Patent Publication Number: US-2019192429-A1

Title: Sublingual formulations comprising cannabis resin, methods for making same and uses thereof

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     The current application claims the benefit of priority to U.S. Provisional Application Ser. No. 62/694,243, filed on Jul. 5, 2018, and U.S. Provisional Application Ser. No. 62/610,706, filed on Dec. 27, 2017, which is hereby incorporated by reference in its entirety. 
    
    
     FIELD OF THE DISCLOSURE 
     The present disclosure relates to solid formulations comprising  cannabis  resin. In one embodiment, the present disclosure provides sublingual tablet formulations comprising  cannabis  resin, and methods for making and using same. 
     BACKGROUND OF THE DISCLOSURE 
       Cannabis  spp. plants produce a highly complex mixture of compounds, with up to 568 unique compounds identified to date (Pertwee, R. G. e.,  Handbook of cannabis . Oxford University Press: Oxford, 2014). Two classes of compounds, cannabinoids and terpenes, account for a significant portion of these molecules, with more than 100 types of each having been identified in  Cannabis  spp. plants (Aizpurua-Olaizola, O.; Soydaner, U.; Ozturk, E.; Schibano, D.; Simsir, Y.; Navarro, P.; Etxebarria, N.; Usobiaga, A. Evolution of the Cannabinoid and Terpene Content during the Growth of  Cannabis sativa  Plants from Different Chemotypes.  Journal of Natural Products  2016, 79, 324-331; incorporated herein by reference).  Cannabis  spp. plants also produce other compounds such as fatty acids, chlorophyll, and flavonoids. 
     Among cannabinoids, the compounds tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most dominant as well as most studied with respect to their biological activity and therapeutic potential. Much of the pharmaceutical research has focused on cannabinoids in purified form. However, there is a growing body of research regarding synergistic effects, buffering effects and antagonistic effects (sometimes referred to together as “entourage effects”) between the various cannabinoid compounds, terpene compounds and other compounds found in  Cannabis  spp. plants (Russo, E. B. Taming THC: potential  cannabis  synergy and phytocannabinoid-terpenoid entourage effects.  British Journal of Pharmacology  2011, 163, 1344-1364; incorporated herein by reference). Accordingly, there is an increased interest in therapeutics which reflect more of the molecular complexity of the original  Cannabis  plant, such as  cannabis  resins. 
     There is also a need for therapeutic forms which can be easily administered. Cannabinoids may be converted to their therapeutically active forms through decarboxylation. To date the simplest method of decarboxylation is by heating, such as by smoking or vaping. However, some people are unwilling to use  cannabis  if it has to be smoked or vaped due to negative perceptions of smoking and vaping, while others may be physically unable to do so, especially in the palliative care context. Accordingly, there is a need for an improved dosage form, such as a rapidly disintegrating sublingual tablet, which can be easily administered by a person or their caregiver, without further heating. 
     SUMMARY OF THE DISCLOSURE 
     The present disclosure relates to solid formulations comprising decarboxylated  cannabis  resin. In particular, the present disclosure provides rapidly disintegrating sublingual tablet formulations comprising decarboxylated  cannabis  resin, and methods for making and using same. The formulations provided herein may be useful as pharmaceutical and/or natural health products for the treatment and amelioration of various symptoms, disorders and/or diseases. 
     &lt;1&gt; A method for making a rapidly disintegrating sublingual tablet from decarboxylated  cannabis  resin, wherein the decarboxylated  cannabis  resin comprises cannabinoids which are at least 50% decarboxylated, the method comprising:
         (a) dissolving the decarboxylated  cannabis  resin in a pharmaceutically acceptable organic solvent to produce a first solution;   (b) dissolving mannitol in a pharmaceutically acceptable polar solvent to produce a second solution;   (c) mixing the first solution of (a) and the second solution of (b);   (d) substantially removing the solvents from the mixture of (c) to produce a powder;   (e) adding one or more pharmaceutically acceptable excipients to the powder of (d) to produce a mixture, solid solution or solid suspension; wherein at least one of the pharmaceutically acceptable excipients is a disintegrant;   (f) triturating or mixing the mixture, solid solution or solid suspension of (e) to produce a homogenous mixture, homogeneous solid solution or homogeneous solid suspension; and   (g) compressing the homogenous mixture, homogeneous solid solution or homogeneous solid suspension of (f) into a tablet using a pressure of up to about 1 ton.       

     &lt;2&gt; The method of &lt;1&gt;, wherein the cannabinoids are at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% decarboxylated. 
     &lt;3&gt; The method of &lt;1&gt;, wherein the ratio of  cannabis  resin to mannitol is about 1:3 to 1:8. 
     &lt;4&gt; The method of &lt;1&gt;, wherein the organic solvent of (a) is ethanol; wherein the polar solvent of (b) is water; and wherein the disintegrant of (e) is cross-linked polyvinylpyrrolidone and/or croscarmellose sodium. 
     &lt;5&gt; The method of &lt;4&gt;, wherein the one or more pharmaceutically acceptable excipients comprise magnesium stearate, cross-linked polyvinylpyrrolidone, and optionally microcrystalline cellulose. 
     &lt;6&gt; The method of &lt;1&gt;, wherein in step (d) the solvents are substantially removed by lyophilization, spray drying, or fluid bed drying. 
     &lt;7&gt; The method of &lt;1&gt;, wherein in step (g) the pressure is from about 0.05 ton to about 0.6 ton or from about 0.1 to about 0.4 ton. 
     &lt;8&gt; The method of &lt;1&gt;, wherein the decarboxylated  cannabis  resin comprises 0 to 95% Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and 0-95% cannabidiol (CBD) including combinations thereof. 
     &lt;9&gt; The method of &lt;1&gt;, wherein the resin is about 2-18 wt % of the tablet, the mannitol is about 40-80 wt % of the tablet, the disintegrant is about 10-50 wt % of the tablet, and optionally other excipients are about 0-25 wt % of the tablet. 
     &lt;10&gt; The method of &lt;9&gt;, wherein the resin is about 7-11 wt % of the tablet, the mannitol is about 50-63 wt % of the tablet, the disintegrant is cross-linked polyvinylpyrrolidone and/or croscarmellose sodium and is about 11-18 wt % of the tablet, and the other excipients are magnesium stearate which is about 0.6-1.1 wt % of the tablet, and microcrystalline cellulose which is about 0-20 wt % of the tablet. 
     &lt;11&gt; The method of &lt;1&gt;, wherein the rapidly disintegrating tablet disintegrates in less than 60 seconds when contacted with a phosphate buffered saline (PBS); and wherein the tablet has a friability of less than 5%. 
     &lt;12&gt; A rapidly disintegrating sublingual tablet from decarboxylated  cannabis  resin, comprising cannabinoids which are at least 50% decarboxylated, wherein the tablet further comprises mannitol, a disintegrant, and optionally one or more other pharmaceutically acceptable excipients, wherein the tablet disintegrates in less than 60 seconds when contacted with phosphate buffered saline (PBS) and wherein the tablet has a friability of less than 5%. 
     &lt;13&gt; The tablet of &lt;12&gt;, wherein the cannabinoids are at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% decarboxylated. 
     &lt;14&gt; The tablet of &lt;12&gt;, wherein the ratio of  cannabis  resin to mannitol is about 1:3 to 1:8. 
     &lt;15&gt; The tablet of &lt;12&gt;, wherein the disintegrant is cross-linked polyvinylpyrrolidone and/or croscarmellose sodium. 
     &lt;16&gt; The tablet of &lt;15&gt;, wherein the one or more pharmaceutically acceptable excipients comprise magnesium stearate and optionally microcrystalline cellulose. 
     &lt;17&gt; The tablet of &lt;12&gt;, wherein the combined total of Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (CBD) is up to about 18 wt % of the tablet. 
     &lt;18&gt; The tablet of &lt;12&gt;, wherein the resin is about 2-18 wt % of the tablet, the mannitol is about 40-80 wt % of the tablet, the disintegrant is about 10-50 wt % of the tablet, and optionally the other excipients are about 0-25 wt % of the tablet. 
     &lt;19&gt; The tablet of &lt;18&gt;, wherein the other excipients are optionally a diluent, a filler, a binding agent, a releasing agent, a lubricant, a flavoring agent, a taste-masking agent, and/or a colorant. 
     &lt;20&gt; Use of a decarboxylated  cannabis  resin in the manufacture of a rapidly disintegrating sublingual tablet, wherein the resin comprises decarboxylated cannabinoids from a  Cannabis  spp. plant, such that Δ9-tetrahydrocannabinolic acid (Δ 9 -THCA) and cannabidiolic acid (CBDA) cannabinoids are each independently 90%-100% decarboxylated to yield Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (CBD) respectively in the  cannabis  resin. 
     Other features and advantages of the disclosure will be apparent from the following detailed description and from the exemplary embodiments. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       In order that the subject matter may be readily understood, embodiments are illustrated by way of examples in the accompanying drawings, in which: 
         FIG. 1A  shows chemical structures of six major cannabinoids present in  cannabis: Δ   9 -THC, Δ 9 -THC-A, Δ 8 -THC, CBN, Δ 2 -CBD and Δ 2 -CBD-A; 
         FIG. 1B  shows the cannabinoic acid synthase pathway of cannabigerolic acid (CBGA) to cannabidiolic acid (CBDA), tetrahydrocannabinolic acid (THCA) and cannabichromenic acid (CBCA); 
         FIG. 2A  shows medical  cannabis  and decarboxylated  cannabis  resin; 
         FIG. 2B  is a mass spectra of Strain 1 before decarboxylation of medical  cannabis;    
         FIG. 2C  is a mass spectra of Strain 1 after decarboxylation of medical  cannabis;    
         FIG. 3  is a block diagram illustrating a process for extracting and decarboxylating cannabinoids from  cannabis  plant material according to one embodiment of the application; 
         FIG. 4  shows a standard curve for Δ 8 -THC (selected ion recording (SIR) chromatograms were integrated and the AUC was plotted vs. concentration (ug/mL); 
         FIG. 5  shows a standard curve for Δ 9 -THC (selected ion recording (SIR) chromatograms were integrated and the AUC was plotted vs. concentration (ug/mL); 
         FIG. 6  shows a standard curve for THCA (selected ion recording (SIR) chromatograms were integrated and the AUC was plotted vs. concentration (ug/mL); 
         FIG. 7  shows a standard curve for CBD (selected ion recording (SIR) chromatograms were integrated and the AUC was plotted vs. concentration (ug/mL); 
         FIG. 8  shows a standard curve for CBDA (selected ion recording (SIR) chromatograms were integrated and the AUC was plotted vs. concentration (ug/mL); 
         FIG. 9  shows a standard curve for CBN (selected ion recording (SIR) chromatograms were integrated and the AUC was plotted vs. concentration (ug/mL); 
         FIG. 10  shows a relative amount of Δ 9 -THC and THC-A present in  cannabis  plant material samples extracted using microwave radiation at various temperatures; 
         FIG. 11  shows concentrations of various cannabinoids in the  cannabis  extracts using ethanol, Soxhlet and SFE, without subjecting  cannabis  to microwave conditions; 
         FIG. 12  shows concentrations of various cannabinoids in the  cannabis  extracts using ethanol, Soxhlet and SFE followed by microwave heating; 
         FIG. 13  shows various cannabinoid concentrations from  cannabis  after microwave heating only at various temperatures; 
         FIG. 14  shows various cannabinoid concentrations from  cannabis  after microwave heating and subsequent SFE extraction at various temperatures; 
         FIG. 15  shows various cannabinoid concentrations from  cannabis  after microwave heating and subsequent SFE extraction at various temperatures, where the acidic and neutral form of THC are added together to represent the total THC extracted by each method; 
         FIG. 16  shows a chromatogram of mass scan in a positive mode (150-500 m/z) of  cannabis  extract obtained from microwave extraction at 170° C., 15 min; 
         FIG. 17  shows single ion recording (SIR) (+ve) detection of m/z=315 for  cannabis  extract obtained from microwave extraction at 170° C., 15 min; 
         FIG. 18  shows SIR (+ve) detection of m/z=359 for  cannabis  extract obtained from microwave extraction at 170° C., 15 min; 
         FIG. 19  shows a chromatogram of a mass scan in a negative mode (150-500 m/z) of  cannabis  extract obtained from microwave extraction at 170° C., 15 min; 
         FIG. 20  shows SIR (−ve) detection of m/z=313 for  cannabis  extract obtained from microwave extraction at 170° C., 15 min; 
         FIG. 21  shows SIR (−ve) detection of m/z=357 for  cannabis  extract obtained from microwave extraction at 170° C., 15 min; 
         FIG. 22  shows a chromatogram of mass scan in a positive mode (150-500 m/z) of  cannabis  extract obtained from microwave extraction at 130° C., 10 min; 
         FIG. 23  shows SIR (+ve) detection of m/z=315 for  cannabis  extract obtained from microwave extraction at 130° C., 10 min; 
         FIG. 24  shows SIR (+ve) detection of m/z=359 for  cannabis  extract obtained from microwave extraction at 130° C., 10 min; 
         FIG. 25  shows a chromatogram of mass scan in a negative mode (150-500 m/z) of  cannabis  extract obtained from microwave extraction at 130° C., 10 min; 
         FIG. 26  shows SIR (−ve) detection of m/z=313 for  cannabis  extract obtained from microwave extraction at 130° C., 10 min; 
         FIG. 27  shows SIR (−ve) detection of m/z=357 for  cannabis  extract obtained from microwave extraction at 130° C., 10 min; 
         FIG. 28A  Overview of select signals as seen in the mass spectra before decarboxylation of  cannabis  extract; 
         FIG. 28B  Overview of select signals as seen in the mass spectra after decarboxylation of  cannabis  extract; 
         FIG. 29  shows graphs of physical property measurements of rapidly disintegrating tablet (RDT) formulations over the course of a 40 day stability study at 40° C.±2° C./75%±5% relative humidity in a stability chamber (Caron 7000-10, Benchtop), where CDS-ML-II-66-1 is Formulation 34, CDS-ML-II-66-2 is Formulation 35, and CDS-ML-II-79 is Formulation 43. 
         FIG. 30A  shows a graph of friability and moisture content measurements of rapidly disintegrating tablet (RDT) Formulation 64 over the course of a 6-month stability study at 40° C.±2° C./75%±5% relative humidity in a stability chamber (Caron 7000-10, Benchtop) at 0, 1, 3 and 6 months. 
         FIG. 30B  shows a graph of hardness and disintegration time measurements of rapidly disintegrating tablet (RDT) Formulation 64 over the course of a 6-month stability study at 40° C.±2° C./75%±5% relative humidity in a stability chamber (Caron 7000-10, Benchtop) at 0, 1, 3 and 6 months. 
         FIG. 31  shows a graph of quantity of cannabinoids Δ 9 -THC, CBD, and CBN of rapidly disintegrating tablet (RDT) Formulation 64 over the course of a 6-month stability study at 40° C.±2° C./75%±5% relative humidity in a stability chamber (Caron 7000-10, Benchtop) at 0, 1, 3 and 6 months. 
     
    
    
     DETAILED DESCRIPTION OF THE DISCLOSURE 
     Definitions 
     Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. 
     “Active cannabinoid” as used herein, refers to a cannabinoid that has high potency at the corresponding receptor, often with an EC 50  1 μM or less; typically a decarboxylated phytocannabinoid that is in its neutral form such as Δ 9 -THC. 
     “Cannabinoid” as used herein, refers to a class of diverse chemical compounds that interact with cannabinoid receptors (for example, CB1 and CB2) on the cell surface of neurons and other cell types; the term encompassing both  cannabis -derived phytocannabinoid compounds and endogenously-produced endocannabinoid compounds, and those synthetically prepared. 
     “ Cannabis  plant” or “ Cannabis  spp. plant” as used herein, refers to any one or more plant(s) from the  Cannabis  genus of flowering plants in the family Cannabaceae; including but not limited to  Cannabis sativa, Cannabis  indica and  Cannabis ruderalis , and all subspecies thereof (for example,  Cannabis sativa  subspecies indica including the variants var.  indica  and var.  kafiristanica ); including wild or domesticated type  Cannabis  plants and also variants thereof; including  Cannabis  plant chemovars (varieties characterized by their chemical composition) which contain different amounts and/or ratios of the individual cannabinoids, terpenes and/or other compounds; including  Cannabis  plants which are the result of genetic crosses, self-crosses or hybrids thereof; including female and “feminized” plants (which may produce a higher concentration of cannabinoids), and male plants (which may produce a lower concentration of cannabinoids). As is known to the person skilled in the art,  Cannabis  spp. includes hemp. 
     “ Cannabis  plant material” as used herein, refers to plant material derived directly from one or more  Cannabis  spp. plants; including live or fresh  cannabis  plants and dried  cannabis  plants; including but not limited to trichomes, flower buds, flower bracts, leaves, stalk and any other part of  cannabis  plant. 
     “Decarboxylated  cannabis  resin” as used herein, refers to the hydrophobic, viscous, glue-like substance that is produced by extraction (chemical or physical) and decarboxylation of various parts of a  cannabis  plant, in particular glandular trichomes of the flower. Such a resin contains predominately (&gt;50%, ideally &gt;90%) decarboxylated cannabinoids, while reflecting at least some of the molecular diversity of the original  cannabis  plant, including some or all of cannabinoids, terpenes, flavonoids and/or other compounds of interest, some of which may have undergone chemical transformation during the processes used for extraction and decarboxylation. The term excludes predominately (&gt;50%) non-decarboxylated resinous substances derived from  cannabis  (for example, kief, hash, hashish, etc.). 
     “Decarboxylation” as used herein, refers to a process of removal of a carboxylic group from a cannabinoid molecule such as Δ 9 -THCA or CBDA (an acid form) to the corresponding neutral form such as Δ 9 -THC and CBD; wherein a carboxyl group is removed from the cannabinoid molecule, and carbon dioxide is released. 
     “Friability” as used herein, refers to the tendency of a solid substance to break into smaller pieces with handling or contact. Friability testing is a laboratory technique to test the durability of tablets during transit or handling. Friability is calculated as the percentage of weight lost by tablets due to mechanical action during a friability test. 
     “Hardness” as used herein, refers to tablet hardness as assayed using a laboratory technique to test the breaking point and structural integrity of a tablet under conditions of storage, transportation and handling before usage. 
     “Inactive cannabinoid” as used herein, refers to a cannabinoid that has poor potency at the corresponding receptor, often with an EC 50  greater than 1 μM; typically a cannabinoid that is in its acidic form such as Δ 9 -THCA, a non-decarboxylated cannabinoid. 
     “Microwaves” as used herein, refer to a form of electromagnetic radiation with wavelengths ranging from one meter to one millimeter; and with frequencies between 300 MHz (100 cm) and 300 GHz (0.1 cm). 
     “Pharmaceutically acceptable”, as used in connection with raw materials and/or formulations and/or compositions of the present disclosure, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (for example, a human). Preferably, as used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia (USP), National Formulary (NF), or other generally recognized pharmacopeia for use in mammals, and more particularly in humans. 
     “Rapidly disintegrating tablet” or “RDT” as used herein, refers to a solid dosage form containing a therapeutic substance or active ingredient which disintegrates rapidly in Phosphate Buffer Solution (PBS) and/or saliva or other similar artificial or natural fluids. 
     “Sublingual” as used herein, refers to the pharmacological route of administration by which a therapeutic substance is placed under the tongue. 
     Abbreviations 
     CB1=cannabinoid receptor type 1, CB2=cannabinoid receptor type 2, CBC=cannabichromene, CBCA=cannabichromenic acid, CBD=cannabidiol, CBDA=cannabidiolic acid, CBG=cannabigerol, CBGA=cannabigerolic acid, CBN=cannabinol, CBNA=cannabinolic acid, CCS=croscarmellose sodium, CMC=carboxymethyl cellulose, DW=deionized water, HPC=hydroxypropyl cellulose, NF=National Formulary, PBS=phosphate buffered saline, RDT=rapidly disintegrating tablet, SFE=supercritical fluid extraction, SSG=sodium starch glycolate, MCC=microcrystalline cellulose, THC=tetrahydrocannabinol, THCA=tetrahydrocannabinolic acid, THCV=tetrahydrocannabivarin, THCVA=tetrahydrocannabivarinic acid, USP=United States Pharmacopeia. 
     I. Decarboxylated  Cannabis  Resin 
       Cannabis  extracts or  cannabis  resins are derived from the flowers or buds harvested from  Cannabis  spp. plants or other parts of this plant where cannabinoids are present. Typically  cannabis  buds or other plant parts are subjected to extraction using various liquid solvents such as ethanol, edible oils among others, or supercritical fluids such as liquid CO 2 , or gases such as butane. When such extraction is carried out, phytocannabinoids and other chemicals from the plant dissolve in these solvents, and upon concentration, the resulting material gives rise to  cannabis  extract or  cannabis  resin. Often, the chemicals in the extract or resin depend on the type of solvent utilized, temperature, pressure, extraction time etc. 
     The rapid disintegrating tablets of the present invention are made with decarboxylated  cannabis  resin derived from  Cannabis  spp. plants, which comprises cannabinoids which are predominately (&gt;50%) decarboxylated. Decarboxylation refers to the conversion of the acid form to the neutral form, whereby a carboxyl group is removed from the cannabinoid molecule, and carbon dioxide is released. For example, Δ 9 -tetrahydrocannabinolic acid (Δ 9 -THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabichromenic acid (CBCA) and tetrahydrocannabivarinic acid (THCVA) may be decarboxylated to yield Δ 9 -tetrahydrocannabinol (Δ 9 -THC), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC) and tetrahydrocannabivarin (THCV), respectively. In certain embodiments, the cannabinoids in the  cannabis  resin are at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% decarboxylated, (or any integer or fractions in these ranges, for example, 96.33%) decarboxylated. As used herein, the term decarboxylated  cannabis  resin excludes predominately non-decarboxylated resinous substances, such as kief, hash, and hashish, which are typically heated (e.g. through smoking, vaping, or cooking) in order to achieve partial decarboxylation. In some embodiments, THC and/or CBD and/or THCV and/or CBG and/or other major cannabinoids are the major components of the decarboxylated resin, and this is dependent on the particular strain of  Cannabis  used in the extraction process. In addition to the decarboxylated cannabinoids, other chemicals found in  Cannabis  spp. and soluble in the solvent used, may be found in the resin. Such compounds may include, for example, terpenes, fatty acids, chlorophyll, flavonoids, and other compounds. Some of the compounds may undergo chemical transformation due to the processes used for extraction and carboxylation. 
     Exemplary Methods for Preparing Decarboxylated  Cannabis  Resin 
     In certain embodiments, the decarboxylated  cannabis  resin which is used to make the rapid disintegrating tablets of the present invention may be made in accordance with the methods disclosed in U.S. Patent Application No. 62/610,706 and PCT Application No. PCT/CA2017/050788, which are herein incorporated by reference. It will be appreciated that the following methods of preparing decarboxylated  cannabis  resin are illustrative only and are not intended to be limiting. In alternative embodiments, other suitable methods of preparing decarboxylated  cannabis  resin may be used. 
     In  FIG. 3 , a method  100  for extracting and decarboxylating cannabinoids from  cannabis  plant material is shown. Generally, method  100  comprises drying raw  cannabis  plant material at step  102 , breaking down the  cannabis  plant material to form  cannabis  plant material of a size and form suitable for extraction at step  104 , extracting cannabinoids from the broken down  cannabis  plant material by contacting the broken down  cannabis  plant material with a solvent to extract the cannabinoids from the  cannabis  plant material and decarboxylating the cannabinoids by subjecting the extract to microwaves to form decarboxylated cannabinoids. Decarboxylation of the cannabinoids may occur when the cannabinoids are in the plant, when the cannabinoids are in the extract, or both. In some embodiments the extract is subjected to microwaves in a closed reaction vessel at a temperature and time sufficient to form decarboxylated cannabinoid. 
     The extracted and decarboxylated cannabinoids are optionally recovered. Recovery can include filtering the solvent from the extract of  cannabis  plant material to isolate the decarboxylated cannabinoids. 
     In some embodiments, the process comprises an extraction step before, during or after decarboxylation. In some embodiments, the process of the disclosure comprises more than one extraction step. 
     In some embodiments, the decarboxylation step can occur before, during or after extraction. 
     In an embodiment, a one-step method for extraction and decarboxylation is used, wherein the  cannabis  plant material (that is suitably prepared, e.g. optionally dried and broken down as described herein) is placed in a suitable extracting solvent (e.g. a pharmaceutically acceptable solvent such as ethanol, glycerol, and isopropanol, and other solvents as is known to those skilled in the art, kept in suspension or solution (e.g. by stirring, agitation, shaking or other means known to those skilled in the art) and subjected to microwave radiation while stirring at a temperature, pressure and time to obtain suitably extracted and decarboxylated cannabinoids that can be recovered for use as either a mixture or individual chemical components (e.g. for use as a therapeutic or pharmaceutical product). Further in some embodiments, the solvent can be food grade oil and/or a medium chain triglyceride, for example, coconut oil. 
     Such a method is more efficient in converting the cannabinoid acid into its decarboxylated form than other known methods of extraction and decarboxylation (such as simple heating). 
     Particularly,  FIGS. 11 and 12  show various concentrations of different cannabinoids in  cannabis  plant material extracts using ethanol, Soxhlet and SFE, without subjecting  cannabis  to microwave conditions and followed by microwave heating, respectively. By comparing concentrations measured through the use of solvent extraction alone, Soxhlet extraction alone (e.g. solvent and heat) and SFE alone (e.g. solvent and heat), as shown in  FIG. 11 , with concentrations measured by using solvent extraction followed by microwave, Soxhlet extraction followed by microwave and SFE followed by microwave, as shown in  FIG. 12 , adding microwave heating to each of solvent extraction, Soxhlet extraction and SFE can greatly increase THC, CBD and CBN concentrations and decrease THCA concentration in the extract. 
       FIGS. 13 and 14  further show that high concentrations of THC, CBD, CBN and THCA in the extract are achieved when the extract is exposed to microwave radiation at about 170° C. for about 20 minutes. Further details regarding working variables are provided below. 
     Drying  102   
     Optional drying step  102  can be used to remove excess moisture from the  cannabis  plant material prior to the  cannabis  plant material undergoing extraction and decarboxylation. Removing water content from the  cannabis  plant material can help to provide even heating at later stages in the extraction and/or decarboxylation process. Alternatively, fresh  cannabis  plant material (e.g. from the plant directly) can be used for the subsequent break down, extraction and decarboxylation steps. Herein, drying of the  cannabis  plant material at step  102  can occur by any means, for example in an oven at temperatures in the range of 60-75° C., or similar conditions, or using a vacuum oven or similar conditions over several hours, for example 4 hours, or 6 hours or 8 hours, depending on the amount of moisture. During the drying process, when heating is employed using heating elements in the ovens or infrared heating among other processes, some of the cannabinoid carboxyl acids forms could be converted into their decarboxylated cannabinoid forms. 
     Break Down  104   
     At break down step  104 ,  cannabis  plant material can be broken down to produce a  cannabis  plant material of a size and form suitable for extraction and decarboxylation by subjecting to microwave heating. 
     Trichomes (i.e. resin glands) of the  cannabis  plant material are nearly microscopic, mushroom-like protrusions from the surface of the buds, fan leaves, and the stalk. While relatively complex, trichomes are comprised primarily of a stalk and a head. The production of cannabinoids such as THC occurs predominantly in the head of the trichome. Cannabinoids are concentrated in the trichomes of the plant. The trichome is built to easily shed from the  cannabis  plant material surface. 
     The term “a size and form suitable for extraction and decarboxylation” refers to a reduction in the particle size of the  cannabis  plant material fragments. 
     Herein, breakdown of the  cannabis  plant material at step  104  can occur by any mechanical means including by crushing, smashing, grinding, pulverizing, macerating, disintegration or equivalent processes as are known to those skilled in the art that reduce the  cannabis  plant material into small pieces suitable in size and form for extraction and/or decarboxylation. 
     In one example embodiment, sonication can also be used to loosen the  cannabis  plant material in contact with an appropriate solvent such as ethanol, and/or by breaking down cellular membranes making it suitable for extraction and/or decarboxylation. In another example embodiment, maceration can be performed with a mortar and pestle to produce a  cannabis  plant material of a size and form suitable for extraction and/or decarboxylation. 
     In certain embodiments, the  cannabis  plant material is reduced in size such that its particle size is within a range of 1 mm to 10 mm. 
     Extraction  106   
     Upon completion of break down step  104 , extraction step  106  may be performed. It should be noted that extraction step  106  may occur as a separate step to decarboxylation step  108  either before or after decarboxylation step  108 , or as will be described below, extraction step  106  and decarboxylation step  108  may occur concurrently. For the avoidance of doubt it should be understood that any extraction, including but not limited to sonication in the presence of a solvent, reflux (Soxhlet) extraction and supercritical fluid extraction (SFE) may occur before or after decarboxylation step  108 . In addition, it should also be understood that break down ( 104 ), extraction ( 106 ) and decarboxylation ( 108 ) may also occur in one step. 
     In one embodiment, extraction step  106  can comprise contacting cannabinoids from the broken down  cannabis  material that is the product of break down step  104  with a solvent. 
     In some embodiments, the solvent treatment in extraction step  106  removes non-cannabinoid impurities to leave a substantially pure preparation of cannabinoids. It has been shown that non-polar, liquid solvents may be useful for this function. Suitable non-polar solvents therefore include essentially any non-polar solvents which are substantially less polar than the cannabinoids, such that impurities which are more polar than the cannabinoids are removed by treatment with the solvent. Filtration and other methods as is known to those skilled in the art can also be used to remove impurities. 
     Useful non-polar solvents include, but are not limited to, C5-C12 straight chain or branched chain alkanes, or carbonate esters of C1-C12 alcohols. The more volatile C5-C12 alkanes may be particularly useful, as they are more easily removed from the extract. Further, solvents that have been approved for use in pharmaceutical compositions, such as ethanol (e.g. 95% ethanol) may be particularly useful. 
     Particularly useful solvents include pentane, hexane, heptane, iso-octane and ethanol, and/or mixtures thereof or the like as is known to those skilled in the art. 
     In one embodiment of extraction step  106 , broken down  cannabis  plant material can be added to a solvent and concurrently sonicated. 
     Herein, sonication refers to the application of ultrasonic vibration (e.g. &gt;20 kHz) to fragment cells, macromolecules and membranes of the dried or undried  cannabis  plant material. Ultrasonic vibration can be provided by any means known in the art. 
     In one exemplary embodiment, sonication of a mixture of  cannabis  plant material and solvent can occur for 5-25 minutes at 25° C., where the ratio of  cannabis  plant material and solvent is such that all  cannabis  plant material is submerged in the solvent completely in the reaction vessel. 
     Upon the completion of sonication of the mixture of  cannabis  plant material and solvent, the solvent is removed from the mixture. Removal of the solvent can occur by any means known in the art, including but not limited to filtration and/or evaporation. One embodiment for filtering after sonication is vacuum filtering over a glass sintered funnel to separate the resultant extract in the filtrate and the plant material. The latter can then be subjected to further extractions such as Soxhlet or other solvent extractions as is known to those skilled in the art, for example, SFE. 
     In yet another embodiment of extraction step  106 , cannabinoids can be extracted from  cannabis  plant material that is broken down in step  104  by reflux (Soxhlet) extraction. 
     During reflux (Soxhlet) extraction,  cannabis  plant material that is broken down in step  104  is generally suspended above a heated solvent in a receptacle. The solvent is heated to reflux in a distillation flask such that solvent vapor travels up a distillation arm and floods into the receptacle housing raw  cannabis  material. A condenser suspended above the raw  cannabis  material ensures that any solvent vapor rising above the raw  cannabis  material cools and subsequently drips back down into the receptacle housing the raw  cannabis  material. The receptacle slowly fills with warm solvent such that cannabinoids begin to dissolve into the warm solvent. When the receptacle fills, it is emptied by a siphon such that the solvent is returned to the distillation flask. This cycle may be allowed to repeat many times, over hours or days. 
     Preferably, reflux (Soxhlet) extraction occurs at a solvent temperature higher than the boiling point of the corresponding solvent used for extraction and is conducted over a period of approximately 3 to 5 hours. 
     Once extraction is complete, removal of the solvent can occur by any means known in the art, including but not limited to filtering and/or evaporation as previously described. 
     In place of either sonication or reflux (Soxhlet) extraction as described above, another embodiment of extraction step  106  encompassed by the subject application is the extraction of cannabinoids from  cannabis  plant material by SFE. 
     SFE refers to a process of separating one or more components (extractant) from another (matrix) using supercritical fluids as the extracting solvent. Extraction is usually from a solid matrix (e.g.  cannabis  plant material), but can also be from liquids or resinous material (for example, hash oil). 
     Although numerous supercritical fluids can be used, carbon dioxide (CO 2 ) is the most commonly used supercritical fluid for SFE. In other exemplary embodiments, CO 2  can be modified by co-solvents such as ethanol or methanol as is known to those skilled in the art. 
     Extraction conditions for supercritical fluids are above the critical temperature (for example, 31° C. for CO 2 ) and critical pressure (for example, 74 bar for CO 2 ). Addition of modifiers such as but not limited to ethanol can require altering these extraction conditions. 
     An exemplary SFE system contains a pump for CO 2  (as well as any other solvents), a pressure cell to contain the  cannabis  material, a means of maintaining pressure in the system and a collecting vessel. The liquid is pumped to a heating zone, where it is heated to supercritical conditions. It then passes into the extraction vessel, where it rapidly diffuses into the solid matrix and dissolves the  cannabis  material to be extracted. The dissolved material (for example, cannabinoids) is swept from the extraction cell into a separator at lower pressure, and the extracted material settles out. The CO 2  can then be cooled, re-compressed and recycled, or discharged to atmosphere. 
     Herein, the temperature of the SFE extraction performed at extraction step  106  can, in some embodiments, be in the range of 35-55° C. 
     Further the pressure the SFE extraction performed at extraction step  106  can in some embodiments be in the range of 65-85 bar (6.5-8.5 MPa). 
     SFE in the present disclosure occurs at about 40° C. with a back pressure regulator pressure of 120 bar (12 MPa) and the extracted compounds are monitored using a photodiode array of 200-600 nm (monitoring at 254 nm). The acquisition time and method times of the system can each vary by a few minutes up to 60 minutes, ideally between 15 and 30 minutes, depending on the ratio of supercritical fluid and the co-solvent is altered for the extraction. 
     In specific embodiments, SFE can be carried out multiple times in succession. In such embodiments, the SFE is a fractional SFE. 
     As previously described for sonication with a solvent and reflux (Soxhlet) extraction, once SFE is complete, removal of the solvent can occur by any means known in the art, including but not limited to filtering and/or evaporation. 
     Microwave-Assisted Extraction and Decarboxylation  108   
     Decarboxylation of phytocannabinoid acids such as Δ 9 -THCA is a function of the time and temperature of the reaction. For instance, the decarboxylation of concentrated Δ 9 -THCA in solution into Δ 9 -THC and the degradation of Δ 9 -THC vary with temperature. Temperature controls are therefore important for controlling desired ratios of decarboxylation products. The use of conventional household microwaves in the processing of  cannabis  has been discussed in the literature, however, with mixed, inconsistent results and not necessarily specifically for extraction in a solvent and decarboxylation. Further, in order to obtain 100% decarboxylation, the temperature must be sustained over a period of time without burning of the  cannabis  material or boiling/evaporation of the solvent. If the temperature is higher than the boiling point of the solvent employed, the solvent will boil over and/or evaporate. In order to sustain the temperature over the required period of time to fully decarboxylate the cannabinoids but not burn the  cannabis  plant material or boil/evaporate the solvent with the  cannabis , the microwave vessel (i.e. the sealed container) must be under pressure. Sealing the vessel or container ensures pressure in the vessel or container. 
     As shown in  FIG. 3 , microwave-assisted extraction can occur either immediately after mechanical breakdown step  104  or after a preliminary extraction step  106  as described above. 
     Microwave assisted extraction and decarboxylation  108  can comprise suspending  cannabis  plant material in a solvent and subjecting the mixture to microwaves in a closed container at a temperature, pressure and time sufficient to form decarboxylated cannabinoids. 
     Herein, the term “microwaves” refer to a form of electromagnetic radiation with wavelengths ranging from one meter to one millimeter; with frequencies between 300 MHz (100 cm) and 300 GHz (0.1 cm). 
     Further, solvent treatment in microwave assisted extraction and decarboxylation step  108  is again to remove non-cannabinoid impurities to leave a substantially pure preparation of cannabinoids. As such, non-polar, liquid solvents are useful for this function. In one embodiment, ethanol is used as the liquid solvent in microwave assisted extraction and decarboxylation step  108 . In another embodiment, 95% ethanol is used as the liquid solvent in microwave assisted extraction and decarboxylation step  108 . 
     As ethanol has a boiling point of 78° C. and the decarboxylation process of  cannabis  is temperature dependent (as described above), temperature control is important in microwave-assisted extraction step  108 . 
     In one exemplary embodiment, suitable conditions to promote decarboxylation of CBDA and THCA to CBD and THC, respectively, are to suspend the  cannabis  plant material in a solvent (such as ethanol) and then subject this mixture to electromagnetic radiation (for example, microwaves) of a wavelength in the range of 10 6 -10 9  nm, and a frequency of 300 MHz-300 GHz. In one embodiment, the conditions further include, for example, the following: temperature range of 40-250° C., temperature increase of 2-5° C./sec, pressure range of 0-20 bar (2 MPa, 290 psi), appropriate microwave power at 2.45 GHz or minor variations and adjustments to suit a particular solvent and/or reaction conditions to reach the required temperature and accomplish decarboxylation. If stirring is required, a variable magnetic stirrer (300-900 RPM) may be used. 
     In another exemplary embodiment, microwave assisted extraction and decarboxylation can be performed at a temperature in the range of 100-200° C. (including all possible integers and fractions of integers in this range, for example, 163.5° C.), 130-170° C., 150-170° C. or 130-150° C. 
     In another exemplary embodiment, microwave assisted extraction and decarboxylation can be performed at a pressure in the range of 2-22 bar (including all possible integers and fractions of integers in this range), for example, 10.7 bar or 17 bar or 18 bar or 19 bar or 20 bar or 21 bar. 
     The  cannabis  plant material can be suspended in a solvent and subjected to microwaves at frequency and wavelength of 2.45 GHz and 1.22×10 8  nm, respectively, and a temperature in the range of 130-190° C. 
     The raw  cannabis  material can be suspended in a solvent and subjected to microwaves at frequency and wavelength of 2.45 GHz and 1.22×10 8  nm, respectively, and a temperature in the range of 150-190° C. and the solvent is ethanol. 
     In another embodiment,  cannabis  plant material can be suspended in a solvent and the mixture stirred for a defined period of time (e.g. 0-30 sec or a reasonable length of time so as to suspend the material) before being subjected to microwaves. In one embodiment, the defined period is 30 seconds. 
     In another embodiment,  cannabis  material can be suspended in a solvent and the mixture can be stirred while being subjected to microwaves. In one embodiment, the defined period is 10 minutes and in another embodiment the defined period is 20 minutes. A table of working microwave variables is provided below for reference. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                   
                 Total 
                 Pre- 
                   
                 Reaction 
               
               
                 Temperature 
                 time 
                 stirring 
                 Stir rate 
                 Pressure 
               
               
                 (° C.) 
                 (mins) 
                 (sec) 
                 (rpm) 
                 (Bar) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 150 
                 20 
                 30 
                 900 
                 12 
               
               
                 150 
                 20 
                 30 
                 900 
                 11 
               
               
                 150 
                 20 
                 30 
                 900 
                 10 
               
               
                 150 
                 20 
                 30 
                 900 
                 13 
               
               
                 150 
                 20 
                 30 
                 900 
                 13 
               
               
                 150 
                 20 
                 30 
                 900 
                 12 
               
               
                 170 
                 15 
                 30 
                 900 
                 18 
               
               
                 150 
                 10 
                 30 
                 600 
                 8.5 
               
               
                 150 
                 10 
                 30 
                 600 
                 8.5 
               
               
                 150 
                 10 
                 30 
                 600 
                 9 
               
               
                 150 
                 10 
                 0 
                 600 
                 8 
               
               
                 150 
                 10 
                 0 
                 600 
                 8.5 
               
               
                 150 
                 10 
                 0 
                 600 
                 8.5 
               
               
                 100 
                 30 
                 0 
                 600 
                 1 
               
               
                 100 
                 30 
                 0 
                 600 
                 2 
               
               
                 100 
                 30 
                 0 
                 600 
                 1 
               
               
                 150 
                 10 
                 30 
                 600 
                 8 
               
               
                 150 
                 10 
                 30 
                 600 
                 9 
               
               
                 150 
                 10 
                 30 
                 600 
                 8.5 
               
               
                 170 
                 10 
                 30 
                 600 
                 17 
               
               
                 150 
                 10 
                 30 
                 600 
                 10 
               
               
                 130 
                 10 
                 30 
                 600 
                 5 
               
               
                 100 
                 5 
                 30 
                 600 
                 2 
               
               
                 100 
                 5 
                 30 
                 600 
                 2 
               
               
                   
               
            
           
         
       
     
     The parameters below can be set by the user, depending on the type of microwave equipment employed and the options available for user settings:
         Power (OFF)=Constant power or the maximum power applied when heating the reaction mixture.   Initial Power (OFF)=Power applied initially when heating the reaction mixture.   Fixed Hold Time (ON)=If ON, the time countdown starts when the target temperature or target pressure is reached, i.e. the initial time taken to reach the set temperature or pressure is not included in the heating time.   Pressure (OFF)=Target pressure for reaction.   Cooling (OFF)=If OFF, cooling is not applied during the heating process.   Absorption (NORMAL)=If NORMAL, power applied is initially between 200 and 400 W, depending on the target temperature.   Temperature=Target temperature. (Note: The temperature is monitored by an external infrared sensor that measures the surface temperature of the glass vial in real time.)   Total time=Total time for all steps.   Pre-stirring=Stirring time before heating process.   Stir-rate=Rotational speed of magnetic stir bar.       

     The parameters below were observed and extrapolated.
         Power supplied=Power used to achieve the target temperature.   Holding power=Power used to maintain the target temperature.   Reaction pressure=Maximum pressure during the reaction.       

     In some embodiments, the decarboxylated cannabinoid product can be used directly or further processed, purified or recovered prior to use. 
     Recovery  110   
     Optionally, after being subjected to microwaves, a preparation of decarboxylated cannabinoids can be recovered from the resulting suspension at recovery step  110 . 
     In one embodiment, extracted and decarboxylated cannabinoids are recovered by filtering the solvent from the extract of  cannabis  plant material to isolate the decarboxylated cannabinoids or decarboxylated cannabinoid comprising fraction. 
     In another embodiment, extracted and decarboxylated cannabinoids are recovered by filtering through an appropriate Celite® pad and/or activated carbon (e.g. charcoal) to obtain clarified solution for subsequent processing or use. In this embodiment, Celite® can be placed in a glass sintered funnel and then layered with activated carbon. Filtering agents can be washed with ethanol via vacuum filtration and extract can be dissolved in appropriate volume of suitable solvent such as ethanol and transferred to a funnel. Vacuum can then be applied and the filtering agent can be washed with the solvent until cannabinoids are completely eluted. The resulting filtrate can then be concentrated to dryness (e.g. at 25° C.). Someone with skill in the art can also conceive employing functionalized membranes, cellulose filters or the like to accomplish the above recovery task, instead of Celite® and activated carbon pad. 
     Alternatively, the resulting preparation of decarboxylated cannabinoids from step  108  can be collected and subsequently processed according to any of the extraction methods described in step  106 , including but not limited to sonication, reflux (Soxhlet) extraction and/or SFE. 
     EXAMPLES 
     The following examples from U.S. Patent Application No. 62/610,706 and PCT Application No. PCT/CA2017/050788, which are herein incorporated by reference, are illustrative of methods of obtaining decarboxylated  cannabis  resin which may be used for making the rapid disintegrating tablets of the present disclosure. It will be appreciated that these examples are illustrative only and other suitable methods may be used. 
     Experiment 1: Decarboxylated  cannabis  Resin 
     Medicinal  cannabis  was subjected to extraction and chemical analysis by UPLC-MS. 
     Extraction Methodologies 
       FIG. 2A  shows medical  cannabis  and decarboxylated  cannabis  resin. Four types of extraction methods were performed as shown in the corresponding flow charts in Scheme 1. (A) Ultrasonication (B) Sohxlet extraction (C) Supercritical Fluid Extraction (Omar, J. Olivares, M. et al. J. Sep. Sci. 2013, 36, 1397-1404, incorporated herein by reference) (D) Closed system microwave extraction, as described in experiments 5-9 below. 
     Scheme 1. Flow Charts of Various Extractions Methods 

 
     UPLC-MS Methodology. Cannabinoid standards,  cannabis  extracts and cannabinoids in the donor samples were analyzed using Waters® ACQUITY UPLC H-Class System equipped with Quaternary Solvent Manager and Sample Manager FTN. The detector used to monitor the samples was Waters® MS 3100 mass spectrometer. Benzophenone, caffeine or Δ 9 -THC-d 3  was used as an internal standard. Conditions are listed in Table 2. 
     
       
         
           
               
             
               
                 TABLE 2 
               
               
                   
               
               
                 UPLC-MS Chromatographic conditions 
               
               
                 UPLC-MS Conditions 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                   
                 Column: BEH (2.1 × 50 mm, C 18 , 1.7 μm) 
               
               
                   
                 Mass scan range (ESI +ve and −ve): 150-500 m/z 
               
               
                   
                 Flow rate: 0.6 mL/min 
               
               
                   
                 Solvent: H 2 O (0.1% formic acid; solvent A) 
               
               
                   
                 MeOH (0.1% formic acid; solvent B) 
               
               
                   
                 Gradient conditions: 
               
               
                   
                 0-4.5 min: 30% A/70% B-100% B 
               
               
                   
                 4.5-5.0 min: 100% B 
               
               
                   
                 5.0-5.2 min: 100% B-30% A/70% B 
               
               
                   
                 5.2-6.0 min: 30% A/70% B 
               
               
                   
               
            
           
         
       
     
     Extraction Results 
       
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Quantities of extracts and major cannabinoids obtained 
               
               
                 from extraction Methods A-D of Strain I. 
               
            
           
           
               
               
            
               
                   
                 Cannabinoid in resin (%) 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Plant 
                 Extract 
                 Total Δ 9 -THC 
                 Total CBD 
               
               
                 Method 
                 used (g) 
                 isolated (g) 
                 (THCA + THC) 
                 (CBDA + CBD) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 A 
                 1.51 
                 0.453 
                 31.2 ± 0.5 
                 66.1 ± 1.4 
               
               
                 B 
                 2.00 
                 0.616 
                 16.7 ± 0.2 
                 33.3 ± 0.6 
               
               
                 C 
                 1.00 
                 0.277 
                 30.4 ± 0.9 
                 59.3 ± 1.9 
               
               
                 D 
                 1.01 
                 0.211 
                 29.4 ± 7.6 
                 33.8 ± 8.6 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Quantities of extracts and major cannabinoids obtained 
               
               
                 after Method D (closed system microwave extraction). 
               
            
           
           
               
               
               
               
            
               
                   
                 Plant 
                 Extract 
                 Cannabinoid in resin (%) 
               
            
           
           
               
               
               
               
               
            
               
                 Strain 
                 used (g) 
                 isolated (g) 
                 Δ 9 -THC 
                 CBD 
               
               
                   
               
               
                 I 
                 1.01 ± 0.0003 
                 0.211 ± 0.01  
                 29.4 ± 7.6 
                 33.8 ± 8.6 
               
               
                 II 
                 1.00 ± 0.0004 
                 0.154 ± 0.004 
                  1.9 ± 0.2 
                 37.6 ± 4.1 
               
               
                 III 
                 1.00 ± 0.002  
                 0.210 ± 0.009 
                 49.8 ± 0.9 
                 0 
               
               
                   
               
            
           
         
       
     
     Chemical Analyses by UPLC-MS 
     Mass spectra of Strain 1 before ( FIG. 2 b   ) and after ( FIG. 2 c   ) decarboxylation of medical  cannabis , indicates 100% conversion of CBDA and THCA into CBD and THC, respectively. 
     Closed system microwave extraction provides simultaneously extraction and decarboxylation of the cannabinoids, as observed during chemical analysis by UPLC-MS. 
     Experiment 2: Further Comparison of Various Extraction Methods, Decarboxylation of Cannabinoids and Production of Standard Curves 
     Method 1A: Ultrasonic Extraction (Sonication). 
     General Procedure:
         1. Dried plant material was weighed and macerated using a mortar and pestle.   2. Solvent was added (25-130 mL) and mixture sonicated for 5 mins at 25° C.   3. Solvent was decanted and filtered over a glass sintered funnel using a vacuum filtration.   4. Steps 2 and 3 were repeated twice with the remaining fibre material.   5. Filtrate was concentrated to dryness (at 25° C.) then weighed (green resin).       

     Table 5 below shows the results of sonication of three common strains of  cannabis . 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Results of sonication extraction with various 
               
               
                 solvents on three strains of  cannabis . 
               
            
           
           
               
               
            
               
                   
                 Solvent 
               
            
           
           
               
               
               
               
            
               
                   
                 Hex- 
                 Isopropanol/hexanes 
                   
               
               
                 Strain 
                 anes 
                 (1:1) 
                 Ethanol 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Strain 1 
                 Plant Used (g) 
                 0.256 
                 1.0013 
                 0.246 
               
               
                 (THC: 7.18/ 
                   
                   
                   
                 1.5084 
               
               
                 CBD: 8.6) 
                 Resin 
                 0.0617 
                 0.4748 
                 0.1802 
               
               
                   
                 produced (g) 
                   
                   
                 0.4531 
               
               
                 Strain 2 
                 Plant Used (g) 
                 N/A 
                 N/A 
                 2.0018 
               
               
                 (THC: 0/ 
                 Resin 
                 N/A 
                 N/A 
                 0.4795 
               
               
                 CBD: 9) 
                 produced (g) 
                   
                   
                   
               
               
                 Strain 3 
                 Plant Used (g) 
                   
                 N/A 
                 2.9475 
               
               
                 (THC: 18.6/ 
                 Resin 
                 N/A 
                 N/A 
                 1.1611 
               
               
                 CBD: 0) 
                 produced (g) 
               
               
                   
               
            
           
         
       
     
     Method 1B: Filtration Over Celite®/Activated Carbon. 
     Following Method 1A (described above), extracts were subjected to filtration over Celite® and activated carbon in order to eliminate the green colour of extracts. The results are shown in Table 6. 
     General Procedure:
         1. Celite® was placed in a glass sintered funnel, then layered with activated carbon.   2. Extract was dissolved in 1 mL ethanol and transferred to funnel.   3. Vial that contained extract was washed twice with 1.5 mL ethanol and transferred to funnel.   4. Vacuum was then applied and filtering agent washed with ethanol until filtrate was no longer UV active (60-70 mL).   5. Filtrate was concentrated to dryness (at 25° C.), then weighed (orange resin).       

     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Results of extract filtration with Celite ®/Activated 
               
               
                 Carbon for three strains of  cannabis   
               
            
           
           
               
               
               
            
               
                 Strain 
                 Extract used (g) 
                 Extract isolated (g) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Strain 1 
                 0.2265 
                 0.2095 
               
               
                 (THC: 7.18/CBD: 8.6) 
                   
                   
               
               
                 Strain 2 
                 0.2026 
                 0.1717 
               
               
                 (THC: 0/CBD: 9) 
                   
                   
               
               
                 Strain 3 
                 0.4984 
                 0.4561 
               
               
                 (THC: 18.6/CBD: 0) 
               
               
                   
               
            
           
         
       
     
     Method 2: Soxhlet Extraction 
     General Procedure:
         1. Dried plant material was weighed and macerated using a mortar and pestle   2. Crushed material was then transferred to a cellulose extraction thimble (43×123 mm; 2 mm thickness)   3. Thimble was then inserted into a large extractor (size: 55/50)   4. Solvent (400 mL) and stir bar were added to a round bottom flask, which was then placed in the suitable DrySyn heating block and connected to the extractor   5. Extractor was then connected to a large condenser (size: 55/50) and refluxing was done at 120° C. for 3.5 hrs   6. Once refluxing was complete, the solvent was concentrated to dryness (at 25° C.) then weighed (green resin)       

     Table 7 below provides the results of Soxhlet extraction of  cannabis  according to the forgoing procedure. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Results of Soxhlet extraction of  cannabis . 
               
            
           
           
               
               
               
            
               
                 Strain 
                 Amount of plant used (g) 
                 Extract isolated (g) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Strain 1 
                 2.0021 
                 0.6163 
               
               
                 (THC: 7.18/CBD: 8.6) 
               
               
                   
               
            
           
         
       
     
     Method 3: Supercritical Fluid Extraction (SFE) 
     General Procedure:
         1. Dried plant material was weighed and macerated using a mortar and pestle   2. Crushed plant material was transferred to a 10 mL extraction vessel and subjected to either of the following conditions below   3. All fractions were combined and concentrated to dryness (at 25° C.) then weighed (green resin)       

     Method 3A: SFE Conditions 
     
       
         
           
               
               
             
               
                   
               
             
            
               
                 Solvent A = CO 2   
                 Solvent B = ethanol 
               
               
                 Temperature = 40° C. 
                 BPR = 12 MPa 
               
               
                 PDA = 200-600 nm (monitoring at 254 nm) 
                   
               
               
                 Acquisition time = 30 mins 
                 Method time = 30.2 mins 
               
               
                   
               
            
           
         
       
         
         
           
             i. 5 mins static with 1:1 A/B 
             ii. 25 mins dynamic with 1:1 A/B (Flow rate=10 mL/min; make up pump=0.2 mL/min) 
             iii. Fractions were collected every 5 mins 
           
         
       
    
     Method 3B: SFE Conditions 
     
       
         
           
               
               
             
               
                   
               
             
            
               
                 Solvent A = CO 2   
                 Solvent B = ethanol 
               
               
                 Temperature = 40° C. 
                 BPR = 12 MPa 
               
               
                 PDA = 200-600 nm (monitoring at 254 nm) 
               
               
                   
               
            
           
         
       
         
         
           
             i. 15 mins dynamic with 100% A (Flow rate=10 mL/min)
           Fractions were collected every 7.5 mins   Acquisition time=15 mins Method time=15.2 mins   
         
             ii. 30 mins dynamic with 80:20 A/B (Flow rate=10 mL/min; make up pump=1 mL/min)
           Fractions were collected every 5 mins   Acquisition time=30 mins Method time=30.2 mins   
         
           
         
       
    
     Table 8 below shows the results of SFE according to the conditions outlined in Methods 3A and 3B for  cannabis . 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Results of SFE extraction of  cannabis  according to two sets of 
               
               
                 conditions. 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Amount 
                   
               
               
                 Strain 
                 Conditions 
                 of plant used (g) 
                 Extract isolated (g) 
               
               
                   
               
               
                 Strain 1 
                 Method 3A 
                 1.0047 
                 0.2164 
               
               
                 (THC: 7.18/CBD: 
                 Method 3B 
                 1.0043 
                 0.2561 
               
               
                 8.6) 
               
               
                   
               
            
           
         
       
     
     Method 4: Microwave-Assisted Extractions with Ethanol (MAE) Followed by SFE. 
     Suitable conditions to promote decarboxylation of CBDA and THCA to CBD and THC, respectively, were determined with MAE. 
     The solvent used for this extraction was ethanol. However, since ethanol has a boiling point of 78° C., the highest temperature that could be achieved when heating only ethanol in a sealed vessel under microwave conditions had to be determined. 
     General Procedure:
         1. Ethanol (11 mL) and a stir bar were placed in a 20 mL microwave vial which was then sealed.   2. General microwave conditions:
           (a) Pre-stirring=30 secs   (b) Run time=15 mins   (c) Absorption=Normal   
               

     The results are shown in Table 9 below. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Determination of highest temperature that could be achieved when 
               
               
                 heating only ethanol in a sealed vessel under microwave conditions. 
               
            
           
           
               
               
               
            
               
                 Attempt # 
                 Temperature (° C.) 
                 Results 
               
               
                   
               
               
                 1 
                 200 
                 Maximum system pressure attained; 
               
               
                   
                   
                 Run aborted due to high pressure 
               
               
                 2 
                 150 
                 Run completed 
               
               
                 3 
                 190 
                 Maximum system pressure attained; 
               
               
                   
                   
                 Run aborted due to high pressure 
               
               
                 4 
                 180 
                 Maximum system pressure attained; 
               
               
                   
                   
                 Run aborted due to high pressure 
               
               
                 5 
                 170 
                 Run completed 
               
               
                   
               
            
           
         
       
     
     Once the maximum temperature that ethanol could be heated was determined, the following conditions were performed with  cannabis:    
     General Procedure:
         1. Dried plant material was weighed and macerated using a mortar and pestle   2. Crushed plant material was transferred to a 20 mL or 5 mL microwave vial along with a stir bar   3. Ethanol (11 mL or 3 mL) was added to the vial such that the plant material was completely submerged. The vial was then sealed and subjected to the microwave conditions below:
           (a) Pre-stirring=30 secs   (b) Run time=10 mins   (c) Absorption=Normal   
           4. The suspension was filtered and the filtrate and plant fibre collected separately   5. Filtrate was concentrated and plant fibre subjected to the SFE conditions below:       

     
       
         
           
               
               
             
               
                   
               
             
            
               
                 Solvent A = CO 2   
                 Solvent B = ethanol 
               
               
                 Temperature = 25° C. 
                 BPR = 12 MPa 
               
               
                 PDA = 200-600 nm (monitoring at 254 nm) 
               
               
                 Acquisition time = 20 mins 
                 Method time = 20.2 mins 
               
               
                   
               
            
           
         
       
         
         
           
             6. Gradient from 100% A to 50%; 0.1 mins-15 mins (Flow rate=10 mL/min; make up pump=1 mL/min) 
             7. Fractions were collected every 7.5 mins 
           
         
       
    
     The results are shown in Table 10 below. 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Extraction of cannabis by Microwave and SFE at various 
               
               
                 microwave temperatures 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Extract 
                 Extract 
               
               
                   
                   
                   
                 Amount of 
                 isolated after 
                 isolated 
               
               
                   
                   
                 Temperature 
                 plant used 
                 microwave 
                 after SFE 
               
               
                 Strain 
                 Method 
                 (° C.) 
                 (g) 
                 (g) 
                 (g) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Strain 1 
                 A 
                 100 
                 1.0012 
                 0.3246 
                 N/A 
               
               
                 (THC: 
                 B 
                 130 
                 0.2554 
                 0.0592 
                 0.0008 
               
               
                 7.18/ 
                 C 
                 150 
                 0.2543 
                 0.063 
                 0.0005 
               
               
                 CBD: 8.6) 
                 D 
                 170 
                 0.2554 
                 0.0644 
                 0.0025 
               
               
                   
               
            
           
         
       
     
     Table 14 (provided below) shows the analyses and quantification of the cannabinoids. 
     Method 5. SFE/Soxhlet/Sonication Extraction Followed by Microwave of the Resin (for Decarboxylation). 
     General Procedure:
         1. Resin isolated from Methods 1A (ethanolic extract), 2 and 3A were dissolved in 3-3.5 mL ethanol and transferred to a 5 mL microwave vial.   2. A stir bar was added and the vial sealed and subjected to microwave conditions below:
           (a) Temperature=150° C.   (b) Pre-stirring=30 secs   (c) Run time=10 mins   (d) Absorption=Normal   
           3. The reaction mixture was then concentrated.       

     The results are shown in Table 11 below. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Weights of resins after subjecting to microwave heating. 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Amount of 
                 Resin isolated after 
               
               
                 Strain 
                 Method 
                 resin (g) 
                 microwave (g) 
               
               
                   
               
               
                 Strain 1 
                 1A (Sonication) 
                 0.2223 
                 0.1692 
               
               
                 (THC: 7.18/CBD: 
                 2 (Soxhlet) 
                 0.2651 
                 0.2211 
               
               
                 8.6) 
                 3A (SFE; 50:50) 
                 0.2164 
                 0.1884 
               
               
                   
               
            
           
         
       
     
     Chromatography Analyses (HPLC/MS/PDA) 
     The chromatographic profiles of the  cannabis  extracts were determined by LC-PDA-MS equipped with a Waters® 2545 binary gradient module LC, Waters® PDA2998 photodiode array detector (190-800 nm) and a Waters® 3100 mass spectrometer (60-2000 Da). 
     LC was performed on an X-Bridge analytical C18 column (4.6 mm×150 mm, 5 um I.D.) with 1.5 mL/min flow rate. Mass spectra were recorded using ESI (+ve) mode. The injection samples were filtered using Millex-GV Syringe Filters (0.22 μm, EMD Millopore). 
     Chromatographic conditions were as follows: 
     Mobile Phase:
         A: Water/0.1% formic acid   B: Methanol/0.1% formic acid       

     Gradient:
         0 to 25 min: 30% A/70% B→100% B   25 to 28 min: 100% B   28 to 30 min: 100% B→30% A/70% B   30 to 35 min: 30% A/70% B       

     Injection volume: 10 μL 
     Flow rate: 1.5 mL/min 
     Total run time: 35 min 
     UPLC/MS. 
     The  cannabis  extracts and cannabinoid standards were analyzed using Waters® ACQUITY UPLC H-Class System equipped with Quaternary Solvent Manager, Sample Manager FTN, Acquity UPLC® BEH column (2.1×50 mm, C18, 1.7 μm). The sample injection plate and the column were maintained at 15° C. and 40° C., respectively. The detector used to monitor the samples was Waters® MS 3100 mass spectrometer. 
     Chromatographic conditions were as follows: 
     Mobile Phase:
         A: Water/0.1% formic acid   B: Methanol/0.1% formic acid       

     Gradient:
         0 to 4.5 min: 30% A/70% B→100% B   4.5 to 5.0 min: 100% B   5.0 to 5.2 min: 100% B→30% A/70% B   5.2 to 6.0 min: 30% A/70% B       

     Injection volume: 2 μL 
     Flow rate: 0.6 mL/min 
     Total run time: 6 min 
     Standard Curves for Cannabinoids: 
     Standard cannabinoids samples were purchased from Cerilliant-Certified Reference Standards in the form of 1.0 mg/mL solution in methanol.
         1. Δ 8 -Tetrahydrocannabinol (Δ 8 -THC, Cat #. T-032, Lot FE10011501)   2. Δ 9 -Tetrahydrocannabinol (Δ 9 -THC, Cat #. T-005, Lot FE05271502)   3. Δ 9 -Tetrahydrocannabinolic acid A (THCA-A, Cat #. T-093, Lot ER02101506)   4. Δ 2 -Cannabidoil (CBD, Cat #. C-045, Lot FE012881502)   5. Cannabidiolic acid (CBDA, Cat #. C-144. Lot FE0181602)   6. Cannabinol (CBN, Cat #. C-046, Lot FE06081502)       

     The chemical structures of cannabinoids 1-6 are provided in  FIG. 1 . 
     Working stock solution of each standard sample was prepared using water/0.1% formic acid and methanol/0.1% formic acid. The final concentration of each stock sample was 50 μg/mL in 30% water/0.1% formic acid and 70% methanol/0.1% formic acid. 
     The stock samples (50 μg/mL) were diluted with mobile phase (30% water/0.1% formic acid and 70% methanol/0.1% formic acid) to obtain the following concentrations: 0, 0.1, 0.5, 1.0, 2.5, 5.0, 7.5, and 10.0 μg/mL 
     Not all the concentrations were included in the construction of the standard curve. Some of the cannabinoids (e.g. 0.1 or 10.0 μg/mL) were excluded due to very low signal of saturation level. 
     Each concentration was run in triplicate. 2 μL injections were made and the signal was recorded for up to 6 minutes. SIR +ve (311, 315, and 359 m/z) or SIR −ve (313 and 357) and mass scan (150-500 m/z) in positive mode were monitored and recorded. SIR chromatograms were integrated and the AUC was plotted vs. concentration (μg/mL). 
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Cannabinoids standard curve - summary. 
               
            
           
           
               
               
               
            
               
                 Reference compound 
                 Retention time (min) 
                 Range (μg/mL) 
               
               
                   
               
               
                 Δ 2 -CBD 
                 1.70 
                  0.1-10.0 
               
               
                 CBD-A 
                 1.90 
                 0.01-1.0  
               
               
                 CBN 
                 2.33 
                 0.1-7.5 
               
               
                 Δ 9 -THC 
                 2.58 
                 0.1-7.5 
               
               
                 Δ 8 -THC 
                 2.70 
                  0.1-10.0 
               
               
                 THCA-A 
                 3.42 
                 0.01-1.0  
               
               
                   
               
            
           
         
       
     
     Standard curves for each of cannabinoids 1-6 as described above are provided in  FIGS. 4-9 . 
       FIG. 4  shows a Standard Curve for Δ 8 -THC. Linear fit: y=10948149x+2153365, R=0.9984 
       FIG. 5  shows a Standard Curve for Δ 9 -THC. Linear fit: y=11609869x+2187215, R=0.9980. 
       FIG. 6  shows a Standard Curve for THCA. Linear fit: y=14550967x+119886, R=0.9992 
       FIG. 7  shows a Standard Curve for CBD. Linear fit: y=9601901x+1448932, R=0.9978. 
       FIG. 8  shows a Standard Curve for CBDA. Linear fit: y=9096880x+111409, R=0.9993. 
       FIG. 9  shows a Standard Curve for CBN. Linear fit: y=2595328x−397594, R=0.9967. 
     Table 13 provides the concentration (μg/mL) of cannabinoids in extracts obtained using microwave extraction method at different temperatures. The solid material (plant fiber) leftover after the microwave reaction was exposed to SFE extraction (method 3A). The total volume of each microwave reaction was 3 mL. 
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 Concentration (μg/mL) of cannabinoids in extracts obtained using 
               
               
                 microwave extraction method at different temperatures 
               
            
           
           
               
               
               
               
               
               
            
               
                 Extraction conditions 
                 Δ 8 -THC 
                 Δ 9 -THC 
                 THCA 
                 CBD 
                 CBN 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Microwave, 100° C., 10 min; 
                 0 
                 554 
                 358 
                 500 
                 252 
               
               
                 No SFE done for this 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
               
               
                 sample 
               
               
                 Microwave, 130° C., 10 min 
                 0 
                 7046 
                 225 
                 7565 
                 443 
               
               
                 SFE 
                 0 
                 243 
                 0 
                 302 
                 32 
               
               
                 Microwave, 150° C., 10 min 
                 0 
                 7201 
                 0 
                 9408 
                 508 
               
               
                 SFE 
                 0 
                 86 
                 0 
                 135 
                 82 
               
               
                 Microwave, 170° C., 10 min 
                 0 
                 6502 
                 0 
                 8566 
                 495 
               
               
                 SFE 
                 0 
                 936 
                 0 
                 1321 
                 120 
               
               
                   
               
            
           
         
       
     
       FIG. 10  shows the amount of Δ 9 -THC and THC-A present in samples extracted using microwave method at different temperatures. The amount of each form of THC is shown as a percentage of total amount of THC (neutral and acidic form). 
     Table 14 shows the amount of cannabinoids in the  cannabis  extracts, after subjecting to Method 5. See also Table 11. Note: CBN appears to be formed during the microwave based decarboxylation of THCA. CBDA was not quantified. 
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 Amount of cannabinoids in the  cannabis  extracts, after subjecting 
               
               
                 to Method 5 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Δ 8 -THC 
                 Δ 9 -THC 
                 Δ 9 -THCA-A 
                 Δ 2 -CBD 
                 CBN 
               
               
                   
                 mg/g 
                 mg/g 
                 mg/g 
                 mg/g 
                 mg/g 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Sonication 
                 0 
                 0 
                 69.47 
                 4.93 
                 0 
               
               
                 (Method 1A) 
               
               
                 Soxhlet alone 
                 0 
                 44.32 
                 40.71 
                 25.4 
                 0 
               
               
                 (Method 2) 
               
               
                 SFE alone 
                 0 
                 1.91 
                 36.91 
                 3.68 
                 0 
               
               
                 (Method 3A) 
               
               
                 Sonication + μw 
                 0 
                 107.18 
                 0 
                 145.1 
                 9.53 
               
               
                 (Method 1A and 5) 
               
               
                 Soxhlet + μw 
                 0 
                 113.98 
                 0 
                 161.75 
                 10.08 
               
               
                 (Method 2 and 5) 
               
               
                 SFE + μw 
                 0 
                 96.48 
                 0 
                 122.66 
                 8.96 
               
               
                 (Method 3A and 5) 
               
               
                   
               
               
                 μW = microwave 
               
               
                 ND = not determined 
               
            
           
         
       
     
     A plot of the above data is shown in  FIGS. 11 and 12 , wherein  FIG. 11  illustrates concentrations in the extracts using EtOH, Soxhlet and SFE, without subjecting  cannabis  to microwave conditions and  FIG. 12  shows the concentrations of cannabinoids first extracting  cannabis  using EtOH or Soxhlet or SFE followed by microwave heating. 
     Table 15 shows the yield (mg/g of plant material) of cannabinoids in the extracts obtained using microwave extraction method at different temperatures. The solid material (plant fiber) left over after the microwave reaction was exposed to SFE extraction (method 3A). The total volume of each microwave reaction was 3 mL. CBDA was not quantified. 
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 Yield (mg/g of plant material) of cannabinoids in extracts obtained 
               
               
                 using microwave extraction method at different temperatures 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Δ 8 -THC 
                 Δ 9 -THC 
                 THCA 
                 CBD 
                 CBN 
               
               
                 Conditions 
                 mg/g 
                 mg/g 
                 mg/g 
                 mg/g 
                 mg/g 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Microwave 100° C., 10 min 
                 0 
                 45 
                 29 
                 41 
                 3 
               
               
                 No SFE 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
               
               
                 Microwave, 130° C., 10 min 
                 0 
                 83 
                 3 
                 89 
                 5 
               
               
                 Follow-up SFE 
                 0 
                 3 
                 0 
                 4 
                 0 
               
               
                 Microwave, 150° C., 10 min 
                 0 
                 85 
                 0 
                 111 
                 6 
               
               
                 Follow-up SFE 
                 0 
                 1 
                 0 
                 2 
                 1 
               
               
                 Microwave, 170° C., 10 min 
                 0 
                 76 
                 0 
                 101 
                 6 
               
               
                 Follow-up SFE 
                 0 
                 11 
                 0 
                 16 
                 1 
               
               
                   
               
            
           
         
       
     
       FIG. 13  shows cannabinoids obtained from  cannabis  after microwave heating only. 
       FIG. 14  shows microwave followed by SFE extraction. The cannabinoids from microwave solvent and SFE extractions added together. 
       FIG. 15  shows various cannabinoid concentrations from  cannabis  after microwave heating followed by SFE extraction. In  FIG. 15 , the cannabinoids from both extractions have been added together. The acidic and neutral form of THC were added together to represent the total THC extracted by each method. 
       FIG. 16  shows a chromatogram of mass scan (150-500 m/z) recorded in positive mode of ESI using Waters MS3100 mass detector. The sample was obtained from microwave extraction at 170° C., 15 min. The arrows point to the retention times of CBD, CBDA, Δ 9 -THC, and THCA. Due to the low sample concentration the peaks are not visible in this chromatogram. Single ion recording (SIR +ve) obtained for this sample shows the individual peaks representing CBD and Δ 9 -THC ( FIG. 17 ), CBDA and THCA ( FIG. 18 ). If an analyte is absent or not detected in this mode, the expected retention time is shown. 
       FIG. 17  shows a Single Ion Recording (SIR +ve, m/z=315) to detect Cannabidiol (CBD) and Δ 9 -Tetrahydrocannabinol (Δ 9 -THC) in a sample obtained from microwave extraction at 170° C., 15 min (mass scan shown in  FIG. 16 ). 
       FIG. 18  shows a Single Ion Recording (SIR +ve, m/z=359) to detect Cannabidiolic acid (CBDA) and Tetrahydrocannabinolic acid (THCA) in a sample obtained from microwave extraction at 170° C., 15 min (mass scan shown in  FIG. 16 ). Positive mode (ESI +ve) is not a favorable one for the detection of the acidic forms of cannabinoids. 
       FIG. 19  shows a chromatogram of mass scan (150-500 m/z) recorded in negative mode of ESI using Waters® MS3100 mass detector. The sample was obtained from microwave extraction at 170° C., 15 min. The arrows point to the retention times of CBD, CBDA, Δ 9 -THC, and THCA. Due to the low sample concentration the peaks are not visible in this chromatogram. Single ion recording (SIR −ve) obtained for this sample shows the individual peaks representing CBD and Δ 9 -THC ( FIG. 20 ), CBDA and THCA ( FIG. 21 ). If an analyte is absent or not detected in this mode, the expected retention time is shown. 
       FIG. 20  shows a Single Ion Recording (SIR −ve, m/z=313) to detect Cannabidiol (CBD) and Δ 9 -Tetrahydrocannabinol (Δ 9 -THC) in a sample obtained from microwave extraction at 170° C., 15 min (mass scan shown in  FIG. 19 ). The neutral forms of cannabinoids are not easily detectable in the negative mode therefore no peaks observed as compared to the positive mode (see  FIG. 17 ). 
       FIG. 21  shows a Single Ion Recording (SIR −ve, m/z=357) to detect Cannabidiolic acid (CBDA) and Tetrahydrocannabinolic acid (THCA) in a sample obtained from microwave extraction at 170° C., 15 min (mass scan shown in  FIG. 19 ). ESI −ve mode is useful for the detection of the acidic forms of cannabinoids. 
       FIG. 22  shows a chromatogram of mass scan (150-500 m/z) recorded in positive mode of ESI using Waters® MS3100 mass detector. The sample was obtained from microwave extraction at 130° C., 10 min. Retention times of CBD, CBDA, Δ 9 -THC, and THCA are shown. Single ion recording (SIR +ve) obtained for this sample shows the individual peaks representing CBD and Δ 9 -THC ( FIG. 23 ) and CBDA and THCA ( FIG. 24 ). If an analyte is absent or not detected in this mode, the expected retention time is shown. 
       FIG. 23  shows a Single Ion Recording (SIR +ve, m/z=315) to detect Cannabidiol (CBD) and Δ 9 -Tetrahydrocannabinol (Δ 9 -THC) in a sample obtained from microwave extraction at 130° C., 10 min (mass scan shown in  FIG. 22 ). 
       FIG. 24  shows a single Ion Recording (SIR +ve, m/z=359) to detect Cannabidiolic acid (CBDA) and Tetrahydrocannabinolic acid (THCA) in a sample obtained from microwave extraction at 130° C., 10 min (mass scan shown in  FIG. 22 ). Due to relatively high concentration of the analyzed sample the acidic forms of the CBD and THC are detected by the negative mode. 
       FIG. 25  shows a chromatogram of mass scan (150-500 m/z) recorded in negative mode of ESI using Waters® MS3100 mass detector. The sample was obtained from microwave extraction at 130° C., 10 min. Retention times of CBD, CBDA, Δ 9 -THC, and THCA are shown. Single ion recording (SIR −ve) obtained for this sample shows the individual peaks representing CBD and Δ 9 -THC ( FIG. 26 ) and CBDA and THCA ( FIG. 27 ). If an analyte is absent or not detected in this mode, the expected retention time is shown. 
       FIG. 26  shows a Single Ion Recording (SIR −ve, m/z=313) to detect Cannabidiol (CBD) and Δ 9 -Tetrahydrocannabinol (Δ 9 -THC) in a sample obtained from microwave extraction at 130° C., 10 min (mass scan shown in  FIG. 25 ). Neutral cannabinoids (CBD and Δ 9 -THC are not visible in the negative mode detection as compared to the positive mode ( FIG. 23 ). 
       FIG. 27  shows a Single Ion Recording (SIR −ve, m/z=357) to detect Cannabidiolic acid (CBDA) and Tetrahydrocannabinolic acid (THCA) in a sample obtained from microwave extraction at 130° C., 10 min (mass scan shown in  FIG. 25 ). Some CBDA and THCA still present showing partial decarboxylation. 
     Summary of Results for Experiment 2 
       FIGS. 4-9  provide standard chromatography curves for Δ 8 -THC, Δ 9 -THC, THC-A, CBD, CBDA and CBN, respectively. These standard curves were generated for concentrations between 0 and 10 μg/mL and subsequently used for determining the concentration of each compound in various products formed using the embodiments described herein. 
     Table 5 shows the use of various solvents during ultrasonic extraction. There were also minimal amounts of  cannabis  plant material lost during the recovery filtration process (see Table 6). This also appears to be similar recovery across different extraction methods—solvent, Soxhlet, SFE extraction (See Tables 7 and 8). 
     When conducting cannabinoid extraction/decarboxylation in ethanol using a microwave, due to the boiling point of ethanol, it was shown that extraction/decarboxylation of cannabinoids using a microwave is best conducted at temperatures below 180° C., for example at 160° C.±10° C. (e.g. +/−the acceptable standard of error). It was also shown under the conditions used that conversion of THCA to THC (the desired decarboxylated product) was better at 130° C. than at 100° C., and that if conducted using microwave alone versus microwave and SFE, temperatures above 130° C., for example from 150° C. to 170° C. showed more efficient conversion. (See Tables 13 and 15 as well as  FIG. 10 ). However, there appears to be significant loss of material if followed by SFE (see Tables 9 and 10, and 15). As such, the least number of steps and processes to obtain the desired results is the one-step extraction/decarboxylation method. 
       FIGS. 11 and 12  and Table 14 show that extraction resulted in minimal or no decarboxylated THC product, while the addition of the microwave step resulted in a significant increase in decarboxylated THC. 
       FIG. 13  shows concentrations of Δ 9 -THC, THC-A, CBD and CBN from  cannabis  after microwave radiation only at temperatures ranging between 100° C. and 170° C.  FIG. 13  shows that microwave radiation at temperatures between 130° C. and 170° C. were optimal when ethanol was used as the solvent. 
       FIG. 14  shows concentrations of Δ 9 -THC, THC-A, CBD and CBN from the  cannabis  plant material after microwave radiation and subsequent SFE extraction at temperatures ranging between 100° C. and 170° C. Use of SFE extraction does not appear to significantly increase yield of decarboxylated cannabinoids. 
       FIG. 15  shows concentrations of total THC, CBD and CBN from the  cannabis  after microwave radiation and subsequent SFE extraction at a temperatures ranging between 100° C. and 170° C., where the acidic and neutral form of THC are added together to represent the total THC extracted by each method. Again, use of SFE extraction does not appear to significantly increase yield of decarboxylated cannabinoids. 
     From the above results, it appears that the significant decarboxylated product THC results from microwave extraction and that the addition of a second extraction step, such as SFE, does not appear to change the cannabinoid profile. It further shows that CBD as well as THC components are present in extract after microwave extraction alone or with microwave and SFE extractions combined. 
     In summary, the present disclosure shows that extraction and decarboxylation of  cannabis  plant material can be done concurrently using a microwave, set at a temperature below the boiling point of the extraction solvent, such as ethanol, without the need for a separate extraction step. This optimizes decarboxylated cannabinoid formation and recovery and can produce a more consistent and reproducible product with consistent and reproducible efficacy and therapeutic results. 
     An extraction step can also be included before use of a microwave. Although an extraction step after the microwave step is possible, it is not necessary. 
     Experiment 3: Supercritical Fluid Extraction (SFE) 
     General Procedure:
         1. Dried plant material was weighed and macerated using a mortar and pestle   2. Crushed plant material was transferred to a 10 mL extraction vessel and subjected to either of the following conditions below   3. Fractions from each run were collected every 5 mins and combined and concentrated to dryness (at 25° C.) then weighed (green resin)   4. Extraction was done three times with same plant fibre SFE conditions:       

     
       
         
           
               
               
             
               
                   
               
             
            
               
                 Solvent A = CO 2   
                 Solvent B = ethanol 
               
            
           
           
               
               
               
            
               
                 Temperature = 25° C. 
                 BPR = 12 MPa 
                 PDA = 200-600 nm 
               
               
                   
                   
                 (monitoring at 254 nm) 
               
            
           
           
               
            
               
                 Flow rate = 10 mL/min; make up pump = 1 mL/min 
               
            
           
           
               
               
            
               
                 Acquisition time = 30 mins 
                 Method time = 30.2 mins 
               
               
                   
               
            
           
         
       
         
         
           
             
               
                 i. 0.1 min-25 mins; gradient of 0-50% B in A
               26 mins; 100% A   30 mins; 100% A   
             
               
             
           
         
       
    
     Table 16 below shows the corresponding results. 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 Weights of extract after SFE. 
               
            
           
           
               
               
               
               
            
               
                   
                 Strain 
                 Run 
                 Extract isolated (g) 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Strain 1 = 1.0023 g 
                 1 
                 0.2634 
               
               
                   
                 (THC: 7.18/CBD: 8.6) 
                 2 
                 0.0038 
               
               
                   
                   
                 3 
                 0.010 
               
               
                   
                   
               
            
           
         
       
     
     Experiment 4: Microwave-Assisted Decarboxylation of Extract with Ethanol (MAE) 
     General Procedure:
         1. Extract isolated from the SFE method described above was dissolved in 5-10 mL ethanol and an appropriate volume transferred to 5 mL microwave vials   2. Added additional volume of ethanol and a stir bar to the 5 mL microwave vials   3. The vials were sealed and subjected to one of two microwave conditions below:
           (a) Temperature=150° C.; run time=10 mins; stir rate=600 rpm; absorption=Normal   (b) Temperature=100° C.; run time=30 mins; stir rate=600 rpm; absorption=Normal   
           4. The solution was then concentrated at 35° C. after transferring to 20 mL vials       

     The results are shown in Table 17 below. 
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 Weights of the resins after subjecting to microwave heating. 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Amount of resin 
                 Extract isolated 
               
               
                 Strain 
                 Method 
                 used (g) 
                 after microwave (g) 
               
               
                   
               
               
                 Strain 1 
                 (a) 
                 0.0832 
                 0.0212 
               
               
                 (THC: 7.18/CBD: 8.6) 
                 (b) 
                 0.0832 
                 0.0612 
               
               
                   
                 (a) 
                 0.2095 
                 0.1589 
               
               
                 Strain 2 
                 (a) 
                 0.1693 
                 0.1114 
               
               
                 (THC: 0/CBD: 9) 
               
               
                 Strain 3 
                 (a) 
                 0.2722 
                 0.1759 
               
               
                 (THC: 18.6/CBD: 0) 
               
               
                   
               
            
           
         
       
     
     Experiment 5: Additional Microwave-Assisted Extractions with Ethanol (MAE), Optimization of Conditions for Decarboxylation 
     General Procedure:
         1. Dried plant material was weighed and macerated using a laboratory blender at 22,000 rpm for 60 secs   2. Crushed plant material was re-weighed and transferred to a 20 mL microwave vial along with a stir bar   3. Ethanol (10 mL) was added to the vial which was then sealed and subjected to the microwave conditions below:
           (a) Temperature=170° C.; run time=15 mins; pre-stirring=30 sec; stir rate=900 rpm; absorption=Normal   (b) Temperature=150° C.; run time=20 mins; pre-stirring=30 sec; stir rate=900 rpm; absorption=Normal   
           4. The suspension was filtered and the filtrate and plant fibre collected separately   5. Filtrate was then concentrated at 35° C., then transferred to a 20 mL vial using ethanol and again concentrated at 35° C., then stored in the refrigerator       

     The results are shown in Table 18 below. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 18 
               
               
                   
               
               
                   
                   
                   
                   
                 Extract 
               
               
                   
                   
                 Amount of 
                 Amount of 
                 isolated 
               
               
                   
                   
                 plant before 
                 plant after 
                 after 
               
               
                   
                   
                 maceration 
                 maceration 
                 microwave 
               
               
                 Strain 
                 Method 
                 (g) 
                 (g) 
                 (g) 
               
               
                   
               
             
            
               
                 Strain 1 
                 (a) 
                 1.0062 
                 0.8256 
                 0.2265 
               
               
                 (THC: 7.18/CBD: 
               
               
                 8.6) 
               
               
                 Strain 2 
                 (a) 
                 1.0042 
                 0.8382 
                 — a   
               
               
                 (THC: 0/CBD: 9) 
                 (b) 
                 1.0050 
                 0.8293 
                 0.2155 
               
               
                 Strain 3 
                 (b) 
                 1.0063 
                 0.7883 
                 0.1166 
               
               
                 (THC: 18.6/CBD: 0) 
               
               
                   
               
               
                   a Desired temperature could not be achieved due to pressure build-up; cap of vial popped off causing solvent and plant fibre to escape from vial. 
               
            
           
         
       
     
     Since condition (b) in step 3 above proved successful at that scale, subsequent decarboxylations were performed using that microwave condition and were done in triplicate. However, the following modifications were made:
         Step 1: Blend at 18,000 rpm for 4 secs   Step 4: Filtration done over celite/activated carbon (as previously described in an earlier report)   Step 5: Filtrate was then concentrated at 35° C., weighed, transferred to a 20 mL vial using ethanol, then stored in the refrigerator       

     The results are shown in Table 19 below. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 19 
               
               
                   
               
               
                   
                   
                   
                 Amount of 
                   
                 Average 
               
               
                   
                   
                 Amount of 
                 plant after 
                   
                 Extract 
               
               
                   
                   
                 plant before 
                 maceration 
                 Extract 
                 isolated (g) ± 
               
               
                 Strain 
                 Runs 
                 maceration (g) 
                 (g) 
                 isolated (g) 
                 SD 
               
               
                   
               
             
            
               
                 Strain 1 
                 1 
                 1.0079 
                 0.9260 
                 0.2044 
                 0.2105 ± 0.007 
               
               
                 (THC: 
                 2 
                 1.0084 
                 0.9594 
                 0.2184 
               
               
                 7.18/CBD: 
                 3 
                 1.0080 
                 0.9254 
                 0.2088 
               
               
                 8.6) 
               
               
                 Strain 2 
                 1 
                 1.0032 
                 0.8287 
                 0.1624 
                 0.1654 ± 0.006 
               
               
                 (THC: 
                 2 
                 1.0038 
                 0.8467 
                 0.1721 
               
               
                 0/CBD: 9) 
                 3 
                 1.0040 
                 0.8585 
                 0.1617 
               
               
                 Strain 3 
                 1 
                 1.0017 
                 0.9169 
                 0.2225 
                 0.2212 ± 0.014 
               
               
                 (THC: 
                 2 
                 1.0054 
                 0.8952 
                 0.2068 
               
               
                 18.6/CBD: 0) 
                 3 
                 1.0033 
                 0.9021 
                 0.2343 
               
               
                   
               
            
           
         
       
     
     This experiments shows the consistency of the extraction method. 
     Experiment 6 : Cannabis  Extractions (1 Gram Scale) 
     General Procedure (˜1.0 g Batch; Before Maceration):
         1. Dried plant material was weighed and macerated using a laboratory blender at 18,000 rpm for 4 secs   2. Crushed plant material was re-weighed (˜0.875 g) and transferred to a 20 mL microwave vial along with a stir bar   3. Ethanol (10 mL) was added to the vial which was then sealed and subjected to the microwave conditions below:
           Temperature=150° C.; run time=20 mins; pre-stirring=30 sec; stir rate=900 rpm; absorption=Normal   
           4. The suspension was filtered over celite/activated carbon and the filtrate and plant fibre collected separately   5. Filtrate was then concentrated at 35° C., then transferred to a 20 mL vial using ethanol and again concentrated at 35° C., then stored in the refrigerator   6. Decarboxylations were performed in triplicate       

     Winterization Procedure:
         1. Resin was dissolved in ethanol (10 mL/g) and heated at 40° C. for 5 mins in a water bath   2. Vial containing extract solution was cooled to −75° C. using a dry ice/acetone bath for 3-4 hrs   3. Solution was filtered with a pre-weighed syringe filter in 20 mL vials Filter specifications: Millex®-GV (sterile), Low Protein Binding Durapore® (PVDF) Membrane; 0.22 μm pore size; 33 mm diameter   4. Filter was washed with ethanol that had been cooled for 5 mins at −75° C. using a dry ice/acetone bath   5. Filtrate was concentrated at 35° C. and extract was weighed   6. Syringe filter was weighed after 2-3 days drying in the fumehood       

     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 The quantities of  cannabis  plants used and the amounts of extract 
               
               
                 obtained before and after winterization. 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Extract isolated 
                 Extract 
               
               
                   
                   
                 Plant before 
                 Plant after 
                 before 
                 isolated after 
               
               
                   
                   
                 maceration 
                 maceration 
                 winterization 
                 winterization 
               
               
                 Strain 
                 Runs 
                 (g) 
                 (g) 
                 (g) 
                 (g) 
               
               
                   
               
               
                 Strain 1 
                 1 
                 1.008 ± 0.0003 
                 0.9369 ± 0.019 
                 0.2105 ± 0.007 
                 0.1962 ± 0.007 
               
               
                 (THC: 7.18/CBD: 
                 2 
               
               
                 8.6) 
                 3 
               
               
                 Strain 2 
                 1 
                 1.004 ± 0.0004 
                 0.8446 ± 0.015 
                 0.1654 ± 0.006 
                 0.1541 ± 0.004 
               
               
                 (THC: 0/CBD: 9) 
                 2 
               
               
                   
                 3 
               
               
                 Strain 3 
                 1 
                 1.003 ± 0.0019 
                 0.9047 ± 0.011 
                 0.2212 ± 0.014 
                 0.2095 ± 0.009 
               
               
                 (THC: 18.6/CBD: 
                 2 
               
               
                 0) 
                 3 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 21 
               
             
            
               
                   
               
               
                 The quantities of cannabinoids (as % of resin and mg/g of plant) in 
               
               
                 the extracts isolated, before and after winterization. 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Cannabinoid in resin before 
                 Cannabinoid in resin after 
               
               
                   
                   
                 winterization 
                 winterization 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Δ 9 - 
                 Δ 9 - 
                   
                   
                 Δ 9 - 
                 Δ 9 - 
               
               
                   
                   
                 CBD 
                 CBD 
                 THC 
                 THC 
                 CBD 
                 CBD 
                 THC 
                 THC 
               
               
                 Strains 
                 Runs 
                 (%) 
                 (mg/g) 
                 (%) 
                 (mg/g) 
                 (%) 
                 (mg/g) 
                 (%) 
                 (mg/g) 
               
               
                   
               
               
                 Strain 1 
                 1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 (THC: 7.18/ 
                 2 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 CBD: 8.6) 
                 3 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Strain 2 b   
                 1 
                 n.d. 
                 n.d. 
                   
                   
                 37.6 ± 
                 67.1 ± 
                 1.9 ± 
                 3.5 ± 
               
               
                 (THC: 0/ 
                 2 a   
                   
                   
                   
                   
                 4.1 
                 7.1 
                 0.1 
                 0.2 
               
               
                 CBD: 9) 
                 3 a   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 strain 3 b   
                 1 
                   
                   
                 n.d. 
                 n.d. 
                   
                   
                 49.8 ± 
                 119.0 ± 
               
               
                 (THC: 18.6/ 
                 2 a   
                   
                   
                   
                   
                   
                   
                 0.8 
                 1.4 
               
               
                 CBD: 0) 
                 3 a   
               
               
                   
               
               
                 n.d. = not determined, samples were used up before re-analysis with internal standard was performed 
               
               
                   a Average calculations based on runs 2 and 3 only. 
               
            
           
         
       
     
     Summary of Results: 
     Extracting and decarboxylating 1 gram scale batch of  cannabis  was successful. 
     Experiment 7: Larger Scale MAE (˜3.75 g Batch; Before Maceration) Using the Modified Conditions 
     
         
         
           
             1. Dried plant material was weighed (˜3.75 g per batch) and macerated using a laboratory blender at 18,000 rpm for 4 secs. 
             2. Crushed plant material was re-weighed and transferred to 3×20 mL microwave vials along with stir bars (˜1.2 g of plant fibre per vial) 
             3. 95%-100% Ethanol (12 mL) was added to the vial which was then sealed and subjected to the microwave conditions below:
           Temperature=150° C.; run time=30 mins; pre-stirring=30 sec; stir rate=900 rpm; absorption=Normal   
         
             4. Note: Time for decarboxylation was increased to 30 mins since analysis revealed that decarboxylation was incomplete at that scale 
             5. The 3×20 mL vials were combined after decarboxylation and the suspension was filtered and the filtrate and plant fibre collected separately 
             6. Filtrate was then concentrated at 35° C., then transferred to a 20 mL vial using ethanol and again concentrated at 35° C., weighed and stored in the refrigerator 
             7. Decarboxylations were performed in duplicate 
           
         
       
    
     The results are shown in Table 22 below. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 22 
               
               
                   
               
               
                   
                   
                 Amount of 
                   
                   
                   
               
               
                   
                   
                 plant 
                 Amount of 
                   
                   
               
               
                   
                   
                 before 
                 plant after 
                 Extract 
                 Average 
               
               
                   
                   
                 maceration 
                 maceration 
                 isolated 
                 Extract isolated 
               
               
                 Strain 
                 Runs 
                 (g) 
                 (g) 
                 (g) 
                 (g) ± SD 
               
               
                   
               
             
            
               
                 Strain 1 
                 1 
                 3.7922 
                 3.6268 
                 0.9967 
                 0.9437 ± 0.075  
               
               
                 (THC: 
                 2 
                 3.7228 
                 3.5800 
                 0.8906 
               
               
                 7.18/ 
               
               
                 CBD: 
               
               
                 8.6) 
               
               
                 Strain 2 
                 1 
                 — b   
                 1.2427 
                 — c   
                 — c   
               
               
                 (THC: 
               
               
                 0/ 
               
               
                 CBD: 
               
               
                 9) 
               
               
                 Strain 3 
                 1 
                 3.7100 
                 3.5978 
                 1.0658 
                 1.1572 ± 0.1293 
               
               
                 (THC: 
                 2 
                 3.8012 
                 3.6035 
                 1.2486 
               
               
                 18.6/ 
               
               
                 CBD: 
               
               
                 0) 
               
               
                   
               
               
                   b Plant fibre is supplied as pulverized buds. Size was appropriate, therefore no further maceration was done. 
               
               
                   c Desired temperature of 150° C. could not be achieved due to pressure build-up. 
               
            
           
         
       
     
     Summary of Results: 
     From the results above, it can be concluded that larger scale microwave assisted extraction was successful, at 3-4 grams scale. This method can be scaled up into multi-gram and larger scales with appropriate adjustments to conditions. 
     Experiment 8: Large Scale Microwave-Assisted Extractions with Ethanol (MAE) 
     (A) General Procedure (˜3.75 g Batch; Before Maceration):
         1. Dried plant material was weighed and macerated using a laboratory blender at 18,000 rpm for 4 secs   2. Crushed plant material was re-weighed and transferred to 3×20 mL microwave vials along with stir bars (˜1.2 g of plant fibre per vial)   3. 95%-100% Ethanol (12 mL) was added to the vial which was then sealed and subjected to the microwave conditions below:
           Temperature=150° C.; run time=30 mins; pre-stirring=30 sec; stir rate=900 rpm; absorption=Normal   
           4. Note: Time for decarboxylation was increased to 30 mins since analysis revealed that decarboxylation was incomplete at that scale   5. All 20 mL vials were combined after decarboxylation and the suspension was filtered and the filtrate and plant fibre collected separately (first batch)   6. Filtrate was then concentrated at 35° C., then transferred to a 20 mL vial using ethanol and again concentrated at 35° C., weighed and stored in the refrigerator   7. Decarboxylations were performed in duplicate       

     Winterization Procedure:
         1. Same as previously described       

     
       
         
           
               
             
               
                 TABLE 23 
               
             
            
               
                   
               
               
                 The quantities of cannabis plants used and the amounts of extract 
               
               
                 obtained before and after winterization. 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 Plant 
                   
                   
                 Extract isolated 
               
               
                   
                   
                 before 
                 Plant after 
                 Extract isolated 
                 after 
               
               
                   
                   
                 maceration 
                 maceration 
                 before 
                 winterization 
               
               
                 Strain 
                 Runs 
                 (g) 
                 (g) 
                 winterization (g) 
                 (g) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Strain 1 
                 1 a   
                 3.7575 ± 
                 3.6034 ± 
                 0.9967 
                 0.9437 ± 
                 0.7794 
               
               
                 (THC: 7.18/ 
                 2 
                 0.049 
                 0.033 
                 0.8906 
                 0.075 
                   
               
               
                 CBD: 8.6) 
                   
                   
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Strain 2 
                 1 
                 1.2427 
                 b 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
               
               
                 (THC: 0/ 
                   
                   
                   
                   
                   
                   
                   
               
               
                 CBD: 9) 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Strain 3 
                 1 
                 3.7556 ± 
                 3.6007 ± 
                 1.0618 
                 1.1543 ± 
                 0.7984 
                 0.8973 ± 
               
               
                 (THC: 18.6/ 
                 2 
                 0.064 
                 0.004 
                 1.2468 
                 0.131 
                 0.9961 
                 0.140 
               
               
                 CBD: 0) 
               
               
                   
               
               
                 n.d. = not determined. Desired temperature of 150° C. could not be achieved due to pressure build-up; nothing further was done with buds. 
               
               
                   a No winterization was performed on run 1; winterization done on run 2 only. 
               
               
                 b Plant fibre is supplied as pulverized buds. Size was appropriate, therefore no further maceration was done. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 24 
               
             
            
               
                   
               
               
                 The quantities of cannabinoids (as % of resin and mg/g of plant) in 
               
               
                 the extracts isolated, before and after winterization. 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Cannabinoid in resin before 
                 Cannabinoid in resin after 
               
               
                   
                   
                 winterization 
                 winterization 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Δ 9 - 
                 Δ 9 - 
                   
                   
                 Δ 9 - 
                 Δ 9 - 
               
               
                   
                   
                 CBD 
                 CBD 
                 THC 
                 THC 
                 CBD 
                 CBD 
                 THC 
                 THC 
               
               
                 Strains 
                 Runs 
                 (%) 
                 (mg/g) 
                 (%) 
                 (mg/g) 
                 (%) 
                 (mg/g) 
                 (%) 
                 (mg/g) 
               
               
                   
               
               
                 Strain 1 
                 1 
                 n.d. 
                 n.d. 
                 n.d. 
                 n.d. 
                 39.0 ± 
                 84.9 ± 
                 30.3 ± 
                 66.1 ± 
               
               
                 (THC: 7.18/ 
                 2 a   
                   
                   
                   
                   
                 2.2 
                 4.7 
                 1.4 
                 3.0 
               
               
                 CBD: 8.6) 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Strain 3 
                 1 
                   
                   
                 68.6 ± 
                 219.0 ± 
                   
                   
                 61.1 ± 
                 153.2 ± 
               
               
                 (THC: 18.6/ 
                 2 
                   
                   
                 8.4 
                 2.7 
                   
                   
                 4.6 
                 35.0 
               
               
                 CBD: 0) 
               
               
                   
               
               
                 n.d. = not determined; samples were used before re-analysis with internal standard was performed. 
               
               
                   a Calculations based on run 2 only. 
               
            
           
         
       
     
     (B) General Procedure (˜7.5 g Batch; Before Maceration):
         1. Dried plant material was weighed and macerated using a laboratory blender at 18,000 rpm for 10 secs   2. Crushed plant material was re-weighed and transferred to 6×20 mL microwave vials along with stir bars (˜1.2 g of plant fibre per vial)   3. See steps 3-6 in (A) above       

     Winterization Procedure:
         1. Same as previously described       

     
       
         
           
               
             
               
                 TABLE 25 
               
             
            
               
                   
               
               
                 The quantities of Variety 1 (THC: 7.18/CBD: 8.6) used and the 
               
               
                 amounts of extract obtained before and after winterization. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Extract isolated 
                 Extract 
               
               
                   
                 Amount of 
                 Amount of 
                 before 
                 isolated after 
               
               
                   
                 plant before 
                 plant after 
                 winterization 
                 winterization 
               
               
                 Runs 
                 maceration (g) 
                 maceration (g) 
                 (g) 
                 (g) 
               
               
                   
               
               
                 1 
                 7.5361 
                 3.6156 ± 0.002 
                 1.0154 ± 0.064 
                 0.8115 ± 0.030 
               
               
                 2 
               
               
                 3 
                 7.5063 
                 3.6640 ± 0.026 
                 0.9327 ± 0.014 
                 0.8247 ± 0.022 
               
               
                 4 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 26 
               
             
            
               
                   
               
               
                 The quantities of cannabinoids (as % of resin and mg/g of plant) in 
               
               
                 the Variety 1 extract isolated, before and after winterization. 
               
            
           
           
               
               
               
            
               
                   
                 Cannabinoid in resin before 
                 Cannabinoid in resin after 
               
               
                   
                 winterization 
                 winterization 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Δ 9 - 
                 Δ 9 - 
                   
                   
                 Δ 9 - 
                 Δ 9 - 
               
               
                   
                 CBD 
                 CBD 
                 THC 
                 THC 
                 CBD 
                 CBD 
                 THC 
                 THC 
               
               
                 Runs 
                 (%) 
                 (mg/g) 
                 (%) 
                 (mg/g) 
                 (%) 
                 (mg/g) 
                 (%) 
                 (mg/g) 
               
               
                   
               
               
                 1 
                 40.6 ± 
                 113.7 ± 
                 31.1 ± 
                 87.3 ± 
                 31.6 ± 
                 70.8 ± 
                 23.1 ± 
                 51.6 ± 
               
               
                 2 
                 3.9 
                 3.7 
                 2.0 
                 0.1 
                 5.5 
                 9.7 
                 4.1 
                 7.3 
               
               
                 3 
                 29.2 ± 
                 74.3 ± 
                 20.9 ± 
                 53.3 ± 
                 44.0 ± 
                 99.0 ± 
                 31.3 ± 
                 70.3 ± 
               
               
                 4 
                 0.1 
                 0.9 
                 1.0 
                 3.0 
                 2.9 
                 4.7 
                 0.7 
                 0.2 
               
               
                   
               
            
           
         
       
     
     (A) General Procedure (˜4.0 and 7.0 g Batches; Before Maceration):
         1. Dried plant material was weighed and macerated using a laboratory blender at 18,000 rpm for 10 secs   2. Crushed plant material was re-weighed and transferred to 20 mL microwave vials along with stir bars (˜1.2 g of plant fibre per vial)   3. For ˜4.0 g batch, see steps 3-5 in (A) above   4. For ˜7.0 g batch, see steps 3-5 in (A) above       

     Winterization Procedure:
         1. Same as previously described       

     
       
         
           
               
             
               
                 TABLE 27 
               
             
            
               
                   
               
               
                 The quantity of Variety 1 plant (THC: 7.18/CBD: 8.6) used and the 
               
               
                 amount of extract obtained before and after winterization. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Amount 
                   
                 Extract isolated 
                 Extract isolated 
               
               
                   
                 of plant 
                 Amount of 
                 before 
                 after 
               
               
                   
                 before 
                 plant after 
                 winterization 
                 winterization 
               
               
                 Runs 
                 maceration (g) 
                 maceration (g) 
                 (g) 
                 (g) 
               
               
                   
               
               
                 1 
                 4.0325 
                 3.8199 
                 0.8889 
                 0.7358 
               
               
                 2 
                 7.1293 
                 6.8717 
                 1.5244 
                 1.4101 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 28 
               
             
            
               
                   
               
               
                 The quantities of cannabinoids (as % of resin and mg/g of plant) in 
               
               
                 the Variety 1 extract isolated, before and after winterization. 
               
            
           
           
               
               
               
            
               
                   
                 Cannabinoid in resin before 
                 Cannabinoid in resin after 
               
               
                   
                 winterization 
                 winterization 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Δ 9 - 
                 Δ 9 - 
                   
                   
                 Δ 9 - 
                 Δ 9 - 
               
               
                   
                 CBD 
                 CBD 
                 THC 
                 THC 
                 CBD 
                 CBD 
                 THC 
                 THC 
               
               
                 Runs 
                 (%) 
                 (mg/g) 
                 (%) 
                 (mg/g) 
                 (%) 
                 (mg/g) 
                 (%) 
                 (mg/g) 
               
               
                   
               
               
                 1 
                 30.2 ± 
                 70.3 ± 
                 27.1 ± 
                 63.0 ± 
                 38.4 ± 
                 73.9 ± 
                 32.1 ± 
                 61.8 ± 
               
               
                   
                 0.0 
                 0.1 
                 0.4 
                 0.0 
                 6.1 
                 11.8 
                 7.5 
                 14.4 
               
               
                 2 
                 33.6 ± 
                 74.5 ± 
                 28.9 ± 
                 64.2 ± 
                 42.5 ± 
                 87.2 ± 
                 37.0 ± 
                 75.9 ± 
               
               
                   
                 2.9 
                 6.5 
                 3.2 
                 7.1 
                 0.5 
                 1.1 
                 2.9 
                 5.9 
               
               
                   
               
            
           
         
       
     
     Summary of Results: 
     Extracting and decarboxylating 3.75 gram scale batch of  cannabis  was successful. 
     Experiment 9: Larger Scale Microwave-Assisted Extractions with Ethanol (MAE) and Winterization 
     
         
         
           
             1. Dried plant material was weighed (˜7.5 g per batch) and macerated using a laboratory blender at 18,000 rpm for 10 secs 
             2. Crushed plant material was re-weighed and transferred to 6×20 mL microwave vials along with stir bars (˜1.2 g of plant fibre per vial) 
             3. 95%-100% Ethanol (12 mL) was added to the vial which was then sealed and subjected to the microwave conditions below:
           Temperature=150° C.; run time=30 mins; pre-stirring=30 sec; stir rate=900 rpm; absorption=Normal   
         
             4. The 3×20 mL vials were combined after decarboxylation and the suspension was filtered and the filtrate and plant fibre collected separately 
             5. Filtrate was then concentrated at 35° C., then transferred to a 20 mL vial using ethanol and again concentrated at 35° C., weighed and stored in the refrigerator 
             6. Resin was dissolved in ethanol (10 mL/g) 
             7. Vials containing extract solution were cooled to −75° C. using a dry ice/acetone bath for 4 hrs 
             8. Solution was filtered with a pre-weighed syringe filter in 20 mL vials 
             9. Filter specifications: Millex®-GV (sterile), Low Protein Binding Durapore® (PVDF) Membrane, 0.22 μm pore size, 33 mm diameter 
             10. Filter was washed with ethanol that had been cooled for 5 mins at −75° C. using a dry ice/acetone bath 
             11. Filtrate was concentrated at 35° C. and vacuum dried for 2 days at 40° C. (via water bath), then extract was weighed 
             12. Syringe filter was weighed after 2-3 days drying in the fumehood 
           
         
       
    
     The results are shown in Table 29 below. 
     
       
         
           
               
               
               
               
               
               
               
             
               
                 TABLE 29 
               
             
            
               
                   
               
               
                   
                   
                 Amount of 
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 plant 
                 Amount of 
                   
                 mg of  
               
               
                   
                   
                 before 
                 plant after 
                 extract 
                 cannabinoid/g 
               
               
                   
                   
                 maceration 
                 maceration 
                 isolated 
                 of plant (%) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Strain 
                 Runs 
                 (g)  
                 (g) 
                 (g) 
                 THC 
                 CBD 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Strain 1 
                 1 
                 7.5036 
                 3.682 
                 0.8403 
                 7.0 
                 10.7 
               
               
                 (THC: 7.18/ 
                 2 
                   
                 3.6459 
                 0.8091 
                 7.7 
                 12.2 
               
               
                 CBD: 8.6) 
                   
                   
                   
                   
                   
                   
               
               
                   
               
            
           
         
       
     
     Summary of Results: 
     7.5 g large scale batch of  cannabis  extraction and decarboxylation was successful. These experiments demonstrate that the methods of the disclosure consistently extract and decarboxylate cannabinoids and can be used on a commercial scale. 
     Experiment 10: Winterization 
     Winterization is a procedure typically used to remove waxes and other partially soluble materials at 0±10° C. temperature range. This process may not be applicable, if there are no waxes present in the extract, or such hydrophobic molecules are broken down, and would be solidify at the ice-bath or below-zero temperatures. 
     Experiment 10A 
     To remove waxes, the solutions of extract which had been stored in the refrigerator (−5° C.) for 1-3 weeks were manipulated as follows:
         1. Solution was filtered using a syringe filter in 20 mL vials
           Filter specifications: Millex®-GV (sterile)   Low Protein Binding Durapore® (PVDF) Membrane   0.22 μm pore size   13 mm diameter   
           2. Filtrate was concentrated at 35° C. and vacuum dried for 3 days at 40° C. (via water bath)   3. Extracts were then re-weighed       

     Experiment 10B 
     
         
         
           
             1. Resin was dissolved in 95%-100% ethanol (10 mL/g) and heated at 40° C. for 5 mins in a water bath 
             2. Vial containing extract solution was cooled to −75° C. using a dry ice/acetone bath for 3-3.75 hrs 
             3. Solution was filtered with a pre-weighed syringe filter in 20 mL vials (see above for filter specifications); filter was washed with ethanol that had been cooled for 5 mins at −75° C. using a dry ice/acetone bath 
             4. Filtrate was concentrated at 35° C. and extract was weighed 
             5. Syringe filter was weighed after 2-3 days drying in the fumehood 
           
         
       
    
     The results are shown in Tables 30a and b below. 
     
       
         
           
               
             
               
                 TABLE 30a 
               
             
            
               
                   
               
               
                 Amount of extract isolated before and after winterization methods 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Before 1 st   
                 After 1 st   
                 After 2 nd   
               
               
                   
                   
                 winterization 
                 winterization 
                 winterization 
               
               
                 Strain 
                 Runs 
                 (g) 
                 and drying (g) 
                 and drying (g) 
               
               
                   
               
               
                 Strain 1 
                 1 
                 0.2044 
                 0.2111 
                 0.2031 
               
               
                 (THC: 7.18/CBD: 
                 2 
                 0.2184 
                 0.2345 
                 0.1964 
               
               
                 8.6) 
                 3 
                 0.2088 
                 0.1981 
                 0.1891 
               
               
                 Strain 2 
                 1 
                 0.1624 
                 0.1677 
                 0.1580 
               
               
                 (THC: 0/CBD: 9) 
                 2 
                 0.1721 
                 0.1622 
                 0.1508 
               
               
                   
                 3 
                 0.1617 
                 0.1677 
                 0.1536 
               
               
                 Strain 3 
                 1 
                 0.2225 
                 0.2088 
                 0.1996 
               
               
                 (THC: 18.6/CBD: 
                 2 
                 0.2068 
                 0.2221 
                 0.2145 
               
               
                 0) 
                 3 
                 0.2343 
                 0.2243 
                 0.2145 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 30b 
               
             
            
               
                   
               
               
                 Average extract isolated before and after winterization methods 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Before 1st 
                 After 1st 
                 After 2nd 
               
               
                   
                   
                 winterization 
                 winterization 
                 winterization 
               
               
                 Strain 
                 Runs 
                 (g) 
                 and drying (g) 
                 and drying (g) 
               
               
                   
               
               
                 Strain 1 
                 1 
                 0.2105 ± 0.007 
                 0.2146 ± 0.018 
                 0.1962 ± 0.007 
               
               
                 (THC: 
                 2 
               
               
                 7.18/CBD: 8.6) 
                 3 
               
               
                 Strain 2 
                 1 
                 0.1654 ± 0.006 
                 0.1659 ± 0.003 
                 0.1541 ± 0.004 
               
               
                 (THC: 0/CBD: 
                 2 
               
               
                 9) 
                 3 
               
               
                 Strain 3 
                 1 
                 0.2212 ± 0.014 
                 0.2184 ± 0.008 
                 0.2095 ± 0.009 
               
               
                 (THC: 
                 2 
               
               
                 18.6/CBD: 0) 
                 3 
               
               
                   
               
            
           
         
       
     
     Tables 31a and b below show the amount of cannabinoid (in milligrams) in the extract per gram of plant material isolated before and after winterization methods 
     
       
         
           
               
             
               
                 TABLE 31a 
               
             
            
               
                   
               
               
                 Amount of cannabinoid (in milligrams) in the 
               
               
                 extract per gram pf plant material 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Before 1 st   
                 1 st   
                 2 nd   
               
               
                   
                   
                 winterization 
                 winterization 
                 winterization 
               
               
                   
                   
                 (mg/g) 
                 (mg/g) 
                 (mg/g) 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Δ 9 - 
                   
                 Δ 9 - 
                   
                 Δ 9 - 
               
               
                 Strains 
                 Runs 
                 CBD 
                 THC 
                 CBD 
                 THC 
                 CBD 
                 THC 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Strain 1 
                 1 
                 92.9 
                 65.1 
                 98.3 
                 76.2 
                 157.4 
                 109.0 
               
               
                 (THC: 
                 2 
                 114.9 
                 82.3 
                 114.3 
                 91.5 
                 124.7 
                 93.7 
               
               
                 7.18/ 
                 3 
                 115.5 
                 85.7 
                 113.7 
                 93.8 
                 184.5 
                 138.1 
               
               
                 CBD: 8.6) 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Strain 2 
                 1 
                 200.5 
                   
                 113.7 
                   
                 149.7 
                   
               
               
                 (THC: 
                 2 
                 211.6 
                   
                 109.5 
                   
                 147.3 
                   
               
               
                 0/CBD: 9) 
                 3 
                 146.9 
                   
                 131.2 
                   
                 161.9 
                   
               
               
                 Strain 3 
                 1 
                   
                 406.1 
                   
                 207.7 
                   
                 235.4 
               
               
                 (THC: 
                 2 
                   
                 185.6 
                   
                 274.8 
                   
                 236.2 
               
               
                 18.6/ 
                 3 
                 92.9 
                 232.9 
                 98.3 
                 301.0 
                 157.4 
                 283.4 
               
               
                 CBD: 0) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 31b 
               
             
            
               
                   
               
               
                 Average cannabinoid (in milligrams) in the 
               
               
                 extract per gram pf plant material 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Before 1 st   
                 1 st   
                 2 nd   
               
               
                   
                   
                 winterization 
                 winterization 
                 winterization 
               
               
                   
                   
                 (mg/g) 
                 (mg/g) 
                 (mg/g) 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Strains 
                 Runs 
                 CBD 
                 Δ 9 -THC 
                 CBD 
                 Δ 9 -THC 
                 CBD 
                 Δ 9 -THC 
               
               
                   
               
               
                 Strain 1 
                 1 
                 107.8 ±  
                 77.7 ±  
                 108.8 ±  
                 87.2 ±  
                 155.5 ±  
                 113.6 ±  
               
               
                 (THC: 
                 2 
                 12.9 
                  11.0 
                  9.1 
                  9.6 
                 29.9 
                 22.6 
               
               
                 7.18/ 
                 3 
                   
                   
                   
                   
                   
                   
               
               
                 CBD: 8.6) 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Strain 2 
                 1 
                 186.3 ±  
                   
                 118.1 ±  
                   
                 153.0 ±  
                   
               
               
                 (THC: 0/ 
                 2 
                 34.6 
                   
                 11.5 
                   
                  7.8 
                   
               
               
                 CBD: 9) 
                 3 
                   
                   
                   
                   
                   
                   
               
               
                 Strain 3 
                 1 
                   
                 274.9 ± 
                   
                 261.2 ±  
                   
                 251.7 ± 
               
               
                 (THC: 
                 2 
                   
                 116.1 
                   
                 48.1 
                   
                 27.5 
               
               
                 18.6/ 
                 3 
                   
                   
                   
                   
                   
                   
               
               
                 CBD: 0) 
               
               
                   
               
            
           
         
       
     
     Summary of Results: 
     Winterization of extracts was successful in removing waxes from the extract. 
     Experiment 11: Chemistry of Medicinal  cannabis  Before and after Decarboxylation 
     Methodology 
     Extraction: 
     Dried plant material (1 g) was weighed and transferred to a mortar and was macerated using a pestle. The crushed plant material was then transferred into a 10 mL vessel and was subjected to supercritical fluid extraction (SFE), with supercritical CO 2  as solvent A and ethanol as solvent B. The photodiode array detector was set to monitor wavelengths in the range of 200-600 nm and the back pressure regulator was set to 12 MPa. The SFE conditions used were: flow rate=10 mL/min (CO 2  and slave pumps) and 1 mL/min (make-up pump); temperature=25° C.; gradient: 100% A—50% A (0.1-25 mins), 100% B (25-26 mins) and 100% A (26-30 mins). Once the method was completed, all fractions were combined and concentrated to dryness under reduced pressure (at 25° C.) to afford 0.28 g of a green sticky resin. This was used for further work-up and analyses. 
     Activation: 
     Activation of phytocannabinoids was conducted by subjecting  cannabis  extract to heat using microwaves. A 5 mL-size microwave vial was charged with  cannabis  extract (27.72 mg) dissolved in ethanol (2 mL). The vial was sealed and was subjected to heat for 10 min at 150° C. in a pressure vessel to afford a green sticky extract. This was concentrated to dryness at 35° C. to obtain the activated  cannabis  extract as a resin (21.2 mg). 
       FIGS. 28A and 28B  show the overview of select signals as seen in the mass spectra before (A) and after (B) decarboxylation of  cannabis  extract, as well as their corresponding compound classes. Bolded signals are compounds identified in the cannabinoid biosynthetic pathway. 
     Table 32. 
     Potential changes in chemical composition after decarboxylation of strain I  cannabis  extract. Left column indicates the potential compounds that were present in  cannabis  extract obtained through a supercritical fluid extraction (SFE), but not in the decarboxylated resin. This extract was then subjected to heating conditions using microwave technology, and the right column shows the new chemicals that were identified, which were not present in the  cannabis  extract prior to employing microwave technology described in this disclosure. 
     
       
         
           
               
               
             
               
                 TABLE 32 
               
               
                   
               
               
                   
                 New Compounds Found Upon 
               
               
                 Compounds Lost Upon Activation 
                 Activation 
               
               
                   
               
             
            
               
                 Roughanic acid (Fatty acid) 
                 Kaempferol (Flavonol) 
               
               
                 α-Linolenic acid (Fatty acid) 
                 Luteolin (Flavonol) 
               
               
                 Quercetin (Flavonoid) 
                 4,7-Dimethoxy-1,2,5-trihydroxyphenanthrene 
               
               
                   
                 (Non-cannabinoid) 
               
               
                 4,5-Dihydroxy-2,3,6-trimethoxy-9,10- 
                 5-Methyl-4-pentyl-2,6,2-trihydroxybiphenyl 
               
               
                 dihydrophenanthrene (Non-cannabinoid) 
                 (Non-cannabinoid) 
               
               
                 Δ 9 -Tetrahydrocannabiorcolic acid (C 1 - 
                 5-Methyl-4-pentylbiphenyl-2,2,6-triol (Non- 
               
               
                 Cannabinoid Acid) 
                 cannabinoid) 
               
               
                 Cannabigerol (C 5 -Neutral Cannabinoid) 
                 Cannabichromevarin (C 3 -Neutral Cannabinoid) 
               
               
                 Cannabichromanon (Neutral Cannabinoid) 
                 Cannabicyclovarin (C 3 -Neutral Cannabinoid) 
               
               
                 Cannabigerovarinic acid (C 5 -Cannabinoid Acid) 
                 Cannabidivarin (C 3 -Neutral Cannabinoid) 
               
               
                 6,7-cis/trans-Epoxycannabigerol (Cannabinoid 
                 Δ 7 -cis-iso-Tetrahydrocannabivarin (C 3 -Neutral 
               
               
                 Derivative) 
                 Cannabinoid) 
               
               
                 7-Hydroxycannabichromane (Cannabinoid 
                 Δ 9 -tetrahydrocannabivarin (C 3 -Neutral 
               
               
                 Derivative) 
                 Cannabinoid) 
               
               
                 C 4 -Tetrahydrocannabinolic acid (C 4 -Cannabinoid 
                 Chrysoeriol (Flavone) 
               
               
                 Acid) 
               
               
                 Cannabitriol (Neutral Cannabinoid) 
                 C 4 -Cannabidiol (C 4 -Neutral Cannabinoid) 
               
               
                 Cannabiripsol (Neutral Cannabinoid) 
                 C 4 -Tetrahydrocannabinol (C 4 -Neutral 
               
               
                   
                 Cannabinoid) 
               
               
                 Cannabigerolic Acid (C 5 -Cannabinoid Acid) 
                 Cannabifuran (Neutral Cannabinoid) 
               
               
                 7R-Cannabicoumaronic Acid (Cannabinoid Acid) 
                 Cannabinol (C 5 -Neutral Cannabinoid) 
               
               
                 Tetrahydrocannabinolic acid-8-one (Cannabinoid 
                 Cannabinodiol (C 5 -Neutral Cannabinoid) 
               
               
                 Acid Derivative) 
               
               
                 5-Acetoxy-6-geranyl-3-n-pentyl-1,4- 
                 10-oxo- Δ 6a -tetrahydrocannabinol (Cannabinoid 
               
               
                 benzoquinone (Non-cannabinoid) 
                 Derivative) 
               
               
                 4-Acetoxycannabichromene (Cannabinoid 
                 7R-Cannabicourmarone (Neutral Cannabinoid) 
               
               
                 Derivative) 
               
               
                 Cannabielsoic Acid-α/β (Cannabinoid Acid) 
                 Cannabichromanone-D (Neutral Cannabinoid) 
               
               
                 6,7-trans/cis-Epoxycannabigerolic acid 
                 Cannabidiol Monoethylether (Cannabinoid 
               
               
                 (Cannabinoid Acid Derivative) 
                 Derivative) 
               
               
                 Δ 9 -Tetrahydrocannabinolic acid + C 2 H 2 O 
                 Cannabielsoic Acid-A/B (Cannabinoid Acid) 
               
               
                 Orientin (Flavone) 
                 Sesquicannabigerol (Cannabinoid Derivative) 
               
               
                 4-Terpenyl-Δ 9 -Tetrahydrocannabinolate 
               
               
                 (Cannabinoid Acid Ester) 
               
               
                 α-Terpenyl-Δ 9 -Tetrahydrocannabinolate 
               
               
                 (Cannabinoid Acid Ester) 
               
               
                 Bornyl/epi-bornyl-Δ 9 -Tetrahydrocannabinolate 
               
               
                 (Cannabinoid Acid Ester) 
               
               
                 α/β-Fenchyl Δ 9 -Tetrahydrocannabinolate 
               
               
                 (Cannabinoid Acid Ester) 
               
               
                   
               
            
           
         
       
     
     Closed system, microwave extraction provided the simultaneous extraction and decarboxylation of the cannabinoids. In the native  cannabis  extract, 63 compounds could be observed ( FIG. 28A ), and in the decarboxylated  cannabis  extract, there could be up to 22 new compounds (Table 32). Up to 26 compounds from the resin were not present in the decarboxylated  cannabis  resin, but were present in the  cannabis  resin prior to decarboxylation step. 
     Experiment 12: Solvent-Free Decarboxylated  cannabis  Resin 
     General Procedure 
     To remove the solvent from the decarboxylated resin, the following procedures are used: distillers or rotary evaporators are used to evaporate solvents employed in extraction and decarboxylation process, concentrate and obtain solvent-free decarboxylated resin. During the evaporation of solvent, a higher temperature than ambient temperature is used to facilitate faster evaporation of the solvent. In addition, a vacuum may be used to facilitate removal of solvent at lower pressure than the atmospheric pressure. In general, such processes are well established and known to those skilled in the art. 
     The resulting decarboxylated  cannabis  resin may comprise less than 5% solvent, or the resin can be solvent-free. 
     II. Sublingual Rapidly Disintegrating Tablet Formulations Comprising Decarboxylated  Cannabis  Resin. 
     The present disclosure provides decarboxylated  cannabis  resin in a solid formulation and methods of making and using same. In an embodiment, the solid formulation is a rapidly disintegrating sublingual tablet formulation. 
     Sublingual formulations comprising the decarboxylated  cannabis  resin of the present invention may be beneficial in that they may (i) provide a faster route of absorption of the cannabinoids and other medicinal ingredients from the decarboxylated  cannabis  resin to the subject compared with absorption through the oral route via gastrointestinal tract; (ii) avoid degradation in the hostile environment of the gastrointestinal tract; (iii) be used at lower doses because they are not metabolized in the liver; and/or (iv) provide an alternative dosage form for patients who do not wish to, or unable to, smoke or vape. 
     Placing the sublingual formulation under the tongue of a subject may result in the absorption of the ingredients of the  cannabis  resin by the oral mucosal lining which comprises capillaries located in connective tissue beneath the epithelium. Once the ingredients are absorbed by the capillaries, they enter venous circulation. 
     Sublingual formulations avoid passage via the stomach, intestines and liver (first pass metabolism) before entering general circulation. Non-sublingual oral drugs are subjected to hostile environments of the gastrointestinal tract and liver. Sublingual formulations are generally only subject to enzymes found in saliva before absorption. 
     Development of rapidly disintegrating tablets from  cannabis  resin is challenging due to the physical properties of  cannabis  resin, which is a hydrophobic, viscous, and glue-like substance. A rapidly disintegrating tablet requires the tablet to be stable in its physical form until the tablet is consumed, and then disintegrate rapidly when placed under the tongue. 
     In an embodiment, sublingual formulations of decarboxylated  cannabis  resin can be formulated to disintegrate rapidly when in contact with a suitable fluid, such as phosphate buffered solution (PBS), saliva, or other similar natural or artificial fluids. In an embodiment, sublingual formulations of  cannabis  resin disintegrate within 60 seconds when in contact with a phosphate buffered saline (PBS). In a further embodiment, sublingual formulations of  cannabis  resin disintegrate in less than 60 seconds, less than 50 seconds, less than 40 seconds, less than 30 seconds, less than 25 seconds, less than 20 seconds, less than 15 seconds, less than 10 seconds, less than 5 seconds, or any integer or fraction in these ranges (for example 7.84 seconds) when in contact with PB S. 
     In one embodiment, a method is provided for producing a rapidly disintegrating tablet comprising decarboxylated  cannabis  resin which disintegrates within 60 seconds in PBS and has desirable levels of friability and hardness. In certain embodiments, the decarboxylated  cannabis  resin is dissolved in a pharmaceutically acceptable organic solvent such as ethanol. A sugar alcohol, such as mannitol, is dissolved in a pharmaceutically acceptable polar solvent such as water, and the solutions are mixed together. Optionally, sonication may be used. In an embodiment, the ratio of  cannabis  resin to mannitol in the rapidly disintegrating sublingual tablet formulations is between 1:3 and 1:8. In certain embodiments, the ratio of  cannabis  resin to mannitol in the formulation is 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8, or any fraction thereof, for example, 1:6.33. In one embodiment, the ratio is 1:6. 
     In certain embodiments, the solvents are substantially or completely removed using lyophilization, spray drying, fluid bed drying, high vacuum, or other suitable method, in order to produce a powder. Following powderization, one or more pharmaceutically acceptable excipients may be added, including a suitable disintegrant such as cross-linked polyvinylpyrrolidone (e.g. Kollidon CL™) or croscarmellose sodium. Other excipients may optionally be added such as diluents, fillers, binding agents, releasing agents, or lubricants. In certain embodiments, the excipients are magnesium stearate and optionally microcrystalline cellulose. In certain embodiments, the rapidly disintegrating tablet may further comprise flavoring agents, taste-masking agents, colorants, or other excipients to enhance the taste, texture and flavor of such tablets. In certain embodiments, the tablet comprises about 2-18 wt % of decarboxylated  cannabis  resin, about 40-80 wt % of mannitol, about 10-50 wt % of disintegrant, and optionally about 0-25 wt % of other excipients. In further embodiments, the tablet comprises 7-11 wt % of decarboxylated  cannabis  resin; about 50-63 wt % of mannitol; about 11-18 wt % of disintegrant, wherein the disintegrant is crosslinked polyvinylpyrrolidone or croscarmellose sodium; and the other excipients are magnesium stearate at an amount of about 0.6-1.1 wt % of the tablet, and microcrystalline cellulose at an amount of about 0-20 wt % of the tablet. 
     The components may be triturated or mixed to produce a homogenous mixture, homogeneous solid solution or homogeneous solid suspension. In certain embodiments, the homogenous mixture, homogeneous solid solution or homogeneous solid suspension is compressed into a tablet at a pressure of up to about 1 ton. In other embodiments, the homogenous mixture, homogeneous solid solution or homogeneous solid suspension is compressed into a tablet at a pressure of about 0.05 to 0.6 ton. In still further embodiments, the homogenous mixture, homogeneous solid solution or homogeneous solid suspension is compressed into a tablet at a pressure of about 0.1 to 0.4 ton. 
     In certain embodiments, there is provided a rapidly disintegrating tablet comprising decarboxylated  cannabis  resin, comprising cannabinoids which are at least 50%, 60%, 70%, 80%, 90%, 95%, or 100% (or any integer or fraction in these ranges, for example 96.33%) decarboxylated. In certain embodiments, the tablet disintegrates rapidly when placed in contact with PBS, saliva, or other similar natural or artificial fluid; the tablet additionally having suitable levels of friability and hardness. 
     Friability describes the tendency of a solid substance to break into smaller pieces with handling or contact. Friability testing is a laboratory technique to test the durability of tablets during transit or handling. Friability is calculated as the percentage of weight lost by tablets due to mechanical action during a friability test. In the examples that follow, tablets were tested for friability on a Sotax® Friabilitor model F1 using the standard protocol, as described by the manufacturer. Similar protocols are also described in various text books such as in Remington: The Science and Practice of Pharmacy (22nd edition), ISBN: 0857110624. 
     In an embodiment, the sublingual formulations of decarboxylated  cannabis  resin have a friability of 5% or less. In certain embodiments, the friability is less than 4%, less than 3%, less than 2%, less than 1%, or 0%, or any fraction thereof, for example 0.87%. 
     Tablet hardness testing is a laboratory technique to test the breaking point and structural integrity of a tablet under conditions of storage, transportation and handling before usage. In the examples that follow, tablet hardness was tested using an Engineering Systems® C50 Hardness Tester following the standard protocol, as described by the manufacturer. Similar protocols are also described in various text books such as in Remington: The Science and Practice of Pharmacy (22nd edition), ISBN: 0857110624. 
     In certain embodiments, the tablet comprises mannitol and a disintegrant such as cross-linked polyvinylpyrrolidone (e.g. Kollidon CL™) or croscarmellose sodium. In an embodiment, the ratio of  cannabis  resin to mannitol is between 1:3 and 1:8. In certain embodiments, the ratio of  cannabis  resin to mannitol in the formulation is 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8, or any fraction thereof, for example, 1:6.33. In one embodiment, the ratio is 1:6. 
     In certain embodiments, the tablet comprises one or more additional pharmaceutically acceptable excipients, such as diluents, fillers, binding agents, releasing agents, or lubricants. In an embodiment, the excipients are magnesium stearate and optionally microcrystalline cellulose. In certain embodiments, the rapidly disintegrating tablet may further comprise flavoring agents, taste-masking agents, colorants, or other excipients to enhance the taste, texture and flavor of such tablets. In certain embodiments, the tablet comprises about 2-18 wt % of decarboxylated  cannabis  resin, about 40-80 wt % of mannitol, about 10-50 wt % of disintegrant, and optionally about 0-25 wt % of other excipients. In further embodiments, the tablet comprises 7-11 wt % of decarboxylated  cannabis  resin; about 50-63 wt % of mannitol; about 11-18 wt % of disintegrant, wherein the disintegrant is crosslinked polyvinylpyrrolidone or croscarmellose sodium; and the other excipients are magnesium stearate at an amount of about 0.6-1.1 wt % of the tablet, and microcrystalline cellulose at an amount of about 0-20 wt % of the tablet. 
     In certain embodiments, the disclosure provides the use of a decarboxylated  cannabis  resin in the manufacture of a rapidly disintegrating tablet. In certain embodiments, the resin is at least 50%, 60%, 70%, 80%, 90%, or 100% (or any integer or fraction in these ranges, for example 96.33%) decarboxylated, or any integer or fraction thereof or between. 
     The tablets of the present disclosure may be used in the treatment, prevention, or amelioration of symptoms, ailments, or diseases, for which  Cannabis  is used. 
     EXAMPLES 
     The disclosure is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the disclosure should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein. The term “resin” is used as a short form for “decarboxylated  cannabis  resin” in the Examples and Tables that follow. 
     Experiment 13: Prototype Solid Formulations 
     Different series of sublingual tablets formulations were prepared according to the ratios set out in Table 33, using different disintegrants. The standard operating procedures used were as follows:
         1. In a porcelain mortar, dry powders of each formulation ingredients were well premixed using spatula/scoopula   2. The mixture powder was triturated to give a homogenous mixture   3. A reasonable amount of the mixture was loaded to the sample holder part of the die set (Special 3 mm tablet die from Specac®)   4. The remaining parts of the die were assembled in place and punched under 0.2 ton pressure using Sirius 0.5 ton Manually Operated Hydraulic Press, to afford a final sublingual tablet of an average of 35-36.5 mg   5. Approximately, 24 tablets of each formulation were obtained and stored in a 4 mL glass vial at room temperature ( FIGS. 29 and 30 ) for further investigations       

     Different series of sublingual tablet formulations were prepared according to the ratios set out in Table 33, using different disintegrants. The procedures used were as follows: 
     
       
         
           
               
             
               
                 TABLE 33 
               
             
            
               
                   
               
               
                 Components of sublingual tablet Formulations 1-15 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Microcrystalline 
                 Magnesium 
                 Sodium starch 
                 Croscarmellose 
                 Polyplasdone ™ 
               
               
                 Formulations 
                 Mannitol 
                 cellulose* 
                 stearate 
                 glycolate 
                 Sodium 
                 crospovidone 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 1 
                 700 mg 
                 210 mg 
                 10.5 mg 
                 — 
                 — 
                 — 
               
               
                 2 
                 700 mg 
                 210 mg 
                 10.5 mg 
                  63 mg 
                 — 
                 — 
               
               
                 3 
                 700 mg 
                 210 mg 
                 10.5 mg 
                 — 
                 63 mg 
                 — 
               
               
                 4 
                 700 mg 
                 210 mg 
                 10.5 mg 
                  35 mg 
                 — 
                 — 
               
               
                 5 
                 700 mg 
                 210 mg 
                 10.5 mg 
                  70 mg 
                 — 
                 — 
               
               
                 6 
                 700 mg 
                 210 mg 
                 10.5 mg 
                 105 mg 
                 — 
                 — 
               
               
                 7 
                 700 mg 
                 210 mg 
                 10.5 mg 
                 140 mg 
                 — 
                 — 
               
               
                 8 
                 700 mg 
                 210 mg 
                 10.5 mg 
                 — 
                 35 mg 
                 — 
               
               
                 9 
                 700 mg 
                 210 mg 
                 10.5 mg 
                 — 
                 70 mg 
                 — 
               
               
                 10 
                 700 mg 
                 210 mg 
                 10.5 mg 
                 — 
                 105 mg  
                 — 
               
               
                 11 
                 700 mg 
                 210 mg 
                 10.5 mg 
                 — 
                 140 mg  
                 — 
               
               
                 12 
                 700 mg 
                 210 mg 
                 10.5 mg 
                 — 
                 — 
                  35 mg 
               
               
                 13 
                 700 mg 
                 210 mg 
                 10.5 mg 
                 — 
                 — 
                  70 mg 
               
               
                 14 
                 700 mg 
                 210 mg 
                 10.5 mg 
                 — 
                 — 
                 105 mg 
               
               
                 15 
                 700 mg 
                 210 mg 
                 10.5 mg 
                 — 
                 — 
                 140 mg 
               
               
                   
               
               
                 *Partially depolymerized from Spectrum Chemicals Company, of density and molecular weight equivalent to the brand Avicel ® PH 102 
               
            
           
         
       
     
     Experiment 14: Disintegration Studies Using Prototype Solid Formulations 
     The procedure used was as follows:
         1. In a 24 multi-well plate, 1 mL of Phosphate Buffer Saline (PBS) or distilled water (DW) was placed in 12 wells each   2. One tablet from each of the Formulations 24-35 was placed in a well of PBS and DW   3. A six minutes video was recorded for the entire experiment comparing the disintegration time and behavior of the 12 formulations in real time basis (head to head)       

     The results are shown below in Tables 34A and 34B. As shown below, croscarmellose sodium and Kollidon CL™ had faster disintegration times than sodium starch glycolate in PBS and in deionized water, suggesting that starch-based substances may increase disintegration time. 
     
       
         
           
               
             
               
                 TABLE 34A 
               
             
            
               
                   
               
               
                 Disintegration times and conditions in PBS for each tablet from 
               
               
                 Formulations 4-15 
               
            
           
           
               
               
               
            
               
                   
                 Time on the video track 
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Variable 
                 Dropped-in at 
                 Disintegrated 
                 Disintegration 
               
               
                 Formulations 
                 Component 
                 (mm:ss) 
                 at (mm:ss) 
                 time (sec) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 4 
                 5% Na. starch 
                 00:28 
                 01:02 
                 34 
               
               
                   
                 glycolate 
               
               
                 5 
                 10% Na. starch 
                 00:36 
                 01:10 
                 34 
               
               
                   
                 glycolate 
               
               
                 6 
                 15% Na. starch 
                 00:43 
                 01:18 
                 35 
               
               
                   
                 glycolate 
               
               
                 7 
                 20% Na. starch 
                 00:51 
                 01:45 
                 54 
               
               
                   
                 glycolate 
               
               
                 8 
                 5% Croscarmellose 
                 00:57 
                 01:10 
                 13 
               
               
                   
                 sodium 
               
               
                 9 
                 10% Croscarmellose 
                 01:03 
                 01:19 
                 16 
               
               
                   
                 sodium 
               
               
                 10 
                 15% Croscarmellose 
                 01:09 
                 01:27 
                 18 
               
               
                   
                 sodium 
               
               
                 11 
                 20% Croscarmellose 
                 01:15 
                 01:36 
                 21 
               
               
                   
                 sodium 
               
               
                 12 
                 5% Kollidon CL 
                 01:22 
                 — 
                 Incomplete 
               
               
                   
                   
                   
                   
                 disintegration 
               
               
                 13 
                 10% Kollidon CL 
                 01:30 
                 01:41 
                 11 
               
               
                 14 
                 15% Kollidon CL 
                 01:35 
                 01:45 
                 10 
               
               
                 15 
                 20% Kollidon CL 
                 01:41 
                 01:54 
                 13 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 34B 
               
             
            
               
                   
               
               
                 Disintegration times and conditions in DW for each tablet from 
               
               
                 Formulations 4-15 
               
            
           
           
               
               
               
            
               
                   
                 Time on the video track 
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Dropped-in 
                 Disintegrated 
                 Disintegration 
               
               
                 Formulations 
                 Variable Component 
                 at (mm:ss) 
                 at (mm:ss) 
                 time (sec) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 4 
                 5% Na. starch glycolate 
                 01:49 
                 02:16 
                 27 
               
               
                 5 
                 10% Na. starch 
                 01:53 
                 02:33 
                 40 
               
               
                   
                 glycolate 
               
               
                 6 
                 15% Na. starch 
                 01:58 
                 02:44 
                 46 
               
               
                   
                 glycolate 
               
               
                 7 
                 20% Na. starch 
                 02:03 
                 02:55 
                 52 
               
               
                   
                 glycolate 
               
               
                 8 
                 5% Croscarmellose 
                 02:08 
                 02:23 
                 15 
               
               
                   
                 sodium 
               
               
                 9 
                 10% Croscarmellose 
                 02:13 
                 02:31 
                 18 
               
               
                   
                 sodium 
               
               
                 10 
                 15% Croscarmellose 
                 02:18 
                 02:31 
                 13 
               
               
                   
                 sodium 
               
               
                 11 
                 20% Croscarmellose 
                 02:23 
                 02:42 
                 19 
               
               
                   
                 sodium 
               
               
                 12 
                 5% Kollidon CL 
                 02:27 
                 — 
                 Incomplete 
               
               
                   
                   
                   
                   
                 disintegration 
               
               
                 13 
                 10% Kollidon CL 
                 02:32 
                 02:52 
                 20 
               
               
                 14 
                 15% Kollidon CL 
                 02:38 
                 02:52 
                 14 
               
               
                 15 
                 20% Kollidon CL 
                 02:44 
                 02:57 
                 13 
               
               
                   
               
            
           
         
       
     
     Experiment 15: Sublingual Formulations Comprising Decarboxylated  Cannabis  Resin 
     Decarboxylated  cannabis  resin was prepared from  cannabis  plants of Strain 1 by microwave-assisted extractions with ethanol (MAE) and winterization, as described in Experiment 9. 
     In the following experiments (Formulations 16-18), various permutations of mixing the excipients and lyophilization were investigated to prepare the powder form for punching the tablets. 
     
       
         
           
               
             
               
                 TABLE 35 
               
             
            
               
                   
               
               
                 Components of sublingual tablet Formulations 16-19 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Mg 
                 Kollidon 
                   
                 No. of tablets 
               
               
                 Formulations 
                 Mannitol 
                 MCC* 
                 stearate 
                 CL ® 
                 Resin 
                 formulated 
               
               
                   
               
               
                 16 
                   600 mg 
                   180 mg 
                  10 mg 
                   150 mg 
                 200.5 mg 
                 9 
               
               
                 17 
                 305.4 mg 
                  91.6 mg 
                 4.6 mg 
                  75.5 mg 
                 101.8 mg 
                 5 
               
               
                 18 
                 589.2 mg 
                 176.8 mg 
                 8.8 mg 
                 142.1 
                 196.4 mg 
                 8 
               
               
                 19 
                 567.3 mg 
                 170.2 mg 
                 8.5 mg 
                 140.3 mg 
                 189.1 mg 
                 9 
               
               
                   
               
               
                 *Microcrystalline cellulose, partially depolymerized from Spectrum Chemicals Company, of density and molecular weight equivalent to the brand Avicel ® PH 102 
               
            
           
         
       
     
     The procedures used for making the solid Formulations 16-19 were as follows: 
     Formulation 16: (contains THC=2.19 mg/tab, and CBD=3.14 mg/tab)
         1. The resin was dissolved in 1 mL ethanol followed by addition of mannitol dissolved in 1 mL water.   2. Mixture was concentrated then lyophilized overnight.   3. Add other excipients to the lyophilized mixture   4. Triturate in a porcelain mortar with a pestle until a homogeneous solid solution is obtained   5. Weigh 115 mg of the mixture for each tablet   6. Load the 115 mg powder to a 10 mm die   7. Punch under 0.4 ton pressure, using Specac® manual hydraulic press   8. Collect tablets in a 20 mL vial       

     Formulation 17: (contains THC=1.24 mg/tab, and CBD=1.57 mg/tab)
         1. The resin was dissolved in 1 mL ethanol and a suspension of microcrystalline cellulose and mannitol in 4 mL water was added followed by 1 min sonication   2. Add 3 more mL of water   3. Lyophilize for 41 hrs   4. Add other excipients to the lyophilized mixture   5. Triturate in a porcelain mortar with a pestle until having a homogeneous solid solution   6. Weigh 96.6 mg of the mixture for each tablet   7. Load the 96.6 mg powder to a 10 mm die   8. Punch under 0.4 ton pressure, using Specac® manual hydraulic press   9. Collect tablets in a 20 mL vial       

     Formulation 18: (contains THC=2.04 mg/tab, and CBD=2.73 mg/tab)
         1. The resin was dissolved in 1 mL ethanol and a suspension of microcrystalline cellulose and mannitol in 4 mL water was added followed by 1 min sonication   2. Add 3 more mL of water   3. Lyophilize for 41 hrs   4. Add other excipients to the lyophilized mixture   5. Triturate in a porcelain mortar with a pestle until having a homogeneous solid solution   6. Weigh 123.7 mg of the mixture for each tablet   7. Load the 123.7 mg powder to a 10 mm die   8. Punch under 0.4 ton pressure, using Specac® manual hydraulic press   9. Collect tablets in a 20 mL vial       

     Formulation 19: (contains THC=2.61 mg/tab, and CBD=3.50 mg/tab)
         1. The resin was dissolved in 1 mL ethanol and a suspension of all ingredients in 4 mL water was added followed by 1 min sonication   2. Add 3 more mL of water   3. Lyophilize for 41 hrs   4. Triturate in a porcelain mortar with a pestle until having a homogeneous solid solution   5. Weigh 107.6 mg of the mixture for each tablet   6. Load the 107.6 mg powder to a 10 mm die   7. Punch under 0.4 ton pressure, using Specac® manual hydraulic press   8. Collect tablets in a 20 mL vial       

                     TABLE 36                  Properties of sublingual tablet Formulations 16-19                                         Disintegration time (s) in       Formulations   Friability (%)   Hardness (N)   1 mL PBS                                     16   0.17   2.79   &gt;6 min       17   0.069   5.49   37       18   0.054   19.12   410       19   0.22   14.80   214                    
From Table 36, Formulation 17 and its preparation method are suitable for making sublingual RDT formulations.
 
     Experiment 16: Potential Excipients for Sublingual Formulations Comprising Decarboxylated  Cannabis  Resin 
     Due to the relatively homogeneous appearance of Formulation 17, the tablet excipient was substituted while keeping the methodology similar to that of Formulation 17 (except with 5 sec sonication). Excipients tested here such as CMC, HPC (both cellulose derivatives), chitosan are to evaluate their role in generating the powderized mixture of  cannabis  resin and mannitol, by enhancing solubility of  cannabis  resin prior to lyophilization. 
     
       
         
           
               
             
               
                 TABLE 37 
               
             
            
               
                   
               
               
                 Components of sublingual tablet Formulations 20-22 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 Mg 
                 Kollidon 
                   
                 No. of tablets 
               
               
                 Formulations 
                 Mannitol 
                 CMC 
                 Chitosan 
                 HPC 
                 stearate 
                 CL ® 
                 Resin 
                 formulated 
               
               
                   
               
               
                 20 
                 305.4 mg 
                 91.6 mg 
                 — 
                 — 
                 4.6 mg 
                 75.5 mg 
                 101.8 mg 
                 5 
               
               
                 21 
                 305.4 mg 
                 — 
                 91.6 mg 
                 — 
                 4.6 mg 
                 75.5 mg 
                 101.8 mg 
                 5 
               
               
                 22 
                 305.4 mg 
                 — 
                 — 
                 91.6 mg 
                 4.6 mg 
                 75.5 mg 
                 101.8 mg 
                 5 
               
               
                   
               
            
           
         
       
     
     The procedure used for making Formulations 20-22 were as follows:
         1. To an ethanolic resin solution (1.02 mL; 100 mg/mL), a suspension of CMC, Chitosan, or HPC, and mannitol in 4 mL water was added, followed by 5 sec sonication   2. Steps 2-9 were the same as for Formulation 17.       

                     TABLE 38                  Properties of sublingual tablet Formulations 20-22                                         Disintegration time       Formulations   Friability (%)   Hardness (N)   in 1 mL PBS                                     20   0.00   9.87   &gt;6 min       21   0.139   6.51   &gt;6 min       22   0.172   20.3   &gt;6 min                    
Excipients tested above increased the hardness of the tablets and disintegration time was not acceptable.
 
     Using a slightly modified methodology from that used for Formulations 20-22, Formulation 23 was done with the list of ingredients shown in Table 39. 
     
       
         
           
               
             
               
                 TABLE 39 
               
             
            
               
                   
               
               
                 Components of sublingual Formulation 23 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 No. of 
               
               
                 Formula- 
                   
                   
                 Mg 
                 Kollidon 
                   
                 tablets 
               
               
                 tion 
                 Mannitol 
                 MCC* 
                 Stearate 
                 CL ® 
                 Resin 
                 formulated 
               
               
                   
               
               
                 23 
                 305.4 mg 
                 91.6 
                 4.6 mg 
                 75.5 mg 
                 101.8 
                 5 
               
               
                   
                   
                 mg 
                   
                   
                 mg 
               
               
                   
               
               
                 *Microcrystalline cellulose, partially depolymerized from Spectrum Chemicals Company, of density and molecular weight equivalent to the brand Avicel ® PH 102 
               
            
           
         
       
     
     Procedure for making Formulation 23:
         1. Ethanolic resin solution (1.02 mL; 100 mg/mL) was diluted to half its concentration and a suspension of microcrystalline cellulose (MCC) and mannitol in 8 mL water was added, followed by 5 sec sonication   2. Steps 2-9 were the same as for Formulation 38       

     
       
         
           
               
             
               
                 TABLE 40 
               
             
            
               
                   
               
               
                 Properties of sublingual tablet Formulation 23 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 Disintegration time in 
               
               
                 Formulation 
                 Friability (%) 
                 Hardness (N) 
                 1 mL PBS 
               
               
                   
               
               
                 23 
                 0.00 
                 9.87 
                 &gt;6 min 
               
               
                   
               
            
           
         
       
     
     This experiment demonstrated that inclusion of MCC prior to the drying (lyophilization) step could increase the disintegration time. 
     Experiment 17: Comparison of Sugar Alcohols for Sublingual Formulations Comprising  cannabis  Resin 
       
     
       
         
           
               
             
               
                 TABLE 41 
               
             
            
               
                   
               
               
                 Formulations 24-26 comprising different sugar alcohols 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 Mg 
                 Kollidon 
                   
                 No. of tablets 
               
               
                 Formulation 
                 Mannitol 
                 Sorbitol 
                 MCC* 
                 HPC 
                 Stearate 
                 CL ® 
                 Resin 
                 formulated 
               
               
                   
               
               
                 24 
                 305.4 mg 
                 — 
                 46 mg 
                 46 mg 
                 4.6 mg 
                 75.5 mg 
                 101.8 mg 
                 5 
               
               
                 25 
                 — 
                 305.4 mg 
                 46 mg 
                 46 mg 
                 4.6 mg 
                 75.5 mg 
                 101.8 mg 
                 — a   
               
               
                 26 
                 — 
                 305.4 mg 
                 92 mg 
                 — 
                 4.6 mg 
                 75.5 mg 
                 101.8 mg 
                 5 
               
               
                   
               
               
                 *Microcrystalline cellulose, partially depolymerized from Spectrum Chemicals Company, of density and molecular weight equivalent to the brand Avicel ® PH 102 
               
               
                   a Tablets could not be made because formulation was a sticky, flake-like residue 
               
            
           
         
       
     
     Procedure for making Formulations 24-26:
         1. To an ethanolic resin solution (1.02 mL; 100 mg/mL), the appropriate suspension of mannitol, sorbitol, HPC or MCC in 4 mL water was added   2. See Formulation 38 for steps 2-7   3. Punch under 0.3 ton pressure, using Specac® manual hydraulic press   4. Collect tablets in a 20 mL vial       

     
       
         
           
               
             
               
                 TABLE 42 
               
             
            
               
                   
               
               
                 Properties of sublingual tablet Formulations 24-26 
               
            
           
           
               
               
               
               
            
               
                   
                 Friability 
                   
                   
               
               
                 Formulations 
                 (%) 
                 Hardness (N) 
                 Disintegration time in 1 mL PBS 
               
               
                   
               
               
                 24 
                 0.31 
                 18.0 
                 &gt;6 min 
               
               
                 25 
                 — a   
                 — a   
                 — a   
               
               
                 26 
                 0   
                  9.5 
                 &gt;6 min 
               
               
                   
               
               
                   a Tablets could not be made because formulation was a sticky, flake-like residue 
               
            
           
         
       
     
     These experiments indicate that inclusion of excipients such as sorbitol, HPC or MCC, or other sugar alcohols (other than mannitol) or other cellulose derivatives, prior to the drying (lyophilization) step may increase disintegration times and create sticky powders that are not suitable for RDT formulations. 
     Once the solvents are removed, the resulting mannitol and  cannabis  resin powder could be mixed or triturated with additional excipients such as the cellulose derivatives to increase lubrication and optimize other properties en route to the punching of tablets. 
     Experiment 18: Evaluation of Excipient Concentrations and Sequence of Addition 
     Procedure for making Formulation 27-29:
         1. Removed 0.51 mL of 200 mg/mL resin solution, then placed in vial and diluted to 1 mL with ethanol (102 mg of resin)   2. A solution of mannitol in 4 mL water was added   3. Added 3 more mL of water   4. Lyophilize for 41 hrs   5. Add other excipients to the lyophilized mixture   6. Triturate in a porcelain mortar with a pestle until having a homogeneous solid solution   7. Weigh ˜96.5 mg of the mixture for each tablet and load into to a 10 mm die   8. Punch under under 0.4 (A) or 0.2 (B) ton pressure, using Specac® manual hydraulic press   9. Collect tablets in a 20 mL vial       

     
       
         
           
               
             
               
                 TABLE 43 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 27A, 27B, 28A and 29A 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Total amounts of 
                 Weights of resin and 
                 # of 
                   
                   
                 Disintegration 
               
               
                   
                 resin and excipients 
                 excipients/tablet 
                 tablets 
                 Friability 
                 Hardness 
                 time (s) in 1 mL 
               
               
                 Formulation 
                 (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 27A 
                 Resin = 102 mg 
                 Resin = 17.0 mg (5.2 mg 
                 5 
                 0.07 
                 8.1 
                 Incomplete 
               
               
                 (light brown 
                 Mannitol = 305.4 mg 
                 THC; 8.0 mg CBD) 
                   
                   
                   
                 (&gt;6 mins) 
               
               
                 tablets; 
                 MCC = 92 mg 
                 Mannitol = 50.9 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mg stearate = 4.6 mg 
                 MCC = 15.3 mg 
                   
                   
                   
                   
               
               
                 ~96.6 mg) 
                 Kollidon CL ® = 75.5 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
               
               
                   
                 mg 
                 Kollidon CL ® = 12.6 mg 
                   
                   
                   
                   
               
               
                 27B 
                 Resin = 102 mg 
                 Resin = 17.0 mg (5.2 mg 
                 5 
                 0 
                 7.9 
                 Incomplete 
               
               
                 (light brown 
                 Mannitol = 305.4 mg 
                 THC; 8.0 mg CBD) 
                   
                   
                   
                 (&gt;6 mins) 
               
               
                 tablets; 
                 MCC = 92 mg 
                 Mannitol = 50.9 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mg stearate = 4.6 mg 
                 MCC = 15.3 mg 
                   
                   
                   
                   
               
               
                 ~96.6 mg) 
                 Kollidon CL ® = 75.5 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
               
               
                   
                 mg 
                 Kollidon CL ® = 12.6 mg 
                   
                   
                   
                   
               
               
                 28A 
                 Resin = 102 mg 
                 Resin = 15.6 mg (4.7 mg 
                 5 
                 0.04 
                 5.9 
                 Incomplete 
               
               
                 (light brown 
                 Mannitol = 350 mg 
                 THC; 7.4 mg CBD) 
                   
                   
                   
                 (&gt;6 mins) 
               
               
                 tablets; 
                 MCC = 92 mg 
                 Mannitol = 53.6 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mg stearate = 4.6 mg 
                 MCC = 14.1 mg 
                   
                   
                   
                   
               
               
                 ~96.5 mg) 
                 Kollidon CL ® = 82.2 
                 Mg stearate = 0.7 mg 
                   
                   
                   
                   
               
               
                   
                 mg 
                 Kollidon CL ® = 12.6 mg 
                   
                   
                   
                   
               
               
                 29A 
                 Resin = 102 mg 
                 Resin = 16.3 mg (4.9 mg 
                 5 
                 0 
                 7.6 
                 Incomplete 
               
               
                 (light brown 
                 Mannitol = 305.4 mg 
                 THC; 7.7 mg CBD) 
                   
                   
                   
                 (&gt;6 mins) 
               
               
                 tablets; 
                 MCC = 92 mg 
                 Mannitol = 48.7 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mg stearate = 4.6 mg 
                 MCC = 14.6 mg 
                   
                   
                   
                   
               
               
                 ~96.6 mg) 
                 Kollidon CL ® = 102 
                 Mg stearate = 0.7 mg 
                   
                   
                   
                   
               
               
                   
                 mg 
                 Kollidon CL ® = 16.3 mg 
               
               
                   
               
               
                 MCC = Microcrystalline cellulose 
               
            
           
         
       
     
     Procedure for making Formulations 30 and 31: 
     Formulations 30 and 31 were prepared similarly to Formulations 27-29, except that tablets were punched under 0.1(A) or 0.4 (B) ton pressure. 
     
       
         
           
               
             
               
                 TABLE 44 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 30A, 30B, 31A and 31B 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Total amounts of 
                 Weights of resin and 
                   
                   
                   
                 Disintegration 
               
               
                   
                 resin and excipients 
                 excipients/tablet 
                 # of tablets 
                 Friability 
                 Hardness 
                 time (s) in 
               
               
                 Formulation 
                 (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 1 mL PBS 
               
               
                   
               
               
                 30A 
                 Resin = 102 mg 
                 Resin = 9.3 mg (2.8 
                 5 
                 0.31 
                 10.2 
                 23 
               
               
                 (cream tablets; 
                 Mannitol = 612 mg 
                 mg THC; 4.4 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 183 mg 
                 CBD) 
                   
                   
                   
                   
               
               
                 ~96.7 mg) 
                 Mg stearate = 9 mg 
                 Mannitol = 55.9 mg 
                   
                   
                   
                   
               
               
                 30B 
                 Kollidon CL ® = 151 
                 MCC = 16.7 mg 
                 5 
                 0.79 
                 11.0 
                 14 
               
               
                 (cream tablets; 
                 mg 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 Kollidon CL ® = 13.9 
                   
                   
                   
                   
               
               
                 ~96.7 mg) 
                   
                 mg 
                   
                   
                   
                   
               
               
                 31A 
                 Resin = 102 mg 
                 Resin = 9.3 mg (2.8 
                 5 
                 0 
                 10.0 
                 Incomplete 
               
               
                 (cream tablets; 
                 Sorbitol = 612 mg 
                 mg THC; 4.4 mg 
                   
                   
                   
                 (&gt;6 mins) 
               
               
                 Weight/tablet = 
                 MCC = 183 mg 
                 CBD) 
                   
                   
                   
                   
               
               
                 ~96.5 mg) 
                 Mg stearate = 9 mg 
                 Sorbitol = 55.9 mg 
                   
                   
                   
                   
               
               
                 31B 
                 Kollidon CL ® = 151 
                 MCC = 16.7 mg 
                 5 
                 0 
                 10.7 
                 Incomplete 
               
               
                 (cream tablets; 
                 mg 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                 (&gt;6 mins) 
               
               
                 Weight/tablet = 
                   
                 Kollidon CL ® = 13.9 
                   
                   
                   
                   
               
               
                 ~96.4 mg) 
                   
                 mg 
               
               
                   
               
            
           
         
       
     
     Tables 44 and 45 illustrate experiments where  cannabis  resin-mannitol powder is developed first, then excipients are added at various concentrations (for example, Kollidon CL®) and/or tablet punching pressure (0.1 or 0.2 or 0.4 ton) to profile for optimal friability, hardness and disintegration times. Higher Kollidon CL® concentrations, and lower tablet punch pressures produced favorable disintegration times and friability properties. 
     Procedure for making Formulations 32 and 33: 
     Formulations 32 and 33 were prepared similarly to Formulations 27-29, except:
         samples were lyophilized for 65 hrs   tablets were punched under 0.1 (A) or 0.4 (B) ton pressure       

     
       
         
           
               
             
               
                 TABLE 45 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 32A, 32B, 33A and 33B 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Weights of resin and 
                 # of 
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts of resin 
                 excipients/tablet 
                 tablets 
                 Friability 
                 Hardness 
                 time (s) in 
               
               
                 Formulation # 
                 and excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 1 mL PBS 
               
               
                   
               
               
                 32A 
                 Resin = 102 mg 
                 Resin = 9.3 mg (2.8 mg 
                 5 
                 0.17 
                  7.9 
                 10 
               
               
                 (cream tablets; 
                 Mannitol = 612 mg 
                 THC; 4.4 mg CBD) 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 183 mg 
                 Mannitol = 55.9 mg 
                   
                   
                   
                   
               
               
                 ~96.9 mg) 
                 Mg stearate = 9 mg 
                 MCC = 16.7 mg 
                   
                   
                   
                   
               
               
                 *repetition of 51A 
                 Kollidon CL ® = 151 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
               
               
                 32B 
                 mg 
                 Kollidon CL ® = 13.9 
                 5 
                 0.10 
                  7.3 
                 15 
               
               
                 (cream tablets; 
                   
                 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                   
                   
                   
                   
                   
               
               
                 ~96.8 mg) 
                   
                   
                   
                   
                   
                   
               
               
                 *repetition of 51B 
                   
                   
                   
                   
                   
                   
               
               
                 33A 
                 Resin = 102 mg 
                 Resin = 11.6 mg (3.5 
                 4 
                 0.07 
                 6.11 
                 16 
               
               
                 (cream tablets; 
                 Mannitol = 400 mg 
                 mg THC; 5.5 mg CBD) 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 183 mg 
                 Mannitol = 45.7 mg 
                   
                   
                   
                   
               
               
                 ~96.5 mg) 
                 Mg stearate = 9 mg 
                 MCC = 20.9 mg 
                   
                   
                   
                   
               
               
                 33B 
                 Kollidon CL ® = 151 
                 Mg stearate = 1.0 mg 
                 4 
                 0.07 
                 5.26 
                 16 
               
               
                 (cream tablets; 
                 mg 
                 Kollidon CL ® = 17.2 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 mg 
                   
                   
                   
                   
               
               
                 ~96.5 mg) 
               
               
                   
               
            
           
         
       
     
     Procedure for making Formulations 34 and 35: 
     The procedures for making Formulations 32B and 33B (0.4 ton pressure only) were repeated on a larger scale to afford &gt;20 tablets. 
     
       
         
           
               
             
               
                 TABLE 46 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 34 and 35 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts of 
                 Weights of resin and 
                 # of 
                   
                   
                 time (s) in 1 mL 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 resin and excipients 
                 excipients/tablet 
                 tablets 
                 Friability 
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation 
                 (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS 
                 saliva 
               
               
                   
               
               
                 34 
                 Resin = 306 mg 
                 Resin = 11.6 mg (5.2 mg 
                 25 
                 0 
                 4.9 
                 71 
                 167 
               
               
                 (beige tablets; 
                 Mannitol = 1200 mg 
                 THC; 8.3 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 549 mg 
                 Mannitol = 45.7 mg 
                   
                   
                   
                   
                   
               
               
                 ~96.5 mg) 
                 Mg stearate = 27 mg 
                 MCC = 20.9 mg 
                   
                   
                   
                   
                   
               
               
                 *repetition of 
                 Kollidon CL ® = 453 
                 Mg stearate = 1.0 mg 
                   
                   
                   
                   
                   
               
               
                 33B 
                 mg 
                 Kollidon CL ® = 17.2 mg 
                   
                   
                   
                   
                   
               
               
                 35 
                 Resin = 306 mg 
                 Resin = 9.3 mg (4.1 mg 
                 32 
                 0 
                 6.1 
                 17 
                 60 
               
               
                 (cream tablets; 
                 Mannitol = 1836 mg 
                 THC; 6.6 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 549 mg 
                 Mannitol = 55.9 mg 
                   
                   
                   
                   
                   
               
               
                 ~96.5 mg) 
                 Mg stearate = 27 mg 
                 MCC = 16.7 mg 
                   
                   
                   
                   
                   
               
               
                 *repetition of 
                 Kollidon CL ® = 453 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                 32B 
                 mg 
                 Kollidon CL ® = 13.9 mg 
               
               
                   
               
            
           
         
       
     
     Procedure for making Formulations 36 and 37: 
     Formulations 36 and 37 were prepared similarly to 27-29, except:
         that samples were lyophilized for 65 hrs   ˜200 mg per tablet   tablets were punched under 0.1(A) or 0.4 (B) ton pressure       

     
       
         
           
               
             
               
                 TABLE 47 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 36A, 36B, 37A and 37B 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Total amounts of 
                 Weights of resin and 
                 # of 
                   
                   
                 Disintegration 
               
               
                   
                 resin and excipients 
                 excipients/tablet 
                 tablets 
                 Friability 
                 Hardness 
                 time (s) in 1 mL  
               
               
                 Formulation 
                 (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 artificial saliva 
               
               
                   
               
               
                 36A 
                 Resin = 195 mg 
                 Resin = 24.1 mg (8.7 
                 4 
                 0.12 
                 18.6 
                 78 
               
               
                 (beige tablets; 
                 Mannitol = 765 mg 
                 mg THC; 13.8 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 350 mg 
                 CBD) 
                   
                   
                   
                   
               
               
                 ~200.4 mg) 
                 Mg stearate = 17 mg 
                 Mannitol = 94.7 mg 
                   
                   
                   
                   
               
               
                 36B 
                 Kollidon CL ® = 289 
                 MCC = 43.3 mg 
                 4 
                 0.25 
                 17.1 
                 66 
               
               
                 (beige tablets; 
                 mg 
                 Mg stearate = 2.1 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 Kollidon CL ® = 35.8 
                   
                   
                   
                   
               
               
                 ~199.8 mg) 
                   
                 mg 
                   
                   
                   
                   
               
               
                 37A 
                 Resin = 204 mg 
                 Resin = 19.3 mg (6.5 
                 5 
                 0.17 
                 26.8 
                 90 
               
               
                 (cream tablets; 
                 Mannitol = 1224 mg 
                 mg THC; 10.3 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 366 mg 
                 CBD) 
                   
                   
                   
                   
               
               
                 ~200.0 mg) 
                 Mg stearate = 18 mg 
                 Mannitol = 115.8 mg 
                   
                   
                   
                   
               
               
                 37B 
                 Kollidon CLO = 302 
                 MCC = 34.6 mg 
                 5 
                 0.13 
                 21.7 
                 98 
               
               
                 (cream tablets; 
                 mg 
                 Mg stearate = 1.7 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 Kollidon CL ® = 13.9 
                   
                   
                   
                   
               
               
                 ~199.7 mg) 
                   
                 mg 
               
               
                   
               
            
           
         
       
     
     Procedure for making Formulations 38 and 39:
         1. Formulations 38 and 39 were prepared similarly to Formulations 36 and 37, except that the tablet weight in Formulations 38 and 39 is about 200 mg/tablet, and in Formulations 36 and 37, it is about 100 mg/tablet. Removed 0.51 mL of 200 mg/mL of resin solution, placed in vial and diluted to 1 mL with ethanol (102 mg of resin)   2. A solution of mannitol (306 mg) in 4 mL water was added   3. Added 3 more mL of water   4. Lyophilized for 65 hrs   5. Added 306 mg amount of mannitol, in addition other excipients in quantities as shown in Table 48   6. Triturated in a porcelain mortar with a pestle until having a homogeneous solid solution   7. Weighed ˜100 mg of the mixture for each tablet and load into a 10 mm die   8. Punched under 0.1 (A) or 0.4 (B) ton pressure, using Specac® manual hydraulic press   9. Collected tablets in a 20 mL vial       

     
       
         
           
               
             
               
                 TABLE 48 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 38A, 38B, 39A and 39B 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Total amounts of 
                 Weights of resin and 
                 # of 
                   
                   
                 Disintegration 
               
               
                   
                 resin and 
                 excipients/tablet 
                 tablets 
                 Friability 
                 Hardness 
                 time (s) in 1 mL 
               
               
                 Formulation 
                 excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 artificial saliva 
               
               
                   
               
               
                 38A 
                 Resin = 102 mg 
                 Resin = 9.3 mg (3.1 
                 4 
                 0.35 
                 7.8 
                 153 
               
               
                 (beige tablets; 
                 Mannitol = 612 mg 
                 mg THC; 5.0 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 183 mg 
                 CBD) 
                   
                   
                   
                   
               
               
                 ~99.9 mg) 
                 Mg stearate = 9 mg 
                 Mannitol = 55.9 mg 
                   
                   
                   
                   
               
               
                 38B 
                 Kollidon CL ® = 
                 MCC = 16.7 mg 
                 4 
                 0.20 
                 7.0 
                 130 
               
               
                 (beige tablets; 
                 151 mg 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 Kollidon CL ® = 13.9 
                   
                   
                   
                   
               
               
                 ~100.1 mg) 
                   
                 mg 
                   
                   
                   
                   
               
               
                 39A 
                 Resin = 102 mg 
                 Resin = 11.6 mg (3.9 
                 4 
                 0.05 
                 7.8 
                 166 
               
               
                 (beige tablets; 
                 Mannitol = 400 mg 
                 mg THC; 6.2 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 183 mg 
                 CBD) 
                   
                   
                   
                   
               
               
                 ~100.1 mg) 
                 Mg stearate = 9 mg 
                 Mannitol = 45.7 mg 
                   
                   
                   
                   
               
               
                 39B 
                 Kollidon CL ® = 
                 MCC = 20.9 mg 
                 5 
                 0.10 
                 6.9 
                 167 
               
               
                 (beige tablets; 
                 151 mg 
                 Mg stearate = 1.0 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 Kollidon CL ® = 17.2 
                   
                   
                   
                   
               
               
                 ~99.1 mg) 
                   
                 mg 
               
               
                   
               
            
           
         
       
     
     Formulations 40 and 41 were made using the same procedure as Formulations 38 and 39. 
     
       
         
           
               
             
               
                 TABLE 49 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 40A, 40B, 41A and 41B 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Total amounts of 
                 Weights of resin and 
                 # of 
                   
                   
                 Disintegration 
               
               
                   
                 resin and excipients 
                 excipients/tablet 
                 tablets 
                 Friability 
                 Hardness 
                 time (s) in 1 mL 
               
               
                 Formulation 
                 (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 artificial saliva 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 40A 
                 Resin =204 mg 
                 Resin = 24.1 mg (3.9 
                 4 
                 0 
                 16.8 
                 170 
               
               
                 (beige tablets; 
                 Mannitol = 800 mg 
                 mg THC; 6.2 mg CBD) 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 366 mg 
                 Mannitol = 95.7 mg 
                   
                   
                   
                   
               
               
                 ~199.7 mg) 
                 Mg stearate = 18 mg 
                 MCC = 43.3 mg 
                   
                   
                   
                   
               
               
                 40B 
                 Kollidon CL ® = 302 
                 Mg stearate = 2.1 mg 
                 4 
                 0.02 
                 12.3 
                 158 
               
               
                 (beige tablets; 
                 mg 
                 Kollidon CL ® = 35.7 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 mg 
                   
                   
                   
                   
               
               
                 ~200.2 mg) 
                   
                   
                   
                   
                   
                   
               
               
                 41A 
                 Resin = 204 mg 
                 Resin = 19.3 mg (6.5 
                 5 
                 0.05 
                  8.5 
                 124 
               
               
                 (beige tablets; 
                 Mannitol = 1224 mg 
                 mg THC; 10.3 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 366 mg 
                 CBD) 
                   
                   
                   
                   
               
               
                 ~199.9 mg) 
                 Mg stearate = 18 mg 
                 Mannitol = 115.8 mg 
                   
                   
                   
                   
               
               
                 41B 
                 Kollidon CL ® = 302 
                 MCC = 34.6 mg 
                 5 
                 0.0 
                  7.5 
                 107 
               
               
                 (beige tablets; 
                 mg 
                 Mg stearate = 1.7 mg 
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 Kollidon CL ® = 13.9 
                   
                   
                   
                   
               
               
                 ~200.0 mg) 
                   
                 mg 
               
               
                   
               
            
           
         
       
     
     Procedure for making Formulation 42:
         1. Removed 0.51 mL of 200 mg/mL solution of resin, placed in vial and diluted to 1 mL with ethanol (102 mg of resin)   2. A solution of mannitol (400 mg) in 4 mL water was added   3. Added 3 more mL of water   4. Lyophilized all vials for 67 hrs   5. Added remaining amount of mannitol (212 mg) as well as other excipients in quantities as shown in Table 50   6. Triturated in a porcelain mortar with a pestle until having a homogeneous solid solution   7. Weighed ˜36 mg of the mixture for each tablet and load into a 3 mm die   8. Punched under 0.1 ton pressure, using Specac® manual hydraulic press   9. Collected tablets in a 20 mL vial       

     
       
         
           
               
             
               
                 TABLE 50 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulation 42 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Disintegration time 
               
               
                   
                 Total amounts of 
                   
                 # of 
                   
                   
                 (s) in 1 mL 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 resin and excipients 
                 Weights of resin and 
                 tablets 
                 Friability 
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation 
                 (mg) 
                 excipients/tablet (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS 
                 saliva 
               
               
                   
               
               
                 42 
                 Resin = 102 mg 
                 Resin = 3.5 mg (1.1 mg 
                 28 
                 0.6 
                 60.4 
                 26.5 
                 43.5 
               
               
                 (beige tablets; 
                 Mannitol = 612 mg 
                 THC; 1.5 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 183 mg 
                 Mannitol = 20.8 mg 
                   
                   
                   
                   
                   
               
               
                 ~35.5 mg) 
                 Mg stearate = 9 mg 
                 MCC = 6.2 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 151 
                 Mg stearate = 0.3 mg 
                   
                   
                   
                   
                   
               
               
                   
                 mg 
                 Kollidon CL ® = 5.1 mg 
               
               
                   
               
            
           
         
       
     
     Experiment 19: Determination of Stability of the Sublingual Tablet 
     Strain 1 resin used was found to contain 31.7% THC and 46.1% CBD. Procedure for making Formulation 43:
         1. Resin (0.2965 g) was dissolved in ethanol (2.965 mL) to give a 100 mg/mL solution   2. Divided ethanolic solution into three portions, then made up volume to 1 mL with ethanol (98.8 mg of resin per vial)   3. A solution of mannitol (593 mg) in 4 mL water was added to each vial   4. Added 3 more mL of water   5. Lyophilized all vials for 42 hrs   6. Combined vials and added other excipients in quantities as shown in Table 51   7. Triturated in a porcelain mortar with a pestle until having a homogeneous solid solution   8. Weighed ˜96.5 mg of the mixture for each tablet and load into a 10 mm die   9. Punched under 0.4 ton pressure, using Specac® manual hydraulic press   10. Collected tablets in a 20 mL vial   11. The tablets were placed in the humidity chamber at 37° C. and 40% humidity on day 2 and the quality of the tablets determined at specific time periods       

     
       
         
           
               
             
               
                 TABLE 51 
               
             
            
               
                   
               
               
                 Components of sublingual tablet Formulation 43 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 # of 
               
               
                   
                 Total amounts of resin 
                 Weights of resin and 
                 tablets 
               
               
                 Formulation 
                 and excipients (mg) 
                 excipients/tablet (mg) 
                 made 
               
               
                   
               
               
                 43 
                 Resin = 296.5 mg 
                 Resin = 9.3 mg (2.9 mg THC; 4.2 mg 
                 31 
               
               
                 (beige tablets; 
                 Mannitol = 1779 mg 
                 CBD) 
               
               
                 weight/tablet = ~96.4 mg) 
                 MCC = 534 mg 
                 Mannitol = 55.8 mg 
               
               
                   
                 Mg stearate = 27 mg 
                 MCC = 16.7 mg 
               
               
                   
                 Kollidon CL ® = 439 mg 
                 Mg stearate = 0.8 mg 
               
               
                   
                   
                 Kollidon CL ® = 13.8 mg 
               
               
                   
               
            
           
         
       
     
                     TABLE 52                  Properties of sublingual tablet Formulation 43                         Disintegration           time (s) in 1 mL                                             Friability   Hardness       Artificial       Formulation   Days   (%)   (N)   PBS   saliva               43   1a   0.78    7.8 ± 0.3   20.5 ± 0.7   64.0 ± 1.4       (CDS-ML-II-   8a   0.40   13.7 ± 0.7   17.5 ± 2.1   54.0 ± 12.7       66-1)   23a    0.05   17.1 ± 1.7   20.5 ± 2.1   87.0 ± 4.2               The same tablets were used for friability first then hardness.       aN = 2 tablets            
This study is meant to observe the changes to the hardness, friability and disintegration times of the tablets over the course of time. A favorable profile will not alter disintegration times significantly, exceeding 120 seconds or so, for example in PBS. While there is no set rule to accept or reject a particular outcome, ideally one would like to have disintegration within 1-2 min (60-120 sec), even after storing the product for several days.
 
     Experiment 20: Further Studies of Sublingual RDT Formulations 
     Formulation 44 comprised decarboxylated  cannabis  resin from strain 5, containing 36.0% THC and 60.0% CBD, and was made by the following procedure:
         1. Resin (0.1025 g) was dissolved in ethanol (1.02 mL) to give a 100 mg/mL solution   2. A solution of mannitol (612 mg) in 4 mL water was added to each vial   3. See steps 4-8 as described above in Formulation 43   4. Punch under 0.1 (A) or 0.4 (B) ton pressure, using Specac® manual hydraulic press       

     
       
         
           
               
             
               
                 TABLE 53 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 44A 
               
               
                 and 44B; physical properties measured on day 0 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Weights of resin 
                   
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts 
                 and 
                 # of 
                   
                   
                 time(s) in 1 mL b   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 of resin and 
                 excipients/tablet 
                 tablets 
                 Friability a   
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation 
                 excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS  
                 saliva 
               
               
                   
               
               
                 44A 
                 Resin = 102.5 mg 
                 Resin = 9.4 mg 
                 5 
                 0.47 
                 11.7 ± 5.9 
                 40 
                 &gt;6 mins 
               
               
                 (beige 
                 Mannitol = 612 
                 (3.4 mg THC; 5.6 
                   
                   
                   
                   
                   
               
               
                 tablets; 
                 mg 
                 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 Weight/table 
                 MCC = 183 mg 
                 Mannitol = 55.9 
                   
                   
                   
                   
                   
               
               
                 t = ~96.6 mg) 
                 Mg stearate = 9 
                 mg 
                   
                   
                   
                   
                   
               
               
                   
                 mg 
                 MCC = 16.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 Mg stearate = 0.8 
                   
                   
                   
                   
                   
               
               
                   
                 151 mg 
                 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 13.8 mg 
                   
                   
                   
                   
                   
               
               
                 44B 
                   
                 Resin = 3.3 mg 
                 5 
                 0.16 
                 10.0 ± 2.9 
                 45 
                 &gt;6 mins 
               
               
                 (beige 
                   
                 (3.4 mg THC; 5.6 
                   
                   
                   
                   
                   
               
               
                 tablets; 
                   
                 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 Weight/table 
                   
                 Mannitol = 55.8 
                   
                   
                   
                   
                   
               
               
                 t = ~96.4 mg) 
                   
                 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 MCC = 16.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.8 
                   
                   
                   
                   
                   
               
               
                   
                   
                 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 13.8 mg 
               
               
                   
               
               
                   a The same tablets were used for friability first then hardness; N = 2 tablets 
               
               
                   b N = 1 tablet 
               
            
           
         
       
     
     Formulation 45 comprised decarboxylated  cannabis  resin from strain 3, containing 49.8% THC and &lt;1% CBD, and was made by the following procedure:
         1. Resin (0.1974 g) was dissolved in ethanol (1.974 mL) to give a 100 mg/mL solution   2. Divided ethanolic solution into two portions, then made up volume to 1 mL with ethanol (98.7 mg of resin per vial)   3. A solution of mannitol (592 mg) in 4 mL water was added to each vial   4. See steps 4-8 as described above in Formulation 43   5. Punch under 0.1 (A) or 0.4 (B) ton pressure, using Specac® manual hydraulic press       

     
       
         
           
               
             
               
                 TABLE 54 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 45A 
               
               
                 and 45B; physical properties measured on day 1 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Weights of resin 
                   
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts 
                 and 
                 # of 
                   
                   
                 time(s) in 1 mL b   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 of resin and 
                 excipients/tablet 
                 tablets 
                 Friability a   
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation 
                 excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS  
                 saliva 
               
               
                   
               
               
                 45A 
                 Resin = 197.4 mg 
                 Resin = 11.1 mg 
                 8 
                 0.26 
                 9.8 ± 0.6 
                 33 
                 224 
               
               
                 (cream tablets; 
                 Mannitol = 1184 
                 (5.5 mg THC) 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 mg 
                 Mannitol = 66.4 
                   
                   
                   
                   
                   
               
               
                 ~96.1 mg) 
                 MCC = 178 mg 
                 mg 
                   
                   
                   
                   
                   
               
               
                 45B 
                 Mg stearate = 9 mg 
                 MCC = 10.0 mg 
                 8 
                 0.36 
                 9.7 ± 0.4 
                 31 
                 191 
               
               
                 (cream tablets; 
                 Kollidon CL ® = 
                 Mg stearate = 0.5 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 146 mg 
                 mg 
                   
                   
                   
                   
                   
               
               
                 ~96.2 mg) 
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 8.2 mg 
               
               
                   
               
               
                   a The same tablets were used for friability first then hardness; N = 2 tablets 
               
               
                   b N = 1 tablet 
               
            
           
         
       
     
     Formulation 46 comprised decarboxylated  cannabis  resin from strain 2, containing 1.9% THC and 37.6% CBD, and was made by the following procedure:
         1. Resin (0.1552 g) was dissolved in ethanol (1.552 mL) to give a 100 mg/mL solution   2. Divided ethanolic solution into two portions, then made up volume to 1 mL with ethanol (77.6 mg of resin per vial)   3. A solution of mannitol (466 mg) in 4 mL water was added to each vial   4. See steps 4-8 as described above in Formulation 43   5. Punch under 0.1 (A) or 0.4 (B) ton pressure, using Specac® manual hydraulic press       

     
       
         
           
               
             
               
                 TABLE 55 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 46A 
               
               
                 and 46B; physical properties measured on day 1 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Weights of resin 
                   
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts 
                 and 
                 # of 
                   
                   
                 time(s) in 1 mL b   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 of resin and 
                 excipients/tablet 
                 tablets 
                 Friability a   
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation 
                 excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS  
                 saliva 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 46A 
                 Resin = 155.2 mg 
                 Resin = 11.1 mg 
                 6 
                 0.05 
                 5.5 ± 0.4 
                 30 
                 362 
               
               
                 (cream tablets; 
                 Mannitol = 931 mg 
                 (0.2 mg THC, 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 140 mg 
                 4.2 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.3 mg) 
                 Mg stearate = 7 mg 
                 Mannitol = 66.5 
                   
                   
                   
                   
                   
               
               
                 46B 
                 Kollidon CL ® = 
                 mg 
                 6 
                 0.05 
                 8.5 ± 0.7 
                 29 
                 361 
               
               
                 (cream tablets; 
                 115 mg 
                 MCC = 10.0 mg 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 Mg stearate = 0.5 
                   
                   
                   
                   
                   
               
               
                 ~96.6 mg) 
                   
                 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 8.2 mg 
               
               
                   
               
               
                   a The same tablets were used for friability first then hardness; N = 2 tablets 
               
               
                   b N = 1 tablet 
               
            
           
         
       
     
     These experiments (Formulations 44-46) suggest that decarboxylated  cannabis  resins containing various ratios of THC and CBD in them may tend to exhibit similar disintegration behavior (under 50 sec), and low friability (&lt;1%), although hardness differed noticeably. A person of skill in the art would be able to make minor adjustments to the disclosed excipients to accommodate the properties of such tablet dosage forms to acceptable levels. 
     Formulation 47 was made according to the procedure used for making Formulation 42 . Cannabis  resin constituents (THC and CBD) are 1.1 mg/1.5 mg in Formulation 42, and 1.3 mg/1.4 mg in Formulation 47, and the total THC+CBD content is 2.6 mg and 2.7 mg, respectively. 
     
       
         
           
               
             
               
                 TABLE 56 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 47; 
               
               
                 physical properties measured on day 1 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Weights of resin 
                   
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts 
                 and 
                 # of 
                   
                   
                 time(s) in 1 mL 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 of resin and 
                 excipients/tablet 
                 tablets 
                 Friability 
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation 
                 excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS  
                 saliva 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 47 
                 Resin = 102 mg 
                 Resin = 3.4 mg  
                 28 
                 0.14 
                 112.0 
                 8 
                 46.5 
               
               
                 (beige tablets; 
                 Mannitol = 612 mg 
                 (equiv. 1.3 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 183 mg 
                 1.4 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~35.7 mg) 
                 Mg stearate = 9 mg 
                 Mannitol = 20.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 MCC = 6.2 mg 
                   
                   
                   
                   
                   
               
               
                   
                 151 mg 
                 Mg stearate = 0.3 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 5.1 mg 
               
               
                   
               
            
           
         
       
     
     Formulation 48 was made according to the procedure used for making Formulation 44. 
     
       
         
           
               
             
               
                 TABLE 57 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 48A 
               
               
                 and 48B; physical properties measured on day 1 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Weights of resin 
                   
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts 
                 and 
                 # of 
                   
                   
                 time(s) in 1 mL 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 of resin and 
                 excipients/tablet 
                 tablets 
                 Friability 
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation 
                 excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS  
                 saliva 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 48A 
                 Resin = 102 mg 
                 Resin = 9.2 mg 
                 5 
                 0.10 
                 5.1 
                 16 
                 2185 
               
               
                 (cream tablets; 
                 Mannitol = 795 mg 
                 (2.6 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mg stearate = 9 mg 
                 3.5 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.6 mg) 
                 Kollidon CL ® = 
                 Mannitol = 72.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                 151 mg 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 13.8 mg 
                   
                   
                   
                   
                   
               
               
                 48B 
                   
                 Resin = 9.3 mg 
                 5 
                 0.10 
                 6.8 
                 27 
                  298 
               
               
                 (cream tablets; 
                   
                 (2.6 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 3.5 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.4 mg) 
                   
                 Mannitol = 72.5 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 13.8 mg 
               
               
                   
               
            
           
         
       
     
     Formulations 49-51 were made according to the procedure used for making Formulation 44. 
     
       
         
           
               
             
               
                 TABLE 58 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 49A, 49B, 50A, 
               
               
                 50B, 51A and 51B; physical properties measured on day 1 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Weights of resin 
                   
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts 
                 and 
                 # of 
                   
                   
                 time(s) in 1 mL 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 of resin and 
                 excipients/tablet 
                 tablets 
                 Friability 
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation 
                 excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS  
                 saliva 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 49A 
                 Resin = 102 mg 
                 Resin = 9.3 mg 
                 5 
                 0.10 
                 8.2 
                 30 
                 203 
               
               
                 (cream tablets; 
                 Mannitol = 612 mg 
                 (3.4 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 183 mg 
                 4.0 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.4 mg) 
                 Mg stearate = 9 mg 
                 Mannitol = 55.8 mg 
                   
                   
                   
                   
                   
               
               
                 49B 
                 *CCS = 151 mg 
                 MCC = 16.7 mg 
                 5 
                 0.10 
                 9.6 
                 18 
                 249 
               
               
                 (cream tablets; 
                   
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 CCS = 13.8 mg 
                   
                   
                   
                   
                   
               
               
                 ~96.4 mg) 
                   
                   
                   
                   
                   
                   
                   
               
               
                 50A 
                 Resin = 102 mg 
                 Resin = 9.3 mg 
                 5 
                 0   
                 6.6 
                 50 
                 &gt;6 mins 
               
               
                 (cream tablets; 
                 Mannitol = 612 mg 
                 (3.4 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 183 mg 
                 4.0 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.3 mg) 
                 Mg stearate = 9 mg 
                 Mannitol = 55.8 mg 
                   
                   
                   
                   
                   
               
               
                 50B 
                 #SSG = 151 mg 
                 MCC = 16.7 mg 
                 5 
                 0.21 
                 9.0 
                 112 
                 &gt;6 mins 
               
               
                 (cream tablets; 
                   
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 SSG = 13.8 mg 
                   
                   
                   
                   
                   
               
               
                 ~96.2 mg) 
                   
                   
                   
                   
                   
                   
                   
               
               
                 51A 
                 Resin = 102 mg 
                 Resin = 9.3 mg 
                 5 
                 0.10 
                 8.0 
                 26 
                 &gt;6 mins 
               
               
                 (cream tablets; 
                 Mannitol = 612 mg 
                 (3.4 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 183 mg 
                 4.0 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.4 mg) 
                 Mg stearate = 9 mg 
                 Mannitol = 55.8 mg 
                   
                   
                   
                   
                   
               
               
                 51B 
                 Polyplasdone = 
                 MCC = 16.7 mg 
                 5 
                 0.16 
                 9.1 
                 26 
                 &gt;6 mins 
               
               
                 (cream tablets; 
                 151 mg 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 Polyplasdone = 
                   
                   
                   
                   
                   
               
               
                 ~96.4 mg) 
                   
                 13.8 mg 
               
               
                   
               
               
                 *CCS = Croscarmellose sodium 
               
               
                 #SSG = Sodium starch glycolate 
               
            
           
         
       
     
     Formulations 52 and 53 were made according to the procedure used for making Formulation 44. 
     
       
         
           
               
             
               
                 TABLE 59 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 52A, 52B, 53A 
               
               
                 and 53B; physical properties measured on day 1 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Weights of resin 
                   
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts 
                 and 
                 # of 
                   
                   
                 time(s) in 1 mL 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 of resin and 
                 excipients/tablet 
                 tablets 
                 Friability 
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation 
                 excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS  
                 saliva 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 52A 
                 Resin = 102 mg 
                 Resin = 9.3 mg 
                 5 
                 0.05 
                 8.8 
                 &gt;6 mins 
                 &gt;6 mins 
               
               
                 (cream tablets; 
                 Mannitol = 612 mg 
                 (3.0 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 183 mg 
                 3.6 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.4 mg) 
                 Mg stearate = 9 mg 
                 Mannitol = 55.8 mg 
                   
                   
                   
                   
                   
               
               
                 52B 
                 Klucel ™ (HPC) = 
                 MCC = 16.7 mg 
                 5 
                 0.05 
                 9.8 
                 &gt;6 mins 
                 &gt;6 mins 
               
               
                 (cream tablets; 
                 151 mg 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 Klucel ™ (HPC) = 
                   
                   
                   
                   
                   
               
               
                 ~96.4 mg) 
                   
                 13.8 mg 
                   
                   
                   
                   
                   
               
               
                 53A 
                 Resin = 102 mg 
                 Resin = 9.3 mg 
                 5 
                 0 
                 7.8 
                 59 
                 &gt;6 mins 
               
               
                 (cream tablets; 
                 Mannitol = 612 mg 
                 (3.0 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 183 mg 
                 3.6 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.2 mg) 
                 Mg stearate = 9 mg 
                 Mannitol = 55.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                 L-HPC = 151 mg 
                 MCC = 16.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 L-HPC = 13.7 mg 
                   
                   
                   
                   
                   
               
               
                 53B 
                   
                 Resin = 9.6 mg 
                 4 
                 0 
                 6.6 
                 73 
                 &gt;6 mins 
               
               
                 (cream tablets; 
                   
                 (3.1 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 3.7 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~99.5 mg) 
                   
                 Mannitol = 57.6 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 MCC = 16.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 L-HPC = 14.2 mg 
               
               
                   
               
               
                 *HPC = hydroxypropyl cellulose 
               
               
                 *L-HPC = low-substituted hydroxypropyl cellulose 
               
            
           
         
       
     
     Formulation 54 was made according to the procedure used for making Formulation 44. 
     
       
         
           
               
             
               
                 TABLE 60 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 54A 
               
               
                 and 54B; physical properties measured on day 1 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Weights of resin 
                   
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts 
                 and 
                 # of 
                   
                   
                 time(s) in 1 mL 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 of resin and 
                 excipients/tablet 
                 tablets 
                 Friability 
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation 
                 excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS  
                 saliva 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 54A 
                 Resin (Strain 1) =  
                 Resin = 9.8 mg 
                 9 
                 2.4 
                 3.7 
                 11 
                 340 
               
               
                 (cream tablets; 
                 197.2 mg 
                 (3.0 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mannitol = 1183 mg 
                 4.1 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~101.7 mg) 
                 MCC = 177 mg 
                 Mannitol = 58.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Mg stearate = 18 mg 
                 MCC = 8.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Pol 407 = 177 mg 
                 Mg stearate = 0.9 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 Pol 407 = 8.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                 292 mg 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 14.5 mg 
                   
                   
                   
                   
                   
               
               
                 54B 
                   
                 Resin = 9.4 mg 
                 9 
                 0   
                 Failed 
                 12 
                 235 
               
               
                 (cream tablets; 
                   
                 (2.9 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 3.9 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~97.3 mg) 
                   
                 Mannitol = 56.3 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 MCC = 8.4 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Pol 407 =  
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 13.9 mg 
               
               
                   
               
            
           
         
       
     
     Experiment 21: A Trial to Substitute Mannitol with Sucrose 
     Procedure for making Formulation 55:
         1. Weighed resin into 2 vials and dissolved in 1 mL EtOH each   2. A solution of sucrose in 4 mL water was added to one vial and another solution of xylitol in 4 mL water was added to the other vial   3. Added 3 more mL of water to each vial   4. Lyophilized all vials for 43 hrs Note: After lyophilization, it was noted that vial with xylitol was a viscous liquid, therefore nothing further was done   5. Added other excipients to sucrose formulation in quantities as shown in table   6. Triturated in a porcelain mortar with a pestle until having a homogeneous solid solution   7. Weighed mixture for each tablet and load into a 10 mm die   8. Punched under 0.1 (A) or 0.4 (B) ton pressure, using Specac® manual hydraulic press   9. Collected tablets in 20 mL vials       

     
       
         
           
               
             
               
                 TABLE 61 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 55A 
               
               
                 and 55B; physical properties measured on day 1 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Weights of resin 
                   
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts 
                 and 
                 # of 
                   
                   
                 time(s) in 1 mL 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 of resin and 
                 excipients/tablet 
                 tablets 
                 Friability 
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation #  
                 excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS  
                 saliva 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 55A 
                 Resin = 101.3 mg  
                 Resin = 9.4 mg 
                 5 
                 0.67 
                 4.5 
                 &gt;6 mins 
                 &gt;6 mins 
               
               
                 (brown tablets; 
                 Sucrose = 608 mg 
                 (3.5 mg THC; 
                   
                   
                 (4.9, 4.1) 
                   
                   
               
               
                 Weight/tablet = 
                 MCC = 182 mg 
                 4.0 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~97.2 mg) 
                 Mg stearate = 9 mg 
                 Sucrose = 56.2 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 MCC = 16.9 mg 
                   
                   
                   
                   
                   
               
               
                   
                 150 mg 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 13.9 mg 
                   
                   
                   
                   
                   
               
               
                 55B 
                   
                 Resin = 9.3 mg 
                 5 
                 0.46 
                 8.4 
                 &gt;6 mins 
                 &gt;6 mins 
               
               
                 (brown tablets; 
                   
                 (3.5 mg THC; 
                   
                   
                 (8.4, 8.3) 
                   
                   
               
               
                 Weight/tablet = 
                   
                 4.0 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.9 mg) 
                   
                 Sucrose = 56.1 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 MCC = 16.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 13.8 mg 
               
               
                   
               
            
           
         
       
     
     Experiment 22: Incorporation of an Effervescent Mixture into the Sublingual Tablet Formulations 
     Formulation 56-59: (A trial to incorporate an effervescent mixture into the RDT formulation along with head-to-head comparison between  cannabis  Strain 1 and Strain 4 resins in the same formulation). 
     Formulations 56-59 were made according to the procedure used for making Formulation 44. 
     
       
         
           
               
             
               
                 TABLE 62 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 56A, 56B, 57A, 
               
               
                 57B, 58A, 58B, 59A and 59B; physical properties measured on day 1 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Weights of resin 
                   
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts 
                 and 
                 # of 
                   
                   
                 time(s) in 1 mL 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 of resin and 
                 excipients/tablet 
                 tablets 
                 Friability 
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation  
                 excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS  
                 saliva 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 56A 
                 Resin (Strain 1) =  
                 Resin = 9.4 mg 
                 5 
                 0 
                 4.3 
                 37 
                 &gt;6 mins 
               
               
                 (cream tablets; 
                 102 mg 
                 (3.0 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mannitol = 612 mg 
                 3.6 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~106.0 mg) 
                 Mg stearate = 9 mg 
                 Mannitol = 56.4 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                 334 mg 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                 Citric acid = 40 mg 
                 30.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                 NaHCO3 = 53 mg 
                 Citric acid = 3.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 NaHCO3 = 4.9 mg 
                   
                   
                   
                   
                   
               
               
                 56B 
                   
                 Resin = 9.4 mg 
                 5 
                 0 
                 6.1 
                 48 
                 &gt;6 mins 
               
               
                 (cream tablets; 
                   
                 (3.0 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 3.6 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~105.8 mg) 
                   
                 Mannitol = 56.3 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 30.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Citric acid = 3.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 NaHCO3 = 4.9 mg 
                   
                   
                   
                   
                   
               
               
                 57A 
                 Resin (Strain 1) =  
                 Resin = 9.2 mg 
                 6 
                 0.05 
                 3.6 
                 33 
                 &gt;6 mins 
               
               
                 (cream tablets; 
                 109.1 mg 
                 (3.5 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mannitol = 654 mg 
                 3.9 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~100.0 mg) 
                 MCC = 196 mg 
                 Mannitol = 55.4 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Mg stearate = 10 mg 
                 MCC = 16.6 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                 161 mg 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                 Citric acid = 21 mg 
                 13.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                 NaHCO3 = 28 mg 
                 Citric acid = 1.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 NaHCO3 = 2.4 mg 
                   
                   
                   
                   
                   
               
               
                 57B 
                   
                 Resin = 9.2 mg 
                 5 
                 0.15 
                 4.36 
                 36 
                 &gt;6 mins 
               
               
                 (cream tablets; 
                   
                 (3.5 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 3.9 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~99.7 mg) 
                   
                 Mannitol = 55.3 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 MCC = 16.6 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 13.6 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Citric acid = 1.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 NaHCO3 = 2.4 mg 
                   
                   
                   
                   
                   
               
               
                 58A 
                 Resin (Strain 4) =  
                 Resin = 9.4 mg 
                 5 
                 0.4 
                 3.0 
                 35 
                   
               
               
                 (cream tablets; 
                 96.2 mg 
                 (THC and CBD = 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mannitol = 577 mg 
                 TBD) 
                   
                   
                   
                   
                   
               
               
                 ~103.1 mg) 
                 Mg stearate = 9 mg 
                 Mannitol = 56.3 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                 275 mg 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                 Citric acid = 36 mg 
                 26.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                 NaHCO3 = 48 mg 
                 Citric acid = 3.5 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 NaHCO3 = 4.6 mg 
                   
                   
                   
                   
                   
               
               
                 58B 
                   
                 Resin = 9.5 mg 
                 5 
                 0.4 
                 4.9 
                 40 
                   
               
               
                 (cream tablets; 
                   
                 (THC and CBD = 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 TBD) 
                   
                   
                   
                   
                   
               
               
                 ~101.5 mg) 
                   
                 Mannitol = 57.2 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.9 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 27.3 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Citric acid = 3.5 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 NaHCO3 = 4.7 mg 
                   
                   
                   
                   
                   
               
               
                 59A 
                 Resin (Strain 4) =  
                 Resin = 9.4 mg 
                 5 
                 0.5 
                 2.3 
                 22 
                   
               
               
                 (cream tablets; 
                 96.2 mg 
                 (THC and CBD = 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mannitol = 577 mg 
                 TBD) 
                   
                   
                   
                   
                   
               
               
                 ~103.1 mg) 
                 Mg stearate = 9 mg 
                 Mannitol = 56.4 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                 315 mg 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                 Citric acid = 19 mg 
                 30.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                 NaHCO3 = 25 mg 
                 Citric acid = 1.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 NaHCO3 = 2.4 mg 
                   
                   
                   
                   
                   
               
               
                 59B 
                   
                 Resin = 9.4 mg 
                 5 
                 0.7 
                 4.1 
                 23 
                   
               
               
                 (cream tablets; 
                   
                 (THC and CBD = 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 TBD) 
                   
                   
                   
                   
                   
               
               
                 ~101.6 mg) 
                   
                 Mannitol = 56.4 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 30.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Citric acid = 1.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 NaHCO3 = 2.4 mg 
               
               
                   
               
            
           
         
       
     
     Experiment 23: Rapidly Disintegrating Sublingual Tablet Formulations Comprising Decarboxylated  cannabis  Resin from Strain 1 (THC: 7.18%/CBD: 8.6% in the Plant Material; THC: 31.7%/CBD: 46.1% and Other Phytochemicals in the Resin) 
     Formulation 60-63: (The RDT formula with an average of best/acceptable disintegration times (&lt;30 sec), i.e., Formulations 44, and 54A and the procedure to make the same) 
     Formulations 60-63 were made according to the procedure used for making Formulation 44. 
     
       
         
           
               
             
               
                 TABLE 63 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 60A, 60B, 61A, 
               
               
                 61B, 62A, 62B, 63A and 63B; physical properties measured on day 1 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Weights of resin 
                   
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts 
                 and 
                 # of 
                   
                   
                 time(s) in 1 mL 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 of resin and 
                 excipients/tablet 
                 tablets 
                 Friability 
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation  
                 excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS  
                 saliva 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 60A 
                 Resin = 102 mg  
                 Resin = 9.3 mg 
                 5 
                 0.20 
                 3.6 
                 11 
                 139 
               
               
                 (cream tablets; 
                 Mannitol = 612 mg 
                 (2.6 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mg stearate = 9 mg 
                 3.5 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.8 mg) 
                 Kollidon CL ® = 
                 Mannitol = 56.0 mg 
                   
                   
                   
                   
                   
               
               
                   
                 334 mg 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 30.6 mg 
                   
                   
                   
                   
                   
               
               
                 60B 
                   
                 Resin = 9.3 mg 
                 5 
                 0.21 
                 5.3 
                 11 
                 128 
               
               
                 (cream tablets; 
                   
                 (2.6 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 3.5 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.2 mg) 
                   
                 Mannitol = 55.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 30.4 mg 
                   
                   
                   
                   
                   
               
               
                 61A 
                 Resin = 116.9 mg  
                 Resin = 9.3 mg 
                 6 
                 0 
                 10.8  
                 17 
                 283 
               
               
                 (cream tablets; 
                 Mannitol = 701 mg 
                 (3.0 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mg stearate = 11 mg 
                 3.6 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.5 mg) 
                 Kollidon CL ® = 
                 Mannitol = 55.9 mg 
                   
                   
                   
                   
                   
               
               
                   
                 383 mg 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 30.5 mg 
                   
                   
                   
                   
                   
               
               
                 61B 
                   
                   
                 6 
                 0.1 
                 8.8 
                 23 
                 278 
               
               
                 (cream tablets; 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                   
                   
                   
                   
                   
                   
               
               
                 ~96.5 mg) 
                   
                   
                   
                   
                   
                   
                   
               
               
                 62A 
                 Resin = 174.2 mg  
                 Resin = 9.3 mg 
                 9 
                 0.1 
                 2.4 
                 13 
                 104 
               
               
                 (cream tablets; 
                 Mannitol = 1044 mg 
                 (3.0 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mg stearate = 16 mg 
                 3.6 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.5 mg) 
                 Kollidon CL ® = 
                 Mannitol = 55.9 mg 
                   
                   
                   
                   
                   
               
               
                   
                 570 mg 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 30.5 mg 
                   
                   
                   
                   
                   
               
               
                 62B 
                   
                 Kollidon CL ® = 
                 9 
                 0.15 
                 2.8 
                 13 
                 116 
               
               
                 (cream tablets; 
                   
                 30.5 mg 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                   
                   
                   
                   
                   
                   
               
               
                 ~96.6 mg) 
                   
                   
                   
                   
                   
                   
                   
               
               
                 63A 
                 Resin = 104.5 mg  
                 Resin = 9.3 mg 
                 5 
                 0.7 
                 1.4 
                 11 
                  80 
               
               
                 (cream tablets; 
                 Mannitol = 629 mg 
                 (3.0 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mg stearate = 9 mg 
                 3.6 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.4 mg) 
                 Kollidon CL ® = 
                 Mannitol = 55.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                 344 mg 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 30.5 mg 
                   
                   
                   
                   
                   
               
               
                 63B 
                   
                 Resin = 9.3 mg 
                 5 
                 0.5 
                 2.7 
                 11 
                 123 
               
               
                 (cream tablets; 
                   
                 (3.0 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 3.6 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~95.7 mg) 
                   
                 Mannitol = 55.4 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 30.2 mg 
               
               
                   
               
            
           
         
       
     
     General procedure for herein reported sublingual RDT formulations, to test the suitability of F-Melt® in the formulation and comparison to mannitol-only formulation (Tables 64-66), for Experiments 24, 25 and 26:
         1. A 100 mg/mL ethanolic solution of resin was prepared and divided into two equal portions into two vials   2. A solution of mannitol in 4 mL water was added to one vial and a suspension of F-Melt® Type C (where the formulation indicated, based on Tables 64-66) in 4 mL water was added to other vial   3. Added 3 more mL of water to each vial   4. Lyophilized all vials for 43 hrs   5. Added other excipients to each vial in quantities as shown in Tables 64-66.   6. Triturated in a porcelain mortar with a pestle until having a homogeneous solid solution   7. Weighed mixture for each tablet and load into a 10 mm die   8. Punched under 0.1 (A) or 0.4 (B) ton pressure, using Specac® manual hydraulic press   9. Collected tablets in 20 mL vials       

     Experiment 24: Rapidly Disintegrating Sublingual Tablet Formulations Comprising Decarboxylated  cannabis  Resin from Strain 3 (THC: 18.6%/CBD: 0% in the Plant Material; THC: 49.8%/CBD: &lt;1% and Other Phytochemicals in the Resin) 
       
     
       
         
           
               
             
               
                 TABLE 64 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 64A, 64B, 65A, 
               
               
                 65B, 66A, 66B, 67A and 67B; physical properties measured on day 0 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Weights of resin 
                   
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts 
                 and 
                 # of 
                   
                   
                 time(s) in 1 mL b   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 of resin and 
                 excipients/tablet 
                 tablets 
                 Friability a   
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation  
                 excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS  
                 saliva 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 64A 
                 Resin (Strain 3) =  
                 Resin = 11.1 mg 
                 8 
                 0.26 
                 9.8 ± 0.6 
                 33 
                 224 
               
               
                 (cream tablets; 
                 197.4 mg 
                 (5.5 mg THC) 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mannitol = 1184 mg 
                 Mannitol = 66.4 mg 
                   
                   
                   
                   
                   
               
               
                 ~96.1 mg) 
                 MCC = 178 mg 
                 MCC = 10.0 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Mg stearate = 9 mg 
                 Mg stearate = 0.5 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                 146 mg 
                 8.2 mg 
                   
                   
                   
                   
                   
               
               
                 64B 
                   
                   
                 8 
                 0.36 
                 9.7 ± 0.4 
                 31 
                 191 
               
               
                 (cream tablets; 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                   
                   
                   
                   
                   
                   
               
               
                 ~96.2 mg) 
                   
                   
                   
                   
                   
                   
                   
               
               
                 65A 
                 Resin (Strain 3) =  
                 Resin = 9.6 mg 
                 6 
                 0 
                 5.3 
                 11 
                 61 
               
               
                 (cream tablets; 
                 147.7 mg 
                 (4.7 mg THC) 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mannitol = 886 mg 
                 Mannitol = 57.3 mg 
                   
                   
                   
                   
                   
               
               
                 ~99.0 mg) 
                 Mg stearate = 13 mg 
                 Mg stearate = 0.9 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                 484 mg 
                 31.3 mg 
                   
                   
                   
                   
                   
               
               
                 65B 
                   
                 Resin = 9.5 mg 
                 6 
                 4.3 
                 5.7 
                 10 
                 79 
               
               
                 (cream tablets; 
                   
                 (4.7 mg THC) 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 Mannitol = 56.7 mg 
                   
                   
                   
                   
                   
               
               
                 ~98.0 mg) 
                   
                 Mg stearate = 0.9 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 31.0 mg 
                   
                   
                   
                   
                   
               
               
                 66A 
                 Resin (Strain 3) =  
                 Resin = 8.2 mg 
                 5 
                 2.1 
                 8.3 
                 11 
                 60 
               
               
                 (cream tablets; 
                 106 mg 
                 (4.1 mg THC) 
                   
                   
                 (8.7, 7.9) 
                   
                   
               
               
                 Weight/tablet = 
                 Mannitol = 612 mg 
                 Mannitol = 47.3 mg 
                   
                   
                   
                   
                   
               
               
                 ~96.3 mg) 
                 Mg stearate = 9 mg 
                 Mg stearate = 0.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Neusilin ® UFL2= 
                 Neusilin ® UFL2= 
                   
                   
                   
                   
                   
               
               
                   
                 184 mg 
                 14.2 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                 334 mg 
                 25.8 mg 
                   
                   
                   
                   
                   
               
               
                 66B 
                   
                 Resin = 8.4 mg 
                 5 
                 1.0 
                 13.7  
                 13 
                 69 
               
               
                 (cream tablets; 
                   
                 (4.2 mg THC) 
                   
                   
                 (14.6, 12.7) 
                   
                   
               
               
                 Weight/tablet = 
                   
                 Mannitol = 48.3 mg 
                   
                   
                   
                   
                   
               
               
                 ~98.2 mg) 
                   
                 Mg stearate = 0.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Neusilin ® UFL2= 
                   
                   
                   
                   
                   
               
               
                   
                   
                 14.5 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 26.4 mg 
                   
                   
                   
                   
                   
               
               
                 67A 
                 Resin (Strain 3) =  
                 Resin = 9.5 mg 
                 5 
                 2.1 
                 49   
                 265 
                 &gt;6 mins 
               
               
                 (cream tablets; 
                 106 mg 
                 (4.8 mg THC) 
                   
                   
                 (4.0, 5.8) 
                   
                   
               
               
                 Weight/tablet = 
                 Mg stearate = 5 mg 
                 Mg stearate = 0.5 mg 
                   
                   
                   
                   
                   
               
               
                 ~95.5 mg) 
                 F-Melt ® Type C = 
                 F-Melt ® Type C = 
                   
                   
                   
                   
                   
               
               
                   
                 612 + 286 mg 
                 80.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                 53 mg 
                 4.8 mg 
                   
                   
                   
                   
                   
               
               
                 67B 
                   
                 Resin = 9.6 mg 
                 5 
                 0 
                 8.5 
                 270 
                 &gt;6 mins 
               
               
                 (cream tablets; 
                   
                 (4.8 mg THC) 
                   
                   
                 (6.2, 10.8) 
                   
                   
               
               
                 Weight/tablet = 
                   
                 Mg stearate = 0.5 mg 
                   
                   
                   
                   
                   
               
               
                 ~96.2 mg) 
                   
                 F-Melt ® Type C = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 81.3 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 4.8 mg 
               
               
                   
               
               
                   a The same tablets were used for friability first then hardness; N = 2 tablets 
               
               
                   b N = 1 tablet 
               
            
           
         
       
     
     Experiment 25: Rapidly Disintegrating Sublingual Tablet Formulations Comprising Decarboxylated  cannabis  Resin from Strain 5 (THC: ˜36%/CBD: ˜60% and Other Phytochemicals in the Resin) 
       
     
       
         
           
               
             
               
                 TABLE 65 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 68A, 68B, 69A, 
               
               
                 69B, 70A, 70B, 71A and 71B; physical properties measured on day 0 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Weights of resin 
                   
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts 
                 and 
                 # of 
                   
                   
                 time(s) in 1 mL b   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 of resin and 
                 excipients/tablet 
                 tablets 
                 Friability a   
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation  
                 excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS  
                 saliva 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 68A 
                 Resin (Strain 5) =  
                 Resin = 9.4 mg 
                 5 
                 0.47 
                 11.7 ± 5.9  
                 40 
                 &gt;6 mins 
               
               
                 (beige tablets; 
                 102.5 mg 
                 (3.4 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mannitol = 612 mg 
                 5.6 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.6 mg) 
                 MCC = 183 mg 
                 Mannitol = 55.9 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Mg stearate = 9 mg 
                 MCC = 16.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                 151 mg 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 13.8 mg 
                   
                   
                   
                   
                   
               
               
                 68B 
                   
                 Resin = 3.3 mg 
                 5 
                 0.16 
                 10.0 ± 2.9  
                 45 
                 &gt;6 mins 
               
               
                 (beige tablets; 
                   
                 (3.4 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 5.6 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.4 mg) 
                   
                 Mannitol = 55.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 MCC = 16.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 13.8 mg 
                   
                   
                   
                   
                   
               
               
                 69A 
                 Resin (Strain 5) =  
                 Resin = 10.4 mg 
                 5 
                 2.4 
                 6.1 
                 40 
                 &gt;6 mins 
               
               
                 (white tablets; 
                 113.6 mg 
                 (3.7 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mannitol = 682 mg 
                 6.2 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~107.6 mg) 
                 Mg stearate = 10 mg 
                 Mannitol = 62.3 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 Mg stearate = 0.9 mg 
                   
                   
                   
                   
                   
               
               
                   
                 372 mg 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 34.0 mg 
                   
                   
                   
                   
                   
               
               
                 69B 
                   
                 Resin = 10.4 mg 
                 5 
                 5.1 
                 5.1 
                 62 
                 &gt;6 mins 
               
               
                 (white tablets; 
                   
                 (3.7 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 6.2 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~107.3 mg) 
                   
                 Mannitol = 62.1 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.9 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 33.9 mg 
                   
                   
                   
                   
                   
               
               
                 70A 
                 Resin (Strain 5) =  
                 Resin = 8.5 mg 
                 5 
                 Failed 
                 3.8 
                 19 
                  80 
               
               
                 (white tablets; 
                 115 mg 
                 (3.0 mg THC; 
                   
                 (both) 
                 (1 tablet) 
                   
                   
               
               
                 Weight/tablet = 
                 Mannitol = 690 mg 
                 5.1 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~102.8 mg) 
                 Mg stearate = 10 mg 
                 Mannitol = 50.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Neusilin ® UFL2 = 
                 Mg stearate = 0.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                 207 mg 
                 Neusilin ® UFL2 = 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 15.2 mg 
                   
                   
                   
                   
                   
               
               
                   
                 377 mg 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 27.7 mg 
                   
                   
                   
                   
                   
               
               
                 70B 
                   
                 Resin = 8.3 mg 
                 5 
                 Failed 
                 7.0 
                 17 
                 217 
               
               
                 (white tablets; 
                   
                 (3.0 mg THC; 
                   
                 (both) 
                 (1 tablet) 
                   
                   
               
               
                 Weight/tablet = 
                   
                 5.0 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~100.9 mg) 
                   
                 Mannitol = 49.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Neusilin ® UFL2 = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 14.9 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 27.2 mg 
                   
                   
                   
                   
                   
               
               
                 71A 
                 Resin (Strain 5) =  
                 Resin = 9.3 mg 
                 5 
                 0.5 
                 2.1 
                 &gt;6 mins 
                 &gt;6 mins 
               
               
                 (white tablets; 
                 115.7 mg 
                 (3.3 mg THC; 
                   
                   
                 (1.7, 2.5) 
                   
                   
               
               
                 Weight/tablet = 
                 Mg stearate = 6 mg 
                 5.6 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~95.8 mg) 
                 F-Melt ® Type C = 
                 Mg stearate = 0.5 mg 
                   
                   
                   
                   
                   
               
               
                   
                 650 + 362 mg 
                 F-Melt ® Type C = 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 81.2 mg 
                   
                   
                   
                   
                   
               
               
                   
                 60 mg 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 4.8 mg 
                   
                   
                   
                   
                   
               
               
                 71B 
                   
                 Resin = 9.4 mg 
                 5 
                 0 
                 6.6 
                 &gt;6 mins 
                 &gt;6 mins 
               
               
                 (white tablets; 
                   
                 (3.4 mg THC; 
                   
                   
                 (6.8, 6.3) 
                   
                   
               
               
                 Weight/tablet = 
                   
                 5.6 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.7 mg) 
                   
                 Mg stearate = 0.5 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 F-Melt ® Type C = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 82.0 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 4.8 mg 
               
               
                   
               
               
                   a The same tablets were used for friability first then hardness; N = 2 tablets 
               
               
                   b N = 1 tablet 
               
            
           
         
       
     
     Experiment 26: Rapidly Disintegrating Sublingual Tablet Formulations Comprising Decarboxylated  cannabis  Resin from Strain 2 (THC: 0%/CBD: 9% in the Plant Material; THC: 1.9%/CBD: 37.6% and Other Phytochemicals in the Resin) 
       
     
       
         
           
               
             
               
                 TABLE 66 
               
             
            
               
                   
               
               
                 Components and properties of sublingual tablet Formulations 72A, 72B, 73A, 
               
               
                 73B, 74A, 74B, 75A and 75B; physical properties measured on day 0 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 Weights of resin 
                   
                   
                   
                 Disintegration 
               
               
                   
                 Total amounts 
                 and 
                 # of 
                   
                   
                 time(s) in 1 mL b   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 of resin and 
                 excipients/tablet 
                 tablets 
                 Friability a   
                 Hardness 
                   
                 Artificial 
               
               
                 Formulation  
                 excipients (mg) 
                 (mg) 
                 made 
                 (%) 
                 (N) 
                 PBS  
                 saliva 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 72A 
                 Resin (Strain 2) =  
                 Resin = 11.1 mg 
                 6 
                 0.05 
                 5.5 ± 0.4 
                 30 
                 362 
               
               
                 (cream tablets; 
                 155.2 mg 
                 (0.2 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mannitol = 931 mg 
                 4.2 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.3 mg) 
                 MCC = 140 mg 
                 Mannitol = 66.5 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Mg stearate = 7 mg 
                 MCC = 10.0 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 Mg stearate = 0.5 mg 
                   
                   
                   
                   
                   
               
               
                   
                 115 mg 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                 72B 
                   
                 8.2 mg 
                 6 
                 0.05 
                 8.5 ± 0.7 
                 29 
                 361 
               
               
                 (cream tablets; 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                   
                   
                   
                   
                   
                   
               
               
                 ~96.6 mg) 
                   
                   
                   
                   
                   
                   
                   
               
               
                 73A 
                 Resin (Strain 2) =  
                 Resin = 10.1 mg 
                 4 
                 4.9 
                  3.7 
                 28 
                 253 
               
               
                 (beige tablets; 
                 82.2 mg 
                 (0.2 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mannitol = 493 mg 
                 4.1 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~104.5 mg) 
                 Mg stearate = 7 mg 
                 Mannitol = 60.5 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 Mg stearate = 0.9 mg 
                   
                   
                   
                   
                   
               
               
                   
                 269 mg 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 33.0 mg 
                   
                   
                   
                   
                   
               
               
                 73B 
                   
                 Resin = 9.5 mg 
                 3 
                 1.0 
                  3.7 
                 25 
                 — 
               
               
                 (beige tablets; 
                   
                 (0.2 mg THC; 
                   
                   
                   
                   
                   
               
               
                 Weight/tablet = 
                   
                 3.8 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~98.0 mg) 
                   
                 Mannitol = 56.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.9 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 31.0 mg 
                   
                   
                   
                   
                   
               
               
                 74A 
                 Resin (Strain 2) =  
                 Resin = 8.3 mg 
                 4 
                 Failed 
                 Not done 
                 18 
                  93 
               
               
                 (cream tablets; 
                 75 mg 
                 (0.1 mg THC; 
                   
                 both 
                   
                   
                   
               
               
                 Weight/tablet = 
                 Mannitol = 450 mg 
                 2.9 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~100.4 mg) 
                 Mg stearate = 7 mg 
                 Mannitol = 49.5 mg 
                   
                   
                   
                   
                   
               
               
                   
                 Neusilin ® UFL2 = 
                 Mg stearate = 0.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                 135 mg 
                 Neusilin ® UFL2 = 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 14.9 mg 
                   
                   
                   
                   
                   
               
               
                   
                 246 mg 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 27.0 mg 
                   
                   
                   
                   
                   
               
               
                 74B 
                   
                 Resin = 8.1 mg 
                 4 
                 2.5 
                 12.6 
                 13 
                  99 
               
               
                 (cream tablets; 
                   
                 (0.1 mg THC; 
                   
                   
                 (1 tablet) 
                   
                   
               
               
                 Weight/tablet = 
                   
                 2.8 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~98.1 mg) 
                   
                 Mannitol = 48.4 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Mg stearate = 0.7 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Neusilin ® UFL2 = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 14.5 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 26.4 mg 
                   
                   
                   
                   
                   
               
               
                 75A 
                 Resin (Strain 2) =  
                 Resin = 9.2 mg 
                 3 
                 2.0 
                  4.9 
                 306 
                 &gt;6 mins 
               
               
                 (cream tablets; 
                 75 mg 
                 (0.2 mg THC; 
                   
                 (1 tablet) 
                 (1 tablet) 
                   
                   
               
               
                 Weight/tablet = 
                 Mg stearate = 2 mg 
                 3.2 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~95.7 mg) 
                 F-Melt ® Type C = 
                 Mg stearate = 0.2 mg 
                   
                   
                   
                   
                   
               
               
                   
                 690 mg 
                 F-Melt ® Type C = 
                   
                   
                   
                   
                   
               
               
                   
                 Kollidon CL ® = 
                 84.8 mg 
                   
                   
                   
                   
                   
               
               
                   
                 12 mg 
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 1.4 mg 
                   
                   
                   
                   
                   
               
               
                 75B 
                   
                 Resin = 9.2 mg 
                 5 
                 1.0 
                 15.4 
                   
                   
               
               
                 (cream tablets; 
                   
                 (0.2 mg THC; 
                   
                   
                 (15.8, 15.0) 
                 295 
                 &gt;6 mins 
               
               
                 Weight/tablet = 
                   
                 3.2 mg CBD) 
                   
                   
                   
                   
                   
               
               
                 ~96.0 mg) 
                   
                 Mg stearate = 0.2 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 F-Melt ® Type C = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 85.1 mg 
                   
                   
                   
                   
                   
               
               
                   
                   
                 Kollidon CL ® = 
                   
                   
                   
                   
                   
               
               
                   
                   
                 1.4 mg 
               
               
                   
               
               
                   a The same tablets were used for friability first then hardness; N = 2 tablets 
               
               
                   b N = 1 tablet 
               
               
                 —Not enough tablets for disintegration 
               
            
           
         
       
     
     Based on the disintegration time data obtained from the tablets (Tables 64-66), inclusion of F-Melt® did not yield faster disintegration of the tablets. However, inclusion of Neusilin® UFL2 appears to help with rapid disintegration. Without being bound by theory, it is noted that this pharmaceutical excipient helps as a carrier for solid dispersions, possesses very large specific surface area and has high oil and water adsorption capacity, makes hard tablets at low compression forces compared to similar binders, increases the hardness synergy with other filler and binder excipients at low concentrations, as well as helps stabilize moisture sensitive as well as lipophilic active pharmaceutical ingredients. 
     Experiment 27: Rapidly Disintegrating Sublingual Tablet Formulations Comprising Decarboxylated  cannabis  Resin from Strain 6 (THC: 22.5%/CBD: 23.1% in the Resin) 
     Formulation 64 comprised decarboxylated  cannabis  resin from Strain 6, containing 22.5% of THC and 23.1% CBD, and was made according to the following procedure:
         1. Resin was dissolved in ethanol to give a solution of about 102 mg/mL   2. Divided ethanolic solution into 1 mL portions (102 mg of resin per vial)   3. Mannitol was weighed and dissolved in water (4 mL per 0.612 g), and 4 mL of solution was added to each vial   4. Added 3 more mL of water to each vial   5. Lyophilized all vials for 44 hrs   6. Combined vials and added other excipients in quantities as shown in Table 67   7. Triturated in a porcelain mortar with a pestle until having a homogeneous solid solution   8. Weighed about 96.5 mg of the mixture for each tablet and load into a 10 mm die   9. Punched under 0.4 ton pressure, using Specac® manual hydraulic press   10. Collected tablets in a 20 mL vial and covered with cotton which were then closed   11. Tablets for stability studies were subjected to humidity chamber at 40° C.±2° C. and 75%±5° C. relative humidity for the following time-points: 0, 1, 3 and 6 mths       

     
       
         
           
               
             
               
                 TABLE 67 
               
             
            
               
                   
               
               
                 Components of sublingual tablet Formulation 64. The resin used 
               
               
                 contained 22.5% THC and 23.1% CBD 
               
            
           
           
               
               
               
               
            
               
                   
                 Total amounts of 
                 Weights of resin and 
                   
               
               
                   
                 resin and excipients 
                 excipients/tablet 
                 # of tablets 
               
               
                 Formulation 
                 (mg) 
                 (mg) 
                 made 
               
               
                   
               
               
                 64 
                 Resin = 0.4021 g 
                 Resin = 9.3 mg 
                 39 
               
               
                 (beige tablets; 
                 Mannitol = 2.413 g 
                 (2.1 mg THC; 2.1 mg CBD) 
               
               
                 Weight/tablet = 96.4 mg) 
                 MCC = 0.724 g 
                 Mannitol = 55.9 mg 
               
               
                   
                 Mg stearate = 0.036 g 
                 MCC = 16.8 mg 
               
               
                   
                 Kollidon CL ® = 
                 Mg stearate = 0.8 mg 
               
               
                   
                 0.595 g 
                 Kollidon CL ® = 13.8 mg 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 68 
               
             
            
               
                   
               
               
                 Quality measurements and stability data of the formulated tablets 
               
               
                 of Formulation 64 stored at 40° C. and 75% Relative Humidity. See also FIGS. 30A, 
               
               
                 30B and 31 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Disintegration 
                   
               
               
                   
                   
                   
                 Moisture 
                 time(s) in 1 mL 
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Time 
                 Friability 
                 Hardness 
                 content 
                   
                 Artificial 
                 % (w/w) Cannabinoid 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 (mths) 
                 (%) 
                 (N) 
                 (%) 
                 PBS 
                 saliva 
                 Δ 9 -THC 
                 CBD 
                 CBN 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 0 
                 0.1 
                 5.1 ± 0.5 
                 2.7 
                 19 ± 3  
                 209 
                 23.8 ± 1   
                 35.7 ± 0.0  
                 — 
               
               
                 1 
                 1.5 
                 9.6 ± 0.4 
                 2.6 
                 16.4 ± 4.5  
                 n.d. 
                 17.9 ± 0.4  
                 35.6 ± 0.3  
                 3.4 ± 0.5 
               
               
                 3 
                 2.3 
                 6.9 ± 0.2 
                 2.8 
                 15.8 ± 5.5  
                 n.d. 
                 16.8 ± 0.8  
                 41.2 ± 0.5  
                 5.3 ± 1.2 
               
               
                 6 
                 2.88 
                 6.2 ± 1.0 
                 2.1 
                 26.1 ± 0.7  
                 n.d. 
                 12.93 ± 0.1  
                 41.3 ± 0.2  
                 4.1 ± 1.2 
               
               
                   
               
               
                 *The same tablet (N = 3) were used for friability and hardness; N = 3 for disintegration in PBS and N = 2 for disintegration in saliva and moisture content 
               
               
                 —Not detected 
               
               
                 n.d. = not determined 
               
            
           
         
       
     
     Although the disclosure has been described with reference to certain specific embodiments, various modifications thereof will be apparent to those skilled in the art. Any examples provided herein are included solely for the purpose of illustrating the disclosure and are not intended to limit the disclosure in any way. Any drawings provided herein are solely for the purpose of illustrating various aspects of the disclosure and are not intended to be drawn to scale or to limit the disclosure in any way. The scope of the claims appended hereto should not be limited by the preferred embodiments set forth in the above description, but should be given the broadest interpretation consistent with the present specification as a whole. The disclosures of all prior art recited herein are incorporated herein by reference in their entirety.