Experimental investigations, cytotoxicity and cellular uptake outcomes of physically modified duloxetine HCl inclusion complexes

Abstract

Duloxetine HCl, an antidepressive drug, has poor water solubility and poor oral absorption leading to low bioavailability of the drug. The drug is also found to be acid labile, resulting in degradation in gastric environment. To overcome such drawbacks, inclusion complexation process was explored to improve the solubility and dissolution rate of duloxetine HCl by formulating its complexes with beta-cyclodextrin using different complexation techniques. Equimolar complexes of the drug with β-CD (1:1 molar) were prepared based on phase solubility analysis. Behaviour of complexes was characterized both in solution state and in solid state using DSC, FTIR, SEM, 1H NMR and PXRD techniques. Molecular docking studies were also carried out to investigate mode of inclusion and stability. Also, the cell culture studies, viz. MTT assay and cellular uptake, were investigated. Apparent stability or association constant (Ks) was predicted to be 165.64 M−1. Results of characterization techniques indicate the drug to be completely included in the hydrophobic cavity of β-CD, and hence, the physicochemical properties of the drug differ from parent molecule. Cytotoxicity studies indicated low IC50 value for complexes in comparison with native drug moiety, and cellular uptake of the complex was also found to be improved in case of complexed drug at different time points. Enhanced solubility and improved drug release was observed for physically characterized less crystalline complexes. Cellular uptake is also reported to be appreciably enhanced in complexed form. Thus, the process has logistic approach in reducing the dose of drug and related side effects.