Exploring Novel Cocrystalline Forms of Oxyresveratrol to Enhance Aqueous Solubility and Permeability across a Cell Monolayer

Abstract

Oxyresveratrol (ORV) is a naturally extracted compound with many pharmacological activities. However, information about the crystalline form is not known when considering the development of a form for oral dosage. Cocrystal engineering offers drug molecular understanding and drug solubility improvements. Thus, we attempted cocrystallization of ORV using 10 carboxylic acids as a coformer at a 1:1 M ratio. Each combination was processed with liquid-assisted grinding, solvent evaporation and a slurry method, then characterized by powder X-ray powder diffraction (PXRD), conventional and low-frequency Raman spectroscopy and thermal analysis. The solubility, dissolution and permeation studies across Caco-2 cell monolayers were conducted to evaluate the ORV samples. A screening study revealed that an ORV and citric acid (CTA) cocrystal formed by ethyl acetate-assisted grinding had characteristic PXRD peaks (14.0 and 16.5°) compared to those of ORV dihydrate used as a starting material. Low-frequency Raman measurements, with peaks at 100 cm 1 , distinguished potential cocrystals among three processing methods while conventional Raman could not. An endothermic melt (142.2°C) confirmed the formation of the novel crystalline complex. The solubility of the cocrystal in the dissolution media of pH 1.2 and 6.8 was approximately 1000 µg/mL, a 1.3-fold increase compared to ORV alone. In vitro cytotoxicity studies showed that the cocrystal and physical blend were not toxic at concentrations of 25 and 12.5 µM ORV, respectively. The ORV-CTA cocrystal enhanced the cellular transport of ORV across Caco-2 monolayers. Therefore, cocrystallization could be used to improve aqueous solubility and permeability, leading to better oral bioavailability of ORV.

Comparative Evaluation of Solubility, Cytotoxicity and Photostability Studies of Resveratrol and Oxyresveratrol Loaded Nanosponges

“…Moreover, OXY also showed the crystalline structure and sharp peaks were observed at a 2θ angle of 14.56, 17.87, 20.30, 21.34, 24.09, and 27.60. The PXRD pattern of both drugs is in agreement with the previous findings [40,42] However, the PXRD pattern of NS alone demonstrated its amorphous nature. RES-NS and OXY-NS do not exhibit any intense peaks in their respective PXRD pattern, which confirmed that both drugs were molecularly dispersed in the amorphous state within the NSs [43].…”

“…Blank NS was stable and does not undergo any endothermic transition as shown in Figure 5. RES alone showed an endothermic melting peak at 266.49 °C and OXY exhibited endothermic melting at 203.37 °C [39,40]. However, RES-NS and OXY-NS do not show any endothermic melting transitions because of possible encapsulation of RES and OXY within NSs.…”

Oxyresveratrol: Sources, Productions, Biological Activities, Pharmacokinetics, and Delivery Systems

“…Cocrystals of ORV and citric acid (CTA) were obtained using the ethyl acetate-assisted grinding method. The ORV-CTA cocrystals showed increased water solubility and enhanced permeability of ORV across the Caco-2 monolayer, without toxicity [ 296 ]. Cocrystals of ORV and proline (ORV-PRO) and nicotinamide (ORV-NCT) also showed enhanced solubility and dissolution in water [ 297 , 298 ].…”

Syntheses and crystal structures of hydrated and anhydrous 1:2 cocrystals of oxyresveratrol and zwitterionic proline

“…It has several biological activities, including neuroprotective and hepatoprotective effects (Shah et al, 2019;Jia et al, 2018;Chao et al, 2008). As the aqueous solubility of OXY is low, there have been attempts to improve its solubility and oral bioavailability by cocrystallization with citric acid and glutaric acid (Suzuki et al, 2019). Proline [(S)-pyrrolidine-2-carboxylic acid; PRO,; C 5 H 9 NO 2 ] is a natural amino acid that has a secondary amino group in the form of a pyrrolydinic ring.…”