**Please note this article is part of a larger series that was first released in the March 2021 Monthly Playbook.  If you would like to receive the complete monthly playbook you can sign up here

Cannabis Manufacturing for the 21st Century

Part 4: Chemical Difficulties of Real-time Cannabis Process Control

The general product types used to be bud, oil and tinctures. Today, they are further separated into flower, extract, ingestible, tinctures, edibles, sublinguals, and topicals. Flower is still the most-used format although extracts are expected to have the most growth over the next decade. Currently, cannabis is defined by the two most common active ingredients: tetrahydrocannabinol (THC, psychoactive) and cannabidiol (CBD, non-psychoactive). However, there is a plethora of other cannabinoids, the chemical compounds in cannabis, not to mention terpenes as well as flavinoids.

The decarboxylation of CBDA to CBA[4]

Problems can begin to arise since the science of understanding how the diverse array of cannabinoids interact, individually and in concert, with the body is still in its fledgling stages. As research continues to explode in this area, growers and manufacturers are looking for new ways to improve the efficiency of their processes while being able to control the various cannabinoids in the proper concentrations.

The cannabis plant has over 400 chemical molecules and at least 60 of those are cannabinoids, chemicals unique to the plant. [1] [2] [3]. In the plant, cannabinoids are synthesized (made) and stored as cannabinoid acids. When dried, stored, and heated, the acid group (-COOH) comes off and we get the compounds that we are used to thinking about: CBD and THC. (see Figure 1)

While drying and storing allows partial decarboxylation, heating allows full conversion rates. However, the cannabinoids and the terpenes begin to break down over 300˚F, which can be avoided if a lower heat is applied over time. Thus, most conversion happens over time in temperatures just over 200˚F. A list of several known major cannabinoids is shown below. [5]

CANNABINOIDS

• Tetrahydrocannabinol (THC)
  • ​Delta-8-tetrahydrocannabinol Δ9-THC (or d-8-THC)
  • Delta-9-tetrahydrocannabinol Δ9-THC (or d-9-THC) (most common)
• Cannabidiol (CBD)
• Cannabigerol (CBG)
• Cannabichromene (CBC)
• Cannibonol (CBN)
• Cannabinodiol (CBDL)
• Cannabidivarin (CBDV)
• Tetrahydrocannabivarin (THCV)
• Cannabigerivarin (CBGV)
• Cannabichromevarin (CBCV)

There are also over 100 known naturally occurring non-cannabinoid terpenes, the aromatic components, in cannabis. [1] [2] [3]. Research has shown that cannabinoids and terpenes work together, though the mechanism is still not fully understood. Common terpenes in cannabis include myrcene (mango), limonene (lemon), pinene (pine tree), linalool (lavender), caryophyllene (black pepper and cinnamon), humulene (hops, basil,
clove). Myrcene is the primary terpene in cannabis plants and is responsible for its distinctive aroma. [3]. However, pot-smelling canines are trained to detect β-caryophyllene. For many growers, they cultivate certain strains with known concentrations of various terpenes to create unique odors for their products. Many manufacturers buy custom blends made from botanically derived terpenes. [8]

By extracting and separating the various compounds, especially the CBD and THC, the manufacturers can use analytical methods, such as spectroscopy, to quantitatively measure their compounds and control the actual concentrations of the active compounds in their products, and the manufacturers can precisely control the concentrations of their products including oils, edibles, etc. A difficulty arises in spectroscopy as many of the compounds are similar and thus will give similar spectra. As mentioned previously, statistical models are used to help differentiate the compounds to help enable real-time spectroscopic monitoring of the compounds of interest.

References:

1. Z. Atakan, “Cannibis, a complex plant: different compounds and different effect on individuals,” Therapeutic
   Advanced in Psycopharmacology, vol. 2, no. 6, pp. 241-254, December 2012.
   
2. National Cannibis Prevention and Information Centre, “Cannabinoids,” Alcohol Drug & Abuse Center / University
   of Washington, 2013.
   
3. M. Jacobs, “The Difference Between Cannaboids and Terpenes,” February 2020 2019. [Online]. Available:
   https://www.analyticalcannabis.com/articles/the-difference-between-cannabinoids-and-terpenes-311502.
   
4. A. Beadle, “CBDA Vs CBD: What are the Differences?,” 18 October 2019. [Online]. Available: https://www.
   analyticalcannabis.com/articles/cbda-vs-cbd-what-are-the-differences-312019#:~:text=Once%20CBDA%20
   has%20been%20formed,lose%20its%20acidic%20carboxyl%20group.
   
5. Way of Leaf, “top 10 Cannabinoids: What Are They and What Do They Do,” Way of Leaf, 28 january 2020.
   [Online]. Available: https://wayofleaf.com/education/top-cannabinoids-and-what-they-do.
   
6. K. Holland, “CBD vs. THC: What’s the Difference?,” 20 July 2020. [Online]. Available: https://www.healthline.
   com/health/cbd-vs-thc#medical-benefits.
   
7. M. Dingman, “Neuroscientfically Challenged,” 7 July 2017. [Online]. Available: https://www.neuroscientificallychallenged.com/.
   
8. E. Friedmann, Interviewee, Internal Company Cannabis Discussions. [Interview]. 8 September 2020.

**Please note this article is part of a larger series that was first released in the February 2021 Monthly Playbook. If you would like to receive the complete monthly playbook you can sign up here

Cannabis Manufacturing for the 21st Century

Part 3: Spectroscopy & Online Process Control for Cannabinoid Manufacturing

Spectroscopy is an analytical tool that started as a qualitative, identification method. However, it soon became apparent that the data can also provide quantitative insights.

Spectroscopy is the measurement of the interaction of electromagnetic (EM) radiation with matter. Visible (Vis) light and heat (infrared/IR light) are the most well-known forms of radiation, but it also includes gamma rays, x-rays, ultraviolet light, microwaves, and radio waves. Each of these types are differentiated by the amount of energy they possess. Ultraviolet light has more energy than visible light, which is one of the reasons it can cause sunburns, skin cancer, and eye damage. For the purposes of spectroscopy, the amount of energy is often denoted in units of wavelength.

A typical seeing person will qualitatively use spectroscopy everyday as they perceive the colors of different objects. Spectroscopic instrumentation allows a user to precisely quantify these observations. For example, branding colors such as Coca-Cola’s or Tiffany & Co.’s have exact colors that are created using specific mixtures of dyes. Online analysis can monitor the creation of the dye during its formulation and blending to ensure that not only is it the right color mixture every single time, but also at every location the dye is manufactured.

SPECTROSCOPY SCHEMATIC

Many spectroscopic instruments utilizes wide-spectrum light that has its broad range of wavelengths physically spread out by an optical component, such as how a prism creates a rainbow of colors. Once the different wavelengths are spaced out, you can place an array of detectors to quantitatively monitor the amount of light at each wavelength. When the light hits a molecule, the two can interact and the molecule can absorb some of the light. Most optical spectroscopies rely on the absorption or transmission of light by a sample and, in general, this absorption of UV, Vis, or IR is non-destructive. [1] The detectors monitor this change (See Figure 1).

​

With advances in technology, data can often be gathered in milliseconds. Quantitative information is possible because there is a strong proportional connection between the concentration of the chemicals of interest and the amount of light absorbed. The main advantages of spectroscopy is that it is a quick, cost effective, and passive technique that can provide both qualitative and quantitative analyses.

Process tank with an integrated
spectroscopic Solution Process Tank

UV-Vis, near-IR, and mid-IR spectroscopies all rely on the transmission/absorption of light at certain wavelengths. UV-Vis spectroscopy works with the excitement of electrons. The spectra tend to have few features that can cover several hundred nanometers. Near-IR and mid-IR work with the excitation of the vibrations of the atoms within the molecule. The absorption of light in the near- and mid-IR ranges causes numerous features that are usually not as broad as UV-VIS spectral features. The combination of all the features are unique to the molecule. Thus, vibrational spectroscopy can be extraordinarily useful for identifications. [1]

A mix of chemical species can create a matrix with overlapping spectral features. Untangling the intertwined data often requires expertise and numerous hours to create a statistical model that can identify and quantify the product(s) of interest. Software uses the model to quickly covert raw data/spectra into useful information such as the identities of the chemicals in the matrix and their concentrations. Using this data, spectroscopy can be the analytical tool for both qualitative and quantitative checks. For example, a quick check of the amount of moisture in a sample. It can also check a reaction’s progress by monitoring the concentrations of the reactants, intermediates, and/or products.

In the real world, methods exist for incorporating these analytical tools directly into a reactor or pipeline to measure the “sample” directly in the process continuously and in real-time (see Figure 2). This saves both the time and necessity of physically taking samples, both of which can cost a chemical plant millions of dollars. It also allows real-time monitoring of a process where it can be immediately apparent if something unwanted is occurring so that corrective steps can be taken. Beyond the value of instant insight, advanced process sensors also give the benefit of big data aggregation, where additional efficiencies and optimizations can be gained over time.

Outside of the chemical industry, spectroscopy is used for a multitude of applications. An example is the aforementioned measurement of color. Spectroscopy is also widely used in the pharmaceutical industry to measure the various steps of the Active Pharmaceutical Ingredient (API) creation. In the world of forensics, spectroscopy is often used in tandem with other methods to help identify unknown compounds, allowing for a strong case file to be built. In the cannabis industry, spectroscopy has already been implemented to quickly determine the CBD and THC levels [2] as well as moisture % and water activity in dried flower [3].

In the next installment of this series, we will cover the chemical difficulties of cannabis.

References:

1. D. a. Skoog, F. J. Holler and T. A. Nieman, Principles of Instrumental Analysis, Orlando: Saunders College Publishing, 1998.
   
2. Purpl Scientific, “Validation of the Purple Pro for Flower Potency Measurement,” May 2019. [Online]. Available: https://www.purplscientific.com/validation-of-the-purpl-pro-for-flower-potency-measurement/.
   
3. Purpl Scientific, “Validation of the Purpl Pro + H2O Pack for Cannabis Water Measurement,” 2020 July. [Online]. Available: https://www.purplscientific.com/validation-of-the-purpl-pro-h2o-pack-for-cannabis-watermeasurement/.

**Please note this article is part of a larger series that was first released in the January 2021 Monthly Playbook.

In the world of manufacturing, things move quickly. The manufacturer’s goal is to manufacture their product with the target quality in the proper quantity with as little waste possible. Many manufacturing outlets will do their quality control before a process starts and after the process ends, but what about while something is being created? 

Cannabis Manufacturing for the 21st Century

Part 2: Process Control in Cannabis Manufacturing

In the world of manufacturing, things move quickly. A manufacturer’s goal is to manufacture their product with the target quality in the proper quantity with as little waste possible. Process control is actively monitoring your processes so that you can react quickly to control your system if something goes wrong.

Many manufacturers have implemented or are looking to deploy analytical techniques to assess not only the incoming and outgoing goods, but also throughout the processes that transform the raw materials into those final goods. Many basic process tanks monitor simple things, such as temperatures and pressures of all the lines and tank, to help ensure safe working conditions. However, many industries, have moved to putting in more complex technologies so that they can monitor the actual chemical processes that are occurring in their tank.

A first step towards understanding a process is to “thief” samples during the process and measure various characteristics of interest (i.e. cannabinoid concentrations, solvent concentration, water content, etc.) in a lab. This helps to get an idea of the progress and performance of a process; however, there are numerous pitfalls associated with this method. The first pitfall is that someone has to physically retrieve a sample from the process.

Unknown Outliers [1]

This can be a simple and easy task, but it can also require major safety precautions and training for all personnel. On the way to the lab, there is ample opportunity for the sample to be contaminated or to morph as a result of the different environment of the carrying container. Finally, to turnaround test results from the lab may take hours to days to weeks, depending if the lab is on-site, local, or remote. What happens to the process if the tests take an hour, or twenty-four, to give the users a result they can act on? A second sample would have to go through the same process, doubling the time needed to make an effective decision of whether or not to stop the production (Figure 1).

Potentially, a manufacturing site could wait weeks to confirm that their products pass Quality Control and can be shipped to their customers. In a process that can have thousands of gallons of sample every second, it can become problematic if the manufacturing site needs to wait even a few hours to get the results from a thieved sample.

SCHEMATIC OF A PROCESS TANK [1]

Older industries are slow to move to some of the newer technologies for numerous reasons. In the pharmaceutical industry, a change in the process of the manufacturing of drugs requires months, perhaps years, of investigating and validating the change. Even for a large pharmaceutical company, this can be a serious strain on resources. Thus, most pharmaceutical companies will not accept any changes unless they absolutely are
forced into the change. Other reasons are that certain technologies have only caught up to the monitoring speeds that are necessary. In a standard process tank there could be numerous inlets and outlets (see Figure 2). Each of these inlets and outlets can have several points where monitors and controls can be added to the process.

Properly specified sample interfaces allow a spectroscopic sensor to be installed directly into the manufacturing stream to collect data as the process flows past the sensor. These
sensors give a user real-time information on the conditions within their process. 

Spectroscopy allows monitoring of the chemical species within the process, and it can be apparent very quickly if an unwanted side-reaction is occurring thereby allowing the user to react and adjust the process. Beyond the value of instant insight, advanced process sensors also give the benefit of big data aggregation, where additional efficiencies and optimization can be gained over time as well. The ultimate goal is to create a control solution that is constantly monitoring the entire system, so that it can proactively, and automatically, change a parameter if something starts to go wrong. This automated
learning would allow for a fully autonomous system that is efficient and safe.

In the next installment of this series, we will begin exploring the benefits of spectroscopy for the inline monitoring of the various stages of manufacturing in the cannabis industry.

References:

1. S. L. Carrier, Impact of Emerging Tools for Process Control, Bethesda: IFPAC 2018 Conference, 2018.