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.

The synthesis of multigram quantities of small molecule PCSK9 inhibitor (R,S)-3 is described. The route features a safe, multikilogram method to prepare 5-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2H-tetrazole (10). A three-component dynamic kinetic resolution between tetrazole 10, acetaldehyde, and isobutyric anhydride was catalyzed by a chiral DMAP catalyst to afford enantiomerically enriched hemiaminal ester (S)-12 on multikilogram scale. Magnesiation, transmetalation, and Negishi coupling provided access to Boc-intermediate (R,S)-13, which was deprotected to provide (R,S)-3 in multigram quantities.

The synthesis of (2-cyclooctyn-1-yloxy)­acetic acid was enabled to allow for the simple and safe production of this material on multigram scale.

Hexahydro‐1,3,5‐trinitroso‐1,3,5‐triazine (TNX) is mostly known as a by‐product in the environmental decomposition of RDX. The original chemistry to TNX was never optimized and thus resulted in low yields due to competitive degradation of the starting material. Enabled conditions to TNX were developed by optimizing pH effects and mitigating foaming by reactor geometry and stirring. The conditions presented herein allow for the inexpensive and simple production of multi‐gram quantities of TNX. The isolated TNX obtained by our new method was characterized by 1H NMR, 13C NMR, DSC, and X‐ray crystallography. A preliminary evaluation of the sensitivity of TNX towards impact and friction is also presented.