Use of 2,2'-azobis(2-amidinopropane) dihydrochloride as a reagent tool for evaluation of oxidative stability of drugs.
OBJECTIVE
To study the oxidative degradation of drugs using a hydrophilic free radical initiator, 2,2'-Azobis(-amidinopropane) dihydrochloride (AAPH).


METHODS
AAPH was used as the free radical initiator to study oxidation of three model compounds (A, B, and C), which represent different oxidizable moieties. In the solution model, the drugs and AAPH were dissolved in a mixture of acetonitrile and aqueous buffer and incubated at elevated temperatures to evaluate oxidative degradation. The effects of pH and drug-AAPH ratio on the kinetics of the reaction were evaluated for compound A. Commonly used antioxidants were also evaluated by addition to solutions of drug and AAPH. In the solid-state model, blends of drug with microcrystalline cellulose were treated with AAPH and placed at elevated temperature and humidity to evaluate solid state oxidation.


RESULTS
Use of AAPH resulted in selective oxidation of the model drugs by a free radical initiated process. The scope of the technique was further investigated in detail using compound A. The rate of oxidation of compound A varied directly with the concentration of AAPH. The pseudo first-order rate constants for the oxidative degradation were calculated from the kinetic data. The antioxidants were rank-ordered based on their quenching activity on the rates of AAPH initiated oxidation for compound A. The concept was extended to oxidation in solid state.


CONCLUSIONS
The proposed AAPH model is useful in assessing oxidative stability of drug candidates in development.
Betigeri
Seema
S
Biopharmaceutics R&D, Pharmaceutical Research Institute, Bristol-Myers Squibb Co, New Brunswick, New Jersey 08903, USA.
Thakur
Ajit
A
Raghavan
Krishnaswamy
K
D000578:Amidines / Q000032:analysis / Q000737:chemistry*; D004355:Drug Stability; D007202:Indicators and Reagents / Q000032:analysis / Q000737:chemistry; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000032:analysis / Q000737:chemistry*
D000578:Amidines; D007202:Indicators and Reagents; D004364:Pharmaceutical Preparations; C046728:2,2'-azobis(2-amidinopropane)