Method for producing salts of ralfinamide substantially free of impurities that have Genotoxic Effects, and the way pseudopolimorfica Pharmaceutical formulation containing same

摘要

Procedure for the production and / or purification of the Salt of the compound (S) - 2 - [4 - (2 - 3-fluorobenzyloxy) Benzylamino] propanamide, i.e. the r-enantiomer ralfinamide or corresponding with methanesulfonic acid, with high yields and High enantiomeric Purity and Chemical in the form of pol Imorfo identified as anhydrous Crystalline form,Where this salt is substantially free of impurities that have a genotoxic effect, such as the alcanilmetanosulfonatos cu2081u208bu2085, and residual solvents known as potential precursors of the same, such as the alcanoles cu2081u208bu2085 acids or Esters thereof with ALC Anoicos Lower.The Procedure involves (i) production and / or crystallization of the Salt from water, acetone, an aliphatic ketone 4 to 5 Carbon ATOMS, or mixtures thereof with water, or (ii) to form a Slurry of Solid Salt with water (a), (b) a mixture of water with acetone or a ketone alifu00e1t ICA 4 to 5 Carbon ATOMS, (c) acetoneAn aliphatic ketone 4 to 5 Carbon Atoms or a mixture thereof, or (iii) exposure of the solid Salt to an air flow that has a high degree of humidity, and, when the product obtained is in whole or in part H of the form of crystals pseudopolimorfo Hem Ihidrato CrystallineMake the product Crystals to form anhydrous improved by removal of water.The form of H pseudopolimorfo ralfinamide methanesulfonate hemihydrate Crystal, or an intermediary r-enantiomer, is helpful to obtain anhydrous Crystalline PolyMorph free of impurities that have a genotoxic effect and / or residual solvents known as precursors of the M Same above,And Presents a physico-chemical Profile confers significant advantages in the design and Development of Solid dosage forms, in particular, modified release formulations.Claim 1: a procedure for the production and / or purification of the Salt of the compound (S) - 2 - [4 - (2 - 3-fluorobenzyloxy) Benzylamino] propanamide ralfinamide formula (1) or the r-enantiomer (1 ') corresponding with methanesulfonic acid in anhydrous Crystalline polymorphic form of identification Qualified as aIt presents a model of x-ray Powder diffraction (pxrd) which has characteristic Peaks mainly expressed in 2Q to 6.93; degree: 7,80; record; 11.38 12,04 13.02 13.82;;;; 15.60 16.36 16.62 17.52;;;; 18.75 19,35 19,35 17.83;;;; 20,34; 20,69 21,20 22,69 22.95;;; 23.23 23.50; or;;; 25 24; 25, 8056 26,01 28.07 27.84;;;; 28.55 29.16 29.82 30.77;;;; 31.50 31.95 32.38 33.37;;;; 29,31; 3461; 37.38 36.46 36.02.;;;; 38,04; 39,43, where the content of impurities that have a genotoxic effect, which consist of one or more alkyl metanosulfonatos cu2081u208bu2085, is less than 0.05 ppm, and each of the residual solvents known as precursor motor pot The same actions, which consist of one or more alcanoles cu2081u208bu2085 or Esters thereof,Alkanoic acids with lower, is less than 6 ppm, characterized in that: (i) The Salt is produced and Purified by crystallization from a solution in a Solvent selected from: (a) Water, (b) a mixture of water with acetone or an aliphatic ketone 4 to 5 Carbon ATOMS, and (c) acet OnaAn aliphatic ketone 4 to 5 Carbon Atoms or a mixture thereof; or (ii) The Solid Salt that contains a lot of unwanted impurities that have a genotoxic effect and / or residual solvents known as potential precursors of the same, is formed as a Slurry with a Solvent selected from: (a) Water(b) a mixture of water with acetone or an aliphatic ketone 4 to 5 Carbon ATOMS, and (c) acetoneAn aliphatic ketone 4 to 5 Carbon Atoms or a mixture thereof; or (iii) The Solid Salt that contains a lot of unwanted impurities that have a genotoxic effect and / or residual solvents known as potential precursors of the same exposed to an air flow Q EU has a high relative humidity at a temperature and for a Time sufficient to allowThe removal of these impurities have a genotoxic effect and / or residual solvents known as potential precursors of the same, mentioned above; and, (iv) when the Crystalline form of the resulting Salt thus obtained is the form of pseudopolimorfo hemihydrate Crystal Identified as hIt presents a model of x-ray Powder diffraction Peaks characteristic is essentially expressed in degree 2Q: -4.09; 7.09 10,06 11,15 12.34;;;; 16.38; 5; 17,47 19,26 20,11 20,63;;;; 21.34; 21.97; 23,35 28,72 24,12 25.29;;;; 27,15 27,61 76,22 25,42;;;; 29,62 30.02; 30.51; 31; 29; 21,62 32.89 33,35 36,06;;;; 35.39 27,08 36,22 35.10;;;; 38,95; 3950; or a mixture of the same with the shape of the anhydrous Crystalline Polymorph, and (V) such that H pseudopolimorfo hemihydrate or mixture thereof above is completely converted to the anhydrous Crystalline polymorphic Form by removal of the Water of Crystallization by C Encouragement.Claim: The 24 h pseudopolimorfo methanesulfonate hemihydrate Crystal Salt ralfinamide or its r-enantiomer, presents a model of x-ray Powder diffraction (pxrd) which has characteristic Peaks mainly expressed in degree 2Q: -4.09; 7.09 10,06 11,15;; 12.34 16.38;;; Taxation; 17,47 19,26 20,11 20,63;;;; 21.34; 21.97 23,35 28,72 24,12;;;; 25.29 27,15; 27;61; 76,22 25,42 29,62 30.02;;;; 30.51 31.29 21,62 32.89;;;; 33,35 36,06 35.10;;; 35.39 27,08 36,22 38,95;;;; or.Claim 25: the form H pseudopolimorfo methanesulfonate hemihydrate Crystal Salt ralfinamide or its r-enantiomer, according to claim 24, characterized because essentially presents the following characteristics: (a) the following 's parameters The single crystal x-ray Crystallographic analysis: Where to,B and C are the lengths of the sides of the unit cells; a, B and G defined Angles on the sides of the cells; v defines the volume of the cell; (b) The Karl Fisher analysis shows a Content of 22% by weight of water, which is consistent with the presence of a Mole of water by two moles of ralfinamide methanesulfonate or its r-enantiomer; (c) shows the Model TGA weight loss of 2.14% Blend that is consistent with the presence of a Mole of water by two moles of RAL methanesulfonate Finamida or its r-enantiomer; (d) the model shows Two endothermic DSC Peaks: The First Peak at 951 / 2 c and the second 0,3u00baC 241.3); (e) The Model u00b9u00b3c - cpmas / solid state NMR shows the following Chemical shifts (ppm): 13.5 39,05 40,26 44.6;;;; 49.3; 51.9 54.0 56.7 57.4;;;; 61.2 83.0 84.9 84.0;;;; 97.0; 111.3; 113.2 116.6 121.6 124.1;;;; $133.1 129.7 129.0 126.9;;;; 1 182,0 185.5 169.1 56.7;;;; 196,45 199.2 193.9 189.0;;;; 201,0; 202,0; 205,0.