ExcipioForm: Operationalizing excipient safety through a deterministic decision system for pediatric extemporaneous formulations – Part i

Abstract

The lack of age-appropriate dosage forms forces a heavy reliance on pediatric extemporaneous compounding, increasing risks of excipient-related toxicity and physicochemical instability, particularly in neonates. However, current digital health tools rarely integrate real-time formulation parameters with age-stratified toxicological metrics. This study introduces ExcipioForm, a deterministic screening framework designed to automate excipient safety assessment in pediatric liquid formulations, using oral antihypertensives as initial models. The system operates risk assessment by processing multi-dimensional inputs through a three-layer validation pipeline: age-dependent clinical toxicity boundaries, active pharmaceutical ingredient pH-stability constraints, and quantitative exposure limits. Powered by a standardized relational database of 81 excipients and 128 clinical rules, the engine evaluated 50 simulated formulation cases with a mean execution latency of 2.27 ms per case. Demonstrative scenarios confirmed reproducible risk detection, including neonatal benzyl alcohol contraindications and concentration-dependent polyol thresholds. By translating static toxicological data into an active, auditable verification workflow, ExcipioForm provides a robust, reproducible foundation to enhance patient safety and compounding governance at the point of care. Ultimately, this framework functions as a robust decision-support tool designed to mitigate toxicological risks and standardize compounding practices, serving to inform and enhance clinician judgment in pediatric pharmacotherapy.

1. Introduction

Historically, the pediatric population has been treated as “therapeutic orphans” due to the scarcity of commercial pharmaceutical formulations in concentrations appropriate for this population [1], [2], [3], [4]. This gap leads healthcare professionals to resort to the off-label use of adult medications or extemporaneous compounding, often involving the crushing of solid dosage forms [2], [3], [4], [5]. This practice increases the risk of dosing errors, adverse reactions, and uncontrolled exposure to excipients [2], [6]. In pediatric patients, especially neonates, immature metabolism is unable to safely process excipients commonly used in adult patients, turning excipients into potential agents of systemic toxicity [5], [7].

The use of standardized, published compounding formularies (e.g., USP compounding monographs, national pediatric hospital formularies) remains the primary strategy for mitigating risks associated with extemporaneous preparation, given their validated stability data and well-characterized excipient profiles [8], [9]. However, pediatric and neonatal pharmacotherapy frequently requires compounding beyond these published standards — for example, when no standardized formula exists for a given orphan drug or required concentration, or when an established formula contains an excipient contraindicated for a specific patient subgroup. It is precisely in these gaps between published standards that the risk of ad hoc, unverified compounding decisions increases, underscoring the need for a complementary, real-time verification layer.

The process of mitigating these risks requires pharmacists to conduct a thorough assessment, cross-referencing physicochemical stability data with age-dependent toxicological safety profiles [5], [7], [10]. However, such verification relies on a manual and fragmented process that requires consulting multiple references, such as official compendia and bibliographic databases, within a short timeframe [5], [11]. In environments such as Neonatal Intensive Care Units (NICUs), for example, this level of complexity within a short timeframe increases the likelihood of human error, highlighting the need for tools that assist and automate pharmacotechnical safety analysis [12], [13].

Clinical Decision Support Systems (CDSS) have been proposed to address this bottleneck [14]. CDSSs can assist healthcare professionals in daily clinical practice by providing support through information from multiple sources, intelligently filtering it, and making it easily accessible and quickly understandable [14], [15]. Current CDSS applications remain limited in pediatric pharmacotherapy, especially in supporting the formulation of individualized liquid medications, where the choice of excipients, concentrations, and volumes requires structured integration between clinical data, pharmacokinetic data, and pharmaceutical knowledge [8], [16], [17], [18]. Furthermore, the absence of instantaneous explainability and validation mechanisms at the point of care limits the reliability of currently available CDSS platforms in critical scenarios.

Therefore, developing systems that automatically integrate and analyze these multidimensional data points is essential to mitigate pediatric compounding risks, such as the use of excipients that pose age-specific toxicities or the preparation of formulations with inappropriate concentration settings for children. Current electronic resources, such as electronic medical databases (e.g., Lexicomp, STEP), digital versions of reference compendia, and static guidelines published by regulatory authorities, function primarily as passive repositories of information. They require healthcare professionals to manually extract data and perform external, cognitive calculations to cross-reference drug stability with patient-specific toxicological thresholds. This operational fragmentation represents a critical vulnerability at the point of care, as static databases cannot dynamically adapt safety parameters to a patient’s rapidly changing physiological status, such as neonatal age milestones.

In this context, excipient safety shifts from a passive reference-checking task to an active, real-time pharmacotechnical decision-making process. This study presents the design and implementation of a structured pharmacotechnical safety classification-support framework (ExcipioForm) for assessing excipient safety in pediatric extemporaneous formulations, using antihypertensive oral liquids as an initial clinical model class. The system integrates curated toxicological data, age-dependent exposure thresholds, and physicochemical compatibility rules into a multi-layer decision model. Rather than providing clinical validation, this study focuses on methodological architecture, data structuring, and decision logic underpinning the system, establishing a reproducible foundation for subsequent expansion to other therapeutic classes.

Download the full article as PDF here: ExcipioForm: Operationalizing excipient safety through a deterministic decision system for pediatric extemporaneous formulations – Part i

or read it here

Fabrício Costa Fanhani, Wellington Martins de Carvalho Ragassi, Luiza Gonçalves Soutier, Bruno Knevitz Hammerschmitt, Roberto Pontarolo, Antônio Eduardo Matoso Mendes, Luana Mota Ferreira, ExcipioForm: Operationalizing excipient safety through a deterministic decision system for pediatric extemporaneous formulations – Part i, European Journal of Pharmaceutics and Biopharmaceutics,
Volume 227, 2026, 115205, ISSN 0939-6411,
https://doi.org/10.1016/j.ejpb.2026.115205.