Kees van der Voort Maarschalk

Inulin, a flexible oligosaccharide I: Review of its physicochemical characteristics

Inulin, a fructan-type polysaccharide, consists of (2→1) linked β-d-fructosyl residues (n=2-60), usually with an (1↔2) α-d-glucose end group. The applications of inulin and its hydrolyzed form oligofructose (n=2-10) are diverse. It is widely used in food industry to modify texture, replace fat or as low-calorie sweetener. Additionally, it has several applications in other fields like the pharmaceutical arena. Most notably it is used as a diagnostic agent for kidney function and as a protein stabilizer. This work reviews the physicochemical characteristics of inulin that make it such a versatile substance. Topics that are addressed include morphology (crystal morphology, crystal structure, structure in solution); solubility; rheology (viscosity, hydrodynamic shape, gelling); thermal characteristics and physical stability (glass transition temperature, vapor sorption, melting temperature) and chemical stability. When using inulin, the degree of polymerization and processing history should be taken into account, as they have a large impact on physicochemical behavior of inulin.

Granule characterization during fluid bed drying by development of a near infrared method to determine water content and median granule size

PurposeWater content and granule size are recognized as critical process and product quality parameters during drying. The purpose of this study was to enlighten the granule behavior during fluid bed drying by monitoring the major events i.e. changes in water content and granule size.MethodsNIR spectra collected during drying and water content of sampled granules were correlated by principal component analysis (PCA) and partial least squares regression (PLSR). NIR spectra of dried granules were correlated to median granule size in a second PCA and PLSR.ResultsThe NIR water model discriminates between various stages in fluid-bed drying. The water content can be continuously predicted with errors comparable to the reference method. The four PLS factors of the granule size model are related to primary particle size of lactose, median granule size exceeding primary particle size and amorphous content of granules. The small prediction errors enable size discrimination between fines and granules.ConclusionFor product quality reasons, discrimination between drying stages and end-point monitoring is highly important. Together with the possibilities to determine median granule size and to distinguish fines this approach provides a tool to design an optimal drying process.

Effect of water on deformation and bonding of pregelatinized starch compacts

This paper evaluates the tabletting process of pregelatinized starch with different moisture contents on the basis of the stress deformation curve. Simplification of the stress deformation curve enables the amount of elastically stored energy to be calculated. That stored energy, which is the driving force for relaxation of tablets, increases with compaction speed and decreases with increasing water activity of the material. This paper suggests a relation between absorbed water and stored energy. Interparticle bonding, however, also decreases with increasing amounts of adsorbed water. The decrease in stored energy with increasing water activity of the pregelatinized starch tends to produce stronger tablets at higher water activities, whereas the decrease of particle bonding with increasing water activity tends to produce weaker tablets at higher water activities. Given these two counteracting effects, the final tablet strength is a balance between viscoelasticity and bonding, resulting in a water activity where tablet strength has a maximum. In this case, the optimum water activity is about 0.70.

How sugars protect proteins in the solid state and during drying (review): Mechanisms of stabilization in relation to stress conditions

&NA; This review aims to provide an overview of current knowledge on stabilization of proteins by sugars in the solid state in relation to stress conditions commonly encountered during drying and storage. First protein degradation mechanisms in the solid state (i.e. physical and chemical degradation routes) and traditional theories regarding protein stabilization (vitrification and water replacement hypotheses) will be briefly discussed. Secondly, refinements to these theories, such as theories focusing on local mobility and protein‐sugar packing density, are reviewed in relationship to the traditional theories and their analogies are discussed. The last section relates these mechanistic insights to the stress conditions against which these sugars are used to provide protection (i.e. drying, temperature, and moisture). In summary sugars should be able to adequately form interactions with the protein during drying, thereby maintaining it in its native conformation and reducing both local and global mobility during storage. Generally smaller sugars (disaccharides) are better at forming these interactions and reducing local mobility as they are less inhibited by steric hindrance, whilst larger sugars can reduce global mobility more efficiently. The principles outlined here can aid in choosing a suitable sugar as stabilizer depending on the protein, formulation and storage condition‐specific dominant route of degradation. Graphical abstract Figure. No caption available.

A density-based segmentation for 3D images, an application for X-ray micro-tomography.

Density-based spatial clustering of applications with noise (DBSCAN) is an unsupervised classification algorithm which has been widely used in many areas with its simplicity and its ability to deal with hidden clusters of different sizes and shapes and with noise. However, the computational issue of the distance table and the non-stability in detecting the boundaries of adjacent clusters limit the application of the original algorithm to large datasets such as images. In this paper, the DBSCAN algorithm was revised and improved for image clustering and segmentation. The proposed clustering algorithm presents two major advantages over the original one. Firstly, the revised DBSCAN algorithm made it applicable for large 3D image dataset (often with millions of pixels) by using the coordinate system of the image data. Secondly, the revised algorithm solved the non-stability issue of boundary detection in the original DBSCAN. For broader applications, the image dataset can be ordinary 3D images or in general, it can also be a classification result of other type of image data e.g. a multivariate image.

The consequences of granulate heterogeneity towards breakage and attrition upon fluid-bed drying.

High-shear granulated lactose granulates were dried in a fluid-bed dryer at various conditions. Granules were characterized by water content and size analysis. It is shown that the drying process is very dynamic in terms of growth and breakage phenomena. Granular size heterogeneity, composition and water content determine the granule behavior upon drying. Large granules consist of small primary particles and contain more water than small granules that consist of large primary particles. This differentiates the drying rate and extent of size reduction of the different granule size classes. The results enable a critical evaluation of process control and process monitoring. Understanding of granule behavior and continuous monitoring of the fluid-bed drying process enables process and product optimization.

Location-Dependent Analysis of Porosity and Pore Direction in Tablets

PurposeSeveral phenomena in tablets indicate that an inhomogeneous pore distribution is formed during the compaction process. Examples are lamination and the capping of corners. In order to gain an understanding of the relation between structure and compact properties, analyzing the structure in a location dependent manner would be extremely useful. Our aim was to visualize and to quantitatively analyze the pore distribution in compacts.MethodsThis was done by embedding a cubic (sodium chloride) compact with polymer, allowing the compact to be cut without disrupting the structure. By doing so, it was possible to make scanning electron microscopic images from different angles at different locations in the compact. These images were made binary with a two-means cluster algorithm (Isodata) after which the porosity could be calculated. Counting the number of transitions from the pixels in the pores to the pixels in the sodium chloride particles in two perpendicular directions allows us to construct a measure for the anisotropic connectivity of the particles.ResultsThe results show an increase in porosity toward the bottom of the compact and showed a preferred orientation of the pores in the direction of compression.ConclusionsThe proposed method is suitable for analyzing the pore distribution quantitatively and for evaluating anisotropy.

In-line near infrared spectroscopy during freeze-drying as a tool to measure efficiency of hydrogen bond formation between protein and sugar, predictive of protein storage stability

Sugars are often used as stabilizers of protein formulations during freeze-drying. However, not all sugars are equally suitable for this purpose. Using in-line near-infrared spectroscopy during freeze-drying, it is shown here that hydrogen bond formation during freeze-drying, under secondary drying conditions in particular, can be related to the preservation of the functionality and structure of proteins during storage. The disaccharide trehalose was best capable of forming hydrogen bonds with the model protein, lactate dehydrogenase, thereby stabilizing it, followed by the molecularly flexible oligosaccharide inulin 4kDa. The molecularly rigid oligo- and polysaccharides dextran 5kDa and 70kDa, respectively, formed the least amount of hydrogen bonds and provided least stabilization of the protein. It is concluded that smaller and molecularly more flexible sugars are less affected by steric hindrance, allowing them to form more hydrogen bonds with the protein, thereby stabilizing it better.

Blending of agglomerates into powders 1: Quantification of abrasion rate

A very common situation in the pharmaceutical arena is that a small amount of cohesive drug substance needs to be distributed in a large bulk of free-flowing filler such as lactose. The key topic of attention is that aggregates of a cohesive drug substance need to be sufficiently broken up in an acceptable time-frame. This implies that there is need for a better mechanistic understanding of the blending process and the reduction in size of the aggregates. The purpose of this study is to obtain more insight in the mechanisms that lead to the break up of assemblies of powder particles in a moving powder bed. The break up of aggregates was studied by application of so-called brittle Calibrated Test Particles (bCTPs). These are well-defined aggregates with brittle fracture properties. The dominant mechanism of the break up of these aggregates is abrasion by multiple impacts. There is evidence of a relationship between strength (expressed as porosity) of the bCTPs and rate of abrasion. This is often a slow process and the rate is determined not only by the (mechanical) properties of the agglomerates and process conditions, but also by the particle size distribution of the bulk filler.

Kinetic energy density and agglomerate abrasion rate during blending of agglomerates into powders

Problems related to the blending of a cohesive powder with a free flowing bulk powder are frequently encountered in the pharmaceutical industry. The cohesive powder often forms lumps or agglomerates which are not dispersed during the mixing process and are therefore detrimental to blend uniformity. Achieving sufficient blend uniformity requires that the blending conditions are able to break up agglomerates, which is often an abrasion process. This study was based on the assumption that the abrasion rate of agglomerates determines the required blending time. It is shown that the kinetic energy density of the moving powder bed is a relevant parameter which correlates with the abrasion rate of agglomerates. However, aspects related to the strength of agglomerates should also be considered. For this reason the Stokes abrasion number (St(Abr)) has been defined. This parameter describes the ratio between the kinetic energy density of the moving powder bed and the work of fracture of the agglomerate. The St(Abr) number is shown to predict the abrasion potential of agglomerates in the dry-mixing process. It appeared possible to include effects of filler particle size and impeller rotational rate into this concept. A clear relationship between abrasion rate of agglomerates and the value of St(Abr) was demonstrated.