Formation of long-term stable amorphous ibuprofen nanoparticles via antisolvent melt precipitation (AMP).

Antisolvent precipitation of poorly water-soluble drugs is a promising formulation technique to synthesize amorphous nanoparticles. The dissolution behavior of these nanoparticles is improved because of the high specific surface area and the amorphous state, leading to an enhanced bioavailability of the drug molecules. Nevertheless, stabilization of precipitated drug nanoparticles against agglomeration and recrystallization, which constitutes a key issue for further processing steps, has turned out to be a major challenge. For that reason, the present study presents a synthesis method to produce long-term stable amorphous ibuprofen nanoparticles via antisolvent precipitation. To reach this goal, a new precipitation method was developed: antisolvent melt precipitation (AMP). Formulation strategies (e.g. varying fraction of stabilizer) as well as process parameters (e.g. temperature) were under study to estimate their influence on particle size, size distribution, crystallinity, morphology and stability of synthesized drug nanoparticles.

Chemical Cross-Linking of Anatase Nanoparticle Thin Films for Enhanced Mechanical Properties.

Titania nanoparticle-based thin films are highly attractive for a vast range of commercial applications. Although their application on polymer-based substrates is particularly appealing, the requirement of low process temperatures results in low mechanical stability. Highly crystalline anatase nanoparticles were used as the building blocks for coatings through a two-stage process. The main benefits of this method, over the more common sol-gel ones, are the relatively low temperature required for the production of metal oxide coatings, allowing the use of polymer-based substrates, and the defined crystallinity of the resulting thin films. Although in several cases moderate temperatures can be utilized for drying the films, the mechanical stability of the respective coatings remains a critical issue. In this contribution, we present a strategy to achieve network formation between TiO2 nanoparticles in a preformed thin film on the basis of the cross-linking of the functionalized nanoparticles. In the first stage, the nanoparticles were functionalized by dicarboxylic acids, concurrently leading to a stable colloidal dispersion that could be utilized for dip-coating to obtain TiO2 thin films with high homogeneity and optical transparence. During the second stage, the films were immersed in a solution of a diamine as the linker molecule, to achieve cross-linking between the nanoparticles within the film. It is demonstrated that indeed covalent bonding was realized and functional coatings with significantly enhanced mechanical properties were obtained by our strategy.

Mechanical characterization of yeast cells: effects of growth conditions.

UNLABELLED: Industrial biotechnology uses microbiological cells to produce a wide range of products. While the organisms in question are well understood regarding their genetic and molecular properties, less is known about their mechanical properties. Previous work has established a testing procedure for single Saccharomyces cerevisiae cells using a Nanoindenter equipped with a Flat Punch probe, allowing the compression between two parallel surfaces. The resulting force-displacement curves clearly showed the bursting of the cells and served to determine characteristic values such as the bursting force, bursting energy and relative deformation. This study examined the mechanical characteristics of yeast cells under the influence of varying cultivation parameters, namely the pH value, temperature, aeration rate, stirrer speed and culture medium composition. It was observed that only temperature and medium composition showed significant effect on the mechanical properties of the cells. Higher temperatures during cultivation caused lower bursting forces and energies. Further analysis of the data showed that the mechanical characteristics of the cells were only influenced by parameters which also had an influence on the growth rate. In conclusion, higher growth rates result in a lower mechanical strength of the yeast cells. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides data on the influence of growth conditions on the mechanical properties of yeast cells. Single cell compression tests on Saccharomyces cerevisiae cells indicate that higher growth rates result in a lower mechanical strength of the cells. As in biotechnological processes mechanical degradation is often part of the downstream process to release the product from the micro-organisms, the knowledge about the mechanical properties of the cells is relevant for process optimization.

Process parameter dependent growth phenomena of naproxen nanosuspension manufactured by wet media milling.

The production of nanosuspensions has proved to be an effective method for overcoming bioavailability challenges of poorly water soluble drugs. Wet milling in stirred media mills and planetary ball mills has become an established top-down-method for producing such drug nanosuspensions. The quality of the resulting nanosuspension is determined by the stability against agglomeration on the one hand, and the process parameters of the mill on the other hand. In order to understand the occurring dependencies, a detailed screening study, not only on adequate stabilizers, but also on their optimum concentration was carried out for the active pharmaceutical ingredient (API) naproxen in a planetary ball mill. The type and concentration of the stabilizer had a pronounced influence on the minimum particle size obtained. With the best formulation the influence of the relevant process parameters on product quality was investigated to determine the grinding limit of naproxen. Besides the well known phenomenon of particle agglomeration, actual naproxen crystal growth and morphology alterations occurred during the process which has not been observed before. It was shown that, by adjusting the process parameters, those effects could be reduced or eliminated. Thus, besides real grinding and agglomeration a process parameter dependent ripening of the naproxen particles was identified to be a concurrent effect during the naproxen fine grinding process.

Physicochemical characterization of sildenafil-loaded solid lipid nanoparticle dispersions (SLN) for pulmonary application.

For the development of any colloidal system, thorough characterization is extremely essential. This article discusses the physicochemical characterization of sildenafil-loaded solid lipid nanoparticle dispersions (SLN) including stability analysis over 6 months time period for possible pulmonary administration for the treatment of pulmonary arterial hypertension (PAH). SLN consisting of phospholipid and triglycerides were manufactured using a novel microchannel homogenization method. These sildenafil-loaded SLN were then subjected to physicochemical characterization namely, particle size and distribution over shelf life, differential scanning calorimetry (DSC), wide angle X-ray diffraction (WAXD) and analysis of nebulization performance of these SLN by the means of next generation impactor (NGI). Additionally, the morphology of nebulized particles was assessed by transmission electron microscopy using negative staining technique. The solubility of sildenafil citrate and base in the lipid matrix was determined and was 0.1% w/w and 1% w/w, respectively. From the particle size measurements, it was observed that SLN without sildenafil demonstrated consistent particle sizes over 6 months. For the sildenafil-loaded SLN, increased particle sizes were found after manufacturing and further increased within weeks. From WAXD studies, after 6 months high intensity reflections corresponding to the stable ß modification were observed. From DSC results, the peak minimum temperatures increased upon storage, hinting at a transformation to the stable ß modification of triglycerides in the case of sildenafil-loaded SLN. Hence, it can be concluded that even small drug concentration influences particle size and stability.

In vitro and ex vivo toxicological testing of sildenafil-loaded solid lipid nanoparticles.

The aim of this study was to investigate the potential cytotoxicity of solid lipid nanoparticles (SLN) loaded with sildenafil. The SLNs were tested as a new drug delivery system (DDS) for the inhalable treatment of pulmonary hypertension in human lungs. Solubility of sildenafil in SLN lipid matrix (30:70 phospholipid:triglyceride) was determined to 1% sildenafil base and 0.1% sildenafil citrate, respectively. Sildenafil-loaded SLN with particle size of approximately 180 nm and monomodal particle size distribution were successfully manufactured using a novel microchannel homogenization method and were stable up to three months. Sildenafil-loaded SLN were then used in in vitro and ex vivo models representing lung and heart tissue. For in vitro models, human alveolar epithelial cell line (A459) and mouse heart endothelium cell line (MHEC5-T) were used. For ex vivo models, rat precision cut lung slices (PCLS) and rat heart slices (PCHS) were used. All the models were treated with plain SLN and sildenafil-loaded SLN in a concentration range of 0-5000 µg/ml of lipid matrix. The toxicity was evaluated in vitro and ex vivo by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Median lethal dose 50% (LD50) values for A549 cells and PCLS were found to be in the range of 1200-1900 µg/ml while for MHEC5-T cells and precision cut heart slices values were found between 1500 and 2800 µg/ml. PCHS showed slightly higher LD50 values in comparison to PCLS. Considering the toxicological aspects, sildenafil-loaded SLN could have potential in the treatment of pulmonary hypertension via inhalation route.

Influence of pyrogenic particles on the micromechanical behavior of thin sol-gel layers.

Coatings based on sol-gel technology with different types of nanoparticles embedded into the sol-gel matrix were fabricated, and the resulting properties were investigated. Pyrogenic silica nanoparticles were added to the sol before coating. The silica particles varied in primary particle size and agglomerate size, and in their surface modification. The particles were wetted in ethanol and dispersed to certain finenesses. The difference in agglomerate size was partly caused by varying particle types, but also by the dispersing processes that were applied to the particles. The resulting coatings were examined by visual appearance and SEM microscopy. Furthermore, their micromechanical properties were determined by nanoindentation. The results show an important influence from the added nanoparticles and their properties on the visual appearance as well as the micromechanical behavior of the sol-gel coatings. It is shown that, in fact, the particle size distribution can have a major impact on the coating properties as well as the surface modification.