A simple screening protocol has been developed for assessing the agglomeration potential of active pharmaceutical ingredients (APIs) using resonant acoustic mixing that minimizes the quantity of API used. This methodology improves upon existing ones as it allows for multiple conditions to be screened in parallel, saving time and allowing for the study of agglomeration and optimization of the drying unit operation to take place early in development. In addition to a qualitative (visual) assessment, quantitative data can be obtained after the material has been dried therefore accounting for a measure of cake hardening. This methodology was also extended to assess the friability of the generated agglomerates and was validated using a scaled-down agitated filter dryer (AFD). The impact of particle size, particle size distribution, solvent selection, and solvent loading on the agglomeration potential for a Takeda API is also discussed which allowed for the development of an improved drying process that was successfully scaled-up in the pilot plant.

Sodium nitrotetrazolate (NaNT) is a key intermediate to copper­(I) nitrotetrazolate (DBX-1), a material of interest as a replacement for lead based primary explosives. Historical syntheses of NaNT were plagued with safety issues that prevented the large-scale manufacturing of NaNT. In this article, we detail the development of a safe process to generate NaNT in a continuous flow reactor via solid phase “catch and release”; a process that also reduces the formation of the most detrimental impurities that inhibit the synthesis of DBX-1. Furthermore, we discuss the demonstration of this process in 100 and 1000 mL continuous stirred tank reactors (CSTRs) and implications of scale-up of this process for robust production of NaNT at the manufacturing scale.