Hans Leuenberger

The compressibility and compactibility of powder systems

Abstract This paper investigates the problem of compressibility and compactibility of powder systems. The term ‘compressibility’ is defined as the ability of a powder to decrease in volume under pressure, and the term ‘compactibility’ is defined as the ability of the powdered material to be compressed into a tablet of specified strength (i.e. radial tensile strength or deformation hardness). A novel approach leads to the following equation, which describes the deformation hardness P of the compact as a function of the applied pressure σ c and the relative density ρ r : P = P max (1 − exp ( − γσ c ρ r )) The parameter P max is equal to the theoretically maximal possible deformation hardness at σ c ρ r → ∞.P max describes the compactibility and the parameter γ, termed the compression susceptibility, describes indirectly the compressibility. The equation is valid for pure substances as well as for binary mixtures An attempt is made to develop ‘additivity rules’ for the parameters P max and γ in case of binary mixtures. For the general case it is necessary to introduce an interaction term, which can be explained qualitatively.

New trends in the production of pharmaceutical granules: batch versus continuous processing

In the pharmaceutical industry, the production of granules is based on a batch concept. This concept offers many advantages with respect to quality assurance as a batch can be accepted or rejected. However, the scale-up of the batch size may lead to problems. The variety of the equipment involved often does not facilitate the scale-up process. In order to avoid scale-up problems, continuous or semi-continuous processes have to be evaluated as alternatives to a batch production. Thus, a quasi-continuous production line is presented, which permits the production of small-scale batches, e.g. for clinical trials and for large-scale batches using the same equipment.

Albumin Nanospheres as Carriers for Passive Drug Targeting: An Optimized Manufacturing Technique

AbstractPurpose. The purpose of this study was to develop a new method to produce albumin particles in the sub-200-nanometer range with a narrow size distribution and in a controlled and reproducible manner. Methods. A new emulsion crosslinking method was developed using ultrasound and static mixing as homogenization steps and a central composite design was used to evaluate the influence of different process parameters on particle size, polydispersity and yield. Results. Response surface analysis allowed the location of the most important factors. Of all the factors investigated, only the albumin concentration and the aqueous phase volume showed a significant influence on response parameters. Albumin nanospheres with sizes below 200 nm in diameter and very narrow size distributions were obtained in high yields (>80%). Conclusions. This study describes a new preparation method for albumin nanoparticles which are suitable for future drug targeting studies.

ATMOSPHERIC SPRAY-FREEZE DRYING : A SUITABLE ALTERNATIVE IN FREEZE-DRYING TECHNOLOGY

Abstract The freeze-drying technique is one of the most useful processes for drying thermosensitive substances that are unstable in aqueous solutions. Because of the rapid evolution of biotechnologically obtained materials, increased attention has been focused on this process, especially in pharmaceutical technology, during recent years. Actually, freeze-drying techniques are used to dry many kinds of mainly biological materials. Food products, in particular, are processed on a large scale with considerable success. As an alternative to the classical freeze-drying process in a vacuum, the feasibility of dehydrating frozen pharmaceutical solutions and liquid foods at atmospheric pressure was investigated. An apparatus and a technique for spray-freezing aqueous solutions in situ at very low temperatures (−90°C) and for subsequent dehydration of the resulting frozen particles in a stream of cold, desiccated air was developed. The influence of various process variables and of certain product characteristics on the drying kinetics as well as on the quality properties of the respective lyophilizates is discussed. Compared to the classical freeze-drying process the following differences can be pointed out: (1) improved heat and mass transfer between the circulating drying medium and the frozen sample; (2) high and homogeneous quality properties of the dry product with an increased retention of volatile aromatic compounds in foods; (3) instead of a cake, a fine, free-flowing powder with a large inner surface area and good instant, i.e. wetting and solubility, properties was obtained.

Advantages of Artificial Neural Networks (ANNs) as alternative modelling technique for data sets showing non-linear relationships using data from a galenical study on a solid dosage form

Artificial Neural Networks (ANN) methodology was used to assess experimental data from a tablet compression study showing highly non-linear relationships (i.e. measurements of ejection forces) and compared to classical modelling technique (i.e. Response Surface Methodology, RSM). These kinds of relationships are known to be difficult to model using classical methods. The aim of this investigation was to quantitatively describe the achieved degree of data fitting and predicting abilities of the developed models. The comparison between the ANN and RSM was carried out both graphically and numerically. For comparing the goodness of fit, all data were used, whereas for the goodness of prediction the data were split into a learning and a validation data set. Better results were achieved for the model using ANN methodology with regard to data fitting and predicting ability. All determined ejection properties were mainly influenced by the concentration of magnesium stearate and silica aerogel, whereas the other factors showed very much lower effects. Important relationships could be recognised from the ANN model only, whereas the RSM model ignored them. The ANN methodology represents a useful alternative to classical modelling techniques when applied to variable data sets presenting non-linear relationships.

Fundamentals of Powder Compression. I. The Compactibility and Compressibility of Pharmaceutical Powders

In spite of the widespread use of tablets, the theoretical understanding of the tableting process has been limited. During the last decades considerable research has been done in the field of powder technology and compaction. A survey of the literature and compression equations reveals many studies on the characterization of powder properties, most of which relate to volume reduction under pressure, i.e., to the compressibility of the powder bed. For practical purposes, however, it is also important to know the compactibility of a powder bed, i.e., the ability of a powdered material to be compressed into a compact of specified strength. This strength has to be defined, e.g., as radial tensile strength or deformation hardness. Thus the first part of this review comprises the theory of powder compression of individual substances, compression parameters, compression equations, and mechanical properties of compacts, including compact strength tests and compact hardness tests.

A new theoretical approach to tablet strength of a binary mixture consisting of a well and a poorly compactable substance

The objective of this study was to analyse the tensile strength of a well and a poorly compactable substance in a tablet mixture. Recent developments in the theory of percolation were taken into account and two power laws are proposed, one for the tensile strength as a function of the relative density of the mixture, and the other for the relationship between the strength and compaction pressure. Both equations are assumed to be valid in a comparatively low pressure range. A universal testing instrument Zwick UPM 1478 was used for the manufacture and testing of the compacts. Mixtures of Avicel PH101 and paracetamol at different ratios were chosen as model systems. The experimental results showed that the proposed model equations fitted the experimental data reasonably well for all mixture ratios. It was observed that the critical solid fraction of the mixture, i.e. the strength percolation threshold, increased with rising amounts of the drug. We investigated the strength threshold not only in terms of the solid fraction, but also in terms of the mass fraction (excipient percolation threshold). It is assumed that a tablet can only be produced with a certain minimal amount of the well compactable substance that is needed to build a percolating cluster in the tablet. An interpretation is therefore provided for the dilution capacity of a direct tableting excipient with a poorly compactable drug. The dilution capacity was experimentally determined according to the method of Minchom and Armstrong (Br. Pharm. Conf. (1987) 69 pp.). Our experimental estimate of 79.9% drug is in perfect agreement with our proposed theoretical calculation of 79.7%. These estimates are, however, much higher than the one reported in a recent study (Y. Habib, L. Augsburger, G. Reier, Th. Wheatley, R. Shangraw, Dilution potential: a new perspective, Pharm. Dev. Tech. 1 (2) (1996) 205-212) where the dilution capacity of the same mixture was investigated. This discrepancy can be explained based on the different pressure ranges and extrapolation techniques that were used. As a conclusion, concepts of the percolation theory can successfully be applied to the kind of mixture studied in this paper. It is conceivable that the theoretical tools presented can also be applied to mixtures of more than two substances if they consist of a single well compactable excipient and several poorly compactable components. Such mixtures are relevant for the development of direct compressible tableting formulations.

Terahertz pulsed imaging and near infrared imaging to monitor the coating process of pharmaceutical tablets

Terahertz pulsed imaging (TPI) and near infrared (NIR) imaging were used to non-destructively monitor the coating process of film-coated tablets. Samples that were taken from a pan coater at different time points were analyzed by both methods. TPI provided coating thickness maps over the whole surface of the tablets, determining the thickness of the coating at each point of the sample surface in mum, this way also giving information about the coating uniformity. The growth of the coating during the coating process was shown. NIR imaging did not provide direct thickness values, but by different absorbance values, inter- and intra-tablet differences were shown. Thus, coating thickness information was also obtained in a way that different tablets could be compared. The growth of the coating layer during the process was shown as well. Both methods provided comparable results; and they were able to detect small defects in the coating. With TPI, the whole tablet surface could be scanned; with NIR imaging information about the tablet ends at the center-band was not obtained due to the strong curvature. NIR imaging proved to be better at thinner coating layers and had a higher spatial resolution whereas TPI had the clear advantage that it provided direct thickness values.

Spray freeze-drying - the process of choice for low water soluble drugs?

Most of the novel highly potent drugs, developed on the basis of modern molecular medicine, taking into account cell surface recognition techniques, show poor water solubility. A chemical modification of the drug substance enhancing the solubility often decreases the pharmacological activity. Thus, as an alternative an increase of the solubility can be obtained by the reduction of the size of the drug particles. Unfortunately, it is often difficult to obtain micro or nanosized drug particles by classical or more advanced crystallization using supercritical gases or by milling techniques. In addition, nanosized particles are often not physically stable and need to be stabilized in an appropriate matrix. Thus, it may be of interest to manufacture directly nanosized drug particles stabilized in an inert hydrophilic matrix, i.e. nanostructured and nanocomposite systems. Solid solutions and solid dispersions represent nanostructured and nanocomposite systems. In this context, the use of the vacuum-fluidized-bed technique for the spray-drying of a low water soluble drug cosolubilized with a hydrophilic excipient in a polar organic solvent is discussed. In order to avoid the use of organic solvents, a special spray-freeze-drying technique working at atmospheric pressure is presented. This process is very suitable for temperature and otherwise sensitive drugs such as pharmaproteins.

The relationship between solid fraction and mechanical properties of compacts — the percolation theory model approach

Abstract A model based on percolation theory has been set up to elucidate the relationship between relaxed complex Youngs modulus, hardness and normalized solid fraction of pharmaceutical compacts. The relationship between the variables is non-linear over the whole range of the solid fraction of the compacts. However, in a semi-logarithmic representation linear relationships could be established in certain ranges of the solid fraction of the compacts. The semi-logarithmic plot of Youngs modulus or hardness against the solid fraction is comprised of segments of straight Unes. The inflexions between the segments indicate a change in the consolidation behaviour as a function of the applied pressure, i.e. as a function of solid fraction of the compact. The number of these segments depends on the mechanical properties of the powder mix. In addition to the solid components, the mechanical properties are affected by the pore system. The straight line relationships allow extrapolations to be made to zero porosity thus furnishing the mechanical property of the soUd components. The model has been illustrated with single and binary solid component compact systems. Single and binary solid component powder systems behave similarly.