Cannabis is a natural plant that contains more than 600 different molecules which have potential therapeutic effects. The Cannabis plant, also contains Terpenoids – Phenols (Cannabinoids), Terpenes, Lipids, Flavonoids, Alkaloids and other natural materials.  Each one of these groups contains many different molecules that differ from each other in their physical and chemical characteristics such as polarity, solubility, boiling point, melting point, size and affinity.

Based on these characteristics, we can develop extraction, separation and purification techniques for the cannabis plant’s active materials API (Active Pharmaceutical Ingredient) that can be used for Cannabis-based drugs manufacturing for clinical trials, as well as for approved drugs manufacturing under GMP (Good Manufacturing Practices).

Additional factors that increase the variety and complexity of working with cannabis for medical purposes is that the Cannabis plant crop (yield) is highly affected from uncontrolled growing conditions that may alter the active material composition, content and cause batch to batch variation.

When we develop strategies for Cannabinoid extraction, separation, and purification, we should also take into consideration that scale up for the manufacturing process is not “straight forward” and success in a small scale process, will not guarantee “smooth” scale up to an industrial scale.

What is a good extraction, separation and purification technology for Cannabis?

  • Robust- The chosen technology and final Cannabis API or product should meet the accepted criteria and assure minor changes in the process that will not affect product quality such as environmental parameters, operator or raw materials.
  • Minimal toxic chemicals usage- In case toxic solvents are being used, there is a risk of toxic material residuals in the final product. Moreover, threshold limits are always on the way down, as a result of the regulatory and GMP requirements and updates.
  • Repeatable- Stable and repeatable manufacturing process parameters, in-process controls and final Cannabis purified API/products that meet the accepted criteria in a repeatable manner.
  • Flexible-Technology that will enable extraction and separate different Cannabis strains and batch sizes.
  • Affordable- The chosen technology should be cost effective
  • Environmentally friendly- Raw materials, solvents and other toxic material should be treated and/or evacuated in order to follow the quality of environmental regulatory standards
  • Safe- Materials and technology should be safe for the operator. When working with solvents, it is very important to keep the process room under pressure, to use explosion-proof process equipment and facilities, and to supply the required protection items and detectors in order to keep employees safe and healthy
  • Scalable- The target is to achieve a robust and stable industrial manufacturing process. The technology to be chosen should be as scalable as possible.

Cannabinoid extraction, separation and purification processes

Cannabis separation and purification technology can be developed for:

  • Undesired materials and component removal from a mixture of components; for example, Alkaloids removal from “whole plant extract”
  • Purifying a single or group of materials or components

The ‘entourage effect’ in Cannabis medical treatment

The Term “whole plant extract” might be misleading. Since there has been a lot of research about the “entourage effect” of the Cannabis plants’ components for therapeutic purposes, for example in RSO (Rick Simpson Oil) or Cannabis botanical drug products, one might think that a “whole plant extract” contains all of the components in the plant, but this is not the case. The nature of the extraction is totally subject to the extraction technology that will extract the plant components based on their affinity to the process.

Since most of the plant’s botanical material and components can be found in other plants, we will focus our discussion on the Cannabis plant’s unique active materials – the Cannabinoids and which separation and purification processes should be chosen in order to achieve an isolated high purity Cannabinoid (over 95%).

Cannabinoids appear naturally in 2 forms:

  • The less stable acid form (as a Carboxylic acid) such as CBDa and THCa.
  • The neutral form (due to degradation or de-carboxylation) such as CBD and THC.

Cannabinoid purification strategies

  1. Purification of acidic Cannabinoids

Acidic Cannabinoids can be purified using ion exchange, acid-based chemical reactions, and decarboxylation. With this approach, we begin with pre-decarboxylated Cannabis plant material. Then, extraction can be done using solvents, gaseous or supercritical fluids. Extra care must be taken to reach a highly purified extract (reduce wax and chlorophylls) in order to achieve sustainable yields and to reduce contamination. Decarboxylation is performed after the purification of acidic Cannabinoids.

  1. Crystallization of cannabinoids

In order to achieve Cannabinoid separation through Crystallization, two terms must be addressed. First, the Cannabinoid of choice must have a tendency to crystallize, and second, it must have a high level of purity so that the crystallization process may occur. To achieve fair crystallization of Cannabidiol (CBD), there should be no wax or chlorophylls, and in HPLC (High-Pressure Liquid Chromatography), the CBD concentration should be higher than 80%. Cannabinoid extraction can be made using solvents, gaseous or supercritical fluids, and decarboxylation can be performed with the extractor directly to the plant material.

  1. Separation of neutral Cannabinoids via chromatography

This purification technology is suitable for Cannabinoids that are harder to purify by the methods mentioned above and is dependent on the scale of production. If the demand is for a few grams, a proper RP column will be sufficient to meet almost every need. Usually, it is recommended to use other technologies in order to reach purity higher than 90%, before entering an RP column. NP separations normally have a much higher loading rate and will be used to purify the extract. As with crystallization, the extract made by solvents, gaseous or supercritical fluids, and decarboxylation can be performed on the extract or directly with the plant material. Another emerging technology is SFC (supercritical fluid chromatography) which utilizes the fair solubility of Cannabinoids in low-pressure CO2 and produces fractions with very little residual solvents.

  1. Fractional distillation

Due to the high boiling points of Cannabinoids (THC boiling point is 157oC, CBD boiling point is 180oC), it is possible to separate Cannabinoids through distillation means, boiling point evaporation and condensation. The starting material is decarboxylated extract, and the process is fairly cheap and solventless. Practically, there must be a gap of at least 20 degrees Celsius between the Cannabinoids of choice and relevant impurities. The process should be controlled and boiling temperatures should be kept precise and homogenous throughout the entire process. The relevant Cannabinoid vapors should be condensed and collected.

Cannabinoids quality and purity levels

Because of the highly complex nature of the Cannabis and as the regulatory and quality requirements becoming stricter over the years, Cannabis products accuracy and repeatable purity levels are an important factor for recreational use as well as in the medical cannabis market.

In order to achieve this process and meet quality challenges, it is recommended to “mix” separation and purification strategies in order to achieve the desired Cannabinoid purity and concentration. For example, there is no need to use RP chromatography to reach 98% CBD extract, because it will be costly and require labor costs versus the combination of NP chromatography and crystallization. The choice for the purification strategy also depends on the nature of the plant’s starting material.

Cannabinoids pharmacokinetics

Most of the research performed on Cannabinoids Pharmacokinetics (Pk) is focused on the bioavailability of THC on different routes of administration (smoking, oral intake, etc.).

Cannabinoid inhalation

Smoking Cannabis cigarettes results in rapid absorption into the bloodstream. THC is detectable in the blood 10 seconds after the first inhalation of a Cannabis cigarette. Bioavailability varies according to the depth of inhalation, puff and lung capacity.  The average bioavailability of THC via smoking is around 30%. It is assumed that 30% of the initial THC is destroyed by pyrolysis, side stream smoke or incomplete absorption into the lungs. Plasma levels reach their peak within minutes after administration and fall rapidly with increasing levels of THC-OH.

Cannabinoid: Oral administration

Oral administration in most cases is slow and erratic. Plasma concentration reaches its peak between 60-120 minutes after administration.  Oral administration bioavailability is around 5%.  The relatively low bioavailability is a result of acid degradation in the stomach, gut absorption, and liver metabolism. First pass metabolism through oral administration creates high levels of THC-OH, a highly psychoactive substance, 4 to 5 times more than THC, that may create an unpleasant experience for patients.

Cannabinoid: Sublingual administration

Absorption of Cannabinoids and Cannabis-based preparations through the buccal mucosa is around 13%.

Cannabinoid: Topical administration

Topical administration avoids the liver first pass metabolism. The administrated paste or cream will be smeared locally and as a result, Cannabinoid metabolism in the liver will be minor. Since Cannabinoids are naturally lipophilic compounds, the absorption step is passed through the skin.  The application of dermal patches resulted in a slow and prolonged delivery. No clinical studies have been completed on humans.

Cannabinoid: Rectal administration

Recently, studies have discovered that taking Cannabinoids rectally via suppositories may possess enhanced bioavailability. Studies on animals have shown bioavailability of 13.5%. Bioavailability levels were very dependent on the matrix which was used.

CBD shows similar or less bioavailability than THC on most routes of administration. Like CBN, CBD demonstrates a better skin penetrability.

About Cannabis GxP consultancy

Cannabis GXP is proud to stand at the forefront of the Cannabis industry in Israel and worldwide thanks to many years of experience in these areas.

Our team is compelled to spread the message of the importance of cannabis science, regulation and standardization as the world enters a new era of cannabis legislation.

We aim to position our clients with their best foot forward when it comes to anything and everything cannabis related.

Our vast expertise allows us to assist companies in a wide range of services and needs: Anything from Cannabis R&D, growing and manufacturing, new products development, facility design, technology, Quality Assurance, Good Practices (GAP/GMP/GLP/GDP/GCP), staff training, local and global regulations.

Cannabis GxP is a subsidiary company of Bio-Chem Ltd. (2007), a consultancy firm for the Pharmaceutical field, medical devices, Cosmetics and food supplements industry based in Israel.

Our cannabis consultancy services include:

  • Product development, delivery system & clinical trials
  • Growing, Manufacturing and Lab Facilities Design
  • Quality Assurance and Good Practices (GxP)
  • Cultivation & Product Manufacturing Technology
  • New product Regulations and Submissions
  • Qualification & Validation
  • Risk Assessment
  • Staff training

If you need one or several of our services, we will be more than happy to assist.

Please do not hesitate to contact us for further information.