Development of a digital twin of a tablet that mimics a real solid dosage form: Differences in the dissolution profile in conventional mini-USP II and a biorelevant colon model

The performance of colon-targeted solid dosage forms is commonly assessed using standardised pharmacopeial dissolution apparatuses like the USP II or the miniaturised replica, the mini-USP II. However, these fail to replicate the hydrodynamics and shear stresses in the colonic environment, which is crucial for the tablet’s drug release process. In this work, computer simulations are used to create a digital twin of a dissolution apparatus and to develop a method to create a digital twin of a tablet that behaves realistically. These models are used to investigate the drug release profiles and shear rates acting on a tablet at different paddle speeds in the mini-USP II and biorelevant colon models to understand how the mini-USP II can be operated to achieve more realistic (i.e., in vivo) hydrodynamic conditions.

The behaviour of the tablet and the motility patterns used in the simulations are derived from experimental and in vivo data, respectively, to obtain profound insights into the tablet’s disintegration/drug release processes. We recommend an “on-off” operating mode in the mini-USP II to generate shear rate peaks, which would better reflect the in vivo conditions of the human colon instead of constant paddle speed.

Introduction

The performance of a drug formulation is commonly accessed using United States Pharmacopeia (USP) dissolution apparatus. Besides drug performance analysis, this in vitro drug testing tool is also used in product development and quality control (Abrahamsson et al., 2005; Stamatopoulos et al., 2015). The USP dissolution apparatus are simplified in vitro models also used to replicate the complex in vivo conditions in the gastrointestinal tract that significantly control the disintegration/dissolution process of a solid dosage form (e.g., shear stresses evoked by wall motion) (Schütt et al., 2021). The USP II is the commonly most used USP dissolution apparatus for evaluating solid oral dosage forms (Stamatopoulos et al., 2015). The USP II is a container equipped with an agitator (paddle) and a fluid volume capacity of approximately one litre (Stamatopoulos et al., 2015). The most commonly used volumes are 500 and 900 mL. A miniaturised version of the USP II, the mini-USP II has received more attention in recent years because this dissolution test device requires significantly less material mass than its larger counterpart (i.e., fluid volume of approximately 100 mL) (Stamatopoulos et al., 2015; Klein and Shah, 2008). This is of particular interest when biorelevant media or cost-intensive samples are used (Klein and Shah, 2008).

The dissolution profile of a solid dosage is of paramount importance in the development and optimisation of new formulations. Furthermore, the dissolution profile serves as a basis for physiologically based pharmacokinetic models (PBPK) to predict the absorption of drugs based on human physiology and their chemical properties (Stamatopoulos, 2022).

Investigations of the USP II showed that the shear rates in this dissolution apparatus depend on the paddle speed used (Hopgood et al., 2018). These results can also be transferred to the mini-USP II (Klein and Shah, 2008). However, Schütt et al. (2021) showed in a computational model of the proximal colon and a modelled tablet that the shear stresses acting on the tablet surface and thus influencing the tablet drug release process mainly depend on the colonic motility and the forces are dynamic.

In this study, we develop a method to model create a digital twin of a tablet with the same disintegration/dissolution behaviour as a real tablet. Additionally, we create a digital twin of the mini-USP II dissolution apparatus and validate the hydrodynamic conditions with experimental and computational data from Stamatopoulos et al. (2015) and Wang and Armenante (2016). Then, we use experimental dissolution data of a tablet from Stamatopoulos et al. (2015) and model a tablet that behaves similarly in the modelled mini-USP II. Finally, this tablet is used in a biorelevant computational model of the proximal colon replicating in vivo motility patterns to evaluate the difference in drug release profile in the simplified in vitro model and the more realistic colon model. The motility patterns used in the colon models (i.e., called ‘PEG’ and Maltose’) are reproduced from Schütt et al. (2021).

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M. Schütt, K. Stamatopoulos, H.K. Batchelor, M.J.H. Simmons, A. Alexiadis, Development of a digital twin of a tablet that mimics a real solid dosage form: Differences in the dissolution profile in conventional mini-USP II and a biorelevant colon model, European Journal of Pharmaceutical Sciences, Volume 179, 2022, 106310, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2022.106310