A real-time and modular approach for quick detection and mechanism exploration of DPIs with different carrier particle sizes.

Dry powder inhalers (DPIs) had been widely used in lung diseases on account of direct pulmonary delivery, good drug stability and satisfactory patient compliance. However, an indistinct understanding of pulmonary delivery processes (PDPs) hindered the development of DPIs. Most current evaluation methods explored the PDPs with over-simplified models, leading to uncompleted investigations of the whole or partial PDPs. In the present research, an innovative modular process analysis platform (MPAP) was applied to investigate the detailed mechanisms of each PDP of DPIs with different carrier particle sizes (CPS). The MPAP was composed of a laser particle size analyzer, an inhaler device, an artificial throat and a pre-separator, to investigate the fluidization and dispersion, transportation, detachment and deposition process of DPIs. The release profiles of drug, drug aggregation and carrier were monitored in real-time. The influence of CPS on PDPs and corresponding mechanisms were explored. The powder properties of the carriers were investigated by the optical profiler and Freeman Technology four powder rheometer. The next generation impactor was employed to explore the aerosolization performance of DPIs. The novel MPAP was successfully applied in exploring the comprehensive mechanism of PDPs, which had enormous potential to be used to investigate and develop DPIs.

Compression of amorphous solid dispersions prepared by hot-melt extrusion, spray drying and vacuum drum drying.

The present study explored vacuum drum drying (VDD) as an alternative technology for amorphous solid dispersions (ASDs) manufacture compared to hot-melt extrusion (HME) and spray drying (SD) focusing on downstream processability (powder properties, compression behavior and tablet performance). Ritonavir (15% w/w) in a copovidone/sorbitan monolaurate matrix was used as ASD model system. The pure ASDs and respective tablet blends (TB) (addition of filler, glidant, lubricant) were investigated. Milled extrudate showed superior powder properties (e.g., flowability, bulk density) compared to VDD and SD, which could be compensated by the addition of 12.9% outer phase. Advantageously, the VDD intermediate was directly compressible, whereas the SD material was not, resulting in tablets with defects based on a high degree of elastic recovery. Compared to HME, the VDD material showed superior tabletability when formulated as TB, resulting in stronger compacts at even lower solid fraction values. Despite the differences in tablet processing, tablets showed similar tablet performance in terms of disintegration and dissolution independent of the ASD origin. In conclusion, VDD is a valid alternative to manufacture ASDs. VDD offered advantageous downstream processability compared to SD: less solvents and process steps required (no second drying), improved powder properties and suitable for direct compression.

Continuous twin screw granulation: Impact of microcrystalline cellulose batch-to-batch variability during granulation and drying - A QbD approach.

Despite significant advances in the research domain of continuous twin screw granulation, limited information is currently available on the impact of raw material properties, especially considering batch-to-batch variability. The importance of raw material variability and subsequent mitigation of the impact of this variability on the manufacturing process and drug product was recently stressed in the Draft Guidance for Industry on Quality Considerations for Continuous Manufacturing by the U.S. Food and Drug Administration (FDA). Therefore, this study assessed the impact of microcrystalline cellulose (MCC) batch-to-batch variability and process settings in a continuous twin screw wet granulation and semi-continuous drying line. Based on extensive raw material characterization and subsequent principal component analysis, raw material variability was quantitatively introduced in the design of experiments approach by means of t1 and t2 scores. L/S ratio had a larger effect on critical granule attributes and processability than screw speed and drying time. A large impact of the t1 and t2 scores was found, indicating the importance of raw material attributes. For the studied formulation, it was concluded that MCC batches with a low water binding capacity, low moisture content and high bulk density generated granules with the most desirable quality attributes. Additionally, an innovative and quantitative approach towards mitigating batch-to-batch variability of raw materials was proposed, which is also applicable for additional excipients and APIs.

Soil degradation and recovery - Changes in organic matter fractions and structural stability.

The combination of concurrent soil degradation and restoration scenarios in a long-term experiment with contrasting treatments under steady-state conditions, similar soil texture and climate make the Highfield land-use change experiment at Rothamsted Research unique. We used soil from this experiment to quantify rates of change in organic matter (OM) fractions and soil structural stability (SSS) six years after the management changed. Soil degradation included the conversion of grassland to arable and bare fallow management, while soil restoration comprised introduction of grassland in arable and bare fallow soil. Soils were tested for clay dispersibility measured on two macro-aggregate sizes (DispClay 1-2 mm and DispClay 8-16 mm) and clay-SOM disintegration (DI, the ratio between clay particles retrieved without and with SOM removal). The SSS tests were related to soil organic carbon (SOC), permanganate oxidizable C (POXC) and hot water-extractable C (HWC). The decrease in SOC after termination of grassland was greater than the increase in SOC when introducing grassland. In contrast, it was faster to restore degraded soil than to degrade grassland soil with respect to SSS at macro-aggregate scale. The effect of management changes was more pronounced for 8-16 mm than 1-2 mm aggregates indicating a larger sensitivity towards tillage-induced breakdown of binding agents in larger aggregates. At microscale, SSS depended on SOC content regardless of management. Soil management affected macroscale structural stability beyond what is revealed from measuring changes in OM fractions, underlining the need to include both bonding and binding mechanisms in the interpretation of changes in SSS induced by management.

Silver-modified octahedral anatase particles as plasmonic photocatalyst.

Octahedral anatase particles (OAPs) were modified with silver nanoparticles (NPs) by photodeposition method. The properties of OAPs influenced the properties of silver deposits, and thus the photocatalytic activity of the obtained silver-modified OAPs. Photocatalytic activities were tested under UV and vis irradiation for oxidative decomposition of acetic acid and oxidation of 2-propanol, respectively. The properties of silver-modified OAPs were investigated by XRD, STEM, DRS, XPS and time-resolved microwave conductivity (TRMC) method. It was found that electron traps (ETs) worked as nucleation sites for silver, resulting in formation of smaller silver NPs on smaller OAPs with larger content of ETs. The modification with silver resulted in enhanced photocatalytic activity under both UV and vis irradiation. It was found that larger crystallite size of silver NPs, and thus larger polydispersity of silver deposits resulted in broad and intense plasmon resonance peak causing enhanced visible activity. The correlation between photocatalytic activity and TRMC data, e.g., slower decay of TRMC signal for more active samples, allowed discussion on property-governed photocatalytic activities of silver-modified titania.

Toxicity determinants of multi-walled carbon nanotubes: The relationship between functionalization and agglomeration.

The elucidation of toxicity determinants of multi-walled carbon nanotubes (MWCNT) is still incomplete. Functionalization with carboxyl groups is, however, commonly used to mitigate MWCNT toxicity, although the rationale for the mitigating effect has not been fully clarified yet. In this work, two optimized chemical vapor deposition methods were employed to obtain MWCNT of comparable length but different diameter, which were subsequently functionalized. For MWCNT of diameter larger than 40 nm, no detrimental effects on cell viability of macrophages were observed, while mild cytotoxicity was recorded for diameters between 15 and 40 nm, with a mitigating effect of functionalization. To investigate the factors responsible for the mitigation, we used the thinnest MWCNT preparation on different cell models, evaluating several endpoints, such as viability, production of nitric oxide (NO), expression of pro-inflammatory markers, the Trans-Epithelial Electrical Resistance (TEER), and clonogenic activity. Substantial mitigation of the changes caused by pristine MWCNT was observed not only with carboxyl- but also with amino-functionalized MWCNT, suggesting that negative or positive surface charge was not the main factor responsible for the effect. Instead, either functionalized preparation exhibited a stronger tendency to agglomerate that was strictly dependent on the presence of proteins. Moreover, we found that either carboxyl- or amino-functionalized MWCNT adsorbed a larger amount of serum proteins than pristine counterparts, with a distinctive pattern for each type of MWCNT. We propose, therefore, that the formation of larger agglomerates, dependent upon different protein coronae, contributes to mitigate the biological effects of functionalized MWCNT in protein-rich biological media.