QUALITY BY DESIGN (QBD) AS A TOOL FOR THE OPTIMIZATION OF INDOMETHACIN FREEZE-DRIED SUBLINGUAL TABLETS: IN VITRO AND IN VIVO EVALUATION

Objective: This study aims to prepare and optimize indomethacin freeze-dried sublingual tablets (IND-FDST) by utilizing a quality by design (QbD) approach to achieve rapid drug dissolution and simultaneously bypassing the GIT for better patient tolerability. Methods: A screening study was utilized to determine the most significant factors which the quality attributes, namely disintegration time and % friability. Then an optimization study was conducted using a full response surface design to determine the optimized formula by varying the amount of the matrix-forming polymer (gelatin) and super disintegrant (croscarmellose sodium (CCS)). The variables' effect on the % friability, disintegration time, wetting time, and amount of drug release after 10 min (%Q10) was studied. The optimized formula was tested for compatibility, morphology as well as stability studies under accelerated conditions in addition to the in vivo pharmacodynamics in rats. QbD was adopted by utilizing a screening study to identify the significant formulation factors followed by a response surface optimization study to determine the optimized IND-FDST formulation. Results: Optimized IND-FDST comprised of gelatin/CCS combination in a ratio of 1:1 possessed adequate %friability (0.73±0.03%), disintegration time (25.40±1.21 seconds), wetting time (3.49±0.68 seconds), and % Q10 (100.99±5.29%) as well as good stability under accelerated conditions. IND-FDST also showed significant inhibition of edema, tumour necrosis factor-alpha, and interleukin-6 release in vivo compared to the oral market product by 70%, 42%, and 65%, respectively. Conclusion: QbD presents a successful approach in the optimization of a successful IND-FDST formula that showed superior in vivo and in vitro characteristics

Surfactant modulated interaction of hydrophobically modified ethoxylated urethane (HEUR) polymers with impenetrable surfaces

Hypothesis: The presence of surfactant modulates the surface-chemistry-specific interaction of hard colloidal particles (latex) with HEUR polymers, principally through introducing a preferential solution interaction rather than a competitive surface interaction; addition of surfactant leads to a preponderance of polymer/surfactant solution complexes rather than surface-bound complexes. Experiments: A range of model formulations comprising a hexyl end-capped urethane polymer (C6-L-(EO100-L)9-C6), sodium dodecylsulfate (SDS) and a series of polystyrene-butylacrylate latices (PS-BA-L) have been characterised in terms of rheology, particle surface area (solvent relaxation NMR), polymer conformation (small-angle neutron scattering) and solution composition to build up a detailed picture of the distribution of the HEUR in the presence of both surfactant and latex. Findings: There is very weak adsorption of C6-L-(EO100-L)9-C6 to only the most hydrophobic latex surface studied, an adsorption that is further weakened by the addition of low levels of surfactant. Macroscopic changes in the hydrophobic latex system may be interpreted in terms of bridging flocculation at low polymer concentrations. No adsorption of C6-L-(EO100-L)9-C6 is observed in the case of hydrophilic surfaces. In most cases, the observed behaviour of the ternary system (polymer/surfactant/particle) is highly reminiscent of the binary (polymer/surfactant) system at the appropriate composition, suggesting that the polymer/surfactant solution interaction is the dominant one

Insights into the behaviour of hydrophobically modified ethoxylated urethane polymers in soft and hard colloid formulation

Hydrophobically modified ethoxylated urethane polymers (HEUR) are used as viscosity modifiers in various formulations, e.g. cosmetics, paints. The HEURS show a complex behaviour in solution owing to the interaction between the hydrophobic segments present in the polymer and other formulation components. Since HEUR containing formulations are complex and multi-component, binary mixtures of HEURs with other formulation components e.g. surfactant, particles and oil were initially examined. The study was then expanded to model ternary formulations - polymer/ sodium dodecylsulphate (SDS)/latex and polymer/SDS/oil. The main techniques used here were nuclear magnetic resonance and small-angle neutron scattering. The HEUR showed evidence of strong interaction with SDS, where the SDS interacts both with the polymer hydrophilic and hydrophobic segments. The effect of varying the HEUR architecture on the behaviour of polymer in solution and the interaction with SDS has been explored by studying three different polymers, C6-L-(EO100-L)9-C6, C10-L-(EO200-L)4-C10, and C18-L-(EO200-L)7-C18. It has been concluded that the linkers play an important role in the behaviour of the polymer, where the polymer that possess more linkers show higher viscosity and lower diffusion coefficient at fixed concentration. The key polymer investigated here C6-L-(EO100-L)9-C6 showed weak adsorption to a hydrophobic (polystyrene-butylacrylate) latex. Decreasing the hydrophobicity of the particles turned off the adsorption of the polymer. The addition of SDS to the polymer/latex mixture further weakened the polymer adsorption to the hydrophobic latex. It was therefore concluded that the polymer/SDS interaction was stronger than polymer/latex interaction. Finally, the three same polymers with different architectures were used to stabilise a model emulsion dodecane in water in which the oil droplets were stabilised in the polymer network. The addition of SDS to the emulsion shows a synergistic effect for the oil solubilisation. Evidence of SDS interaction with the polymer in the emulsion has been observed. This work developed insights into the interaction of the HEUR in model formulation by highlighting the key interactions and factors in the formulation