We have developed a new technique to better understand what happens to the microstructure inside a tablet during rapid disintegration. 

Background

Terahertz pulsed imaging (TPI) was first introduced in 2007 to non-destructively measure the coating thickness of pharmaceutical tablets. Ever since then, there has been a concerted research effort throughout the PSSRC to further develop and exploit this technique for improving the quality of pharmaceutical coatings and to shed light on the intricacies behind the pharmaceutical tablet coating process.

Introduction

Continuous processing is a promising approach for solid dosage manufacturing. High-shear wet granulation is performed in continuous mode using twin screw granulators (TSG), characterized by a modular screw profile including a sequence of different screw elements with various shapes, orientation and functions. For process engineers it is a challenge to come up with prediction models to establish the relationship between equipment and material attributes, process data and the end-product testing results. If a reliable model is available which is able to predict the quality of the product, it can be inverted to obtain the design space, corresponding to that set of operating conditions required for achieving the target product quality (Figure 1). Such a modelling framework combined with in-process measurements, can provide a good mechanistic insight into the important parameters of continuous

Introduction

The inter-tablet coating uniformity is a critical quality attribute in active coating processes. In this project an active coating process is performed in order to produce a fixed dose combination of a sustained release formulation in the tablet core and an immediate release dose in the coating layer. The tablet cores consist of a push-pull osmotic system containing nifedipine as API (Adalat GITS). They are coated with Candesartan cilexetil as a second API. As the inter-tablet coating uniformity is a critical quality attribute to comply with regulatory requirements, the purpose of this work is to enhance the process understanding and to optimize the coating process with regard to the coating uniformity. Besides experimental investigations, PAT tools such as Raman spectroscopy [1] and terahertz pulsed imaging [2] have been applied to study this active coating process. In recent years, numerical simulations of coating processes have been gaining interest as analytical tool [3]. The discrete element method (DEM) in particular is suitable to simulate the tablet motion [4]. In this project, both experimental and numerical analysis of an active coating process is combined to investigate the influence of different process parameters with respect to the optimization of the coating uniformity.

Magnetic Resonance Imaging

The use of MRI as a powerful imaging and characterization modality in pharmaceutical dissolution research is now well established [1]. The non-invasive and non-destructive nature of MRI enables the investigation of structural, chemical and dynamical processes in many optically opaque systems at the microscopic level. Spatial maps of water penetration, tablet swelling and dissolution, as well as the mobilization and distribution of drug products can now be quantified and visualized [2,3]. In addition, the hydrodynamics within a USP recommended flow-through dissolution apparatus can also be visualized by MRI [4]. Such comprehensive information is essential in pharmaceutical research for: (i) the correct interpretation of conventional drug dissolution profiles and (ii) the optimal design (QbD) of controlled release formulations.

Terahertz Pulsed Imaging

Since 2007 when terahertz pulsed imaging (TPI) was first developed to non-destructively measure the coating thickness of pharmaceutical tablets there has been intense research in the PSSRC into how this technique can help improve the quality of pharmaceutical coatings and thus make controlled release technology based on coatings of single dosage forms attractive to industry.