Four Novel Pharmaceutical Cocrystals of Oxyresveratrol, Including a 2 : 3 Cocrystal with Betaine.

Cocrystal engineering can alter the physicochemical properties of a drug and generate a superior drug candidate for formulation design. Oxyresveratrol (ORV) exhibits a poor solubility in aqueous environments, thereby resulting in a poor bioavailability. Extensive cocrystal screening of ORV with 67 cocrystal formers (coformers) bearing various functional groups was therefore conducted using grinding, liquid-assisted grinding, solvent evaporation, and slurry methods. Six cocrystals (ORV with betaine (BTN), L-proline (PRL), isonicotinamide, nicotinamide, urea, and ethyl maltol) were found, including four novel cocrystals. Powder X-ray diffraction, low frequency Raman spectroscopy, and thermal analysis revealed unique crystal forms in all obtained samples. Conventional Raman and infrared data differentiated the cocrystals by the presence or absence of a hydrogen bond interacting with the aromatic ring of ORV. The crystal structures were then elucidated by single-crystal X-ray diffraction. Two new cocrystals consisting of ORV : BTN (2 : 3) and ORV : PRL : H2O (1 : 2 : 1) were identified, and their crystal structures were solved. We report novel cocrystalline solids of ORV with improved aqueous solubilities and the unique cage-like crystal structures.

Quantitative prediction of intestinal metabolism in humans from a simplified intestinal availability model and empirical scaling factor.

This study aimed to establish a practical and convenient method of predicting intestinal availability (F(g)) in humans for highly permeable compounds at the drug discovery stage, with a focus on CYP3A4-mediated metabolism. We constructed a "simplified F(g) model," described using only metabolic parameters, assuming that passive diffusion is dominant when permeability is high and that the effect of transporters in epithelial cells is negligible. Five substrates for CYP3A4 (alprazolam, amlodipine, clonazepam, midazolam, and nifedipine) and four for both CYP3A4 and P-glycoprotein (P-gp) (nicardipine, quinidine, tacrolimus, and verapamil) were used as model compounds. Observed fraction of drug absorbed (F(a)F(g)) values for these compounds were calculated from in vivo pharmacokinetic (PK) parameters, whereas in vitro intestinal intrinsic clearance (CL(int,intestine)) was determined using human intestinal microsomes. The CL(int,intestine) for the model compounds corrected with that of midazolam was defined as CL(m,index) and incorporated into a simplified F(g) model with empirical scaling factor. Regardless of whether the compound was a P-gp substrate, the F(a)F(g) could be reasonably fitted by the simplified F(g) model, and the value of the empirical scaling factor was well estimated. These results suggest that the effects of P-gp on F(a) and F(g) are substantially minor, at least in the case of highly permeable compounds. Furthermore, liver intrinsic clearance (CL(int,liver)) can be used as a surrogate index of intestinal metabolism based on the relationship between CL(int,liver) and CL(m,index). F(g) can be easily predicted using a simplified F(g) model with the empirical scaling factor, enabling more confident selection of drug candidates with desirable PK profiles in humans.