Novel phenolate salts of bioactive agents: Cannabidiol phenolate salts

Pulikanti Guruprasad Reddy, Ayala Bar-Hai, Amnon Hoffman, Sir Marc Feldmann, Abraham J. Domb*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Bioactive phenolic compounds are commonly found in medications, with examples including apomorphine, estrone, thymol, estradiol, propofol, o-phenylphenol, L-Dopa, doxorubicin, tetrahydrocannabinol (THC), and cannabidiol (CBD). This study is the first to explore the creation and assessment of metal and ammonium phenolate salts using CBD as an example. CBD is used in medicine to treat anxiety, insomnia, chronic pain, and inflammation, but its bioavailability is limited due to poor water solubility. In this study exploit a synthetic route to convert CBD into anionic CBD-salts to enhance water solubility. Various CBD-salts with metal and ammonium counterions such as lithium (Li+), sodium (Na+), potassium (K+), choline hydroxide ([(CH3)3NCH2CH2OH]+), and tetrabutylammonium ([N(C4H9)4]+) have been synthesized and characterized. These salts are obtained in high yields, ranging from 74 % to 88 %, through a straightforward dehydration reaction between CBD and alkali metal hydroxides (LiOH, NaOH, KOH) or ammonium hydroxides (choline hydroxide, tetrabutylammonium hydroxide). These reactions are conducted in either ethanol, methanol, or a methanol:water mixture, maintaining a 1:1 molar ratio between the reactants. Comprehensive characterization using Fourier-Transform Infrared Spectroscopy (FT-IR), Nuclear Magnetic Resonance (NMR) spectroscopy, and elemental (CHN) analysis confirms the formation of CBD-salts, as evidenced by the absence of aromatic hydroxyl resonances or stretching frequencies. The molecular formulas of CBD salts were determined based on CHN analysis, and CBD quantification from acid regeneration experiments. Characterization data confirms that each CBD phenolate in a specific CBD salt was electrostatically stabilized by one of the either alkali metal or ammonium ion. The CBD-salts are highly susceptible to acidic conditions, readily reverting back to the original CBD. The percentage and purity of CBD in the CBD-metal/ammonium salts have been studied using High-Performance Liquid Chromatography (HPLC) analysis. Solubility studies indicate that the conversion of CBD into CBD salts significantly enhances its solubility in water, ranging from 110 to 1606 folds greater than pure CBD. Furthermore, the pharmacokinetic evaluation of oral administration of CBD-salts compared to CBD were determined in rats.

Original languageAmerican English
Article number106914
JournalBioorganic Chemistry
Volume141
DOIs
StatePublished - Dec 2023

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Inc.

Keywords

  • Bioactive phenolic compounds
  • Cannabidiol
  • Cannabidiol alkali metal and ammonium salts
  • Pharmacokinetics evaluation
  • Water soluble salts

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