WEAKLY CRYSTALLISED β-MODIFICATION OF (S)-ISOPROPYL 2-((S)-(((2R,3R,4R,5R)-5-(2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-(2H)-YL)-4-FLUORO-3-HYDROXY-4-METHYLTETRAHYDROFURAN-2-YL)METHOXY)-(PHENOXY)PHOSPHORYLAMINO)PROPANOATE, METHOD FOR PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION BASED THEREON

摘要

FIELD: chemistry.;SUBSTANCE: invention relates to a new anhydrous modification of (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate for the treatment of chronic viral hepatitis C, a method for its preparation and a pharmaceutical composition based thereon, which can be used in the pharmaceutical industry. Disclosed is a new β-modification of (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate, characterised by the following set of interplanar distances (d, Å) and the corresponding intensities (I_rel, %): 25.638 Å – 15.95 %; 21.101 Å – 17.80 %; 16.458 Å – 21.57 %; 13.368 Å – 26.61 %; 12.290 Å – 28.21 %; 11.343 Å – 31.14 %; 11.032 Å – 40.14 %; 10.287 Å – 36.18 %; 9.083 Å – 39.89 %; 8.458 Å – 43.59 %; 7.641 Å – 40.40 %; 7.148 Å – 46.78 %; 7.013 Å – 54.75 %; 6.528 Å – 46.01 %; 5.975 Å – 55.33 %; 5.225 Å – 79.00 %; 5.093 Å – 100.00 %; 4.892 Å – 86.15 %; 4.707 Å – 98.40 %; 4.614 Å – 84.56 %; 4.535 Å – 94.38 %; 4.405 Å – 90.68 %; 4.371 Å – 89.60 %; 4.259 Å – 75.49 %; 4.008 Å – 62.48 %; 3.792 Å – 57.69 %; 3.741 Å – 54.50 %; 3.539 Å – 47.35 %; 3.500 Å – 46.01 %; 3.263 Å – 46.27 %; 3.172 Å – 38.54 %; 3.141 Å – 40.71 %; 2.999 Å – 25.82 %; 2.839 Å – 25.82 %; 2.773 Å – 25.06 %; 2.722 Å – 27.38 %; 2.542 Å – 25.02 %; 2.359 Å – 23.68 %; 2.192 Å – 22.85 %; 2.117 Å – 21.83 %, and the presence of two endothermic effects on the DSC curve at temperatures 39.7–48.1 °C and 120.7–125.9 °C with improved efficiency.;EFFECT: disclosed is a new effective method for the preparation of said form, characterised in that sofosbuvir is dissolved in an organic solvent at 25–70 °C, the resulting solution is mixed with distilled water in a ratio of 1:2–1:10, frozen at a cooling rate of at least 60 deg/min, freeze-dried and further annealed at temperatures of 50–85 °C for at least 1 hour, followed by cooling to room temperature at a rate not higher than 5 deg/h.;4 cl, 4 tbl, 6 dwg, 5 ex