In the past decades SC, also called spray chilling or spray cooling, has attracted increasing attention because it is a simple technique, less time and energy consuming compared to other methods to obtain SD [14,15]. Other advantages include the ability to obtain spherical free-flowing MPs suitable for tableting or capsule filling without the need of other downstream processes (e.g., secondary drying, milling, granulation) and high encapsulation efficiency values (90–100%). From the industrial perspective, SC is easily scalable and can be adapted to the “continuous manufacturing”. As regards the equipment and mechanism of atomization, SC is closely associated with spray drying. Generally, spray drier apparatus can be used for SC processes with modifications. Although both techniques are based on the generation of droplets through atomization of a fluid, the mechanisms of MPs formation in spray drying and spray congealing are basically different, as centered on the evaporation of solvent and on the hardening of a molten material, respectively. Essentially, in the spray drying process a liquid solution (or suspension) is converted to a powdered solid by pumping the liquid feed into a drying chamber via a nozzle where fine droplets rapidly encounter a hot drying gas. The wet gas and dry particles are then separated by a cyclone and/or bag filter and the powdered product is dispensed into a collection vessel and/or bag filter [12]. On the other hand, SC is based on the atomization of a fluid (solution or a suspension of a drug in a melted carrier) into a chamber maintained at a temperature below the carrier melting point. The steps of the process are schematized in Figure 1. The first step involves the preparation of the fluid consisting of the molten carrier, kept at a temperature above its melting point, and the active ingredient. Excipients suitable for SC are substances with melting temperatures generally ranging from 35 to 90 °C. In the second step, the molten fluid stream is broken into small droplets by means of an atomizer. Subsequently the molten droplets solidify upon cooling in the chamber, producing the final solid spherical MPs. The performance of the spray congealing process strictly depends on the atomization efficiency of the molten fluid. Thus, the most important step is the atomization phase, which can be performed using various type of atomizers: pressure, two-fluids (also called pneumatic or air nozzles), rotary and ultrasonic nozzles. The reader interested in details on the different equipment and nozzle utilized in the spray congealing is referred to a recent review, where they are presented and fully discussed [16].

SC has been used in a wide range of applications, including food and pharmaceutical area. The applications of SC in the production of different oral and non-oral drug delivery systems have been described in a recent review [15]. Specifically, the pharmaceutical applications of this technology cover a wide area, including modified release systems, taste masking, bioavailability enhancement, API protection from different causes of degradation, and encapsulation of biologic drugs.

Spray congealed MPs are a multiparticulate dosage form as they consist of a multiplicity of small discrete units, each containing a fraction of the total amount of the administered API. Multiparticulate oral drug delivery systems are preferred over single unit dosage forms because of their comparatively greater dispersibility in the GIT, reduced-risk of dose dumping and systemic toxicity, decreased dosing frequency, increased patient compliance, lesser variability in concern to absorption, and accurate dosing [17]. Moreover, because of the small size, multiparticulates are less dependent on gastric emptying, resulting in less inter and intra-subject variability in gastrointestinal transit time. Above all, they represent a flexible dosage form and, therefore, they are particularly attractive for developing patient-tailored pharmaceutical products.

Spray congealed SD for bioavailability enhancement of poorly water soluble drug can be considered SD in form of hydrophilic MPs, consisting in spherical particles with a size in the range of 10 μm–500 μm. More specifically, the spray congealed product consists on microspheres. Opposite to microcapsules, where the API is confined within the microcapsule by a surrounding layer of excipient, spray-congealed microspheres are a matrix system where the active compound is evenly distributed throughout the carrier. In particular, the carriers employed in SC for bioavailability enhancement application include hydrophilic low-melting materials such as polyethylene glycol (PEG) and its surface active derivatives poloxamers and polyoxylglycerides (commercially known as Gelucires^®). They are all semicrystalline carriers, as they contain both crystalline and amorphous domains [18,19,20].

The dispersion of poorly water soluble APIs in these carriers by SC can result in the formation of either solid dispersions with crystalline or amorphous drug molecules, or solid solutions of the drug molecularly dispersed within the carrier. Often, an intermediate situation is likely to occur, especially at high drug contents, when there is an excess of drug (superior than its solubility in the carrier). Therefore, MPs with the API in different physical states (crystalline, amorphous, or partially crystalline) can be obtained [21], according to the drug and carrier chemico-physical characteristics, their miscibility and potential interactions (Figure 2). The type of the obtained system is strictly dependent on the specific properties of API and carrier (API melting point, API solubility/miscibility in the carrier, API:carrier ratio), and thus it has to be determined on a case-by-case basis.

Among the semicrystalline carriers, PEG has been widely used as a hydrophilic carrier in the preparation of SD formulation, because of its low toxicity and low costs [22]. It is a polymer of ethylene oxide, available in a range of molecular weights ranging from 200 to millions g/mol. The most commonly used for SD are solid PEGs with molecular weight of 1500–6000 g/mol. PEG exhibits a melting point ranging from ca. 55 °C to 65 °C depending of its molecular weight and it is often used as excipient for melting-based processes. Because of its very low Tg values (from −95°C to −17°C) [23], the stabilization of the amorphous form it is extremely difficult and therefore most PEG-based SD are characterized by PEG crystallization during the preparation process or during storage. Recent studies [24] highlight that the API can be located in various domains within the semicrystalline SD and thus multiple microstructures can be obtained, resulting in systems with different properties. For example, aceclofenac and chlorpropamide SD favored the interlamellar incorporation of the drug in the PEG matrix. Haloperidol, a rapidly crystallizing compound, was excluded from the interlamellar region. Loratadine, with a low solubility in PEG, showed more complex phase behavior that depended on the crystallization temperature [20].