Process optimization of twin-screw melt granulation of fenofibrate using design of experiment (DoE)

The purpose of this study was to optimize the melt granulation process of fenofibrate using twin-screw granulator. Initial screening was performed to select the excipients required for melt granulation process. A 3 × 3 factorial design was used to optimize the processing conditions using the % drug loading (X1) and screw speed (X2) as the independent parameters and granule friability (Y1) % yield (Y2) as the dependent parameters. The effect of the independent parameters on the dependent parameters was determined using response surface plots and contour plots. A linear relationship was observed between % drug loading (X1) and % friability (Y1) and a quadratic relationship was observed between the independent parameters (X1 and X2) and % yield (Y2). The processing conditions for optimum granules were determined using numerical and graphical optimization and it was found that 15% drug loading at 50 rpm results in maximum % yield of 82.38% and minimum friability of 7.88%. The solid-state characterization of the optimized granules showed that the drug turned from crystalline state to amorphous state during melt granulation process. The optimized granules were compressed into tablets using Purolite® as the super disintegrating agent. The optimized formulation showed >85% drug release in 0.75% SLS solution within 60 min. Continue on Process optimization of twin-screw melt granulation of fenofibrate 

Conclusion
A directly compressible granules with improved solubility of active pharmaceutical ingredient was prepared and optimized using hot melt granulation. The design space obtained from the experimental design suggested that granules with optimum CMAs can be obtained with 15% drug loading and processing at 50 rpm. The results of this work show that % yield and % friability of the granules are the two most important CMAs of melt granules. The results of this study show that design of experiments (DOE) can be a powerful tool to optimize the melt granulation process to obtain granules with high % yield and low friability. Choice of super-disintegrant like Purolite® is very crucial for rapid disintegration of tablet prepared using such granules. The dissolution studies in the biorelevant media did not show any recrystallization or precipitation, indicating that a formulation maintain drug in solubilized state. Thus, twin-screw melt granulation using co-processed silica with TPGS enables a continuous process that can produce granules with improved compressibility and dissolution profile.

Keywords: Twin-screw granulator, Melt granulation, Design of Experiments (DoE), Fenofibrate, Co-processed excipient, Polyvinyl alcohol (Parteck® MXP), D-α-Tocopherol polyethylene glycol 1000 succinate (Kolliphor® TPGS), crosslinked polyvinylpyrrolidone (Kollidon® CL-SF, Kollidon® 12PF), and poly (ethylene oxide) poly (propylene oxide) copolymer (Kollisolv® P 124), Poly-ethylene Glycol (PEG 3350), Croscarmellose Sodium (Ac-Di-Sol®),  Polymethacrylic crosslinked with divinylbenzene (Purolite® C115KMR/5100)