Addressing printability of poorly flowable drug by wet granulation: understanding interplays of formulation and process variables on critical quality attributes of sulfadiazine printlets

Abstract

The aim of this study was to improve the printability of poorly flowable sulfadiazine (SFZ) using selective laser sintering (SLS) 3D printing. To enhance flowability, the drug was converted into granules via wet granulation using a sugar solution. A fractional factorial screening design was employed to evaluate the influence of formulation and process variables including surface temperature, chamber temperature, laser scanning speed (LSS), and Kollidon® VA64 concentration on printlet quality attributes. Among the investigated factors, surface temperature and LSS significantly influenced printlet characteristics. Printlet hardness ranged from 1.9 ± 0.5 to 9.1 ± 1.9 N, while disintegration time varied between 2.7 ± 0.5 and 12.7 ± 1.4 s. The drug dissolve ranged from 69.1 ± 4.2% to 80.6 ± 1.2%. Hyperspectral imaging confirmed homogeneous distribution of drug and excipients within the printed matrix. Powder X-ray diffraction analysis demonstrated significant amorphization (p < 0.05) of the drug in both the printlets and the powder exposed to the printing process. Pharmacokinetic evaluation revealed that the printlets were bioequivalent to compressed tablets, as key parameters (T_max, C_max, and AUC_0–∞) showed no statistically insignificant differences (p > 0.05). In summary, the findings demonstrate that poorly flowable powders can be successfully processed through wet granulation prior to SLS printing, and the resulting printlets meet pharmacopeial quality standards while maintaining bioequivalence.

Introduction

In general, the selection of dosage form and route of administration for adult patients is based on drug physicochemical properties, excipient safety, dosage accuracy, stability, disease characteristics, and duration of therapy. Additionally, ease of administration and patient adherence are considered, particularly when the drug has poor palatability (Suarez-Gonzalez et al., 2021). However, the development of pediatric formulations is considerably more complex than that of adult formulations due to developmental differences in physiological function and the distinct needs of this population. In addition to addressing the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of a drug, pediatric formulation development requires careful consideration of dose flexibility across various age groups, including neonates, infants, children, and adolescents. Because of these challenges, manipulation of adult dosage forms such as crushing tablets or splitting them into smaller portions is a common practice in pediatric medication administration (Mfoafo et al., 2021). However, such manipulation may compromise the quality, safety, and efficacy of the original FDA-approved formulation.

Recent advancements in pharmaceutical manufacturing have shifted attention toward innovative technologies, such as three-dimensional printing (3DP), for the development of age-appropriate formulations (Mfoafo et al., 2021). 3DP, also referred to as additive manufacturing (AM), is expected to play a transformative role in the fourth industrial revolution by enabling mass customization of medicines. This technology facilitates the production of personalized fixed-dose combinations with tailored drug-release profiles, thereby optimizing therapeutic outcomes and minimizing adverse effects associated with under- or overdosing. Moreover, 3D-printed dosage forms can be readily customized in terms of shape, size, color, and flavor, thereby enhancing acceptability and improving patient adherence, an especially critical consideration in pediatric and geriatric populations (Pyteraf et al., 2023). Among the various 3DP techniques, selective laser sintering (SLS) is a powder bed–based fabrication method that has gained substantial attention in biomedical and pharmaceutical applications. Originally developed by Carl Deckard in 1984 at the University of Texas and patented in 1990, SLS was initially used to fabricate physical models through the selective solidification of powdered materials. Classified as a powder bed fusion AM technology, SLS employs a high-energy laser to selectively sinter or partially melt layers of powder, typically polymeric, metallic, or resin-based resulting in particle fusion and solid structure formation (Tabriz et al., 2023b). SLS has been applied in oral and maxillofacial prosthetics, implant fabrication, tissue engineering, and the development of neurosurgical tools. In pharmaceutical sciences, SLS has demonstrated the capability to manufacture patient-specific dosage forms and fixed-dose combinations (Davis et al., 2021). Despite certain limitations, particularly the requirement for thermal stability of both drug and excipients, SLS has been extensively explored for drug delivery system development due to its distinct advantages over other 3DP. Notably, SLS does not require solvents, binder solutions, polymerization processes, filament-based feedstock, or extensive post-processing steps such as drying or UV curing (Goyanes et al., 2017, Mohamed et al., 2020, Vithani et al., 2019).

Sulfadiazine (SFZ) is an FDA-approved antibacterial agent indicated for the treatment of various bacterial infections (HIVinfo.NIH.gov, 2024). It exerts its therapeutic effect by inhibiting dihydropteroate synthase, thereby disrupting folic acid synthesis within bacterial cells and ultimately suppressing bacterial proliferation (Morais et al., 2023). Clinically, SFZ is used in the management of urinary tract infections, otitis media, prophylaxis of rheumatic fever, meningococcal meningitis, toxoplasmosis, nocardiosis, chancroid, and trachoma (Rajapakse et al., 2013, Ventura et al., 1989). For the treatment of ocular and congenital toxoplasmosis in pediatric patients, SFZ is commonly administered in combination with pyrimethamine to achieve a synergistic antiparasitic effect (CDC, 1992). However, only a single tablet strength (500 mg) is currently commercially available, offering limited dose flexibility. This represents a significant limitation in pediatric therapy, where dosing is weight-based (e.g., 25 mg/kg/day) and requires precise adjustment to minimize toxicity while maintaining therapeutic efficacy (DailyMed, 2023). Therefore, the objective of the present study was to evaluate the feasibility of fabricating SFZ printlets using a design of experiments (DoE) approach and to characterize their physicochemical properties.

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Materials

SFZ was purchased from Fisher Scientific. Kollidon® VA64 (KVA) was obtained from BASF (Germany). Sucrose was procured from Walmart Inc., Bentonville, AR. Candurin® NXT Ruby Red was supplied by Merck. Methanol, acetonitrile, and glacial acetic acid were purchased from Fisher Scientific, Asheville, NC. Deuterated sulfadiazine (SFZ-d4) was obtained from Toronto Research Chemicals, Ontario, Canada. In-house Milli-Q water was used for analytical and dissolution studies.

Mohammad Kashif Iqubal, Gereziher Sibhat, Rizwan Shaikh, Sunil K. Thota, Mahipal Reddy Donthi, Tahir Khuroo, Canberk Kayalar, Swaroop J. Pansare, Mathew A. Kuttolamadom, Ziyaur Rahman, Mansoor A. Khan, Addressing printability of poorly flowable drug by wet granulation: understanding interplays of formulation and process variables on critical quality attributes of sulfadiazine printlets, International Journal of Pharmaceutics, 2026, 126820, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.126820.