Corroborating various material-sparing techniques with hot melt extrusion for the preparation of triclabendazole amorphous solid dispersions.

Amorphous solid dispersions (ASD) are one of the most adopted technologies for improving the solubility of novel molecules. Formulation of ASDs using solvent free methods such as hot melt extrusion (HME) has been in the spotlight off-lately. However, early-stage formulation development is tricky and a difficult bridge to pass due to limited drug availability. Material-sparing techniques (theoretical & practical) have been used for selecting suitable polymeric carriers for formulating ASDs. However, these techniques have limitations in predicting the effect of process parameters. The objective of this study is to use both theoretical and practical material-sparing techniques to optimize a polymer for the developing Triclabendazole (TBZ) ASDs. Initial screening by theoretical approaches suggested that TBZ is highly miscible with Kollidon®VA64 (VA64) and poorly miscible with Parteck®MXP (PVA). However, results from ASDs prepared using SCFe were opposite to these predictions. ASDs prepared using either technique and both VA64 and PVA showed >200x increase in solubility. Each formulation released >85% of drug in less than 15 mins. Although the thermodynamic phase diagram suggested that VA64 was the ideal polymer for TBZ-ASDs, it has certain limitations in factoring the different elements during melt-processing and hence, practical approaches like SCFe could help in predicting the drug-polymer miscibility for HME processing.

Material-Sparing Approach using Differential Scanning Calorimeter and Response Surface Methodology for Process Optimization of Hot-Melt Extrusion.

The objective of the present investigations was to demonstrate the applicability of DSC combined with response surface methodology as a material-sparing tool for determination of the processing conditions for HME during initial stages of development. Mefenamic acid (MFA) and Eudragit EPO (EPO) were used as a model drug and the polymeric carrier, respectively. Initial screening was performed using film-casting, polarized light microscopy, and TGA analysis to determine the levels for the experimental design. A Box-Behnken design was used to study the effect of the independent parameters, viz. drug loading, heating rate, and processing temperature, on the dependent parameters, viz. residual crystallinity and drug degradation. The results showed a quadratic relationship between independent and dependent parameters. Based on the design space, MFA-EPO dispersions with 20% drug loading were prepared using HME and vacuum compression molding (VCM). Both the HME and VCM samples did not show any signs of residual crystallinity. However, degradation of MFA was observed in VCM sample and the HME filaments processed at 100 rpm, but not at 150 rpm. The results demonstrate that DSC has potential to be a material-sparing tool to optimize drug loading and processing temperature for HME and will help product development using HME cost-effective.

Application of Thermodynamic Phase Diagrams and Gibbs Free Energy of Mixing for Screening of Polymers for Their Use in Amorphous Solid Dispersion Formulation of a Non-Glass-Forming Drug.

The objective of the present investigations was to assess the use of thermodynamic phase diagrams and the Gibbs free energy of mixing, ΔGmix, for the screening of the polymeric carriers by determining the ideal drug-loading for an amorphous solid dispersion formulation and optimum processing temperature for the hot-melt extrusion of a non-glass-forming drug. Mefenamic acid (MFA) was used as a model non-glass-forming drug and four chemically distinct polymers with close values of the solubility parameters, viz. Kollidon® VA64, Soluplus®, Pluronic® F68, and Eudragit® EPO, were used as carriers. The thermodynamic phase diagrams were constructed using the melting point depression data, Flory-Huggins theory, and Gordan-Taylor equation. The Gibbs free energy of mixing was estimated using the values of the drug-polymer interaction parameter, χ, and Flory-Huggins theory. The rank order miscibility of MFA in the four polymeric carriers estimated based on the difference in the values of their solubility parameters, Δδ, did not correlate well with the thermodynamic phase diagrams and Gibbs free energy plots. The study highlights the limitation of using the solubility parameter method in screening the polymeric carriers for poorly glass-forming drugs and reiterates the applicability of thermodynamic phase diagrams and Gibbs free energy plots in determining the ideal drug-loading and optimum processing temperature for hot-melt extrusion.

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.