Pediatric Formulation Optimization Using a Rational Design: Exploring Amorphous Solid Dispersion Technology with Terbinafine Hydrochloride as a Case Study

Developing orally administered pediatric formulations presents significant challenges due to the unique characteristics of pediatric patients. Terbinafine hydrochloride (TER), a powerful antifungal agent, is effective against various fungal infections, including Tinea capitis, which is common in children. However, its low aqueous solubility necessitates innovative pharmaceutical strategies to enhance its effectiveness. This study describes a rational approach to selecting suitable carriers, approved for use in children, to increase the apparent solubility of TER and to guide the development of amorphous solid dispersions containing this drug.

Assessments of solubility parameters, equilibrium solubility measurements, and calculations of pediatric dose numbers guided formulation development using theoretical and experimental methodologies. Carriers like Plasdone S-360 ULTRA®, HPMCAS L, and Soluplus® demonstrated favorable solubility parameter values with TER, indicating potential for drug solubilization. The solubility of TER was strongly dependent on pH. In buffer pH 6.5 containing 10% (w/v) of Soluplus®, TER presented the highest solubility value. The solid-state characterization techniques employed to assess the precipitate formed after equilibrium solubility studies during preformulation demonstrated that there were no phase transitions and no significant interactions between the drug and the evaluated carriers.

Furthermore, the results demonstrate that Soluplus® achieved the lowest dose number (0.23) for pediatric patients over 6 years old. So, it was selected for preparing the amorphous solid dispersion via spray drying, which significantly enhanced the apparent solubility of TER while maintaining prolonged supersaturation, offering a promising alternative for developing solid formulations of this drug, particularly for pediatric patients, as it aims to improve oral bioavailability.

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Materials

TER was kindly donated by Galena® (Brazil); the polymers and sugars Plasdone S 360 ULTRA®, K12®, K25® and HPMCAS L obtained by Ashland® (Brazil); Soluplus® was donated by BASF (São Paulo, Brazil); saccha-rin, maltitol, sucralose, lactitol and tagatose were kindly donated by SweetMix and Pharmaceutical Laboratory Elofar (Florianópolis, Brazil), respectively. Biorelevant medium was obtained from Biorelevant (Surrey, UK) and Fasted State Simulated Intestinal Fluid (FaSSIF) and Fasted State Simulated Stomach Fluid (FaSSGF) were prepared according to the manufacturer’s instructions. Ultrapure water from the MilliQ® system (Millipore) was used in all experiments. All other chemicals were analytical grade or Ultra-High Per-formance Liquid Chromatography – UPLC grade.

Boza, I.A.F., da Silva, S.L., Guedes, N.B. et al. Pediatric Formulation Optimization Using a Rational Design: Exploring Amorphous Solid Dispersion Technology with Terbinafine Hydrochloride as a Case Study. AAPS PharmSciTech 26, 40 (2025). https://doi.org/10.1208/s12249-024-03012-4

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