Preformulation studies of a prodrug of Delta9-tetrahydrocannabinol

AAPS PharmSciTech. 2008;9(3):982-90. doi: 10.1208/s12249-008-9136-7. Epub 2008 Aug 28.

Abstract

Preformulation studies were performed on a hemiglutarate ester prodrug of Delta(9)-tetrahydrocannabinol (THC-HG), to facilitate the development of stable formulations by hot-melt methods. The various studies performed included solid-state thermal characterization, pKa, logP, aqueous and pH dependent solubility, pH stability and effect of moisture, temperature and oxygen on solid-state stability. A hot-melt method was utilized to fabricate THC-HG incorporated poly (ethylene oxide) (PEO) matrices and the bioadhesive properties, release profiles and post-processing stability of these matrices were assessed as a function of the polymer molecular weight. The prodrug exhibited a T (g) close to 0 degrees C, indicating its amorphous nature. Thermogravimetric analysis revealed a rapid weight loss after 170 degrees C. The prodrug exhibited a seven-fold higher aqueous solubility as compared to the parent drug (THC). Also, the solubility of the compound increased with increasing pH, being maximum at pH 8. The prodrug exhibited a v-shaped pH-rate profile, with the degradation rate minimum between pH 3 and 4. The moisture uptake and drug degradation increased with an increase in relative humidity. Solid-state stability indicated that the prodrug was stable at -18 degrees C but demonstrated higher degradation at 4 degrees C, 25 degrees C and 40 degrees C (51.6%, 74.5% and 90.1%, respectively) at the end of 3-months. THC-HG was found to be sensitive to the presence of oxygen. The release of the active from the polymeric matrices decreased, while bioadhesion increased, with an increase in molecular weight of PEO.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Chemistry, Pharmaceutical
  • Dronabinol / chemistry*
  • Dronabinol / pharmacokinetics
  • Dronabinol / standards
  • Drug Stability
  • Humidity / adverse effects
  • Hydrogen-Ion Concentration
  • Prodrugs / chemistry*
  • Prodrugs / pharmacokinetics
  • Prodrugs / standards
  • Solubility
  • Temperature

Substances

  • Prodrugs
  • Dronabinol