Risk management and statistical multivariate analysis approach for design and optimization of satranidazole nanoparticles

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• 作者：Shalaka Dhat^a ; ^c ; ¹ ; ^{shalakapd@gmail.com} ; Swati Pund^b ; ¹ ; Chandrakant Kokare^c ; Pankaj Sharma^a ; Birendra Shrivastava^a
• 关键词：Design of experiments ; Formulation by design ; Ishikawa diagram ; Plackett-Burman ; Risk assessment
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：96
• 期：Complete
• 页码：273-283
• 全文大小：1080 K
• 卷排序：96

文摘

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 30 min in pH 7.4 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; 216 nm, polydispersity index; 0.250, zeta potential; − 3.75 mV 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 pH 1.2 and pH 6.8 in 5 h, while, complete release (> 95%) in pH 7.4 in next 3 h, 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.