Soluble itraconazole in tablet form using disordered drug delivery approach: critical scale-up considerations and bio-equivalence studies.

The present research work explores formulation design, critical scale-up considerations and bio-equivalence studies of soluble itraconazole (ITZ) in a tablet form using disordered drug delivery approach. Disordered system of ITZ with a lower viscosity grade of hydroxypropyl methyl cellulose (Pharmacoat 603) was developed for the first time and extensively characterised at three different stages, namely development of glass system, pellet coating and tablet compression using advanced analytical techniques. Complete molecular embedment of ITZ resulting in amorphisation was observed and found to be sustained until end of the real-time and accelerated stability studies. Developed formulation exhibited comparative in vitro dissolution profile (similarity factor>70) with reference product (Sporanox, Janssen Pharmaceutica) in simulated gastric fluid without enzymes. Formulation was scaled up in three batches (50,000 tablets/batch) with detailed validation of critical process parameters using process capability index method. Critical scale-up considerations like control of residual solvent content, effect of pellet size on dissolution, process variables in pellet coating, compressibility of coated pellets and cushioning effect required for desired compressibility were thoroughly discussed. Bioequivalence study of single dose of test and reference product in seven healthy human volunteers under fed condition exhibited significant bioequivalence with results (AUClast and AUC∞) lying between 90% confidence interval. With increase in number of subjects to 24, a significant effect on pharmacokinetic parameters of both reference as well as developed ITZ tablets was observed.