Purpose: Surfactants are commonly used additives in amorphous solid dispersions (ASDs) to modify drug release. ASD consisting of vitamin E TPGS (TPGS), Celecoxib (CEL) and Copovidone (PVPVA64) was selected as a model to study the effect of surfactant on the properties of ASD. The first objective is to study the effect of CEL on the miscibility between TPGS and PVPVA64 in ASD. The second objective is to investigate the effect of surfactant level on the dissolution behavior, physical stability, and particle morphology of CEL ASDs.
Methods: CEL ASDs containing 25% drug and various levels of TPGS were prepared using spray drying. Four different formulations containing TPGS at 0, 5, 10 and 20%, respectively, were processed under the same spray drying conditions. Differential scanning calorimetry (DSC) was used to investigate TPGS-PVPVA64 miscibility at various weight ratios (0:15, 1:14, 2:13 and 4:11) in the presence or absence of CEL. Non-sink dissolution was conducted to evaluate the dissolution behavior of CEL ASDs at different TPGS ratios. Biphasic diffusion test was performed to investigate the diffusion of CEL across the membrane. Dynamic light scattering (DLS) was used to measure the CEL nano-particles formed in the dissolution media. Surface tension measurement was applied to determine the critical micelle concentration (CMC) of TPGS in the dissolution media. Scanning electronic microscope (SEM) was used to investigate the morphology of CEL ASDs particles.
Results: In the absence of CEL, melting of crystalline TPGS phase was observed when the ratio of TPGS to PVPVA64 reaches 4:11. In contrast, CEL-TPGS-PVPVA64 ASD remained single-phase material even at the weight ratio of 5:4:11 (highest level of TPGS among all formulations). CEL-TPGS-PVPVA64 (5:4:11) ASD demonstrated the fastest dissolution rate, highest supersaturation, and fastest diffusion as compared to all other formulations. Formation of nanoparticles in the dissolution media was observed for CEL-TPGS-PVPVA64 (5:4:11) ASD. The average particle size of these nanoparticles is about 96 nm. In contrast, nano-particles were not observed with other CEL ASDs. The CMC of TPGS in the dissolution media was measured to be 103 μg/mL, which is close to the concentration of TPGS when CEL-TPGS-PVPVA64 (5:4:11) ASD dissolves. It was observed under SEM that higher the TPGS level was, the more spherical the spray-dried powders were.
Conclusion: The improved miscibility between TPGS and PVPVA64 due to the presence of CEL made it feasible to prepare CLE ASD at 20% TPGS loading. TPGS affected the dissolution and diffusion behavior of CEL ASDs. Specifically, CEL ASD containing 20% TPGS demonstrated the fastest dissolution, diffusion and highest supersaturation, due to in situ nano-particle formation and micelle formation. TPGS concentration also affected the morphology of spray-dried particles. Higher TPGS level lead to more spherical particles.