| 1. |
- Borgquist, Per, et al.
(författare)
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Simulation and parametric study of a film-coated controlled-release pharmaceutical.
- 2002
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Ingår i: Journal of Controlled Release. - 1873-4995. ; 80:1-3, s. 229-245
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Tidskriftsartikel (refereegranskat)abstract
- Pharmaceutical formulations can be designed as Multiple Unit Systems, such as Roxiam CR, studied in this work. The dose is administrated as a capsule, which contains about 100 individual pellets, which in turn contain the active drug remoxipride. Experimental data for a large number of single pellets can be obtained by studying the release using microtitre plates. This makes it possible to study the release of the individual subunits making up the total dose. A mathematical model for simulating the release of remoxipride from single film-coated pellets is presented including internal and external mass transfer hindrance apart from the most important film resistance. The model can successfully simulate the release of remoxipride from single film-coated pellets if the lag phase of the experimental data is ignored. This was shown to have a minor influence on the release rate. The use of the present model is demonstrated by a parametric study showing that the release process is film-controlled, i.e. is limited by the mass transport through the polymer coating. The model was used to fit the film thickness and the drug loading to the experimental release data. The variation in the fitted values was similar to that obtained in the experiments.
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| 2. |
- Borgquist, Per, et al.
(författare)
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Simulation of the release from a multiparticulate system validated by single pellet and dose release experiments
- 2004
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Ingår i: Journal of Controlled Release. - 1873-4995. ; 97:3, s. 453-465
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Tidskriftsartikel (refereegranskat)abstract
- A previously described single-pellet release model has been simplified and modified to give predictions of the release from multiple-pellet systems, besides describing the release from single pellets. The simplified single-pellet model has been verified using single-pellet data and has been used to estimate three release-controlling parameters, namely the pellet core radius, the overall mass transfer coefficient, and the lag time. Single-pellet release experiments showed that the release from the individual film-coated drug cores resulted in a wide distribution of release profiles, a phenomenon not observed on the dose level. Therefore, the parameter estimations resulted in distributions of these parameter values. The core radius and the lag times compared well with the experimental data. The distributions were used as input data for the multiple pellet model, in order to predict the release profiles on the dose level, showing results consistent with the measured dose release. The dose-predictive ability of the model was demonstrated in simulations by studying the effect of a change in the size of the single subunits (of constant total dose), showing that smaller pellets give an increased release rate with less variation. The model for predicting dose-release profiles could be of great value in optimising the performance of an existing formulation, as well as in the development of a new control led-release pharmaceutical. (C) 2004 Elsevier B.V. All rights reserved.
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| 3. |
- Gutenwik, Jan, et al.
(författare)
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Coupled diffusion and adsorption effects for multiple proteins in agarose gel
- 2004
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Ingår i: AIChE Journal. - : Wiley. - 1547-5905 .- 0001-1541. ; 50:12, s. 3006-3018
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Tidskriftsartikel (refereegranskat)abstract
- A mathematical model for the hindered diffusion and competitive adsorption of two proteins in an agarose gel has been developed. In a simulation program the model has been used to study the competing and displacement effects on a single bead for lysozyme and bovine serum albumin (BSA) bound to the ligand Cibacron Blue in agarose gel. The model takes into account hindered diffusion described by the Renkin model, competitive Langmuir adsorption kinetics, pore size distribution of the gel, and a shrinking effective pore radius attributed to molecule-to-ligand binding. The simulation model can easily explain displacement of BSA or lysozyme dependent on the binding capacity, kinetics, and diffusion. The influence of a bimodal pore size distribution is demonstrated. It also provides insight into the phenomenon of static vs. dynamic binding capacity observed in experimental determinations of the isotherm.
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| 4. |
- Gutenwik, Jan, et al.
(författare)
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Determination of protein diffusion coefficients in agarose gel with a diffusion cell
- 2004
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Ingår i: Biochemical Engineering Journal. - : Elsevier BV. - 1369-703X. ; 19:1, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- A diffusion cell has been used to measure the effective diffusion coefficients of proteins. The method is applied to lysozyme and BSA at different pH and ionic strength. A parameter optimization technique is used to estimate the diffusion coefficients directly from experimental data. The importance and influence of pH and ionic strength on the diffusive properties in an agarose gel have been demonstrated. A comparison with other methods showed that there is good agreement. The diffusion cell is an accurate and easy-to-use method for the measurement of protein diffusion coefficients, in spite of the long time required for a protein diffusion experiment. For smaller proteins this time can be shortened considerably by the present parameter optimization technique. (C) 2003 Elsevier B.V. All rights reserved.
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| 5. |
- Gutenwik, Jan, et al.
(författare)
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Effect of hindered diffusion on the adsorption of proteins in agarose gel using a pore model
- 2004
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Ingår i: Journal of Chromatography A. - 0021-9673. ; 1048:2, s. 161-172
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Tidskriftsartikel (refereegranskat)abstract
- The hindered diffusion and binding of proteins of different sizes (lysozyme, BSA and IgG) in an agarose gel is described using adsorption kinetic and diffusional data together with an experimentally determined pore size distribution in the gel. The validity of the pore model, including variable diffusion coefficients and porosities is tested against experimental confocal microscopy data. No fitting parameters were used in the present model. The importance of knowing the gel structure is demonstrated especially for large proteins such as IgG. Experimental confocal microscopy data can be explained by the present model. (C) 2004 Elsevier B.V. All rights reserved.
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| 6. |
- Gutenwik, Jan, et al.
(författare)
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Mass transfer effects on the reaction rate for heterogeneously distributed immobilized yeast cells
- 2002
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Ingår i: Biotechnology and Bioengineering. - : Wiley. - 1097-0290 .- 0006-3592. ; 79:6, s. 664-673
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Tidskriftsartikel (refereegranskat)abstract
- Here we examine the efficiency of different immobilized cell gradients applied to immobilized Saccharomyces cerevisiae fermenting glucose to ethanol. We developed a simulation model to fully study the competing effects of mass transfer hindrance and kinetics. It is based on a diffusion-reaction model and can be used to analyze the different cell concentration profiles inside an immobilized gel bead, in terms of effectiveness factors, productivity, and mass flux. The internal diffusion coefficient, which varies with the local cell concentration, as well as the external mass transfer, is taken into account when describing the efficiency. Although the diffusion hindrance is greater at higher cell concentrations, high cell concentration is still advantageous in the present case because the increase in reaction rate outweighs the diffusion hindrance. Thus, high cell concentrations contribute to increased productivity. The influence of the cell concentration gradient on the efficiency of the beads is negligible, Within the range of cell profiles studied it has been established that the location of the cells within the bead is of lesser importance. However, a steep cell gradient increases the importance of the external mass transfer. (C) 2002 Wiley Periodicals, Inc.
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| 7. |
- Karlsson, David, et al.
(författare)
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Methodologies for model calibration to assist the design of a preparative ion-exchange step for antibody purification
- 2004
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Ingår i: Journal of Chromatography A. - : Elsevier BV. - 0021-9673. ; 1033:1, s. 71-82
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Tidskriftsartikel (refereegranskat)abstract
- This work proposes methodologies using a model-based approach to gain knowledge on and assist the development of an ion-exchange step in a protein purification process; the separation of IgG from a mixture containing IgG, insulin and transferrin. This approach is suitable for capture and intermediate steps in a process. Both methods involve four consecutive steps. Firstly, the retention of the different protein components is determined giving a retention map of the system. From this the optimal pH and buffer can be determined. Secondly, additional salt gradient experiments are performed at the selected pH. Thirdly, experimental breakthrough curves have to be generated for the protein if the adsorption capacity of the medium for each component is not known. Fourthly, a validation experiment is performed. In method 1, where the capacity for the medium is assumed to be known, the protein adsorption is described by Langmuir kinetics with a mobile phase modulator (MPM). In this description salt is considered to be inert. In method 2 the adsorption behavior is described by steric mass action (SMA), where the salt component competes with the proteins for the available binding sites. Both methods use a dispersion model to describe transport in the mobile phase in the column. The methods are able to predict the separation and loading behavior of the three components. The methods can, with reasonable accuracy, predict the breakthrough of transferrin in a mixture of insulin, IgG and transferrin. Method I requires fewer experiments and predicts the mean volume of breakthrough for the loading step in the validation experiment more accurately than method 2. On the other hand, method 2 has a better accuracy to predict the position of 10% breakthrough and the shape of the breakthrough curve. The methods suggested in this work are shown to be efficient in process development. Some additional experiments have to be performed to obtain the unknown parameters in the models. However, the predictability that is achieved results in less experimental work in the process design as a whole. (C) 2004 Elsevier B.V. All rights reserved.
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| 8. |
- Karlsson, David, et al.
(författare)
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Model-based optimization of a preparative ion-exchange step for antibody purification
- 2004
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Ingår i: Journal of Chromatography A. - : Elsevier BV. - 0021-9673. ; 1055:1-2, s. 29-39
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Tidskriftsartikel (refereegranskat)abstract
- A method using a model-based approach to design and optimize an ion-exchange step in a protein purification process is proposed for the separation of IgG from a mixture containing IgG, BSA and myoglobin. The method consists of three steps. In the first step, the model is calibrated against carefully designed experiments. The chromatographic model describes the convective and dispersive flow in the column, the diffusion in the adsorbent particles, and the protein adsorption using Langmuir kinetics with mobile phase modulators (MPM). In the second step, the model is validated against a validation experiment and analyzed. In the third and final step, the operating conditions are optimized. In the optimization step, the loading volume and the elution gradient are optimized with regard to the most important costs: the fixed costs and the feed cost. The optimization is achieved by maximizing the objective functions productivity (i.e. the production rate for a given amount of stationary phase) and product yield (i.e. the fraction of IgG recovered in the product stream). All optimization is conducted under the constraint of 99% purity of the IgG. The model calibration and the analysis show that this purification step is determined mainly by the kinetics. although as large a protein as IgG is used in the study. The two different optima resulting from this study are a productivity of 2.7 g IgG/(s m(3)) stationary phase and a yield of 90%. This model-based approach also gives information of the robustness of the chosen operating conditions. It is shown that the bead diameter could only be increased from 15 mum to 35 mum with maximum productivity and a 99% purity constraint due to increased diffusion hindrance in larger beads. (C) 2004 Elsevier B.V. All rights reserved.
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| 9. |
- Kaunisto, Erik, et al.
(författare)
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A mechanistic modelling approach to polymer dissolution using magnetic resonance microimaging
- 2010
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Ingår i: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 147:2, s. 232-241
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Tidskriftsartikel (refereegranskat)abstract
- In this paper a computationally efficient mathematical model describing the swelling and dissolution of a polyethylene oxide tablet is presented. The model was calibrated against polymer release, front position and water concentration profile data inside the gel layer, using two different diffusion models. The water concentration profiles were obtained from magnetic resonance microimaging data which, in addition to the previously used texture analysis method, can help to validate and discriminate between the mechanisms of swelling, diffusion and erosion in relation to the dissolution process. Critical parameters were identified through a comprehensive sensitivity analysis, and the effect of hydrodynamic shearing was investigated by using two different stirring rates. Good agreement was obtained between the experimental results and the model. (C) 2010 Elsevier B.V. All rights reserved.
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| 10. |
- Kaunisto, Erik, et al.
(författare)
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Drug dissolution rate measurements - evaluation of the rotating disc method.
- 2009
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Ingår i: Pharmaceutical Development and Technology. - : Informa UK Limited. - 1083-7450 .- 1097-9867. ; 14, s. 400-408
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Tidskriftsartikel (refereegranskat)abstract
- Dissolution rate measurements are important to understand the behaviour of drugs or drug formulations. Many methods for measuring dissolution rates are available and a good choice should be based on method limitations as well as drug characteristics. In the present study the rotating disc method was critically evaluated for dissolution rate measurements, using aspirin and benzoic acid as model substances. Existing theory for the rotating disc was compared with experiments and a computational fluid dynamics (CFD) model simulating the USP vessel. Simulations showed that it is possible to predict mass transfer controlled drug release rates within the laminar flow regime. Mass transfer coefficients obtained from the CFD model were in better agreement with experimental data than those obtained from existing theory. It was concluded that the hydrodynamic boundary layer controlling release rates was in reality thicker than existing theory would suggest.
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