Formulation of Cinnarizine for Stabilization of Its Physiologically Generated Supersaturation

Physiologically generated supersaturation and subsequent crystallization of a weakly basic drug in the small intestine leads to compromised bioavailability. In this study, the pH-induced crystallization of cinnarizine (CNZ) in the presence of different polymers was investigated. Inhibitory effect of Eudragit L100 (Eu) on crystallization of CNZ at varying supersaturation ratios was examined. The effect of Eu on the dissolution behavior of CNZ from CNZ/Eu physical mixtures (PMs) and solid dispersions (SDs) was assessed. Results showed that both Eu and hydroxypropyl methylcellulose (HPMC) have a considerable maintenance effect on supersaturation of CNZ but Eu was more effective than HPMC. When Eudragit was used the phenomenon of liquid-liquid phase separation (formation of colloidal phase) was observed at supersaturation ratio of 20 times above the solubility of the drug. PMs showed a higher area under the dissolution curve (AUDC) compared with plain CNZ. In contrast, SDs showed a lower AUDC than plain CNZ. For SDs, the AUDC was limited by the slow release of the drug from Eu in acidic pH which in turn hindered the creation of CNZ supersaturation following the transition of acidic to neutral pH. From these findings, it can be concluded that the ability of the formulation to generate supersaturation state and also maintain the supersaturation is vital for improving the dissolution of CNZ.