Enhancing the bioavailability of clozapine through microwave-assisted formulation of a stable β-cyclodextrin inclusion complex

Abstract

The low oral bioavailability of clozapine due to its poor aqueous solubility, poor dissolution rate, and extensive hepatic first-pass metabolism poses a challenge to the effective treatment of psychiatric disorders. The objective of the current research was to address the above issues by developing a clozapine inclusion complex (CLZ-IC) using the microwave irradiation method. To optimize the formulation and processing variables, namely the molar ratio of CLZ to β-CD (X1) and the irritation reaction time (X2), a 32 factorial design was performed. The phase solubility study revealed the formation of a stable inclusion complex with a stoichiometry of 1:1, suggesting that β-cyclodextrin could effectively solubilize clozapine. The characterization data confirmed the formation of the inclusion complex of clozapine in β-cyclodextrin. The optimized inclusion complex showed a solubility of 342 ± 26 µg/ml and a percentage dissolution of 91.1 ± 3.4% after four hours. The inclusion-complex tablets exhibited excellent physical properties and showed an improved in vitro dissolution profile, with 80% of the drug being released within 100 minutes, compared to marketed tablets (80% release in 300 min). In vivo pharmacokinetic studies conducted in a rat model demonstrated an increase in Cmax, area under the curve (AUC), and relative bioavailability by a factor of 2.26 with the optimized formulation, indicating a significant improvement in drug absorption compared to the marketed tablet. The techno-economic analysis suggests a cost-benefit ratio of 25.08 after 7 years, indicating the suitability for large-scale production. Overall, using Design of Experiment, in silico, and in vivo studies proved effective in optimizing the inclusion-complex formation and enhancing the bioavailability of clozapine. In conclusion, the optimized clozapine-β-cyclodextrin inclusion complex prepared using a time-saving (90 sec) and cost-effective microwave irradiation method exhibited excellent physical properties and demonstrated significant improvements in the drug's solubility, dissolution rate, and pharmacokinetic performance.