Surendra M. Sardar

The objective of this study was to develop pH independent immediate release (IR) tablet formulation of Glipizide (GPZ) incorporating β-cyclodextrin (β-CD) and a ternary agent produced by high energy air jet milling complexation technique. GPZ (pKa of 5.9) is poorly water soluble (3.9µgm/ml) exhibiting pH dependent solubility (1.1µgm/ml at pH 2.0 and 26.6 µgm/ml at pH 6.8) owing to which it demonstrates dissolution rate limited absorption and bioavailability. Several complexation techniques involving formation of binary and ternary complexes were evaluated for achieving pH independent release of GPZ. Ternary complex involving GPZ:β-CD: Arginine (1:2:1) prepared using high energy air jet milling was found to be most promising in terms of significant enhancement in solubility, further attaining pH independent dissolution. Molecular modelling (MM) was carried out in order to understand the GPZ:β-CD orientation and GPZ group interactions with the cyclodextrin cavities. Molecular modelling suggested interaction of cyclohexyl and methylpyrazinecarboxamido groups of GPZ with the cyclodextrin cavities and favorability of head to tell (HT) orientation due to its minimum interaction energy. XRD and DSC study showed partial amorphization of GPZ. Scanning electron microscopy (SEM) studies revealed formation of new solid phase of ternary complex indicating partial amorphization. Tablets prepared using optimized ternary complex of GPZ showed immediate and pH independent drug release as compared to marketed tablet formulation and plain drug.