Abstract

Minitablets represent a promising oral solid dosage form that allows for a wide range of doses within a single formulation. They are particularly suitable for pediatric and geriatric patients. Their small size facilitates administration by improving swallowability, making them an effective alternative for patients who have difficulty swallowing conventional tablets or capsules. This study describes the composition and manufacturing method of minitablets containing atomoxetine hydrochloride as a model drug. The minitablets were prepared using a direct compression method, utilizing the synergistic action of two fillers/diluents with different deformation properties: plastic microcrystalline cellulose and brittle anhydrous dibasic calcium phosphate. The resulting minitablets demonstrated satisfactory mechanical strength and met the required dosage unit uniformity. They also achieved dissolution rates consistent with the relevant monograph. Comparison with commercially available reference products in the form of hard capsules filled with a powder mixture confirmed the potential of minitablets as an effective alternative form of the drug.

Introduction

Minitablets are a type of oral solid dosage form (OSDF), defined as tablets with a diameter of up to 3 mm. Their production does not require specialized manufacturing equipment. The main difference compared to the production of standard tablets lies in the use of special, highly precise tablet tooling, such as single- or multi-tip punches and dies [1-4].

Due to their small size, minitablets are a practical option for oral drug administration, especially for patients with swallowing difficulties, including children and the elderly. Their compact form facilitates ingestion, allows dose flexibility, and improves patient acceptability, making them a promising alternative to conventional dosage forms, such as tablets or capsules. It is worth noting that dosing is considerably more precise, and the reliability of drug release is more consistent with minitablets compared to the aforementioned traditional dosage forms [5-8].

Paediatric patients, in particular, represent a highly diverse group. They are typically divided into subgroups that differ significantly in physiological and pharmacokinetic characteristics, swallowing ability, and drug metabolism, necessitating tailored dosage forms and delivery systems [9,10]. Multiple studies have reported the high acceptability and practicality of minitablets in children. For instance, Klingmann et al. demonstrated that even very young children could swallow over 25 minitablets with 5 – 10 mL of syrup. Children aged 2–5 years tolerated up to 100 minitablets without difficulty [11]. Similarly, Mitsui et al. found that infants aged 6–11 months were able to swallow 4 minitablets more easily than fine granules dispersed in water [12]. Minitablets can be administered not only with water but also with beverages or even food, such as porridge, further enhancing their acceptability and ease of use [13].

The benefits of minitablets extend to elderly patients, particularly those suffering from dysphagia or managing polypharmacy. Research has long shown that the physical characteristics of tablets, such as size, shape, and texture, can significantly influence their transit through the pharynx and oesophagus [14-17]. However, it is also important to consider age-related physiological changes that may affect drug bioavailability in the elderly, including delayed oesophageal transit and reduced fluid availability in the gastrointestinal tract, both of which can impact drug dissolution and absorption [18]. The small size and rapid dispersion of minitablets may help mitigate these challenges, making them a valuable option for improving medication adherence and therapeutic effects in this patient group. Minitablets, like granules or pellets, can be classified as multiple-unit dosage forms (MUDFs), which can enhance bioavailability and reduce the risk of issues such as dose dumping [19-21]. In the context of treatment involving multiple pharmaceuticals, minitablets offer an interesting option for the simultaneous administration of several drug substances. These can be delivered as separate minitablets enclosed within a single capsule (fixed-dose combination, FDC) [5]. An additional advantage of this approach is the mitigation of potential incompatibilities between different drug substances, which helps improve the stability of the final dosage form.

In a study utilizing the Sydney Swallow Questionnaire (SSQ), Liu et al. found that minitablets were among the most well-tolerated solid dosage forms in elderly patients, surpassed only by orodispersible and soluble tablets [22]. Additional studies have confirmed the high acceptability of minitablets among older adults, including those with swallowing difficulties [23].

Perhaps the greatest advantage of minitablets is their high degree of dose flexibility, which enables individualized therapy. By adjusting the number of units administered, a wide dosage range can be prepared from a single formulation. This is particularly important in pediatric pharmacotherapy, where dosing must be tailored to age, body weight, or body surface area. Minitablets are also an effective solution for drugs with a narrow therapeutic index or dose-dependent efficacy, as they provide a reliable and safe means of precise adjustment. In geriatric patients, the ability to rapidly modify doses can help mitigate or prevent adverse effects. Inconvenience related to unit counting can be addressed with dedicated dispensing devices, which offer a practical and accurate alternative to such methods as powder dispensing [24-27].

Of course, minitablets also have their drawbacks. From the user’s perspective, such a small dosage form can present difficulties in counting, particularly when large quantities of tablets are required, especially for older patients. Therefore, additional dosing/counting devices may be necessary to facilitate this process. In the production of minitablets, achieving high precision can be challenging. Due to their low weight, even small standard deviations in mass can result in significant variations in the amount of API. This necessitates the development of formulations with excellent technological properties (e.g. flowability), which often requires the use of excipients specifically designed for direct compression. Similarly, with regards to tablet press equipment, dies and punches must exhibit very high precision and accuracy to minimize variability in the mass of the produced tablets [3,28].

The present study aimed to develop and evaluate minitablets containing atomoxetine hydrochloride as a model drug substance. Atomoxetine is a centrally acting sympathomimetic. Although its exact mechanism of action is not fully clarified, it is believed to act as a selective inhibitor of the presynaptic noradrenaline transporter. Atomoxetine is used to treat attention-deficit/hyperactivity disorder (ADHD) in children over 6 years of age and in adults. Treatment typically begins with a low dose, which is gradually increased until a therapeutic effect is achieved. The pharmacokinetics of atomoxetine are linear across the range of doses used and, importantly, are similar in both adults and children. No differences in linearity have been observed between slow and fast metabolizers (approximately 7% of the population are slow metabolizers) [29,30].

After oral administration, atomoxetine has an absolute bioavailability ranging from 63% to as high as 94%. The time to reach maximum plasma concentration is typically 1 to 2 hours. Approximately 98 – 99% of the drug binds to plasma proteins, primarily albumin. Atomoxetine is metabolized mainly by the cytochrome P450 enzyme CYP2D6. The elimination half-life is around 5 hours in extensive metabolizers but can extend up to 22 hours in poor metabolizers. The drug is primarily excreted by the kidneys in the form of its O-glucuronide metabolite. Due to differences in metabolism and treatment needs across patient populations, it is necessary to formulate atomoxetine in a wide range of doses [29-31]. Currently, the drug is available on the market as hard gelatine capsules containing atomoxetine in doses ranging from 10 to 100 mg (i.e., 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, and 100 mg) [32,33]. The wide range of available doses makes the minitablet form an attractive alternative, not only for patients, due to the potential for individualized dosing and easier dose adjustments (especially in paediatric use), but also for manufacturers, who can benefit from using a single formulation and production technology to prepare multiple dosage strengths of the drug product.

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Materials

Drug substance: atomoxetine (ATX) hydrochloride from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Anhydrous dibasic calcium phosphate (DCPA): PharSQ® Coarse A 60 from Chemische Fabrik Budenheim KG (Budenheim, Germany), Microcrystalline cellulose (MCC): Vivapur® 102 from JRS Pharma (Rosenberg, Germany). Croscarmellose sodium (CCS): Ac-Di-Sol® SD-711 from FMC BioPolymer (Brussels, Belgium). Magnesium stearate (MgSt): Ligamed® MF-2-V from Peter Greven Fett-Chemi (Venlo, The Netherlands). Transparent hard gelatin capsule shells, size “00” (Pharmapol Arzneimittelvertrieb GmbH, Daegeling, Germany). Strattera® 10 mg, 40 mg, and 100 mg hard capsules (Eli Lilly S.A., Madrid, Spain). Konaten 40 mg hard capsules (Glenmark Arzneimittel GmbH, Grobenzell, Germany).

Minitablets Enabling Dosing and Dose Iindividualization in Oral Solid Dosage Forms: A Case Study With Atomoxetin, Dorota Haznar-Garbacz, Piotr Muszyński, Daniel Żakowiecki, Received: 12.02.2026 / Revised: 23.04.2026 /Accepted: 03.05.2026 / Published: 31.08.2026, https://prospects.wum.edu.pl/index.php/pps

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