# Formulation Strategies to Improve Oral Bioavailability of Ellagic Acid
## 4 Formulation Strategies for Improving EA Oral Bioavailability
### Micronized EA (m-EA)  
According to Noyes-Whitney law, an effective way to increase dissolution rate and oral absorption of a substance is the size reduction of powder particles [51]. For this purpose, anti-solvent precipitation may represent a valid processing technique. In comparison to more popular micro and nanocariers that will be discussed in the following sections, this approach presents several advantages, such as easy realization and rapidity. In addition, the process allows the reduction of organic solvents use and the one-step processing favors scalability. The anti-solvent precipitation of a poorly water-soluble substance is simply obtained by dissolving it in a solvent, followed by rapid mixing with a solvent-miscible anti-solvent. After mixing, the substance precipitates in micro-sized particles, since a supersaturated solution forms. The critical step of this method is to produce crystal nuclei rapidly, avoiding their excessive growth. For process optimization, precipitation time and temperature, addition speed of the solution to the anti-solvent, their volume ratio, drug concentration and stirring intensity are the keys parameters that have to be checked. [PERSON] et al. set the best conditions to produce m-EA by anti-solvent precipitation with an accurate preformulative study [52]. An EA solution in NMP (30 mg/mL) was added to water, used as anti-solvent, at a rate of 30 mL/h with 2 min precipitation time, at 3 \({}^{\circ}\)C and 2500 rpm stirring. Then, the precipitate was dispersed in a maltodextrin aqueous solution to have a solid concentration of 1 mg/mL and was lyophilized. The authors verified that residual NMP (class 2 residual solvent) in the final product was in agreement with the established International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) limit [53]. The m-EA freeze-dried powder, whose mean particle diameter was 428 nm, in a comparison to raw EA and to a physical mixture of EA in maltodextrin, showed the fastest dissolution rate. Surely, maltodextrin acted as hydrotrope, but the result could be attributed exclusively to the high specific surface of the lyophilized powder and to the low crystallinity of the incorporated EA. All in all EA water dissolution was improved up to 11.67 \(\mu\)g/mL at 37 \({}^{\circ}\)C.  
In addition, the 2, 2-diphenyl-1-1-pycrylhydrazzyl (DPPH)-scavenging activity was higher than that of not-micronized EA and oral bioavailability in rats increased twice in comparison to raw EA. In another study, [PERSON] et al. obtained m-EA using the anti-solvent precipitation method by injecting into deionized water a 10 mg/mL ethanolic solution of EA at a fixed flow rate [54]. m-EA particles, collected by filtration and vacuum dried, showed modified morphology with respect to the parent material and appeared as needle-shaped or rod-like structures. In vitro and in vivo experiments, performed by intraperitoneal injection in mice, showed a significantly improved m-EA activity against blood parasites as Babesia and Theileria. However, the authors concluded that EA activity requires further investigations to understand whether EA inhibits parasites grow or causes their death. A similar approach was performed using supercritical CO2 as anti-solvent. In this procedure a solution of EA in NMP was sprayed into a vessel where a CO2 stream was continuously flowed under supercritical conditions. Solution atomization led to a fast mass transfer between supercritical CO2 and the solution itself, which caused supersaturation and subsequent rapid precipitation of EA in the form of micro-sized particles [55]. The study focused on the influence of process parameters and EA concentration on size, polydispersity index (PDI) and morphology. Moreover, a co-precipitation with Eudragit(r) L 100 was also carried out and, starting from EA:Eudragit(r) 1:1 weight ratio, a drug loading (DL) of 49% was achieved.