Identification of reaction products between drug substances and excipients by HPLC-SPE-NMR: ester and amide formation between citric acid and 5-aminosalicylic acid.
The reaction between the high-dose drug substance 5-aminosalicylic acid (5-ASA) and the excipient citric acid during storage of an experimental enema preparation has been studied and three isobaric reaction products, i.e., an ester and an amide with non-symmetrically substituted citric acid moieties and a symmetrical amide, were identified by combined use of HPLC-SPE-NMR and HPLC-MS. After storage for 1 week at 70 degrees C, approximately 5% of the 5-ASA present in the formulation was transformed into these impurities. Storage of the enema for 32 months at room temperature led to loss of approximately 10% of the original amount of 5-ASA, with the ester as the main reaction product.
Larsen
Jesper
J
Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark. jl@farma.ku.dk
Staerk
Dan
D
Cornett
Claus
C
Hansen
Steen H
SH
Jaroszewski
Jerzy W
JW
D000577:Amides / Q000032:analysis; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000032:analysis*; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D019343:Citric Acid / Q000032:analysis*; D004733:Enema; D004952:Esters / Q000032:analysis; D005079:Excipients / Q000032:analysis*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D019804:Mesalamine / Q000032:analysis*; D004364:Pharmaceutical Preparations / Q000032:analysis*; D019999:Pharmaceutical Solutions; D052617:Solid Phase Microextraction
D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004952:Esters; D005079:Excipients; D004364:Pharmaceutical Preparations; D019999:Pharmaceutical Solutions; D019343:Citric Acid; D019804:Mesalamine