US us United States 2) Patent Application Publication co) Pub. No.: US 2016/0228385 Al oy ow 2 (60) ievers et al PURIFIED CBD AND CBDA, AND METHODS, COMPOSITIONS AND PRODUCTS EMPLOYING CBD OR CBDA Applicants:Robert E. Sievers, Boulder, CO (US): ia Rebits, Thoraton, CO (US) Inventors: Robert E. Sievers, Boulder, CO (US) ia Rebits, Thoraton, CO (US) Assignee: COLORADO CAN LLC, Boulder, CO ws) Appl. Now 15/017,384 Filed: Feb. 5,2016 Related US. Application Data Provisional aplication No, 62/158,908, fled on May 8.2015, provisional application No. 62/112,695, fled on Feb, 6, 2015, provisional application No, 62/112, 616. filed om Feb, 5, 2015. SAL 201602283! (43) Pub. Date: Aug. 11, 2016 Publication Classification (1) Ine AGIK 31/05 2006.01) core san (200501) 461K 920 (2006.01), (A6IK 367185 (200501), A6IK 9/14. (200501), (2) US.CI AGIK 31/05 (2013.01): ABIK 36/185 (013.01); 461K 9/146 2013.01): 461K 9/2027 (2013.01); CO7E 003 (2013.01) on ABSTRACT A purified eannabidiol (CBD) extract andor cannabidiolie acid (CBDA) extract is isolated from industrial hemp and ‘comprises less than 0.5 wt organic impurities a measured by HPLC and "lI NMR spectroscopy exhibits no detectable peak at 407 ppm as meastred by "NMR spectroscopy. The CBD and/or CHDA extract sin erystalline form. The CBD extract exhibits @ melting point as measured by differential ‘Scanning calorimetry (DSC) of 69-70° C. Dry powder com: positions comprise such extrics, Additional dry powder ‘Compositions comprise polyvinypyrolidone and an amor phous CBD extract. An adduct contprises CBD and/or CBDA bonded to a paramagnetic trivalent lanthanide (II) metal chelatePatent Application Publication Aug. 11,2016 Sheet 1of15 US 2016/0228385 A1 CBD UV Spectrum from Backer et, Collected C80 Peak g a 8 & reeon o aama sie mia gor as oa vas a Fig. 2A Fig. 2BPatent Application Publication Aug. 11,2016 Sheet 2 of 15 US 2016/0228385 Al Collected COG Peak Fig.2¢ a Collected THCA PeakPatent Application Publication Aug. 11,2016 Sheet 3 of 15 US 2016/0228385 A1 Pigment/Ballast: Elutes with f Dead Volume toh " * * : =Patent Application Publication Aug. 11,2016 Sheet 4 of 15 US 2016/0228385 A1 Open te Air,Patent Application Publication Aug. 11,2016 Sheet Sof 15 US 2016/0228385 AlPatent Application Publication Aug. 11,2016 Sheet 6 of 15 US 2016/0228385 A1 ab AsReced na ater — ' Enrecton th Neer im / Siprertn € at 58093 = ul sor Te oy \ ae After Extraction i be 4 psteceived pope ool eit 7 . Ce Te eee Fig. SA 4 NRAR of Pure CBD after liquid carbon dioxide extraction HNMR of “minor constituent” removed SueuwNbAN ee avgypE Sean ew ET TE Fig. 5BPatent Application Publication Aug. 11,2016 Sheet 7of15 US 2016/0228385 A1 CNM of CBD with NO THC (<0.001 %) poe CNM of “minor constituent” remaining after dissolution of ‘CBD in liquid carton dioxide Se SENT ENTE aha CRPETLIN ES EBS SE TE Se Fig. SC FTIR Spectrum of CBD Fig. 5DPatent Application Publication Aug. 11,2016 Sheet 8 of 15 US 2016/0228385 Al Differential Scanning Calorimetry (DSC) Curve for CBD Fig. SE‘US 2016/0228385 AI Aug. 11, 2016 Sheet 9 of 15 Patent Application Publication panjeoes se ‘901s dAd 40 wnoeds YN HE ols Gao. Poutind Jo wrujdeds YN Hi (QQuenjos YIN Ut paurewoo) 07H | | 4 Bursseoo1d G-NVO Joe dAd:dgo 14 Jo winuoeds YN HE‘US 2016/0228385 AI Aug. LI, 2016 Sheet 10 of 15 Patent Application Publication %OS dAd/%0S on’ 8. i On “pauig-21qqng dg2 96OT SUIIONI2IN/%S9 jouuueni/est-aaa———}-——~ paug-siqang aad | fH UBM pas Gg 40 suoHeredaig snojien 10) susa}eg UONDENYIC ACY-K‘US 2016/0228385 AI Aug. 11, 2016 Sheet 11 of 15 Patent Application Publication WL B14 usp VEVENC OV Ee PES CHOS TE HESS OS OG TENET jonppe aa3“(poy)na AREY ee eI PR sawooter et st eteze ye ee ez or: | | 4 | | ec. a is J} z | (92}6 (sven) ab ! & } yonppe qgo-“(poy)ng a i pue ago jo endeds YIN Hy oF‘US 2016/0228385 AI Aug. LI, 2016 Sheet 12 of 15 Patent Application Publication ac ‘Bld . wr ge os se os a aaa“(wad)ar ny nk ag> —7 i HO“ | O-, a v 1 z (8p) 6 {suon) 6 yonppe aao-*(Wda)aA pue ago Jo exoeds YIN Hr 9‘US 2016/0228385 AI Aug. 11, 2016 Sheet 13 of 15 Patent Application Publication uojssiuie Gg-*(poy}ng uoissiuia *(poj}ng: occa sociaaiasnitssieanimisnitssiiesniawacisetaiseaiioa Leow‘US 2016/0228385 AI Aug. LI, 2016 Sheet 14 of 15 Patent Application Publication Shey ery bias cnet Bi: ii a “314 0) Po wOCT ZIYI wLeT ORLY yEeLETOE IE YE SE ELOY EY Hy oe er osrErsHE NsON ESET onppe ag>“(poy)na + ausuown F \\y" ‘poser er Sy y we auoW} + ag) ; i icone pes as pet Le yonppe Ggd-*(poy)n3 + eueuowy pue ausuowil| + gd JO BND3dS YAN Hr‘US 2016/0228385 AI Aug. 11, 2016 Sheet 15 of 15 Patent Application Publication a2 ‘Bld 265 905 05 95 os ove ws oo vs os eed Shas on sw py eps ars tee He 8 Stonppe gg9-"{poy)ng + suauowy 208 yonppe qad-“(poy}ng + auauowy pue suauowy + Gg Jo eN28ds NWN HrUS 2016/0228385 AI PURIFIED CBD AND CBDA, AND METHODS, ‘COMPOSITIONS AND PRODUCTS EMPLOYING CBD OR CBDA FIELD OF THE INVENTION [0001] ‘The present invention is directed to purified canna- bidiol (CBD) extracts and purified cannabidiolie acid (CBDA)extracts, andto methods for producing such extracts and compositions and products comprising CBD andlor ‘CBDA, including, but not limited to dey powder composi- tions, single unit oral dosages, and adducts of CBD or CBDA ‘with paramagnetic tvalent lanthanide (ID) metal chelates 0002} Inthe present disclosure, the term "Cannabis plant” ‘encompasses wild type Cannabis sativa and also variants thereol, including carnabis chemovars or cultivars which naturally contain different amounts of the individual eannab- ‘noid, Cannabis sativa subspecies indica, inching the var- ‘ants var. indica and vr. kafristanica, Cannabis indica, and also plants whichare the resultof genetic erosses, solf-erosses ‘or hybrids thereof. The term “Cannabis plat material” is 10 be interpreted accordingly as encompassing plant material “derived from one or more cannabis plants and includes dried ‘carmabis biomass BACKGROUND OF THE INVENTION [0003] | Cannabidio! (CBD) is the decarboxylated product ‘of camabidiolic acid (CBDA) and results from heating CRDA at about 130° C. CED is of the formu at OH 10004] | CBD has boon demonstrated to be a promising and effective treatment for substance use disorders. This has been ‘demonstrated in both pre-clinical studies as well as clinical trials on human subjects. These studies have shown CBD to reduce drug-secking behavior and withdrawal symptoms resulting fromchronic wseand addiction tocommonly abused substances including opiates (cocaine, hesvin, morphine) nicotine and mariana (Crippa et aly Clin Pharm Ther 382): 162-4 (April 2013), Preliminary elinicl trials using CRD to teat nicotine addiction have been highly promising, In human subjects secking to quit smoking. CBD adainis- tered viaan inhaler evcod eigaretteuse by 40% compared to no reduction for subjects administered placebo inhaler Aug. 11, 2016 (Moran et al, Addict Behav, 38(9}:2433-6 (September 2013) Thesestudies demonstrate theelicctive useo!CBD 10 ‘reat substance abuse disorders and addiction to commonly suse substances, [0005] _Adiitional studies ofmedical uses of BD have also been directed to treatment of epileptic seizures, uncontrol- Jable seizes inpediati patients, cancer treatment, reducing adverse effect of ther cancer treatments, pain management, And teatment of autovimmune disorders, among others. See, Tor example, Friedman et al, Engl J Med, 373:1048-1058 (Sep. 10, 2015). Nora Volkow, the Director of the National Institute of Drug Abuse (NIDA), testified in the US Sense (Caucus on Intemational Narcoties Control an Jun. 24, 2014 ‘hat CBD (and other cannabinoids) havea range of effects that ‘may be therapeutically useful including anti-oxidant, ant seizure, neuroprotective, ant-inflammatory, analgesic, ant ‘umor, and antianxiety properties. Treatment of multiple sclerosis, Parkinson's disease, alcohol abuse, tumor metas sis, postaraumatic stress disorders were also documented in humans or animal models {0006} However, medical use of CBD or CBDA, as well as ‘ther cannabinoids, is complicated by a lack of standardiza- tion in both composition and methods of delivery, as well as poorly known degradation pathways of the various cannab- Jods. Accordingly. improved methods of obtaining purified CBDand CBDA. and compositions and products comprising CBD and/or CBD for research and medicinal purposes are desired, SUMMARY OF THE INVENTION [0007] Accordingly it san abject ofthe invention to pro- vide purified CBD extras anor CBDA extrcis, and 10 provile compositions and products comprising CBD extract andlor CBDA extract, and methods of producing purified products and compositions [0008] In one embodiment, the invention is directed 0 ‘annabidiol (CBD) extrct or # cannabidiolic acid (CBDA) extract isolated from industrial hemp, and comprising less than 0.5 wt % onganic impurities as measured (1) by high performance liquid chromatography (HPLC) at 30° C,, and {Q) by proton auclese magnetic resonance CH NMR) spec- moseony at 300 megahert using a 0.1 wt % solution of the CBD of CBDA eximet in deuterated ebloroform solution relative ta tetramethylsilane internal standard. The CBD or CBDA isin crystalline form and a 0.1 wt % solution of the exttact in deuterated chloroform exhibits no detectable peak 14.07 ppm, relative toa teramethybslane intemal standard ‘as measured by 'H NMR spectroscopy at 300 megahertz [0009] In another embodiment, the invention is diected to ‘dry powder composition of such an extrac. [0010] In another embodiment, the invention is directed to ‘dey powder composition comprising polyvinylpyrotidone (PVP) and a CBD extrot or a CBDA extract isolated from ‘industrial hemp, wherein the CBD or CBDA is amorphous, [0011] In another embodiment, the invention is directed 19 ‘amiethod of producing a dry powder composition, the method ‘comprising mixing at least one eater, a extract containing CBD or CDA anda supercritical or near supercritical Hui ‘and rapidly reducing the pressure on the mixture, whereby “droplets are formed, and passing the droplets Uhrugh & Most ‘of heated gas [0012] In another embodiment, the invention is directed to ‘method of purifying CHD extractors CBDA extract in cil orm, the method comprising dissolving the ol extractUS 2016/0228385 AI near-supereritcal carbon dioxide and remo\ tated impurity exhibiting 8 peak at 4.07 pps ‘etrametiylsilane internal standard, as messured by proton nuclear magnetic resonance ("H NMR) spectroscopy at 300 megahertz, 10013] In another embodiment, the invention is directed 10 method of sterilizing a CBD extret of & CBDA extract, the method comprising dissolving the extract in liquid carbon dioxide, pressurizing the solution t a pressure in a rmge of 2000 to 3000 psi and repeatedly inereasing and decreasing the pressure of the soution inthe range of 2000 to 3000 psi. 10014) In another embodiment, the invention is directed 10 ‘an adduet comprising CED or CBDA bonded to paramag- nef trivalent lanthanide (11) metal chelate 10015] These and additional aspects ofthe invention and the advantages thereof will be more fully deseribed in and parent from the detailed description. BRIEF DESCRIPTION OF THE DRAWINGS. 10016] The present disclosure will be more fly under stood in view ofthe Drawings, in whiels [0017] FIG. 1 shows the HPLC chromatogram of « Can- nabs extract as deseribod in Example | [0018] FIGS, 2A.2F show the ultaviolet (UV) spectra of theminor peak materials ia PIG. 1 as deseribed in Example 1 [0019] FIG. 3 shows the HPLC chromatogram of a Can- nabs extract as deseribed in Example 2 [0020] FIGS. 4A.4D show the HPLC chromatograms of a CGamabis extract processed in the manners 2s described in Example 3. [0021] | FIGS.8A-SE show the results of analytical analysis ‘of CBD extracts as described in Pxample 4 [0022] FIGS. 6A and 6B show the results of HNMR and X-ray difration analyses, respectively, of aCBD-contsining ‘dry powder composition as described in Example 7 10023] FIGS, 7A-7D show tho results ofanaltial analysis ‘ofan (fod CBD adkuct, as wellas comparative materials, as deseribed in Example & 10024] Additional detils of the drawings and specie ‘embosdiments of the invention willbe more fully apparent in view of the Detailed Description and the Examples DETAILED DESCRIPTION 10025] | Theinventionisdirected to purified Cannabis mate- rials, and more specifically, r© purified cannabidiol (CBD) ‘exinicis and purified cannabidiolie acid (CADA) extracts, methods for purifying such extracts, and compositions and products comprising purified CBD oF CBDA. 10026) _Inspecific embodiments, the invention is directed 10 ‘a cannahidiol (CBD) extract ora cannabidioli acid (CBDA) ‘extract isolated from industrial hemp, and comprising less than 0.5 wt % onganie impurities as measured (1) by high Performance liguid chromatography (HPLC) at 30° C., and (2) by proton nuclear magnetic resonance ('H NMR) spec- ttoscopy at 300 megahertz using a 0.1 wi % solution of the CBD oF CBDA exioet ia deuterated chlomform solution relative toa tetramethylsilane internal standard, The CBD or ‘CBDA isin crystalline form and a 0.1 wt % solution ofthe ‘extract in deuterated chloroform exhibits no detectable peak ‘at4.07 ppm, relative toa tetramethylsilane intemal standard, fs mearired by fT NMR spectroscopy. In a more specific ‘embodiment, the extactis'@ CBD exteaet and the extract Aug. 11, 2016 xii melting point a cased by differential seanaing Calorimetry (DSC) of 69-70" C {0027] The Cannabis plant material employed in dhe present methods is refombly one producing high CBD nor CBDA coatet extract. In one embodiment, the Can- abis plant material may be self polinating, i monde cious, while in anober embediea, the Cannabis plat ‘atta be dioecious. Ina spevifi emboximent, the Cun rabis plant material contains less than 03% THC by dry ‘weight and js within the definition of “indstral hemp” in Section 7606 ofthe Federal Agicltra Act of 2014, {0028} Inspecitie embodiments, the methods result in puri lid exits having lite or to detectable ttabydrocansu- in (THC) or its acid form, tovabydcannabinolic acid (THCA),lamorespeciicembodimeats, the compositions or products of the invention contain greater than 50 wt %, rcater than 60 wt Yo grater than TOW, greater than 80 5%, greater than 90%, greater than 9566, restr than 97 ‘wie, greater than 89 wor greater than 89.5 wi % CBD antfor CBDA, based onthe weight of ll cannabinoids in the compositions or produ. In fuer embodiments, tbe con postions or products contains les than 3 wr % less than 2 wt lesan 1 WH, less than. 1% less than 1 Wt less thanO.OT wt% Tes than 004 we% oes than 0.001 wt, THC and THCA, based on the Weight of al cannabiids in the compositions or prods, when analy using high por formance Tiquid chromatogreply (HPLC), Ina furher embodiment, the extact contains 90 deteaable THC or TTHCA whe analyzed sing HPLC. [0029] "According to the invention, the pte, high eon- teat CBDICBDA ‘extract is lated from Cannabis plat ‘material by solvent extretion of CBDA, plus any CBD that shay be presen inthe eamnabissran, eer wi elhae ol, eano, isopropanol, ety acetate, hexanes, heptane, chloroform, or her pupil solvent. Atemativels, the high content CBDICBDA exit i soloed from Cannabis plant material by extraction with pressurized Tiguid carbon Soxide, for example tor near ambient temperature, with Supereniical or near superetial carbon dione, oe With prcsurized spercated water at 100" to about 230° Cor {sing combinctons of soch pressurized technique in combi- ‘ation with one or more ofthe aforementioned solvent extrac: tions at ambint presstre {0030} Following extraction, the extract is farther teat by removing most or all ofthe solvent, for example, by esting under a protective blanket of nitrogen gas toa Teme perature athe boiling point of the slvent. The extract my be Turter heated t temperatures of about 110" C- 1 about 150° (Cha devurboxylate the CBDA snd for CBD. for expe, Torabout 10 minitest about 4 hours. In one embodiment, a CBDA extract is uniformly heated in a mineral ot bath, preferably at 110° C-130? Cfor2040 minutes, and provides EBD yields of preter than 75%. The heating i i one embodiment, conducted inthe dark Care must be exercised to decaroxylatethe CDA to form CBD without decompos: ing the CiD product The decarboxylation reaction ean be conducted under vacwuss and ean be monitored by HPLC ‘The CAD producti inthe form os highly pure ol extoc. {0031} In an altemate embevliment, the Cannabis plant material, for example in finely ground fon, may be ist Tested to decarboryate CBDA therein to CBD. prior to eniraction, sing similar heating temperatures and times. {0032} In one eabodiment, the CBDICBDA is exacted ‘sing ethanol ia which the CBDICBDA is dissolved, falUS 2016/0228385 AI lowed by the addition of inereasing amounts of water to the ‘etuanol solution to crystallize the CBDCBDA. Advanta eousy, a crystallized produet, rather than anol, is obtained. 10033] Solvent extcction methods can produce an exact Which includes an impurity exhibiting a detectable peak at 407 ppm, relative oa tetametiyslane interalstandaed, as measured by "HNMR spectroscopy. This impurity can be ‘isolated in the form ofa white residue in methods according to the invention. Ina specific embodiment, hydrocarbon (eg n-heptane) extracts of Cannabis sativa industeal hemp con- taining lees than 0.3% of THC which are devolvated to fon white erstalites of impure CBD and/or CBDA. The white ‘eystals are then redissolved in ethanol, pressurized liquid ‘carbon dioxide, for example at or near ambient temperature, ‘or supercritical or neur supercritical carbon dioxide, and & ‘white impurity witha melting point of about 81°C. precipi tates to form a separate solid seum hich can be removed from the ethanol-CBD solution by sedimentation andl decan- tation, fiction, centrifugation, or other recognized methods ‘of separating sols from liquid solutions. These impurities are believed to be one or more long chain wax esters, War. ‘esters are commonly encountered inthe cuticleof plant leaves ‘and serve to proteet the plat from dely dation. It has bees, siscovered thatthe use of ethanol as an extraction liquid or pressurized liquid carbon dioxide, for example at or near mbient temperature, or supercritical oF near supercritical ‘carbon dioxide allows removal of such impurities from 3 ‘CBDorCRDA extracts they arenot soluble in ethanol or the indicated forms of earbon dioxide. Ia specific embodiments, ‘once the impurity is removed, CBD andlor CBDA with less than 11% onganie impurities, Tess than 0.5% wt % organic impurities, or ess than 0.1 wt % organic impurities, can be isolated by solvent evaporation. In 3 more specific emboxl- ‘meat, precipitated CBD and/or CBDA are obtained by pro- pressvely adding pure water, whereupon CBD andor CBDA ‘of uaprecedented purity in crystalline form can be obtained alter drying. The CBD erystals exhibit a meting point esti= ‘ated by diferential scanning calorimetry to be 69-70° C 10034) In another specific embodiment, the CBDICBDA ‘extract product may be sterilized by dissolving it in liquid ‘earhon dioxide. The CAD/CBDA product saciid by pro- Tonged pressurization, followed by rapid depressurization with pressure swings, for example as described in U.S. Pat. No. 6,149,864. In-a specific embodiment, the material is treated with supercritical fil earbon dioxide at pressures in the range of from about 2000 t0 3000 psi and temperatures preferably fromabout 210 45°C. for periods of from about 20 minutes to six hours, more preferably fiom about 0.5 0 2 hours. Agitation, pressure eyeing, und ihe presence of water may enhance the sterilization method, which promotes diffa- sion of the supercritical Mud carbon dioxide to thereby alter the pif within the cells of any bacteria to kill the bacteria ‘and/or rupture cells to kill the bacteria, The magnitude and Jrequency of the pressure cycling, as well a te process time ‘and temperature, may vary according othe formof the CBD! ‘CBDA material be sterilized and the type of organisms to be killed 10035] In specific embostiments, the purified CBD andlor CBDA consists of CRD andlor CBDA, with no detectable impurities. Infther embodiments, the purified CBD andlor ‘CBDA consists essentially of CBD and/or CBDA, containing ‘atleast 99 W1% CAD andor CBDA and less than 1 wt % of ny onganic impurity, or more spcifcally containing at last 9915 «1% CBD andor CDA and lest than 0.5 80% of any Aug. 11, 2016 mxanie impurity, reves CBD andor CBD: inpusiy. (0036) to furhor embodiments, the purified CBD andlor CRDA is i the form of write, odorless crystals. Various Cannabisindustial hemp materiascotaina umber fit cous componcis itciuding one sever or more of monene, (=) inene, lino, -) eayophyllene,echunn- lac. earyopivllens wxide, texpinolene, AMcarene, (+) Frpinene, ) camphor, wpinene, (-) Bpinee, eterpine, lerpinen, poral, Pearyoplene, (-) borneol, 1c. ole, 1 -eineole evcalypol). The put products which fr edorest contin no detctale amotints a tens compo- ‘nents when th product are subjected to high performance liguid ehrmstoprphyas described hes, {0037 The puriied CBD andior CBDA extact, ino or rcipitated prot oem, can beadninstere taney ‘vith woven fiber patches, placed or dripped under the tongse ‘whore itis absorbed or exerwise ake into blood apllares br sed as a food additive or supplement, alone of with a dient {0038} ‘To void fst pass removal bythe lve and for aster action, the CBD can be vaporized, o folate as a dry powder as discussed below and inal [0039] ‘The puted CBD andlor CDA produced accorde Jing othe invention ean be used a an anata standard in ‘rious therapeutic applications, Party maybe eonliemed by aunlysis using High Perfomance Liguid Chromatography, Nuclear Magnetic Resonance Spectroscopy andor Mass Spoctometry (0040) The purified CBD andor CBDA may also be included 36a component of a pharmaceutically acceptable composition for administration to a patient for terapetic eect in teatment of disorder. Th one embodiment, the ‘hamaceutically acceptable compositions of the invention ‘may include CBD andlor CBDA in an amount above the Placebo eft inelaling hascopathic compositions), up An incloding 99 wt % pure CBD andor CBDA. In specific ebodiment the eompesitions comprise about 110 90 wt%, Tod wis, 10t0TOwt 4, 15-60 0%, 20.6014 025-50 \W1% CED aide CBDA. The compositions may be ia ay conventional administration fonn, inlaing solid unit dos- faze forms such as tablets, wafers pelts, lozenge, slions orexampe, in wateror ethanol, saves, reams, lotions, nd the lke, and may contain conventional adv, inlading hamacetical carrier, excipient, andthe like. {0041} ‘The extracts, compositions and prodcts of the invention may be ministered to 8 mammal (human, at sow, monkey, dog cat ors, et) fr anyone of various therapetie effects for which CBD andor CBDA are know inthe atl this regard, the extract, compositions and pro ‘els of the invention may be administered to provide ant fxidant, anseizae, neuroprotective, ast-iflammnatory aumlgesc ant-tuner, ntestess an-psyehati, andor ant aunty properties, among oes Treatment of multiple scle- rosis, Parkinson's disease, alcohol abuse, tumor metastasi Ses, including postimatic sess dnonlrs, migraines Fain, concussion, anxiety, diabetes, andthe like may be treated withthe extracts, compositions and prodets ofthe {0042} In another embodiment, the CBD andlor CBDA extract can be formated sa dey powder Ina specific tmbodiment, the CHD andlor CBD extract ca be form Jnted as adry powder by forming a composition comprising a nore specifically at east 99.9 wi % les than 0.1 wt % of any organicUS 2016/0228385 AI solution or emulsion ofthe extract, for example in water ora solvent, and a supercritical or near ertcal uid, for example, ‘carbon dioxide, and rapidly reducing the pressure on the ‘composition, whereby droplets are formed, and passing the ‘droplets through « Now of heated gas. Such methods are disclosed in the Sievers et al U.S. Pat, No. 6,630,121, incor- porated herein by reference and known asthe CAN-BD pro= ‘ess. Further, the extract can be Jormulated with one or more additives, including, but not limited to sugars, polymers, amino acids, preservatives, andor other excipients, andor ‘ther setive ingredients, forexample, an antibioticor vaccine, before forming the dry powder ofthe composition with the supercritical o near critical id. Suitable excipients include, bbutare not limited o, thse used to increase solubility andor dissolution rate of lipophilic cannabinoid, for example in Jung fluid. Examples of suitable additives include, but are not Timited to, myo-inositol, mannitol, sucrose, trehalose, leu- «ing, lactose, tricine, sodium phosphate buffer, arginine, his- tidine alanine, gelatin, lactalbumin hydrolysate, hydroxyeth- ‘ystarch, maltodextrin, Tween 80, sodium citrate, phosphatidylcholine, alpha lipoie acid, methionine, pli- ‘cosamine sulfate, phenylslanine polyethyfene glycol (PEG), poly(latic-co-lyeolie acid) (PLGA), and polyvinylpycrol= ‘done (PVP), and the like. Ina specific embodiment, one oF more surfctants may be included in order to increase the solubility of the CBD and/or CRD extrac inthe solution oF ‘emursion. One suitable surfactant comprises lecithin, bt one still inthe art will appreciate that other conventional st- ‘actans may also be employed. Inspectic embodiments, the ‘eight tio of CAD andlor CADA tothe excipientsmay bein rage of from about I:100 to 101, more special, Hom about 1:50 to about 50:1, more specifically, fom about 1:25 to about 25:1, In futher embodiments, the Weight ratio of CBD andlor CBDA to the excipients may be ina range of from about 1:25 t0 1:1, [0043] In specticembodtiments, the composition for use ia orming a dry powder comprises CBD and/or CBDA and ‘manniol,o¢ mannitol and eeithin. Thecomposition may also include "2 physiologically acceptable antioxidant, for ‘example, methionine, or other additive, as desire. 10044] In another specific embodiment, the composition for use in forming a dry powder comprises CBD andlor CBDA and polyvinyipyrrolidone (PVP). Various PVPS are ‘commercially available at different molecular’ weights (Gvcight avenge) andl are suitable for use in the present com- positions. Ina specific embodiment, the PVP has a moleculae ‘weight na range of from about 5000 t 500,000 Da, or, more specially, from about $000 to about 50,000 Da. In more specific embodiments, the PVP hus a molecular weight of bout 10,000 or 40,000 Da. The weight tio of CRD andor CBDAtoPYP may beina range of from about 1:100t0 10:1 ‘more specifically, from about 1:50 to about 50:1, more spe ‘ically, from about 1:25 to about 25:1. In further embodi- ments, the weight ratio of CBD andor CBDA to PVP may be ‘na range of from about 1:10 10:1. The CBD andor CBDA PVP may be dissolved ina solvent forthe powder-form- ing process, for example the CAN-BD process. Surprisingly, the dry powder compositions formed from a composition ‘comprising CBD and/or CBDA, and PVP presents the CBD and/or CBDA inan amorphous form, andthe powder contains no crystalline CBD andlor CBDA as measured by X-ray powder diffction, The amomhous form may provide Improved dissolution of the CBD and/or CBDA when admin- Aug. 11, 2016 istered in vivo for improved of expedited bioavailability oF clhenvise altered phamnicokinelic properties, [0045] Formulation ofthe cannabinoid active pharmacen- tical ingredient into dry powders facilitates the incorporation ‘of such excipients which have boon shovsn to increase sol- bility and dissolution rate, and therefore bioavailability. of Jipophilie molecules such as cannabinoids. In one embed meat, the dry powder may be provided to include a particle faction having an aerodynamic diameter effective to reach the deep lung for maximal absomption upon inhalation, for ‘example, less than $ jm, more specifically, in a range of 3 um, a5 measured using an Andersen Cascade Impactor. in a ‘more specific embodiment, atleast 90 wt % ofthe particles have an aerodynamic diameter les than $ jm, as measured vusing an Andersen Cascade Impactor. [0046] The dey powder formulations are advantageous exhibiting good storage stability and are much less suscep- tible to loss of material to packaging wall, in contrast wo oils in Which the active ingredients are dissolved in solution la ‘one specific embodiment, dry powder formulations are pro- Yided in single-dose blister packaging, forexample formedof ‘an aluminum-polymer laminate, to proet the powders rom ambient moisture, bacterial and fungal ingress, and degrada- ‘ion by ligt [0047] The dry powders are suitable for administration as dy powder acrosos, for example, deliverable from dry pow ‘er inalers lke the Pull-Haler®, available from Sievers Bio- tech, oF other such devices. Additionaly, the dry powders may be compressed into 4 solid unit dosage form, for ‘example, a tablet, wafer or pee fonm, alone ox. aptionall, in ‘compositions including one or more excipients or additives. Inspecife embodiments, the dosage font isa tablet having & thickness oF at least about | mm of, more specifically, of at least 2 mm. In additional embodiments, the dosage form is 2 wafer baving a thickness less than about mm, or, more specifically. less than about 0-S mm. The wales, in one embodiment, are quick dissolving, i, they dissolve in less ‘than about 2 minutes, less than about 1 minute, less than about 445 seconds, of less than about 30 seconds, when contacted ‘with a figuid or saliva, and, in one embodiment, may be adapted for sublingual use when placed under the tongue ofa patient. [0048] In another embodiment, the invention is dicted to adducts which comprise CAD or CDA bonded to paramag- pati trivalent Lanthanide (IT) metal chelates (metal com- plexes). As noted above, CBD has been disclosed as usefil in the treatment of a wide variety of disorders and conditions, including, inter alia, ansety, posttraumatic stress disorder cancer and epileptic seizures. As with any pharmaceutical ‘compound, diseovery of the optimal dosage form with whieh the compound can be delivered most effectively is highly desirable. Derivatization and. methods of delivery that increase bioavailability, provide atime-rolease for consistent elivery throughout the day, or decrease the occurrence of side-effects or toxicity serve to enhance the inherent pharma- ecological properties of the compound and should be thor- ‘oughly explored and developed. The adducts of the invention providea mechanism by which the properties of CBD andor CRDA may be favorably altered throwgh the formation of ‘non-covalent bonds with another molecule, i. as a Lewis acid-base adduct, Non-covalent interactions have the poten- tial to alter the effect that CBD has on the body through differences in solubility. absorption, and time-reease, while ‘not permanently or ireversiby altering the composition orUS 2016/0228385 AI properties of the CBD moiety within the adduct molecule. Aa Heal method for examining the formation of addicts is inelear magnetic resonance (NMR) spectoscopy. 10049] The inventive adducts which comprise CBD andioe ‘CBDA bonded to paramagnetic tevalent lanthanide (Il) rela cheltes are url for medical and dignostic applica tions in eoncent with fluorescence spectroscopy. Paramag- nie transition metal complexes that ur also coondinatively ‘saturated ean ala form sofa adduct with Lewis bases [0050] The lanthanide trivalent ions include cerium (Ce), praseodymium (Pr), neodymium (Nd), samarium (Sm) ‘uropiim (£0), gadolinium (Gd) eri (Tb), dssposine {Dy holminn (Ho) ebium (E),thlium (Tis), and yter- binim (Vb). In a specific embodiment, the metal ion is europium (Fa) or yterbium (YP). Stable ligands include batare not inited to es (11,1,22.8beptattoon7 Time loctne 4 Gdionatoy, tis (11k. 2233,077 deca Iuoro-4.6heplaneionato): ts(1,11.22.3.33-hepaforo- T-dimesbyloetane-4,6-lonst) tL LSSS- hexaloro-24-pentanedonao} perduterated ts 1,122, 3 3-heptatioro-7,7-dimethyloctane- ons) perdetteratd ris 1,1,22.3+heptafor?,timetyloe- fone-d(-dionaa), tris (iluoroacetyed-camphorsto ts (inivaloyimethanato), andl he like as disclosed in U.S. Pat No. 3846333, incorporated ersin by relernee. Am exem- play transition metal complexes ate those famed with cop- per such as bis((11,1,5.,S-hexafluoro-2,4-pentanedionato) ‘copper(I [0081] NMR spectroscopy is based upon the differential absorption of electromagnetic radiation by nuclear spin states ‘of aucled of aloms whose energy levels have been made non-degenerate by the presence ofa strong magnetic ld. A hydrogen nucleus contains one proton, which possesses in angular momentum and may exist none of two possible spin slates: #1/2 or -1/2. The energy levels ofthe two spin states fre degenrate, and the spin produces a local magnetic field near the nicleus. Upon introduction ofa strong extemal mag netic field by the instrument, the energy levels of the spin states diverge te spin state aligned with the magnetic feld becomes lower energy than the unaligned statesnd an energy gap between the spin states s produced. The instrument then Inmates the sample with electromagnetic radiation in the radiofrequency range while holding it ina stong magnetic field created by a superconducting magact. A number ofthe hydrogen protons that possess spin states ofthe lower enemy Jevel will absorb the radiation, reversing thie spins to match those ofthe higher energy level. The frequency of radiation ‘absorbed is recorded By the instrument and displayed a the ‘difference in parts per million (ppm) fom the absorption of ‘an arbitrary standard, tetramethylsilane [0082] The local environment around the nucleus affects the sizeof the eneny gap produced between spin state enenzy levels. Plectronegative atoms such as oxygen draw electron density sway from carbon and hydrogen, ths removing inter- ference from the spins ofthe electrons, which produce theit ‘own local magnetic felds that obseure the nucle magnetic fiekd. Such hydrogens are said to be “deshielded” and are shifted downfield (1 the left) in the NMR spectrum. The ‘enoray gap increases as deshioling increases, asthe exteral ‘magnetic field ofthe instrament is able to exert 8 more pro- nounced effect on the exposed nice. Phe NMR spectram ‘of CBD in the absence of addvet-forming eoondinatively unsaturated paramagnetic. lanthanide metal ions like ‘europiumn( II) spans the region of 08 t 6 4 ppm, cecupying Aug. 11, 2016 upfield areas in which peaks cosresponding aliphatic, shielded liydrogen nuclei appear as well as downtield regions ‘due fo the electronegative hydroxyl groups. [0083] CBD is capable of ating as a Lewis base and is ‘capable of Forming acid-base adducts with sufficiently strong Lewis acids, inchiding the metal complexes formed between the metal ions and ligands described above. Specific Lewis acids include, but are not limited to, trs(1.1,1,22,33-bep- tafluoro-7,7-limethyl4,6-octanedionato europinea( Ii), (Ev (fod),), and. tris(dipivaloylmethanato)yterbinm(l), (Yb (DPM),)- Depending on theratio af eoncentrationsof CBD or other Lewis bases tothe metal oa, and steric eroding and ‘leetronegativity considerations adets with more than one CBD or other Lewis base may form with molar ratios other than I:1, such as 2:1, The ligands may be rapidly exchanging instead state equilfria with other adducts when dissolved in solvents. Nevertheless, significant effects can he observed ‘and taken advantage of in both the organic al inoranie parts ‘ofthe adds by measuring both the NMR proton (andor the ‘arbon-13 nucle’), and the Nuoreseence spectrin which exe tation and emission spectra characteristics of complexed ‘etal ions, ic, europium (Il) ions, aid in diagnosis and selective detection of eannabinoids like CRD in the presence of temenoids such as myreene, whieh has no oxygens and ‘does not ordinarily bind tothe tvalent metal ons such as [Eu(I) or significantly affect its fuorescence, [0054] The following Examples illustrate various aspects ofthe methods, compositions and products ofthe invention. EXAMPLE 1 Ethanol Extraction of Dioecious Industrial Hemp [005s] Extraction Procedure [036] A cultivar of OTTO-2 industrial hemp registered and developed by Centennial Seed Distributors, LLC, Lalay~ fete, Colo, as part of the Colorado Department of Ageiultare Research Program authorized in Section 7606 ofthe Federal Agriculture Act of 2014, was employed in this Example. ‘Sees were removed and leaves and blossoms were dried for cannabinoid analysis, with focus on cannabidiolic acid (CRDA) content in leaves and bods, Plant material (-S00 mig) ‘vas ground using a mortar and peste, in triplicate. The pul- verized sample was placed ina glass val t0 which 10 ml of ‘anhydrous ethanol was added. The vial was vortexed for 10 seconds, sonicated at setting 80" (maximum) for 1S minutes, ‘and vortexed asin for 10 seconds, portion ofthe superna tant was removed and fisred through acelhulose acetate 0.2 imieron syringe filter into a clean glass vial. The extract was shed 2:13:10 (extrctimethanoliwater) into an HPLC vil. [0057] "HPLC Analysis [058] ‘The HPLC method was taken from Backer & al (innovative development and validation of an HPLC/DAD ‘method forthe qualitative and quantitative determination of ‘major cannabinoids in comabis plant material, J. Chro- ‘matogr:B, 877:41 15-4124 (2008), and was composed of the following gradient, with 50 mM ammonium formate, pil 5.1], the aqueous component Tine wind SeNetaoel __SAaieueUS 2016/0228385 Al — [0089] | The parameters were as follows: Exon isnt a0 10060] The chromatogram is shown ia FIG. 1 [0061] Because the three peaks with retention times of 19-21 minutes eluted very close together, the identity ofeach was examined by UV spectrophotometry and the UV Spectra ‘of minor peaks are shown in FIGS. 24.28 The presence of thre peaks in the UV spectrum of this peak suggests that itis predominately the THCA eannabinoi acid, while the shapes ‘of the other two UV spectra curves suggest that they are ‘neutral cannabinoids 10062] The onder of elution from the column comesponds “withthe order of elution from Backer et al: CBD, CBG, and THCA, respectively. The weight percent of cansabi based on the dry sample mass, were as follows: Comabiit at Dy Supe Mae [0063] _A diffewent lot of OTTO-2 industrial lyzed independently by HPLC using the describ ‘nd determined to contain 12.6% CBDA burt less than 0.03% THCA and <0.004% THC (0.001% being the detectable lower fii, EXAMPLE2 Analysis of Monoecious Hemp, High CBDA Content 10068] Extraction Procedure 10065] A cultivar of INFINITY" (trademark Colorado ‘Can, LLC) industrial hemp (defined by U.S. Federal aw as having less than 0.3% THC) was employed in this Example Seeds were removed and lewves and blossoms were dried for ‘cannabinoid. analysis, with focus on canmbidiolie acid (CBDA) content in leaves and bods. Plant material (502.3 mg) was ground using @ mortar and pestle. The powder was placed ina glass val to which 10 ml of ankyrows methanol ‘wat aided. Tho vial was vortexed for 10 seconds, sonicated at setting "$0" (maximum) for 15 minutes, and vortexed again Tor 10 seconds. portion af the supernatant was removed and filtered through a cellulose acetate 0.2 micron syringe filter Jno a clean pass vil Aug. 11, 2016 [0066] HPLC Analysis [0067] ‘Tae extract was diluted $70:1550 (extractsolvent) nan HPLC vial: Waser ‘Ho i [0068] ‘The HPLC method was taken from Backer el. as described in Example 1, except using Prazepam (70 mg/L) as ‘internal standard [0069] ‘The chromatogram is shown in FIG. 3 [0070] ‘The peaks were integrated, and beeause a reference Standard was not obtained for CBDA, its peak area was eor- reed using molar extinction coefficients at 210 nm found in the literature Hazekamp eal, Chromatographic and specteo- scopie dataof cannabinoids ftom Cannabis sativa, Jowrsal Of Liquid Chromatography and Related Technologies, 28:2361-2382 (2008) The CBD concentration was ealew- Jated using the formule where Couns is the concentration of CBDA, Acar is the integrated area under the CRDA peak, Ap, is the integrated area under the prazepam peak, can isthe molar extinction coellcient at 210am for CADA.e,,. isthe molar extinction coellicient at 210 am for prazepaim, and C,,,. i the spiked ‘internal standard concentration of prazepam, [0071] The mass percent ofthe identified cannabinoids in the sample areas follows: EXAMPLE3 Pyrolysis of Methanol Extract of INFINITY! ‘Monoecious Hemp [0072] Extraction Procedure [0073] INFINITY" plant material ($023 mg) was ground using a mortar and pestle. The possder was placed ina glass Vial to which 10 mil of anhydrous methanol was added. The Vial was vortexed for 10 seconds, sonicated at seting "80" (cuaximum) for 15 minutes, and vortexed again for 10 see- fonds. portion of te supernatant was removed and filtered through a cellulose acetate 0.2 micron syringe filler into a lean glass vil. [0074] Pyrolysis [0075] Aliquots (250 x of the ftered extract were placed into HPLC vals, and let open to air dry st room temperatare inthe dark for ewo days to an oly green solid The vials were heated o 130° C. (except fora no-heat control sample) for 40 es in heated desieator oven, ether at atmosphericUS 2016/0228385 AI pressure or under a Vacuum of 635 tomo n'a heavy mineral Oil bath under either a aitrogen atmosphere oF open to the ‘ambient air, The vials were remaved, cooled, snd their con teats resuspended with methanol water (50/50 Vy), 10076) HPLC Analysis 10077] The HPLC method was taken from Backer etal as described in Example 1 10078] The chromatograms ae shown in FIGS. 44-4D. ain Mtn 10079] None ofthe small peaks eluting during the liquid ‘chromatography analysis had retention times corresponding ‘with THC (above detectable amounts of 0.001%). Attempt ing to prevent the formation ofthe impurity by heating the samples under a slight (635 torr) vacuum was unsuecessful the vacuum may have been sullicient to reduce the boiling point of the CBD (160°C, at 760 torr) and evaporate it from the sample vial under the 130° C. conditions. Heating the samples by immersion ina heavy mineral oil bath reduced the “amount of the impurity by 37% as compared to heaving inthe heated desiccator oven; however, the Yield of CBD was not janificantly increased, Heating the samples by immersion in sno bath under nitrogen atmosphere didnot further reduce the amount of the impurity. The concentration of oxygen ia the niteogen atmosphere could not be measured. A glovebox as purged with dey nitrogen for greater than 40 minutes unt the relative humidity dropped from ambient (~6%) 101.6% EXAMPLES Purification of CBD Using Near-Supercritcal Carbon Dioxide [0080] | Sample Fxtmetion [0081] A partially purified polycrystalline CBD, imported Under intemational treaty provisions less than 100 mg for dae first mun, about S00 mg forthe second run) was tied into & small bag made of white cotton muslin and placed ito @ stainless see! 10sml Thar high-pressure vessel and attached to a valve, tee and 7S jm silica restrictor The sample was ‘extracted with CO, at [380 ps into aclean glass vial. The firs run was stopped aflerabout 1 hour. During the second run, the run was interrupted partway through doe to leaking of the “Thar vessel: about 350mg of sample remained inthe bag. The ‘extrcted portion in the vial andthe residue in the Thar vessel were analyzed by NMR, [0082] "Nuclear Magnetic Resonance (NMR) Analysis [0083] | Samples were dissolved in deuterated chloroform (CDC) (1 ml) and 'H spectra was collected on a Bruker Avance-III 300 NMR spectrometer, at default settings, for 128 seans, The NMR Specia are shown ia FIG, SA. Exteaet= ing the as-received sample with pressurized liquid CO. elimi- ies the impurity showing «triplet at 4.07 ppm relative ro tetramethylsilane in an "F NMR spectrum from the exact. ‘The CO, was allowed to slowly vaporize through a flow restrictor into a new vessel where pure CBD was collected ‘and analyzed by ‘H and !°C NMR, Fourierransform infra red spectroscopy (PTIR), differential seanning calorimetry (DSC), and chemical ionization mass spectzometry (CMS), Aug. 11, 2016 shown in FIGS, SB-SE, DSC was measured on a 3.0 mg Sample encapsulated into aluminum pans designed for use ‘with volatile substances and erimped to form a seal using a Perkin-Elmer Diamond Differential Scanning calorimeter and analyzed using Pyris software. The initial temperatare ‘Was set a 0.00°C. for 5.0 mia. and the temperature Was thea raiped from 0,00° C. to 350°C. ata rate of 20.00° Cini EXAMPLE 5 Puifcation of CBD Oil fr Extraction [0084] CBD fiom a carbon dioxide extraction process on industrial hemp cannabis containing less than 023 wi % THC ‘was collected in the form ofa honeyike oil. Theil ws frst run through asilica column using tolueneas the mobile phase, ‘and then was dissolved in ethanol and winterized overnight in fa Frsezer to allow removal of Wax impurities. The solution ‘was then cun though a bed of aetvated carbon, a reverse phase (C18 modified) silica column using ethanol and acetic Acids the mobile phase, and, nally, another silica column, CBD was recrystallized a white, odorles Solid from an thal solution with water. EXAMPLE 6 CBDA: Mannitol Inalable Powder Using OTTO-2 Hep Extrict (0085) Exwaction Procedure [0086] Pulverized OTTO-2 lea and blossom dey plast satel (1g), previously moasired to have 3.3% CBDA by ‘wet as ground using a mortar and peste The pulverized Sample was placed ina glass vial to whieh 20sml of anhydrous ethanol was added. The vial was vortexed for 10 seconds, Soniated a setting "80" (marimum) for 1 mints, sid Tortexed again for 10 soconds. The elhanolic ext was ‘emoved and filtered though a celuloseaccate 0.2 micron Syringe filtro clean glass Vi {00871 Sample Preparation {0088} Mannitol (1g) was dissolved in 15 ml of distil an deionized HO. The filtered extract was ade, mixed, and te resting precipitate (ehlorophyl te.) was gravity Tiered wsing 8 Whatma liter. reeling in yellow-arcen, slighdy cloudy solution [0089] Carhon-Dioxide Asisted Nebulizaton wilh CAN- BD Processing (0090) "The solution was died ito a powder sing $0 ml Thar vessel with floating piston a the ethanolic solution simple chamber. A S050 ethanoliwater mixture wos placed ing the sample pump to prevent precipitation shoud the Piston scl leak Parbon Dioxide {0091} ‘The parameters were as follows Sen fie ae a 0092} During the CAN-BD nebulizing and drying proce- ‘dure, as deserbed in US. Pat, No, 6630,121, the earboa ‘oxide low rate factasted inthe range 3 mlimin,whilethe ‘ethanol ater solution pressure was maintained at about 1440 pi. Some larger chunks of powder were observed collecting fon the inner surfice of the drying chamber. The pressure ‘zug connected tothe deying chamber remained af about | psi during the procedure,US 2016/0228385 AI 10093] | Powder Colleetion 0094} The powder was pale yellow in color and flaked Upon Scraping. Several larger chunks were sitting loosely on top of the powder cake and were gently removed and ‘excluded from the final powder sample, Powder mass-0.53 153% yield having att approximate 20:1 mannitokCBDA weight ratio, 10095] | Wafer Formation 10096} An aliquot ofthe powder (28.7 mg) was placed into an International Ceysal Laboratories £-Z Press 7 mm diam- ‘ter die for wafer formation, and a pressure of 800 psig was ‘applied forone minutoto forma water Another aliquot of the power (3.8 mg) was placed into a 4 mm diameter dic, and 2 pressure of 1400 psig was applied for one minute to form a ‘water. EXAMPLET CBD-PVP Amorphous Powder 10097] Sample Preparation [0098] | PVP (0.25g)ofapproximately 10,000Da molecular ‘weight and CRD isolate (0.25 g) were dissolved in 30 ml of ‘methanol, Both solids dissolved completely into solution, 10099] | Carbon-Dioxide Assisted Nebulization with Bubble Dryer (CAN-BD) Processing [0100] The solution was dried into powder with carbon- dioxide assisted nebulization with a bubble dryer (CAN-BD) ‘using a 50 ml Thar vessel with floating piston asthe metha- nolie solution sample chamber. Ethanol was placed into the sample pump to prevent precipitation should the piston seal Teak, 0101) The parameters were a follows: Trample ow ae Taina Sanple ohne 30 ml 0, Presse 110 pel Teepe ae Aug. 11, 2016 continued [0102] During the CAN-BD nebulizing and drying process, the carbon dioxide flow rate vetted in a range of 34 n/n, while the methanol solution presse was ~1120 psi ‘The pressure gauge connected to the dying chamber remained at -1-psi during the nan, No phigging of the tec tapillary Was observed. The powder product was pure white jn colorand faked upon scraping. The lakes collapsed into @ {ee-tlowing powder after being placed ina sample vial. Yield was 52% [o103] NMR Analysis [0104] Sampies ofthe powder were dissolved in dimethyl sulfoxide-d, and "IY spectra were collected on a Braker Avance-II1 300 MElz NMR spectrometer, at default stings, for 32 scans. A comparison of the NMR analysis of the powder with that ofthe CBD prior to powder formation, FIG. 8 nee tht he CBD rns emily wehangst after processing, 0108} "X-Ray Diflaction (XRD) Analysis [0106] Powder samples were lightly dusted onto a Vase- linc-coated silicon zero-difaction XRD plate (pype, Bedoped) of 24.6 mm diameter and 1.0 mm thickness. The samples were then analyzed on a Broker D2 Phaser Difae- fometer a 60 rpm. The XRD analysis indicates thatthe CBD! PVP bubble-dried possder is amorphous, in contrast previously prepared bubhle-dried CHD/Monnital/Methion- Ine powder, FIG. 6B, and the purfiod, as-received CBD, ‘whieh are both erystalline EXAMPLES Adducts of Metal Complex Compounds with CBD 0107] Adducts of metal complexes with CBD were ormed with tis(11,1,22:3.3heptlluoro-7,7-limetty- ‘ctatedionatoeuropiunn(I),(Eu(fod) and with ist dipiv~ aloylmethanato} ytterbium( Ti), (Yb(dpm),). The following structures show (Eu(fod)) alone (a) and complexed with BDOUS 2016/0228385 AI 10108] These formed adds of metal complenes are new ‘compositions of matter of the formula Eu(fod),-CED and Yo(DPM),-CBD in which one ofthe hydroxyl groups inthe ‘CBD on the phenyl ring is reversibly bound to the coordina tively unsaturated europium( II} or ytterbium(ID fon, The ‘adc complexes were subjected to NMR analysis a shows, in FIGS. 7A and 7B. [0109] FIGS, 7A and 7B demonstrate that inthe adducts, several ofthe CBD moiety peaks appear a different shifted ‘downfield positions in the presence ofthese advct-forming paramagnetic reagents, especially inthe ease of Eu(lod),- CBD, elativeto free CBD that i not adducted by bonding (0 ‘8 paramagnetic metal ioa, The aliphatic chain containing ‘carbons I" through 5" ae remote enough from the paramag~ netic Fu (If) ion to be relatively unaffected and the NMR peaks for these protons remain at the same positions as the ‘CD-only sample. Protons in the vicinity of the 2-OH oF 6-OH display the greatest difference in shift positions, indi- ‘atingthat the acdc metal in added shit reagent has boundo the oxygen in the basic hydroxyl groups in the CBD mol- ‘cule, ad not tote hydrophobic carbon chain whieh hs no ‘oxygen atoms with unshared electron pairs. J0110} When the non-sdductod metal complex But fod), is ‘eradiated and excited at 240 nanometers, a fluorescence ‘emission band is emitted at 480 nanometers with relatively Title background noise at other wavelengths. By itself, CBD ‘docs not significantly fluoresce when ieraciated with ltvio= Jet light at 240 nanometers, But more intense violet light appears in other spectral bands when CHDis bound as stable ‘kt to Eu(fod) 8 shown in FIG, 7C. The phenomenon of ‘ew peaks appearing inthe proton NMR in the presence of these Lewis acids ovcurs due tothe paramagnetic nature of the trivalent europium chelate adduct. While a casa obser- vation may make it seem that NMR poaks are “shifting” sctully a new compound and compositionaf matter has been formed with truly different NMR and fluorescence spectra. Fluorescence measurements and other independent single- ceqstal Xray diffraction structural analyses of lanthanide bete-diketonste adducts have provided confinnstion that new useful stable rare earth compounds, rather than physical ‘admixtures, have been formed. Isolated regions of unpaired ‘electrons within Fu(fod), and Y6(DPM),adduets produce an ‘overall magnetic moment aeross the molecule that ats a 3 supplement to the extemal magnetic fiekd provided by the NMR instrument. Protons i the vicinity ofthe bound shift reagent therefore experience a slightly greater magnetic field tnd the enengy gap betwen spin sats is increased, resulting in the absorption of higher frequency radiation anda down- field shifting of peaks. In contrast covalently bound mol- ‘ecules in which the paramagnetic effect i accomplished vis spin polarization through bonds the Lewis acid-base adduct results in psevdocontaet peakshifts, in which the effect is smaller and occurs due to spatial proximity tothe paramag- netic center. This psoudocontact effect decays rapidly as ise tances from the paramagnetic center increase (Ir, where ris the distance between paricular proton and the bound shift reagent), which accounts for the observation of negligible differences in the magnetic environments for the peaks or- responding to hydrogens further removed from the hydroxyl ‘ennups [0111] The formation of a CBD-lanthanide(ID) adduct is ‘urther confirmed by the selective shifting of CBD peaks even fin solution with another componnd, For example. in FIGS. 7 and 7E, NMR specira of solutions of CBD and limonene, Aug. 11, 2016 ‘common terpene found in Cannabis, are shawn before and alter the addition of Eu(fod),. The limonene peaks remain ‘unbounded and therefore unshified due to the absence of basic fuetional groups, while the protons near the hydroxy] groups in the CBD moiety within the adduet produce new peaks tha appear dowafield. LanthanidetII}) shift reagents ‘ill therefore not bind to every molecule present in a sample; ‘only those compounds with Lewis basic moicties have the potential for adduct formation [0112] ‘The various Examples and embodiments described herein are exemplary only and are not to be construed as limiting the scope of the invention defined by the following claims. Throughout ths speification, when a range of eon- ‘tions oF a group of substances is defined with respect to 8 particular charicteristic (eg, temperature, _ pressure mounts, andthe like) of the present invention, the present invention relate wo and explicitly incorporates every specific ‘member and combination of subranges or subgroups therein Any specified range or group is to be understood asa short hand way of referring to every member of «range or group individually aswell as every possible subrange and subgroup encompassed therein; and similarly with respect to any suh- ranges or subgroups therein ‘What is claimed is 1. A canmbidiol (CBD) extract isolated from industrial Dbemp, comprising less than 0.5 wt °% organic impurities as sieatured (1) by high performance liquid chromatography (HPLC) at 30° C,, and (2) by proton nelear magnetic reso- nance CH NMR) spectroscopy at 300 megahert using 80.1 ‘W1% solution ofthe CBD extract in deuterated chloroform solution relative to a tetmimethylsilane intemal standard ‘wherein the CI3D is in crystalline form, wherein a 0.1 wt % solution of the extract in deuterated chloroform exhibits no detoctable peak at 4.07 ppm, relative wo a tetramethylsilane internal standard, as measured by ‘HNMR spectroscopy at '300 megahertz and wherein and the exteaetexhibitsameliing point as measured by differential seanningealorimetry (DSC) fF 69-70°C. 2. The extmt of elas 1, comprising less than 0.1 1% ‘organic impurities as measured by the HPLC and 'H NMR. 3. The extract of claim 1, comprising less than 0.008% of {etrahydrocamabinol (THC) and tetahydrocannabinolic acid (THCA), based on total eannabinoidls content, as mea- sted by HPLC at 30°C. 4. Theextractof claim I, isolated from monoecious indus ‘eal emp, 5. Theextract of claim I isolated from dioecious industrial emp. 6. dey powder composition, comprising the extract of claim 1 7. The dey powder composition of elaim 6, whereinat least 90 wt 6 ofthe powder comprises particles have an aerody- sami diameter less than Syn, as measured using an Ander- sen Cascade Impactor 8. The dry powder composition of elaim 6, comprising at Jest one ational component select from the group con 1, mannitol, sucrose, tealose, leucine, ‘odium phosphate butler, arginine, histidine, alanine, gelatin, Tactalbumin hydrolysate, hydroxyethyl: Starch, maltodextrin, Tween 80, sodium citrate, phosphatidy|- choline, alpha ipoie acid, methionine, glucosamine sulfate phenylalanine polyethylene glycol (PEG), poly(lactic-co- alyeolie acid) (PLGA), and polyvinylpyzrlidone (PVP)US 2016/0228385 AI 9. A dey powder composition, comprising poly rolidone and a cannabidiol (CBD) extract isola industrial hemp, wherein the CBD is amorphous. 10, The dry powder composition of claim 9, wherein the ‘extmci comprises less than 0.5 wt % oxganic impurities as measured (1) by high performance liquid ehromatography (HPLC) at 30° C., and (2) by proton nuclear magnetic reso- nance CH NMR) spectroscopy’ at 300 megahertz using 20.1 st % soliton of the CRD extract in denterated chloroform Solution relative to a tetramethylsilane internal standard, wherein @ O.1 wt % solution of the extract in deuterated ’hloroform solution exhibits no detectable peak at 4.07 ppm, relative to tetrameihylsilane interoal standard, as measured by 'HINMR spocttoscopy at 300 meyahertz 11. single unit dosage for oral delivery, comprising the ‘dry powder composition oF claim 6 in a compressed form, 12, The single unit dosage fom ofelaim 11, comprising a wafer having a thickness less than 1 mm, 13. The single unit dosage fom ofelaim 11, comprising & tablet having a thickness ofa least 1 mm, 14..A method of producing the dry powder composition of ‘claim 6, comprising mixing atleast one carter, an extract ‘containing CD or CBDA an a superritial or near super- ‘tical Mid, and rapidly reducing the pressure onthe mix ture, whereby droplets are formed, and passing the deoplets through a How of heated gas. 15, The method of elsim 14, wherein the supercritical or near supercritical is carbon dioxide Aug. 11, 2016 CBDA and the method is conducted at a temperature of not ‘more than about 40°C. 17. A method of purifying a cannahidiol (CRD) extract oF acannabidiolie acid (CDA) extract in oil fom, comprising ‘iscolving the ol extract in near-superriial carbon dioxide ‘and removing & precipitated impurity exhibiting « peak at 4.07 ppm relative to a tetramethyIsilane internal standaed, as ‘measured by proton nuclear magnetic resonance CH NMR) spectroscopy ai 300 megaherz 18. The method of claim 17, wherein the nea-supercritical carbon dioxide iat a pressure of about 1300 1500 psig and @ femperature less than about of not more than about 40°C. 19, A method of sterilizing a caanabidiol (CBD) extractor ‘4 cannabidiolie acid (CBDA) extract, comprising dissolving ‘he extract in guid carbon dioxide, pressurizing the solution {oa pressure ina range of from about 2000 to 3000 psi, and repentedly increasing and decreasing the pressure of the sol fiom in the range a from about 2000 t0 3000 psi. 20, The method of claim 19, wherein solution temperature is rom about 2° C. to 48°C. und the pressure is inereased and decreased fora period of from about 20 minutes to about six hours. 21. An adduct comprising eannabidiol (CRD) bonded toa peramiognetic trivalent lanthanide (II) metal ebelate. 22. The adduct of claim 20, comprising CBD bonded t tes(11.2.2,33-heptatuoro-7,7-dimethyl-4 octane ato europium}, (Bu(fod),)- oF to tes(dipivaloylmethana- ‘o)stterdium(ID, CYHDPM},)-