Elucidating the particle size effect of andrographolide suspensions on their IVIVC performance in oral absorption

Abstract

The study aimed to explore the size effect on the in vitro-in vivo correlation (IVIVC) in the oral absorption of andrographolide nanosuspensions (Ag-NS). Ag-NS with controllable particle sizes were prepared by ultrasonic dispersion method, and the formulation and process parameters were optimized through single factor experiments using mean particle size, polydispersity index, and stability as evaluation indicators. The morphology of Ag-NS was observed by scanning electron microscopy (SEM), and the crystalline state of the nanosuspensions was characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The dissolution tests were carried out with the paddle method in two different mediums simulating the pH conditions in intestinal fluid (pH 6.8) and gastric fluid (pH 1.2), respectively. The pharmacokinetic behaviors were investigated in rats after oral administration, and a deconvolution approach was introduced to determine the correlation between in vitro dissolution and in vivo absorption (IVIVC). The formulation with the use of lecithin and PEG-800 as stabilizers showed its potential in the size-controllable preparation of Ag-NS. Via altering the ultrasonication amplitude and time, three Ag-NS suspensions with three particle sizes, i.e., Ag-NS 250 (249.8 ± 1.3 nm), Ag-NS 450 (485.2 ± 3.7 nm), Ag-NS 1000 (1015 ± 36.1 nm) were prepared. Their morphological and crystal characteristics were not changed during the size reduction process, but both of their in vitro dissolution and in vivo absorption were improved. Relatively better IVIVC performance was observed with the in vitro dissolution data at pH 6.8 (r > 0.9). With the reduction of particle size, the in vivo absorption fraction was more closed to the level of the in vitro dissolution. In conclusion, the decrease in particle size would improve the dissolution and absorption of Ag-NS, and also affect their IVIVC performance. The study would facilitate the design and quality control of Ag-NS in terms of particle size and dissolution specifications.