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No / A precipitation process is considered in which completely miscible solution and supercritical antisolvent are passed through premixing and diluting zones of a turbulent flow. The influence of flow velocity on particle size and nuclei concentration is discussed in terms of mixing and precipitation time constants and their supersaturation dependencies. The proposed model allowed the major process parameters such as supersaturation profile, mixed fluid fraction and mean particle size to be calculated and compared with experimental data. For the crystallization system paracetamol/ethanol/CO2 studied, the supersaturation profile becomes established at Re104. The particle size and shape are defined, firstly, by increase of supersaturation and relative volume of mixed (on molecular scale) fluid with increase of flow velocity and, secondly, by decrease of residence time available for nucleation with increase of flow velocity. These competitive processes can result in minimum particle size at a defined flow rate.

<p>There are today strong incentives for an increased understanding of material properties and manufacturing processes to facilitate the development of new technologies in the pharmaceutical industry. The purpose of this thesis was to suggest methods requiring a low sample amount for characterization of technical properties of powders.</p><p>Compression analysis was used to evaluate the formulation relevance of some compression equations. Using the mechanics of single granules to estimate powder functionality was part of this work. It was concluded that the formability of granular solids and the plasticity of single granules could be determined with compression analysis by using the Kawakita model for single components and binary mixtures of ductile granules.</p><p>Further on, the fragmentation propensity of solid particles could be estimated from compression analysis by using the Shapiro equation, enabling indicators of both the fragmentation and the deformation propensity of particles to be derived in one single compression test.</p><p>The interpretations of the compression parameters were only valid if the influence of particle rearrangement was negligible for the overall compression profile. An index indicating the extent of particle rearrangement was developed and a classification system of powders into groups dependent on the incidence of particle rearrangement was suggested as tools to enable rational interpretations of compression parameters.</p><p>The application of compression analysis was demonstrated by investigating the relevance of the mechanics of granular solids for their tableting abilities. The plasticity of single gran-ules was suggested to influence both the rate of compactibility and the mode of deformation, and consequently the maximal tablet strength. The degree of granule bed deformation was shown to be a potential in line process indicator to describe the tableting forming ability.</p><p>This thesis contributes to a scheme, suitable in formulation work and process control, to describe manufacturability of powders for an enhanced tablet formulation technology.</p>

Electrostatic properties of formulation component materials and blends play an important role in dry powder inhalation (DPI) products, and that valid measurement of charge distribution will lead to more precise control of powder behavior in DPI manufacturing processes. Ultra-fine powders are known to be bipolarly charged, have non-spherical shapes and tend to be highly cohesive. Real time, non-invasive techniques need to be developed to obtain a precise and accurate time-history characteristic of electrically charged powders as they aerosolize from a DPI product, and how this measure relates to materials behavior throughout the various steps of a manufacturing process i.e. from drug micronisation, blending with lactose, through to filling dose units. A novel non-invasive technique for simultaneous measurement of size and charge of pharmaceutical powders is considered which employs the Phase Doppler Anemometry (PDA) system. Previous research demonstrated the advantages of this technique in measuring the bipolar charge distribution on a population of particles. These findings led to significant improvements in understanding performance of dry powder formulations, manufacturing processes and development of new platforms for inhaled drug delivery. The main aim of this research is to perform an investigation of electrostatic propertiesof pharmaceutical dry aerosols using the PDA system. The PDA technique was used to track the motion of charged particles in the presence of an electric field. The magnitude as well as the polarity of the particle charge can be obtained by solving the equation of particle motion in DC and AC fields combined with the simultaneous measurement of its size and velocity. The results show the capability of the technique to allow real-time size and charge distribution in the control of dry powder attributes that are critical to fully understanding manufacturing design space. The data obtained from initial investigations of electrical properties of pharmaceutical powders and bipolar charge measurements was used to perform an in-depth study of electrostatic properties of pharmaceutical aerosols dispensed by dry powder inhaler (DPI) devices. The delivery of a drug to the lungs can only be achieved by a combination of inhaler device and drug formulation which is capable of producing an aerosol of an aerodynamic diameter smaller than 5 μm and of appropriate charge. The aerosols generated by these devices are often bipolarly charged and can influence specific site deposition in human lung. By controlling the electrostatic charge generated by tribielectrification, it may be possible to achieve the desired drug deposition in the airways. Bipolary charged dispensed ultrafine particles are inhaled through the extrathoracic and tracheobronchial airways down into the alveolar region. Anatomically realistic respiratory airways and computation fluid dynamics (CFD) models have been created to study airflow structures and predict aerosol deposition within the human respiratory system using visible human data sets, human casts and morphometric data. Many theoretical studies of charged aerosol deposition in human respiratory systems have been developed, however getting real time, non-intrusive data of bipolar charge levels on aerosols dispensed from DPI’s within the human respiratory system represents a challenging issue. This research project presents a simplified human upper airway model which combined with the modified Phase Doppler Anemometry (PDA) system is able to provide real time bipolar charge distributions of aerosols delivered from several commercially available DPI devices. A three dimensional (3D) reconstruction of the upper respiratory system was performed from two dimensional (2D) images obtained from computerized tomography (CT), magnetic resonance imaging (MRI) and cryosectioned images available from Visible Human Server data set (Ecole Polytechnique Fédérale de Lausanne). The resulting dimensions of the model were consistent with morphometric data from the literature from which the simplified upper airway model consisting of two connected segments, i.e., the oral airways from the mouth to trachea (Generation G0), was created. The findings of this study provided a better understanding of the interaction between specific active ingredients and DPI devices. These results may be used in designing future generation DPI devices and a better understanding of aerosol transport and deposition efficiency within the human airways.

There are today strong incentives for an increased understanding of material properties and manufacturing processes to facilitate the development of new technologies in the pharmaceutical industry. The purpose of this thesis was to suggest methods requiring a low sample amount for characterization of technical properties of powders. Compression analysis was used to evaluate the formulation relevance of some compression equations. Using the mechanics of single granules to estimate powder functionality was part of this work. It was concluded that the formability of granular solids and the plasticity of single granules could be determined with compression analysis by using the Kawakita model for single components and binary mixtures of ductile granules. Further on, the fragmentation propensity of solid particles could be estimated from compression analysis by using the Shapiro equation, enabling indicators of both the fragmentation and the deformation propensity of particles to be derived in one single compression test. The interpretations of the compression parameters were only valid if the influence of particle rearrangement was negligible for the overall compression profile. An index indicating the extent of particle rearrangement was developed and a classification system of powders into groups dependent on the incidence of particle rearrangement was suggested as tools to enable rational interpretations of compression parameters. The application of compression analysis was demonstrated by investigating the relevance of the mechanics of granular solids for their tableting abilities. The plasticity of single gran-ules was suggested to influence both the rate of compactibility and the mode of deformation, and consequently the maximal tablet strength. The degree of granule bed deformation was shown to be a potential in line process indicator to describe the tableting forming ability. This thesis contributes to a scheme, suitable in formulation work and process control, to describe manufacturability of powders for an enhanced tablet formulation technology.