- 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 BibTeX entry too long. Truncated
