Experimentelle Untersuchungen und mathematisch-theoretische Vorhersagen des Freisetzungsverhaltens aus extrudierten Fettmatrices

Created by W.Langdon from gp-bibliography.bib Revision:1.3963

@PhdThesis{Gures:thesis,
  author =       "Sinan Gures",
  title =        "Experimentelle Untersuchungen und
                 mathematisch-theoretische Vorhersagen des
                 Freisetzungsverhaltens aus extrudierten Fettmatrices",
  title2 =       "Experimental investigations and
                 mathematical-theoretical prdictions of release
                 behaviour from fat matrices",
  school =       "der Mathematisch-Naturwissenschaftlichen Fakultat der
                 Heinrich-Heine-Universitat Dusseldorf",
  year =         "2011",
  address =      "Germany",
  month =        "21 " # dec,
  keywords =     "genetic algorithms, genetic programming",
  URL =          "http://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=21838",
  URL =          "http://docserv.uni-duesseldorf.de/servlets/DerivateServlet/Derivate-23446/Gures_thesis.pdf",
  size =         "118 pages",
  notes =        "In German.

                 Supervisor Prof. Peter Kleinebudde",
  abstract =     "The present work focused on the dissolution behaviour
                 of solid lipid extrudates. It was possible to analyse
                 the influence of different groups of excipients on the
                 release of a model API from solid lipid extrudates
                 systematically. Three groups of excipients were
                 determined, each including several substances. Pore
                 formers, hydrocolloids and super-disintegrants were
                 chosen. The extrudate matrix into which 5percent
                 release modifier were incorporated basically consisted
                 of diprophylline as a model API and tristearin as a
                 matrix former (50:45percent w/w). In each case it was
                 possible to obtain suitable extrudates. The DSC
                 analysis showed that the physical properties of the
                 physical mixture were also existent in the extrudate
                 matrix, representing a successful extrusion process.
                 Dissolution experiments resulted in different behaviour
                 of the extrudates. Not all of the excipients led to a
                 faster dissolution rate. Within the pore former group
                 mannitol and sodium chloride did not influence the
                 release rate, compared to the reference extrudate,
                 consisting of diprophyllin and tristearin (55:45percent
                 w/w). PEG of a mean molecular weight of 10.000 instead
                 increased the release rate significantly. The extrusion
                 temperature of 65degrees celcius could be identified as
                 reason for this exceptional behaviour of PEG 10.000.
                 Since its melting point of around 62degrees celcius is
                 exceeded during extrusion process, PEG 10.000 was
                 assumed to melt and become a fluid within the mass. At
                 the same time, it gets better distributed in the
                 matrix. Thus, a fine PEG network is constructed in the
                 extrudate leading to a faster dissolution rate. These
                 findings lead to the idea to check the influence of
                 different polyethyleneglycols. Polyethylene glycols and
                 polyethylene oxides of different molecular weights,
                 varying from 1.500 up to 7.000.000 were tested by
                 incorporating them into the same basic matrix. For
                 these studies also a lower melting powdered lipid,
                 trimyristin, was used. The studies led to the result,
                 that primarily the extrusion temperature and thus, the
                 solid state of the PEG/PEO was responsible for release
                 enhancement.",
  abstract =     "Within the group of hydrocolloids, the aim was to
                 investigate the influence of different viscosity grades
                 of different types on the dissolution rate of
                 diprophylline. Higher viscosity grade of a hydrocolloid
                 (HPMC 4000 and HEC 30000), led to a full disintegration
                 of the matrix whereas lower viscosity grades (HPMC 50
                 and HEC 20) just resulted in locally eroded matrix
                 surfaces.

                 The super-disintegrants also showed different effects
                 on the release behaviour of diprophylline containing
                 extrudates. Croscarmellose sodium and sodium starch
                 glycolate led to fast disintegration of the matrix and
                 to full release within a few minutes. Crospovidone
                 (PVP-CL) of two different mean particle sizes instead,
                 did not cause disintegration of the lipid matrix. These
                 two super disintegrants showed different behaviour. In
                 the case of Kollidon CL-SF, that one with the smaller
                 particle size, the matrix was still intact after
                 dissolution and the drug was dissolved from pores, as
                 it was in the pore former group. Kollidon CL containing
                 extrudates exhibited a much higher release rate. Here,
                 surface erosion was the case, but not
                 disintegration.

                 Since all the above mentioned experiments were
                 performed using the excipients as received and as a
                 consequence of this, the particle size influence on the
                 release rate was not considered, additional trials with
                 sieved excipients were performed. The excipients were
                 sieved to a particle size range from 0-80 micrometer
                 and the experiments were repeated. A significant
                 influence of the particle size of the excipients could
                 not be detected.",
  abstract =     "A further approach of the present work was to develop
                 mathematical and empirical models which are able to
                 predict the release profiles of solid lipid extrudates.
                 The suitability of these models was tested by
                 predicting the release profiles of different
                 dimensioned extrudates. For these investigations
                 extrudates with the composition of diprophylline,
                 tristearin and PEG 20.000 or Kolldion CL-SF were
                 chosen.

                 For the development of the mathematical model the
                 physicochemical properties of the extrudates were
                 analysed first. Based on these results, fickian
                 diffusion could be identified as the main transport
                 mechanism during dissolution. Fick's second law of
                 diffusion for cylindrically shaped systems served as
                 the basic equation of the model. As Fick's second law
                 of diffusion is a partial differential equation, an
                 analytical solution via Laplace transformation had to
                 be derived. The result was an equation, which could
                 directly be used to calculate the released drug
                 amount.

                 Extrudates of the abovementioned composition with PEG
                 20.000 of 0.6, 1.0, 1.5, 2.7 and 3.5 mm diameter were
                 produced by using different die plates and were
                 physicochemically characterised. After dissolution
                 testing, the data of these extrudates were compared to
                 the calculated release data, obtained by inserting
                 diameter and length of the extrudates into the model
                 equation. The calculation of the similarity factor f2
                 proved the sameness of the dissolution curve pairs
                 (theory and experiment), indicating the good quality of
                 the mathematical model. In order to validate the
                 predictability of the model further experiments,
                 considering only the length of an extrudate were
                 performed. Extrudates of 1.0 mm diameter and the
                 abovementioned composition were cut to different
                 lengths. Dissolution experiments were performed and
                 again the model equation was used to predict the
                 release behaviour of these extrudates. Experiment and
                 theory showed good accordance again. In order to
                 demonstrate the limits of the mathematical model, a
                 disintegrating extrudate (containing Kolldion CL-SF)
                 was used. Since the model does not consider
                 disintegration, it was not able to correctly predict
                 the release behaviour in this case.

                 As a comparison to the mechanistic model based on
                 Fick's second law of diffusion, an empirical approach
                 was applied to the same problem (extrudates of 0.6-3.5
                 mm diameter). Artificial neuronal networks (ANNs) are
                 well known as empirical modelling tools, which are able
                 to learn from a set of experimental data and to
                 identify a pattern in these data. Three parameters,
                 extrudate length, extrudate diameter and the
                 dissolution time were determined as input units for the
                 ANNs. The released drug fraction was chosen as the
                 output unit, since this was the parameter of interest.
                 The ANNs was able to identify the diameter and time as
                 a crucial parameters determining the release rate. The
                 number of input units could thus be reduced from three
                 to two.",
  abstract =     "In the second step, the Weibull-equation, a function
                 mostly used in the industry to determine the lifetime
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