• Evaluation of the Use of Hydroxypropyl methylcellulose acetate succinate (HPMCAS) in Enteric Coating of Tablets and Solubility Enhancement of BCS Class II Compounds

      Deshpande, Tanvi Mahesh; Hoag, Stephen W. (2017)
      Hydroxypropyl methylcellulose acetate succinate (HPMCAS), an anionic polymer, demonstrates wide applicability in drug delivery. The goal of this dissertation is twofold: Applicability of HPMCAS in aqueous enteric coating of tablets and in solubility enhancement of BCS Class II compounds. HPMCAS used for aqueous enteric coating has a tendency to aggregate and clog the spray-nozzle during the coating process. This limitation motivated us to design and develop a stable aqueous enteric coating formulation that minimizes aggregation and spray-nozzle clogging, and maintains the enteric coating profile of tablets. Results show that elevated processing temperature activates polymer particle coalescence in plasticized dispersions, forming large aggregates that clog the spray-nozzle. We successfully developed a stable formulation containing PEG 4000, sodium lauryl sulfate (SLS), and Aerosil® R972 Pharma that formed hydrogen bonds with HPMCAS (steric repulsion), provided electrostatic stabilization, and provided hydrophobicity to the aqueous coating respectively, which in turn prevented nozzle clogging and maintained the tablet's enteric profile. The second application of HPMCAS focused on spray dried dispersions (SDDs), which is one of the most successful solubility enhancement techniques for BCS Class II compounds (e.g. Itraconazole (ITZ), a model drug for this study). Selection of suitable drug carriers (polymers) was found to be crucial for solubility enhancement and for ensuring the stability of ITZ. Incorporation of surfactants with polymers could further enhance ITZ solubility by micellar solubilization mechanism. The project goal was to develop a screening methodology for selecting polymer/surfactant combinations for enhancing solubility and kinetic stability of ITZ spray-dried dispersions (SDD). 1H NMR and fluorescence spectroscopy aided in screening polymer/surfactant combinations by determining critical micelle concentration (CMC) of the system. Observations indicated that stronger surfactant/polymer interactions (inferred by the decrease in CMC) show limited solubility and kinetic stability enhancement (due to their unavailability to interact with ITZ). Further screening of excipients for SDD preparation was performed based on the supersaturation ratio and the precipitation induction time of ITZ in the presence of different surfactant/polymer combinations. ITZ/HPMCAS-HF SDD was found to be most efficient since it enhanced and maintained the solubility of ITZ by 60-fold for up to 24 h in simulated intestinal fluid.