Investigation of Lithium Acetyl Phosphate Synthesis Using Process Analytical Technology

Acetyl phosphate salts are common phosphate donors for enzymatic phosphorylation with kinases and are used in a variety of industrial biocatalytic processes. Due to their ever-increasing demand, synthesis of high-quality acetyl phosphate salts is critical for pharmaceutical process development, especially given that common impurities such as acetic acid and phosphate can inhibit the intended reaction. Current offline analytical methodologies for investigating the acetyl phosphate reagent quality are limited due to the hydrolytically unstable nature of the chemical species, resulting in its potential degradation before complete analysis may occur. It is therefore advantageous to synthesize high-purity acetyl phosphate using process analytical technology (PAT) tools to monitor reaction progress in real time. In this work, several PAT tools were employed specifically for the investigation of lithium acetyl phosphate synthesis, including in situ Fourier transform infrared spectroscopy, pH and temperature sensing, online optical microscopy, and focused beam reflectance measurements. These PAT tools offer a significant benefit by providing insights into reaction optimization, through observing the timing of temperature and pH changes, realizing a particle size target, and directly monitoring the consumption of reagents and formation of products. Results indicate that these online in situ methods are successful in detailed reaction monitoring and process characterization for the production of quality lithium acetyl phosphate, allowing for real-time reaction understanding.