Concerta A/B extraction plan with n-hexane, will this work ? Any comment ?

alchemist137

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Planned steps:
  • take 10 x 54 mg Concerta
  • put them into 100mL distilled water
  • dissolve the outer layer (= some paint, wax and MPH)
  • filter out the red paint
  • let's call the remaining filtered water+MPH as S1 (for solution 1)
  • take the pills out
  • cut down the green parts
  • put the rest into a coffee grinder (electric) 20k RMP or so
  • make fine powder out of the 10 pills using the coffee grinder, let's call this powder as P1
  • put the S1 solution into freezer (including the container too, say glass)
    and cool both (S1 and the container in which it is) near to freezing point
  • put P1 into S1 and stir it for a few minutes
    for how long... that is a good question, depends on the solubility of MPH at 5 degree Celsius, below are a few solubility curves.
  • If water is cold then most of the Gelatine stays out of the solution, hence the cooling.
  • Now filter S1 (which has MPH + some Gelatine and other fillers whatnot in it), let's call the filtered version as S2
  • Add n-hexane on top of S2, it should be a separate layer, let's call this two layer "system" as S3, how much n-hexane, that is a good question. I do not know. Here some help would be welcome.
  • Add NaOh to S3 , make it a bit alkaline (how much, that is a good question), say there should be twice as many Na ions in the solution than MPH molecules.
    • So there will be a point where there will be NaCl (table salt) MPH base and the fillers from the liquid, but no excess Na. But just to be on the safe side, add twice as many NaOh molecules as MPH molecules are in the solution, S3.
  • Shake it.
  • Remove n-hexane, put it into a new "jar", let's call this solution as S4 (this should contain MPH in base form)
  • Add pure water to S4 (water because of the following other solvents are out of question):
    • n-hexane is soluble in ethanol, ethyl ether, chloroform
    • miscible with alcohol in general
  • There is a big question here how much water one really needs here... in principle 10mL is more than enough, which is handy because it evaporates quickly.
  • Add HCl to S4 just enough to make the solution a bit acidic, say twice as many molecules as MPH molecules are in S4.
  • Remove n-hexane (now this can be tricky without good equipment if there is only 10mL water. But in the worst case one leaves a bit of n-hexane and then heats S4 to 80 degree in a water bath and since the boiling point of n-hexane is 70 degree Celsius, it will boil away and we are left with pure water, a bit of Cl and MPH (in theory).
  • Evaporate the water. Let's call what is left as M1 , as in MPH-CL
  • Do recrystallisation:
    1. Dissolve M1 in as little pure as possible IPA at 50 degree Celsius (in water bath)
      • or more IPA ? =>I am not sure because I do not have a deep understanding on how two solvent crystallisation works exactly, it might be that a bit more IPA might be better because "chemistry is complicated" ... I don't want to go into deep theories here)
    2. add n-hexane up to the point when the solution starts to become "cloudy". Let's call the resulting liquid as S5.
  • Put S5 into freezer.
  • Collect crystals.
  • Put crystals into your vitrine. Next to your other crystal collections, after all, you are just a crystal collector. Some people collect stamps, some people collect crystals.
Any comments ?

Cheers,

ac137
 

cj

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I haven't done concerta in 15 years but from what I remember the time release works by having the drug on one side and a filter material on the other. So if you cut the pill in half you more or less have instant release methylphenidate. Seems simpler then all that chemistry.
 

alchemist137

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Looks like a robust method. I like that, "crystal collector." Welcome to BL!
Thanks, like Barrington Levy - here i come .

I haven't done concerta in 15 years but from what I remember the time release works by having the drug on one side and a filter material on the other. So if you cut the pill in half you more or less have instant release methylphenidate. Seems simpler then all that chemistry.
Actually I am thinking about that... though I read a few patents on concerta ... and even that is slow release... to make IR... is not simple I use a mortar to crush shit out of it... if it stays in plain water for too long it disintegrates... unless there is acid in the water... at 3.0 pH
 
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sekio

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two things spring to mind:
1. n-hexane is not a good solvent for most alkaloids even as freebase because it is incredibly nonpolar and most alkaloids are at least moderate polarity (even if they are not water soluble as freebases). This is why people prefer dichloromethane or chloroform as extraction solvents.
1a. N-hexane is also neurotoxic
2. Strong base + water (esp. If heated) will hydrolyse methylphenidate to methanol and ritalinic acid. This is probably an issue even with a weaker base like sodium carbonate but likely less so. certainly adding 2eq of sodium hydroxide would be conditions that you'd probably want to avoid. Maybe try as close to 1N of sodium carbonate and monitor the pH carefully while adding cold base solution with vigorpus stirring.

A simpler way to me would be to just homogenize the pills with a grinder then extract repeatedly with boiling methanol (pref. in a soxhlet) and then evaporate the alcohol. You'd get better yield and take less time and effort.

also, mixtures of hexane and 80%methanol/20% water will actually produce 2 seperate phases (alcohol and water on bottom, hexane on top). Same with ether/hexane and water. (Water on bottom, ether/hexane on top).
 

alchemist137

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two things spring to mind:
1. n-hexane is not a good solvent for most alkaloids even as freebase because it is incredibly nonpolar and most alkaloids are at least moderate polarity (even if they are not water soluble as freebases). This is why people prefer dichloromethane or chloroform as extraction solvents.
1a. N-hexane is also neurotoxic
2. Strong base + water (esp. If heated) will hydrolyse methylphenidate to methanol and ritalinic acid. This is probably an issue even with a weaker base like sodium carbonate but likely less so. certainly adding 2eq of sodium hydroxide would be conditions that you'd probably want to avoid. Maybe try as close to 1N of sodium carbonate and monitor the pH carefully while adding cold base solution with vigorpus stirring.

A simpler way to me would be to just homogenize the pills with a grinder then extract repeatedly with boiling methanol (pref. in a soxhlet) and then evaporate the alcohol. You'd get better yield and take less time and effort.

also, mixtures of hexane and 80%methanol/20% water will actually produce 2 seperate phases (alcohol and water on bottom, hexane on top). Same with ether/hexane and water. (Water on bottom, ether/hexane on top).
Hi Seikio,


Hmmm.... nice !
Fantastic, this was really helpful, many thanks !
This methanol thing is a bit... again neurotoxic.

I was also thinking about osmosis. Cellophane.

https://en.wikipedia.org/wiki/Semipermeable_membrane

I would think that the jelly part would stay on one side and
mph would go to the other side...

Perhaps a bit of electrolysis thrown into the picture also might help...

A bit of ion transport.

Somehow ?

And this
https://en.wikipedia.org/wiki/Soxhlet_extractor
is some pretty clever stuff ...

"boiling methanol" => is methanol not going to dissolve the other stuff ?

I tried IPA and it did... I have some methanol around too... but that is a bit toxic... so...

Perhaps using gravity ... in some way ..combined with electrolysis, or two solvents plus electrolysis...

hmm... anyway...

Thanks for the tips!

AC137
 

alchemist137

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What if I "just" filter it, after adding sodium carbonate?

Will it not just get stuck at the filter? Will it not crystallize?

Appear at the bottom?

Or maybe just simple electrolysis?

-----

Quick update:
1) polymers at 100C seem to separate. Which is a bit strange, F=E-TS is min in equilibrium, so at increasing T one would expect S to dominate and mix even more. Maybe the gel phase is some sort of a glass phase. Sort of having a very slow equilibrium time. Heating speeds up equilibration. Hence the separation. Once equilibrated then cooling back should not cause gel formation. So heating and the freezing might be a nice way to get rid of those annoying polymers.

1b) I am bit afraid of heating this, PEG can maybe turn into EG (antifreeze) ? => fucks up kidney for life?

2) Salting out.
Adding NaCl might make MPH-Cl insoluble in water/polymer mix. Cooling. Removing water. Scraping off MPH-Cl/NaCl solids. Somehow separating the two.

Maybe wiith dry IPA.

-----

Quick addition:

For pulverizing pills : https://youtu.be/d_HSZAsnB8s

I am not sure if pulverizing can be done really with any machine. If they are not some automatic/electric mortars.
 
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sekio

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Electrolysis is not in general used as a seperation method for anything organic because it tends to induce oxidation/reduction reactions rather than seperating compounds intact.

Methanol is toxic sure, but it is not a bioaccumulative neurotoxin the same way that hexane is, as your body has means to dispose of it via the kidneys.

PEG does not degrade to ethylene glycol with just "mild" heat (boiling water temps), ether cleavage is not a very easy reaction.

Adding NaCl might make MPH-Cl insoluble in water/polymer mix.
somehow I doubt you'd make much more than a salty mess. In general trying to salt out compounds only works well when you are using organic compounds with limited water solubility and no ionic groups.
 

alchemist137

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What do you think about cooking the "gel" which will separate, polimer is not soluble at higher temperatures. But at higher temperatures the MPH might decompose... so I would need to add some acid?
 

alchemist137

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But won't methanol also dissolve PEG ? (The jelly polymer pain in the ass.) Why boiling ? Why not cold ? Will the boiling methanol not dissolve the PEG?

I tried 0 degree ish IPA extraction, it worked to some extent. Not 100% sure but it seemed to me that PEG got geled up at higherss temperatures. At low temperatures PEG is not easily soluble.

I still need to look into this soxhlet.

Also funnily heating PEG makes it not "soluble" in water anymore.

for example:


"With increasing temperature, PEG (the hydrophilic part) becomes partially dehydrated and less hydrophilic, and the hydrophobic interaction between PLGA segments dominates leading to micellar aggregation and therefore sol?gel transition. With a further increase in temperature, significant dehydration of PEG occurs which disrupts the core-shell structure and thus results in gel?sol transition at higher temperature [24]. Another evident feature from table 1 is that the sol? gel transition temperature of the hydrogel/HA composites increases slightly with decreasing polymer concentration. ..."


So if I can raise the temperature without decomposing MPH, then I can "just" collect the polymer, get clean water. No gel.

From there it is easy sailing.

Cheers

ac137
 

alchemist137

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A simpler way to me would be to just homogenize the pills with a grinder then extract repeatedly with boiling methanol (pref. in a soxhlet) and then evaporate the alcohol. You'd get better yield and take less time and effort.

also, mixtures of hexane and 80%methanol/20% water will actually produce 2 seperate phases (alcohol and water on bottom, hexane on top). Same with ether/hexane and water. (Water on bottom, ether/hexane on top).
Few comments.

I was looking into this soxhlet thing.

The problem is that PEG 200K seems to be soluble in alcohol, so the soxhlet thing won't work. AFAI can imagine... this Concerta extraction is pretty tricky.

If heated above 80 in water it hydrolyzes. But above 100C the PEG200K "crystallizes", precipitates (polymers get tangled up at higher temperature - some funny phase transition).

The problem with concerta that it contains polymers (PEO, PEG) :

11403

Some (not so closely related info):

11404

11405

11406

11408

11409


Some related link ^ .


Just collecting some info.

Gotta run to shrink.

Might post some more info.

Cheers

AC137
 

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sekio

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The problem is that PEG 200K seems to be soluble in alcohol, so the soxhlet thing won't work
PEG is only soluble in hot alcohol, it's solubility in methanol is pretty damn low, OK so you end up with a mixture of methylphenidate and some PEG in methanol, cool it down to r.t. or lower and you will crash out the PEG? Or add some antisolvent (ether, acetone, MEK maybe) to force the MPH out?

PEGs require heat to be soluble in toluene, methanol, ethanol, and isopropanol. PEGs are not soluble in ethers, ethylene glycol, hexane, and are not soluble in most alcohols at room temperature.
 

alchemist137

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PEG is only soluble in hot alcohol, it's solubility in methanol is pretty damn low, OK so you end up with a mixture of methylphenidate and some PEG in methanol, cool it down to r.t. or lower and you will crash out the PEG? Or add some antisolvent (ether, acetone, MEK maybe) to force the MPH out?



Interesting! Thank you Sekio !


I have two different parts in this answer, the first part is related to the methanol based extraction, the second part is a water + weak acid + filter based "extraction".

First part:

In principle, is there any difference between using a Soxhlet or not if both materials are solvable in the solvent? Would in that case using a Soxhlet not give exactly the same result as not using one? The reason I am thinking this is that if the Soxhlet membrane has larger pore sizes than the PEGs then PEGs too will go through the membrane. The longer the Soxhlet runs the more PEGs go through the membrane. So this is suggesting me that in this case a Soxhlet won't make much difference in filtering out the PEGs as compared to simply dissolving the concerta into hot methanol and then do the antisolvent trick. Maybe I am not understanding the Soxhlet approach very well.

Nevertheless, this anti-solvent sounds interesting, at least some nice crystals could be obtained. Of course not all MPH will be precipitated, but the idea of cooling down methanol to get rid of the PEG and then using an anti solvent to get out the MPH, that sounds pretty easy. The "only" thing is that I need to be careful with methanol - not to poison myself - however, just simply dissolving Concerta into anhydrous methanol should not release much methanol into the air, cooling down methanol neither, adding antisolvent neither. So if the Soxhlet does not add too much value to the story then maybe it is "just" fine to do the dissolution of Concerta into methanol without the Soxhlet.

Bottom line, would the Soxhlet make any difference in this case as compared to just dissolving Concerta into r.t. methanol? Especially if I do not want to dissolve the PEGs ? I mean, it makes no difference in the end if I dissolve the Concerta at r.t. or in boiling methanol, if in the end the solution will be cooled down to r.t. anyway the final solubility at r.t. will be the same no matter at what temperature the two compounds were dissolved into methanol initially. (Here I am only talking about the PEGs as the "main enemies").



Second part:

I did a bit of an experiment now. (Not the Soxhlet way, much simpler).

Got a bit of Coca Cola, 20 mL, put 2 concertas (without the red outer layer) into it for 10 hours - was stirring it around a lot, it had pH around 3. Then I took 5 mL, sucked it up to a syring which had a 2 cm diameter PTFE (if I remember this correctly) membrane filter with 0.22 umeter pore size.

Then I compared the original unfiltered solution with the filtered one and the filtered one was not opaque and was less viscous.

The 0.22 micrometer filter got totally clogged up after 2-3 mL of the solution that went through.

Nevertheless, this filtering approach does not seem to be that bad.

I need to think a bit about the Soxhlet way too, however this filtering way seems to be pretty easy.

The PEG gets even more "crystalline" at 100°C - ish. So larger pore sizes could work too (hopefully they don't get clogged up too quickly).

I have a few questions regarding to this approach:

1) I was using Cola because it has phosphoric acid and that pulls down the pH to 3-ish so stirring concerta in Cola should dissolve all MPH from the strange little "micro-particles" that contain the MPH and are embedded into the PEG ... I wonder what would be the best filter to get out the PEGs ? I am not such a big filter expert.

Is hydrophilic or hydrophobic better in this case ? If clogging is an issue?

2) Would it be "better" to use IPA (99%, but not anhydrous) + phosphoric acid to extract the MPH from the micro-particles than water + phosphoric acid ? Would that cause some transesterification to IPA ? It would be easier to evaporate IPA.

3) AFAI understand, it is hydrolysis that breaks down MPH, so I wonder, if I were to use methanol (as you suggested) to dissolve the concies into methanol then I would not need any phosphoric acid to prevent breakdown of MPH since the reaction is already pushed heavily towards the methanol rich limit, so it would not be favorable from an entropic point of view to push some more methanol into the methanol itself. So the change in Free Energy would be purely due to the potential energy difference on the two sides of the reaction - where I can imagine that the more chemical bonds "something" has the lower the total potential energy is. As a very crude "rule". So this reasoning would suggest that in methanol MPH does not break down even at pH 7 - it should be stable there.

So the question is : does this make any sense?

4) I did the same experiment before, started to "evaporate" 10 mL of this solution in a 10 mL baker at 100°C ish, and suddenly the whole shit just "exploded". Why did this happen? Was the Cola + Concerta solution overheated and suddenly the PEGs became untangled ? They crystallized and this crystallization energy got turned into kinetic energy which increased the temperature and pushed the water above boiling point which "exploded". Does this make sense? This interpretation ?

Also the antisolvent idea is interesting ! Acetone is not such a dangerous chemical.





Side note:
This gives me a mischievous idea: let's filter out these micro-particles first and let the the PEG-s pass through the PTFE filters, I think these particles are so large that they are even visible ! Hmm...


Thanks for the comments / answers !

Need to sleep a bit now... but first I give a bit of a try to this filtered version.

Cheers,

AC
 
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