Towards a standard toolbox for compatibility testing of pediatric drug products: verification of standard vehicles for fruit juice, apple sauce, yogurt, and pudding through comparative biorelevant dissolution testing using pediatric furosemide mini-tablets

Abstract

In vitro compatibility assessments are a valuable tool for the early identification of potential drug–vehicle interactions. To standardize such evaluations, a set of standard vehicles, also referred to as simVehicles (simJuice, simApplesauce, simYogurt, and simPudding) because they simulate the key physicochemical properties of commonly used pediatric dosing vehicles, was previously developed using a Design of Experiments (DoE) approach to replicate these properties while ensuring reproducibility under controlled conditions. The present study aimed to validate selected simVehicles through comparative in vitro dissolution experiments using pediatric furosemide mini-tablets as a model drug product. The simVehicles successfully reproduced the furosemide release behavior observed with the corresponding original vehicles, supporting their suitability for standardized compatibility testing. Analysis further confirmed pH and buffer capacity as key determinants of furosemide release, highlighting their dominant role across vehicle types. These findings also emphasize the limitations of relying on a single vehicle type and the importance of accounting for vehicle-related variability, including parameters not yet covered by the current model, such as viscosity. Overall, the developed simVehicles provide a robust, scalable, and broadly applicable approach for early-stage drug–vehicle compatibility assessment

Introduction

Among all routes of drug administration, the oral route remains the most widely adopted, owing to its ease of use and good patient compliance. However, the specific conditions of administration may vary depending on the patient population. While adults typically have the ability to swallow conventional oral dosage forms with a glass of water [1], swallowability and palatability are critical considerations in pediatric populations [2], [3]. Factors such as size, taste, and mouthfeel of a dosage form can significantly affect acceptability and adherence in children. One widely used strategy to enhance swallowability and mask unpleasant taste is the co-administration of the drug product with small volumes of liquids or soft foods, also referred to as vehicles [4]. In such cases, the drug is either mixed with or dispersed in a vehicle prior to administration. Common vehicles include apple sauce, yogurt, pudding, or fruit juices, which have been shown to improve palatability and ease of ingestion in pediatric patients [5], [6].

Given that liquid or semi-solid dosing vehicles can influence the stability and performance of the drug product, drug–vehicle compatibility studies are essential to ensure therapeutic efficacy and patient safety [5], [7]. These studies are relevant not only during drug development but also in the re-evaluation of approved (particularly pediatric) formulations. In vitro compatibility assessments serve as a valuable tool for the early identification and evaluation of potential drug–vehicle interactions, providing important insights into formulation robustness and product performance [3], [8]. However, these studies can be resource-intensive in terms of both cost and time, particularly when multiple types of vehicles must be evaluated. This complexity arises from the fact that co-administration with different vehicles can affect drug stability and release, owing to variations in physicochemical properties of these vehicles, such as pH, buffer capacity, and surface tension [8], [9], [10], [11]. A recent investigation into the composition and physicochemical properties of selected vehicles listed in the FDA draft guidance document “Use of Liquids and/or Soft Foods as Vehicles for Drug Administration” [5] indicated that while pH is a critical factor, it is not the sole parameter to consider when evaluating the compatibility of liquids and soft foods as drug administration vehicles in pediatric populations [11].

In addition, other studies have demonstrated that various physicochemical properties, such as buffer capacity, osmolality, surface tension, and viscosity can also differ significantly between different vehicle types [11], [12], [13], [14]. However, such variability is not limited to comparisons between distinct categories of vehicles. A previous study by Eckert et al. showed considerable product-to-product variability within individual vehicle types, including fruit juices, apple sauce, yogurt, and pudding [6]. These findings underscore the importance of accounting for variability in both vehicle categories and specific commercial products when conducting drug–vehicle compatibility assessments.

These considerations formed the basis for the development of a standard vehicle toolbox to support initial in vitro drug–vehicle compatibility screening. To capture the variability in composition and physicochemical properties of commonly co-administered products, a set of liquid standard vehicles, referred to as simulated vehicles (simVehicles), were established. These simVehicles, i.e., simJuice, simApplesauce, simYogurt, and simPudding, were designed to replicate the key characteristics of their respective product categories. Developed using a Design of Experiments (DoE) approach, they provide a reproducible and controlled platform for assessing drug–vehicle interactions [6].

The objective of the present study was to validate a set of standard vehicles from the novel toolbox through an initial series of in vitro dissolution experiments using pediatric furosemide mini-tablets. Furosemide was selected as a model drug due to its known sensitivity to administration conditions, including the composition and physicochemical properties of co-administered vehicles, which can significantly affect its dissolution and, consequently, its bioavailability. Previous studies have demonstrated that the in vitro furosemide release of these mini-tablets is highly dependent on such factors [9], [13]. The primary aim was to demonstrate, through comparative testing, that the standard vehicles exert an influence on the drug release behavior of the mini-tablets in a manner comparable to their respective original vehicles. A secondary objective was to assess whether reliance on a single original vehicle adequately captures the range of potential vehicle effects on drug product performance.

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2.1.3. Pediatric furosemide mini-tablets

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