I tried to make a statement last night but my post became all fucked up when I attempted to post it.

Keep it chemistry related, keep it at a higher standered, AKA I dont wanna here the word gakk or eudogrit to be honest I want to hear the name of the chemical your talking about. Speak of solubility issues and hydrophobic interactions other then calling things gakks,


For the most part all of you get the idea of what and why the Vespiary is what it is. I doubt I need to make a ruling because I doubt any of yall will take it to such a stupid level that one would need to rule with an iron fist.

Is this clear for all of you?

BTW the digestive system is nothing more the HCl and it appears these polymers are undergoing an acid catalysed hydrolysis invivo. That would be a walk in the park to replicate.

The polymers used to bind the aminoalcohol in place will not be removed by a simple pill wash and while 65% gets thrown around I have yet to see so much as a melting point cited by way of characterization.

You just haven't been looking for it, embezzler. I started a thread on this board about equipment that could be used for melting point measurement, and started two, IIRC, at WD on chromatography. But your point is well taken. The most you normally see is that a burn test was used as a purity check--which is more effective than might be realized at first.

The problem is that few own an NMR machine, or even spectrophotometers. It's endlessly frustrating when there are problems with the result of an extraction or a reaction, yet no way to be certain exactly what those results are. The only method an amateur chemist ordinarily has available is chromatography, and paper chromatography at that. TLC plates are very expensive if purchased. I'm skeptical that home made TLC plates would be much more accurate than using PC methods.

I believe that PC could be done well enough to make it possible for results to be compared. That's because it only has to separate PSE from everything else--the polymers and others can remain mixed for all we care, as long as the compound under study is neatly removed. It seems like that should be pretty easy, but in several years of searching I have yet to identify a solvent or combination that will do the job every time. But once that happens it would be a short step to incorporate the same solvents for some adaptation of column chromatography. I should mention that I've restricted my searches to OTC solvents, and the search has been rather  sporadic. The testing necessary to make the determination is messy, and gets lots of glassware dirty. I go in bursts, get sick of it and put it on the back burner for a while, etc. I have seen some limited success fairly recently, but there are issues remaining before it will be a reliable method. It would be REALLY NICE to get the input of someone really experienced with chromatography!

The polysorbate (read TWEEN) 80 and 20 polymers hold the active moiety in place by having attraction sites for both the hydrophobic and hydrophilic regions. The degree of crosslinking will affect the rate of degradation and with it the release of the drug.

This sounds a bit like the research Fester did several years ago, boiling the materials in KOH to break down the polymers. I'm not well informed about the results of these tests, but have the impression that it worked well in some cases. Maybe you or someone else can say more, Embezzler.

Polysorbate came into the picture a long time ago. It followed the debut of PEG. In fact it appeared that polysorbate was the response to the spread of knowledge on ways to defeat PEG--primarily through a procedure know as the "tetra trap". Most are probably familiar with it as it's still being used in a modified form.

As you know PEG/TWEEN is made in many molecular weights, and I believe that there have been several employed.

That's not to say that separating organic salts from PEG or Polysorbate now is a piece of cake, but there are other, newer polymers as well, acrylics and what have you to deal with. Eudragit is believed to be another. It's not always easy to know what polymer you're dealing with, and often that's part of the problem. A new one has been seen recently that has the peculiar color pink when it's visible at all. It would be great to know what it is in order to deal with it more effectively.

The degradation of these polymers is studied and these studies are released for public consumption. It is not easy for the pharmaceutical industry to change these due to having to conduct clinical trials for bioavailability and to carry out safety testing on the in vivo degradation products of the cleverly designed polymers. 

True. That's why in every case that I know, they've used something that's already been approved, usually in something else. I'm not aware that anyone has prepared a compound especially for use as an extraction or reaction foilant.

These were originally added to frustrate the LWR (alright also there were probably legitimate medical uses for these too and commercial incentives) as they contain a relatively high number of ether bonds which will scavenge the HI generated by the RP and Iodine. The key to these polymers is that they are designed to degrade at certain temperature and pH ranges otherwise they would be useless since no-one wants to deliver 65% of the pill load to a patient.

I think you may not have said exactly what you intended here. The LWR is long, wet reaction. I'm not aware of any of the materials under discussion that targets a specific type of reaction. Also there are several ways of running a LWR, and I'm wondering if you actually had something else in mind.

Depending upon the type of delivery system you're dealing with, there are definitely time release forumulations, and these release the active ingredient based mostly on time, although it stands to reason that the environment at the time of release is going to make a difference. However, it's also widely recognized that most of these systems can be defeated by grinding the material, thereby releasing the active ingredient immediately.

These polymers are not indestructible and can be cleaved at the ester group  since they are not chemically inert. I think the key here is physical degradation  .

You're certainly right that they aren't indestructable, but the trick is to destroy the polymer without destroying anything else. This was Fester's goal as I understand it. Also, don't forget that once a polymer is destroyed you're usually left with a lot of monomers, which can be almost as much trouble as the parent molecule.

  The polysorbates undergo autooxidation, cleavage at the ethylene oxide subunits and hydrolysis of the fatty acid ester bond. Autooxidation results in hydroperoxide formation, side-chain cleavage and eventually formation of short chain acids such as formic acid ... [see ref 1 below ]

I believe these are the primary chemicals of concern while polymers like PEG are also used as binders in the pharmaceutical industry. The days of a methanol wash are gone because people keep asking questions about these damned pills online.

I am not for censorship and if questions were phrased such that the chemistry involved was discussed not just crude protocols with no objective data then this would be a little less frustrating for me. There is a good reason that no correct answer is posted in its entirety on the internet and that is the same reason these polymers changed in the first place  [/quote]

That's certainly an issue, and one that needs to be carefully considered. There was a time when every new procedure was posted to one or more of the boards, and it got to where manufacturers could respond within a month or two with a new formulation that wasn't vulnerable to the current method.

Headstrong and Prepuce seem like they know about chemistry and probably know more than I do. That said there will be no straightforward chemical way to remove the bound ephedrine from these polymers. Reconstructing a human digestive system is not possible though one could mimic some of the  digestive reactions in vitro. Perhaps a long acid digestion with agitation following transfer to a more basic environment as a start.

I think this could be discussed once it was phrased correctly and that would be along the lines of "removing a phenylaminoalcohol from a large crossmesh of polyethyleneoxides and ether bridges" - Not a mention of AB of pills since those days are now over. That said I neither moderate or administrate on this site and will follow the instructions as they appear. The pill questions can surface as a blight as many of you already know. They may be overlooked if the chemistry were presented and no mention made of name brand OTC cleaners etc. If I had my way such details wouldn't make it as far as the vacuous posts forum lest they mess up the search engine [/rant]

@Iknowjt:

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*Here's a juicy example, a poster named HeadStrong over on the UK drugs forum site, puts his vast expertise to use in his posts regarding pill extraction.  He has made a mini-science of it, that is on a drastically higher level than I've ever seen anywhere else.  The example is that he sounds damn sure about there being a specific complication when polysorbate 80 is present in a HI based reduction of pseudoephedrine.  He says that a different strange, toxic amine is formed, with very little of anything else being yielded.  My friend can attest to experiencing a very specific allergic reaction, when he had ingested certain substances, that according to headstrong's claim, where very likely to have been contaminated by this strange amine.  This very allergic reaction had been experienced by this friend, when ingesting a high tech, recent adulterant commonly found in street bought meth.  Namely Isopropylbenzylamine HCl, a non-psychoactive, structural isomer of meth, that has almost all physical properties identical to that of meth, so say DEA microgram journal forensics chemists.  Nifty stuff, ain't it?

The RP/I reduction of PSE leads to a number of other substances and I have a nice paper on this though it is as out of date as the technique. Even if pure PSE were used the product would not be due to a number of side reactions. I imagine that these are increased in the presence of polymer degradation products. In fact I wouldn't doubt it for a second.

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[quote Which is based on the idea that time release technology is sopisticated, and it functions on a physical, not just chemical level.  Sort of like coatings, inside of coatings, inside of coatings.  And these coatings actually have a set time to work, so the best way to extract the active ingredient of a pill would be to build a model of the human body, preferebly from reycled components from the cemetery/morgue.  65% Is roughly the amount of the ingredient that a congested customer should feel set in at first, and the remaining 35% is left to stretch it out.  So most likely having a pseudo-stein monster, would still yield only 65%, unless one had the patience to actually wait out the 12 hours or whatever, that the pills are intended to last for. 

This is probably the case and it is not as difficult as one may think to get polymers of varying composition to form in layers - this is established pharmaceutical technology.
 
@ Prepuce1

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I don't believe I ever seen a box listing Eudragit, for example, but we know it's used.

There is never a requirement for pharmaceutical companies, within the FDA territories at least, to list the excipients and these are often of a secretive and proprietary nature for many reasons.

@ akom

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It's a basic solubility issue just like any sort of recrystallization I'd imagine.  Whenever you extract, some of your PSE is left behind in the layer you discard.

It is more complicated than that and it comes under the branch of science known as posology. Evapping a layer to dryness will tell you whether or not you had something left in it.

@headstrong

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YES! That's it!
So many routes is discussed in this business but separation is rarely discussed, do you think available work up procedures are proper enough to separate amine from similar amines? I think not.

I think that chromatography can separate even enantiomers so resolution will not be your constraint. Capacity will be an issue and you will still have to break the attraction between the PSE and the polymer.

The only way I've ever heard of doing that is by using cream of tartar. There may be a way of doing with chromatography, but I think it would rather exotic. I could be wrong. . .

I've long wanted to try size exclusion, as I think headstrong mentioned as a possibility. It should work quite well, and what I've read seems to indicate the same thing. PSE is a much smaller molecule than any of the polymers, so it should be a simple thing if you identify the correct solvents and substrate.

PP

Sedit, I was just thihking about the same thing as I came to your post. If what we have here is representative it won't be a problem. But what would you and Vesp think of the idea of a small private forum?

This is a small private forum. How much smaller do you want?

Should we invent some sort of member promotion system, akin to BL? That's really the only step forward from here...

Embezzler:
"I am not sure that PC or any other chromatography is quite needed but the separation is not going to be a simple AB separation if that is what is desired in this thread. I cannot promise that this will end all woes either and may introduce some new ones. "

Em, you and many others apparently haven't had time to read the first post in this thread. The idea that we're looking for an A/B separation or something that simple is so off-base it's ridiculous.  Don't get the idea that I'm flaming you about this. Not at all--I do the same thing all the time. It's generally not a good thing, of course, and in this case it's really twisted the original purpose of the thread. That's been both good and bad, and I'm not going to obsess over it because this is still such a good thread.

I've done just as badly by not stating my reasons for wanting a better solvent mix for PC. It definitely wouldn't make a good separation method. My hope was to use it first to identify the inactives before you begin working with them. Once that was done, and if it was required, column chromatography could be performed at the batch level. That assumes that the same solvents used for PC would be equally useful in a column. I"m not sure but think that's a reasonable assumption most of the time, depending upon the substrate/support used.

The Rhodium archive has several methods that work much more quickly than methods you may already be familiar with. I think one of them is performed in a funnel. I'm familiar with something similar that was tried, and in spite of the fumbling that results from working an unfamiliar process, it went fairly quickly and suceeded in separating the sample.

PC was a pain in the ass when first begun, but after a little practice it's no big deal. When you already know what colomn would be used as well as other equipment and the configuration, it cuts off most of the time it took to put it together the first time.

"The thing is I want this method to live for a while and the source of the info to remain viable, I have sat on this for a bit but I am sure that others are aware despite my never having discussed it with anyone online. "

I'm afraid that even announcing the existence of an effective new procedure is going to be it's downfall. That's because those who don't have it will start asking others, and sooner or later someone will give it to them. The next thing you know the method has been released in the wild. This is not criticism. It's your technique and you have every right to do with it as you please. I only mentioned it as food for thought. Seriously.

Cheers,
PP

Embezzler,

the threads on PC may not be worth your time looking them up. The solvents used for the mobile phase were methanol and ammonium hydroxide, 100 - 2.5, v-v. This worked sometimes, but if there are polymers in the mix it sometimes does not work. That is, a strip that showed nothing other than PSE was used to judge the cleanliness of a batch that was reacted. Post reaction it was obvious that the feedstock was not at all clean. Other solvent pairs have been tried but none have reliably separated the PSE from all of the possible nasties. Finding suggestions for the mix of the mobile phase has been difficult.

PP

So here's the problem just described. Solvent pairs used for PC have resulted in the contaminant following the PSE so closely that the two cannot be distinguished. In fact it's not obvious that there are two or more compounds present. The other common result is a long smear. The last experiment produced a smear from the starting position to the end.

Like you say, headstrong, you've got to think the problem through if you want good results. It seems as though this should be easy, because the objective is to separate one compound from all the others. Polymers don't behave like other compounds, however. One often suggested solvent for the purpose is DCM, but short of ordering it from a chemical supplier it's not easily available. I'm not sure it would work any better than MEK, but would like to try it. I may have to distill it out of some paint remover.

PP

DCM based paint strippers re readily available in the large stores in the brittish isles. Same stores sell pure HCL in 5L qtys.

I imagine that the wax in the pills will come over in DCM. There is a thread on WD incorrectly titled super critical DCM extraction that proposes extraction with DCM in a closed vesse at elevated temperatures l.

I've long felt that the answer to questions like those we're discussing is better understanding of the chemistry, and it seems that the more I dig into the matter the easier it becomes to understand what's happening. As a case in point, a partial answer to my initial question occurred to me.

Acid/base extractions involve two chemical reactions. I don't think there is anything that exempts these reactions from rules applicable to any others. That is, the process obviously favors to formation of PSE HCl, but that's probably not the only compound formed by the time the molecule has been based then re-acidified. Assuming that there were no polymers in the mix (for now) what would tend to be formed besides PSE HCl, what might favor the formation of PSE HCl, and what could be done enhance formation of PSE and deter formation of anything else.

I definitely agree that we've already seen the effects of putting polymers/monomors through reduction. It would be nice to know what unintended compounds are finding their way into the mix. Although the RP/I process tends to be a dirty one, it's been optimized in many ways, in terms of product quality, and methods have been developed to assure that the final product is relatively clean. Now that those methods are old and new compounds have entered the mix, new methods need to be identified before people start making themselves and others sick. I think this last has actually been happening to a small extent for a couple of years.

PP

Regarding PKa - I have just been learning about it as part of studying extraction chemistry techniques and am rather frustrated trying to find numerical, emperical solubility information.  There is probably some great chemistry site in the sky I just haven't found yet, but I would think by now there would be good numbers for solubility out there.  I have 2 Mercks, a CRS of Chemistry & Physics, A Perry's Industrial, Lange's Handbook and am a whiz at google but can't find something like a Partition coefficient for ephedrine in Xylene for example.  NIST solubility database doesn't even come close to covering this, so I'm suspecting it's published in books that cost $$$$.  I'm planning a trip to the library to build a chart I'm building of common OTC solvent solubilities.  

As I'm learning basic extraction and separation techniques, I am finding myself with a soup of solvents and no way of knowing which one's azeotrope and/or mix with others.  There are rules of thumb but I would really prefer specifics.

On another related note, I have up a copy of the handbook of cosmetic and drug excipients and could scan some of the chapters if that would be helpful.  Excipients are going to continue to be a problem for home chemists because they are being added to so many different OTC products.  Even ordering supposedly pure chemicals online doesn't preclude getting a package full of gunk.

Salat

Sedit, Salat,

It's been a very long time, but one thing I clearly recall of the chemistry classes I took is pulling my hair out over acid/base equilibrium reactions. Those are where the subject gets most complicated--to my knowledge--because of the math. Later I knew math a lot better and have wondered ever since if that would have made much of a difference as far as difficulty of learning. I think it would have.

I may not be remembering everything that needs to be considered, but I'm fairly certain that you only end up with an equilibrium problem when you're dealing with a weak acid and/or base. As we all know HCl isn't a weak acid, and believe that it reacts fully with PSE. I'm not sure that there isn't a secondary compound formed, however, and suspect there must be. Maybe it only occurs with acidification, maybe just basification, or maybe both. Researching this kind of thing is difficult because there doesn't seem to be an awful lot of published data relating directly to the reaction in question, so I've started searching for similar reactions that might correlate. It's slow going, though.

PP