# The synthesis of indomethacin prodrugs for the formation of nanosuspensions by emulsion templated freeze drying

## TL;DR

This study shows that increasing the hydrophobicity of indomethacin prodrugs improves the formation of stable nanosuspensions using a freeze-drying method.

## Contribution

The research demonstrates a direct link between drug hydrophobicity and nanosuspension stability in ETFD.

## Key findings

- Higher log P values in prodrugs correlate with better nanosuspension formation.
- Specific stabiliser combinations consistently supported nanoparticle formation.
- Esters with higher log P showed better dispersion stability in dry formulations.

## Abstract

Emulsion-templated freeze drying (ETFD) is a versatile technique for producing nanosuspensions of poorly water-soluble drugs, but predicting formulation success remains a significant challenge. In this study, we investigate how structural modification of the model drug indomethacin, through esterification with a series of alkyl and aromatic groups, influences nanosuspension formation via ETFD. A panel of seven indomethacin prodrugs was synthesised and screened across binary combinations of water-soluble stabilisers. The resulting formulations were assessed based on particle diameter, polydispersity index (PDI), and visual dispersion quality. Analysis of stabiliser combinations revealed specific systems that consistently supported nanoparticle formation across multiple prodrugs. Additionally, there was a positive relationship between increased hydrophobicity, represented by the calculated log P, and the formation of viable nanosuspensions. Moreover, the stability of these nanosuspensions was assessed, revealing that esters with higher log P values exhibited better dispersion stability. The findings provide valuable insights into the selection of active pharmaceutical ingredients for nanosuspension formulation and further the understanding of the influence of drug properties on nanosuspension stability and production. This research contributes to the development of effective nanosuspension strategies for a wide range of poorly water-soluble pharmaceutical compounds.

Increasing log P in a rational series of indomethacin prodrugs improves nanosuspension formation by emulsion-templated freeze drying to give stable dispersible dry formulations.