| CPC C07D 211/90 (2013.01) [A61K 9/2013 (2013.01); A61K 9/2054 (2013.01); A61K 9/2059 (2013.01); C07B 2200/13 (2013.01)] | 15 Claims |
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1. A method for preparing an amlodipine mesylate monohydrate, wherein said method comprises following steps: dissolving an amlodipine free base in a water-containing organic solvent and adding methanesulfonic acid dropwise under low temperature condition to give a saturated solution, stirring and adding a seed crystal of amlodipine mesylate monohydrate thereto, adding methanesulfonic acid dropwise continuously under stirring to give crystals, growing the crystals, centrifuging, washing and vacuum drying before obtaining;
wherein the organic solvent is one or more selected from the group consisting of ethyl acetate, acetone, acetonitrile and isopropanol;
a molar ratio between the water contained in the organic solvent and the amlodipine free base is 1.0-10.0;
a ratio (m:v) between the amlodipine free base and the organic solvent is 1:3-1:15;
a total amount of methanesulfonic acid added is 0.9 to 2.0 equivalents of the amlodipine free base;
an amount of methanesulfonic acid added before adding the seed crystal of amlodipine mesylate monohydrate is 10%-30% (mass percentage) of the total amount of methanesulfonic acid added;
the low temperature condition is 0° C.-30° C.;
the growing of the crystals is conducted under a temperature of −10° C.-30° C.;
the growing of the crystals is conducted for 0.5-24 hours;
a stirring rate utilized before the adding of the seed crystal is 150-200 rpm/min, and a stirring rate utilized after the adding of the seed crystal is 100 rpm/min-60 rpm/min; and
the monohydrate is in crystal form, the crystal has a particle size distribution of D10: 20-40 μm, D50: 55-85 μm, D90: 95-140 μm, a carr index of 10-25%, an angle of repose (α) of 15-35°, a bulk density of 0.25-0.45 g/mL, and a purity of more than 99.5%.
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