Tricalcium Citrate Tetrahydrate TB as Filler in Direct Compression of Minitablets

Abstract

Minitablets are an innovative dosage form with a diameter of ≤ 3 mm that offer solutions for many unmet needs in pediatric patient populations, as they are easy to swallow and allow for individual dosage adjustments based on current body weight. They provide a valuable alternative to often-used normal-sized tablets or liquid drug formulations, while combining palatability with improved drug product stability. However, producing minitablets via direct compression is challenging, as excipients must meet high demands to ensure excellent flowability, suitable content uniformity, rapid disintegration times and good palatability simultaneously. To address these challenges, the use of tricalcium citrate tetrahydrate (TCC TB), a brittle direct compression excipient with outstanding flow properties, excellent hardness yield and neutral taste was investigated. In this context, a direct comparison to the frequently used fillers Tablettose® 80, galenIQ™ 721, Vivapur® 102 and Vivapur® 200 was undertaken. Minitablets with a total weight of 8 mg were produced using a StylOne® Classic 105 ML compaction simulator. As model drug for pediatric use, furosemide was chosen in a drug load of 6.25% or 12.5%. Superior performance of TCC TB minitablets was found in terms of disintegration time, content uniformity and tensile strength. For galenIQ™ 721, tableting was challenging, as tablet defects occurred due to material sticking to the punches. Tablettose® 80 failed to achieve acceptable content uniformity and tensile strength values. Both Vivapur® grades achieved comparable results to TCC TB minitablets. Consequently, TCC TB presents high potential as filler for minitablet production in an extended industrial setting.

Introduction

The selection of safe excipients for child-appropriate dosage forms is limited, as not only active pharmaceutical ingredients can have different effects in children than in adults, but also excipients are able to trigger adverse effects [1]. This is especially relevant for liquid drug formulations, as they often rely on the use of various additional ingredients such as sweeteners, preservatives, antioxidants, co-solvents or surfactants, all of which can cause additional side effects and require careful use in formulation development [1,2,3,4,5]. Furthermore, liquid formulations are associated with error-prone volumetric filling and measuring processes, which can result in over- or underdosing for the child [6, 7]. Nevertheless, liquid forms of medication remain the most common, especially for young children and infants.

Most of these excipients can be avoided by using a solid drug formulation like small-sized minitablets instead, as they require less excipients while also providing better stability [8]. In comparison to other solid dosage forms like pellets or granulates, minitablet production via direct compression is favorable as minitablets are more uniform in size and weight and can be easily counted out for the correct dose [9,10,11].

The development of minitablets gained particular interest in recent years with a focus on geriatric and pediatric patient groups, as minitablets are adjustable to the current body weight and, because of their small size of under 3 mm, are easy to swallow [8, 12,13,14,15] (Fig. 1). Studies have shown that young children of 6 months accept and swallow multiple minitablets without any problems [16,17,18]. Additionally, a randomized controlled trial showed superior acceptability of minitablets compared to syrups in young children [19]. Geriatric patients with swallowing disorders also profit, as shown by an improved acceptability [20].

However, excipients need to meet high demands in order to produce minitablets via direct compression effectively, as the manufacturing process requires specialized small-diameter tableting tooling. Therefore, the final formulation needs excellent powder flowability to ensure an even and complete filling of the die [21]. A narrow particle size distribution with a maximum particle size below 1/3 of the die diameter is also favorable to prevent occlusion and allow for an even filling process [21, 22]. Additionally, higher wall friction compared to normal-sized tablets occurs, resulting in a higher shear stress applied to the used materials [12].

The disintegration time of produced minitablets has to be very short to allow young children or elderly people good accessibility, while an acceptable or neutral taste is of advantage as well. At the same time, minitablets should contain sufficient tensile strength to allow safe handling during processing and packaging. Fulfillment of the pharmacopeial requirements with regard to content uniformity is also crucial to ensure precise and safe dosing.

To address these challenges, we investigated the use of Tricalcium citrate (TCC) TB as filler for direct compression of minitablets in comparison to other often used excipients like Tablettose® 80, galenIQ™ 721, Vivapur® 102 and Vivapur® 200. TCC TB is a new brittle direct compression tableting excipient, combining excellent flowability with a high mechanical strength while maintaining a short disintegration time without the addition of disintegrants [23]. With a calcium content of 21%, TCC is already well-established in the food industry, where it is used as a calcium source for dairy products, baby food and clinical nutrition while also being allergen-free [24]. The TCC TB grade, however, was developed especially for applications in direct compression, where it already showed excellent results in the investigation performed by Hagelstein et. al [23]. Additionally, scanning electron microscopy revealed that TCC TB appears as almost spherical shaped agglomerates consisting of smaller platelets with a mean size of 135 µm, making it suitable for high performance direct compression applications [23].

Furosemide was chosen as a model drug, as it is used for geriatric and pediatric patient groups alike for treatment of heart failure, edema and renal diseases. It is also part of the model list of essential medicines for children, which is published by the WHO [25]. The dosage of furosemide for young children depends on the desired diuretic effect and is recommended between 0.5–2 mg/kg/bodyweight administered 1 to 3 times per day [26, 27]. To meet these dose requirements, furosemide minitablets with a strength of 0.5 mg and 1 mg and an average weight of 8 mg per minitablet were produced.

Download the full article as PDF here Tricalcium Citrate Tetrahydrate TB as Filler in Direct Compression of Minitablets

or continue reading here

Materials

Furosemide was purchased from SRIS Pharmaceuticals (Hyderabad, Telangana, India). MCC (Vivapur® 102, Vivapur® 200), isomalt (galenIQ™ 721), lactose (Tablettose® 80), TCC TB, were kindly provided by JRS Pharma (Rosenberg, Germany), BENEO GmbH (Mannheim, Germany), MEGGLE GmbH & Co. KG (Wasserburg an der Inn, Germany) and Jungbunzlauer (Ladenburg, Germany), respectively. Magnesium stearate (Ligamed MF-2-V) and Aerosil® 200 were kindly donated by Peter Greven GmbH & Co. KG (Bad Münstereifel, Germany) and Evonik Industries AG (Essen, Germany).

Hafels, M., Mattusch, A., Wagner, K.G. et al. Tricalcium Citrate Tetrahydrate TB as Filler in Direct Compression of Minitablets. AAPS PharmSciTech 27, 104 (2026). https://doi.org/10.1208/s12249-026-03360-3

See our next webinar: