An experimental investigation of temperature rise during compaction of pharmaceutical powders.

During pharmaceutical powder compaction, temperature rise in the compressed powder can affect physiochemical properties of the powder, such as thermal degradation and change in crystallinity. Thus, it is of practical importance to understand the effect of process conditions and material properties on the thermal response of pharmaceutical formulations during compaction. The aim of this study was to examine the temperature rise of pharmaceutical powders during tableting, in particular, to explore how the temperature rise depends on material properties, compression speed and tablet shape. Three grades of microcrystalline cellulose (MCC) were considered: MCC Avicel pH 101, MCC Avicel pH 102 and MCC DG. These powders were compressed using a compaction simulator at various compaction speeds (10-500mm/s). Flat faced, shallow convex and normal convex tablets were produced and temperature distributions on the surface of theses tablets upon ejection were examined using an infrared thermoviewer. It was found that an increase in the compaction speed led to an increase in the average surface temperature. A higher surface temperature was induced when the powder was compressed into a tablet with larger surface curvature. This was primarily due to the increasing degree of powder deformation (i.e. the volume reduction) and the effect of interparticule/wall friction.

A novel use of friability testing for characterising ribbon milling behaviour.

Dry granulation using roll compaction (DGRC) has been increasingly adopted in the pharmaceutical industry due to its unique advantage of not requiring liquid binder and a subsequent drying process. However the DGRC process presents also some challenges, in particular, a high fine fraction generated during the milling stage significantly limits its application. Although the fines produced can be recycled in practice, it may lead to poor content uniformity of the final product. At present there is a lack of mechanistic understanding of milling of roll compacted ribbons. For instance, it is not clear how fines are generated, what are the dominant mechanisms and controlling attributes and whether any measurement technique can be used to characterise ribbon milling behaviour. Therefore, the aim of this paper was to assess whether ribbon milling behaviour can be assessed using some characterisation methods. For this purpose, friability was evaluated for ribbons made of microcrystalline cellulose (MCC) powders using a friability tester that was originally developed for characterising the tendency of pharmaceutical tablets to generate small pieces while being abraded. Granules were also produced by milling of the ribbons and their size distributions were measured. The correlation between the fine fraction of the granules with ribbon friability was then explored. It was found that there was a strong correlation between ribbon friability and the fine fraction of granules generated during milling. This implies that friability tests can be performed to characterise ribbon milling behaviour, and ribbon friability provides a good indication of the fraction of fines generated during ribbon milling.

The amide III vibrational circular dichroism band as a probe to detect conformational preferences of alanine dipeptide in water.

The conformational preferences of blocked alanine dipeptide (ADP), Ac-Ala-NHMe, in aqueous solution were studied using vibrational circular dichroism (VCD) together with density functional theory (DFT) calculations. DFT calculations of three most representative conformations of ADP surrounded by six explicit water molecules immersed in a dielectric continuum have proven high sensitivity of amide III VCD band shape that is characteristic for each conformation of the peptide backbone. The polyproline II (PII ) and αR conformation of ADP are associated with a positive VCD band while ß conformation has a negative VCD band in amide III region. Knowing this spectral characteristic of each conformation allows us to assign the experimental amide III VCD spectrum of ADP. Moreover, the amide III region of the VCD spectrum was used to determine the relative populations of conformations of ADP in water. Based on the interpretation of the amide III region of VCD spectrum we have shown that dominant conformation of ADP in water is PII which is stabilized by hydrogen bonded water molecules between CO and NH groups on the peptide backbone.

The structure of poly-L-lysine in different solvents.

Understanding the factors that affect the conformational stability of the polypeptide main chain provides insight not only into the molecular basis of unfolded states but also into the earliest event that occurs during the protein folding. The presented study was concentrated on finding the conformational distributions of poly-L-lysine (PLL) by applying infrared spectroscopy. We assigned the amide bands for different conformations of PLL in water. At low pH values PLL mainly possesses the PII and ß structures while at higher pH values and low temperatures characteristic bands for the α-helical conformation are found. The increase in temperature induces the formation of ß structures. The obtained assignment of the infrared bands for various conformations was used to determine the conformational populations of PLL in non-aqueous solvents. In TFE, PLL possesses an α-helix structure that is after heating partially transformed into the PII conformation. DMSO enables a uniform α-helical conformation of PLL. A similar uniform conformation (PII, 88%) was found for PLL dissolved in ethylene glycol, suggesting that the PII structure is not limited to the presence of water molecules or charged side chains. The role of intermolecular interactions between the solvent molecules and PLL in stabilizing the PII conformation is discussed.

Mechanisms of amyloid fibril formation--focus on domain-swapping.

Conformational diseases constitute a group of heterologous disorders in which a constituent host protein undergoes changes in conformation, leading to aggregation and deposition. To understand the molecular mechanisms of the process of amyloid fibril formation, numerous in vitro and in vivo studies, including model and pathologically relevant proteins, have been performed. Understanding the molecular details of these processes is of major importance to understand neurodegenerative diseases and could contribute to more effective therapies. Many models have been proposed to describe the mechanism by which proteins undergo ordered aggregation into amyloid fibrils. We classify these as: (a) templating and nucleation; (b) linear, colloid-like assembly of spherical oligomers; and (c) domain-swapping. In this review, we stress the role of domain-swapping and discuss the role of proline switches.