Dhat Shalaka, Pund Swati, Kokare Chandrakant, Sharma Pankaj, Shrivastava Birendra
School of Pharmaceutical Sciences, Jaipur National University, Jaipur, Rajasthan 302017, India; Department of Pharmaceutics, S.T.E.S's Sinhgad Institute of Pharmacy, Narhe, Pune, Maharashtra 411041, India.
Department of Biosciences and Bioengineering, Indian Institute of Technology, Powai, Mumbai 400076, India.
Eur J Pharm Sci. 2017 Jan 1;96:273-283. doi: 10.1016/j.ejps.2016.09.035. Epub 2016 Sep 28.
Rapidly evolving technical and regulatory landscapes of the pharmaceutical product development necessitates risk management with application of multivariate analysis using Process Analytical Technology (PAT) and Quality by Design (QbD). Poorly soluble, high dose drug, Satranidazole was optimally nanoprecipitated (SAT-NP) employing principles of Formulation by Design (FbD). The potential risk factors influencing the critical quality attributes (CQA) of SAT-NP were identified using Ishikawa diagram. Plackett-Burman screening design was adopted to screen the eight critical formulation and process parameters influencing the mean particle size, zeta potential and dissolution efficiency at 30min in pH7.4 dissolution medium. Pareto charts (individual and cumulative) revealed three most critical factors influencing CQA of SAT-NP viz. aqueous stabilizer (Polyvinyl alcohol), release modifier (Eudragit® S 100) and volume of aqueous phase. The levels of these three critical formulation attributes were optimized by FbD within established design space to minimize mean particle size, poly dispersity index, and maximize encapsulation efficiency of SAT-NP. Lenth's and Bayesian analysis along with mathematical modeling of results allowed identification and quantification of critical formulation attributes significantly active on the selected CQAs. The optimized SAT-NP exhibited mean particle size; 216nm, polydispersity index; 0.250, zeta potential; -3.75mV and encapsulation efficiency; 78.3%. The product was lyophilized using mannitol to form readily redispersible powder. X-ray diffraction analysis confirmed the conversion of crystalline SAT to amorphous form. In vitro release of SAT-NP in gradually pH changing media showed <20% release in pH1.2 and pH6.8 in 5h, while, complete release (>95%) in pH7.4 in next 3h, indicative of burst release after a lag time. This investigation demonstrated effective application of risk management and QbD tools in developing site-specific release SAT-NP by nanoprecipitation.
药品研发中快速演变的技术和监管环境使得有必要通过使用过程分析技术（PAT）和质量源于设计（QbD）进行多变量分析来进行风险管理。难溶性高剂量药物沙硝唑（Satranidazole）采用设计处方（FbD）原则进行了优化的纳米沉淀（SAT-NP）。使用石川图确定了影响SAT-NP关键质量属性（CQA）的潜在风险因素。采用Plackett-Burman筛选设计来筛选影响pH7.4溶出介质中30分钟时平均粒径、zeta电位和溶出效率的八个关键处方和工艺参数。帕累托图（个体和累积）显示了影响SAT-NP CQA的三个最关键因素，即水性稳定剂（聚乙烯醇）、释放调节剂（Eudragit® S 100）和水相体积。通过FbD在既定设计空间内优化这三个关键处方属性的水平，以最小化SAT-NP的平均粒径、多分散指数，并最大化其包封效率。Lenth分析和贝叶斯分析以及结果的数学建模允许识别和量化对所选CQA有显著活性的关键处方属性。优化后的SAT-NP表现出平均粒径为216nm、多分散指数为0.250、zeta电位为-3.75mV和包封效率为78.3%。该产品使用甘露醇冻干形成易于再分散的粉末。X射线衍射分析证实了结晶态沙硝唑向无定形形式的转变。SAT-NP在逐渐变化pH值的介质中的体外释放显示，在pH1.2和pH6.8中5小时内释放<20%，而在接下来的3小时内在pH7.4中完全释放（>95%），表明在滞后时间后有突释。本研究证明了风险管理和QbD工具在通过纳米沉淀开发位点特异性释放的SAT-NP中的有效应用。
