Login | Register

Pharmaceutical Stability Testing

 

Understanding pharmaceutical stability is of fundamental importance to the industry.
Stability studies at varied temperature, humidity and purposeful degradation experiments using chemical and thermal methods are widely applied to study the stability and degradation of active pharmaceutical ingredients and formulated drug products. Many pharmaceutical degradation reactions occur by REDOX mechanisms and with the availability of ROXY EC with its flow through electrochemical (EC) cells, a fast and convenient method of studying these reactions is now available.  By online coupling of EC with LC-MS, immediate identification and quantification of the degradation product profiles under varied experimental conditions becomes possible. The EC reactions are selective and tuneable simply by altering the pH or potential. 

Furthermore, EC reactions can be scaled up for fast synthesis of mg quantities of degradation products. 

 

Here an example of the degradation pathways of drug compound #1 ((2S,3S)-2-(diphenylmethyl)-N-[2-methoxy-5-(propan-2-yl) benzyl]-1-azabicyclo[2.2.2]octan-3-amine) using accelerated, forced and electrochemical degradation.

Degradation Pathways Drug Compound #1:


 

Overview of oxidation products of drug compound #1. Compounds 2–6 and degradation pathways (a–e) were obtained from accelerated stability studies (  ). Compounds 3 and 4 could be generated both by: forced degradation (  ) and electrochemically (  ). Compound 6 and 16 were only electrochemically generated. Chemical structures for compounds 3, 4, 4’, 6, 7, 8 and 16 were derived on the basis of exact masses, and MS/MS fragmentation patterns.
Courtesy Dr. Mark Taylor, Pfizer Worldwide R&D, Sandwich, Kent, UK


LC–UV chromatogram at 225 nm of forced degradation. Samples after 3 days of challenge condition: (A) 0.3% H2O2, (B) 5 mM AIBN; 2,2’-Azobis(2-methy-lpropionitrile), radical initiator.



LC–UV chromatograms at 225 nm for electrochemically oxidized samples at 1200 mV at pH = 3.9, 7.1, 8.8. Peak 1 corresponds to the drug substance under study. For proposed structures of other oxidation products, see degradition pathway above.


References

27526403 - Electrochemical oxidation coupled with liquid chromatography and mass spectrometry to study the oxidative stability of active pharmaceutical ingredients in solution: A comparison of off-line and on-line approaches.
S. Torres et al.; J. Pharm. Biomedical Analysis 131 (2016) 71-79

26299525 - The application of electrochemistry to pharmaceutical stability testing--comparison with in silico prediction and chemical forced degradation approaches
S. Torres et al.; J. Pharm. Biomedical Analysis 115 (2015) 487-501

op500312e - Rapid Synthesis of Pharmaceutical Oxidation Products Using Electrochemistry: A Systematic Study of N-Dealkylation Reactions of Fesoterodine Using a Commercially Available Synthesis Cell
S. Torres et al.; Org. Process Res. Dev. 19 (2015) 11, 1596–1603


Posters

  • 221_226_01 - The Application of ElectrochemistryMS to Pharmaceutical Stability Testing and Degradant Synthesis
  • 221_116_01 - Enhanced Pharmaceutical Stability ElCheMS2015


27526403 - Electrochemical oxidation coupled with liquid chromatography and mass spectrometry to study the oxidative stability of active pharmaceutical ingredients in solution: A comparison of off-line and on-line approaches.
S. Torres et al.; J. Pharm. Biomedical Analysis 131 (2016) 71-79

26299525 - The application of electrochemistry to pharmaceutical stability testing--comparison with in silico prediction and chemical forced degradation approaches
S. Torres et al.; J. Pharm. Biomedical Analysis 115 (2015) 487-501

op500312e - Rapid Synthesis of Pharmaceutical Oxidation Products Using Electrochemistry: A Systematic Study of N-Dealkylation Reactions of Fesoterodine Using a Commercially Available Synthesis Cell
S. Torres et al.; Org. Process Res. Dev. 19 (2015) 11, 15961603