Slurry Conversion: A General Method for Formulating Amorphous Solid Dispersions and Fully Integrating Drug and Polymer Components.

A solvent-sparing method, called "slurry conversion", has been tested as a general approach to preparing amorphous solid dispersions (ASDs). In this method, a solid mixture of a drug and a polymer is stirred in the presence of a small quantity of a solvent, which is subsequently removed. In previous work, the method enabled more complete salt formation between lumefantrine (LMF), a basic antimalarial, with acidic polymers, than the common methods of hot melt extrusion and spray drying, leading to improved physical stability and release. Here, we apply this method to 18 poorly soluble drugs formulated as binary and ternary ASDs. For a rigorous test, the drugs were formulated with a single polymer, poly(acrylic acid) (PAA), under the same condition: room temperature stirring in 1:1 ethanol-dichloromethane at 4:1 solvent/solid ratio. ASDs were prepared for 16 of the 18 drugs at 25% drug loading and 11 at 50% drug loading. The drugs that were not fully amorphized did not dissolve in the default solvent or crystallized during drying. For most drugs, an abrupt "clearing" of the slurry occurred during stirring, indicating complete dissolution and amorphization before drying. While clearing did not occur for some drugs (e.g., clofazimine), the product was still fully amorphous, through solvent-mediated conversion. For a basic drug, the degree of protonation by PAA increases smoothly with PAA concentration and is ordered by its basic strength, supporting the conclusion that the method allows the system to reach thermodynamic equilibrium. In addition to binary ASDs, ternary ASDs containing two drugs (LMF and artemether or LMF and artesunate) were successfully prepared to support applications in combination therapies. In these ternary formulations, the protonation of LMF follows the trend established for binary systems. We find that slurry conversion can be scaled up 60-fold from the typical batch size without any difficulties or adverse effect on the structure and properties of the product. Overall, our results demonstrate that slurry conversion is a general, low-cost, and green alternative to conventional methods for manufacturing ASDs where the components are fully integrated.