Sample preparation techniques to enhance uniformity of low-dose blends mixed by resonant acoustic mixing technology

In our previous work we presented the very first examples of uniform mixtures of < 0.1 % w/w API in a single step dry powder mixing process where caffeine (CAF), a morphologically challenging API, was successfully blended under finely tuned optimized RAM parameters in an idealized binary matrix. Presently, we introduce several effective methods to improve BU results for a lesser compatible formulation for which we had thus far been unable to prepare to acceptable levels of homogeneity to meet AV specification criteria. Simple, practical strategies for overcoming BU issues are proposed assessing a range of techniques, with results demonstrating a powerful potential for RAM performance to be improved upon through only small adjustments to initial sample conditions. Several anomalous results and behavior are reported which have eluded mechanistic understanding through conventional means. In the course of pursuing a unified theory capable of correct mechanistic interpretations of RAM results, a fresh perspective is offered from a refined theoretical development of RAM-specific principles, and mechanisms such as vibrational forcing and exponential amplification are proposed. By investigating the roles of RAM operational mechanics and fundamental acoustic principles, satisfactory explanations can begin to be obtained. By considering these facets to RAM mixing processes, microscale mixing potential was increased by a factor of 4x and allowed for homogeneity to be established at 150 μg using a semi-fine CAF sample and extend to levels down to at least 32.5 μg.