Improving Solubility of Cannabinoids

February 2, 2020
Felicity Thomas

Editor of Pharmaceutical Technology Europe

Pharmaceutical Technology, Pharmaceutical Technology-02-02-2020, Volume 44, Issue 2
Page Number: 27-29

Lipid-based solutions offer a natural approach to improving the solubility of cannabinoid-derived products.

In recent years, marketing authorizations of cannabinoid-based pharmaceuticals (namely nabiximols [Sativex] in Europe and plant-derived cannabidiol [Epidiolex] in both Europe and the United States) have been issued globally, although legal and regulatory concerns around cannabis-based products are still apparent (1). As more cannabinoid derivatives are currently in development, there is a drive for developers and formulators to address the challenges these ingredients pose.

To explore the common issues that can be encountered with cannabinoids during formulation and development and the potential solutions that are available to overcome these challenges in more detail, Pharmaceutical Technology spoke with Alyn McNaughton, technical director, Lonza Pharma & Biotech, and David Fulper, director, Technology Support, Softgel and Oral Technologies, Catalent.

Ingredient challenges

PharmTech: What are the specific challenges facing formulators and developers when approaching cannabinoid-derived products?

McNaughton (Lonza): Cannabinoids, generally, have a very low solubility in water and are highly lipophilic. As an example, cannabidiol (CBD) has a solubility of only 0.7 µg/mL (2). Consequently, these materials cannot readily be absorbed orally and, therefore, a large quantity is required to have a medicinal effect. The bioavailability is also significantly affected by dietary fat, which can lead to variability. Alternative routes of administration, such as smoking, present additional challenges, such as potentially producing toxic by-products. These other routes of administration also do not have a significantly better bioavailability and the variability is generally even higher than the oral route.

Fulper (Catalent): Stability and first-pass metabolism are probably the two biggest technical challenges. Cannabinoids tend to be oxidatively sensitive, which can be affected by both the formulation and manufacturing process. Tetrahydrocannabinol (THC), and probably CBD, undergo extensive first-pass metabolism, which can be particularly challenging for oral formulations.

An additional challenge is the desire to use extract or “broad spectrum” material that contains multiple components. The variability of these extracts makes it difficult to establish API specifications, develop analytical methods, and even to interpret clinical data. Then there is the political/regulatory challenge for anything related to cannabis, which can often complicate the process.

Synthetic versus plant

PharmTech: Are there any inherent differences between plant-based cannabinoids or synthesized ones that may impact drug development and formulation?

Fulper (Catalent): Molecularly, there are no differences in plant-based cannabinoids and synthetic cannabinoids. As with any raw material supply, there is always the question of purity and related substances, which could differ between the two. The question more often seems to stem from the desire to include other components of plant-based material for a therapeutic effect. The validity of this approach can only be determined through application of adequate science.

McNaughton (Lonza): The source, synthesized or extracted, is becoming less relevant to the drug development cycle for cannabinoids as regulators apply pharmaceutical practices. Combinations of different cannabinoids become costly and challenging to get approved due to the permutations of safety and clinical trials required with variations in ratios of these materials required to prove efficacy and safety. From either source, single, pure cannabinoids present the most straightforward route for approval.

While some evidence exists that there are benefits in certain cases for mixtures of cannabinoids, the approval path for this approach is prohibitive and it is likely, at least in the near future, that development of a single, pure cannabinoid will be the preferred route for a pharmaceutical. In other sectors, such as the nutraceutical market, it is likely that some mixtures will still be developed. These mixtures may return to pharmaceutical development areas once the properties of the cannabinoids are more fully characterized individually.

The nature of some cannabinoids to be psychoactive, and consequently by their presence turn any materials into a controlled drug substance, also presents a challenge, mainly for the extracted products. However, extracted materials or those synthesized at a late stage from extracted starting materials still appear to be cheaper than those fully synthesized, at least for the moment, but this is likely to change as the chemistry of synthesis becomes more commonly used.


Currently available solutions

PharmTech: Could you highlight the currently available solutions that can help formulators overcome the solubility and bioavailability challenges associated with cannabinoids?

McNaughton (Lonza): Although other solubility-based bioavailability enhancement approaches, such as solid dispersion, can present some improvement, lipid formulations are the natural approach for molecules with high lipophilicity and low water solubility. Solubility of the cannabinoid in the lipid, and associated excipients, creates an overall solubilized formulation that avoids solid-state limitations for absorption.

Fulper (Catalent): Cannabinoids tend to fall into Developability Classification System (DCS) Class IIb (solubility rate-limited absorption), and formulation technologies that improve intrinsic solubility, such as lipid-based systems or solid dispersion systems, may help to address the solubility aspect of poor bioavailability; however, if the compound suffers from high first-pass metabolism overall, bioavailability will remain low. Increasing the dose can sometimes saturate the enzymes involved, but this approach can result in an increase in undesired side effects.

The log P for these compounds tend to be in a range conducive to lymphatic absorption. Using lipid formulations that contain long-chain unsaturated fatty acid components help promote chylomicron production, which are then lymphatically transported into the blood stream and bypass first-pass liver metabolism. The degree to which a specific cannabinoid is incorporated into chylomicrons remains an open and important question.

Benefits of lipid-based approaches

PharmTech: Why are lipid-based solutions particularly beneficial for cannabinoid-derived products?

Fulper (Catalent): Cannabinoids are generally oxidatively unstable. Softgel delivery platforms used to deliver lipid-based formulations are excellent oxygen barriers, and the manufacturing process to make softgels is conducive to protection from exposure to air. Cannabinoids generally have good solubility in triglyceride lipid bases, allowing for easy solubilization in lipid formulations. These formulations, in turn, are readily digested by the body into mixed micelle systems that are readily absorbed into the enterocytes, the intestinal absorptive cells. Cannabinoids can suffer from first-pass liver metabolism. Lipid formulations that promote the formation of chylomicrons offer a path to bypass first-pass liver metabolism.

McNaughton (Lonza): Along with the generic potential for lipids to overcome the solid-state limitations for absorption and present the cannabinoids in a solubilized form for intestinal absorption, lipids also present further benefits for highly lipophilic molecules. A secondary contribution to the low bioavailability is the potential for many of these molecules to suffer from first-pass metabolism, where the drug is metabolized, usually by the liver, reducing the quantity reaching systemic circulation. For drugs with a LogD > 4.7 and solubility of >50 mg/g in LCT (long-chain triglycerides) (3), appropriate formulation can promote intestinal lymphatic absorption, over the normal hepatic portal system, undergoing transport directly to the systemic circulation and avoiding first passing through the liver.

Lipid selection

PharmTech: Could you provide any advice on lipid selection for cannabinoid formulations?

McNaughton (Lonza): The selection of excipients comes down to the expertise of the formulator, though there are some general approaches that can be applied. The incorporation of an LCT is preferable, if the cannabinoid is soluble enough in the LCT and the LogD > 4.7. Formulations where LCT, or other triglyceride, is the only excipient are very likely to have large patient and dietary variability. The formulator, therefore, needs to refine the formulation with appropriate excipients, such as surfactants and co-solvents, to allow an emulsion, or preferably a micro-emulsion, to be formed. Ideally, the cannabinoid should also be as soluble in the additional excipients. The closer the formulation is to a micro-emulsion, the less likely it is to have patient variability. As well as being able to form and sustain the emulsion through dilution in the gastric system, it is also critical that the solubilization survives the change into the intestinal system and that the digested species of the lipid formulation also continue to solubilize the cannabinoid long enough for absorption to take place.


Fulper (Catalent): Lipid selection should always include an assessment of their impact on stability. Many lipids themselves can undergo oxidation. If a less stable lipid is chosen, for instance to target lymphatic absorption, then the source of that lipid should be evaluated for incoming quality. When selecting a lipid to promote lymphatic uptake, long-chain fatty acids are preferred, and unsaturation is preferred to saturated lipids. Solubility should be good in most triglyceride-based excipients. In-vitro digestive studies can be used to evaluate the relative ability of the formulation to maintain solubility during digestion.

Regulatory advantages

PharmTech: Do lipid-based systems provide advantages in terms of time to achieve regulatory approval?

Fulper (Catalent): Lipids mimic food and participate in the body’s natural digestive process. In this sense, when you use lipids you are trying to create a food effect (with less calories). In the end, other approaches may work as well or even better, but in my opinion, working within the body’s natural absorption process is a good starting point. Once you have a better picture of the pharmacodynamics involved, you can then decide if another approach might make sense.

From a regulatory perspective, if you plan to produce a generic version of a branded lipid formulation, there may be less concern if you maintain the same or similar formulation approach. Also, [it is helpful that] there is a level of intrinsic abuse deterrent for lipid-based formulations compared to some other delivery platforms.

McNaughton (Lonza): From a regulatory standpoint, most bioavailability enhancement technologies are now considered to be well understood and accepted. Generally, any technology that is used to improve bioavailability should aim to minimize the overall quantity of drug substance required and minimize the variability in the patient population. Where the cannabinoid is poorly soluble in water and highly lipophilic, then lipid systems offer the best opportunity to achieve this, making it the most likely approach to be readily approved by the regulators.

Future trends

PharmTech: What future trends do you predict for solubility and bioavailability enhancement options for

McNaughton (Lonza): More formulations may appear that have been refined to achieve the best bioavailability for each cannabinoid. Beyond this, more synthetic cannabinoid analogues may be produced, either as prodrugs or to modify other properties of the molecule. It is possible that many of these analogues will be derived to promote properties that can be used to enhance bioavailability, which for many is likely to be combined with lipid technologies to maximize efficacy with minimal drug substance. Others may be derived to improve selectivity and efficacy in specific areas, and these may still require significant formulation development to ensure bioavailability.

Fulper (Catalent): As the pharmacology of cannabinoids and the endocannabinoid system become better understood, I would expect synthetic cannabinoid derivatives to begin to appear. As part of that process, I think you will see a focus on molecular changes to improve stability and reduce metabolism issues, which are probably the two main challenges with the existing analogues.


1. FDA, ‘FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD),”, Public Health Focus, Jan. 15, 2020.
2. E. Samara and M. Bialer, Drug Metab. Dispos., 16 (6) 875–879 (1988).
3. C.J. Porter, N.L. Trevaskis, and W.N. Charman, Nat. Rev. Drug Discov., 6 (3) 231–248 (2007). 

Article Details

Pharmaceutical Technology
Vol. 44, No. 2
February 2020
Pages: 27-29


When referring to this article, please cite it as F. Thomas, “Improving Solubility of Cannabinoids,” Pharmaceutical Technology 44 (2) 2020.



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