(97c) High Drug-Loaded Surfactant-Free Nanocomposite Microparticles for Enhanced Dissolution of Poorly Soluble Drugs

About 80% of newly discovered drug molecules pose some poor water-solubility related issues, which makes them difficult to formulate into efficacious medications. Dissolution of a poorly soluble drug can be improved by breaking the drug crystals down to nano-size in the form of a nanosuspension and subsequently drying it into nanocomposite microparticles (nanocomposites). A major challenge in this field is that depending on the dispersants used, drug nanoparticles may aggregate, and they may not be recovered fast during dissolution from the nanocomposites. The aim of this study is to investigate the impact of various classes of dispersants on the dissolution of drug nanoparticles from nanocomposites and elucidate the mechanisms for enhanced dissolution. Precursor suspensions of itraconazole (ITZ), a model poorly water-soluble drug, in the presence of various dispersants were prepared via wet stirred media milling and spray dried to form nanocomposites. Hydroxypropyl cellulose (HPC, water-soluble polymer) alone, sodium dodecyl sulfate (SDS, anionic surfactant) alone, and their combination were used as baseline stabilizers/dispersants. Mannitol and Sucrose were used as typical water-soluble dispersants in addition to HPC. As a major novelty of this investigation, swellable dispersants such as wet-milled superdisintegrants were used in the nanocomposites. Specifically, three superdisintegrants most commonly used in pharmaceutical industry, i.e., sodium starch glycolate (SSG), crospovidone (CP), and croscarmellose sodium (CCS) were wet-co-milled along with ITZ. Laser diffraction, viscometry, SEM, XRD, DSC, UV spectroscopy, wettability testing, and dissolution testing were used for characterization. Our experimental results indicate that HPC–SDS combination or higher HPC concentration allowed for faster drug dissolution due to reduction of drug nanoparticle aggregation and enhanced wettability. Wet co-milled superdisintegrants were much more effective than Mannitol and Sucrose in dissolution enhancement of ITZ. With judicious selection of superdisintegrant concentration, their performance matched that of HPC­–SDS combination, suggesting that the use of wet-milled superdintegrants obviates the need for surfactants that could be toxic, especially at high concentrations for various pharmaceutical applications. The impact of the wet-milled superdisintegrants positively correlated with their swelling capacity (SSG > CCS > CP), signifying the dominance of a swelling-induced erosion/disintegration mechanism during drug dissolution from the nanocomposites with wet-milled superdisintegrants. This study overall demonstrates that fast-dissolving, high drug-loaded, surfactant-free nanocomposites could be prepared with either HPC‒co-milled superdisintegrants or optimal HPC concentration via spray drying. Since many patients find surfactants to be irritating in particular for orally dispersing dosage forms, such surfactant-free drug composites are expected to alleviate that aspect of patient compliance issues.