Tinkering with Mechanochemical Tools for Scale Up.

Mechanochemistry provides an environmentally benign platform to develop more sustainable chemical processes by limiting raw materials, energy use, and waste generation while using physically smaller equipment. A continuously growing research community has steadily showcased examples of beneficial mechanochemistry applications at both the laboratory and the preparative scale. In contrast to solution-based chemistry, mechanochemical processes have not yet been standardized, and thus scaling up is still a nascent discipline. The purpose of this Minireview is to highlight similarities, differences and challenges of the various approaches that have been successfully applied for a range of chemical applications at various scales. We hope to provide a discussion starting point for those interested in further developing mechanochemical processes for commercial use and/or industrialisation.

Understanding the Adsorption and Desorption of Sitagliptin Phosphate Monohydrate on SS2343, Glass, and PTFE Using QCM-D and Raman Spectroscopy.

Cross-contamination during pharmaceutical drug manufacturing can result in expensive recalls. To counter that, companies spend significant time and resources to ensure equipment cleanliness, often relying on the compound solubility data in various solvents as the main indicator of cleaning success. The aim of this work is to provide an alternative way to analyze the fouling and cleaning of surfaces in pharmaceutical manufacturing processes by using the quartz crystal microbalance with dissipation (QCM-D) and Raman spectroscopy. In this study, we chose an active pharmaceutical ingredient (API), sitagliptin phosphate monohydrate (SIT), as the model drug compound and observed its adsorption and desorption on stainless steel (SS2343), borosilicate glass (glass), and polytetrafluoroethylene (PTFE) surfaces. SIT was selected as the model API since it is a product manufactured on a large scale and is part of the widely used dipeptidyl peptidase-IV inhibitor class of oral hypoglycemics used to treat type 2 diabetes mellitus, while the chosen surfaces mimic the wall materials of manufacturing equipment and components such as reactors, transfer lines, and valves. Both the QCM-D and Raman spectroscopy results show the highest physisorption on PTFE, followed by SS2343 and glass. Additionally, QCM-D revealed a harder removal of SIT from SS2343 compared to glass and PTFE. Raman analysis of the chemical interactions disclosed C-F and C═O bond interactions between SIT and the surfaces, and the lack of a peak shift suggested dipole-dipole interactions. Furthermore, contact angle measurements indicate that hydrophobic attraction contributed to SIT adhesion to the PTFE surface. Subsequently, SIT coverage upon deposition on a PTFE surface has a significantly smaller surface area than on SS2343 and glass due to surface hydrophobicity, hence resulting in a longer removal time. These results provide a practical use of QCM-D and Raman spectroscopy to enhance the understanding of fouling and improve the cleaning of complex small molecules on relevant surfaces during the pharmaceutical manufacturing process.

Synthesis of potential HIV integrase inhibitors inspired by natural polyphenol structures.

Drawing inspiration from the structural features of some natural polyphenols, the synthesis of two different model compounds as potential inhibitors of HIV integrase (IN) has been described. The former was characterised by a diketo acid (DKA) bioisostere, such as a ß-hydroxycarbonyl moiety, between two fragments containing aromatic groups, while in the latter an epoxide linked two polyoxygenated aromatic residues. The moieties present in the structures are thought to function by chelating divalent metal ions on the enzyme catalytic site. Overall, 10 compounds were prepared and some of that submitted to molecular modelling studies (to investigate their interactions with the active site of IN), to metal titration studies (to detect their chelating capability) and to biological assays.

Synthesis, molecular modeling and biological evaluation of two new chicoric acid analogs.

Two conformationally constrained compounds similar to chicoric acid but lacking the catechol and carboxyl groups were prepared. In these analogues, the single bond between the two caffeoyl fragments has been replaced with a chiral oxirane ring and both aromatic residues modified protecting completely or partially the catechol moiety as methyl ether. Preliminary molecular modelling studies carried out on the two analogues showed interactions near the active site of HIV integrase; however, in comparison with raltegravir, the biological evaluation confirmed that CAA-1 and CAA-2 were unable to inhibit infection at lower concentration.

A Resin-linker-vector approach to radiopharmaceuticals containing 18F: application in the synthesis of O-(2-[18F]-fluoroethyl)-L-tyrosine.

A Resin-linker-vector (RLV) strategy is described for the radiosynthesis of tracer molecules containing the radionuclide (18)F, which releases the labelled vector into solution upon nucleophilic substitution of a polystyrene-bound arylsulfonate linker with [(18)F]-fluoride ion. Three model linker-vector molecules 7a-c containing different alkyl spacer groups were assembled in solution from (4-chlorosulfonylphenyl)alkanoate esters, exploiting a lipase-catalysed chemoselective carboxylic ester hydrolysis in the presence of the sulfonate ester as a key step. The linker-vector systems were attached to aminomethyl polystyrene resin through amide bond formation to give RLVs 8a-c with acetate, butyrate and hexanoate spacers, which were characterised by using magic-angle spinning (MAS) NMR spectroscopy. On fluoridolysis, the RLVs 8a,b containing the longer spacers were shown to be more effective in the release of the fluorinated model vector (4-fluorobutyl)phenylcarbamic acid tert-butyl ester (9) in NMR kinetic studies and gave superior radiochemical yields (RCY≈60%) of the (18) F-labelled vector. The approach was applied to the synthesis of the radiopharmaceutical O-(2-[(18)F]-fluoroethyl)-L-tyrosine ([(18) F]-FET), delivering protected [(18) F]-FET in >90% RCY. Acid deprotection gave [(18)F]-FET in an overall RCY of 41% from the RLV.