Mechanistic Multiscale Modelling Of Drug Release from Immediate Release Tablets

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Immediate release (IR) tablets manufactured via direct compression are the most popular oral solid dosage forms to deliver active pharmaceutical ingredients (APIs) to patients. In order to absorb the drug molecues, the tablet needs to be disintegrated in the gastrointestinal (GI) tract to release the API crystals for dissolution. In vitro dissolution testing plays a vital role throughout the IR tablet product development life-cycle, aiming to probe API release profile to inform selection of formulation candidates and identify the impact of variants of the formulation and/or manufacturing processes on in vivo performance. Current compendial dissolution tests can neither reflect the actual conditions of the GI tract of a patient nor are they suitable to predict the drug release performance in vivo. The best way to achieve this is to model the tablet drug release profile based upon a thorough understanding of the underlying physics. However, the current dissolution model cannot predict the drug release from an IR tablet accurately because it assumes the spherical shape of the dissolving particles, without considering crystal morphology and its face specific dissolution properties. There is no direct connection between the disintegration and dissolution models, where the disintegration process is simply treated as a time delay function to initiate API dissolution, although IR tablet disintegration is considered as the key step in controlling API dissolution. Additionally, there is no mathematical model available which can accurately capture the overall physics of an IR tablet disintegration. The situation is further complicated by diversity of excipients used in the formulation, processing and manufacturing facilities and dissolution environments. This proposal will explore how the drug release profile of an IR tablet in the GI tract can be predicted based on the integrated mechanistic models for disintegration and novel API dissolution models, leading to a step change in our ability to model, analyse, and predict API release profiles. The challenges will be tackled by two leading research groups from De Montfort University and University of Surrey, representing a new multidisciplinary collaboration. The group brings together essential expertise in crystallisation science, molecular dynamics, formulation science, pharmaceutical manufacturing, and Raman spectroscopy/imaging. Through experimental and computational efforts, we will develop a modelling framework that accurately predicts the drug release behaviours of IR tablets in the GI tract. This will enable IR tablets to be designed and tested virtually to provide clinically relevant dissolution specifications for the desired clinical performance, having potential to revolutionise IR product design as well as the opportunity to speed up innovation to bring pharmaceuticals to market more quickly and cost-effectively and save lives.