Kinetics and crystallization process of naphazoline hydrochloride in methanol-ethyl acetate system
Naphazoline hydrochloride(NPZ)is a vasoconstrictor drug that acts on the circulatory system.However,it has some poor crystal properties such as small average particle size and uneven distribution of particle size.Intermittent dynamic method was proposed to investigate the crystallization kinetics of NPZ in methanol-ethyl acetate system,and the influence of different technological conditions on the yield,particle size and variable coefficient were systematically investigated.The experimental results showed the nucleation mechanism of NPZ changed from heterogeneous nucleation to homogeneous nucleation with increase of supersaturation,and the crystal surface growth process followed a continuous growth mode.Growth kinetics model,nucleation rate and growth rate equations were:B0=9.591×104G2.10,B=2.031×1020 exp(-4.796×105/RT)M0.309T ΔC1.40ω1.37r and G=4.094×107 exp(-8.358×105/RT)ΔC1.36,respectively.The optimized conditions were as follows:crystal seed addition of 1.5%,crystallization temperature of 313.15K,stirring rate of 200r/min,supersaturation of 1.04,ethyl acetate addition rate of 7.037×10-4L/min,ethyl acetate to methanol mass ratio of 4∶1 and aging time of 2h.Crystals prepared under above conditions had a 30.49%increase in average particle size,a 32.30%reduction in variable coefficient,a 14.65%increase in bulk density,a 7.62%improvement in repose angle,a 30.76%improvement in Carr's index,and a 26.99%improvement in Hausner's ratio.The crystal size,particle size distribution and flowability were all improved.
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