Hydrothermal liquefaction (HTL) of microalgae, a process that uses water at high temperature and high pressure to make a renewable crude bio-oil, is receiving increased attention. Understanding the governing reaction pathways for the biomolecules in the microalgae cell could lead to improved conversion processes. This review collects information pertinent to the behavior of microalgae biomolecules (e.g., proteins, polysaccharides, lipids, chlorophyll) and their hydrothermal decomposition products (e.g., amino acids, sugars, fatty acids) in high temperature water (HTW). We report on studies involving individual compounds and their mixtures. The mixture systems are particularly important as they move closer to mimicking the true chemistry of HTL of microalgae by providing opportunities for interactions between different molecules that would be present during HTL. Throughout this review, we highlight gaps in the understanding of different chemical reactions that may take place during HTL of microalgae.

We examined the behavior of phenylalanine in high-temperature water (HTW) at 220, 250, 280, and 350 °C. Under these conditions, the major product is phenylethylamine. The minor products include styrene and phenylethanol (1-phenylethanol and 2-phenylethanol), which appear at higher temperatures and longer batch holding times. Phenylethylamine forms via decarboxylation of phenylalanine, styrene forms via deamination of phenylethylamine, and phenylethanol forms via hydration of styrene. We quantified the molar yields of each product at the four temperatures, and the carbon recovery was between 80-100 % for most cases. Phenylalanine disappearance follows first-order kinetics with an activation energy of 144 ± 14 kJ mol⁻¹ and a pre-exponential factor of 10(12.4 ± 1.4)  min⁻¹. A kinetics model based on the proposed pathways was consistent with the experimental data. Effects of five different salts (NaCl, NaNO₃, Na₂ SO₄, KCl, K₂ HPO₄) and boric acid (H₃BO₃) on phenylalanine behavior at 250 °C have also been elucidated. These additives increase phenylalanine conversion, but decrease the yield of phenylethylamine presumably by promoting formation of high molecular weight compounds. Lastly, binary mixtures of phenylalanine and ethyl oleate have been studied at 350 °C and three different molar concentration ratios. The presence of phenylalanine enhances the conversion of ethyl oleate and molar yields of fatty acid. Higher concentration of ethyl oleate leads to increased deamination of phenylethylamine and hydration of styrene. Amides are also formed due to the interaction of oleic acid/ethyl oleate and phenylethylamine/ammonia and lead to a decrease in the fatty acid yields. Taken collectively, these results provide new insights into the reactions of algae during its hydrothermal liquefaction to produce crude bio-oil.

This paper presents a case study in establishing the operation space of a Grignard reaction in a continuous stirred tank reactor (CSTR). The operation space is the multivariate space with the boundary defined by the proven acceptable range of every CSTR process parameter such as flow rates and temperature. The mapping of the operation space was conducted by a thorough understanding of reaction kinetics, magnesium (Mg) sequestration efficiency, equipment characterization, and the impact of process disturbances has on steady state. A fit-for-use reaction kinetics model was developed to parametrize the kinetics and mass transfer rates of the batch Grignard reaction across different scales from 250 mL to 500 gallons. The reaction kinetics model was applied to design the Mg recharge frequency accounting operational variability to ensure a state of control can be maintained. Furthermore, reactor temperature was determined to be suitable to detect process failures to ensure process safety and product quality at manufacturing scale. Computational fluid dynamics (CFD) models were also applied to aid equipment design to maximize Mg sequestration in the CSTR. Based on the optimal equipment design, the unit operation was scaled-down to test the sequestration efficiency. The resulting process understanding enabled the team to define the final operation strategy to ensure a safe and robust commercial process.

The large-scale manufacture of complex synthetic peptides is challenging due to many factors such as manufacturing risk (including failed product specifications) as well as processes that are often low in both yield and overall purity. To overcome these liabilities, a hybrid solid-phase peptide synthesis/liquid-phase peptide synthesis (SPPS/LPPS) approach was developed for the synthesis of tirzepatide. Continuous manufacturing and real-time analytical monitoring ensured the production of high-quality material, while nanofiltration provided intermediate purification without difficult precipitations. Implementation of the strategy worked very well, resulting in a robust process with high yields and purity.