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Nanoparticles of BCS Class II drugs are produced in wet stirred media mills operating in batch or recirculation mode with the goal of resolving the poor water-solubility issue. Scant information is available regarding the continuous production of drug nanoparticles via wet media milling. Griseofulvin and Naproxen were milled in both recirculation mode and multi-pass continuous mode to study the breakage dynamics and to determine the effects of suspension flow rate. The evolution of the median particle size was measured and described by an empirical breakage model. We found that these two operation modes could produce drug nanosuspensions with similar particle size distributions (PSDs). A reduced suspension flow rate slowed the breakage rate and led to a wider PSD and more differentiation between the two operation modes. The latter part of this study focused on the roles of stabilizers (hydroxypropyl cellulose and sodium lauryl sulfate) and elucidation of the so-called Rehbinder effect (reduction in particle strength due to adsorbed stabilizers such as polymers and surfactants). Milling the drugs in the absence of the stabilizers produced primary nanoparticles and their aggregates, while milling with the stabilizers produced smaller primary nanoparticles with minimal aggregation. Using laser diffraction, BET nitrogen adsorption, scanning electron microscopy imaging, and a microhydrodynamic analysis of milling, this study, for the first time, provides sufficient evidence for the existence of the Rehbinder effect during the milling of drugs. Not only do the polymers and surfactants allow proper stabilization of the nanoparticles in the suspensions, but they also do facilitate drug particle breakage.

Ensuring the physical stability of drug nanosuspensions prepared via wet media milling has been a challenge for pharmaceutical scientists. The aim of this study is to assess the combined use of non-ionic cellulosic polymers and anionic surfactants in stabilizing multiple drug nanosuspensions. Particle size of five drugs, i.e. azodicarbonamide (AZD), fenofibrate (FNB), griseofulvin (GF), ibuprofen (IBU) and phenylbutazone (PB) was reduced separately in an aqueous solution of hydroxypropyl cellulose (HPC) with/without sodium dodecyl sulfate (SDS) via a stirred media mill. Laser diffraction, scanning electron microscopy, thermal analysis, rheometry and electrophoresis were used to evaluate the breakage kinetics, storage stability, electrostatic repulsion and stabilizer adsorption. Without SDS, drug particles exhibited aggregation to different extents; FNB and GF particles aggregated the most due to low zeta potential and insufficient steric stabilization. Although aggregation in all milled suspensions was reduced due to HPC-SDS combination, FNB and IBU showed notable growth during 7-day storage. It is concluded that the combination of non-ionic cellulosic polymers and anionic surfactants is generally viable for ensuring the physical stability of wet-milled drug nanosuspensions, provided that the surfactant concentration is optimized to mitigate the Ostwald ripening, whereas cellulosic polymers alone may provide stability for some drug suspensions.

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The advantages of using superdisintegrants, sodium starch glycolate (SSG), croscarmellose sodium (CCS) and crospovidone (CP) over traditional high molecular weight (MW) viscosity enhancing agents, guar gum (GG), xanthan gum (XG), pectin and high MW HPMC are examined for improving drug content uniformity without compromising dissolution of films containing nanoparticles of griseofulvin (GF), used as a model poorly water-soluble drug. Films were fabricated by preparing low MW HPMC solutions to which a fixed amount of viscosity enhancing agents were added and mixed with GF nanosuspensions produced via wet milling, followed by casting and drying. The addition of superdisintegrants and high MW HPMC, led to an increase in viscosity of precursor suspensions without GF particle aggregation, and hence excellent drug content uniformity along with retention of the high surface area of the GF nanoparticles in dried films. In contrast, addition of XG and pectin resulted in aggregation of GF particles in suspensions, leading to poor content uniformity and incomplete recovery of GF nanoparticles upon redispersion of dried films. In spite of their high precursor viscosity, the films containing superdisintegrants did not lead to increased mechanical strength and demonstrated fast drug release, suggesting faster matrix erosion. In contrast, films with high MW polymers (GG, XG, and pectin and high MW HPMC) had increased mechanical strength and their subsequent slow erosion/disintegration along with longer hydration times resulted in significant delay of drug release, which was found to be directly proportional to their MW. These results demonstrate novel use for superdisintegrants as economical and superior alternative to traditional viscosity enhancing agents in forming drug laden biocompatible polymer films.