Abstract:

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: B_{\mathrm{0}}=\mathrm{9.591}\times {\mathrm{10}}^{\mathrm{4}}{G}^{\mathrm{2.10}}, B=\mathrm{2.031}\times {\mathrm{10}}^{\mathrm{20}}\mathrm{e}\mathrm{x}\mathrm{p}\left(\frac{-\mathrm{4.796}\times {\mathrm{10}}^{\mathrm{5}}}{RT}\right)M_{\mathrm{T}}^{\mathrm{0.309}}\mathrm{\Delta }{C}^{\mathrm{1.40}}{\omega }_{\mathrm{r}}^{\mathrm{1.37}} and G=\mathrm{4.094}\times {\mathrm{10}}^{\mathrm{7}}\mathrm{e}\mathrm{x}\mathrm{p}\left(\frac{-\mathrm{8.358}\times {\mathrm{10}}^{\mathrm{5}}}{RT}\right)\mathrm{\Delta }{C}^{\mathrm{1.36}},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.

Key words: naphazoline hydrochloride, crystallization, kinetics, particle size distribution, optimization

摘要：

盐酸萘甲唑啉（NPZ）是一种作用于循环系统的血管收缩类药物。针对原料药平均粒径偏小及粒度分布不均的问题，本文提出运用间歇动态法对NPZ在甲醇-乙酸乙酯体系中的结晶动力学进行研究，并系统考察了不同结晶工艺条件对晶体析出率、粒径以及变异系数的影响规律。结果表明：随着溶液过饱和度的增大，NPZ晶体成核机制由非均相成核转为均相成核，晶体表面生长符合连续生长模式；NPZ生长动力学模型、成核速率与生长速率方程分别为B_{\mathrm{0}}=\mathrm{9.591}\times {\mathrm{10}}^{\mathrm{4}}{G}^{\mathrm{2.10}}、B=\mathrm{2.031}\times {\mathrm{10}}^{\mathrm{20}}\mathrm{e}\mathrm{x}\mathrm{p}\left(\frac{-\mathrm{4.796}\times {\mathrm{10}}^{\mathrm{5}}}{RT}\right)M_{\mathrm{T}}^{\mathrm{0.309}}\mathrm{\Delta }{C}^{\mathrm{1.40}}{\omega }_{\mathrm{r}}^{\mathrm{1.37}}和G=\mathrm{4.094}\times {\mathrm{10}}^{\mathrm{7}}\mathrm{e}\mathrm{x}\mathrm{p}\left(\frac{-\mathrm{8.358}\times {\mathrm{10}}^{\mathrm{5}}}{RT}\right)\mathrm{\Delta }{C}^{\mathrm{1.36}}。优化的结晶工艺参数为：晶种加入量1.5%（质量分数）、结晶温度313.15K、搅拌速率200r/min、溶液过饱和度1.04、乙酸乙酯滴加速率7.037×10^-4L/min、乙酸乙酯与甲醇质量比4∶1、陈化时间2h。该条件下制得的NPZ晶体较原料药平均粒径增大30.49%、变异系数降低32.30%、堆密度提高14.65%、休止角改善7.62%、卡尔指数提升30.76%、豪斯那比优化26.99%，晶体粒径、粒度分布及流动性均得到明显改善。

关键词: 盐酸萘甲唑啉, 结晶, 动力学, 粒度分布, 优化