Atecegatran fexenetil

Drug product dissolution is a key input to Physiologically Based Biopharmaceutics Models (PBBM) to be able to predict in vivo dissolution. The integration of product dissolution in PBBMs for immediate release drug products should be mechanistic, i.e. allow to capture the main determinants of the in vitro dissolution experiment, and extract product batch specific parameter(s). This work focussed on the Product Particle Size Distribution (P-PSD), which was previously shown to integrate the effect of dose, volume, solubility (pH), size and concentration of micelles in the calculation of a batch specific input to PBBMs, and proposed new hydrodynamic (HD) models, which integrate the effect of USP2 apparatus paddle rotation speed and medium viscosity on dissolution. In addition, new models are also proposed to estimate the quantitative impact of formulation and drug sedimentation or "coning" on dissolution. Model "HDC-1" predicts coning in the presence of formulation insoluble excipients and "HDC-2" predicts the sedimentation of the drug substance only. These models were parameterized and validated on 166 dissolution experiments and 18 different drugs. The validation showed that the HD model average fold errors (AFE) for dissolution rate prediction of immediate release formulations, is comprised between 0.85 and 1.15, and the absolute average fold errors (AAFE) are comprised between 1.08 and 1.28, which shows satisfactory predictive power. For experiments where coning was suspected, the HDC-1 model improved the precision of the prediction (defined as ratio of "AAFE-1"values) by 2.46 fold compared to HD model. The calculation of a P-PSD integrating the impact of USP2 paddle rotation, medium viscosity and coning, will improve the PBBM predictions, since these parameters could have an influence on in vitro dissolution, and could open the way to better prediction of the effect of prandial state on human exposure, by developing new in silico tools which could integrate variation of velocity profiles due to the chyme viscosity.

A study has been carried out to investigate controlled release performance of caplet shaped injection moulded (IM) amorphous solid dispersion (ASD) tablets based on the model drug AZD0837 and polyethylene oxide (PEO). The physical/chemical storage stability and release robustness of the IM tablets were characterized and compared to that of conventional extended release (ER) hydrophilic matrix tablets of the same raw materials and compositions manufactured via direct compression (DC). To gain an improved understanding of the release mechanisms, the dissolution of both the polymer and the drug were studied. Under conditions where the amount of dissolution media was limited, the controlled release ASD IM tablets demonstrated complete and synchronized release of both PEO and AZD0837 whereas the release of AZD0837 was found to be slower and incomplete from conventional direct compressed ER hydrophilic matrix tablets. The results clearly indicated that AZD0837 remained amorphous throughout the dissolution process and was maintained in a supersaturated state and hence kept stable with the aid of the polymeric carrier when released in a synchronized manner. In addition, it was found that the IM tablets were robust to variation in hydrodynamics of the dissolution environment and PEO molecular weight.