Improving Lurasidone Hydrochloride's Solubility and Stability by Higher-Order Complex Formation with...

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• Physical Chemistry

Background:

• Many new drugs, including lurasidone hydrochloride for schizophrenia and bipolar depression, exhibit poor solubility and stability, hindering effective pharmaceutical formulation.
• Lurasidone hydrochloride's susceptibility to alkaline hydrolysis and oxidation limits its use in liquid dosage forms.
• The biopharmaceutical classification system categorizes drugs with low solubility into Class II and IV, necessitating strategies to improve bioavailability.

Purpose of the Study:

• To investigate the enhancement of lurasidone hydrochloride solubility and stability through the formation of higher-order inclusion complexes.
• To explore various stoichiometric ratios of hydroxypropyl-β-cyclodextrin to lurasidone hydrochloride.
• To characterize the resulting inclusion complexes and assess their impact on drug properties.

Main Methods:

• Formation and characterization of hydroxypropyl-β-cyclodextrin-lurasidone hydrochloride inclusion complexes at different molar ratios (0.5-3).
• Assessment of solubility and stability of the drug-cyclodextrin complexes.
• Solid-state characterization using infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction.
• Phase solubility studies, 1H-NMR, and docking simulations to determine stoichiometry and binding interactions.

Main Results:

• Inclusion complex formation dramatically increased lurasidone hydrochloride solubility, with higher ratios yielding greater solubility.
• Characterization confirmed the drug's transition from crystalline to amorphous state within the complexes, inhibiting recrystallization.
• Phase solubility, NMR, and computational studies indicated a primary 1:1 stoichiometric ratio, with potential for a 1:2 complex enhancing stability.

Conclusions:

• Higher-order inclusion complexes of lurasidone hydrochloride with hydroxypropyl-β-cyclodextrin are a successful strategy for improving drug solubility and stability.
• The amorphous state and inhibited recrystallization contribute to enhanced drug dissolution and formulation potential.
• This approach offers a viable solution for overcoming formulation challenges associated with poorly soluble and unstable drugs like lurasidone hydrochloride.