Novel high-loaded, nanoparticulate and thermally stable macromolecular prodrug design of NSAIDs based on hydroxypropylcellulose

Macromolecular prodrugs (MPDs) of aspirin and salicylic acid were synthesized by covalent attachment to hydroxypropylcellulose (HPC) using p-toluenesulfonyl chloride in N,N-dimethylacetamide. The present synthesis strategy resulted in organo-soluble MPDs with 78–86 % yield and degree of drug substitution 0.53–1.96 and 0.68–2.10 for aspirin and salicylic acid, respectively. The size exclusion chromatography showed DP 192 and 214 for HPC–aspirin and HPC–salicylic acid conjugates, respectively. HPC–aspirin and HPC–salicylic acid conjugates were found thermally more stable than native drugs. The activation energy (Ea) of thermal degradation of drugs, polymer and prodrugs was calculated with the help of Broido and Chang kinetic models. Order of reaction (n) was calculated from thermal data using Chang model. Various thermodynamic parameters, i.e., enthalpy (ΔH), Gibbs free energy (ΔG) and entropy (ΔS) were also calculated. Doyle’s method was employed on thermal data of MPDs to calculate integral procedural decomposition temperature and comprehensive index of intrinsic thermal stability. Amphiphilic HPC–aspirin conjugates showed formation of nanoparticles at water/DMSO interface with size distribution from ~500 to 750 nm by transmission electron microscopy.