PREFORMULATION STUDIES FOR THE PREPARATION OF AMORPHOUS SOLID DISPERSIONS

The major challenges in the formulation of amorphous solid dispersions (ASDs) using hot-melt extrusion (HME) are the selection of an ideal polymeric carrier, optimization of HME processing conditions, and screening of the physical stability of the ASDs. Addressing these challenges using traditional approaches require extensive experimentation and large amounts of active pharmaceutical ingredients (API) which may not be feasible during the initial stages of product development. Therefore, there is a need to develop material-sparing techniques for the successful formulation of ASDs. The objective of the present study was to develop material-sparing techniques that can be used as pre-formulation tool during the formulation of ASDs. For this purpose, mefenamic acid (MFA) was used as a model 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 polymeric carriers. The selection of an ideal polymer was carried out based on the solubility parameter approach, melting point depression method, thermodynamic phase diagrams, and Gibbs free energy plots. Then the HME processing conditions were determined based on a material-sparing technique using differential scanning calorimeter (DSC). The physical stability of the ASDs was estimated using the modified Avarami equation. Based on the results of the melting point depression, thermodynamic phase diagrams and Gibbs free energy plots, Eudragit® EPO was found to be an ideal polymer for the preparation of amorphous solid dispersion formulation of mefenamic acid. The design space for HME determined using DSC method showed that when 20% drug loaded MFA-EPO blends was heated at a rate of 5.5 °C/min to a temperature of 146 °C, the resulting ASD contained a residual crystallinity of 13.6% and drug degradation of 3.8%. The physical stability of the MFA-EPO ASDs determined using a modified Avarami equation showed that the rate of recrystallization changed significantly with the change in process temperature as compared to the change in the relative humidity. The study results show that the time frame and experiments required in the formulation of ASDs can be significantly reduced by using the material-sparing techniques developed based on the theoretical and experimental approaches