Novel determination of powder mixing qualities and study of dry coated particles

Meyer, Thomas Alexander. Novel determination of powder mixing qualities and study of dry coated particles. 2008, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_8366

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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
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.
Advisors:Leuenberger, Hans
Committee Members:Hoogevest, Peter van
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmazeutische Technologie (Huwyler)
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:8366
Thesis status:Complete
Number of Pages:141
Identification Number:
edoc DOI:
Last Modified:23 Feb 2018 11:43
Deposited On:13 Feb 2009 16:33

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