It is challenging to achieve mechanically robust drug-release profiles from hydrophilic matrices containing a high dose of a drug with good solubility. However, a mechanically robust drug release over prolonged period of time can be achieved, especially if the viscosity and amount of the polymer is sufficiently high, above the "threshold values." The goal of this research was to determine the hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) polymer threshold amount that would enable robust drug release from matrix tablets containing a high dose of levetiracetam as a class I model drug according to the Biopharmaceutical Classification System (BCS). For this purpose, formulations containing HPC or HPMC of similar viscosity range, but in different amounts, were prepared. Based on the dissolution results, two final formulations were selected for additional in vitro and in vivo evaluation to confirm the robustness and to show bioequivalence. Tablets were exposed to various stress conditions in vitro with the use of different mechanically stress-inducing dissolution methods. The in vitro results were compared with in vivo results obtained from fasted and fed bioequivalence studies. Under both conditions, the formulations were bioequivalent and food had a negligible influence on the pharmacokinetic parameters C max and area under the curve (AUC). It was concluded that the drug release from both selected formulations is mechanically robust and that HPC and HPMC polymers with intrinsic viscosities above 9 dL/g and in quantities above 30% enable good mechanical resistance, which ensures bioequivalence. In addition, HPC matrices were found to be more mechanically robust compared to HPMC.

Abstract. The aim of this work was to establish alternative in vitro dissolution method with good discrimination and in vivo predictability for the evaluation of HPMC extended release matrix tablets. For this purpose, two different HPMC matrix tablet formulations were first evaluated by a range of conventional dissolution testing methods using apparatus 1, apparatus 2, and apparatus 3 according to US Pharmacopoeia. Obtained results showed low discrimination between the tested samples. Afterward, a novel dissolution testing method which combines plastic beads and apparatus 3 was developed with the aim to better mimic the mechanical forces that occur in vivo. Results showed that sufficiently large mechanical stress with high dips per minute program setting (apparatus 3) was needed to obtain in vitro discriminative results, which are in accordance with the in vivo data. The in vivo relevance of the method was confirmed with the establishment of the level A in vitro-in vivo correlation.

A novel dissolution apparatus has been proposed as an alternative apparatus for dissolution testing. In this study, we evaluated the performance of the new intestine model for simulating the peristaltic action (IMSPA), generating the movement that closely mimics peristaltic contractions of the small intestine. Two polyethylene oxide matrix tablet formulations, containing a model drug belonging to class III of the Biopharmaceutics Classification System, were tested. Dissolution was also performed in the USP2 apparatus. The release profiles were further compared to the in vivo data to evaluate the in vivo relevance of the new apparatus. The results demonstrated that the novel apparatus showed good discriminatory power between different polyethylene oxide formulations. Moreover, a better relation to the in vivo data was established by the IMSPA as compared to the USP2 apparatus. In conclusion, the model parameters were efficiently controlled to ensure the dissolution conditions crucial for evaluating the in vivo release performance of the tested formulations.