基于质量源于设计的原理对利伐沙班片的工艺参数进行优化

Optimization of Process Parameters of Rivaroxaban Tablets Based on the Principle of Quality by Design

目的:基于利伐沙班片的原研处方,对其工艺参数进行优化。方法:对利伐沙班片的关键质量因素进行风险评估,以流化床制粒时物料温度、粘合剂喷液流速、进风风量为考察因素,并以利伐沙班片的溶出度、制粒收率为响应指标,进行3因素的全因子设计。最终找到关键工艺参数,并对关键工艺参数进行空间设计,降低风险至可接受程度。结果:全因子设计结果显著,失拟度不显著。物料温度在既定的参数范围内对溶出以及收率的影响不显著。随着进风风量的增加,自研片的溶出速度加快,但是收率降低;粘合剂喷液流速增加,溶出减慢,收率提高。满足标准的参数范围为:物料温度25~35℃,喷液速度16~21 g/min,进风风量37~42 m^(3)/h。结论:最终得到风险可接受的,能够保证利伐沙班片质量的工艺过程。

Objective:To optimize the technological parameters of Rivaroxaban tablets based on their original formulation.Method:Risk assessment was performed on the key quality factors of rivaroxaban tablets,taking the material temperature,fluid flow rate of binder spray,and the amount of incoming air during fluidized bed granulation as factors,and the dissolution rate of rivaroxaban tablets The granulation yield is a response index,and a three-factor full factorial design is performed.Finally,the key process parameters are found,and the key process parameters are spatially designed to reduce the risk to an acceptable level.Results:The full factorial design results were significant,and the degree of misfit was not significant.The influence of material temperature on the dissolution and yield within the predetermined parameter range is not significant.With the increase of the inlet air volume,the dissolution rate of the self-developed tablets is accelerated,but the yield is reduced;the flow rate of the adhesive spray liquid is increased,the dissolution is slowed,and the yield is increased.The parameters that meet the standards are:material temperature 25~35℃,spraying speed 16~21 g/min,and inlet air volume 37~42 m^(3)/h.Conclusion:The key quality indicators are determined through risk assessment.For high-risk indicators,the full factorial design method is used to adjust the influencing factors affecting key quality indicators to obtain a controllable parameter space,reduce the risk to acceptable standards,and finally obtain an acceptable risk,Can guarantee the quality of the process of rivaroxaban film.