The effect of pH modifying excipients on the chemical stability of a model peptide (VYPNGA) and the degradation of poly(DL-lactide-co-glycolide)(PLGA) was studied in PLGA films under accelerated storage conditions. pH modifiers included a basic amine (proton sponge), a basic salt (magnesium hydroxide) and two pH buffers (ammonium acetate and magnesium acetate). Changes in film pH were monitored using 13 C NMR, peptide degradation products were quantified by LC/ MS/MS and PLGA degradation was analyzed by TGA, DSC and SEC. Inclusion of pH modifiers had little impact on PLGA degradation. The proton sponge affected an initial decrease in pH but reduced peptide deamidation and chain cleavage relative to an unbuffered control. Magnesium hydroxide produced an initial increase in pH but also showed increased peptide deamidation. Ammonium acetate decreased pH and increased peptide chain cleavage, presumably due to increased PLGA hydrolysis. Magnesium acetate buffer increased the initial pH but resulted in increased peptide loss. The extent of peptide acylation increased in all formulations, most notably in the proton sponge modified films. The effectiveness of pH modifiers in PLGA formulations under storage conditions is dependant on both the mechanism of pH alteration and the peptide degradation reaction of interest.

In recent years, metal−metal oxide catalysts have proven to be robust catalysts for hydrodeoxygenation (HDO) of oxygenated compounds derived from biorenewable feedstocks to value-added products. Herein, the conversion of 1,2,6-hexanetriol (1,2,6-HT) to 1,6-hexanediol (1,6-HD) in aqueous media over a Pt-WO x /TiO 2 catalyst is examined via isotope incorporation in HDO of a model compound, 1,2-pentanediol (1,2-PD). Absence of a primary kinetic isotope effect (k H /k D = 0.84 ± 0.11) disproves a potential direct C−O bond scission mechanism. The observation of nearly complete deuterium incorporation in both the α-C and the β-C is inconsistent with the reverse Mars−van Krevelen mechanism and suggests an enol formation pathway. Evidence consistent with the intermediacy of an oxocarbenium ion as a minor contributor has also been observed. In drawing the conclusions, it was necessary to characterize the facile isotope exchange between surface activated hydrogen and the water solvent. Hydrogenation of a water-soluble olefin, tetra(ethylene glycol) diacrylate (TEGDA) in H 2 /D 2 O revealed predominant incorporation of deuterium instead of hydrogen in the reduced product, confirming the rapid exchange of surface activated hydrogen. The methods used in this study provide clarification about a reaction mechanism currently under debate, and these findings can be applied to other systems involving HDO of linear polyols over metal−metal oxide catalysts, improving catalyst design and utilization of sustainable feedstocks.

The efficient generation of novel, N-linked benzamidines resulting from a regiospecific rearrangement of quinazolinones is described. This methodology study explored reaction parameters including the effect of changing solvent and temperature, as well as varying electronic substituents on the structural core. The transformation was extensively optimized in terms of reaction conditions and scope, resulting in a protocol that consistently affords diversely functionalized amidines in high yield. The process permits regional structural derivatization that was previously inaccessible, and the multistep process was also reduced to a telescoped, five-step sequence that efficiently affords pharmacologically unique (E)-benzamidoamidines from N-BOC protected γ- and δ-amino acids.

The utility of the effective method is demonstrated by its incorporation in the synthesis of various novel benzamidine structures of pharmaceutical interest.