Accelerated Forced Degradation of Therapeutic Peptides in Levitated Microdroplets

• Published in: Pharmaceutical research Vol. 37; no. 7; p. 138
• Main Authors: Li, Yangjie, Hu, Yanyang, Logsdon, David L., Liu, Yong, Zhao, Yuejie, Cooks, R. Graham
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.07.2020; Springer; Springer Nature B.V
• Subjects: Analysis; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Buserelin - chemistry; Deamino Arginine Vasopressin - chemistry; Degradation; Desmopressin; Drug Compounding; Drug development; Drug Stability; Health aspects; Hot Temperature; Hydrogen-Ion Concentration; Kinetics; Leuprolide - chemistry; Medical Law; Octreotide; Octreotide - chemistry; Oxidation; Particle Size; Peptides; Pharmacology/Toxicology; Pharmacy; Protein Stability; Proteolysis; Research Paper; Tetracycline; Tetracyclines; Workflow; reaction acceleration; tandem mass spectrometry; droplet chemistry; Leidenfrost effect
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-020-02868-y

Purpose Forced degradation is critical to probe the stabilities and chemical reactivities of therapeutic peptides. Typically performed in bulk followed by LC-UV or LC-MS analysis, this traditional workflow consists of a reaction/analysis sequence and usually requires half a day to several days to form and measure the desired amounts of degradants. A faster method is needed to study peptide degradation in a shorter time in order to speed up the drug development process. Methods In the new rapid method developed in this study, peptide degradation occurs in levitated aqueous microdroplets using the Leidenfrost effect. Results This two-minute reaction/analysis workflow allows major degradation pathways of Buserelin, Octreotide, Desmopressin and Leuprorelin to be studied. The reactions include deamidation, disulfide bond cleavage, ether cleavage, peptide bond hydrolysis, and oxidation. Conclusions The accelerated forced degradation method requires a minimal amount of therapeutic peptide per stress condition, and the appropriate extent of degradation can be readily generated in seconds by adjusting the droplet levitation time. Levitated microdroplets should be applicable in pharmaceutical development to rapidly determine the intrinsic stability of therapeutic peptides and to aid formulation development by screening the effects of excipients on the stability of the peptides. Graphical abstract