# Formulation Strategies to Improve Oral Bioavailability of Ellagic Acid
## 4 Formulation Strategies for Improving EA Oral Bioavailability
### EA in Spray Dried and lyophilized Powders  
Solid dispersions are semi-crystalline or amorphous dispersions (ASDs) of a molecule in an inert matrix. ASDs represent a valid alternative for the development of microsystems entrapping poorly water-soluble molecules. ASDs can be prepared from a solution by spray drying, freeze drying, co-precipitation, rotary evaporation, film casting, or hot-melt extrusion. In all cases, a suitable polymeric excipient should have functional groups able to form H-bonds with EA, thus allowing the formation of metastable amorphous EA dispersions with adequate stability over time. In this context, a first attempt was made with maltodext, a saccharide-based excipient extensively used in food industry. Using a freeze drying technique, maltodextrin DE5-8 or DE18.5 were applied to form a solid network around a cloudberry phenolic extract [56]. The amorphous matrices were prepared starting from a maltodextrin (9% _w/w_) and a cloudberry extract (1% _w/w_) aqueous solution, mixed under slight heating for about 0.5 h to avoid ET degradation. DE5-8 complexed phenolics in a more efficient way, rationally due to its higher molecular weight. The microencapsulation improved the extract storage stability to hydrolysis, and also in this case the improvement contribution of DE5-8 was better than that of DE18.5. Microencapsulation always resulted in a decrease of EA formation by ET hydrolysis during storage, but the stability was strongly dependent on relative vapor pressure (RVP). At 66% RVP and 25 C maltodextrin DE5-8 protected phenolics up to 32 days, then the degradation reactions occurred in a major extent. On the contrary, the antioxidant properties did not alter during storage either in the extract alone or in the presence of DE5-8, probably because the loss of original phenolics was compensated by new formed molecules with equal antioxidant activity. In another study, polymers as the hydrophilic hydroxypropylmethyl cellulose acetate succinate (HPMCAS), the rather hydrophobic carboxymethyl cellulose acetate butyrate (CMCAB), and the very hydrophobic cellulose acetate adipate propionate (CAAdP) were compared with polyvinylpyrrolidone (PVP), taken as reference excipient being widely used in ASD formulations [57]. Mixtures of EA and PVP, CMCAB or HPMCAS at different weight ratios (1:9 and 1:3), dissolved in acetone:ethanol (1:4 _v/v_), were spray dried with yields of 50%-60%. ASD from CAAdP were instead prepared by co-precipitation method, due to the limited quantity of polymer available. EA was amorphous up to 25% _w/w_ in solid dispersions with PVP and HPMCAS, and up to 10% with CMCAB and CAAdP. Consequently, EA-PVP and EA-HPMCAS reached the highest solution concentration of 1500 and 280 \(\upmu\)g/mL, respectively. In a stability study performed in aqueous buffer (pH 6.8) for 24 h at room temperature (rt), pure EA showed a degradation degree by lactone ring opening of 20%, while lower values--16% for CMCAB, 14% for CAAdP, 6% for PVP and just 5% for HPMCAS--were found in the ASD samples. Dissolution rate at pH 6.8 was remarkably superior to that of pure EA, both from PVP and HPMCAS ASDs, while from CAAdP or CMCAB ASDs it was very slow and did not achieve adequate EA concentration. As expected, under acidic conditions EA release from PVP was quite fast, whereas from cellulose esters it was minimal, but this advantage was nullified by crystallization of a large amount of the EA released from PVP. Since the 1:9 ASDs with HPMCAS effectively stabilized EA against crystallization and degradation, the authors concluded that this could be considered the most promising formulation. To prepare an ingredient for functional foods, a fine microdispersed powder containing EA was obtained by spray drying using low methoxyl pectin, characterized by high biocompatibility, good palatability, taste, and prebiotic properties [58]. Pectin represents a common natural food additive (E440) authorized in several food categories [59]. By varying EA:pectin weight ratio, different formulations were prepared.