Title

Effect of process parameters and the role of stabilizers in nanosuspension stability

Date of Completion

January 2009

Keywords

Health Sciences, Pharmacy

Degree

Ph.D.

Abstract

Poorly water soluble compounds are formulated as nanosuspensions to achieve increased bioavailability, faster onset of action, reduced food effects and decreased side effects. Nanosuspensions offer all these advantages due to their small size and high surface area and therefore, it is critical that the particles are maintained in an unaggregated state. Stabilizers play an important role in the creation of nanosuspensions and preservation of their functionality (thorough prevention of particle growth). In addition, processing conditions can also influence the physical stability of nanosuspensions. In this research, the effect of various factors; preparation method, processing conditions, stabilizer type and drug stabilizer ratio, on the preparation and stability of nanosuspensions was investigated. Furthermore, as stabilizers constitute an important component of these formulations drug:stabilizer interactions were also investigated through a novel atomic force microscopy method. ^ To investigate the effect of the preparation method on the formation and stability of nanosuspensions, ibuprofen nanosuspensions were prepared with various stabilizers using two different techniques: microfluidization (top-down approach); and precipitation (bottom-up approach). The formulations were characterized for particle size and zeta potential. The trends in the initial particle size and short-term stability profile of suspensions prepared with various stabilizers were similar for both processes. HPMC's were the most effective stabilizers, in achieving both small particle size and short term stability. The superior stabilization efficacy of HPMCs, compared to other non-ionic stabilizers, was attributed to the increased adsorption of the HPMC molecules onto the nanoparticles. Direct evidence of higher surface coverage of ibuprofen nanoparticles with HPMC's was obtained using a novel atomic force microscopy (AFM) method. Ibuprofen pellets with extremely smooth surfaces were obtained by compressing the drug powder between two mica sheets in a die using Carver press. AFM images clearly showed the superior adsorption characteristics (extent and pattern) of the HPMC layer, compared to PVP and poloxamers. This method provided a unique tool to investigate drug:stabilizer interactions to facilitate nanosuspension stabilizer selection. ^ A half five factorial design was used to investigate the effects of various processing and formulation variables on the preparation of indomethacin (model drug) nanosuspensions using microfluidization. Nanosuspensions were characterized for particle size, zeta potential and physical form of the drug. Critical parameters affecting the particle size obtained can be arranged in the following order of importance; milling time, microfluidization pressure, stabilizer type, temperature and stabilizer type. Various two way interactions affecting the process were also detected in this study. Stability studies of indomethacin nanosuspensions at elevated temperatures were conducted to determine the effect of stabilizer type (small molecule versus polymeric) and micellar solubilized drug on Ostwald ripening. No effect of micellar solubilized drug on Ostwald ripening was observed. The most likely mechanism for Ostwald ripening was determined to be surface nucleation, compared to the more common diffusion controlled mechanism. ^