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Preparation and characterization of inclusion complexes of a hemisuccinate ester prodrug of delta9-tetrahydrocannabinol with modified beta-cyclodextrins.
AAPS PharmSciTech 2010; 11(2):509-17AP

Abstract

Delta(9)-Tetrahydrocannabinol hemisuccinate (THC-HS), an ester prodrug of Delta(9)-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 A(L) 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 (1)H 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.

Authors+Show Affiliations

Department of Pharmaceutics, The University of Mississippi, P.O. Box 1848, University, Mississippi 38677, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

20333489

Citation

Upadhye, Sampada B., et al. "Preparation and Characterization of Inclusion Complexes of a Hemisuccinate Ester Prodrug of Delta9-tetrahydrocannabinol With Modified Beta-cyclodextrins." AAPS PharmSciTech, vol. 11, no. 2, 2010, pp. 509-17.
Upadhye SB, Kulkarni SJ, Majumdar S, et al. Preparation and characterization of inclusion complexes of a hemisuccinate ester prodrug of delta9-tetrahydrocannabinol with modified beta-cyclodextrins. AAPS PharmSciTech. 2010;11(2):509-17.
Upadhye, S. B., Kulkarni, S. J., Majumdar, S., Avery, M. A., Gul, W., ElSohly, M. A., & Repka, M. A. (2010). Preparation and characterization of inclusion complexes of a hemisuccinate ester prodrug of delta9-tetrahydrocannabinol with modified beta-cyclodextrins. AAPS PharmSciTech, 11(2), pp. 509-17. doi:10.1208/s12249-010-9401-4.
Upadhye SB, et al. Preparation and Characterization of Inclusion Complexes of a Hemisuccinate Ester Prodrug of Delta9-tetrahydrocannabinol With Modified Beta-cyclodextrins. AAPS PharmSciTech. 2010;11(2):509-17. PubMed PMID: 20333489.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Preparation and characterization of inclusion complexes of a hemisuccinate ester prodrug of delta9-tetrahydrocannabinol with modified beta-cyclodextrins. AU - Upadhye,Sampada B, AU - Kulkarni,Swapnil J, AU - Majumdar,Soumyajit, AU - Avery,Mitchell A, AU - Gul,Waseem, AU - ElSohly,Mahmoud A, AU - Repka,Michael A, Y1 - 2010/03/24/ PY - 2009/12/16/received PY - 2010/02/19/accepted PY - 2010/3/25/entrez PY - 2010/3/25/pubmed PY - 2010/10/12/medline SP - 509 EP - 17 JF - AAPS PharmSciTech JO - AAPS PharmSciTech VL - 11 IS - 2 N2 - Delta(9)-Tetrahydrocannabinol hemisuccinate (THC-HS), an ester prodrug of Delta(9)-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 A(L) 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 (1)H 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. SN - 1530-9932 UR - https://www.unboundmedicine.com/medline/citation/20333489/Preparation_and_characterization_of_inclusion_complexes_of_a_hemisuccinate_ester_prodrug_of_delta9_tetrahydrocannabinol_with_modified_beta_cyclodextrins_ L2 - https://dx.doi.org/10.1208/s12249-010-9401-4 DB - PRIME DP - Unbound Medicine ER -