Thermotropic phase behavior and supramolecular organization of N,O-diacyl-l-alaninols: effect on stratum corneum model membrane

Abstract

In recent years, chemical enhancers that increase the permeability of stratum corneum (SC) attracted the attention of clinicians and researchers due to their utility in developing transdermal drug delivery systems. N-Lauroyl glycine lauryl ester (NLGLE) was reported to induce higher SC permeability than N-lauroyl serine lauryl ester (NLSLE). Earlier, we proposed a similar activity could be obtained by N-acyl-l-alanine esters (NAAEs) towards SC, which are homologous to NLGLE. In this study, we synthesized a homologous series of N,O-diacyl-l-alaninols (DAAOHs) (which are isomers of NAAEs) with saturated acyl chains. We investigated their thermotropic phase behavior and supramolecular organization, and the results are discussed with the properties of isomeric NAAEs. Most DAAOHs exhibited one polymorphic phase transition (solid-solid transition) before the melting transition in the first heating thermogram. The solid-solid transition disappeared in further heating thermograms. Odd chainlength DAAOHs exhibited higher transition enthalpy and transition entropy values than even chainlength DAAOHs. Interestingly, the even chainlength DAAOHs exhibited higher transition temperature and d-spacing values than odd chainlength DAAOHs. Further, Laurdan fluorescence studies revealed that N,O-dilauroyl-l-alaninol increases the fluidity of SC model membrane more efficiently as compared to NLGLE, suggesting that DAAOHs can potentially be used as chemical enhancers in developing transdermal drug delivery systems. Graphical abstract: Synopsis: PXRD and DSC studies on N,O-diacyl-L-alaninols (DAAOHs) indicate that odd- and even chainlength compounds exhibit differences in molecular packing, and odd-even alternation in transition enthalpies of the solid-liquid transition. N,O-Dilauroyl-L-alaninol increased the fluidity of stratum corneum model membrane, suggesting that DAAOHs would be useful in designing transdermal drug delivery systems. [Figure not available: see fulltext.]