Kinetics and Mechanism for the Reaction of Cysteine with Hydrogen Peroxide in Amorphous Polyvinylpyrrolidone Lyophiles

Abstract

When reactive intermediates are involved, differences in degradant profiles and other characteristics (e.g., rate constants, apparent reaction order) in the amorphous-state may simply reflect altered rates for individual reaction steps due to glass-induced changes in relative reactant mobilities rather than a change in overall mechanism.

Application of a Two-State Kinetic Model to The Heterogeneous Kinetics of Reaction between Cysteine and Hydrogen Peroxide in Amorphous Lyophiles

“…This method was shown previously by modulated temperature differential scanning calorimetry (MTDSC) and powder X‐ray diffraction (PXRD) to produce amorphous lyophiles 35. The glass transition temperature for an amorphous lyophile prepared from a 20 mg/mL PVP solution also containing 50 mM sodium phosphate buffer, and 5 mM each of CSH and H 2 O 2 and stored at 25°C for one week was 182.3°C on heating and 180.4°C on cooling, which was similar to the value recorded for pure PVP 35. Residual moisture in the lyophiles was determined by Karl Fischer titration as described previously 35…”

“… Solution to solid‐state concentration conversionSolution concentrations of CSH, H 2 O 2 , CSSC, CSO 2 H, and CSO 3 H were generated by HPLC analysis at different reaction times. These concentrations were converted to solid‐state concentrations (mol/L) by using the calculated McGowan volumes36 of all solid phase components in the lyophiles, as described previously 35. The primary contributors to the total volume of solid in the amorphous lyophiles are PVP {(C 6 H 9 NO) n where n = 3243} or trehalose (C 12 H 22 O 11 ) and the phosphate buffer salts. Two‐state kinetic modelA mathematical model (Eqs.…”

“…The primary contributors to the total volume of solid in the amorphous lyophiles are PVP {(C 6 H 9 NO) n where n = 3243} or trehalose (C 12 H 22 O 11 ) and the phosphate buffer salts. Two‐state kinetic modelA mathematical model (Eqs. 1–6) was derived reflecting the mechanism shown in Scheme 35 but neglecting cysteine ionization (see later discussion). Reactant (CSH and H 2 O 2 ) and product (CSSC, CSO 2 H, and CSO 3 H) concentrations versus time in lyophiles prepared at different starting concentrations of CSH and H 2 O 2 , different storage temperatures and pH, and in either PVP or trehalose were fit to this model using nonlinear least squares regression analysis (SCIENTIST®, Micromath, Inc., Salt Lake City, UT).…”

“…The reactive intermediate then combines with a second thiolate to form a disulfide (RSSR) as the final product of the reaction. More recently, we conducted an initial rate study of the kinetics of the same reaction between cysteine (CSH) and hydrogen peroxide (H 2 O 2 ) as a function of reactant concentration at fixed pH in amorphous polyvinylpyrrolidone (PVP) in an effort to determine the degree to which an understanding of the reaction mechanism in solution could facilitate understanding of the reaction kinetics in an amorphous glass 35. Even in the initial rate region, the amorphous solid‐state reaction exhibited a more complex rate law in comparison to the solution reaction and produced multiple degradation products.…”

Effect of Antioxidants and Silicates on Peroxides in Povidone

“…[1][2][3][4][5][6][7][8][9] Regulatory guidelines require characterization and toxicological evaluation of drug substance impurities if they accumulate in the drug product above a threshold concentration, depending upon the drug's daily dose. 10 Also, lot-tolot and manufacturer-to-manufacturer variation in the concentration of reactive peroxides in excipients and change in the peroxide concentration on storage of excipients and drug products can lead to unpredictability of drug product stability.…”