Crystal engineering of bioactive plumbagin using anti-solvent precipitation, melt solidification and sonocrystallization techniques

Plumbagin, a bioactive natural lipophilic molecule, has wide pharmacological actions. It shows solubility limited low oral bioavailability. The aim of this study was to improve biopharmaceutical properties of plumbagin using crystal engineering techniques. Plumbagin crystals were prepared using anti-solvent precipitation (PPL), melt solidification (MPL), melt quenching (MQPL), sonocrystallization (SPL) and melt sonocrystallization (MSPL) processes and compared with properties of reference plumbagin. No significant changes in solubility and dissolution rate were observed for sintered MPL and MQPL crystals, whereas slightly higher Q _30min (cumulative percentage release in 30 min) and lower t _50% (time required for 50% w/w drug release) was observed for irregular shaped PPL crystals due to a two-fold decrease in the crystal size. As compared to needle shaped reference plumbagin crystals, the spongy and thread shaped crystals of SPL and MSPL showed two- and three-fold increase in solubility, seven- and eight-fold increase in Q _30min due to five- and ten-fold reduction in crystal size with increased surface area and reduced diffusion pathway of SPL and MSPL, respectively. Higher sonication amplitude, time, concentration and lower processing temperature favored formation of smaller crystals due to instantaneous supersaturation and nucleation. DSC and FT-IR spectra did not show significant difference. Low-intensity peaks in x-ray diffraction and improved flow properties were noticed for SPL and MSPL. Moreover, an in vivo study in Wistar rats also justified improvement in the therapeutic efficacy of SPL and MSPL. The study demonstrated the utility of sonoprocess to improve pharmaceutical properties of bioactive plumbagin. (papers)