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What is Dielectric Spectroscopy?

Dielectric properties relate to the ability of a material to polarise under the influence of an electromagnetic field. The polarisability of the materials depends on the structure and molecular properties, and therefore dielectric measurements can provide information in these terms. The technique for measuring dielectric properties is known as Dielectric Spectroscopy.

The facility to vary the measurement environment (temperature, pressure and humidity) and to take measurements over a very broad frequency band means that a diverse range of processes can be examined.

Dielectric relaxation spectroscopy is increasingly being recognised as a tool for materials characterisation, and has advantages which could be of particular benefit in the characterisation, manufacture and quality control of pharmaceuticals, in addition to applications in the characterization of biological systems and interfaces.

Details of the temperature dependence of the dielectric relaxation time differentiate between Arrhenius and other types of behaviour, such as Vogel-Taman-Fulcher (commonly exhibited by super-cooled liquids). Arrhenius behaviour is typical of localised motion of dipolar groups, whereas VTF behaviour is typical of co-operative motions.

Temperature effects, such as the percolation of charge delocalised, enable detailed mesoscopic studies on systems such as emulsions, hydrated powders and biological tissues. For example, the dielectric response of amorphous powders is extremely sensitive to the addition of very low concentrations of water (~1%). Dielectric spectroscopy is therefore well placed to investigate the hydrogen bonding states and mobility of water dipoles, that will certainly impact on both the physical and chemical stability of these systems.

Applications in Drug Delivery, Material Science and Biotechnology

  CONTENTS

• Polymeric Drug Delivery Systems
• Hydrated Powders
• Moisture analysis
• Freeze-dried/spray dried amorphous formulations
• Wet granulation
• MDI Systems
• Microcapsules
• Cell Monolayers and Membranes
• Cells and Viruses
• Separation media
   

Polymeric Drug Delivery Systems

Dielectric relaxation spectroscopy can be used to study the configuration and dynamic properties of polymeric systems. For example, alkyl methacrylates exhibit two relaxation processes, an alpha-process at low frequency and a beta-process at high frequency. The alpha-process is analogous to the static glass transition (as determined by DSC). This process is due to micro-Brownian segmental motions of the polymer chain (e.g. guache-trans transitions) that result in the rotation of dipoles around the polymer chain. Like the glass transition there is a dependence on molecular weight and chain architecture. The process occurs in the dense environment of amorphous polymers and therefore intermolecular interactions contribute. The beta-process is associated with localised reorientations of dipole vectors, i.e. the methacrylate side chain. Temperature dependence of the time constants for each process (alpha and beta) will probe the dynamics and energetics of the polymer. These parameters may correlate with release kinetics, especially if drug release is a function of diffusion through the polymer matrix. Broadening of each relaxation corresponds to an increase in the diversity of environments that the polymer chains occupy, and will therefore be sensitive to the distribution of drug in the matrix.

Hydrated Powders

Microwave DRS is of particular value in the study of hydrated powders. Dielectric relaxation of any permanent molecular dipole, like water, is affected by the bonding state of the molecule with its nearest neighbours, as it is the bonding state that affects the ability of the molecule to orient (i.e. polarise) in the applied field. Any change in ratio of free and bound water in the system will therefore by picked up by changes in the parameters characterising the dielectric relaxation of water molecules. These parameters are:

Dielectric increment (which depends on the concentration and the extent to which water dipoles can reorient in the material, under the influence of the applied field)
Mean relaxation time (characterising the rate at which the molecular dipoles can orient in the applied field)
Distribution function (e.g. the Cole-Davidson parameter characterising the distribution of relaxation times)
The molecular dipoles of free, (or bulk) water have a mean relaxation time of 9.3 ps (at 293 K), whereas the molecular dipoles of hydration water have relaxation times that are greater by a factor between 2-30, depending on the affinity of the water for the hydrated surface.

Temperature studies of the relaxation time, enables the determination of the activation energy for reorientation, and provides an estimation of the relative bonding energies of water in different systems. The polarisability of water is much lower in the first hydration layer of a hydrated material than in the second and third hydration layers, and the bulk, and therefore this parameter also provides information on the reorientational freedom of water in the matrices and embedded drugs.

Moisture analysis

De Montfort University (in collaboration with IDC Expertise) has the necessary engineering and scientific expertise to develop new and customer oriented applications for microwave moisture analysis.

These devices have the following features:

• On-line (or at-line) measurement of moisture in nearly dry to fully-hydrated systems.
• Suited to bulk materials, dusty/steamy environments, materials with heterogeneous moisture content (e.g. during drying), and both high and low water content material.

Freeze-dried/spray dried amorphous formulations

De Montfort University has expertise in the characterization of nearly-dry amorphous powders (especially proteins and sugars). We have shown that it is possible to determine the fractalilty of the hydration surface and the activation energies for protonic diffusion in these low hydrated systems. These parameters are likely to provide predictive measures of both physical and chemical stability of amorphous materials.

Wet granulation
We have shown that the properties of water in wetted powders (and granules) correlate with the surface properties of the dry powders. Such data could be used to develop predictive algorithms for determining the optimum amount of granulation fluid for any particular combination of powder blend and binding agent.

De Montfort University has also demonstrated the utility of dielectric measurements in tracking the process of wet granulation and has evidence to suggest that these measurements relate directly to the formation of granules during the latter stages of blending.

MDI Systems
De Montfort University has capabilities in a number of aspects of MDI device/formulation characterization.

Characterization of the surface potential of the metering chamber of an MDI device, for the purpose of monitoring drug adsorption.
Characterization of particle aggregation, via the determination of the fractal dimension of the suspension.
Characterization of the integrity of polymer coated aerosol canisters
Determination of water content in propellants, using microwave adsorption techniques.
 
Microcapsules
The release of drugs from microcapsule suspensions is dependent on the thickness and porosity of the capsule wall and the polydispersity in capsule size, and can vary from capsule to capsule. DRS has been used to monitor the progress of drug release and may also be used to study the ageing of microcapsules.

Emulsions and Creams
The non-invasive nature of DRS, and the fact that the sample does not require dilution, makes it particularly useful for obtaining structural information on concentrated disperse systems, such as water-in-oil emulsions. High frequency studies (10 MHz to 10 GHz) can be used to derive the emulsion type and water content. This and the ability to study the oil-water interface provide, once again, the potential for on-line process monitoring.

Cell Monolayers and Membranes
Impedance analysis on biological membranes and cell monolayers can provide useful information on the sub-structure of these systems. For example, studies on epithelial cell monolayers provide detailed information on the formation of tight junctions and the properties of the membranes of the component cells. De Montfort University is also active in the application of impedance spectroscopy to lipid bilayers. This work is aimed at resolving the substructure of the bilayer in terms of head group and hydrocarbon core domains, with a view to understanding the mechanisms by which penetration enhancers modulate stratum corneum bilayer properties.

Cells and Viruses
De Montfort University is in the process of developing a time domain method for the determination of the dielectric properties of whole cells and their structural counter-parts.

The potential use of this technology is for on-line monitoring of bacteria, yeast, and, viruses. The new instrument would be simple in operation, compact, and based upon fundamental parameters of individual cells (as determined by single-cell, dielectric spectroscopy measurements).

Dielectric spectroscopy can determine the properties of the nuclear envelope independently form the cytoplasmic envelope, in a single non-invasive approach. This approach could be exploited to determine the selective permeabilization of the nuclear envelope for gene transfection purposes.

Separation media
Many types of aqueous filled porous materials (such as silica and ion exchange beads) exhibit pronounced dielectric responses that can be ascribed to surface conductance. It would therefore be possible to use this behaviour to characterise the surface loading of a separation media for the purpose of determining the capacity and surface saturation a separation medium.