TY - JOUR
T1 - Kinetics of the esterification of active pharmaceutical ingredients containing carboxylic Acid functionality in polyethylene glycol
T2 - formulation implications
AU - Schou-Pedersen, Anne Marie V
AU - Hansen, Steen Honoré
AU - Moesgaard, Birthe
AU - Ostergaard, Jesper
N1 - © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.
PY - 2014/8
Y1 - 2014/8
N2 - Polyethylene glycols (PEGs) are attractive as excipients in the manufacture of drug products because they are water soluble and poorly immunogenic. They are used in various pharmaceutical preparations. However, because of their terminal hydroxyl groups, PEGs can participate in esterification reactions. In this study, kinetics of two active pharmaceutical ingredients, cetirizine and indomethacin possessing carboxylic acid functionality, has been studied in PEG 400 and PEG 1000 at 50C, 60C, 70C, and 80C. HPLC-UV was applied for the determination of concentrations in the kinetic studies, whereas HPLC-MS was used to identify reaction products. The esterification reactions were observed to be reversible. A second-order reversible kinetic model was applied and rate constants were determined. The rate constants demonstrated that cetirizine was esterified about 240 times faster than indomethacin at 80C. The shelf-life for cetirizine in a PEG 400 formulation at 25C expressed as t95% was predicted to be only 30 h. Further, rate constants for esterification of cetirizine in PEG 1000 in relation to PEG 400 decreased by a factor of 10, probably related to increased viscosity. However, it is important to be aware of this drug-excipient interaction, as it can reduce the shelf-life of a low-average molecular weight PEG formulation considerably.
AB - Polyethylene glycols (PEGs) are attractive as excipients in the manufacture of drug products because they are water soluble and poorly immunogenic. They are used in various pharmaceutical preparations. However, because of their terminal hydroxyl groups, PEGs can participate in esterification reactions. In this study, kinetics of two active pharmaceutical ingredients, cetirizine and indomethacin possessing carboxylic acid functionality, has been studied in PEG 400 and PEG 1000 at 50C, 60C, 70C, and 80C. HPLC-UV was applied for the determination of concentrations in the kinetic studies, whereas HPLC-MS was used to identify reaction products. The esterification reactions were observed to be reversible. A second-order reversible kinetic model was applied and rate constants were determined. The rate constants demonstrated that cetirizine was esterified about 240 times faster than indomethacin at 80C. The shelf-life for cetirizine in a PEG 400 formulation at 25C expressed as t95% was predicted to be only 30 h. Further, rate constants for esterification of cetirizine in PEG 1000 in relation to PEG 400 decreased by a factor of 10, probably related to increased viscosity. However, it is important to be aware of this drug-excipient interaction, as it can reduce the shelf-life of a low-average molecular weight PEG formulation considerably.
U2 - 10.1002/jps.24062
DO - 10.1002/jps.24062
M3 - Journal article
C2 - 24961667
SN - 0022-3549
VL - 103
SP - 2424
EP - 2433
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 8
ER -