Dataset Information

Preparation and characterization of inclusion complexes of a hemisuccinate ester prodrug of delta9-tetrahydrocannabinol with modified beta-cyclodextrins.

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.

SUBMITTER: Upadhye SB

PROVIDER: S-EPMC2902337 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Preparation and characterization of inclusion complexes of a hemisuccinate ester prodrug of delta9-tetrahydrocannabinol with modified beta-cyclodextrins.

Upadhye Sampada B SB Kulkarni Swapnil J SJ Majumdar Soumyajit S Avery Mitchell A MA Gul Waseem W ElSohly Mahmoud A MA Repka Michael A MA

AAPS PharmSciTech 20100324 2

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 lyophilizat ...[more]

PMID: 20333489

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Project description:The study aimed to prepare inclusion complexes of 1,3-diphenylurea (DPU) with β-cyclodextrin (βCD) and 2-hydroxypropyl-β-cyclodextrin (HP-βCD) using a three-dimensional ground mixture (3DGM). Their physicochemical properties, intermolecular interactions, solubilities, and plant growth-promoting activities were investigated on broccoli sprouts. Phase-solubility diagrams indicated the stability constant (Ks) and complexation efficiency (CE) of βCD/DPU were found to be K1/1 = 250 M-1, CE = 2.48× 10-3. The Ks and CEs of HP-βCD/DPU were found to be K1/1 = 427 M-1, CE = 3.93 × 10-3 and K2/1 = 196 M-1, CE = 1.93 × 10-3 respectively. The powder X-ray diffraction results of 3DGM (βCD/DPU = 2/1, HP-βCD/DPU = 2/1) showed that the diffraction peaks originating from the DPU and βCD disappeared, indicating a halo pattern. Differential scanning calorimetry results showed an endothermic peak at 244 °C derived from the melting point of DPU, but the endothermic peak disappeared in the 3DGM (βCD/DPU = 2/1, HP-βCD/DPU = 2/1). Near-infrared absorption spectra showed peak shifts in 3DGM (βCD/DPU and HP-βCD/DPU) at the -CH and -NH groups of DPU and the -OH groups of βCDs and free water. In the dissolution test (after 5 min), the concentration of intact DPU was 0.083 μg/mL. However, the dissolution concentrations of DPU in the 3DGM (βCD/DPU = 1/1), 3DGM (βCD/DPU = 2/1), 3DGM (HP-βCD/DPU = 1/1), and 3DGM (HP-βCD/DPU = 2/1) were 3.27, 3.64, 5.70, and 7.03 μg/mL, respectively, indicating higher solubility than that of the intact DPU. Further, 1H-1H NOESY NMR spectroscopic measurements showed cross-peaks between H-A (7.32 ppm) and H-B (7.12 ppm) of DPU and H-6 (3.79 ppm) in the βCD cavity of the 3DGM (βCD/DPU = 2/1). A cross-peak was also observed among DPU H-A (7.32 ppm), H-B (7.11 ppm), and H-6 (3.78 ppm) in the βCD cavity. The results of the broccoli sprout cultivation experiment showed that 3DGM (βCD/DPU = 1/1), 3DGM (βCD/DPU = 2/1), 3DGM (HP-βCD/DPU = 1/1), and 3DGM (HP-βCD/DPU = 2/1) increased the stem thickness compared with that of the control group (DPU). These results indicated that the βCD/DPU and HP-βCD/DPU inclusion complexes were formed by the three-dimensional mixing and milling method, which enhanced the solubility and plant growth-promoting effects.

Dataset Information

Preparation and characterization of inclusion complexes of a hemisuccinate ester prodrug of delta9-tetrahydrocannabinol with modified beta-cyclodextrins.

Publications

Preparation and characterization of inclusion complexes of a hemisuccinate ester prodrug of delta9-tetrahydrocannabinol with modified beta-cyclodextrins.

Similar Datasets

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