Microwave Extraction vs. Other Techniques for Industrial Scale Cannabis Extraction

Cannabis is a flowering plant that has long been used for medicinal, therapeutic, and recreational purposes. Cannabis contains more than 500 different compounds, including a unique class of terpeno-phenolic compounds known as cannabinoids; Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most prevalent cannabinoids and have been associated with the therapeutic and medicinal properties of the cannabis plant. In this paper, continuous flow microwave assisted extraction (MAE) is presented and compared with other methods for commercial cannabis extraction. The practical issues of each extraction method are discussed. The main advantages of MAE are: continuous-flow method which allows for higher volumes of biomass to be processed in less time than existing extraction methods, improved extraction efficiency leading to increased final product yields, improved extract consistency and quality because the process does not require stopping and restarting material flows, and ease of scale-up to industrial scale without the use of pressurised batch vessels. Moreover, due to the flexibility of changing the operation conditions, MAE eliminates additional steps required in most extraction methods, such as biomass decarboxylation, winterisation, which typically adds at least a half day to the extraction process. Another factor that sets MAE apart is the ability to achieve high extraction efficiency even at the industrial scale. Whereas the typical recovery of active compounds using supercritical CO¬2 remains around 70-80%, via MAE up to 95% of the active compounds from cannabis biomass can be recovered at the industrial scale.

. Cannabis plant [1] Cannabis has a long history of being used for medicinal, therapeutic, and recreational purposes.
Cannabis is known, for example, to be capable of relieving nausea (such as that accompanying chemotherapy), pain, vomiting, spasticity in multiple sclerosis, and of increasing appetite. The importance of cannabis in therapeutics is emphasized by the ever-increasing number of research publications related to the use of cannabis and cannabis products to treat various indications [2][3][4][5].
Cannabis contains more than 500 different compounds, which include terpenes, flavonoids, lipids, sterols, chlorophyll, fatty acids, salts, sugars, and a unique class of terpeno-phenolic compounds known as cannabinoids or phytocannabinoids. More than 100 cannabinoids have been identified in different cannabis plant strains. Examples include Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG) and cannabichromene (CBC) [5][6][7]. THC and CBD are the most prevalent cannabinoids and have been associated with the therapeutic and medicinal properties of the cannabis plant and associated products - Figure 2. THC is mainly recognized for its psychotropic effects when consumed, but lately has also been found to effectively treat pain, muscle spasticity, glaucoma, insomnia, lack of appetite, nausea, and anxiety while CBD is used to treat migraines, inflammation, seizures, IBS, depression, insomnia, and anxiety [2,3,8]. CBD is non-psychoactive and is the major cannabinoid constituent in hemp cannabis.
The terms hemp and marijuana are classifications of cannabis adopted into culture even though they do not represent legitimate nomenclature for cannabis. Hemp and marijuana are both cannabis; hemp, however, refers to cultivars of cannabis that contain very low concentrations of psychoactive THC (typically less than 0.3% by dry weight). Hemp (sativa) is an industrially grown plant that is cultivated outdoors, better suited for warm climates with a long season. Industrially grown hemp is used to produce textiles from the hemp fibre, and foods and supplements such as protein and essential fatty acids from the seeds. Hemp seed oil is rich in unsaturated omega-3 and omega-6 fatty acids and is almost entirely devoid of cannabinoids. Marijuana, on the other hand, is often deliberately bred and cultivated in controlled environments in order to optimize the cultivar's characteristics, including the composition of cannabinoids such as THC and CBD. Controlled growing and cultivation is designed to produce female plants that yield budding flowers rich in cannabinoid content. Harvesting of industrial hemp has traditionally avoided collection of flowers to minimize cannabinoid content of industrial products. This practice is however changing as the 3 of 15 production of CBD from farmed hemp becomes legalized in more and more jurisdictions world-wide. Cannabinoids are particularly concentrated in the glandular hairs (trichomes) distributed across the surface of the cannabis plant. These trichomes are particularly concentrated in the bracts and leaves of the female inflorescence. Resin glands form at the tips of these trichome stalks and secrete an aromatic terpenoid containing resin with a very high content of cannabinoids.
The proportion of cannabinoids in the plant may vary from species to species, as well as vary within the same species at different times and seasons. Furthermore, the proportion of cannabinoids in a plant may depend upon soil, climate, and harvesting methods. Thus, based on the proportion of the cannabinoids present in a plant variety, the psychoactive and medicinal effects obtained from different plant varieties may vary.
Historical delivery methods of cannabis have involved smoking, i.e. combusting, the dried cannabis plant material [10]. Smoking results, however, in adverse effects on the respiratory system via the production of potentially toxic substances. Alternative delivery methods such as oral administration of edible forms, transdermal delivery of topical forms and buccal administration of sprays for oral or nasal administration all require some method of extraction of the cannabinoids and other compounds from the plant. to extract them is very important in terms of accomplishing the quantity and quality of the product.
Moreover, economics of the processes is a very important parameter in its commercialization.
The scope of this paper is to present an overview of the extraction methods currently used commercially for cannabis extraction with particular attention to the relative advantages of continuous flow microwave-assisted extraction.

Commercial Cannabis Extraction Methods
There are several important considerations to consider when choosing an extraction method for cannabis. The most important are as follows: • Extraction efficiency, the percentage of bioactive compounds recovered through the entire extraction process; • Extract quality and consistency, including the purity or "potency" of cannabinoids in the extract and also the relative amounts or "profile" of other potentially synergistic compounds such as terpenes; • Throughput capacity and scalability, assessment of the extraction method and its efficient implementation at commercial scales vs. market demand; • Environmental control, e.g., carbon footprint and safety, i.e. minimize risks to the consumers and worker safety.
The potency (a term often used in lieu of purity or concentration) of cannabis extracts and extract-derived products is equivalent to cannabinoid (e.g., Δ 9 -tetrahydrocannabinol, THC) content.
Depending upon the psychoactive and medicinal effects obtained from different varieties of the cannabis plant or the different methods of cultivation for cannabis, a specific variety of cannabis may be considered more effective or more potent than others (e.g., in providing the desired physiological effect at a desired level in an individual). Similarly, some specific combinations of pharmacologically active compounds in a cannabis variety may be more desirable in comparison to other varieties.
When preparing cannabis plant extracts, the retention of the full mix of cannabinoids present in the original plant may be desirable for some varieties, while other varieties may be preferred in altered form due to the variances in the specific cannabinoid composition and concentrations. Such variance is further exacerbated by the presence of certain terpenoid or phenolic compounds, which may have pharmacological activity of their own and which may be desired at different concentrations in different combinations.
In many cases, additional processing steps, both upstream and downstream of the extraction itself, are required to obtain the final cannabis extract product. The incorporation of these steps with the extraction method and their impact on the overall process efficiency and product quality must also be considered. Some common processing steps discussed further below include: • Decarboxylation, the process of converting non-active native acidic cannabinoids into their active, neutral forms via a thermal reaction; • Winterization, the process of removing plant lipids and unwanted waxes by a secondary solvent, freezing and filtration; • Decolorization, the process of removing chlorophyll and unwanted pigments; • Secondary purification, the process of further purifying the extract to increase the potency of cannabinoids and other components, via various methods including distillation, chromatography, or crystallization.
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 11 July 2020 doi:10.20944/preprints202007.0234.v1 The cannabinoids are biosynthesized in the cannabis plant in acidic forms known as acidic cannabinoids. To be therapeutically active, these acidic cannabinoids must be converted to their neutral forms by a decarboxylation reaction. Decarboxylation is instant when cannabis is combusted during smoking [12]. All other consumption forms containing cannabis extracts must however involve a decarboxylation step to produce the active neutral forms. Many traditional methods of extracting inactive cannabinoids from raw cannabis biomass require subjecting the biomass to a heating process to decarboxylate the cannabinoids prior to extraction [13]. While it is relatively straightforward to heat dried cannabis for decarboxylation at particular temperature for specific time, in small quantities (kg or tens of kg), it becomes increasingly more difficult to carry it out if multiple tonnes of cannabis biomass must be subjected to decarboxylation prior to entering the extraction process. In addition, subjecting the biomass to a heating process may cause combustion, modification of the plant profile, negative effect on terpenes, or cause other undesirable effects that could lower quality or purity of the cannabis extract. For example, the process of decarboxylation of cannabis biomass can increase the number of cannabinoids occurring as artefacts by oxidative degradation or isomerization. Further, extraction of cannabis biomass that has been subjected to a thermal decarboxylation can lead to loss of valuable compounds including terpenes. Still further, decarboxylation of cannabis biomass prior to extraction does not provide an ability to control the amount of decarboxylation reaction to a desired percentage of neutral cannabinoids and so provide extract products with varying ratios of cannabinoid acids and corresponding neutral cannabinoids. So, any method of extraction that requires the cannabis biomass to be decarboxylated prior to extraction will hamper quality and purity of the cannabis extract.
In some extraction methods, many of the plant lipids and heavy waxes are co-extracted with the cannabinoids and other desirable components. As these are generally undesirable, they must be subsequently removed in the downstream process of winterization. Winterization involves dissolving the extract in alcohol, keeping it at sub-zero temperatures for a prolonged period to precipitate the heavy lipids, removing them by filtration and subsequently evaporating off all the alcohol to obtain the desired extract. This process is lengthy and usually costly and can result in loss of overall efficiency, i.e. loss of valuable cannabinoids. Similarly, if excessive chlorophyll or other pigmentation is extracted, this must be removed by a decolorization step (e.g., treatment with activated carbon), which can again lead to loss of efficiency. Any extraction method that eliminates the need for these steps is desirable

Scale-up Considerations and Cannabis Commercial Extraction Methods
Extraction is the first step to separate the desired natural compounds from the raw biomass materials. Conventional extraction methods that have been applied to various natural products for many years include solvent extraction, distillation, mechanical pressing, and sublimation according to the extraction principle. Solvent extraction is the most widely used method. The extraction of biomass generally proceeds via the following stages: (i) the solvent is mixed with the solid biomass; (ii) the system is heated to the desired temperature, if needed (iii) the solvent diffuses into the solid particles; (iv) solute diffuses out of the solid biomass and dissolves in the liquid solvent; (v) the solvent is removed to provide the extracted solutes separated from the spent biomass. Any factor enhancing the diffusivity and solubility in the above steps will facilitate the extraction. The properties of the extraction solvent, the particle size of the raw materials, the solvent-to-solid ratio, Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 11 July 2020 doi:10.20944/preprints202007.0234.v1 the extraction temperature, and the extraction duration will affect the extraction efficiency and extraction selectivity.
The scale-up of an extraction process is not simply a case of using a larger reaction vesselmany factors need to be considered just to keep biomass and solvent contained, let alone achieve successful scale-up. Factors such as chemical and physical safety, availability of chemicals, analytical, chemical and engineering aspects, commercial considerations (cost and time), environmental and legal demands, etc. are just a few of the important initial factors that need to be taken into account for the scale-up.
In addition to biomass availability and specification changes underlined above, almost without exception, solvent will be the largest [ [14][15][16], when considering cannabis extraction, none of these is optimal in all aspects. Molecules extracted through these processes may differ in the quality (physiochemical properties) and quantity hence altering the chemical composition of the extract; in addition, many of these methods have limitations when it comes to scaling up to suit mass production. Thus, it is very important to search for environmental-friendly and safer techniques and solvents allowing to obtain better quality and quantity of a cannabis extract from a given biomass, as well as maintaining the consistency in the cannabinoid profile of the extracts.

Available Methods Currently Used for Commercial Cannabis Extraction
There are generally three typical extraction methods currently being used for commercial cannabis extraction, albeit at only modest scale: • Supercritical CO2 (SC-CO2) extraction • Pressurized gas (hydrocarbon) extraction • Conventional ethanol solvent extraction These are discussed in more detail below.
In addition to these "big three", there are several non-conventional, alternative extraction methods that have been applied to cannabis extraction, including for example ultrasound-assisted extraction, Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 11 July 2020 doi:10.20944/preprints202007.0234.v1 hydrodynamic extraction and instant-controlled pressure drop extraction. Given that none of these have yet been demonstrated at any reasonable commercial scale, they are not further discussed.

Supercritical CO2 (SC-CO2) Extraction
Supercritical fluids are a well-documented alternative to traditional organic solvents suitable for various extractions. Any material s in its critical state when it is both heated above its critical temperature (Tc) and pressurized above its critical pressure (Pc) and hence there are no distinct liquid and gas phases. The specificity of this technique relies on solvent's physicochemical properties, which can be 'tuned' by an increase of pressure and/or temperature beyond its critical values [17][18][19][20][21].
Supercritical CO2 extraction is a very common technique for cannabis extraction-separation, which uses supercritical CO2 (74 bar, 31 0 C) in a batch process. Although non-toxic and non-flammable, SC-CO2 is, however, dangerous and requires very high pressures to be employed. In addition, the method is somehow inefficient and, therefore, not conducive to high throughputs, as well as environmentally damaging (e.g., producing large amounts of the greenhouse gas carbon dioxide as a by-product). The resulting extracts are, however, considered to be solvent-free.
Another major drawback of SC-CO2 extraction for cannabis is that decarboxylation must be carried out on the cannabis biomass upstream the extraction process (acidic cannabinoids are poorly soluble in SC-CO2). This increases overall costs (decarboxylation must be performed in advance on what may be large quantities of cannabis biomass) and leads to the loss of some light volatile terpenes. SC-CO2 also co-extracts heavy fats and waxes which must be subsequently removed in downstream processing steps (winterization), leading to further cannabinoid losses and reduction in overall efficiency or recovery of available cannabinoids. Finally, the scale up of SC-CO2 is only possible by addition of multiple machines. This results in large capital costs and increased QA/QC costs when going to mass production scales.

Pressurized gas (hydrocarbon) extraction
Hydrocarbon extraction is the most popular technique that uses liquified gases such as n-propane and n-butane pressurized into liquids (2-10 bar) as solvents for extraction of cannabinoids. An advantage of the method is the possibility of these gases to remain in liquid phase at low pressure and the possibility to remove them from the system at the end of the extraction by gentle heating leading to an extract with low traces of residual solvent. Hydrocarbons such as n-butane and n-propane are good solvents for the low-polarity cannabinoids [17,22,23]. In this method, butane or propane is pressurized to a liquid state for extraction and then either depressurized or heated for removal from the obtained extracts. This extraction process is carried out in batch and creates what are known as cannabis "concentrates", e.g., shatter, a viscous material with very high concentration of THC and other cannabis compounds like terpenes, which is popular for recreational users. Decarboxylation can be carried out upstream or downstream of the extraction. Although effective, the process is undesirable for medicinal and consumer products, due to the risk of solvent contamination. Safety is also a major concern given the high flammability/explosivity of the hydrocarbon solvents employed. In principle, the scale-up is only possible by the addition of multiple machines.

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This extraction method is perhaps the most efficient method for capturing cannabinoids in either batch or continuous flow processing. Ethanol extraction can use decarboxylated biomass or decarboxylation can be performed on the extracted product. The main drawbacks of the method are linked to the high input ratios of biomass-ethanol and implicitly to the high quantities of solvent to be separated from the extract and recycled and also to the co-extracted molecules, such as fats, waxes, and pigments, which means more complex downstream processing (separation, purification, etc.).

Microwave-Assisted Extraction
Microwave-assisted extraction (MAE) is different from the methods presented above because the extraction occurs as a result of the volumetric heating as opposed to transferring heat from the surface inwards, making the process more efficient and more uniform due to the ability to precisely control temperature and contact time.
The field of MAE of natural compounds is quite young. In the last two decades, new investigations have been prompted by an increasing demand of more efficient extraction techniques, amenable to automation; shorter extraction times, reduced organic solvent consumption, energy and costs saved, were the main tasks pursued. Driven by these goals, advances in microwave extraction have resulted in a number of innovative techniques such as microwave assisted solvent extraction, vacuum microwave hydro-distillation, microwave Soxhlet extraction, microwave-assisted Clevenger distillation, compressed air microwave distillation, microwave headspace extraction, microwave hydro-diffusion and gravity, and solvent-free microwave extraction [14,15,17,13]. One of the success stories of the 21 st Century has been the partial replacement of conventional extraction processes, with green procedures (reducing energy, time, solvent, and waste) based on microwave irradiation [24].
The fundamentals of the microwave-assisted extraction process are different from those of conventional solvent extraction methods (solid-liquid or simply extraction) because the extraction can occur as the result of changes in the cell structure caused by electromagnetic waves, Figure 3, Table 1. Even if cell structure is unchanged, the instant volumetric heating possible with microwaves as opposed to transferring heat from the surface, inwards, is more efficient, uniform and less prone to overkill. Controllability is by far the greatest advantage of microwaves over conventional thermal technologies. In processing applications, the ability to instantaneously apply and turn off the heat source as desired makes enormous difference to the product quality and hence the production economics. The very nature of heating through the involvement of the raw material under processing (instead of using fossil fuels or less efficient, indirect electrical heating systems) brings about quality consistency as well as positive environmental impacts [25,26].
An important element of MAE is that the driving force for extraction is not limited to the process of diffusion. Conventional solid-liquid extraction involves soaking, washing or contacting the solid material with usually hot (50°C to 80°C) solvent to extract the target compounds and normally two or three extractions are needed, increasing the solvent and energy usage. Moreover, extraction occurs by diffusion, meaning that the only driving force for the process is the concentration gradient of the product between the biomass and the solvent. With MAE the solvent requirement is lesser as compared to coventional methods and material is exhausted with one extraction only. Moreover the microwave energy can be directed directly to and selectively absorbed by the water (free or bound water) if water present in the biomass. This creates a very Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 11 July 2020 doi:10.20944/preprints202007.0234.v1 rapid temperature increase within the biomass cells, leading to pressure build-up and forcing the bioactives out into the surrounding solvent by a pressure-enhanced mass transfer. This mass transfer may be further enhanced by the fact that the thermal gradient is in the same direction as the mass transfer - Figure 3. The basics of the MAP TM1 continuous flow microwave-assisted extraction of cannabis consists of coupling microwave heating and continuous flow technology and as such creating a very promising way to produce high value-added extracts since unlike batch processing, the continuous flow has been demonstrated to facilitate process intensification and contributes to a safe, efficient and sustainable production. By employing continuous-flow microwave-assisted extraction, it is possible to control extraction time and temperature very precisely, both of which can greatly influence extraction efficiency and the composition of the extract.
A schematic of one process involved in the extraction of the cannabis biomass and decarboxylation of the extracted products is presented in Figure 4 while results are listed in Table 2 2 .
In this method, the raw milled cannabis biomass is mixed with a solvent (e.g., ethanol, IPA, pentane, The extract is treated to obtain a final product containing the target compounds in sufficiently high yield and high purity. The spent biomass may be processed to yield less than 0.3% concentration of THC naturally produced by plants and disposed of once this condition has been achieved. The microwave-assisted extractor consists of a food grade stainless steel tube within which a mechanical stirrer is placed. Microwaves are provided from a 75 kW (max. power), 915 MHz microwave generator consisting of a low ripple switch mode power supply, a magnetron head and a circulator + water cooled load with reflected power meter. The microwave generator can be operated  As described in Figures 4 and 5, the main advantages of the microwave-extraction related to cannabis biomass are: • Continuous-flow method at atmospheric pressure which allows for much higher volumes of cannabis biomass to be processed in much less time than existing extraction methods; • Achieved higher rates of consistency and quality because the process does not require stopping and restarting material flows; • Scale-up to industrial scale without the need to purchase an endless supply of new machinery and without the use of pressurised batch vessels; • Eliminates additional steps required in most extraction methods, such as biomass decarboxylation and winterisation; • Ability to achieve high extraction efficiency at industrial scale. Typical recovery of active compounds using supercritical CO2 remains around 70-80%, via microwave-assisted up to 95% of the active compounds (Table 1) from cannabis biomass can be recovered.
From a process intensification view, the continuous flow extraction and its heating via microwaves comes with several additional benefits, including significantly increased flexibility and safety with respect to operation: • The contact time between the biomass and solvent before, during and after microwave treatment can be adjusted much more easily; • It is possible to precisely control biomass residence time in the microwave zone and -if desiredseparate the biomass from the solvent very quickly after treatment, or continue contact for any length of time at any temperature, depending on the desired outcome; • The use of multiple microwave field deposition points through the use of a split waveguide and a "ridge wave deposition" allowing for non-uniform dispersal of the wave from the inlet to the outlet to account for changing dielectric properties as the material is treated; • It has an automatic impedance matching unit that allows for constant, automatic adjustment of the field strength and microwave energy absorption maximization; • It has a built-in mechanical agitator with variable speed control to randomize movement of biomass thus making the field uniform for the materials at all times; • It is fully-automated (operators simply input desired MW parameters on an HMI and it runs itself while connected to the plant PLC systems); • It is fully "ATEX" or "Hazardous zone" classified, meaning it can be used with any flammable liquid and be completely safe.
The extractor is also easily scalable. The continuous flow approach eliminates the requirement for having geometric similarity between scales, i.e. the equipment shape and dimensions do not have to scale proportionately. Classically, even geometric similarity does not ensure thermal similarity in scaled systems; for example, heat transfer is an interface-controlled process and so the surface area relative to the volume is critical. As the volumetric scale increases, the area relative to the volume decreases and the overall efficiency of heat transfer can decline considerably. There is no thermal inertia with microwaves, on the other hand. Since penetration depth is not an issue with the continuous flow design, the energy is deposited uniformly throughout the mixture resulting in rapid energy transfer and direct dielectric heating -hence the thermal inertia inherent to classical methods is not an issue.