Beyond Immediate Release: FDM-Printed Pediatric 6-Mercaptopurine Chewable Tablets with Spontaneous In Situ Nanostructure Formation

Abstract

Pediatric maintenance therapy for acute lymphoblastic leukemia requires prolonged daily administration of 6-mercaptopurine (6-MP), a drug characterized by a narrow therapeutic index and substantial interindividual variability, creating a need for flexible and patient-friendly dosage forms. This study aimed to develop pediatric chewable tablets 6-MP using hot-melt extrusion and fused deposition modeling (FDM) 3D printing. Preformulation studies and rheological characterization were performed to support formulation development. The influence of internal architecture on porosity, disintegration, mechanical properties, and chewability was investigated by varying infill density.

Among the evaluated architectures, 30% infill provided the best balance between structural integrity, porosity, rapid disintegration, and softening after saliva exposure, ensuring adequate chewability. Tablets exhibited accurate drug content (99.5 ± 2.2%). Beyond their immediate-release behavior, complete drug release was achieved within 15 min, while colloidal nanostructures were spontaneously formed, associating approximately 11% of dissolved 6-MP, suggesting a hybrid release mechanism combining rapid drug availability with nano-mediated modulation. Dynamic light scattering and transmission electron microscopy confirmed these findings. Overall, the developed platform demonstrates the potential of FDM-based structural engineering to produce personalized pediatric medicines and reveals that thermally processed polymeric matrices may function as dynamic drug delivery systems rather than conventional immediate-release dosage forms.

Introduction

The development of age-appropriate pharmaceutical formulations remains a major challenge in pediatric pharmacotherapy. Children exhibit age-dependent physiological and metabolic characteristics that influence drug disposition and response, making simple extrapolation of adult dosing regimens inappropriate and often requiring individualized dose adjustment [1,2,3,4]. At the same time, sensory and psychomotor factors strongly influence the acceptability of pharmaceutical dosage forms. Increased sensitivity to bitter taste, preference for sweet flavors, and difficulties swallowing conventional tablets, particularly among children younger than six years, may compromise drug administration and treatment adherence [1, 5,6,7]. Together, these challenges highlight the need for pediatric formulations that combine dose flexibility and accurate drug delivery with improved palatability, ease of administration, and patient acceptability.

These formulation-related challenges are particularly relevant in acute lymphoblastic leukemia (ALL), the most common childhood malignancy, which originates from the uncontrolled proliferation of immature lymphoid cells in the bone marrow [8, 9]. Although survival rates exceed 90% in high-income countries, relapse remains the leading cause of mortality and is strongly associated with poor adherence to oral maintenance therapy [8, 10]. Maintenance therapy relies on the long-term daily administration of 6-mercaptopurine (6-MP) in combination with weekly methotrexate for approximately two years [11,12,13]. Importantly, inadequate adherence to 6-MP has been associated with a 2.5- to 3.9-fold increase in relapse risk, and up to 59% of relapses have been attributed to poor treatment compliance [10, 14].

In addition to adherence-related challenges, 6-MP exhibits a narrow therapeutic index and marked interindividual variability arising from pharmacogenetic factors, particularly thiopurine S-methyltransferase and nudix hydrolase 15 polymorphisms [15, 16]. Consequently, the optimal dose is not fixed but adjusted according to hematological parameters, emphasizing the need for flexible pharmaceutical strategies capable of supporting individualized therapy and safe handling during preparation and administration [13, 17].

Despite these clinical requirements, currently available 6-MP dosage forms are limited to conventional fixed-dose tablets, which inadequately accommodate frequent dose adjustments [13, 15]. Tablet splitting remains common in clinical practice but is associated with mass variability, drug loss, and the risk of under- or overdosing [18, 19]. Moreover, as an antineoplastic agent classified as both a high-alert medication and a hazardous drug, 6-MP requires strict safety measures during handling and administration. Manipulation of this cytotoxic drug outside controlled environments may increase both occupational and household exposure risks [13, 20, 21]. In fact, 6-MP may generate drug residues and increase the risk of cutaneous exposure and contamination of caregivers, household surfaces, and other family members [22, 23].

In parallel, the lack of age-appropriate formulations and inadequate palatability may further impair adherence during prolonged therapy. Although chewable tablets offer improved acceptability, ease of administration, and superior stability compared with liquid formulations [24,25,26,27], no pediatric chewable formulation containing 6-MP is currently available. In addition, 6-MP has been reported as a Biopharmaceutics Classification System (BCS) class II drug, with low aqueous solubility representing a potential challenge for oral formulation development.

Recent advances in pharmaceutical manufacturing technologies have created new opportunities for personalized pediatric medicines. Hot-melt extrusion (HME) enables homogeneous incorporation of drugs into polymeric matrices and may contribute to taste masking, physicochemical stability, and the formation of amorphous solid dispersions [28,29,30]. When coupled with filament-based fused deposition modeling (FDM), HME also serves as a preparatory step to produce continuous drug-loaded filaments with controlled composition and suitable mechanical and rheological properties for reliable printer feeding and material deposition. This approach enables precise control of geometry, internal architecture, and dose, providing a robust platform for digitally driven and reproducible dose individualization [31,32,33].

Therefore, an important unmet need persists at the interface between pediatric oncology and pharmaceutical technology: the lack of a dosage form capable of simultaneously combining dose flexibility, handling safety, pharmaceutical performance, and patient acceptability. In this context, the present study aimed to develop pediatric 3D-printed chewable tablets containing 6-MP to provide a personalized platform capable of improving adherence and supporting safer and more effective maintenance therapy in pediatric acute lymphoblastic leukemia. To support rational formulation design, preformulation studies and rheological characterization were performed, followed by evaluation of the influence of internal architecture on porosity, mechanical properties, disintegration, and chewability. Pharmaceutical performance was further investigated through drug content and dissolution studies, while the dynamic behavior of the hydrated matrix was explored by assessing the spontaneous formation of colloidal nanostructures and their potential impact on drug release.

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Materials

6-MP (batch MKCQ4491) and citric acid (batch MKBZZ7078V) were purchased from Sigma-Aldrich (St. Louis, MO, USA). Commercial 6-MP 50 mg tablets (Purinethol®, batch 401773) were obtained from Excella GmbH & Co. KG (Feucht, Bavaria, Germany). Parteck® MXP (polyvinyl alcohol, PVA; batch F2304664422) and Parteck® ODT (batch F1977890) were supplied by Merck KGaA (Darmstadt, Hesse, Germany). Glycerol (batch 129208) and lactose (batch 102276) were obtained from Dinâmica (São Paulo, Brazil). Grape flavoring (batch 24111078) was purchased from Adicel (Belo Horizonte, Brazil).

Oliveira, G.S., Lima, A.L., Muñoz, P.G. et al. Beyond Immediate Release: FDM-Printed Pediatric 6-Mercaptopurine Chewable Tablets with Spontaneous In Situ Nanostructure Formation. AAPS PharmSciTech 27, 302 (2026). https://doi.org/10.1208/s12249-026-03556-7