Over the past twenty years, ionic liquids (ILs) and deep eutectic solvents (DESs) have gained recognition across various fields, including catalysis, extraction and purification, materials science, and biotechnology. Notably, the use of ILs and DESs in pharmaceutical research, especially in drug delivery, has seen remarkable expansion over the past decade. This review offers a comprehensive analysis of ILs and DESs specifically designed for the oral administration of drugs having unfavorable biopharmaceutical properties. The classification and characteristics of ILs and DESs, along with their newer natural (Bio-ILs and NaDESs) and therapeutic subcategories (API-ILs and TheDESs) are outlined. Additionally, a further subgroup of ILs, known as surface active ionic liquids (SAILs), is described. Then, a detailed examination of the available manufacturing methods in a sustainable, time-consuming, and scalable perspective, and toxicity concerns in relation to their subdivision are evaluated. Finally, their specific applications in oral drug delivery, whether used as neat solvents or converted into administrable dosage forms, are analyzed and discussed. Despite the significant advancements in recent years regarding the use of these solvents in oral drug delivery, there are still many aspects that need further investigation. These include their interaction with biological systems (gastrointestinal fluids and mucosa), their long-term stability, and the development of effective drug delivery systems.

The low and variable oral bioavailability of poorly water soluble drugs remains a major concern for the pharmaceutical industry. Spray congealing is an emerging technology for the production of solid dispersion to enhance the bioavailability of poorly soluble drugs by using low-melting hydrophilic excipients. The main advantages are the absence of solvents and the possibility to obtain spherical free-flowing microparticles (MPs) by a relatively inexpensive, simple, and one-step process. This review aims to fully describe the composition, structure, physico-chemical properties, and characterization techniques of spray congealed-formulations. Moreover, the influence of these properties on the MPs performance in terms of solubility and dissolution enhancement are examined. Following, an overview of the different spray congealed systems developed to increase the oral drug bioavailability is provided, with a focus on the mechanisms underpinning the bioavailability enhancement. Finally, this work gives specific insights on the main factors to be considered for the rational formulation, manufacturing, and characterization of spray congealed solid dispersions.

Despite the growing interest in lipid-based formulations, their polymorphism is still a challenge in the pharmaceutical industry. Understanding and controlling the polymorphic behavior of lipids is a key element for achieving the quality and preventing stability issues. This study aims to evaluate the impact of different oral-approved liquid lipids (LL) on the polymorphism, phase transitions and structure of solid lipid-based formulations and explore their influence on drug release. The LL investigated were isopropyl myristate, ethyl oleate, oleic acid, medium chain trigycerides, vitamin E acetate, glyceryl monooleate, lecithin and sorbitane monooleate. Spray-congealing was selected as an example of a melting-based solvent-free manufacturing method to produce microparticles (MPs) of tristearin (Dynasan^®118). During the production process, tristearin MPs crystallized in the metastable α-form. Stability studied evidenced a slow phase transition to the stable β-polymorph overtime, with the presence of the α-form still detected after 60 days of storage at 25 °C. The addition of 10% w/w of LL promoted the transition of tristearin from the α-form to the stable β-form with a kinetic varying from few minutes to days, depending on the specific LL. The combination of various techniques (DSC, X-ray diffraction analysis, Hot-stage polarized light microscopy, SEM) showed that the addition of LL significantly modified the crystal structure of tristearin-based formulations at different length scales. Both the polymorphic form and the LL addition had a strong influence on the release behavior of a model hydrophilic drug (caffeine). Overall, the addition of LL can be considered an interesting approach to control triglyceride crystallization in the β-form. From the industrial viewpoint, this approach might be advantageous as any polymorphic change will be complete before storage, hence enabling the production of stable lipid formulations.