School of Pharmacy-Faculty of Medicine, The Hebrew University of Jerusalem, and Centre for Cannabis Research and the Institute of Drug Research, The Alex Grass Centre for Drug Design and Synthesis, Jerusalem, Israel.
Kennedy Institute of Rheumatology, University of Oxford, UK.
Bioorg Chem. 2023 Dec;141:106914. doi: 10.1016/j.bioorg.2023.106914. Epub 2023 Oct 12.
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 ([(CH)NCHCHOH]), and tetrabutylammonium ([N(CH)]) 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.
生物活性酚类化合物通常存在于药物中，包括阿扑吗啡、雌酮、百里酚、雌二醇、异丙酚、邻苯二酚、左旋多巴、阿霉素、四氢大麻酚（THC）和大麻二酚（CBD）。本研究首次探索了使用 CBD 作为示例创建和评估金属和铵酚盐。CBD 用于治疗焦虑、失眠、慢性疼痛和炎症，但由于水溶性差，其生物利用度有限。在这项研究中，我们利用一种合成途径将 CBD 转化为阴离子 CBD-盐以提高水溶性。已经合成并表征了各种具有金属和铵抗衡离子的 CBD-盐，例如锂 (Li+)、钠 (Na+)、钾 (K+)、胆碱氢氧化物 ([(CH)NCHCHOH]) 和四丁基氢氧化铵 ([N(CH)])。这些盐通过 CBD 与碱金属氢氧化物（LiOH、NaOH、KOH）或铵氢氧化物（胆碱氢氧化物、四丁基氢氧化铵）之间的简单脱水反应以 74-88%的高收率获得。这些反应在乙醇、甲醇或甲醇：水混合物中进行，反应物之间保持 1:1 的摩尔比。使用傅里叶变换红外光谱 (FT-IR)、核磁共振 (NMR) 光谱和元素 (CHN) 分析进行全面表征，确认 CBD-盐的形成，这是由于不存在芳族羟基共振或拉伸频率。根据 CHN 分析和从酸再生实验中 CBD 的定量确定 CBD 盐的分子式。表征数据证实，每种 CBD 盐中的特定 CBD 酚盐都被一个碱金属或铵离子静电稳定。CBD-盐对酸性条件非常敏感，容易恢复为原始 CBD。使用高效液相色谱 (HPLC) 分析研究了 CBD-金属/铵盐中 CBD 的百分比和纯度。溶解度研究表明，将 CBD 转化为 CBD 盐可显著提高其在水中的溶解度，与纯 CBD 相比，溶解度提高了 110-1606 倍。此外，还在大鼠中确定了口服 CBD-盐与 CBD 相比的药代动力学评估。
