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 50°C, 60°C, 70°C, and 80°C. 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 80°C. The shelf-life for cetirizine in a PEG 400 formulation at 25°C 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. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2424-2433, 2014.

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 50°C, 60°C, 70°C, and 80°C. 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 80°C. The shelf-life for cetirizine in a PEG 400 formulation at 25°C 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. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2424-2433, 2014.

U2 - 10.1002/jps.24062

DO - 10.1002/jps.24062

M3 - Journal article

C2 - 24961667

VL - 103

SP - 2424

EP - 2433

JO - Journal of Pharmaceutical Sciences

JF - Journal of Pharmaceutical Sciences

SN - 0022-3549

IS - 8

ER -