Comparative Study of Approaches Used for Dissolution Enhancement of BCS Class II Drug

Abstract

The major challenge of formulations containing low soluble drugs are their dissolution criteria, stability and in-vivo performance of the drugs which are highly hydrophobic (log P > 0) and possess pH dependent solubility. The drug used for this study is a non-selective beta blocker for the treatment of mild to moderate congestive heart failure. It is a BCS Class II Drug (insoluble in water) and has pH dependent solubility in the range of 4-6, which results in the poor bioavailability after oral administration. In the present study, solubility was proved on the basis of chemistry. Based on this chemistry, decision tree and docking study (SYBYL-X), Inclusion complex and Liquisolid Compacts were chosen. Inclusion complexes were prepared by physical mixture and kneading method in different molar ratios of drug: β-cyclodextrin. In kneading method, kneading time was varied. On comparing both the techniques kneading method was found to be best for inclusion efficiency and % drug release. Liquisolid compacts were prepared using drug: PEG 400 (liquid medication), Neusilin US 2(Carrier) and Aerosil 200(coating). The load factor and drug: PEG 400 ratio was optimized. Further trial batches were performed by varying the load factor and ratio of excipients to check their effects on flowability and % drug release. DoE (32 full factorial design) was applied to optimize the batch. Confirmation was done by FTIR, DSC and XRD. Dissolution profile modeling was studied to check the release kinetics of the optimized batch. Stability study was performed at 40oC/75%RH for 1 month with no significant change in drug content and dissolution profile which proved that the formulation is stable and robust. On comparing both the techniques, Liquisolid Compact was proved to be best approach for solubility and dissolution enhancement.