Novel Strategies for the Formulation of Poorly Water-Soluble Drug Substances by Different Physical Modification Strategies with a Focus on Peroral Applications

Abstract

The number of newly developed substances with poor water solubility continually increases. Therefore, specialized formulation strategies are required to overcome the low bioavailability often associated with this property. This review provides an overview of novel physical modification strategies discussed in the literature over the past decades and focuses on oral dosage forms. A distinction is made between ‘brick-dust’ molecules, which are characterized by high melting points due to the solid-state properties of the substances, and ‘grease-ball’ molecules with high lipophilicity. In general, the discussed strategies are divided into the following three main categories: drug nanoparticles, solid dispersions, and lipid-based formulations.

Introduction

High bioavailability of medicinal products is often a prerequisite for effective drug therapy. Among other critical parameters, drugs’ solubility in relevant fluids of the human body (e.g., gastrointestinal fluids in the case of an orally administered dosage form) and their ability to cross the biological barrier [1] are two key determinants of their bioavailability. Formulation scientists worldwide are continuously working on new ways to ensure that high percentages of a drug can be absorbed by an organism. However, the differing physicochemical properties of drugs can cause considerable challenges. One of the most prominent challenges is poor solubility in water. As many newly discovered drug candidates are poorly water soluble [2], overcoming this challenge becomes increasingly important, necessitating various strategies to solve this limitation.

Poorly water-soluble drugs are classified in the BCS (Biopharmaceutics Classification System) classes II or IV, which means that a single dose of the drug is not fully soluble in 250 mL of aqueous liquid [3,4]. Despite sharing this characteristic, further physicochemical properties of the substances in these classes can vary significantly. According to the General Solubility Equation (GSE) for organic nonelectrolytes, developed by Yalkowsky and Valvani [5], the following two key factors generally influence the solubility of a substance: the melting point (Tm) and the octanol-water partition coefficient (logP) [6]. In order to enable rough distinction among poorly water-soluble drugs, they are differentiated according to the component that mainly limits their solubility. High melting points indicate the limited solubility of a substance due to solid-state properties and are referred to as ‘brick-dust’ molecules. When solubility is mainly limited by solvation, indicated by high logP values, they are called ‘grease-ball’ molecules [7]. Dependent on these factors, a rough estimation of a suitable formulation strategy can be derived. Lipophilic compounds (‘grease-ball’ molecules), characterized by high logP values, are often formulated in lipid-containing formulations, while high melting points indicate hydrophobic compounds, which are usually formulated in a modified solid state [4].

Download the full article as PDF here Novel Strategies for the Formulation of Poorly Water-Soluble Drug Substances by Different Physical Modification Strategies with a Focus on Peroral Applications

or read it here

Quodbach, J.; Preis, E.; Karkossa, F.; Winck, J.; Finke, J.H.; Steiner, D. Novel Strategies for the Formulation of Poorly Water-Soluble Drug Substances by Different Physical Modification Strategies with a Focus on Peroral Applications. Pharmaceuticals 2025, 18, 1089. https://doi.org/10.3390/ph18081089