True bridging liquid-solid ratio (TBSR): Redefining a critical process parameter in spherical agglomeration

Spherical agglomeration of crystals via addition of an immiscible bridging liquid can improve active pharmaceutical ingredient handling and tabletability. Bridging liquid amount is quantified by the bridging liquid-solid ratio (BSR). However, the optimal range of the BSR for agglomerates to form is highly dependent on the bridging liquid/solvent/antisolvent system. Here, a new definition is introduced to account for bridging liquid-solvent miscibility; true bridging liquid-solid ratio (TBSR). A method for calculating TBSR from the system ternary phase diagram is demonstrated for five different common binder liquids with acetone/water as the solvent/ antisolvent system. Results show the value of BSR varies dramatically for a given TBSR as a function of both the system and the solids loading. Experimental salicylic acid agglomeration studies confirm optimal BSR varied widely with binder liquid and solids loading between 0.2 and 2, but the optimum TBSR for all experiments was in a narrow range between 0.05 and 0.15. Thus, TBSR is a robust dimensionless parameter for design and scale up of spherical agglomeration processes.