Hydrophilic polymers represent the basis for prolonged-release dosage forms. High molecular weight (Mw) polyethylene oxides (PEO), which are non-toxic, non-ionic and well-soluble polymers, are commonly used. The Mw of the PEO polymer is a crucial property that determines the properties of the polymer on the solutions, films, powders, and tablets levels. Identification of these properties is crucial for the proper design of the matrix tablets with the desired release kinetics and constant and safe plasma concentration of the active substance. Our doctoral thesis thus focused on the determination of the critical properties of the PEO polymer and their impact on the final properties of prepared PEO polymers on the solutions, films, powders, and tablets levels. We systematically studied the impact of PEO polymers with several Mw (1 x 106 g / mol, 2 x 106 g / mol and 4 x 106 g / mol) and their concentrations on the properties of their solutions, films, powders and tablets, with emphasis on explaining the difference in the release kinetics of the active substance from the prepared matrix tablets. Using the rotation and oscillation methods for determining polymer viscosity, we detected significant differences between the studied solutions of selected Mw of PEOs. We confirmed that Mw is a crucial property of polymers that determines the viscosity of prepared PEO solutions and consequently also their properties on the films and tablets levels. Using the oscillation method, we determined critical solution concentrations, which represent the polymer solution concentration at which the gel is formed. The critical polymer solution concentrations decrease as the Mw increases, and were 4.4% for a PEO with Mw of 1 x 106 g / mol, 3.2% for a PEO with Mw of 2 x 106 g / mol, and 1.8% for a PEO with Mw of 4 x 106 g / mol.
Further, we used X-ray diffraction (XRD), differential dynamic calorimetry (DSC), small-angle X-ray scattering (SAXS), wide-angle X-ray scattering (WAXS), and nanoindentation (NI) methods to confirm the differences between individual Mw of PEOs on the films and powders levels. No differences between individual Mw of PEOs on any of the studied levels were detected using the DSC, XRD, WAXS, and NI methods, while results obtained with the SAXS method confirmed a different physical behaviour of PEO with a Mw of 4 x 106 g / mol on the powders level due to the differences in the size of nanostructures and fractal dimensions of surfaces, which have an impact on the resistance of the diffusion system, and slow down the release of the active substance. Additionally, we used the DSC method with hot-stage optical microscopy to determine the heat of coalescence for PEO powders bteween 164 and 170 °C. The correlation between fractal surface dimensions obtained by the SAXS method and the ratio between the heat of coalescence and the heat of fusion measured by the DSC method indicates the differences between the selected PEO polymer Mws. We established that at the film level, the NI method can detect statistically significant differences between the different types of polymers (PEO, hydroxypropyl methylcellulose (HPMC), xanthan, and polyvinyl alcohol (PVA)). Further on, the detected differences in the solutions, powders, and films levels were confirmed on the level of tablets by using magnetic resonance imaging (MRI). We identified the penetration, swelling, and erosion fronts that form during the swelling of PEO polymers with selected Mw, and evaluated the effect water-soluble substances (excipients and active substance) have on them. The matrix tablets were exposed to static (no medium flow) and dynamic (medium flow: 12 ml / min and 64 ml / min) conditions. The release of the active substance was significantly faster under dynamic conditions and was even further accelerated by increased media flow. Under static conditions, the swelling rate of the PEO matrix tablets is independent of its Mw. The differences between individual PEO Mw are detected only at the beginning of the medium penetration rate. This rate is the highest in PEOs with the highest Mw (4 x 106 g/mol), and comparable in PEOs with lower Mw (1 x 106 g / mol and 2 x 106 g / mol) due to the differences in the crystallinity and complexity of the polymer structure, which decrease as the Mw increases. In contrast, the erosion rate is the highest in PEOs with the lowest Mw. It becomes proportionaly pronounced under dynamic conditions. The differences in gel thickness are the result of different levels of viscosity of the formed gels and polymer connections, which depend on PEO Mw and the addition of water-soluble excipients (fillers, binders and polyethylene glycol), which accelerate the formation and decomposition of the gel and cause the release of the active substance from the matrix tablets. Our conclusions were further confirmed by model calculations, and we proved that under static conditions the release of the active substance from matrix tablets is diffusion-controlled, and the proportion of the released active substance strongly correlates (r2 = 0.91) with the thickness of the formed gel layer. Under dynamic conditions, the release of the active substance depends on both processes; diffusion of the active substance and erosion of the polymer, which is confirmed by the relationship between the erosion coefficient and the thickness of the gel layer (r2 ≥ 0.98). On the level of tablets, we prepared binary systems of PEO polymers with selected Mw and the active substance, and determined their percolation threshold. The percolation threshold correlate well with Mw (r² = 1.00), and was 18% for PEO with Mw of 1 x 106 g / mol, 16% for PEO with Mw 2 x 106 g / mol, and 12% for PEO with Mw 4 x 106 g / mol. We concluded that the addition of water-soluble excipients and the increased surface area of tablets significantly increased (>27%) the percolation threshold of the PEO polymer with a Mw of 2 x 106 g / mol. Our results were further supported by the correlations with in vivo results, and demonstrated a good correspondence between solution viscosity and the maximum plasma concentration (Cmax) (r² = 1.00), as well as with area under the curve (AUC) (r² = 0.94). Additionally, good correlation (r² ≥ 0.88) was detected between the in vivo data (Cmax and AUC), and the elastic modulus (E) determined by the NI method. In the last part of our thesis, we showed that by use of appropriate PEO polymer concentration (53%) with Mw of 5 x 106 g / mol, we can produce matrix tablets with efficacy and robustness properties similar to those of matrix tablets containing 37% HPMC K4M (substitution type 2208). We showed how the choice of in vitro methods for evaluating the mechanical resistance of matrix tablets impacts the similarity between the selected PEO and HPMC dosage forms. Through research concluded within the scope of our doctoral thesis we showed that Mw represents a crucial property of the PEO polymer in that it determines the mechanical properties of its powders, solutions, films, and tablets.
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