267121 Wet-Media Milling of Colloidal Drug Suspensions Stabilized by Means of Charged Nanoparticles
Tailoring poorly water-soluble drugs into products with colloidal drug particle size is a proven formulation approach to improve general issues in drug delivery . Colloidal drugs are often produced by wet-media milling technology, due to the availability from pre-clinical to production scale, reliable up-scaling and regulatory acceptance . Colloidal drug suspensions obtained by wet-media milling can be converted by suitable techniques into regular drug products, e.g., tablets and injectables. Stabilization of colloidal drug suspensions is provided by steric and/or electrostatic stabilization using polymers and/or surfactants [2, 3]. Beside these conventional stabilization mechanisms, colloidal particles can be also stabilized by charged nanoparticles providing high electrical charge to the otherwise negligibly charged colloidal particles [4, 5].
We investigated the stabilization of colloidal drug particles by charged nanoparticles in order to explore the mechanism of nanoparticle-stabilized colloids as a complementary method compared to conventional stabilization mechanisms. The stabilization mechanism was investigated with the simultaneous size reduction of drug particles by wet-media milling. Aqueous colloidal drug suspensions were produced for a poorly water-soluble drug compound with constant process parameters, pH and content of a non-ionic polymer to facilitate wetting of the hydrophobic drug compound. Stabilization of colloidal drug particles was investigated for positively and negatively surface functionalized charged nanoparticles from silica and polystyrene. Particle size and shape was characterized by dynamic light scattering (DLS) and scanning electron microscopy (SEM). Stabilization of colloidal drug suspensions was characterized without further preparation by rotational and oscillational rheometry. The structural arrangement of charged nanoparticles in relation to colloidal drug particles was determined by cryo transmission electron microscopy (cryo-TEM).
Colloidal drug particle size and shape were identified for all compositions investigated with comparable characteristics. Hence, stabilization of colloidal drug suspensions is obviously determined by the charged nanoparticles for the compositions investigated. Through variations in nanoparticulate matter, size, sign of charge and concentration, colloidal drug suspensions with pronounced stability were produced, in contrast to a strongly agglomerated colloidal drug suspension in gel state without addition of charged nanoparticles. Upon addition of negatively charged polystyrene nanoparticles up to a lower critical concentration, stabilization of negligible charged drug colloids is facilitated into liquid state and almost Newtonian shear behavior. A further increase in nanoparticle concentration resulted in pronounced stability of the colloidal drug suspension without any detectable thixotropy. Interestingly, the lower critical nanoparticle concentration to facilitate drug colloid stabilization is in good agreement with the results obtained by Chan and Lewis  for binary mixtures of negligibly charged colloidal silica stabilized by charged polystyrene nanoparticles. In contrast to Chan and Lewis  and Zhang et al. , we have identified no preferred enrichment of charged nanoparticles near colloidal drug particles for a suspension that undergoes pronounced stabilization.
We have demonstrated the successful application of charged nanoparticles to facilitate stabilization of a colloidal drug compound produced by an industrial relevant production technology. The application of charged nanoparticles can potentially replace conventional molecularly dissolved ionic stabilizers and opens up new opportunities in drug colloid stabilization without need for drug specific anchor segments.
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 Bhakay A, Merwade M, Bilgili E, Dave RN, Drug Dev Ind Pharm 37 (2011) 963-976.
 Tohver V, Smay JE, Braem A, Braun PV, Lewis JA, Proc Nat Acad Sci 98 (2001) 8950-8954.
 Chan AT, Lewis JA, Langmuir 24 (2008) 11399-11405.
 Zhang F, Long GG, Jemian PR, Ilavsky J, Milam VT, Lewis JA, Langmuir 24 (2008) 6504-6508.
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