In the past Olivier Mozziconacci has collaborated on articles with Theodore W. Randolph and Asha Hewarathna. One of their most recent publications is RESEARCH ARTICLE – Pharmaceutical BiotechnologyDo Not Drop: Mechanical Shock in Vials Causes Cavitation, Protein Aggregation, and Particle Formation. Which was published in journal Journal of Pharmaceutical Sciences.

More information about Olivier Mozziconacci research including statistics on their citations can be found on their Copernicus Academic profile page.

Olivier Mozziconacci's Articles: (5)

RESEARCH ARTICLE – Pharmaceutical BiotechnologyDo Not Drop: Mechanical Shock in Vials Causes Cavitation, Protein Aggregation, and Particle Formation

ABSTRACTIndustry experience suggests that g-forces sustained when vials containing protein formulations are accidentally dropped can cause aggregation and particle formation. To study this phenomenon, a shock tower was used to apply controlled g-forces to glass vials containing formulations of two monoclonal antibodies and recombinant human growth hormone (rhGH). High-speed video analysis showed cavitation bubbles forming within 30 μs and subsequently collapsing in the formulations. As a result of echoing shock waves, bubbles collapsed and reappeared periodically over a millisecond time course. Fluid mechanics simulations showed low-pressure regions within the fluid where cavitation would be favored. A hydroxyphenylfluorescein assay determined that cavitation produced hydroxyl radicals. When mechanical shock was applied to vials containing protein formulations, gelatinous particles appeared on the vial walls. Size-exclusion chromatographic analysis of the formulations after shock did not detect changes in monomer or soluble aggregate concentrations. However, subvisible particle counts determined by microflow image analysis increased. The mass of protein attached to the vial walls increased with increasing drop height. Both protein in bulk solution and protein that became attached to the vial walls after shock were analyzed by mass spectrometry. rhGH recovered from the vial walls in some samples revealed oxidation of Met and/or Trp residues.

Research ArticlePharmaceutical BiotechnologyChemical Stability of the Botanical Drug Substance Crofelemer: A Model System for Comparative Characterization of Complex Mixture Drugs

AbstractAs the second of a 3-part series of articles in this issue concerning the development of a mathematical model for comparative characterization of complex mixture drugs using crofelemer (CF) as a model compound, this work focuses on the evaluation of the chemical stability profile of CF. CF is a biopolymer containing a mixture of proanthocyanidin oligomers which are primarily composed of gallocatechin with a small contribution from catechin. CF extracted from drug product was subjected to molecular weight–based fractionation and thiolysis. Temperature stress and metal-catalyzed oxidation were selected for accelerated and forced degradation studies. Stressed CF samples were size fractionated, thiolyzed, and analyzed with a combination of negative-ion electrospray ionization mass spectrometry (ESI-MS) and reversed-phase-HPLC with UV absorption and fluorescence detection. We further analyzed the chemical stability data sets for various CF samples generated from reversed-phase-HPLC-UV and ESI-MS using data-mining and machine learning approaches. In particular, calculations based on mutual information of over 800,000 data points in the ESI-MS analytical data set revealed specific CF cleavage and degradation products that were differentially generated under specific storage/degradation conditions, which were not initially identified using traditional analysis of the ESI-MS results.

Neighboring amide participation in the Fenton oxidation of a sulfide to sulfoxide, vinyl sulfide and ketone relevant to oxidation of methionine thioether side chains in peptides

AbstractOxidation of Met affects the stability of proteins, and was identified as a step in the beta amyloid-dependent pathogenesis of Alzheimer's disease. One-electron oxidation of Met is facilitated through stabilization of sulfide radical cations with electron-rich heteroatoms. The formation of such 2-center-3-electron bonds, formed between sulfide radical cations and amides, leads to pronounced product selectivity during biologically relevant oxidation conditions. Conformationally constrained methionine analogs embedded within a norbornane framework, i.e., 2,6-endo, endo- and 2,6-exo, endo-pyrrolidine amide thiomethyl bicyclo[2.2.1]heptanes were synthesized. Oxidation of both methionine analogs in the Fenton oxidation yielded some sulfoxide. In addition, the oxidation of the endo, endo-derivative generated a vinyl sulfide while the exo, endo-derivative was converted into a ketone, indicating a selective influence of a sulfur-oxygen 2-center-3-electron bond on product formation. Mechanistic details of product formation were investigated through the incorporation of stable isotopes.

Chemical degradation of proteins in the solid state with a focus on photochemical reactions☆

AbstractProtein pharmaceuticals comprise an increasing fraction of marketed products but the limited solution stability of proteins requires considerable research effort to prepare stable formulations. An alternative is solid formulation, as proteins in the solid state are thermodynamically less susceptible to degradation. Nevertheless, within the time of storage a large panel of kinetically controlled degradation reactions can occur such as, e.g., hydrolysis reactions, the formation of diketopiperazine, condensation and aggregation reactions. These mechanisms of degradation in protein solids are relatively well covered by the literature. Considerably less is known about oxidative and photochemical reactions of solid proteins. This review will provide an overview over photolytic and non-photolytic degradation reactions, and specially emphasize mechanistic details on how solid structure may affect the interaction of protein solids with light.

Original ContributionSuperoxide radical anions protect enkephalin from oxidation if the amine group is blocked

AbstractThe pentapeptide methionine-enkephalin (Met-enk) is a natural opiate that inhibits signals of pain. The N-terminal tyrosyl residue is important in the recognition of the peptide by its receptor. In oxidative stress, this residue can be oxidized by reactive oxygen species. The one-electron oxidation of Met-enk and of tert-butoxycarbonyl-methionine-enkephalin (Boc-Met-enk) was studied by γ- and pulse radiolysis in the absence and in the presence of superoxide radical anions (O2−) and oxygen, using azidyl radicals as oxidants. Without oxygen, both peptides behaved similarly. The tyrosyl radical resulting from the oxidation of tyrosyl residue produced the dimer linked by dityrosines. Methionine was also oxidized to its sulfoxide; however, this reaction is of minor importance. When O2− was present, it added to tyrosyl radical giving a hydroperoxide. For Met-enk, this adduct cyclized via an intramolecular Michael addition of the amine on the aromatic ring. Conversely, for Boc-Met-enk, the adduct eliminated oxygen which led to 97% regeneration of the nonmodified peptide. Blocking the terminal amine group had thus a key role in protection of the tyrosyl residue. This finding might be exploited in the search for new pain inhibitors.

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