benzylamino]propanamide, i.e. ralfinamide, or the respective R-enantiomer, with methane sulfonic acid in high yields and very high enantiomeric and chemical purity in the form of the crystalline anhydrous polymorph identified as form A, wherein said salt is substantially free from impurities having genotoxic effect, such as (C1-C5)alkanylmethanesulfonates, and residual solvents known as potential precursors thereof, such as (C1-C5)alkanols or esters thereof with lower alkanoic acids.
Core Innovation
The invention relates to a process for the production and/or purification of a methanesulfonate salt of (S)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide ralfinamide (Ia), or its respective R-enantiomer (I′a), in crystalline anhydrous polymorph identified as form A. The salt is characterized by an X-ray powder diffraction pattern defined by specified 2θ peak positions, and the process controls both the crystalline form and the impurity profile of the salt.
The process addresses the presence of genotoxic effect impurities consisting of one or more (C1–C5) alkylmethanesulfonate(s) and residual solvents known as potential precursors thereof consisting of one or more (C1–C5) alkanol(s) or ester(s) thereof with lower alkanoic acid(s). Each genotoxic impurity is present in an amount lower than 0.05 ppm, and each residual solvent or precursor is present in an amount lower than 6 ppm.
The process includes crystallization and/or slurrying from specified solvent systems, including water; mixtures of water with acetone or water with an aliphatic ketone of 4–5 carbon atoms; and acetone or aliphatic ketones of 4–5 carbon atoms or mixtures thereof. It further includes exposing the salt containing undesired amounts of impurities and/or residual solvents to an air stream having relative humidity higher than 65% at a temperature from 5°C to 30°C for a time sufficient to remove those impurities and solvents.
When the resulting solid is the crystalline hemihydrate pseudopolymorph form identified as form H, the process wholly converts form H, or a mixture with form A, into crystalline anhydrous polymorph form A by removal of water on heating.
Claims Coverage
The consolidated independent claim coverage includes four inventive features: a specific ralfinamide methanesulfonate crystalline form A defined by PXRD peaks, quantitative impurity limits, specified crystallization and slurrying solvent systems, and humid-air exposure with conversion of form H to form A by removal of water on heating.
Crystalline anhydrous polymorph form a of ralfinamide methanesulfonate defined by pxrd peaks
Producing and/or purifying the methanesulfonate salt of (S)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide ralfinamide (Ia) or its R-enantiomer (I′a) in crystalline anhydrous polymorph form A, characterized by a PXRD pattern with specified 2θ peaks.
Immunity thresholds for genotoxic alkyl methanesulfonate impurities and residual solvent precursors
Each genotoxic impurity consisting of one or more (C1–C5) alkylmethanesulfonate(s) is present at less than 0.05 ppm, and each residual solvent known as a potential precursor thereof consisting of one or more (C1–C5) alkanol(s) or ester(s) thereof with lower alkanoic acid(s) is present at less than 6 ppm.
Crystallization or slurrying from specified water acetone ketone solvent systems
Producing or purifying the salt by crystallization from water; mixtures of water with acetone or water with an aliphatic ketone of 4–5 carbon atoms; or acetone, an aliphatic ketone of 4–5 carbon atoms, or mixtures thereof, and/or slurrying the salt with undesired impurities with a solvent selected from the same categories.
Humid air exposure to remove impurities and precursor residual solvents
Exposing the salt containing undesired amounts of impurities having genotoxic effect and/or residual solvents known as potential precursors thereof to an air stream having relative humidity higher than 65% at a temperature from 5°C to 30°C for a time sufficient to remove those impurities and/or residual solvents.
Conversion of hemihydrate pseudopolymorph form h to anhydrous form a by removal of water on heating
When the resulting crystalline form is crystalline hemihydrate pseudopolymorph form H, or a mixture thereof with form A, wholly converting the hemihydrate pseudopolymorph form H, or the mixture, into crystalline anhydrous polymorph form A by removal of the water on heating.
The claim scope centers on obtaining ralfinamide methanesulfonate in crystalline anhydrous polymorph form A while keeping genotoxic alkyl methanesulfonate impurities below 0.05 ppm and residual solvent precursors below 6 ppm, using specified crystallization, slurrying, and humid-air exposure conditions, with a defined conversion step for form H to form A by removal of water on heating.
Stated Advantages
Produces or purifies the ralfinamide methanesulfonate salt in crystalline anhydrous polymorph form A.
Substantial freedom from genotoxic alkyl methanesulfonate impurities, including MMS/EMS/IMS, and from residual solvents or precursors within the claimed impurity limits.
Stability in humid conditions for the form H described as a wet intermediate, together with a lower intrinsic dissolution rate for form H versus form A.
Ensures genotoxic impurities consisting of one or more (C1–C5) alkylmethanesulfonate(s) are present in an amount lower than 0.05 ppm.
Ensures residual solvents known as potential precursors thereof are present in an amount lower than 6 ppm.
When form H is obtained, enables wholly converting crystalline hemihydrate pseudopolymorph form H, or a mixture, into crystalline anhydrous polymorph form A by removal of the water on heating.
Documented Applications
Drug substance and formulation use cases, including wet granulation and aqueous film coating, tied to the crystalline forms and their stated behavior.
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