DOI: 10.6084/m9.figshare.26362413.v1
title: Central composite design augmented quality-by-design-based systematic formulation of erlotinib hydrochloride-loaded chitosan-poly (lactic-co-glycolic acid) nanoparticles

description: <b>Aim:</b> This study aimed to formulate erlotinib hydrochloride (ERT-HCL)-loaded chitosan (CS) and poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) using Quality-by-Design (QbD) to optimize critical quality attributes (CQAs). <b>Materials & methods:</b> Quality target product profile (QTPP) and CQAs were initially established. Based on L8-Taguchi screening and risk assessments, central composite design (CCD) design was used to optimize NPs. <b>Results:</b> ERT-HCL-loaded CS-PLGA NPs had a mean particle diameter, zeta potential and entrapment efficiency of 226.50 ± 1.62 d.nm, 27.66 ± 0.64 mV and 78.93 ± 1.94 %w/w, respectively. The NPs exhibited homogenous spherical morphology and sustained release for 72 h. <b>Conclusion:</b> Using systematic QbD approach, ERT-HCL was encapsulated in CS-PLGA NPs, optimizing CQAs. These findings propel future research for improved NSCLC treatment. Innovative erlotinib-loaded chitosan-PLGA nanoparticles, developed through a systematic QbD approach, promise enhanced drug delivery for NSCLC. Optimized for size, potential and entrapment efficiency, these particles demonstrate sustained release over 72 h. #DrugDelivery #QBD #NSCLC The study presents a rational Quality-by-Design (QbD) methodology for the systematic development of ERT-HCL-loaded CS-PLGA NPs, improving the characteristics of drug delivery. The approach successfully identified the product-centric Quality Target Product Profile (QTPP), with the selected Critical Quality Attributes (CQAs) for this study being mean particle diameter, zeta potential and entrapment efficiency of ERT-HCL-loaded CS-PLGA NPs. Key independent variables (CMAs, FVs and PPs) affecting drug product CQAs were identified through rigorous initial risk assessments, comprising Ishikawa cause-effect diagram and methodologies like risk estimation matrix (REM), and failure mode effect analysis (FMEA) allowing for proactive risk mitigation. Quantitative FMEA analysis yielded seven independent variables with Risk Priority Score (RPN) of ≥25, which were used in factor screening studies. As per L8 orthogonal Taguchi design, out of seven factors, two factors namely drug: polymer ratio and CS concentration showed significant effect on the selected CQAs and would be later used in the DoE model. A 21 experimental run, 2-factor, and 5-level (-α, -1, 0, +1, +α), central composite design (CCD) was utilized where two independent variables namely drug: polymer ratio (X1) and CS concentration (X2) were optimized for their effects on the dependent variables; mean particle diameter (Y1), zeta potential (Y2) and entrapment efficiency (Y3) of the developed ERT-HCL-loaded CS-PLGA NPs. As per the model desirability factor, a final optimized batch was obtained with a mean particle diameter of 226.50 ± 1.62 nm, a zeta potential of 27.66 ± 0.64 mV, and an entrapment efficiency of 78.93 ± 1.94%. The NPs had a drug loading capacity of 4.33% w/w along with a satisfactory PDI value of less than 0.3 and exhibited a uniform spherical morphology. The <i>in vitro</i> release studies showed sustained ERT-HCL release up to 72 h, attributed to CS mitigating initial burst release, kinetic modeling affirmed a zero-order drug release and Fickian drug release behavior. The study lays the groundwork for further studies on ERT-HCL-loaded CS-PLGA NPs, which show promise in treating non-small-cell lung cancer and offer a solid foundation for therapeutic validation.