Patent ID: 8344139
Filing Date: 2013-01-01
Classification: A61P,C07D

Abstract:
1. A process for preparing a crystalline form of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å): for form A, which is a crystalline polymorph: 15.5 (vs), 12.0 (m), 4.89 (m), 3.70 (s), 3.33 (s), 3.26 (s), and 3.18 (m); or as exhibited in or for form F, which is a crystalline polymorph: 17.1 (vs), 4.92 (m), 4.68 (m), 3.49 (s), 3.46 (vs), 3.39 (s), 3.21 (m), and 3.19 (m); or as exhibited in or for form J, which is a crystalline polymorph: 14.6 (m), 3.29 (vs), and 3.21 (vs); or as exhibited in or for form K, which is a crystalline polymorph: 14.0 (s), 6.6 (w), 4.73 (m), 4.64 (m), 3.54 (m), 3.49 (vs), 3.39 (m), 3.33 (vs), 3.13 (s), 3.10 (m), 3.05 (m), 3.01 (m), 2.99 (m), and 2.90 (m); or as exhibited in or for form C, which is a crystalline hydrate: 13.9 (vs), 8.8 (m), 6.8 (m), 6.05 (m), 4.25 (m), 4.00 (m), 3.88 (m), 3.80 (m), 3.59 (s), 3.50 (m), 3.44 (m), 3.26 (s), 3.19 (vs), 3.17 (s), 3.11 (m), 2.97 (m), and 2.93 (vs); or as exhibited in or for form D, which is a crystalline hydrate: 8.6 (s), 5.56 (m), 4.99 (m), 4.67 (s), 4.32 (m), 3.93 (vs), 3.17 (m), 3.05 (s), 2.88 (m), and 2.79 (m); or as exhibited in or for form E, which is a crystalline hydrate: 15.4 (s), 4.87 (w), 3.69 (m), 3.33 (s), 3.26 (vs), 3.08 (m), 2.95 (m), and 2.87 (m); or as exhibited in or for form H, which is a crystalline hydrate: 15.8 (vs), 3.87 (m), 3.60 (m), 3.27 (m), 3.21 (m), 2.96 (m), 2.89 (m), and 2.67 (m); or as exhibited in or for form O, which is a crystalline hydrate: 8.8 (m), 6.3 (m), 5.65 (m), 5.06 (m), 4.00 (m), 3.88 (m), 3.69 (s), 3.64 (s), 3.52 (vs), 3.49 (s), 3.46 (s), 3.42 (s), 3.32 (m), 3.27 (m), 3.23 (s), 3.18 (s), 3.15 (vs), 3.12 (m), and 3.04 (vs); or as exhibited in or for form G, which is a crystalline ethanol solvate: 14.5 (vs), 7.0 (w), 4.41 (w), 3.63 (m), 3.57 (m), 3.49 (w), 3.41 (m), 3.26 (m), 3.17 (m), 3.07 (m), 2.97 (m), 2.95 (m), 2.87 (w), and 2.61 (w); or as exhibited in or for form I, which is a crystalline acetic acid solvate: 14.5 (m), 3.67 (vs), 3.61 (m), 3.44 (m), 3.11 (s), and 3.00 (m); or as exhibited in or for form L, which is a crystalline mixed ethanol solvate/hydrate: 14.01 (vs), 10.4 (w), 6.9 (w), 6.5 (w), 6.1 (w), 4.71 (w), 3.46 (m), 3.36 (m), and 2.82 (w); or as exhibited in or for form M, which is a crystalline ethanol solvate: 18.9 (s), 6.4 (m), and 3.22 (vs); or as exhibited in or for form N, which is a crystalline polymorph: 19.5 (m), 6.7 (w), 3.56 (m), and 3.33 (vs), 3.15 (w), or as exhibited in for form A, comprising dissolving (6R)-L-erythro-tetrahydrobiopterin dihydrochloride at ambient temperatures in water, and (1) cooling the solution to a temperature sufficient to solidify the solution, and removing water under reduced pressure, or (2) removing water from said aqueous solution; or for form F, comprising dispersing particles of solid form A of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a solvent, which is methanol, ethanol, propanol or isopropanol, below room temperature, stirring the suspension for a time sufficient to produce polymorph form F; or for form J, comprising preparing form E and removing the water from form E by treating form E in a vacuum drier at a moderate temperature of about 25 to 70° C.; or for form K, comprising dissolving (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a mixture of acetic acid and an alcohol containing water and ascorbic acid forming a solvent mixture, lowering the temperature to crystallise the dihydrochloride, thereby forming a precipitate, isolating the precipitate and drying the isolated precipitate optionally under vacuum; or for form C, comprising suspending (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a non-solvent, adding sufficient water to allow the formation of a monohydrate by stirring the suspension at or below ambient tempterature to form a monohydrate; or for form D, comprising adding at about room temperature a concentrated aqueous solutions of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride to a non-solvent and stifling the resultant suspension at an ambient temperature; or for form E, comprising adding a concentrated aqueous solution of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride to an excess of a non-solvent, determined by volume, cooled to a temperature of about 10 to −10° C. and stifling the suspension at said temperature; or for form H, comprising dissolving at ambient temperatures (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in a mixture of acetic acid and a less amount than that of acetic acid of water, determined by weight, adding a non-solvent, cooling the obtained suspension to a temperature of −10 to 10° C., and stirring the suspension at said temperature; or for form O, comprising exposing polymorphic form F to a nitrogen atmosphere containing water vapour with a resulting relative humidity of about 52% for about 24 hours; or for form G, comprising dissolving at about room temperature to a temperature of 75° C. (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in water or in a mixture of water and ethanol, if the temperature is above room temperature, then first cooling the resultant heated solution to room temperature, and then down to 5 to 10° C., adding optionally ethanol to complete precipitation, stirring the obtained suspension at a temperature of 20 to 5° C., filtering off a white, crystalline solid and drying the solid under air or a protection gas or nitrogen at about room temperature; or for form I, comprising dissolving L-erythro-tetrahydrobiopterin dihydrochloride in a mixture of acetic acid and water at elevated temperature, adding further acetic acid to the solution, cooling down to a temperature of about 10° C., then warming up the formed suspension to about 15° C., and then stirring the obtained suspension for a time sufficient for phase equilibration; or for form L, comprising suspending hydrate form E at room temperature in ethanol and stirring the suspension at a temperature of 0 to 10° C. for a time sufficient for phase equilibration; or for form M, comprising dissolving L-erythro-tetrahydrobiopterin dihydrochloride in ethanol and evaporating the solution under nitrogen at ambient temperature or drying of form G under a flow of dry nitrogen at a rate of about 20 to 100 ml/min; or for form N, comprising dissolving L-erythro-tetrahydrobiopterin dihydrochloride in a mixture of isopropanol and water, adding isopropanol, cooling the resulting suspension to about 0° C., stirring for several hours at this temperature, filtering the suspension, washing the solid residue with isopropanol at room temperature and drying the obtained crystalline material at ambient temperature and reduced pressure.