Quality-by-design based fabrication of febuxostat-loaded nanoemulsion: Statistical optimization, characterizations, permeability, and bioavailability studies.

The present work deals with QbD-based development of FEB-loaded nanoemulsion (FEB-NE) in order to enhance bioavailability and permeability. In the beginning, the risk assessment was performed on different experimental variables using the Ishikawa diagram followed by FMEA study in order to find critical process parameter (CPP) and critical material attributes (CMAs). To build quality in nanoemulsion, the quality target product profiles (QTPP) and critical quality attributes (CQAs) were determined. The different batches of FEB-NE were produced by the microemulsification-probe sonication method. Effect of varying levels of independent variables such as oil concentration (X1), Smix concentration (X3), and amplitude (X3) on responses such as globule size (Y1), zeta potential (Y2), and entrapment efficiency (Y3) were studied using Box-Behnken design (BDD). FEB-NE formulation was optimized using a graphical and numerical method. The optimized formulation concentrations and their responses (CQAs) were located as design space in an overlay plot. The spherical shapes of globules were visualized by surface morphology using AFM and TEM. In vitro dissolution study showed 93.32% drug release from the optimized FEB-NE formulation. The drug release mechanism followed by the formulation was the Higuchi-matrix kinetics with a regression coefficient of 0.9236 (R2). FEB-NE showed enhanced permeability using PAMPA (artificial non-cell membrane) and everted gut sac model method. The developed optimized FEB-NE exhibited the enhancement of bioavailability by 2.48 fold as compared to FEB-suspension using Wistar rats suggesting improvement of solubility of a lipophilic drug. The optimized batch remained stable for 90 days at 4 °C and 25 °C. Thus, QbD-based development of FEB-NE can be useful for a better perspective on a commercial scale.

Quantification and Validation of Stability-Indicating RP-HPLC Method for Efavirenz in Bulk and Tablet Dosage Form using Quality by Design (QbD): A Shifting Paradigm.

The present study endeavors quality by design (QbD) assisted chromatographic method for the quantification of Efavirenz (ERZ) in bulk and tablet dosage form. Analytical QbD instigated with assignment of analytical target profile (ATP) and critical analytical attributes (CAAs). Risk assessment studies and factor screening studies facilitate to identify the critical method parameters (CMPs). Optimization was performed by employing 32 full factorial design using identified CMPs i.e., flow rate (X1) and pH of buffer (X2) at three different levels and evaluating selected CAAs i.e., retention time (Y1) and peak area (Y2). The individual and interactive influence of CMPs on CAAs were tested by statistical data and response surface plots. Analysis of variance (ANOVA) confirmed that method parameters are significant (P < 0.05). Chromatographic separation was achieved using methanol, 10 mM ammonium acetate buffer (70:30 v/v), pH adjusted at 3.1 with 0.05% ortho-phosphoric acid as a mobile phase at flow rate 1.0 mL/min, and a Nucleosil C18 (4.6 mm I.D. × 250 mm, 5 µm) column with UV detection at 247 nm. The method validation and subsequent stresses degradation studies according to ICH guidelines supported the method to be highly efficient for regular drug analysis and its degradation products. The proposed method was successfully demonstrated QbD based approach for the development of highly sensitive, reliable and suitable for routine analysis, and clinical applications.

Development of ritonavir-loaded nanostructured lipid carriers employing quality by design (QbD) as a tool: characterizations, permeability, and bioavailability studies.

The objective of the present work was to optimize ritonavir (RTV)-loaded nanostructured lipid carriers (NLCs) to improve bioavailability using a quality by design (QbD)-based technique. Risk assessment was studied using "cause and effect" diagram followed by failure mode effect analysis (FMEA) to identify the effective high-risk variables for the formulation development. Quality target product profile (QTPP) and critical quality attributes (CQAs) were initially assigned for the proposed product. Central composite rotatable design (CCRD) was used to identify the individual and combined interactions of formulation variables. RTV-loaded NLC (RTV-NLC) was prepared using emulsification-ultrasonication method. The effect of formulation variables like ultrasound amplitude, lipid concentration, surfactant concentration on their responses like particle size, polydispersity index (PDI), and entrapment efficiency (EE) were studied by CCRD. The optimized formulation was subjected to lyophilization to obtain dry NLCs for solid-state analysis. DSC and PXRD investigations showed that RTV was molecularly dispersed in lipid matrix indicating amorphous form present in the formulation. FESEM and AFM depicted the spherical and uniform particles. The increase in solubility and dissolution rate is expected to be related to the molecular dispersion, amorphous state, of the drug in the nanoparticle. The optimized NLCs showed good physical stability during storage for 6 months. RTV-NLC was further subjected to in vitro studies and found a successful sustained release rate of 92.37 ± 1.03%. The parallel artificial membrane permeability assay (PAMPA) and everted gut sac model have demonstrated the permeation enhancement of RTV. In vivo study observed the enhanced bioavailability with 2.86-fold suggesting optimized NLC successfully overcome the issue of solubility.

Quality by design (QbD)-based fabrication of atazanavir-loaded nanostructured lipid carriers for lymph targeting: bioavailability enhancement using chylomicron flow block model and toxicity studies.

Atazanavir (ATV) is widely used as anti-HIV agent having poor aqueous solubility needs to modulate novel drug delivery system to enhance therapeutic efficiency and safety. The main objective of the present work was to fabricate ATV-loaded nanostructured lipid carriers (NLCs) employing quality by design (QbD) approach to address the challenges of bioavailability and their safety after oral administration. Herein, the main objective was to identify the influencing variables for the production of quality products. Considering this objective, quality target product profile (QTPP) was assigned and a systematic risk assessment study was performed to identify the critical material attributes (CMAs) and critical process parameter (CPP) having an influence on critical quality attributes (CQAs). Lipid concentrations, surfactant concentrations, and pressure of high-pressure homogenizer were identified as CMAs and CPP. ATV-NLCs were prepared by emulsification-high pressure homogenization method and further lyophilized to obtain solid-state NLCs. The effect of formulation variables (CMAs and CPP) on responses like particle size (Y1), polydispersity index (Y2), and zeta potential (Y3) was observed by central composite rotatable design (CCRD). The data were statistically evaluated by ANOVA for confirmation of a significant level (p < 0.05). The optimal conditions of NLCs were obtained by generating design space and desirability value. The lyophilized ATV-NLCs were characterized by DSC, powder X-ray diffraction, and FT-IR analysis. The morphology of NLCs was revealed by TEM and FESEM. In vitro study suggested a sustained release pattern of drug (92.37 ± 1.03%) with a mechanism of Korsmeyer-Peppas model (r2 = 0.925, and n = 0.63). In vivo evaluation in Wistar rats showed significantly higher (p < 0.001) plasma drug concentration of ATV-NLCs as compared to ATV-suspension using chylomicron flow block model. The relative bioavailability of ATV-NLCs was obtained to be 2.54 folds. Thus, a safe and promising drug targeting system was successfully developed to improve bioavailability and avoiding first-pass effect ensures to circumvent the acute-toxicity of liver.