Encapsulating cannabinoids in lipid-based nanoparticles: THC vs. CBD – Part 2 of the series

Enhancing cannabinoids’ therapeutic efficacy

In our previous technical note, we reported on the encapsulation of CBD vs CBDA (1). The work here-in continues on that theme in terms of studying the differences in encapsulating different cannabinoids into the same lipid-based drug delivery system that was specifically developed for one of the major cannabinoids, THC. The overarching hypothesis in our series of experiments is that the similarities in cannabinoids could enable similar results in terms of encapsulation efficiency and characteristics. But as we note in the various comparisons developed in this series, small changes in structure can have curious outcomes. Let us take a closer look here at THC vs CBD.

Cannabinoids have a long history in medicine given their therapeutic effects (2). However, due to their lipophilic nature, they are poorly absorbed by the digestive system which hinders their potential as therapeutics (3).

Nanoparticles offer a solution to this problem. By encapsulating these hydrophobic molecules into water miscible vehicles, they can be better absorbed by the digestive system, thus enhancing their therapeutic effect (4).

Lipid-based nanoparticles
Figure 1: Lipid-based nanoparticles

At Ascension Sciences, we have explored different types of nanoparticles to encapsulate cannabinoids. Specifically, lipid-based formulations have been successfully optimized for the encapsulation of (−)-trans-Δ9-tetrahydrocannabinol (THC). One of the next steps in our research and development explorations was to use these optimized parameters to encapsulate cannabidiol (CBD), other major cannabinoid, into three types of lipid-based nanoparticles: emulsions, liposomes and solid-lipid nanoparticles (SLNPs) – Figure 1.

Find Part 1 here


This technical note presents the comparison between the encapsulation of THC vs. CBD using formulation parameters that were previously optimized for THC. The goal of the study was to provide insights into how the formulation optimized for one cannabinoid translates into another, and where one lead formulation concept can become the starting point for an alternate active ingredient.


Molecular structure of CBD
Molecular structure of CBD

Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two most common cannabinoids found in cannabis plants with similar molecular structure (5). However, even small structural differences (Fig. 2) result in THC and CBD having different chemical properties and effects on our body’s endocannabinoid system(6). THC and CBD have been found to have opposing actions (6). For example, in a study by Engluns et al., it was shown that CBD decreases the memory and learning impairments caused by THC in well-controlled human and animal studies (7).  On the one hand, THC is the primary psychoactive compound in cannabis and works as a partial agonist of cannabinoid receptors (CB1 and CB2) and has effects on emotion, pain, digestion, and appetite (8, 9). On the other hand, CBD has poor affinity for the cannabinoid receptors and works as a partial antagonist of CB1 and has some anti-inflammatory, anti-anxiety and anti-psychotic activity (10).

Molecular structure of THC
Molecular structure of THC

In this specific study, we compared the encapsulation efficiency and nanoparticle stability of each cannabinoid formulation. Encapsulation efficiency is the amount of cannabinoid that is encapsulated into the nanoparticle upon formulation. Nanoparticle stability is determined by measuring the particle size and polydispersity index (PDI) every 7 days for a month of storage at different conditions to monitor any significant changes in the properties of the particles. A stable nanoparticle does not significantly change in size and PDI remains below 0.2, meaning that the particle population is uniform in size and there is no aggregation of the particles over time. Lastly, we determined the cannabinoid retention, which is the amount of cannabinoid that remained encapsulated inside the nanoparticles after 30 days of storage.


The formulation parameters for each nanoparticle type can be found in Table 1. Each formulation type was used on either THC or CBD using the same formulation parameters.

All of the nanoparticle formulations were prepared using a low energy approach achieved by the NanoAssemblr Benchtop microfluidic instrument from Precision Nanosystems.

Emulsion Liposome SLNP
Lipid composition Tween 80 : Span 80 : Hemp Seed Oil POPC : Chol : DSPE-PEG2000 Chol : POPC : DSPE-PEG2000
Organic solvent Ethanol
Aqueous solvent Deionized water PBS pH 7.4
Solvent removal Dialysis in aqueous media
Lipid:Cannabinoid 10:1

Table 1: Formulation parameters for the different types of nanoparticles


Encapsulation efficiency (EE%)

Encapsulation efficiency of THC and CBD in each type of nanoparticle
Encapsulation efficiency of THC and CBD in each type of nanoparticle

* SLNP: Solid-Lipid Nanoparticle

Figure 3: Encapsulation efficiency of THC and CBD in each type of nanoparticle

Type of nanoparticle THC concentration, mg/mL CBD concentration, mg/mL
Liposome 0.97 0.88
Emulsion 3.89 3.98
SLNP 0.30 0.31

Table 2: Encapsulated cannabinoid concentration

* THC solubility in water: 2.8 ug/mL (11)
* CBD solubility in water:  0.1 ug/mL (12)

  •  All the nanoparticles allow a higher concentration of the cannabinoids in an aqueous solution compared to the free drug.
  • Similar EE% (range of 70 to 75%) is observed for Liposome and SLNP nanoparticles across nanoparticle types and APIs (i.e. between nanoparticles and for both THC and CBD).
  • CBD emulsion nanoparticles show the highest encapsulation efficiency within the three types of nanoparticles at 95%.

Nanoparticle stability over 35 days of storage at 4°C

SLNP: Solid-Lipid Nanoparticle
Figure 4: Stability of the nanoparticles over 35 days of storage at 4°C.
  • Both THC and CBD liposomes and emulsions were stable at 4°C for 35 days. However, a drastic increase is observed for CBD SLNP and slight decrease is observed for THC SLNP.
  • Both THC and CBD loaded liposomes show similar particle size of approximately 60 nm.
  • Liposomes have the lowest particle size within the three types of nanoparticles ranging from 50 to 60 nm for both THC and CBD; then emulsions range from 200 – 300 nm with comparable size between the two APIs; lastly SLNPs have the greatest variability in size ranging from 300 to 900 nm having bigger particles for CBD.
  • All PDI values were below 0.3, except for the CBD liposome at day 35, which indicates that there was no aggregation of the particles and the particle population of the specific size remained stable.

Cannabinoid retention over 35 days of storage at room temperature – dark and light

Cannabinoid retention over 35 days of storage at room temperature - dark and light
Figure 5: Cannabinoid retention in the nanoparticle over 35 days of storage at room temperature, dark
  • THC and CBD were both retained (57 to 69%) in comparable amounts in all nanoparticle formulations stored in the dark at room temperature.
  • All nanoparticles’ drug retention is within a similar range at room temperature dark.
  • THC liposomes show significantly higher drug retention compared to CBD liposomes at room temperature light. CBD liposomes show no retention at room temperature light however, CBD in emulsion and SLNP show similar retention to THC.


No significant difference observed between CBD and THC particle size and PDI for liposomes and emulsions. Some increase in the particle size is observed for the SLNP formulation after 35 days of storage for THC. However, this instability is also seen for the CBD SLNP.  The encapsulation efficiency for all nanoparticle types for both THC and CBD was high and  exceeded 70%. However, a significant difference is seen between CBD and THC drug retention for liposomes at room temperature exposed to light . The small difference in the molecular structure of THC and CBD could be a possible reason for this. However, this result is unexpected and needs further investigation. A certain amount of drug leakage (up to 50% depending on the specific application) is expected for liposomes and indicates their ability to release the drug and provide the expected therapeutic effect. Of note, unusual stability (drug retention above 90%) is sometimes associated with insufficient drug release in vivo. Based on the abovementioned results it can be concluded that the formulation developed to encapsulate THC serves as a good starting point  for CBD nanoparticle formulations.


ASI aims to develop and optimize a formulation that shows the highest EE% (<90%), API stability and bioavailability for each cannabinoid individually.

Find out more about Ascension Sciences here!


  1. https://www.pharmaexcipients.com/news/encapsulating-cannabinoids-lnp/
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