(643b) The Use of Low Volatility Solvents to Enhance Spray Drying Throughput

Spray dried dispersions (SDDs) are a common formulation approach to enhance the bioavailability of active pharmaceutical ingredients (APIs) with poor aqueous solubility. In the manufacturing process, API and enabling excipients (often polymers) are co-dissolved in a common organic solvent such as acetone, methanol, methylene chloroform, etc., or blends of such solvents. These solvents are amenable to spray drying due to their relatively high volatility. However, APIs that have both poor aqueous solubility and poor solubility in these organic solvents are increasingly common. One approach to spray drying such APIs is to use alternative solvents like dimethyl sulfoxide, dimethylformamide, or dimethylacetamide. With relatively low volatility, it is more challenging to remove these solvents in the spray dryer and achieve high yields of SDD with good chemical and physical stability.

This talk demonstrates the feasibility of spray drying with low volatility solvents by identifying useful solvent blend compositions and operating parameters for the spray dryer (e.g., outlet temperature and liquid-to-drying gas ratio). To guide process development with minimal material consumption, benchtop techniques such as differential scanning calorimetry and dynamic vapor sorption are combined to develop understanding of thermodynamic relationships between the relative saturation of the vapor outlet stream from the spray dryer and the resulting glass transition temperature of the solvent laden SDD powder (i.e., the wet T_g). The wet T_g is then compared to the outlet temperature of the spray dryer to predict process yield and physical stability of the wet SDD. Theoretical predictions are compared to experimental data through several case studies.

The results highlight that there is an optimal outlet temperature for the spray dryer that enables a maximum liquid feed rate. Moreover, optimal polymers for manufacturing tend to balance high T_g values in the dry state with moderate affinity for the low volatility solvent. Polymers with high solvent affinity tend to have higher solvent levels in the wet SDD, which can lead to poor yield and physical instability. Thermodynamic predictions alone do not fully explain the behavior of experimental systems, and the importance of droplet drying kinetics and non-ideal API-solvent interactions are discussed. Finally, this talk provides practical guidelines around optimal formulations, target solubility enhancements, and API physicochemical properties that can identify ideal candidates for spray drying with low volatility solvents.