D-limonene, derived from citrus essential oils, holds significant therapeutic potential but faces challenges due to its high volatility, especially in pharmaceutical formulations. This study investigates microemulsions as a promising delivery system for volatile compounds, emphasizing their thermal protection for D-limonene. The formulation development was guided by a pseudo-ternary phase diagram and involved assays with different surfactants. Microemulsions were achieved solely with Labrasol^® (Gattefossé Brasil, São Paulo, Brazil), encompassing concentrations of 7.1% to 30.8% D-limonene, 28.6% to 57.1% Labrasol^®, and 20.0% to 64.3% water. All formulations were homogeneous, transparent, and presented low viscosity, with adequate D-limonene content, indicating that the production is feasible at room temperature. While the formulations demonstrated robust physical stability under mechanical stress, they exhibited destabilization at temperatures exceeding 50 °C. In terms of oxidative stability, pure D-limonene exhibited an induction period of 4.88 min, whereas microemulsions extended this period by four to eight times. Notably, the induction period of the microemulsions remained practically unchanged pre and post-heating (70 °C), suggesting the formulation’s ability to enhance the D-limonene thermal stability. This highlights the value of oxidative stability analysis as a quicker tool than conventional oxidative tests, while affirming microemulsions as a viable encapsulation strategy for D-limonene protection against elevated temperatures.

This study aimed to develop a biopredictive dissolution method for desvenlafaxine ER tablets using design of experiments (DoE) and physiologically based biopharmaceutics modeling (PBBM) to address the challenge of developing generic drug products by reducing the risk of product failure in pivotal bioequivalence studies. For this purpose, a PBBM was developed in GastroPlus^® and combined with a Taguchi L9 design, to evaluate the impact of different drug products (Reference, Generic #1 and Generic #2) and dissolution test conditions on desvenlafaxine release. The influence of the superficial area/volume ratio (SA/V) of the tablets was observed, mainly for Generic #1, which presented higher SA/V than the others, and a high amount of drug dissolved under similar test conditions. The dissolution test conditions of 900 mL of 0.9% NaCl and paddle at 50 rpm with sinker showed to be biopredictive, as it was possible to demonstrate virtual bioequivalence for all products, despite their release-pattern differences, including Generic #3 as an external validation. This approach led to a rational development of a biopredictive dissolution method for desvenlafaxine ER tablets, providing knowledge that may help the process of drug product and dissolution method development.

The development of distinct biopredictive methods for fasted and fed states using a physiologically based biopharmaceutics modeling (PBBM) approach is essential for accurately evaluating drug release from solid oral dosage forms, especially extended-release products. However, a fed state biopredictive method for desvenlafaxine tablets is not currently available. Hence, the study aimed to investigate the application of the USP 3 apparatus to develop biopredictive methods for desvenlafaxine tablets. Initially, an existing fasted state biopredictive USP 2 dissolution method was adapted to increase dissolution hydrodynamics by scaling the rotation speed to 75 and 100 rotations per minute (rpm). Subsequently, two dissolution methods were developed using the USP 3 apparatus to emulate fasted and fed conditions. The fed biopredictability of the methods was assessed using a previously developed GastroPlus model to simulate fed conditions under 800 kcal and 50% fat meal. Statistical analysis of dissolution profiles obtained in the paddle apparatus revealed no significant difference from the original 50 rpm method and lacked biopredictive for the fed state, indicating the unfeasibility of developing such a method in this apparatus. In contrast, USP 3 proved to be an important tool to develop a fed state method, since it was biopredictable based on simulation analysis. Additionally, no significant differences were observed between USP 3 methods employing pH-gradient media and those using 0.9% NaCl as the sole medium. These findings highlight a hydrodynamic-driven approach for applying USP 3 to develop distinct biopredictive dissolution methods for fasted and fed states, particularly for high-solubility drugs formulated in robust hypromellose matrices.