Abstract
Objective: The purpose of this study was an implementation of quality by design (QbD) for the formulation and characterization of econazole nitrate loaded flexisomal nanocarriers (EN-FS) to improve antifungal activity and to enhance skin permeability.
 Methods: Initially quality target product profile (QTTP) elements were identified and later critical quality attributes (CQA) elements were defined from QTPP elements. Particle size, entrapment efficiency and deformability index were defined as CQAs. Risk assessment was performed by using fishbone diagram and failure mode and effect analysis (FMEA). Design space was created by using fractional factorial design 25-2 as screening design and 32 full factorial design as optimization design to optimize two variables soya phosphatidylcholine concentration(X1) and sodium deoxycholate concentration (X2).
 Results: Optimized batch of EN-FS was 249.5±3.48 nm, with entrapment efficiency of 88.6±0.89 % and deformability index of 31.75±0.98. Zeta potential analysis showed value of-22.5 mV. Morphological analysis by TEM showed spherical shaped flexisomes, which confirmed the vesicular characteristics. The optimized batch of EN-FS was further made into hydrogels by using sepineo P600 as gelling agent. The % drug diffusion of EN-FS hydrogels had shown 24.68%. With higher skin deposition and higher value of zone of inhibition in antifungal study as compared to plain EN hydrogel. CLSM studies indicated deep penetration of EN-FS in skin layers. Lastly control strategy for EN-FS were developed.
 Conclusion: It was concluded that EN-FS showed high flexibility and enhanced antifungal activity therefore found to be a potential nanocarriers for drug deposition in skin layers without disturbing skin integrity.
Highlights
Quality by design (QbD) ensures that ‘quality should be built into product rather than tested in product’ as stated by quality expert Joseph M
Based on scientific prior knowledge and preliminary studies three critical quality attributes (CQA) were defined from quality target product profile (QTPP) elements as particle size, entrapment efficiency and deformability index
All three CQAs as particle size, deformability index and % entrapment efficiency was highly dependent on the concentration of soya phosphatidylcholine (SPC) and EA(SDC)
Summary
Quality by design (QbD) ensures that ‘quality should be built into product rather than tested in product’ as stated by quality expert Joseph M. According to ICH Q8 R2 guidelines QbD is defined as “A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management” [2]. QbD made up of three ICH guidelines i.e. ICH Q8, Q9 and Q10 namely pharmaceutical development, quality risk management and pharmaceutical quality systems respectively. QbD has mainly four important elements (i) To identify quality target product profile (QTPP) based on prior knowledge. Three important tools of the QbD are design of experiments (DoE), process analytical technology (PAT) and risk management [3,4,5,6]
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