Unveiling tablet structural changes: A micro computed tomography analysis of aqueous coating effects

Introduction

Tablet coating represents a prevalent pharmaceutical procedure employed for diverse purposes, such as taste masking, as well as the modification of the release profile of the active ingredient. Organic solvents are often employed to solubilize film-forming agents due to their quick evaporation, facilitating rapid film formation. Solvent-based coating methods may have advantages in terms of coating uniformity and manufacturing reproducibility, which are important for achieving desirable tablet quality (Seo et al. 2020). However, the use of organic solvents requires particular attention due to the greater risk of traces of these solvents in formulations, the risk of explosion and higher environmental pollution compared to the use of aqueous polymeric solutions (Seo et al. 2020).
Indeed, aqueous tablet coating offers several advantages, including cost-effectiveness, non-toxicity, and non-hazardous nature, making it more beneficial than organic solvent-based coatings (Khurana et al. 2014). The use of low environmental impact processes has become nowadays a mandatory requirement even in the pharmaceutical field.
However, the impact of aqueous coatings on tablet structure modification, such as porosity changes and micro-cracks formation remains undisclosed. In fact, the tablet exposure to high humidity environment may result in structural modifications, particularly in the case of tablets with hydrophilic core (Mabrouki and Hakim, 2022).

Microcrystalline cellulose (MCC) is a typical hydrophilic and multifunctional excipient, often used in tablet formulation, as diluent and disintegrant, but also to improve the compressibility of the tablet due to its plastic deformation behaviour (Mohylyuk et al. 2024). In addition, the use of super disintegrants such as sodium starch glycolate (SSG), may further affect changes in tablet structure as a consequence of a rapid variation in temperature and humidity leading to high residual stresses in tablet coatings, which may cause delamination and cracking (Haldar et al. 2022). Thus, examining alterations in the internal structure of the tablet could yield positive implications for process optimization and quality amelioration. Ciprofloxacin is an antimicrobial which, from a 2022 global survey, appears to have exceeded safety limits in 64 river sampling sites, and therefore represents a real risk in the increase of antimicrobial resistance (Wilkinson et al. 2022). For this reason, it represents a paramount example of active ingredients requiring a careful approach in the formulation and tablet production processes to avoid the risk of performance failure (suboptimal release and absorption upon oral administration) eventually resulting in an undesired environmental spreading.

The porosity of the tablets is classically investigated by gas pycnometry and mercury porosimetry; however, these techniques do not provide detailed information about the exact topographical distribution of the cracks or pores which instead require advanced image analysis methods. Furthermore, accurate porosity values can be obtained with gas pycnometry and mercury porosimetry only when the pores or micro-cracks in the tablet are interconnected (Farber, Tardos, and Michaels 2003). X-ray microcomputed tomography (XμCT) is a non-destructive imaging technique that provides high-resolution, three-dimensional visualizations of the internal structures of solid objects.

It is based on X-ray computed tomography principles but operates at a microscale level, allowing for detailed imaging of small and delicate samples. XμCT is widely utilized across various fields, including materials science, biology, geology, and medicine and already represents another useful tool in the inspection of tablets (Ferdoush et al. 2023). The projections of the sample are reconstructed to obtain a high-resolution three-dimensional image which allows the detailed examination of the objects. It has been applied to study the porosity of granules and compared with data obtained from a mercury porosimeter (Farber, Tardos, and Michaels 2003), to observe the assembled modules of the Dome Matrix® technology system, as well as to investigate their swelling behaviour (Losi et al., 2013, Strusi et al., 2010); in another study, XμCT was used to investigate the impact of droplet size on tablet coating porosity (Dennison et al. 2016). More recently this technique has been adopted to obtain information about tablet micro-cracks and film coating thickness (Borjigin et al. 2023) and to observe water absorption, tablet swelling and cracking over time (Ferdoush et al. 2023). Additionally, XμCT has been used for assessing the quality of 3D printed tablets, including parameters such as relative density, porosity, and pore distribution (Larsen et al. 2024). This instrument therefore represents a powerful tool for the characterization of oral solids.

The present study aimed to assess the impact of the aqueous film coating on the tablet’s physical changes using XµCT in combination with the material densification properties upon compression. The study was carried out on tablets containing ciprofloxacin as a model drug, MCC as diluent and SSG as disintegrant.

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Materials

The materials used in this study include Ciprofloxacin (Ph. Eur. Grade, Sigma Aldrich, Germany) as the model drug. Fine microcrystalline cellulose Avicel PH-105 (Pharma Excipients (Switzerland) was employed to create a compact with low initial porosity and high mechanical resistance due to the increased surface area of contact between particles (Wünsch et al. 2021). Sodium starch glycolate (Viva Star®, Germany) was used as a superdisintegrant. Methocel E3 Premium LV (Colorcon®, United Kingdom) served as the polymeric film former, and polyethylene glycol (PEG) 4000 (ACEF, Italy) was used as a plasticizer. Magnesium stearate (MS) (ACEF, Italy) was utilized as a lubricant for mixture compaction. Additionally, poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) dispersion (Eudragit® FS30D), generously provided by Pharma Excipients (Switzerland), was adopted for tablet enteric coating.

Methods

For the tablet production, 9 batches of mixtures of CPFX, MCC, SSG and MS (Table 1) were produced by mixing at 35 rpm (Turbula®, Willy A. Bachofen, Maschinen Fabrik, Basel, Switzerland) for 10 min. The weight of the powder mixture batch was around 75 g. Tablets (260 mg each) were produced using a Styl’One Evolution compaction simulator (MEDELPHARM, Beynost, France) equipped with 8 mm Euro D concave punches, using a compression force of 15kN and manually filling the die.

Davide D’Angelo, Eride Quarta, Gianluca Bazzoli, Annalisa Bianchera, Ruggero Bettini, Unveiling tablet structural changes: A micro computed tomography analysis of aqueous coating effects, International Journal of Pharmaceutics,
Volume 668, 2025, 125014, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.125014.

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