Application of Theoretical Solubility Calculations and Thermal and Spectroscopic Measurements to Guide the Processing of Triamcinolone Acetonide by Hot-Melt Extrusion

<b>Background/Objectives</b>: Triamcinolone acetonide (TA), a poorly water-soluble corticosteroid, presents formulation challenges due to limited membrane permeability. This study aimed to identify suitable drug-polymer-plasticizer systems for TA using combined theoretical and experimental methods. <b>Methods</b>: Using Hansen solubility parameters, seven hot-melt extrusion (HME)-grade polymers and four plasticizers were initially screened for miscibility with TA. Based on Δδt values, four polymers-Eudragit^® L100 (EUD), Parteck^® MXP (PVA), Plasdone^® S-630 (PVPVA), and Aquasolve™ AS-MG (HPMCAS)-along with triethyl citrate (TEC), were selected for experimental evaluation. Differential scanning calorimetry, thermogravimetric analysis, and Fourier transform infrared spectroscopy assessed thermal behavior, miscibility, and chemical compatibility. <b>Results</b>: Amorphous TA content was highest with EUD (81.1%), followed by PVA (67.5%), PVPVA (45.6%), and HPMCAS (8.5%). Thermal incompatibility and TEC evaporation were observed in PVA, PVPVA, and HPMCAS systems. FTIR suggested TEC should be avoided in melt-based formulations with PVA and PVPVA due to PVA degradation and partial TA oxidation. No significant interactions were detected in HPMCAS samples heated to 220 °C, aligning with theoretical predictions. In contrast, the EUD-TEC system showed limited chemical reactivity and maintained TA's structural integrity. Infrared bands at 1758 and 1802 cm^-1 indicated minor anhydride formation above 160 °C with partial TEC evaporation. <b>Conclusions</b>: EUD/TEC were identified as a promising combination for the HME processing of TA. This work supports the rational formulation of stable amorphous systems for thermolabile drugs with poor solubility.