Sodium hydride was found to be the best base for a displacement reaction on a chloropyrimidine. Due to the insolubility of sodium hydride in all solvents and high reactivity with atmospheric moisture, solutions dealing with the associated safety concerns on kilogram scale are described. The use of sodium hydride in premeasured dissolvable bag packaging (SecuBags), online process analytical technology (PAT) to monitor the hydrogen off-gas, and the development of analytical methods to monitor residual polymer and potential degradation products allowed for a successful scale-up and on-time delivery of a quality product.

To address time lost due to inadequate assessment and understanding of solids suspension issues, empirical studies were conducted at pilot scale using a calcium carbonate and de-ionized water (DIW) system. Three tools were used and evaluated to understand suspension status: (1) turbidity meter response, (2) off-line sample analysis, and (3) difference between baffle and bottom temperatures. The data from these studies demonstrated that the most effective tool that also required the least effort was the difference between baffle and bottom temperatures. A standardized experimental procedure was developed and can be used to gain empirical suspension data at scale for any desired solid-liquid system. This procedure involved performing temperature adjustments in the vessel and observing the associated baffle/bottom temperature changes for varying agitator speeds.