Mechanistic Modeling of Wet Stirred Media Milling for Production of Drug Nanosuspensions.

Drug nanocrystals have been used for a wide range of drug delivery platforms in the pharmaceutical industry, especially for bioavailability enhancement of poorly water-soluble drugs. Wet stirred media milling (WSMM) is the most widely used process for producing dense, stable suspensions of drug nanoparticles, also referred to as nanosuspensions. Despite a plethora of review papers on the production and applications of drug nanosuspensions, modeling of WSMM has not been thoroughly covered in any review paper before. The aim of this review paper is to briefly expose the pharmaceutical scientists and engineers to various modeling approaches, mostly mechanistic, including computational fluid dynamics (CFD), discrete element method (DEM), population balance modeling (PBM), coupled methods, the stress intensity-number model (SI-SN model), and the microhydrodynamic (MHD) model with a main focus on the MHD model for studying the WSMM process. A total of 71 studies, 30 on drugs and 41 on other materials, were reviewed. Analysis of the pharmaceutics literature reveals that WSMM modeling is largely based on empirical, statistically based modeling approaches, and mechanistic modeling could help pharmaceutical engineers develop a fundamental process understanding. After a review of the salient features and various pros-cons of each modeling approach, recent advances in microhydrodynamic modeling and process insights gained therefrom were highlighted. The SI-SN and MHD models were analyzed and critiqued objectively. Finally, the review points out potential research directions such as more mechanistic and accurate CFD-DEM-PBM simulations and the coupling of the MHD-PBM models with the CFD.

Convective Drying Kinetics of Polymer Strip Films Loaded with a BCS Class II Drug.

Polymer strip film is a promising dosage form for oral delivery of poorly water-soluble drugs. Drying is an important step in the production of polymer strip films with significant effects on critical quality attributes (CQAs). In this study, a custom-made batch drying setup was used to study convective drying kinetics of wet polymer strip films loaded with dry-coated micronized griseofulvin (GF) at various drying conditions. A rate-based semi-empirical model was formulated and parameters were estimated by integral method of analysis using a coupled optimizer-ordinary differential equation solver. Despite its simplicity with three parameters, the model could fit the experimental data very well for all drying conditions, which enabled us to examine the effects of air velocity, temperature, and initial wet film thickness on drying kinetics quantitatively. The modeling results clearly delineate a drying mechanism with constant-rate and falling-rate periods. One set of kinetic parameter estimates reasonably predicted the drying kinetics for two different wet film thicknesses in the selected process conditions, which demonstrates the predictive capability of the model. After reporting the limitations of the semi-empirical model, upon future modification and refinement, its potential use in drying process development and process control was highlighted.

Multi-faceted Characterization of Wet-milled Griseofulvin Nanosuspensions for Elucidation of Aggregation State and Stabilization Mechanisms.

Characterization of wet-milled drug suspensions containing neutral polymer-anionic surfactant as stabilizers poses unique challenges in terms of assessing the aggregation state and examining the stabilization mechanisms. Using a multi-faceted characterization method, this study aims to assess the aggregation state of wet-milled griseofulvin (GF) nanosuspensions and elucidate the stabilization mechanisms and impact of stabilizers. Two grades, SSL and L, of hydroxypropyl cellulose (HPC) with molecular weights of 40 and 140 kg/mol, respectively, were used as a neutral stabilizer at concentrations varying from 0 to 7.5% (w/w) without and with 0.05% (w/w) sodium dodecyl sulfate (SDS). The aggregation state was examined via laser diffraction, scanning electron microscope (SEM) imaging, and rheometry. Zeta potential, stabilizer adsorption, surface tension, and drug wettability were used to elucidate the stabilization mechanisms. The results suggest that deviation from a uni-modal PSD and pronounced pseudoplasticity with power-law index lower than one signify severe aggregation. Polymer or surfactant alone was not able to prevent GF nanoparticle aggregation, whereas HPC-SDS combination led to synergistic stabilization. The effect of polymer concentration was explained mainly by the stabilizer adsorption and partly by surface tension. The synergistic stabilization afforded by HPC-SDS, traditionally explained by electrosteric mechanism, was attributed to steric stabilization provided by HPC and enhanced GF wettability/reduced surface tension provided by SDS. Zeta potential results could not explain the mitigation of aggregation by HPC-SDS. Overall, this study has demonstrated that the elucidation of the complex effects of HPC-SDS on GF nanosuspension stability entails a multi-faceted and comprehensive characterization approach.

Quiescent and Agitated Redispersion as a Tool for Evaluating Dispersant Effectiveness in Dissolution Enhancement of Drug-Laden Nanocomposites.

Nanocomposite microparticles (NCMPs) have been used in various solid dosage forms with the goal of enhancing the dissolution rate and bioavailability of poorly water-soluble drugs. Nanoparticle recovery from NCMPs, i.e., redispersion, is the preliminary step in drug dissolution. This study aims at exploring aqueous redispersion of NCMPs with various dispersants under quiescent vs. agitated conditions as potential dispersant screening tool in the development of fast-dissolving NCMP formulations. NCMPs were prepared by coating wet-milled suspensions of a poorly water-soluble drug, griseofulvin (GF), formulated with the dispersants hydroxypropyl cellulose (HPC), sodium dodecyl sulfate (SDS), as-received/wet co-milled croscarmellose sodium (CCS), and mannitol, onto Pharmatose® carrier particles in a fluidized bed dryer. The NCMPs were added to quiescent water kept in a cuvette, and the redispersion was visualized and investigated by turbidimetry and dynamic light scattering. The morphological evolution of a single NCMP exposed to a drop of water was studied via optical microscopy, which provided further insight into the self-redispersibility. As a comparison, the NCMPs were also redispersed in water agitated by a paddle stirrer followed by centrifugation and drug assay of the resultant supernatant, which yielded the percentage of GF recovered as nanoparticles. Both quiescent and agitated redispersion methods yielded similar rank-ordering of the dispersants: NCMPs with either HPC/SDS or HPC/CCS exhibited effective nanoparticle recovery and fast dissolution, whereas those with HPC or HPC/mannitol led to poor redispersibility and slow dissolution. This study demonstrates that both quiescent and agitated redispersion tests could be used for screening/optimizing dispersants for fast-dissolving drug NCMP formulations.

Prevalence of tinea capitis in primary schools in Turkey.

The aim of our study was to determine the prevalence of tinea capitis in Middle Anatolia. Between February 2000 and April 2000, a school survey of 4760 primary school children was carried out and 34 cases of tinea capitis were clinically diagnosed. Sixteen (0.3%) of them were diagnosed both clinically and using culture. Eighteen cases (52.9%) were diagnosed microscopically whereas the remaining 16 cases (47.0%) had a clinical diagnose. We also isolated and identified the following species of fungi causing the infection: Trichophyton verrucosum (five cases), T. rubrum (three), T. mentagrophytes var. mentagrophytes (three), Microsporum canis (three) and T. tonsurans (two). We detected a higher rate of infection than that of the country's average.