455945 Elucidating the Physical Stability of Griseofulvin Nanosuspensions Via Combined Use of Surface Charge, Stabilizer Adsorption, and Wettability Measurements

Thursday, November 17, 2016: 4:35 PM
Peninsula (Hotel Nikko San Francisco)
Ecevit Bilgili, Otto H. York Department of Chemical Biological and Pharmaceutical Engineering, New Jersey Institute of Technology, Newark, NJ, Meng Li, Chemical, Biological, and Pharmaceutical Engineering, New Jersey Institute of Technology, Newark, NJ, Paulina Alvarez, Chemical, Biological and Pharmaceutical Engineering, New Jersey Institute of Technology, Newark, NJ and Paul Orbe, Union City High School Academy for Enrichment & Advancement, Union City, NJ

Almost 40% of the new chemical entities in drug pipeline of pharmaceutical companies have low aqueous solubility, which leads to poor bioavailability. Reduction of drug particle size down to nano-scale via wet stirred media milling (WSMM) has been an effective way for increasing the dissolution rate of poorly water-soluble drugs and thus their bioavailability. A major challenge for formulators has been to stabilize milled suspensions as drug nanoparticles are prone to aggregation and size-growth. Polymers and surfactants either alone or in combination have been used to ensure physical stability of the nanosuspensions. Selection of proper stabilizers and their optimum concentration plays a major role in formulating a stable drug nanosuspension. It is generally agreed that inadequate concentration of stabilizers cannot suppress drug nanoparticle aggregation, while their excess may promote Ostwald ripening. In this study, multiple characterization techniques were used to elucidate the impact of presence of an anionic surfactant and polymer concentration–molecular weight (MW) on the stability of drug suspensions. Particles of griseofulvin (GF), which is a poorly water-soluble drug, were wet media-milled with various polymer–surfactant formulations. Two grades of hydroxypropyl cellulose (HPC) with different MWs (i.e. ~40 and 140 kDa) were used as stabilizers from 0–7.5% (w/w) with/without 0.05% (w/w) sodium dodecyl sulfate (SDS). As a novelty of current work, rheometry with a power-law rheological model was used along with laser diffraction (LD) and scanning electron microscopy (SEM) data to assess the aggregation state of the milled drug suspensions. Moreover, complementary characterization methods such as stabilizer adsorption, electrophoresis–zeta potential, and wettability tests were used to explain the physical stability of the suspensions. We found that for a drug nanosuspension stabilized sterically or electrosterically, zeta potential measurements could be misleading, while polymer adsorption and wettability enhancements could better explain the observed physical stability. This study demonstrates the need for multiple characterization techniques to elucidate the complex and elusive nature of the physical stability of drug nanosuspensions.

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