Preformulation Characterization of a Novel Delta-9-Tetrahydrocannabinol Amino Acid Prodrug

The current study evaluates the preformulation characteristics of THC-Serine, a novel prodrug of the poorly water soluble compound Delta-9-Tetrahydrocannabinol (THC). Aqueous solubility and stability and solubility in different surfactants and 2-hydroxypropyl-β-cyclodextrin (HPβCD) were studied. The LogP and pKa were calculated using computer modeling. Chemical, thermal and enzymatic stability of the prodrug was assessed at different pH (25°C), elevated temperature (120°C) and in human saliva, respectively. THC-Serine demonstrated pH dependent solubility. Highest solubility was observed at pH 2.0 (92-fold greater than THC). Solubility of the prodrug in Tween® 80 was 320-fold higher (256.65 ± 20.52 µg/ml) than THC. With increasing concentrations of HPβCD solubility of THC-Serine was also observed to increase. Log P and pKa of THC-Serine were 3.18 and 7.05, respectively. Prodrug was most stable at pH 2.0, with a degradation rate constant of 3.17 × 10⁻⁴ h⁻¹. Almost 80% of the prodrug remained intact after heating at 120°C for 8 minutes. The degradation rate constant in saliva was found to be 11.52 × 10⁻² h⁻¹. The above results indicate that THC-Serine is a lead candidate for transmucosal THC delivery and warrants further investigation. Acknowledgements: This work was supported by Grant Number P20RR021929 from the National Center for Research Resources (NIH/NCRR).