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Preparation and Characterization of Inclusion Complexes of a Hemisuccinate Ester Prodrug of Δ9-Tetrahydrocannabinol with Modified Beta-Cyclodextrins

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  • Theme: Advanced Technologies for Oral Controlled Release
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Abstract

Δ9-Tetrahydrocannabinol hemisuccinate (THC-HS), an ester prodrug of Δ9-tetrahydrocannabinol (THC) has been investigated for its potential to form inclusion complexes with modified synthetic beta-cyclodextrins (CDs). Phase solubility studies were performed to determine the stoichiometric ratio of complexation of THC-HS with random methylated beta-cyclodextrin (RAMEB) and 2-hydroxypropyl beta-cyclodextrin (HPBCD). THC-HS/RAMEB and THC-HS/HPBCD solid systems were prepared by lyophilization and the lyophilized complexes were characterized by Fourier transform infrared (FT-IR) spectroscopy, proton nuclear magnetic spectroscopy, and molecular modeling techniques. The formation of inclusion complexes of THC-HS/RAMEB and THC-HS/HPBCD was demonstrated by an AL type curve with the slopes less than unity by the phase solubility method. The association constants for THC-HS/RAMEB and THC-HS/HPBCD were found to be 562.48 and 238.83 M−1, respectively. The stoichiometry of both of the complexes was found to be 1:1 as determined from the Job's plot. This was confirmed by 1H NMR and FT-IR techniques. The results obtained from the molecular modeling studies were in accordance with the data obtained from nuclear magnetic resonance and FT-IR. The docking studies revealed the most probable mode of binding of THC-HS with RAMEB in which the alkyl chain was submerged in the hydrophobic pocket of the CD molecule and hydrogen bonding interactions were observed between the hemisuccinate ester side chain of THC-HS and the rim hydroxy groups of RAMEB. The solubility of THC-HS was significantly higher in RAMEB compared to HPBCD. Solid dispersions of THC-HS with CDs will be further utilized to develop oral formulations of THC-HS with enhanced bioavailability.

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Acknowledgements

The work was supported by grant numbers P20RR021929 (NCRR/NIH) and 2R42GM067304-02 (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. The authors also acknowledge the technical expertise provided by Mr. Pankaj Daga from the Department of Medicinal Chemistry for the molecular modeling studies.

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Authors and Affiliations

  1. Department of Pharmaceutics, The University of Mississippi, P.O. Box 1848, University, Mississippi, 38677, USA

    Sampada B. Upadhye, Soumyajit Majumdar & Michael A. Repka

  2. Department of Medicinal Chemistry, The University of Mississippi, University, Mississippi, 38677, USA

    Swapnil J. Kulkarni & Mitchell A. Avery

  3. ElSohly Laboratories Incorporated, Oxford, Mississippi, 38655, USA

    Waseem Gul & Mahmoud A. ElSohly

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  1. Sampada B. Upadhye
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  2. Swapnil J. Kulkarni
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  6. Mahmoud A. ElSohly
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Correspondence to Michael A. Repka.

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Guest Editors: Michael Repka, Joseph Reo, Linda Felton, and Stephen Howard

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Upadhye, S.B., Kulkarni, S.J., Majumdar, S. et al. Preparation and Characterization of Inclusion Complexes of a Hemisuccinate Ester Prodrug of Δ9-Tetrahydrocannabinol with Modified Beta-Cyclodextrins. AAPS PharmSciTech 11, 509–517 (2010). https://doi.org/10.1208/s12249-010-9401-4

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