Solubilization of Phytocannabinoids Using Cyclodextrins

August 23, 2019
Figure 1
Figure 1 (click to enlarge): X-ray crystallographic view (a) of β-cyclodextrin clatrate hydrate (5) (entry BCDEXD03, Cambridge Crystallography Data Center; translucent white spheres are some of the entrapped water molecules) and (b) general chemical structure of β-CD.
Figure 2
Figure 2 (click to enlarge): Generalized structure of common cyclodextrins used in nutritional, personal care, and pharmaceutical applications. A number of substituents per single glucopyranose repeat unit is expressed as an average fractional value that lies in the range 0.5–2 in most commercially available products.
Abstract / Synopsis: 

Two major active components of cannabis, cannabidiol (CBD) and tetrahydrocannabinol (THC), as well as minor cannabinoids and associated terpenes, are very poorly soluble in water. This property of cannabis presents major problems for product design and formulation that are difficult to overcome. One of the strategies for effective solubilization is based on using cyclodextrins (CD) that are cyclic polysaccharides capable of forming inclusion complexes with hydrophobic molecules. Cyclodextrins are considered generally recognized as safe (GRAS) by the U.S. Food and Drug Administration (FDA) and have been widely used in food, personal care, and pharmaceutical applications. This article reviews state-of-the-art approaches to produce CD-phytocannabinoid complexes, related processing and analytical techniques, and implications for cannabis product development. Continued interest for improved water solubility has been dictated by both highly desirable improvements in low and variable bioavailability of phytocannabinoids as well as development of better end user experience (such as taste, ease and convenience of use, better shelf product stability, and so on). Thus, the supply of liquid ingredients will be critically important for the rapidly expanding scope of novel consumer products for the recreational use, cannabis-enriched food, food additives, and personal care markets.

Solubility of tetrahydrocannabinol (THC) in water is so low that traditional direct methods were found unusable for accurate measurements (1). THC solubility estimates were derived from the more soluble water–ethanol mixtures with variable ethanol content, by the linear extrapolation of the 240 nm ultraviolet (UV) band for 5–15% ethanol solution to 100% aqueous. This classical experiment produced an often-cited THC solubility value of 2.8 µg/mL at 23 °C that gets further reduced (almost to a quarter of that number) by desalting effects, to 0.77 µg/mL, in 0.15 M NaCl. The water solubility of CBD falls in the same low range and has been reported at 0.1 µg/mL (2).

Historical recreational use of phytocannabinoids has been almost exclusively limited to inhalation of the cannabis-derived smoke or concentrate’s vapors. So the first phytocannabinoids solubilization approaches came mostly from pharmaceutical development and relied on using alcohol or oil mixtures (solubility enhancement enabling concentrations >100 mg/mL). These found use in Marinol softgel capsules of THC (glycerol and sesame oil), oromucosal Sativex THC–cannabidiol (CBD) spray (ethanol, propylene glycol, and peppermint oil), and recently the U.S. Food and Drug Administration (FDA)-approved orally administered CBD liquid dose of Epidiolex (ethanol and sesame oil; recommended doses as high as >5 mg/kg).

Complexation with cyclodextrins (CDs) has several important benefits when compared to other solubilization approaches. Cyclodextrins keep the active molecules solubilized at high dilutions without precipitation and helps to avoid using organic solvents, surfactants, emulsifiers, and other polymeric additives. This process therefore reduces toxicological concerns and offers simple production options (3).

Cyclodextrins form a toroid (truncated conical) configuration with multiple hydroxyl groups at each side and a lipophilic inner cavity. Their interactions with hydrophobic substrates are often described within a concept of the noncovalent “host–guest” complexes, optimization of the hydrophobic interactions, and the best spatial fit of the substrate in the available binding pocket of the ligand. The cyclodextrin solubility in water at 25 °C differs considerably, with γ-cyclodextrin being the most soluble (0.249 g/mL) followed by α-cyclodextrin (0.184 g/mL) and β-cyclodextrin (0.12 g/mL) (4). Typical cyclodextrins contain six to eight glucose monomer units. The rings are cone-shaped with a cavity depth of ~0.7–0.8 nm and cavity diameter of ~0.5–0.8 nm. Molecules with larger rings have also been made, but so far remain primarily in the realm of academic research. As an example, Figure 1 shows the chemical and crystallographic structures of β-cyclodextrins (5). (See upper right for Figure 1, click to enlarge.) Solvent molecules are easily drawn into the inner cavity and bind outside via hydrogen bonding giving rise to various clathrate structures, which are particularly plentiful with water.


Supply and Derivatives

CDs are commercially manufactured from starch, by its treatment with two key enzymes, amylase and cyclodextrin glucosyltransferase. The use of CDs has continued to grow across the industries to an estimated >400,000 metric tons in 2016, with food grade materials costing $50–400/kg. The most common CD derivatives are shown in Figure 2. (See upper right for Figure 2, click to enlarge.)

Post-processing chemical modifications (usually, alkylation or acylation of the hydroxy groups, with variable numbers of molar substitutions per sugar unit, 0.5–2) provide access to adjusting the solubility profile of cyclodextrins. One of the biggest suppliers of high quality materials  (including pharma grades) worldwide is Wacker Chemie that distributes and supports the products in the U.S. market via Ashland Group under the trademarks CAVITRON, CAVAMAX, and CAVASOL.

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Alex Nivorozhkin, PhD, is an Adjunct Professor at the Center for Drug Discovery at Northeastern University in Boston, Massachusetts where his interests are focused on the translational research related to new drugs targeting the endocannabinoid system. Alex is a principal in several biotech and phytocannabinoid startup companies and an expert consultant to the cannabis industry in the area of drug formulation and drug delivery. Direct correspondence to: [email protected]

How to Cite This Article

A. Nivorozhkin, Cannabis Science and Technology 2(4), 58-64 (2019).