Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione], a phenolic active substance extracted from turmeric, has been well known for its wide therapeutic properties such as anti-inflammatory [1,2], antioxidant [3], antimicrobial [4], and anticancer activities [5]. The potential biological functions of CUR, however, have not been fully realized due to its low oral bioavailability resulting from various factors such as the low water solubility, poor gut absorption, fast metabolism, and chemical instability in gastrointestinal fluids as suggested by many recent studies [[6], [7], [8]]. Due to its hydrophobic nature, CUR is virtually insoluble in water. Even having high amount conventional curcumin, the levels of plasma curcumin were very low. Different formulation strategies were developed in the past several decades attempting to improve its oral bioavailability. The most direct ways to tackle the limitations of CUR were to enhance its bioavailability, protect it from oxidation and metabolism, and increase its potential to target diseased sites [6,9]. One of the strategies included coadministration of curcumin with metabolism enzyme inhibitors such as piperine, quercetin, silibinin with the aim to decrease the metabolism of curcumin so as to eventually increase the curcumin absorption [10,11]. The other strategies directly tackled the poor solubility problems of curcumin by incorporating it into micelles, micro/nano emulsions, nanoparticles, liposomes, solid dispersions [6,9,12,13]. Although increases in plasma curcuminoids levels occur primarily through their conjugated metabolites, many studies have shown that these conjugated metabolites lack biologically significant effects because of their large size, quick renal elimination, limited membrane and blood-brain barrier permeability [[14], [15], [16]]. Therefore, one key goal of all formulation strategies is to increase its aqueous solubility and/or enhance its chemical stability in gastrointestinal fluids, and subsequently lead to enhance its bioavailability via its free curcumin form.

Among the methods to improve the oral bioavailability of CUR, nanocrystal based delivery system is one of the very attractive strategies which provides improved oral bioavailability of poorly water-soluble drugs, enhanced chemical stabilities, and very high drug loadings. The small size of the nanocrystal (10–1000 nm) leads to a greater surface area for extensive drug-solvent interaction, leading to more rapid dissolution. Moreover the saturation solubility of the nanocrystal becomes higher compared to that of normal drug particle as per Ostwald-Freundlich equation [17]. The oral bioavailability of CUR was reported to be very low (1% in Rat) and undetectable in human blood even after high dose of CUR oral uptake (8 g/day) [18,19]. Combining more rapid dissolution rate and higher saturated solubility with high drug loading, CUR nanocrystal can potentially be a promising device to deliver free CUR with enhanced bioavailability and stabilities.

Drug nanocrystals can be prepared using both top-down and bottom-up approaches [20]. The top-down methods (primarily high pressure homogenization and ball milling) often involve issues related to high costs and energy consumption [21]. The bottom-up methods allow for control over particle size through molecular arrangement processes like precipitation or crystallization [22]. Antisolvent precipitation is a common and effective method to prepare drug nanocrystals in bottom-up techniques. Particle size reduction to a nanometer range provides an enhanced specific surface area resulting in enhanced dissolution rate, saturation solubility, more concentrated local drug solution. However, due to their small particle sizes, nanocrystals tend to form aggregates and require certain stabilizing mechanism to prevent formation of aggregates. Surfactants, polymers, and amphiphilic biopolymers which can often act as stabilizers through adsorbing onto the hydrophobic particle surface, provided spatial stability to inhibit the formation of crystal aggregates [23]. The presence of stabilizers also helps to prevent crystal growth. Commonly used polymers for such purpose are polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), dextran, chitosan, pullulan etc. Surfactants like sodium oleate and dodecylamine have also been used for stabilizing nanocrystals. In addition, hydrophilic stabilizer when used can increase the wettability of hydrophobic drugs, which in turn can further enhance the solubility and then oral bioavailability [22,24].

Stabilizer plays a crucial role in manufacturing and stabilizing nanocrystals. However, certain stabilizers suffer from drawbacks such as poor biocompatibility or irritability. For instance, studies by Zong et al. [25] using F127 and CTAB to prepare CUR nanocrystals showed that nanocrystals prepared with CTAB as a single stabilizer exhibited similar cytotoxicity to the original drug. The use of SDS as a stabilizer may induce skin or respiratory irritation [26]. Additionally, high concentrations of Tween-80 were reported to have severe neural, and cellular toxicity [27]. Given the potential safety concerns associated with long-term use of chemically synthesized stabilizers, exploring the potential of using natural biocompatible biomolecules to stabilize nanocrystals is of great importance for the application of nanocrystal technology in food and pharmaceutical application. Starch is a naturally non-toxic, renewable, and biocompatible biopolymer [28]. OSA-S is a type of modified starch that introduces hydrophobic groups into starch to increase its hydrophobicity and is suitable for delivering lipid-soluble bioactive substances [29] and approved for use in food industry by FDA.

OSA-S as an emulsifier was successfully used to prepare lycopene oil-in-water nanoemulsions through high-pressure homogenization and the interaction between lycopene and OSA molecules on the effects of emulsion stability was investigated [30]. In addition, OSA-S was employed to prepare self-assembled micelles containing β-carotene at a maximum concentration of 53.14 μg/mL to improve the solubility of β-carotene [31]. However, the stabilizing effects of OSA-S as a stabilizer for CUR nanocrystals have not been studied to the best of authors’ knowledge. OSA-S, a natural biopolymer, was exhibited to having an excellent safety profile, but also showing promising properties of enhancing stability as well as solubility for delivering poorly soluble sensitive pharmaceutical ingredients. The purpose of the present study was therefore to develop CUR-NCs using the green biocompatible OSA-S as a stabilizer with the aim to improve its oral bioavailability through enhanced chemical stability and solubility in gastrointestinal fluids so as to effectively deliver its intended therapeutic effects. CUR nanocrystals were prepared using combined antisolvent and ultrasonic methods. Formulation and process development was firstly conducted to find the optimum formulation compositions and process parameters for manufacturing CUR nanocrystals with good particle size distributions. The physicochemical properties of the nanocrystals manufactured at the optimum conditions were then extensively characterized which included morphology, crystalline form, particle size distribution, and stability. This was followed by the in vitro cytotoxicity study. Finally, the dissolution and in vitro permeability of the nanocrystal devices were thoroughly investigated. The results obtained from the current study would be useful for further developing curcumin based products.