Comparative study of two processes to improve the bioavailability of an active pharmaceutical ingredient: Kneading and supercritical technology

Abstract

Two processes have been developed for the enhancement of bioavailability of a poorly-soluble active substance, Eflucimibe by associating it with γ-CD (γ-cyclodextrin). In the first process (process a), Eflucimibe was added to an aqueous slurry of CD, in a kneading device. The evolution of the transformation was followed by DSC, FTIR, Eflucimibe dissolution kinetics, as well as semi-solid state change of the mixture. An optimization of the process was performed and a prevision of the scaling-up was made using dimensionless numbers. This process is simple and robust. It can be compatible at the industrial scale with a good economy and appropriate control. In the second process (process b), Eflucimibe and CD are co-crystallized using an anti-solvent process, dimethylsulfoxide being the solvent and supercritical carbon dioxide being the anti-solvent. Then, the co-crystallized powder is held in a static mode under supercritical conditions for several hours. A final stripping step, is used to extract the residual solvent. The coupling of the first two steps brings about a significant synergistic effect to improve the dissolution rate of the drug. Both processes resulted in a strong acceleration of the in vitro dissolution rate of the drug. Finally, in an in vivo test, these two processes appeared to be very effective, process (a) and (b) giving respectively an 8-fold and 11-fold increase in bioavailability.