Hard Gelatin Capsules Compounded and Dispersed in Water in Pediatrics: Real Versus Theoretical Dose Administered

Background: In pediatric practice, dose individualization often requires the manipulation of solid oral dosage forms, such as dispersing capsules in water and administering only part of the volume. Despite its frequent use, this practice is poorly documented and may lead to inaccurate dosing. Objectives: This study aimed to assess the actual dose administered when compounded hard gelatin capsules are dispersed in water and partially withdrawn, and to evaluate the influence of different manipulation protocols on dose recovery. Methods: Ten active pharmaceutical ingredients (APIs) routinely compounded as pediatric hard gelatin capsules were studied. Content uniformity was first verified according to European Pharmacopoeia (EP) requirements. One capsule was dispersed in 2 mL of water, and 1 mL was withdrawn using three protocols: (1) no mixing, (2) gentle manual mixing with immediate sampling, and (3) gentle manual mixing followed by a 10 s resting period before sampling. Drug content in the withdrawn volume was quantified using validated HPLC-UV methods. Results are expressed as the mean percentage of the theoretical dose ± standard deviation. Results: All capsules complied with EP content uniformity criteria. However, partial volume administration resulted in marked and protocol-dependent deviations from the theoretical dose. Without mixing, recovered doses ranged from 17% to 58% of the target dose, with high variability. Gentle mixing improved dose recovery, particularly for APIs forming solutions, such as captopril, thiamine hydrochloride, and clonidine hydrochloride, which achieved values close to 90%. In contrast, APIs forming suspensions consistently resulted in underdosing, even after mixing, with further reductions observed after a short resting period, indicating rapid sedimentation. Conclusions: Fractional administration of dispersed hard gelatin capsules leads to unpredictable and often clinically relevant underdosing, especially for poorly soluble APIs. Whenever possible, capsules should be compounded at the prescribed dose, and liquid formulations should be preferred when dose fractionation is required.