Fayed Mohamed H, Abdel-Rahman Sayed I, Alanazi Fars K, Ahmed Mahrous O, Tawfeek Hesham M, Al-Shedfat Ramadan I
Acta Pol Pharm. 2017 Jan;74(1):235-248.
Application of quality by design (QbD) in high shear granulation process is critical and need to recognize the correlation between the granulation process parameters and the properties of intermediate (granules) and corresponding final product (tablets). The present work examined the influence of water amount (X,) and wet massing time (X2) as independent process variables on the critical quality attributes of granules and corresponding tablets using design of experiment (DoE) technique. A two factor, three level (32) full factorial design was performed; each of these variables was investigated at three levels to characterize their strength and interaction. The dried granules have been analyzed for their size distribution, density and flow pattern. Additionally, the produced tablets have been investigated for weight uniformity, crushing strength, friability and percent capping, disintegration time and drug dissolution. Statistically significant impact (p < 0.05) of water amount was identified for granule growth, percent fines and distribution width and flow behavior. Granule density and compressibility were found to be significantly influenced (p < 0.05) by the two operating conditions. Also, water amount has significant effect (p < 0.05) on tablet weight unifornity, friability and percent capping. Moreover, tablet disintegration time and drug dissolution appears to be significantly influenced (p < 0.05) by the two process variables. On the other hand, the relationship of process parameters with critical quality attributes of granule and final product tablet was identified and correlated. Ultimately, a judicious selection of process parameters in high shear granulation process will allow providing product of desirable quality.
质量源于设计（QbD）在高剪切制粒过程中的应用至关重要，需要认识到制粒过程参数与中间体（颗粒）及相应最终产品（片剂）性质之间的相关性。本研究采用实验设计（DoE）技术，考察了作为独立工艺变量的加水量（X₁）和湿混时间（X₂）对颗粒及相应片剂关键质量属性的影响。进行了两因素、三水平（3²）的全因子设计；对每个变量在三个水平上进行研究，以表征其强度和相互作用。对干燥后的颗粒进行了粒度分布、密度和流动模式分析。此外，对生产的片剂进行了重量均匀度、抗压强度、脆碎度和裂片百分率、崩解时间和药物溶出度的考察。发现加水量对颗粒生长、细粉百分率、分布宽度和流动行为有统计学显著影响（p < 0.05）。发现颗粒密度和可压性受两个操作条件的显著影响（p < 0.05）。而且，加水量对片剂重量均匀度、脆碎度和裂片百分率有显著影响（p < 0.05）。此外，片剂崩解时间和药物溶出度似乎受两个工艺变量的显著影响（p < 0.05）。另一方面，确定并关联了工艺参数与颗粒和最终产品片剂关键质量属性之间的关系。最终，在高剪切制粒过程中明智地选择工艺参数将有助于提供质量符合要求的产品。
