Abstract
Disulfiram (DSF) is an approved treatment for chronic alcoholism by inhibiting acetaldehyde dehydrogenase to increase ethanol sensitivity. It is also being explored for the treatment of autoimmune, inflammatory, and viral diseases. However, DSF is a Class II drug under the Biopharmaceutics Classification System. Hence, it has low solubility (4.09 mg/L at 25 °C) but high permeability. This limits its dissolution rate, hence the bioavailability. Previous studies have shown that dissolution rate is positively correlated with solubility, and the solubility can be improved by dispersing solids that are crystalline at room temperature in a suitable excipient. This study aimed to improve the solubility and dissolution of DSF for its improved bioavailability. This was achieved by particle size reduction and preparation of solid dispersions of DSF using the spray drying technique. Solid dispersions of DSF in a polymer carrier, Soluplus® (SOL), were prepared at different DSF to SOL solid weight ratios of 1:5, 1:1, and 5:1. The powder samples were characterised using scanning electron microscopy (SEM) to assess particle morphology, Fourier-transform infrared spectroscopy (FTIR) for molecular interactions and dynamic scanning calorimetry (DSC) to analyse solid-state properties. Drug content and water solubility tests were conducted at room temperature. The dissolution test was performed using the US Pharmacopeia Apparatus 2. SEM analysis revealed that the DSF-SOL powder particles were smooth and non-spherical, with an average size of 10.09 ± 6.93 μm. Vibrational energy changes were observed in FT-IR analysis, potentially due to dipole-dipole intermolecular interaction between the oxygen atom on SOL and the sulfur atom on DSF. DSC data showed crystalline events for spray-dried DSF, while DSF-SOL displayed amorphous events, confirming the solid dispersion of DSF-SOL particles.
The water solubility of spray-dried DSF-only powder was not significantly different from the water solubility of raw material DSF. Compared to the supplied DSF, the DSF-SOL spray-dried powders with the highest solubility showed up to an 8.7-fold increase in the DSF solubility and showed rapid dissolution, releasing over 80% DSF within 5 minutes. This study successfully developed DSF-SOL solid dispersions with improved solubility and dissolution of DSF. The powder formulations have the potential to be further developed into solid dosage forms for improved bioavailability of DSF. Future studies, such as diffusion through a dialysis membrane and cell culture studies, can be conducted to determine if the solid dispersions have unchanged permeability and improved bioavailability.