• 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.
    • Itraconazole-HPMCAS amorphous spray dried dispersions: composition and process factors impacting performance

      Honick, Moshe Avraham; Polli, James E. (2019)
      Despite their potential for improving the oral bioavailability of poorly water soluble drugs, spray dried dispersions (SDDs) have properties that make them challenging to formulate. The objective of this dissertation was to elucidate composition and process factors for favorable SDD performance and to develop fast-, medium-, and slow-release formulations for an IVIVC study. Itraconazole (ITZ) was used as a model poorly soluble drug and hypromellose acetate succinate (HPMCAS) was used as a carrier polymer for the SDDs. Film casting proved to be a useful screening method for demonstrating the feasibility of producing amorphous SDDs of ITZ and HPMCAS as well as for rank ordering the grades of HPMCAS (i.e. HPMCAS-L > HPMCAS-M > HPMCAS-H) in terms of in-vitro dissolution performance. Producing solid oral dosage forms of ITZ-HPMCAS SDDs proved challenging due to the low particle size, poor flowability, and low bulk density of the SDDs. Initial tableting on a Natoli hand-operated press showed that drug release from tablets containing SDDs of ITZ and HPMCAS-L were very sensitive to small differences in compaction pressure and porosity. Interestingly, the same sensitivity was not observed in SDDs of ITZ and HPMCAS-M. Using a compaction simulator, reproducible fast-, medium- and slow-release tablet formulations of ITZ and HPMCAS SDDs was developed by varying polymer grade (HPMCAS-L, HPMCAS-M), slugging pressure (20, 40 MPa), and compaction pressure (70, 85, 100 MPa). The performance of SDDs was further evaluated by comparing the compaction behavior of ITZ-HPMCAS SDDs and physical mixtures of ITZ and HPMCAS. Although the compressibility of both the SDDs and physical mixtures were similar, the SDDs had a greater tendency to laminate, especially at higher compression speeds. Tablets of SDDs containing ITZ and HPMCAS-L were particularly prone to lamination compared to the SDDs containing HPMCAS-M or HPMCAS-H. Interestingly, when the SDDs were not laminated they had a greater tensile strength than tablets produced with the physical mixtures. In conclusion, there are significant challenges associated with formulating SDDs of ITZ and HPMCAS. In addition to elucidating composition and process factors impacting performance, fast-, medium-, and slow-release formulations for an IVIVC study were developed.