Overcoming the Poor Solubility of Cannabinoids

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology, June 2023, Volume 47, Issue 6
Pages: 19-20, 23

Nanotech-based delivery technologies are receiving significant attention.

Numerous pharmaceutical companies from startups to well-established firms are exploring the potential of cannabinoid-based drug substances as therapeutic agents for the treatment of a wide range of disease indications. Developmental cannabinoid medications must follow the same approval pathway established for all other small-molecule drug candidates. Early in 2023, the agency also determined that a new regulatory pathway for cannabidiol (CBD) products is needed that “balances individuals’ desire for access to CBD products with the regulatory oversight needed to manage risks” (1). “Smart companies,” says Jordan Tishler, president and CEO of inhaleMD, President of the Association of Cannabinoid Specialists, and an Instructor of Medicine at Harvard Medical School, “will see the value of following the pharmaceutical pathway and pursuing clinical trials and FDA approval, while the rest will simply make recreational products.”

Regardless of whether companies are seeking to develop therapeutics or dietary supplements based on cannabinoids, they face the challenge of realizing effective delivery of these highly hydrophobic compounds. “Cannabinoids present many of the same difficulties that other poorly soluble and/or absorbable APIs present,” states Gavin Chandler, CEO of Trokie, a company working on novel delivery systems for cannabinoids for use as dietary supplements in strict compliance with FDA and Federal Trade
Commission (FTC) rules.

In addition to being highly lipophilic molecules, cannabinoids can also undergo extensive first-pass metabolism, which creates difficulties for dosing and titration and impacts the speed of therapeutic onset, according to Chandler. He points to testosterone and triptans as being examples of other APIs that share these difficulties.

Furthermore, Tishler notes that bioavailability of cannabinoids is poor regardless of route of administration, and it is also quite variable, particularly for oral delivery. The challenge, agrees John A. MacKay, founder and CEO of Synergistic Technologies Associates, is to get nonpolar cannabinoids into some type of media or delivery vehicle that will enable sufficient quantities of them to be transported across membranes to targeted areas.

Growing numbers of patent filings and publications regarding the pharmacodynamics of cannabinoid delivery using novel technologies indicate high interest in addressing the shortcomings of cannabinoid products delivered via the standard oral routes of administration, according to Chandler. Technologies of interest include buccal, intra-nasal, and transdermal delivery systems, as well as the use of various nanoscale approaches to enable improved oral delivery.

Of the more than 120 different phytocannabinoids that have been identified, Δ9-tetrahydrocannabinol (Δ9-THC, or THC) and CBD are the most abundant and most investigated (2). Many synthetic cannabinoids have also been produced and evaluated. Most cannabinoids that have been shown to be pharmacologically active are Class II compounds under the Biopharmaceutics Classification System, which are considered to have low water solubility and high lipophilicity.

Inhalation gives best bioavailability, but presents many problems

Although inhalation of cannabis-derived products is the most common method of administration and does generally provide the best bioavailability and fast onset of action (5–10 minutes) as well bypasses first-pass metabolism (2), smoking and vaping oil extracts supply the cannabinoids in conjunction with toxic byproducts. In addition, the bioavailability still only reaches 20–30%. “The best solution to date,” says Tishler, “is a flower vaporizer, but this device is costly and the results are typically very user-dependent.”

Inhalation must be done appropriately, too, adds Mackay. “If patients don’t inhale correctly, the cannabinoids can be delivered into the mouth instead of the lungs. In addition, some people experience a gag-reflex when using an inhaler.” Due to the “stickiness” of these hydrophobic compounds, Tishler adds that it is difficult to put them in metered-dose inhalers because the devices fail after just a few uses.

Buccal and intranasal delivery could be alternatives

Buccal and intranasal delivery are other approaches to avoiding first-pass metabolism. These delivery methods also may offer reduced variability compared to oral administration of cannabinoids, according to Chandler. “We see increasing clinical evidence coming out in various publications both domestically and internationally that these types of formulations provide higher and more reliable absorption of cannabinoids that will benefit clinicians and their patients,” he observes. He does, stress, however, that there is still much work to do.

Whether one form of administration is better than another remains to be seen. In addition, Chandler remarks that cannabinoids are a diverse set of molecules, so what would be an advantage for one might be a disadvantage for another depending on the specific attributes of the cannabinoids. “On the purely theoretical side, buccal formulations are potentially easier to use because they are solids rather than liquids,” he comments.

On the other hand, intranasal delivery, based on the results with other similar APIs, could have slightly faster speed of onset at the expense of total absorption because of the washout down the throat, according to Chandler. There are concerns, however, about irritation of the nasal mucosa and mucociliary clearance, and it has been suggested that this route of administration may be most appropriate for highly potent APIs that require small dosage amounts (3).

Separately, depending on the cannabinoid, buccal or intranasal might provide for better patient tolerability, as some cannabinoids can be either very bitter or spicy, and where one technology or the other might provide a better patient experience. “We need more clinical data, but I expect there will be a place for both technologies depending on the clinical context and specific cannabinoids,” Chandler says.


For buccal formulations specifically, Chandler notes that analogous cases such as buccal delivery of testosterone show that buccal improves total absorption and reliability. Similarly, improvement of efficacy has been reported when going from oral gastric tablets of triptans to sublingual or intranasal delivery. The published literature on buccal delivery of cannabinoids, he continues, suggests that there is evidence that buccal delivery improves total absorption with pharmacokinetic (PK) profiles swinging from predominantly first-pass metabolites towards more non-metabolized actives in patients. “These papers, however,” says Chandler, “describe small trials with only a handful of patients and not powered or controlled at a level to really address the question of variability.”

Developing buccal formulations (orally disintegrating tablets, buccal mucoadhesive tablets, films and patches, sublingual disintegrating thin films, sprays, chewing gum, and lozenges) can be challenging for cannabinoids because buccal delivery comprises a group of technologies, all of which might not be suitable for all cannabinoids, according to Chandler. In addition, he notes that cannabinoids have diverse flavor profiles, which can be an issue.

“Buccal delivery tends to involve greater residence times in the mouth, and depending on the unit dose they can be highly concentrated,” Chandler explains. Furthermore, the small size of the oral cavity limits the volumes that can be comfortably delivered compared to traditional tablets/capsules. Some cannabis and hemp extract products are in development.

It is worth noting that buccal and intranasal delivery are just two forms of transmucosal drug administration, which is intended to deliver drug substances through the mucosal epithelium into systemic circulation. Others include rectal and vaginal delivery. Several different cannabinoid candidates are being developed as transmucosal products, with many of them based on THC or CBD and most as oromucosal formulations (2).

Nano products claim to tackle GI tract absorption issues

Given that oral delivery via tablets and capsules is generally the preferred route of administration due to simplicity, many developers of cannabinoid medicines are focused on overcoming the poor absorption of these molecules in the gastrointestinal (GI) tract, which is typically 15–20%. Nanoscale solutions are receiving the greatest attention, according to Tishler, but solid data has yet to be supplied, he says.

Nano-based technologies are attractive because they have the potential to not only improve solubility and bioavailability, but increase stability and provide mechanisms for controlled- and other types of modified-release profiles and taste masking (2,4).

Various solutions are being developed, including those based on lipid and polymeric nanoparticles (2,4). Other lipid-based formulations such as nanomicelles, nanoemulsions, lipid nano capsules, and nanostructured lipid carriers, self-micro emulsifying drug-delivery systems, and self-nano emulsifying drug-delivery systems are being explored, as are ethosomal systems containing phospholipids, ethanol, and water; complexation by cyclodextrins; extracellular vesicles or exosomes; mesoporous silica; and electrospun fibers (2,4).

Nanoemulsions are particularly popular, according to MacKay, with different companies using a number of different approaches to generate them. “The challenge is selecting the right emulsifiers and emulsification technology (for example, controlled cavitation) for a given cannabinoid to achieve nanoemulsions of the correct particle size that maintain their emulsified state for throughout shipment, storage, and use,” he contends.

Stability is essential, as formulations in which the emulsion has degraded will not have a consistent concentration of the cannabinoid active throughout the entire solution. The particle size is important because it not only determines how efficiently the nanoparticles will cross membranes, but which cells are targeted and how the nanoparticles interact with them, Mackay observes.

Chemical modification

Another way to improve the solubility and bioavailability of cannabinoids is to chemically modify them in such a way as to reduce their lipophilicity without affecting the parts of the molecule involved in receptor binding and thus their pharmacological activity. Examples of modifications include adding long-chain alkyl substituents to the main ring structure to increase hydrophilicity and preparing conjugates with polar molecules.

MacKay points to the work of Alexander Makriyannis, George Behrakis Chair of Pharmaceutical Biotechnology at Northeastern University, and John W. Huffman, now deceased, previously a professor of organic chemistry at Clemson University, as being the most well known in the field. These two and many others have produced hundreds of synthetic cannabinoids with wide-ranging properties, some of which are now in preclinical or early-stage clinical development.

Application to the skin

Cannabinoid receptors exist in the skin, and some companies are seeking to develop topical or transdermal cannabinoid formulations to skin conditions, such as psoriasis, atopic dermatitis, and acne. A common approach in this case is to generate synthetic prodrugs that can cross both the lipophilic stratum corneum and the aqueous dermis (2). Many of these formulations are also nanoscale solutions.

No one perfect delivery solution

The key takeaway about cannabinoid drug delivery is that no one delivery approach will be effective for all natural and synthetic cannabinoids. “There is too much variability in the physicochemical characteristics of the many different pharmacologically active cannabinoids being investigated today,” MacKay states. As with other drugs, different indications and different
patient populations will require different routes of administration to meet
therapeutic, patient, and physician needs. A formulation intended to treat acute pain, which requires fast onset, will be different from one to treat chronic conditions, for which extended release will be preferable.


  1. Woodcock, J. FDA Concludes that Existing Regulatory Frameworks for Foods and Supplements are Not Appropriate for Cannabidiol, Will Work with Congress on a New Way Forward. FDA Statement, Jan. 26, 2023.
  2. Stella, B. et al. Cannabinoid Formulations and Delivery Systems: Current and Future Options to Treat Pain. Drugs. 2021 81(13): 1513–1557. doi: 10.1007/s40265-021-01579-x/
  3. Tijani, A. O., et al., Delivering Therapeutic Cannabinoids via Skin: Current State and Future Perspectives. Journal of Controlled Release, 2021 Vol. 334, June 10, 2021, pp 427-451. https://doi.org/10.1016/j.jconrel.2021.05.005
  4. Palrasu, M. et al., Perspectives on Challenges in Cannabis Drug Delivery Systems: Where Are We? Med Cannabis Cannabinoids 2022 5:102–119. https://doi.org/10.1159/000525629.

About the author

Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology.

Article details

Pharmaceutical Technology
Vol. 47, No. 6
June 2023
Pages: 19-20, 23


When referring to this article, please cite it as Challener, C. Overcoming the Poor Solubility of Cannabinoids. Pharmaceutical Technology 2023 47 (6).