https://doi.org/10.1016/j.bioorg.2023.106914
Can anyone get a link or copy of this paper…
“”Novel phenolate salts of bioactive agents: Cannabidiol phenolate salts””
The subject matter should become an independent subject on the board.
NOTE: a pdf link has been appended by @321MBT 321MBT . Many thanks.
My local university has this. I can go in and read it but I’m not sure they will let me take copies of it with me. <3 But probably your local university library also has this.
I’ve also reached out to the authors to see if they want to share the article and anything else nice. I assume other people do this kind of thing as well.
I know I still get requests for more information and articles for my work and I haven’t published anything academic in like… 8 years. 
The subject matter should become an independent subject on the board.
Maybe add a key word or two to your thread title like water-soluble or ionized?
Novel phenolate salts of bioactive agents - Cannabidiol phenolate salts.pdf (2.8 MB)
Supporting Information.docx (2.3 MB)
So nice to see an academic paper which discusses and mimics the work I was doing back in 2018. Always nice to see reported solubility. Always nice to see discussion of pharmacokinetics.
Thank you for sharing the whole thing. <3
@Cassin
We will add your name to the short list of “water works”.
Now if you want to read some further chemistry of phenolic anions of neutral cannabinoids, I refer you to the 2005 Patent: https://patentimages.storage.googleapis.com/12/0c/5d/af8cd680ac4763/EP2289509B1.pdf
Which is EP 2 289 509 B1 (European Patent).
Read the details of the “caustic contact step”.
Lots to learn here in procedural “water works”…notice they don’t really tell you exact details…LOL.
So uh… any tales of bioassays from 2018? Your friend SWIM perhaps 
If you take a really close look at their gavage-feeding studies and the nano-formulation in a lipid matrix…do these studies really support salt enhancement of uptake…or perhaps a better nano dispersion preparation…they admit that eating the salts only reverts the CBD to neutral forms at stomach pH. Take a close look at the supplementary information that is supposed to support their conclusions…or the lack of it at least? Moreover, they seem ignorant of the Lipid Lymphatic absorption pathway/no mention/ especially concerning since they are using a lipid nano emulsions…
I think the extra -late eluting peak found in the HPLC (notice no details of chromatography system used) of the K+ salt is most interesting…??? But not in Na+ salt. Those who have worked with the cannabinoics at high pH probably have noticed some differences with the choice base and reacidification.
Why would this group have an entire section labeled:
“Acid regeneration experiments and HPLC-UV quantification.”
Titrating a phenol in aqueous from phenolate to phenol is “acid regeneration”???seriously?
I am sure you might have similar reserves about this work on close inspection.
I didn’t give all the details in my pending patent either… but I went over all the important bits I think and pointed to the prior art where I was attempting to make things more environmentally friendly. Because prior art didn’t seem to care about what kinds of hazardous wastes were left over. -shrug-
I’m not exactly sure what you mean here. But I tracked assays from starting biomass, extracted biomass, flush, wastewater, extracted cakes, and pre-recrystallization cakes. All of this to try to prove that less caustic substances could be used (waste outputs and yields compared to halogenated acids and lye).
Yes - I definitely noticed this myself. 
I’m not sure I have the same reservations. But then I’m used to academics publishing unfinished works. They already responded to my inquiries about sharing more data, talking through analysis, and working on international standards. So while I might be concerned about the thoroughness of the work - I’m also confident that they want to keep doing more work, because I reached out to them personally and they said as much. 
Might even get them to share more specifics - working on talking to the analyst (since there are five “authors” and only one of them appears to have been involved in analysis).
Yes. I thought interesting usage of the terminology as well. But then I did a search on the referenced publications which all seem to imply this is the case - especially when they are doing titration in the presence of electrode (which maybe they were?).
I thought perhaps they are doubling down on this from the biochemistry side of things (as their other works seem to present that way…) in which case those would be the terms used.
Its either acid regeneration OR phenolic salt production in the other references, yeah? So maybe they were trying to be consistent?
It appears that being on different sides of the planet means that I send them a note in the middle of the night, and the following night I get a response maybe.
Do we have other questions we might want to ask? I’m always excited when I get a response to my inquiries within about 2 days. <3
And yeah - I agree they seemed not to know some of the things that we take as general assumptions now. I don’t know if they don’t know at all - or if they decided to keep it as a variable control and didn’t mention it - or if they really published partially unfinished works and there will be more forthcoming.
The only people citing their work are doing so as part of analytical chemistry advancements - so maybe all these questions are giving other people jumping off points to try new things?
My gut reaction to the title of the paper was “seems boring/redundant” and after reading it, i think i was spot on
I’ll be more cut and dry: anyone eat some and get high? 
Many people drank some and got high. 
I don’t think cooking things in brownies worked at all… although we tried. Perhaps the recipe was terrible?
But the real deal was trying to make the extraction processes more environmentally friendly AND safer for workers. <3
The cake at the end was packed full of cannabinoids - we were using the salts to make things water soluble remove the biomass, then using microfiltration after pH shift collect all the cannabinoids in a cake. That cake could them be post-processed (distillation, recrystallization, decarb, whatever).
That then become the hard part - because when you are running +39,000lbs an hour you get a lot of cake… and existing systems at the time were rather small on the throughput side of things. Such is life.
Hemp?
In the big batches - yes. But I did test it all out small batch as well. Worked just as well - only time I found that it doesn’t work great was when the biomass was really potent - because there would be too much left behind in the material. 22% and lower, no problem. Higher than that and I was leaving A LOT behind, and I don’t like leaving any cannabinoids behind. <3
Since…2018…hemp has become dirt cheap…you can now get a kilo of cbd isolate for about the price of a kilo in 2018. So I wouldn’t worry about leaving anything behind.
Was that material fresh or kiln died? At large scale how big were your soak tanks…
And you were doing pH altered water? Correct?
Target was CBDA? there was a group in Washington working at that scale…and patent published…was that you?
I used both dried (huge gas dryers, like the kinds at chicken egg facilities) and fresh fresh - like just cut from the field, rolled, baled, and driven over to me.
The tanks were fucking huge - not the biggest I have ever used ever, but still darn huge. We had 4 10,000 gallon milk decanter/mixers. Dual prop tanks, with dual 8 inch bottom ports. Those went into fucking giant centrifuges to remove as much of the liquid as possible and then the biomass went off to be pelletized (I thought we would use them for animal bedding…but the USDA freaks out about animals eating cannabis and things…)
And yes - pH altered water.
I was not working in Washington. I worked in California, Colorado, and finally Kentucky.
I read about the team in Washington - they were not using microfluidics and they also didn’t seem concerned about environmental stuff, like using 5-10 times the water we ended up needing to use.
And yeah. CBD is dirt cheap, but soon it may be worth more again. If the Senate gets its way then CBD will be able to be put in all kinds of stuff “officially” and the big guns will come out for cosmetics and stuff. I was working with some of the biggest names in cosmetics at the time - and then BAM FDA puts the ban hammer on it. x.X
And the whole point was to try to get as close as possible to a zero waste system where all materials had a specific output. You know?
This is where water really shines, IMO. I don’t know any cultivator that loves the expense and pain in the ass of drying biomass.
This is the ideal. We use a fair bit of water - right now we’re tossing around a higher L/kg than we used in the flammable solvent days, but we also recover close to 100% of our pH-modified liquid fraction, and without centrifuges.
I want a second RO system to clean up and re-use the neutral fraction / waste water as well, but that’s a lot more equipment and effort, and our water is functionally free, so it’s hard to justify investing there at the moment.
The solid waste fraction is pretty innocuous as well. It sucks that the government won’t let us do anything with the hemp waste, even though it’s fully neutralized and has fuck all cannabinoids in it.
I’ve got some ideas for that but convincing the regulator to let their ears maybe get cold isn’t something I’m very good at.
This is where water really shines
Arggg shit never thought of that one
You got my attention now oeffff that’s briljant
Especially if you just use water to knock off the trichomes with shear… who wants all the rest of the shit.
Here are some additional comments of Phenolate chemistry in aqueous base:
“The same analytes were further tested using the same column, but under basic conditions, where tetramethylam- monium hydroxide was used as the pH modifier. A fast separation was again obtained. The pH of the mobile phase (ca. pH 11.4 for the A/B 40:60 mixture, see caption to Fig. 3)is above the pKa for a protonated amine, i.e., the pKa values for the protonated forms of methyl amine, dimethyl amine, and trimethyl amine are 10.62, 10.64, and 9.76, respec- tively [32], so we expect the column to exist in a substantially deprotonated (neutral) state at this pH (see Fig. 1). Clearly one would expect the retention of an anionic species to decrease with increasing mobile phase pH on this column, i.e., with increasing pH there will be fewer protonated amines in the stationary phase. Figure 3B shows the isocratic separation of THCA, CBN, CBD, and THC at pH ca. 11.4 (see Supporting Information Fig. S2 for magnified views of CBN, CBD, and THC in Fig. 3B). As expected, the order of elution (selectivity) is substantially changed compared to the separation at low pH in Fig. 3A. The more polar, acidic THCA, which will certainly be deprotonated, is retained less and elutes early. The neutral species that were less retained (CBN, CBD, and THC) at low pH now elute after THCA.
All of the cannabinoids considered in this study are phe- nolic in nature. The pKa of phenol in water is 9.98 [33, 34]. Accordingly, one would expect (i) phenol in water to be sub- stantially deprotonated at pH 11.4, and (ii) that in its depro- tonated state, it would behave similarly to a deprotonated carboxyl group on the C18, mixed-mode column. However, the pKa values of anionic analytes in water are substantially different from the corresponding pKa values of the same an- alytes in water/organic mixtures. For example, Sarmini and Kenndler showed that the pKa of benzoic acid changes by ca. two units with a change in solvent from 100:0 water/ethanol to 40:60 water/ethanol [35]. However, even a change of this magnitude would not alter the fact that THCA is deproto- nated under the conditions corresponding to the separation in Fig. 4. Sarmini and Kenndler also showed that Ga (kJ/mol) for ionization of acetic acid, benzoic acid, and phenol in wa- ter and methanol change from 27.1 to 54.2, 24.0 to 53.0, and 56.9 to 82.0, respectively [35]. These results suggest that the pKa values of the phenolic –OH groups in our analytes sim- ilarly increase in a substantial way as they are surrounded by a progressively more organic medium, and that a signif- icant fraction of the phenolic –OH groups are protonated under the conditions of our elevated pH separation. Thus, the greater retention of CBN, CBD, and THC at pH ca. 11.4 is not unexpected. Finally, Sarmini and Kenndler showed that the pKa values of protonated amines in methanol are very similar to their values in water. Accordingly, it is expected that the pKa values of the amine groups in the stationary phase remain nearly unchanged in a water/organic mixture compared to water [35]. Thus, at ca. pH 11.4, the amines in the stationary phase should be in a mostly neutral (deproto- nated) state, able to retain cannabinoids through hydrophobic interactions [28, 29]. (Hung, et al., 2015: DOI 10.1002/jssc.201500156). Reference 35 in this paper is worth reading as well: J. Biochem. Biophys. Methods 38 (1999) 123–137 (Sarmini and Kenndler mentioned in discussion above)
If it is not totally obvious anyone working with classic base water extraction (pH 11-13) when doing the reacidification step by a simple titration with choice of acid , one has to pass through the phenolate salt phase to phenol transition in the pH 9 to 8 range (mysterious precipitation) on the way down to pH4 or less to protonate the carboxylate. I am speaking Aqueous protic polar (no organic additives).
Organic additives can play havoc with the concept of pKa values
Each type of havoc is dependent on choice of organic additive and concentration. So keep this in mind when doing a precipitation of cannabinoic acids.
@Lincoln20xx
“The solid waste fraction is pretty innocuous as well. It sucks that the government won’t let us do anything with the hemp waste, even though it’s fully neutralized and has fuck all cannabinoids in it.”
A couple of questions? I am not exactly familiar with the concept of “fuck all cannabinoids”. We will just skip over the adjective for now…and assume you mean cannabinoids remaining in the water-extracted biomass.
Since the topic is phenolates and extraction of phenolates with base, and as you are well aware this is subject that has a history that goes back into the early part of the 20th century.
Since cannabinoids in general have at least a phenol or rescorcinol core structure , both of which are ionized in base (pH 11-13) water, whether they are neutral cannabinoid or cannabinoic acids both are presents in the base water extraction. In fact, those who are familiar with the process understand that the target is the cannabinoics and it somewhat problematic to get rid of neutral species from the base water extract.
So I am curious as to what type of cannabinoids you speak of are left-over in the biomass. Of course the improper pH and or wrong mole ratio of cannabinoate counter ion can lead to inefficient extraction of all cannabinoids, but you speak of high efficiency, so your “cannabinoids” which remain after extraction in wet biomass seem enigmatic?
With regards, to remaining biomass, just hearsay, but I have been informed that cows love it and if given the choice will prefer to eat spent Hemp. Since base water soak-washing and subsequent neutralization is a standard “food processing” step (olives for instance)…why is it you say government frowns upon it?
@Cassin
I am not sure about some people drinking the “water” and getting high…?? Pure THC in vodka or pure grain will do the “moon” trick, but drinking neutralized aqueous extracts of THCA/CBDA from fresh biomass isn’t going anywhere other than analgesia.
Please advise…