Abstract
<title>Abstract</title> <p>Background Cannabinoids are highly lipophilic compounds characterized by poor aqueous solubility. This poses significant challenges in cannabinoid extraction, purification, and formulation. They are classified as Biopharmaceutics Classification System (BSC) Class II drugs. Despite their increasing relevance in pharmaceutical and industrial applications, comprehensive data are limited on their solubility across a wide range of solvents, solvent mixtures, and temperatures. Methods An automated computational workflow was used to predict the solubility (log S, mol L⁻¹) of 19 cannabinoids and reference compounds across 18 processing solvents and carrier oils at three different temperatures: 0°C (273.15 K), 25°C (298.15 K), and 50°C (323.15 K). This was done using MIT Reaction Mechanism Generator (RMG) Solid Solubility Prediction Tool (SolProp) using an automated Python-based workflow. A total of 1026 log S data points were generated and analyzed. Results The predicted values showed a consistent trend in solubility based on the polarity of the solvent. In our study, the predicted solubility increased consistently with temperature across all solute-solvent systems. This indicates an endothermic dissolution process, which agrees with established thermodynamic findings in the literature. Polar aprotic solvents, such as Dimethyl Sulfoxide (DMSO) and acetone, as well as protic alcohols, such as ethanol, isopropanol, and methanol, showed the highest solubility, while non-polar hydrocarbons, such as hexane and heptane, showed significantly lower solubility. These findings aligned with previous experimental and computational findings. Acid-cannabinoids (Cannabinolic acid, Δ⁹-THCA, 9(R)-HHC Acid, 9(S)-HHC Acid, and Cannabinol acetate) had slightly higher solubility than natural cannabinoids (e.g., Cannabidiol, Δ⁹-THC, Cannabinol, Cannabigerol, Cannabifuran, and Cannabidivarin) at tested temperatures. This is likely due to the presence of a carboxylic acid group, which enhances the interactions with polar solvents. All three hexahydrocannabinol stereoisomers-9(R)-HHC, 9(S)-HHC, and iso-hexahydrocannabinol (iso-HHC)-showed similar solubility, with acetone at 273.15 K indicating predicted Log S values of + 1.62, + 1.62, and + 1.54, respectively. Meanwhile, non-cannabinoid references (acetazolamide and melatonin) showed positive log S value in polar solvents such as DMSO and ethanol but negative values in nonpolar hydrocarbon solvents. Conclusion This study provides a large-scale, temperature-dependent computational cannabinoid solubility dataset across industrial solvents and offers understanding for process optimization in extraction, purification, and formulation.</p>