HPLC and LC-MS Studies of the Transesterification Reaction of Methylparaben with Twelve 3- to 6-Carbon Sugar Alcohols and Propylene Glycol and the Isomerization of the Reaction Products by Acyl Migration

Abstract

Sugar alcohols and parabens are commonly used ingredients in oral suspension formulations. However, their possible incompatibility because of transesterification reaction is a concern during formulation development. In order to gain more knowledge about the reaction, a high-performance liquid chromatographic (HPLC) method is developed to separate the transesterification reaction products of methylparaben preservative with twelve 3- to 6-carbon sugar alcohols and propylene glycol. It is found that the number of peaks separated or partially separated correlate well with the number of distinct hydroxyl groups present in the sugar alcohol molecules. This means that all the hydroxyl groups in a sugar alcohol molecule can react with methylparaben to form transesterification reaction products. These products are positional isomers that have identical UV spectra with a maximum at 255 nm and the same m/z ratio for molecular ions by liquid chromatography-mass spectrometry. When isolated individually, they can isomerize (interconvert) under suitable conditions to form other positional isomers by intramolecular acyl migration. The acyl migration pathway for each of the isolated positional isomers from the transesterification reaction of methylparaben with sorbitol, ribitol, and xylitol is followed by HPLC. Based on the information, a tentative assignment of the six isomer peaks generated from the transesterification reaction between methylparaben and sorbitol is proposed.

Simultaneous Determination of NSAID and Antimicrobial Preservatives Using Validated RP-HPLC Method: An Application in Pharmaceutical and Clinical Laboratories

“…[21][22][23][24][25][26][27][28][29][30][31][32], gradient HPLC [33], solid phase extraction HPLC [34], HPLC-MS [35].…”

Interaction of methylparaben preservative with selected sugars and sugar alcohols

“…Although hydrolysis is the most frequent degradation reaction in aqueous pharmaceutical formulations, other factors may also decrease the antimicrobial activity of the parabens such as sorption onto solid9–11 and plastic container,12–14 solubilization by nonionic surfactants,15–17 partitioning into flavoring oils,18 and perhaps more importantly interaction/reaction with excipients. A wide range of excipients have been reported to interact/react with parabens, which include cellulose derivatives,19 ethanol,20 ethanolamine,21 β‐cyclodextrin,22 and sugar alcohols (or polyols) 23–26. In this article, we report the interaction of methylparaben with selected sugars through transesterification reaction, which to our best knowledge has not been reported in the literature.…”

“…In a recent study on the transesterification reactions of methylparaben with 12 three‐ to six‐carbon sugar alcohols, we demonstrated that each of the hydroxyl groups of a sugar alcohol molecule could react with methylparaben to form transesterification reaction products 26. These reaction products were positional isomers with the same m/z ratio as determined by LC‐MS.…”

“…In fact, transesterification reaction between methylparaben and sugar alcohols or sugars involves n parallel second‐order reversible reactions because of the presence of n hydroxyl groups in the molecule. The possible interconversion between the transesterification reaction products (positional isomers) as demonstrated in a previous study26 could further complicate the situation. For such a complex system, it would be extremely difficult if not impossible to derive the rate equations for all involved reactions.…”

Drug-Excipient Interactions: Case Studies and Overview of Drug Degradation Pathways

“…During the stability, study of an experimental batch of an oralsuspension formulation that contained sorbitol and paraben preservatives shows approximately 1% degradation for the samples stored at 30˚C for one year (Figure 11). 3, 4, 5 carbon sugar alcohols reacts with methyl paraben to form 6 isomer products were identified by HPLC and NMR by Minhui Ma et al [28]- [30].…”