Utilising terahertz pulsed imaging to analyse the anhydrous-to-hydrate transformation of excipients during immediate release film coating hydration

Abstract

Pharmaceutical tablets are routinely film-coated to improve appearance, reduce medication errors and enhance storage stability. Terahertz pulsed imaging (TPI) can be utilised to study the liquid penetration into the porous tablet matrix in real time. Using polymer-coated flat-faced tablets with anhydrous lactose or mannitol, we show that when the tablet matrix contains anhydrous material, the anhydrous form transforms to the solid-state hydrate form in the tablet core while the immediate release coating dissolves. The process starts at the interface between the coating and the core. It commences inward for more than 7 min, resulting in a shell of hydrate form on the order of a few hundred microns thicknesses immediately underneath the dissolving coating. TPI is sensitive enough to detect and spatially resolve this process based on the subtle change in the refractive index of the two materials. TPI can further resolve tablets with different components using the time-domain waveforms in reflection and provide insights into the presence of hydrate material (lactose monohydrate) in altering the water mass transport mechanism. The kinetics data obtained from TPI fit the power law model ( $y = k t^{m}$ ), whose constants enable us to infer the different mass transport mechanisms.

Highlights

The immediate-release film coating behaves like a temporary water transport barrier.

The soluble polymers in the coating dissolve in water to enhance permeability.

Trace amounts of water molecules can diffuse through the coating into the tablet core.

The diffusion is facilitated thermodynamically by the anhydrous core excipients.

A thin layer of channel hydrates can develop in the core with lactose or mannitol.

Introduction

Oral solid dosage forms (OSDFs) provide a convenient platform to administer drugs to patients, and tablets are the most common OSDF due to their ease of manufacture, use, and storage (Bittorf et al., 2010, Zaid, 2020). To maintain the stability of the drug, tablets are routinely film-coated with a polymer barrier to shield the sensitive components from exposure to ultra-violet light and moisture to slow down degradation reactions (Göran Frenning, 2022, Zaid, 2020). Tablets are tested for their disintegration and dissolution profiles in the quality assurance lab (Göran Frenning, 2022). Although such tests can ensure that the tablets comply with the compendial standards to dissolve in the gastrointestinal (GI) tract rapidly, the mechanism of tablet disintegration cannot be understood from the outcome of such compliance tests.

Tablets are formulated with different excipients, in addition to the drug (or active pharmaceutical ingredient), to achieve the target product profile. One of these attributes is the mechanical strength of the tablets. In commercial tablet formulations, the binder (ductile material) and the filler (to support good compactibility) are necessary components to ensure that good mechanical properties can be achieved (Bittorf et al., 2010). While microcrystalline cellulose (MCC) is a very common binder because of its plasticity, lactose acts as the filler or diluent in the formulation to improve the tablet hardness (Göran Frenning, 2022). Lactose and mannitol also function as brittle fracture materials that help to mitigate strain rate sensitivity (short dwell time) effects during scale-up often observed with plastically deforming excipients like MCC (Paul et al., 2019). For immediate-release tablets, disintegrants, such as croscarmellose sodium (CCS) that rapidly swells by a considerable amount in contact with water, are also added to the formulation to promote immediate tablet disintegration in the GI tract (Göran Frenning, 2022). During the tablet hydration process, the collective interactions between these materials and water result in the tablet disintegration (Ekmekciyan et al., 2018). However, the disintegration and dissolution testings cannot investigate and quantify these interactions, which prevents the mechanistic understanding of the hydration process.

The introduction of process analytical technologies (PATs) facilitates the fundamental understanding towards the mechanism of OSDF disintegration (Peng et al., 2015). The application of magnetic resonance imaging (MRI) (Zhang et al., 2013, Quodbach et al., 2014), UV imaging (Gaunøet al., 2013, stergaard et al., 2014), holographic interferometry and electronic speckle pattern interferometry (Axelsson and Marucci, 2008), broadband acoustic resonance dissolution spectroscopy (O’Mahoney et al., 2020) and 3D tomographic laser-induced fluorescence imaging (Lenz et al., 2022), to name a few, has provided quantitative information to enrich the knowledge on the said mechanism. The dissolution of coated OSDF systems has been visualised by MRI (Malaterre et al., 2009) or UV imaging (Gaunøet al., 2013). These methods focussed principally on visualising and/or characterising the general aspects of the disintegration or dissolution process, while the interactions between the disintegration medium (e.g., water) and the film-coated tablet are not investigated in depth. Meanwhile, the contribution of individual components in tablet formulation has not been well-studied because of the measurement limitations.

Terahertz spectroscopy is another PAT to investigate the process of tablet disintegration or dissolution. Pulsed terahertz radiation in reflection mode can be utilised to detect the changes in the effective refractive indices
of the sample studied in the time domain Fitzgerald et al. (2005). This technique is also known as terahertz pulsed imaging (TPI). Since the dissolution medium (a liquid) has a different to the dry tablet core, TPI allows for investigating the liquid penetration process in real-time (Yassin et al., 2015b) and analysing the interactions between the liquid and the material in the porous matrix of the tablet core during this process (Yassin et al., 2015a, Markl et al., 2018, Al-Sharabi et al., 2020, Dong et al., 2021, Lee et al., 2023a). In addition to the hydration process of the tablet core, TPI can also be employed to study thin samples such as the film coating (Fitzgerald et al., 2005, Ho et al., 2008, Zhong et al., 2011, May et al., 2011, Brock et al., 2013, Lin et al., 2015, Lin et al., 2017). TPI can not only measure the thickness of the coating but also can characterise the dissolution process of the film coating (Dong and Zeitler, 2022, Dong et al., 2023). Coupled with optical coherence tomography, TPI plays a critical role in understanding the disintegration mechanism of immediate release film-coated MCC tablets (Ma et al., 2024). Other potential applications of TPI are discussed in Section 3.6.

This study focusses on the influence of the change in tablet formulation on the tablet hydration process. The pure MCC tablets have been extensively used in our TPI studies, that are discussed in the previous paragraph (Dong et al., 2023, Ma et al., 2024), in order to isolate the influences between different components in the formulation and simplify the characterisation of the disintegration mechanism. However, the commercial tablets are usually formulated with several components that response differently to the hydration process. The capillary liquid rise model for the water penetration within the MCC porous matrix is less applicable if significant interactions exist between the dissolution liquid and the porous matrix wall of the tablet core (Yassin et al., 2015a). An alternative water penetration mechanism is also expected to take place in the tablet core with soluble components. This study extends the investigation to tablets formulated with MCC and a soluble excipient (i.e., anhydrous lactose, monohydrate lactose, or anhydrous mannitol) to characterise the novel processes that take place as the tablet disintegration progresses. The erosion can complicate the investigation on the liquid–solid interaction during the tablet hydration, therefore, the disintegrant is not included in the scope of this study. Hence, this can facilitate our study from a fundamental science perspective in order to develop mechanistic insights rather than empirical understanding. The purpose of this study is for the results to further contribute to the fundamental understanding of the hydration mechanism and the predictive modelling of the disintegration process of the film-coated immediate release tablets.