Melting vs Dissolving freebase in recrystallization process

[Samvidbuho]

So, is it 'bad' to have your freebase melted during any stage of the re-x process?
I read that the boiling point of the solvent should be below the melting point point of the solute, but that of course makes things tricky for freebase.
Yet, I wonder if it's not such a bad thing to do afterall, to have the alkaloids phase change temporarily. Anybody have any insight or observations from experiments?

The plan is to have the solvent mixture reflux for at least a half hour, preferably 1 - 3 hr before allowing to cool and precipitate. If it's better for the crystals to remain in dissolution rather than being melted for this, then only thing I could think of would be to do the reflux in pentane, or pentane-ethanol / pentane-acetone azeotrope at ~35 C or w/e, then introduce say hexane, evaporate the azeotrope off, then cool?

Thanks in advance

Post Script: This forum has been such a tremendous help. I'm attaching some crystals of recent experiments, to give a little back..

 

[downwardsfromzero]

Given that heptane is so often recommended for recrystallisation of DMT freebase, I'd say melting is unavoidable in that instance. Unless people are willing to experiment with low-boiling solvents as you appear to have done, we'll just have to take DMT as an important exception to the rule.

Your pics ( :thumb_up: ) - are they of re-x products and what solvent(s) and method did you use in the end?

 

[Samvidbuho]

Thanks downwardsfromzero

These are different batches, but all coming from FASA from toluene.
I believe the real changes done which might account for the way the crystals have been forming are mildly a gradual improvement in purification steps, but mainly the way of isolating the freebase after the conversion from salt.
Before, would just add hexane (hot) to the sodium carbonated water mix, but lately been making sure the freebase-carbonate mix is fully dried, then experimenting with acetone pulls first (next time will use anhydrous ethanol, seems to hold some advantages over the acetone) and then introducing hot hexane.
Twice now there have been extreme crashes when maybe an equal amount of heated hexane is added to the warm acetone pull. A great deal of yellow - brown residue is left behind. I'll attach a picture. So, a single pull with acetone, and then pull with hexane.
Its actually a mixture of hexane and heptane, maybe 85 - 15, but not really a fan of heptane, it might extend the evaporation time which can be good, but it also kinda makes a for a slightly sticky bottom of the crystals. I suspect it does anyway.
I think it's crucial the converted salt (new freebase) is completely dry, and also the hexane very hot. It's capacity to hold freebase seems to increase a lot as the temperature gets higher. This makes for a pretty strong precipitation once it cools. The container must be narrow, I now prefer small beakers to crystallizing dishes now.

.. My observations so far.

 

[downwardsfromzero]

Could you say a bit more about your experiences with dissolving the freebase in ethanol? By my observation, DMT is so soluble in ethanol that even one drop makes the whole lot liquefy. Maybe some kind of eutectic formation?

Anything you have to say about this would be most helpful.

 

[Samvidbuho]

Hmm..
So last night 200 proof ethanol was used on some old leftovers of excess sodium carbonate with dried freebase mixed in as a quick proof of concept study to see if it would be better at picking up the freebase while leaving the Na2CO3. Recent use of acetone and hexane for this part became such a hassle when water was later introduced to capture up any sodium carbonate pulled up by mistake, and even after separating out and drying residual salt was still found to remain in a 0.2 um PTFE syringe filter.
Using just a few drops here initially this looked good - blowing on it caused some precipitate to form and remain, and it seemed like it would evaporate off.

Now I just did some playing around with some residual freebase left on some glassware, and I see what you're saying. Forms a viscous solution, high surface tension, and even when something comes out from blowing which looks like it will solidify, it just slides back down as a fluid. (Interestingly, I did notice some separation occur initially, with a clear layer on the outside and within it a yellowed layer which looked more oily. Have you noticed this too?)
Adding few drops of hexane reduced the size of the overall remaining solution a little, but didn't change much beyond the color. Water was then added, seeing if it would crash the freebase out as the water is made miscible with the alcohol, but the freebase remained in solution, probably because of the high solubility in ethanol. Although, here, a hardened residue did form on the bottom more and more. Maybe evaporating that would be better?

Haven't had it fully evaporate yet but not even working with freebase crystals, could be some mixed results from different sample selection.

However, it might not be an issue. Curious how the way a larger quantity would be left after full evaporation, especially compared to the oil left behind when acetone evaporates. But since such small quantities are needed to dissolve, adding a significant amount of another solvent then bringing to a boil should get rid of the ethanol.

The whole thing just comes from a desire to try and apply something I've been doing at work, working with polymorphic drugs. If you, say, look at the Google patents for lansoprazole polymorphs, you see they are made simply by refluxing in one solvent (acetone for Form II) and allowing to cool and crystallize. From Form II recrystallize using ethanol, and concerts the crystals to Form I.
The Form III is made from methanol, but also interesting is that it's only required to be at 25 C while the solution mixes.
So, in theory, by extension just dissolving freebase in one solvent, allowing to fully dry, then using another could change the crystals in different ways than usual.

Lots to still experiment with..

 

[downwardsfromzero]

As far as getting crystals from ethanolic solution goes, I've only managed to get success (largely by accident) by evaporating 50% ('100 proof') aqueous ethanol solution very slowly in a freezer. This was during an attempt at applying freeze precipitation methods to that solvent system.

Results of the temperature gradient recrystallisation attempt were illustrative of DMT's extreme solubility in ethanol. At around -18°C, a dark yellow coloured liquid phase containing practically all of the DMT sank to the bottom of the test tube. The clear, essentially colourless supernatant was removed and found to contain only extremely minimal amounts of DMT.

It may be worth trying chilling more dilute ethanol as the solvent, such as the typical 37% ABV vodka - although the problem then starts to arise of the water freezing out at the temperature where DMT might be precipitating. And given the seemingly extreme affinity of Ethanol for DMT - or rather, perhaps, vice versa - it looks to me as though evaporation is the only semi-practical approach for obtaining crystals with this solvent system.

 

[Samvidbuho]

Interesting. That is very clever..
Water has been somewhat of a thorn in my side too lately when it comes to the crystallization processes, I now try and do everything in my power from preventing it from complicating things down the road.

I've actually been doing some experiments with ethanol too lately, and something also interesting happened just now.
As a side project I've been interested in creating DMT-cannabinoid cocrystals. Pulled toluene was introduced to a pile of kief, and after numerous filtrations and re-re-recrystallizations using a variety of solvents still only an oily substance would be the end result. But, thinking that since DMT definitely crystallizes then maybe it's just a question of ratios, a small quantity of additional freebase was incorporated.
My way of dealing with the extreme solubility of DMT in ethanol has been to just boil the ethanol off while gradually adding another solvent to replace it.
Two reactions ago, ethanol (anhydrous) was used to dissolve all of the starting material and the solution heated on a hot plate with a stir bar, stirring for 15 minutes (should have been 1-3 hr..) at which point hot heptane was gradually added. At 70 - 75 deg C the ethanol all boiled off, confirmed by the cessation of boiling from the solution.
Taking the solution off, immediately a great deal of precipitate had crashed and was seen floating about, gradually coalescing. I didn't isolate this, though. When everything evaporated off there remained what looked like a quasi-crystalline structure, yet this too turned out to be more oily than I assumed it to be.

Ok so the interesting thing now is that when I redissolved *this in ethanol, the solute didn't dissolve fully. Very much at all, actually. I was very surprised. I added plenty more ethanol than should have been needed, but no amount could get rid of the insolubles.
(Methanol, acetonitrile, heptane - - neither of these could dissolve this mass either. Confusing.)
I did isolate the precipitate this time, which was white and crystallized white. I can only assume this is the DMT, but who knows what else may have been incorporated into its lattice.
Why this was insoluble in every solvent I had I can't say yet, but it definitely warrants further investigation I think.

Have you tried using the ethanol as a throwaway medium? It forms azeotropes with many things, I think some cool science could be done which takes advantage of DMT's affinity for ethanol as well as the fact that ethanol can be quickly removed by boiling, leaving all that freebase to be forced into a medium suitable for crystallization.

 

[downwardsfromzero]

Thanks for sharing your results! I was solely focussed on the ethanol/water/DMT system as a food grade approach, so the other solvents are largely incidental for me at the moment. Anyhow, my rate of experimental progress is quite limited due to circumstances.

I've done something similar to what you've described in the way of solvent-swapping. Starting with an acetone cannabis extract, this was first added dropwise to hot ethanol in a distillation setup so that the acetone was distilled off and recovered. The resulting ethanolic solution was then added in the same manner to hot glycerine to produce a full spectrum cannabinoid glycerite with only low levels of chlorophyll and minimal acetone residue, without having to use butane.

I can't really comment on the identity of the material from your co-crystallisation experiment but it's possible another compound could have been formed by reaction with something in the cannabinoid extract. You could send a sample to Endlessness for analysis.

Thanks, too, for pointing out that boiling off the ethanol is a possible approach when working with aqueous alcohol DMT extracts. I'd been focussed on emulating freeze precipitation but it was indeed evaporating the ethanol that produced the best result. I would be inclined to try reduced pressure as well; it would seem likely that boiling the ethanol out of a DMT solution in vodka would result in an emulsion of DMT in water. Perhaps that would crystallise out in the fridge? Would this then be an advantage over simply evaporating high-proof ethanol?

Keep on experimenting!

 

[Samvidbuho]

Hey, thanks for the encouragement and sharing your experimental results too ! It's so weird - today at work both glycerine and ethanol / water solutions came up.. I gotta try glycerine with the cannabis extract, I've been looking for other solvents to try. Makes me really want to start getting around to setting up a distillation apparatus too.

I attached a picture of what crashed out in my cocrystallization experiment. I think you're right that another compound was formed, because the color and shape of the crystals is just a little unusual and outside of what I'm used to seeing. I appreciate the heads up about what endlessness can provide too. I do hope / plan on coming up with something in the future which merits characterization

I've been thinking about your experiments - -
1. What if you salted a 37% ABV ethanol - water solution with CaCl2? The salt would lower the freezing point of water, and also calcium chloride is soluble in ethanol as well, so maybe that could help provide a driving force for the freeze precipitation? Without salt, I guess determining if a more dilute ethanol solution would work would depend on the freezing behavior of the solution - - I imagine a slush would start to happen first in the whole solution, and then as the water started freezing more it would expand and push towards the top surface? So if the water did freeze, maybe it would happen only at the surface, by which time the DMT would already be falling underneath?
2. Infinite dilution thought experiment - - could you get your DMT to precipitate out of ethanol without much freezing by diluting with large amounts of water? At a certain point, the ethanol might lose its solvating capacity for DMT from interactions with the water? I wonder this because I was just reviewing a project regarding a poorly soluble API - in 32% ethanol the drug stayed in solution, but at 24% ethanol (adding 10g water to the 32% solution) the drug precipitated.
3. I think there would be advantageous to using more dilute ethanol and precipitating it rather than boiling off the high proof by itself. DMT probably has multiple polymorphs depending on the solvents used and the way the crystals are precipitated out.. You could be getting a crystal out of the water which can be used to make another polymorph that wouldn't have been able to come from a crystal from a different solvent. Who's to say but it'd be a neat experiment !

 

[downwardsfromzero]

Ew, that does look rather odd! (And, careful with that thumbprint visible on the glassware... !)

Thanks for the tips. I'm planning on doing some dilution experiments just as you describe. Ideally there'll be a concentration somewhere between 25 and 40% ABV where a precipitate forms on cooling in the refigerator. The calcium chloride idea is great too, so that's going on the 'to do' list as well.

 

[Samvidbuho]

Do update on your results, I'm very interested to see what fruit this bears!

And hehe, good catch thanks