Supersolubilization and amorphization of a model basic drug, haloperidol, by interaction with weak acids

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery
• Physical Chemistry

Background:

• Poor aqueous solubility is a major challenge in drug formulation.
• Developing stable amorphous solid dispersions is crucial for enhancing drug bioavailability.
• Haloperidol, a model weakly basic drug, exhibits limited aqueous solubility.

Purpose of the Study:

• To develop a novel method for greatly enhancing the aqueous solubility of haloperidol.
• To achieve physically stable amorphous forms of haloperidol using an organic solvent-free approach.
• To investigate the use of weak organic acids that do not form salts with the drug for solubilization.

Main Methods:

• Determined haloperidol aqueous solubility in the presence of increasing concentrations of malic, tartaric, citric, and fumaric acids.
• Prepared concentrated aqueous solutions with varying drug-to-acid molar ratios.
• Characterized dried materials using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), dissolution testing, and stability studies.

Main Results:

• Malic, tartaric, and citric acids significantly increased haloperidol solubility (>300 mg/g), termed supersolubilization, far exceeding haloperidol HCl solubility (4 mg/g).
• Fumaric acid showed limited solubilization due to its low water solubility.
• Dried solids consisted of amorphous haloperidol dispersed in amorphous or partially crystalline acids, exhibiting physical stability and improved dissolution rates compared to the HCl salt.

Conclusions:

• A novel, organic solvent-free method for drug solubilization in aqueous media via acid-base interactions has been demonstrated.
• This approach enables the preparation of physically stable amorphous drug systems.
• The findings offer a promising strategy for improving the formulation of poorly soluble drugs.