A highly absorbing substrate based on functionalized calcium carbonate for personalized dosing of clonidine by drop-on dispensing

Abstract

As precision medicine advances, the need for customizable drug delivery systems has become increasingly important. In this study, we developed porous tablets as substrates for drop-on dispensing of drug-containing ink in personalized doses. We evaluated this approach with clonidine hydrochloride, a hydrophilic drug prescribed in low doses for pediatric patients with hypertension. Porous tablets were compacted from functionalized calcium carbonate (FCC), a filler with a mesoporous structure that can absorb water-based ink without loss of tablet integrity. To improve the compactibility of FCC, the powder was dry granulated and mixed with two different binders: either microcrystalline cellulose (MCC) or ethylcellulose (EC). This was done in various ratios either intragranularly or extragranularly. Tablets (6 mm diameter × 1.6–1.7 mm thickness) with 9.5% (w/w) MCC as intragranular or with 5.0% (w/w) EC as extragranular binder could be loaded with 30 µl clonidine-containing ink. Dissolution experiments in acidic medium (pH 2.0 at 37 °C), mimicking the conditions of the stomach, showed release of clonidine with almost complete dissolution of the drug after 1–2 h. Our findings demonstrate the potential of FCC porous tablets as substrates for drop-on dispensing in the context of personalized dosing of medicines.

Introduction

Tablets remain the most widely used dosage form valued for their convenience and acceptance among most patient groups. However, the prevailing “one dose fits all” approach in oral medications leaves little room for personalization. This is particularly problematic for vulnerable populations such as babies, children, the elderly, and patients with special needs, for whom appropriate commercial dosage forms are often unavailable. Flexible dosing strategies have great potential to enhance therapeutic outcomes and reduce the risks of over- or under-dosing in these populations. For example, reviews in pediatric antibiotic therapy show that standard dosing often leads to drug exposure outside therapeutic ranges, whereas model-informed or individualized therapy reduce variability in exposure and minimize the risk of toxicity or therapeutic failure (Abdulla et al., 2021, Darwich et al., 2006).

Pediatric formulations require individualized dose adjustments typically based on body mass or body surface area, which poses several challenges. Classical extemporaneous compounding methods, such as the preparation of oral solutions and capsules, may offer accuracy but are often limited by issues related to patient compliance, palatability, stability, and content uniformity (Khan et al., 2022, van Riet-Nales et al., 2017). Additionally, such methods are time-consuming and require trained personnel to compound the formulations. An alternative practice involves manipulating registered medications by patients, e.g. splitting or crushing of tablets, which is imprecise and potentially unsafe when performed by untrained individuals in home settings (Helmy, 2015, Zaid et al., 2013). Therefore, minimizing these manual interventions is essential for ensuring safe and accurate dosing.

There is a need for developing novel dosage technologies to address the gap in pediatric-appropriate formulations (Khan et al., 2022). Exploring innovative compounding methods such as 2D and 3D printing, which can be automated and validated, is particularly relevant for achieving accurate compounded dose formulations. 3D printing technologies have been extensively investigated for the fabrication of personalized oral dosage forms, including fused deposition modeling, binder jetting, and selective laser sintering (Krause et al., 2021, Pawar and Pawar, 2022, Shammout et al., 2025, Windolf et al., 2022). These approaches enable flexible dose adjustment and complex geometries, like tablets in different shapes (Aina et al., 2025, Goyanes et al., 2017), cereals (Karavasili et al., 2022), and dosage forms (Poudel et al., 2024). However, 3D printing requires large formulation volumes for the manufacturing of dosage forms that result in exaggerated effects of drug distribution inhomogeneities, especially for low-dose medications. Additionally, many 3D printing techniques require high processing temperatures, which may not be suitable for heat-sensitive drugs (Kollamaram et al., 2018, Murugan et al., 2024). In contrast, drop-on dispensing of drug-containing inks onto solid supports, e.g. by pipetting or 2D printing, offers greater dose accuracy and flexibility, particularly for formulations with low drug content, making it a promising alternative approach for the compounding of personalized medicine (Evans et al., 2021, Alomari et al., 2015, Genina et al., 2013). Drop-on dispensing also serves as a segue to 2D inkjet printing, which follows the sample application principle but in an automated manner.

In this study, we explored the feasibility of using functionalized calcium carbonate (FCC; Omyapharm 500-OG) as major component in tablets that can be used for drop-on dispensing or 2D inkjet drug printing. FCC is offered in different grades for pharmaceutical compounding, and is commercially available in GMP grade via commercial suppliers (EXCiPACT, 2025). FCC was selected due to its mesoporous lamellar structure, which, upon compaction, forms strong tablets (Stirnimann et al., 2013). The porous structure of FCC facilitates rapid water absorption via capillary forces. While this feature will favor the uptake of water based inks by FCC tablets, FCC readily dissolves in the acidic environment of the stomach, making it well-suited for immediate-release formulations where drug dissolution needs to occur rapidly (Niu et al., 2022). Unlike freeze-dried tablets or printed oral films which also have been used for 2D printing (Öblom et al., 2020, He et al., 2025), FCC tablets retain the familiar ‘look and feel’ of traditional tablets, improving compliance. Additionally, the high porosity of FCC allows for ink absorption, overcoming dose limitations often encountered in film-based 2D printing (Iftimi et al., 2019, Turković et al., 2021).To address this limitation, progress has been made in the field of 2D printing on polymeric substrates, where freeze-dried hydrophilic polymers (HPMC; Metolose 60SH-4000) were used to create porous tablet-like substrates, which subsequently were precisely loaded with the antidepressant drug citalopram and carvedilol (Ahola et al., 2024, He et al., 2025). While their work highlights the potential of engineered porous scaffolds obtained from lyophilized polymers, our study offers a scalable alternative using conventional compacted tablets.

As a model drug, we selected clonidine hydrochloride, a BCS I drug with high solubility and permeability. Clonidine is on the list of the top 20 active pharmaceutical ingredients (APIs) most compounded globally as pediatric oral extemporaneous preparations (Fadda et al., 2024). Clonidine is commonly prescribed in pediatric patients for conditions such as hypertension, sedation, and behavioral disorders (Erickson and Duncan, 1998). Its commercially available formulations are primarily designed for adults, necessitating significant dose adjustments in pediatric use. This increases the risk of dosing errors and variability (Suchard and Graeme, 2002). Clonidine’s low required pediatric dose (0.5–25 µg/kg) makes it particularly suitable for 2D printing, where high drug solubility in the ink is critical for precise dosing.

The primary objective of this study is to establish porous FCC tablets as a viable substrate for 2D-printed personalized medication. We optimized the formulation of FCC tablets for controlled ink absorption, evaluated the conditions for ink deposition and drying to ensure accurate drug loading, and demonstrated a proof-of-concept by printing clonidine onto FCC tablets and assessing drug release through in vitro dissolution testing.

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Materials

Functionalized calcium carbonate (Omyapharm 500-OG) was generously provided by Omya (Oftringen, Switzerland). Microcrystalline cellulose PH102 (MCC) and magnesium stearate were purchased from Fagron (Rotterdam, the Netherlands). Aqualon EC-T10 (Aualon T 10)ethylcellulose (EC) was provided by Ashland (Wilmington, USA). Clonidine hydrochloride was purchased from BUFA, Spruyt Hillen (Capelle aan de IJssel, the Netherlands). Sulfan blue dye was purchased from Sigma-Aldrich (Saint Louis, USA). Demineralized water was utilized as the solvent for the ink solution.

T. Lashkari, W.E. Hennink, S.M. Hassanizadeh, J.H.J. Quodbach, R.J. Kok, A highly absorbing substrate based on functionalized calcium carbonate for personalized dosing of clonidine by drop-on dispensing, International Journal of Pharmaceutics, Volume 693, 2026, 126677, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.126677.