Abstract by Maria Pereverzina

Oral solid dosage forms, such as tablets and capsules, are the preferred choice for drug administration, offering patient convenience, cost‑effectiveness, non‑invasiveness, as well as simplified production, handling, and storage. However, oral drug formulations face a persistent challenge: a significant proportion of small molecules, both on the market (40%) and in development (90%), suffer from poor aqueous solubility, which severely limits their gastrointestinal tract absorption and bioavailability. Addressing this issue is a major priority in pharmaceutical research and development, as overcoming solubility limitations has the potential to significantly improve the bioavailability of poorly soluble drugs and accelerate the delivery of essential therapies to those in need.

This thesis investigates a novel approach to enhance drug solubility by utilizing an in situ activated thermal energy source post oral administration. This approach aims to improve solubility and thereby oral bioavailability while addressing stability and manufacturing challenges associated with conventional amorphous solid dispersions. Through the work presented, magnesium chloride (MgCl₂) was investigated for its suitability as an excipient to generate sufficient exothermic energy upon contact with fluid in the gastrointestinal tract. Its reaction with water leads to a rapid increase in temperature and energy release sufficient to induce a phase transition of the formulation ingredients, i.e., drug and/or polymer. The temperature output was found to be controlled by several factors, including the salt-to-water ratio, change in the surface area of MgCl₂ by compaction, and insulation of the reaction. It was hypothesized that an oral device-based approach could be utilized to transfer the in situ-generated exothermic energy to induce a phase change of the drug. The proposed oral device prototype featured a two-compartmental design to physically separate the drug from the MgCl₂. Solid-state properties and the dissolution behavior of the drug were investigated, and improvement in the intrinsic dissolution rate was observed. Additionally, a self-contained, thermally activated drug delivery (TADD) system was developed. The TADD system comprises of a physical mixture of the drug, a low-melting-point polymer, and MgCl₂. Upon contact with GI fluid, TADD rapidly generates heat, melting the polymer and dispersing the drug, enabling its efficient solubilization at the site of release. The TADD system was tested with fulvestrant, an anticancer drug, and albendazole, an antiparasitic drug, both of which showed significantly enhanced in vitro dissolution, demonstrating the system’s broad applicability. Finally, an in vivo study in rats showed an improvement in the oral bioavailability of fulvestrant when formulated in TADD.

In summary, this work conceptualizes, develops, and characterizes the use of in situ-generated thermal energy to enhance the solubility of poorly soluble drugs and provides a platform for further research.