Browsing by Author "Langguth, Peter"

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    Development of a Universal In Vivo Predictive Dissolution Method for a Borderline BCS III/IV Drug Guided by Modeling and Simulations-Acyclovir as a Case Study
    (2025) García, Mauricio A.; Tapia, Fernando; Escares, Benjamín; Langguth, Peter
    Establishing in vivo predictive dissolution (IPD) conditions requires the consideration of biopredictive aspects during dissolution. For acyclovir, lower dose strengths (200 and 400 mg) can dissolve completely in the gastrointestinal fluids. However, luminal concentrations after administering the highest strength (800 mg) exceed the BCS solubility threshold. Given its poor permeability, sink conditions are not granted for the highest strength. In this study, a universal IPD method for acyclovir tablets was developed using the mini-vessel/mini-paddle apparatus. Computational simulations in a physiologically based pharmacokinetic (PBPK) model further guided the development. Apparatuses with different volumes and stirring conditions were explored, and results served as input for the model. Dissolution of 800 mg of acyclovir tablets in 900 mL of medium largely overpredicted observed plasma profiles due to poor resemblance of nonsink conditions in the lumen. Conversely, dissolution in the mini-vessel filled with 135 mL of HCl, pH 2.0, at 150 rpm, produced accurate predictions of plasma profiles, without affecting previous successful predictions with the lowest strength tablets. Furthermore, in-human and virtual bioequivalence studies confirmed the predictive potential of this method. Therefore, the aforementioned dissolution conditions can be considered as a universal IPD method for acyclovir immediate-release tablets.
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    Solubility vs Dissolution in Physiological Bicarbonate Buffer
    (Springer, 2024) Claussen, Felix; Al-Gousous, Jozef; Salehi, Niloufar; García Alcalde, Mauricio Andrés; Amidon, Gordon L.; Langguth, Peter
    Background: Phosphate buffer is often used as a replacement for the physiological bicarbonate buffer in pharmaceutical dissolution testing, although there are some discrepancies in their properties making it complicated to extrapolate dissolution results in phosphate to the in vivo situation. This study aims to characterize these discrepancies regarding solubility and dissolution behavior of ionizable compounds. Methods: The dissolution of an ibuprofen powder with a known particle size distribution was simulated in silico and verified experimentally in vitro at two different doses and in two different buffers (5 mM pH 6.8 bicarbonate and phosphate). Results: The results showed that there is a solubility vs. dissolution mismatch in the two buffers. This was accurately predicted by the in-house simulations based on the reversible non-equilibrium (RNE) and the Mooney models. Conclusions: The results can be explained by the existence of a relatively large gap between the initial surface pH of the drug and the bulk pH at saturation in bicarbonate but not in phosphate, which is caused by not all the interfacial reactions reaching equilibrium in bicarbonate prior to bulk saturation. This means that slurry pH measurements, while providing surface pH estimates for buffers like phosphate, are poor indicators of surface pH in the intestinal bicarbonate buffer. In addition, it showcases the importance of accounting for the H2CO3-CO2 interconversion kinetics to achieve good predictions of intestinal drug dissolution.