@misc{Staniszewska_Marcela_Application_2024,
 author={Staniszewska, Marcela},
 address={Kraków},
 howpublished={online},
 year={2024},
 school={Rada Dyscypliny Nauki farmaceutyczne},
 language={eng},
 abstract={Biopharmaceutical evaluation of immediate release (IR) solid oral dosage forms relies on the understanding of their interaction with a gastrointestinal environment. However, fasted gastric conditions are characterized by substantial variability of fluid properties, e.g., pH, temperature, emptying rate, and motility patterns. The in vitro simulation of the above-mentioned gastric conditions is challenging due to a number of physiological parameters, their variability and the limited ability of compendial tests to recreate the mechanical stresses. To address this challenge, the aim of this thesis was to develop a new strategy for characterizing IR drugs. To complete it, the dissolution experiments had to be conducted in an apparatus able to simulate the fasted gastric conditions, especially gastric motility patterns. These requirements were fulfilled by PhysioCell - a novel bio-mimicking dissolution device, which was used for evaluating various IR formulations under bio-relevant conditions. Its ability to simulate gentle gastric movements was investigated using flow pattern visualization and with dissolution tests of a solid oral dosage form. Then, a single dissolution test protocol with fixed simulated pressure events was applied to characterize several IR tablets of the originator product and generic product candidates with vortioxetine hydrobromide. Next, a novel framework for},
 abstract={evaluating IR dosage forms' interaction with variable fasted gastric conditions was proposed. A number of physiologically-relevant test scenarios were constructed based on the Design of Experiments (DoE) methodology. These scenarios included defined ranges of timing and magnitude of pressure events and dissolution medium pH. Three types of IR formulations - soft capsules with ketoprofen and hard capsules and pellets with dabigatran etexilate mesylate - were tested and characterized regarding their susceptibility towards the simulated fasted stomach conditions. Lastly, machine learning (ML) algorithms were used to build the drug dissolution models using the experimental data generated using the DoE approach. The initial investigations showed how the mixing contractions of the PhysioCell's elastic sleeve influenced the pH gradient of the dissolution medium and accelerated the dissolution rate of IR tablets. The test conditions were optimized and used for further dissolution experiments. In the next step, the bio-relevant test protocols that included fixed timing of intragastric stress and gastric emptying events, were successfully used to differentiate between the originator product and newly developed IR tablets with vortioxetine hydrobromide of the same strength. The dissolution profiles obtained in PhysioCell showed that the originator’s dissolution was enhanced by the simula},
 abstract={ted intragastric stresses. After proving the system’s applicability for IR dosage form characterization, PhysioCell was utilized in the novel framework. The scenarios with varied timing and magnitude of pressure events constructed using DoE methodology were able to indicate how ketoprofen dissolution from soft capsules depended on the simulated gastric motility patterns. Next, the in vitro dissolution studies with simulated variable gastric pH and motility patterns were run. Results showed the dependence of dabigatran etexilate release from pellet-filled hard capsules and bare pellets on the tested physiological parameters. Lastly, the ML models constructed using the experimental data were used to generate multiple individual dissolution profiles as a function of simulated physiological parameters: pressure events and pH of gastric fluid. The simulated dissolution profiles covered a wide range of parameter combinations that were not included in the DoE-based experimental matrices. They comprehensively predicted how the tested formulations would disintegrate and dissolve within the full range of the parameters characterizing a fasted stomach. In summary, this dissertation proposed a new strategy for characterizing IR solid dosage forms in variable fasted gastric conditions. It showed that combining bio-relevant dissolution apparatus with model supported experiments design and ML},
 abstract={modeling techniques may broaden the understanding of IR formulations.},
 title={Application of biomimicking dissolution system for the characterization of oral dosage forms under variable fasted conditions of gastric motility and gastric fluid pH},
 type={Praca doktorska},
 keywords={biomimicking dissolution apparatus, in vitro dissolution, design of experiments, machine learning, fasted stomach, immediate release dosage forms},
}