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Novel determination of powder mixing qualities and study of dry coated particles
Research Area: thesis Year: 2008
Type of Publication: Phd Thesis  
  • Thomas Alexander Meyer
Powder mixing represents a common process with broad applications from domestic to industrial areas. In pharmaceutical technology, where active pharmaceutical ingredients must be uniformly distributed to ensure safety and efficacy, mixing represents an important process in the manufacturing of solid dosage forms. With a long and rich historical background, the scientific and economic relevance is a proved certainty. Up to today, the diversity of powders, products and applications has led to a multiplicity of mixing apparatus, mixing theories and process descriptions and therefore difficulties of generalization. Mixing of non- interactive or interactive particles can involve diffusive, convective and shear mixing mechanisms, which can lead to incomplete random, complete random or perfect mixture qualities or even to segregation where the components do not form a mixture at all. In order to receive information about mixing, sampling is necessary. Even though the requirements for the assessment and descriptions of powder mixtures are high, only basic principles are known for best sampling results so far. The aims of the study contained the development, construction and evaluation of a sampling apparatus, which included special devices for the Turbula? mixer in respect to the current sampling theory. In this context, the dry coating process was studied besides common mixing. This process has recently gained special interests in pharmaceutical technology in dry solids mixing. The following factors were studied: identification of the important particle properties, the mixing mechanism and the influences of mixing times upon mixture qualities. The implementation of the percolation theory to the dry coating process has led to propose a critical fine particle concentration, which corresponds to the percolation threshold. Based on the known sampling theory, the development and construction of the sampling equipment including the sampling apparatus followed the ?Golden Rules of Sampling?. The sampling equipment consists of a hopper element and a sampling train with sampling vessels where the sampling train has a constant speed. The linear movement of the sampling train represents the time resolved. By disallowing structural disturbances of the mixtures and excluding affection of the received results, the simple, short and reliable procedure was evaluated by investigating separate parts of the sequential mixing and sampling procedure as well as the whole system with non- interactive mixtures to identify possible influences on the system and the emerging results. By evaluating sequentially sample analysis, impacts of sampling and handling and mixing, the obtained results showed the requested properties of the developed and constructed sampling equipment. The obtained sampling results reflected clearly the content distributions due to the flow properties of binary mixtures. The evaluation of the whole system by applying noninteractive particles in the Turbula? mixer followed by sampling with the novel determination method showed good agreement compared to theoretical calculations based on the common mixing theory. It was concluded that the developed and constructed sequential system of mixing and sampling could be applied for further investigations of various mixing processes as well as investigations of other mixture types. Originating from the old concept of ?ordered mixing?, dry coating offers an application in pharmaceutical technology to produce particles with attractive properties by simply mixing. By applying the developed and constructed mixing and sampling system, different non- interactive carrier particles were used with interactive Methylene blue to analyze the mixing mechanism and the resulting particles to identify the important process parameters. Thereby, the important particle properties were identified as the density, the particle size and the surface texture on the carrier properties side. As most important, the density difference between the carriers and the guest particles is shown to assist the dry coating process. The particle size is determined to support the process as well, whereas with increasing particle sizes, the dry coating process is more productive. The surface texture has been determined to support the dry coating process whereas the density and the size differences must be considered as more important. On the guest particle side, further investigations must consider the influence of the residual moisture content to form the dry coating layer. The mixing mechanism was identified as a rolling shear mixing mechanism where the carrier particles roll the active on their surfaces supported by the three dimensional movement of the Turbula?, whereas the produced particles display a thin layer. Mixing times, identified as the only variable process parameter, has been shown as distinctively prolonged compared to non- interactive mixing whereas the determined mixing times demonstrate clearly the necessary optimization of mixing processes supporting the general opinion of separate studies of mixing processes for all mixture types and mixture compositions. Additional investigations were carried out to investigate the mechanical stability of the produced dry coated particles where it was demonstrated that the particles were more resistant than conventionally coated particles with suspensions. By regarding the received results, it was concluded that the presented prospects of the dry coating process displayed distinctively the need of further investigations as well as the opening of interesting new application fields. By proposing a critical fine particle concentration, the percolation theory was introduced to the dry coating process to identify impacts on mixture qualities and the saturation process of carrier particles. The existence of a saturation concentration was shown for all dry coated particle mixtures representing the basis for the assumption of the critical fine particle concentration. However, the obtained results of the estimation of the critical fine particle concentration displayed that an exact determination is not simple. Nevertheless, the existence of the critical fine particle concentration could be shown in 4 out of 6 cases. The implementation of the percolation theory to the dry coating process is therefore legitimated qualitatively whereas the critical fine particle concentration can be equated to the percolation threshold, where the behavior is expected to change abruptly. To conclude, investigations of the application of the percolation theory in dry coating must be advanced, which would support the development of robust dosage forms, their design and as a consequence reduce time to market, economic losses and most important risks to patient?s health.
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