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pseudo from pills, sulphate pills and new ideas
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loki
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Mon May 16, 2005 12:29 am
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I originally started this post as a reply to the pseudoephedrine sulphate thread, but after a while it kinda took on a life of its own and grew to the point that I thought I'd better make it an independent thread, and simply point that other thread to this one.

This post goes through a long analysis and lots of explanations and lots of speculations, mostly based on facts, some extrapolated from facts and the trends indicated, about the process of extracting pseudoephedrine from pills.

The first section deals with a 90% tested method which produced about 90% purity and 80% yield, on a pill whose full ingredients I tracked down, a pill which is available globally I believe.

The second section expounds a theory of extraction which utilises only liquid/solid extractions and exploits solubilities of different chemicals in various conditions.

The third section, the variations section in the conclusion, takes the same theories a step further and attempts to produce the perfect extraction, which, according to theory, should permit a nearly 99% yield from virtually any pill. (I know that sounds a bit bold but when you read it you will see that it's not an exaggeration, that it could well be).

This is the list of contents of this particular one, loratadine is the antihistamine in it:
Quote:
DESCRIPTION:
Each ****** ***** Tablet contains 5mg loratadine in the tablet coating and 120 mg pseudoephedrine sulfate equally distributed between the tablet coating and the barrier-coated core. The two active components in the coating are quickly liberated; release of the decongestant in the core is delayed for several hours. Inactive ingredients: acacia, calcium sulfate, carnauba wax, gum rosin, microcrystalline cellulose, oleic acid, medicinal soap, sucrose, talc, titanium dioxide, white wax, zein, lactose anhydrous, corn starch, povidone, magnesium stearate and purified water.


As far as i know, loratadine is not soluble in much of anything, if this person is dealing with the same or similar pill formulation. It does not appear to come across in a standard acid/base extraction to any degree.

I can't quite say with certainty which ingredients are in the barrier layer but by starting with the coloured ones, as it has a yellowish colour, i can pick the most likely ones (the rest is white): oleic acid, medicinal soap, acacia, gum rosin, corn starch (it's usually at least offwhite and is not common in standard simple chalky pills). It's a pretty good bet that the PVP (povidone) is in that mixture as well, to make the starch bind better with the rest of the ingredients in the barrier.

Here's the info on PVP

Quote:
Polyvinylpyrrolidone (PVP) is a white, hygroscopic powder with a weak characteristic odor. In contrast with most polymers, it is readily soluble both in water and in a large number of organic solvents, such as alcohol, amines, acids, chlorinated hydrocarbons, amides, and lactams. On the other hand, the polymer is insoluble in common esters, ethers, hydrocarbons, and ketones.


When they were heated in the microwave i think that the trace water in the inner layer is what caused them to swell up and burst, the heat also softening the barrier and the entire pill matrix. This method keeps the undesired materials from entering the aqueous solution, simply by reducing contact time.

I don't know if there is a more optimal method to perform this extraction. These pills are compounded EXTREMELY densely and are difficult to break apart, the idea of cracking them to get the centre layer is impractical. I think they are so hard in part because there's a lot of that white wax in them, but in any case, they cannot be easily cracked open, and that evil barrier layer tends to crack at the same time.

On previous occasions, soaking in toluene did not significantly help with eliminating the majority of junk, not surprisingly, because all except the oleic acid and white wax would not come out into toluene. An extraction into alkaline and plain ethanol resulted in a glue-like substance to come out, and this gunk would not separate from the goods in a/b extraction. And in both prior attempts, also, a lot of lost yield.


I think that the optimal method of extracting from these pills would be as follows:

Getting the pill separated from the barrier:
1. microwave in a minimal amount of water with a small amount of magnesium sulphate until they swell and burst.
(The use of magnesium sulphate is to ensure that fatty acids in the pills are precipitated out as insolubles, preventing them increasing emulsion reducing the phase transfer of undesirable materials.)
2. Pour the solution out through a tea strainer, cut the burst barrier layers up thoroughly, and rinse a small amount of water through them while agitating them to ensure that all of the fine residual pill mass slurry is washed off them.

Cleaning the water extract:
4. Place solution into the refrigerator and allow it to settle for about half an hour to an hour.
(the pseudoephedrine sulphate is very soluble in water, according to BASF's MSDS, so cooling and using a minimal amount of water should ensure that a minimum of other things end up in the water. The cooling of the solution will further drive waxes and other junk more completely out of the solution)
5. Decant solution, and then collect the slurry at the bottom and press it to remove as much water as possible.
(I figure a garlic press with the slurry wrapped in a double or triple layer of filter paper would work. Further water extractions could be done but probably will increase the gunk that comes out. A large syringe and a clod of toilet paper plugging the nozzle would allow pretty thorough pressing too. If one has access to a centrifuge, the slurry could be made to compact into a hard, virtually dry solid, also bypassing the next step. Of course if one has a nice thick slow clogging super fine filter paper and a vacuum filtration setup this is easier and probably just a bit more efficient, a small amount of cold water could be dropped on it after finishing, and then pulled again and repeated to ensure full removal of water solubles.)
6. Filter the solution with a super-fine filtration method (unscented toilet paper scroll plugging funnel stem ('charmin filter') is a good ghetto way).
7. Add a minimal amount of an acid and then defat the solution using toluene or xylene.
(I reccommend this because if one does not do a nonpolar wash of it, it appears that a few things get across, seeming to be things like the rosin and oleic acid. This combined with the addition of an alkaline earth metal salt added in the beginning should ensure that nothing undesirable gets into the end result. a small amount of acid should be added to doubly ensure that nothing wanted is taken up, although already as the neutral sulphate it should not matter.)

From this point one does a standard acid/base extraction. To make double sure of total cleanliness, a pinch of carbon in the nonpolar, and baked epsom salts to dry it before gassing or titration, to ensure everything watery and possibly smelly and icky is removed. As PVP is soluble in chlorinated hydrocarbons, do not use chlorinated hydrocarbons for extraction.

As for ensuring removal of loratadine:
Quote:
Loratadine is a white to off-white powder; insoluble in water; soluble in acetone, alcohol, and chloroform.

What this basically means is that it won't even get into the water in the first place. This is why not to do the initial extraction with alcohol. It didn't seem to get across to the end product in any signifcant degree when extraction was started with the microwave/water method. If one is concerned about it, a chloroform wash of the aqueous pseudoephedrine hydrochloride solution one has titrated from the freebase, before evoporation, would remove it. It is probable that chloroform could be substituted for tri- or tetra- chloroethylene. As the info about PVP solubility I quoted above says it is soluble in such chemicals, do not use these for the initial acid/base extraction because they will extract the PVP in the water.

This method prescribed here is exactly the same as the one which produced crunchy crystalline results, but with added steps to ensure maximum yield, minimum losses and boost purity.

Random related thoughts about this process

things i'm not certain or clear about

Chlorinated Hydrocarbons Presoak?
Just as I was appending the info about not using chlorinated hydrocarbons with the method I described, it occurred to me that a soak in TCE or DCM would probably be one way that one could work with the pills after crushing and powdering them. This would have the double benefit of removing PVP, waxes, oils and loratadine right at the beginning... Unless pseudoephedrine sulphate is slightly soluble in chlorinated hydrocarbons... I cannot find any info saying so, but pseudoephedrine sulphate is said to be 'practically insoluble' in ether, and chlorinated hydrocarbons are generally a bit more polar, the more chlorine atoms the more polar. As such I cannot reccomend this without positive data on pseudoephedrine sulphate solubility. Making the pseudoephedrine into the hydrogensulphate (adding sulphuric acid equimolar to the present ephedrine sulphate ions) might enable one to do this without losing any pseudoephedrine sulphate to the chlorinated hydrocarbon. Making the chlorinated hydrocarbon dry might be helpful too.

Extraction via Solubility Differentials, Some Possible Methods
Another idea that strikes me during my post-first draft edit as I am reading back over the section on defatting, it occurred to me that it might be possible to add an acid to the aqueous solution which makes the pseudoephedrine precipitate readily out of the water, but I am not aware of any documented method effective for this.

Secondary to this, through selectivity of dry alcohols for alkaloid salts by a great degree of difference to elemental salts, one can then pull the desired salt free of the undesired salts.

And this idea also suggests the use of adding salts to other salts causing precipitating salt and non precipitating salt to appear, where before there was two salts which were soluble, as a means to end up with a hydrochloride salt without having to undergo an acid/base extraction.

Tartrate Precipitates
Tartrates of potassium are insoluble, and tartrates of numerous other bases seem to be of much lower solubility, and most likely adding tartaric acid to the solution would probably make pseudoephedrine precipitate quite readily after reducing volume to about 1/4 and then chilling. The precipitation from this would presumably be primarily pseudoephedrine tartrate. the ratio of moles of tartaric acid and pseudoephedrine are 150:165 for the bitartrate (acidic), and 150:330 (tartaric acid:pseudoephedrine freebase in both) for the tartrate(2:1 salt - tartaric acid is a di-acid). I would say that the tartrate is the lower solubility salt form due to the greater amount of insoluble hydrocarbon in the salt.

(IMPORTANT NOTE: those ratios are best calculated as molar ratios to prevent confusion, and also note that pseudoephedrine sulphate is actually more correctly di-pseudoephedrine sulphate, 'sulphate' indicates a 2:1 freebase:sulphuric acid ratio, as opposed to hydrogensulphate. It makes sense to, right at the beginning, convert you theoretical pseudoephedrine content into moles of pseudo so you can more accurately use acids and bases on it. I am just pointing this out because as a self-taught chemist these issues have caused me a lot of frustration.).

Precipitation
Regarding the process of boiling it down to drive it out of solution, one could add the right amout of the tartaric acid, reduce it in volume via boiling, and watch for the first signs of significant precipitation, and then stop it there and let it cool and then put it in the refrigerator to ensure maximum precipitation.

Mixing in a significant amount of a solvent in which the new salt is insoluble would also help, for example, acetone, which, with a 3-4x volume of acetone to water would allow the solution to be cooled to freezer temperature, further ensuring complete precipitation.

Caveats
The problem with this method, in any case is you are going to end up with non-pseudoephedrine salts in the mixture, because it is not really very easy to make salts fractionate nicely. One could conceive of methods to do a fractional crystallation but it's probably time consuming and complicated.

Further things are going to have to be done anyway, even fractionally crystallised salts are not going to be as pure as what could be had with other methods, and so the following might be better thinking:

Salting Out - Simpler and Better?
Something else which comes to mind is salting out, which works with some things, by adding a more soluble salt to the solution to precipitate lesser solubility salts.

Adding sodium chloride, at the right rate, should allow the pseudoephedrine sulphate to be driven out of the solution, along with other things like magnesium stearate, microcrystalline cellulose, small amounts of calcium sulphate and so forth.

The point of precipitating the desired product out of the material is that non-ionic solutes, such as sugars and ketones (PVP) can be readily removed entirely, simply by following the separation of the precipitate with a wash with something like acetone or a light ester (ethyl acetate) which will dissolve the garbage but not touch the desired product.

For this reason too, the mono-acid forms of di-acid (eg tartaric, sulphuric) salts of the desired material will almost certainly be more polar and thus less soluble in the wash solvents, which need to be fairly polar to remove pvp, so it may make sense to deliberately turn the salt into the more polar form - the differences are likely to be pretty much negligable though, and probably not worth any further mention than to raise the point.

If one desires to do this, one must add, in the case of sulphate, sulphuric acid of an equal quantity of moles as is already present (remember that pseudoephedrine sulphate contains two moles of pseudoephedrine base in it), and in the case of the tartrate, one adds an equimolar amount of tartaric acid as the amount of pseudoephedrine. The resulting solution will be acidic by the way, but it is almost certain that this will effectively double the number of ionic terminals (a bound pair and a free acid for each molecule) which should increase polarity and thus resistance to dissolving in a less polar solvent like a ketone (which is one of the things we want to ensure we get out).

Displacing Dissolved Salts with NaCl
One could just intentionally drive out all dissolved salts completely by adding sodium chloride (the most soluble salt that could form in this system with the recombination of ions that occurs in liquids, and thus will tend to remain dissolved in preference to any other) to the point of total satuaration, rather than aiming to push the desired salt to the bottom of the solubility ladder in the solution - which is probably the easiest way to do this. Just drive all salts in the solution out and replace them with sodium chloride.

Be aware that most forms of pourable/shakeable salt have sodium aluminium silicate in them and the presence of this (a relatively insoluble and highly hygroscopic) in the salt will end up in the precipitate, so get proper sodium chloride, easiest way is with rock salt. Also, there usually is trace sodium iodide but this is not likely to cause any problems... but one can't get free flowing salt that doesn't have that aluminum salt... (! which is why one would be better off not eating it too of course)

Water holds about 10g of sodium chloride per 100ml at 20 degrees C (average RT water is about 23 degrees C), so for simplicity, add 10g of sodium chloride (use rock salt) per 100ml of the nearest 100ml increment from what you have already got, and top it up to that nearest 100ml. Heat up and allow to cool to about 4-6 degrees in a refrigerator and all the polar, salty, and semi-nonpolar but denser than water chemicals in there should fall out.

Cleaning Precipitates
This precipitate in this method and the methods discussed above will be virtually free of sugars (sugars are extremely soluble in water and don't tend to precipitate unless the amount of sugar dissolved is beyond sugar's solubility in water - sugars are cyclic polyalcohols) and could be washed more thoroughly in toluene and dry acetone and chlorinated hydrocarbons after drying it out to remove these sugars and other things (PVP, for example). It probably will contain a lot of excess salt as the final temperature is lower than the temperature of saturation mentioned, however, most inorganic salts do not dissolve in dry alcohol very well, which is what we will exploit here.

Isolating Pseudoephedrine Sulphate/Tartrate from the Trash
One could proceed to the next step by dissolving the precipitate, after drying it, in dry methanol or IPA, which will dissolve the alkaloid salt but will not dissolve the elemental ionic salts such as sodium chloride, calcium sulphate, magnesium sulphate.

These salts do not dissolve in a dry alcohol because they cannot separate due to a lack of water. Pseudephedrine sulphate/tartrate will dissolve in the dry alcohol as a bound salt in the alcohol. For this reason, this step is done mainly for separation, the final step of converting to HCl without an a/b requires the salt to dissociate and so either it has to have water added or be re-dried and re-dissolved in water.

The Purpose of the MgSO4 in the Initial Extraction
The stearates and oleates and other fatty acids that may be present in the pills do dissolve moderately in alcohol. This is why at the beginning we start by adding a little magnesium sulphate before soaking up the contents of the pill mass, because these magnesium fatty acid salts precipitate out of water (the cause of clouding in the bath from soap). A significant amount of the fatty acids in the pills are in that insoluble barrier layer as free fatty acids so not much magnesium will be required to ensure they are converted to insoluble magnesium salts.

Salt Conversion via Combinations and Precipitation
After evaporating the extracted pseudoephedrine salts in the dry alcohol, then we can convert to the hydrochloride. One could probably add some calcium chloride (an equimolar amount to the expected pseudoephedrine molarity) to the pseudoephedrine sulphate, resulting in calcium sulphate precipitate and pseudoephedrine hydrochloride.

The conversion to the hydrochloride could be performed if one had formed the tartrate salt of pseudoephedrine by using potassium chloride. In the initial concept I put forward the tartrate salt was specifically chosen because it has an insoluble salt combination which can be caused to precipitate in the same way.

Theory of conversion of Salts by Combinations
I thought I should probably explain this in case anyone reading does not understand the theory behind this idea. Salts in water solution are not static entities but precipitate and dissolve constantly, at quite a rapid rate, hence introducing new salts to a solution means that the ions in the solution will form the permutations of combinations that the number of dissolved salts allows, in the case of this example, there are four possible salts: calcium chloride, calcium sulphate, pseudoephedrine hydrochloride and pseudoephedrine sulphate. Because one of them is insoluble, in theory, this should be a viable method of going from sulphate to hydrochloride without having to acid/base extract.

In these two cases, and in any other variation of this idea, one must ensure at this point that whatever ratio of acid to base alkaloid salt you start with, that the salt you add to form an insoluble precipitate and pseudoephedrine HCl, the ratios in the salts one gets at the end match up. As it happens sulphate and tartrate are both di-acids, and insoluble precipitates are formed in both cases as 1:1, one because of calcium being, in effect, a di-base (has two spare electrons vs potassium/sodium's 1) and the other because the potassium bitartrate is the insoluble (i'm not sure if the tartrate, 1:2 K:tartrate, is, but it's most probable.)

Precipitating the Pure Salt
And then, by using a minimal amount of the alcohol to dissolve the salt with (ie dissolve hot and with stirring) in the first place, one should then be able to add dry acetone to the mixture, about 3x the volume of the alcohol, and put it in the freezer and it should precipitate out the crystals in pure form, the addition of this much acetone will bring the solubility down to 1/4 of normal and dropping temperature to -18 or so should result in a nearly 100% insolubility of the pseudoephedrine hydrochloride.

Conclusion of Theoretical Solubility Purification Method, and Implications
In conclusion, this method could make it possible to not have to perform a phase transfer operation (acid/base extraction) during the extraction, the advantage of this being that there are mechanical losses associated with acid/base extraction, which are difficult to avoid.

In any case, both methods can be optimised with full theoretical anayisis to calculate the proper amounts of chemicals to put in. But the method I have proposed, right up until the crystallisation at the end can be deliberately engineered to ensure that one always brings across more than the desired salt, ensuring that every last bit of it is transferred.

The separation from the excess salts will draw across very little other than what one wants, and then, in the conversion process, one can slightly overshoot with it (again to ensure that as near to 100% of the desired materials are precipitated as possible), and then use the dry alcohol preference for organic ions to separate from the impurities again.

Going this extra distance introduces a few problems in the case of calcium chloride with the sulphate because calcium chloride is difficult to dry. The tartrate salt has advantages in this respect, because excess salts to the pseudoephedrine sulphate will be potassium chloride, which is nowhere near as hygroscopic (technically, not at all) and thus easier to dry and separate with dry alcohol.

Appendix: Variations and More Theory
Taking this method to the extreme, one could start by cooking up the pills in the microwave, in the first instance in the changing of the water we boil the pills in into 10g/100ml sodium chloride solution. This solution would not allow anything to be actually extracted, all of the precipitate, minus a few other unwanted things, progresses to the next step.

Rationale
The advantage of doing this would be in reduced effect of the solution on the barrier layer, the more polar the solution, the less likely it is to disturb its evilness. Concentrated salt solution is somewhat similar functionally to a dry solution because there is very little room in the water for much else other than cosolvents.

PVP is not at liquid state at the temperature of the exploding (gently) pills in the microwave scenario, and thus, salty water would significantly impede it's solvation. Not because of the salt specifically, but because the salty water is 'drier', that is to say, at any given time, 1/10th of the volume of liquid in contact is actually salt, and this salt polarises the water surrounding it so that quite a few water molecules are diminished in their reactivity.

The barrier would still swell and the whole thing would fall apart just the same as it does in non-salty water, the innards spewing forth, but there would be a much slower ingress of the barrier layer's components into the solution, and in any case, the solution is intended to be thrown away.

Removing Soaps
The soaps, in their natural state, do not dissolve well in anything, and the fatty acids form relatively insoluble salts with calcium and so forth, which we are adding.

The acid will attach to the alkali ions of the two soap chemicals in the formulation, magnesium stearate and the 'medicinal soap' which we can probably safely assume is sodium or potassium fatty acids of vegetable oil, presumably palm or coconut mainly, and result in the liberation of the free fatty acids.

The result of adding the acid to the extraction system will be that after the pills burst open, the soapy compounds in the pills will be converted to the salts of the acid we add, and the fatty acids will form a layer at the top of the solution. This layer is going to be entirely poured off when we are finished with ensuring that the inner barrier layer has divested all of its solid contents into the solution. This layer is nonpolar, and thus other nonpolars in the formulation will end up there so this feature will be exploited, in a step further down.

Before anyone complains that they can't find tartaric acid, ask your local home-brewing store about it. It's a flavouring for tart drinks, it is common, not quite as common as citric acid in lollies and sweets, but fairly common. Tartaric acid is a byproduct of winemaking, the tart flavour of grape juices and wines is tartaric acid. Tartaric acid has a lot of fascinating properties, and serves a double purpose here, changing the pseudoephedrine salt and breaking up the soaps in the formula.

Pseudoephedrine Bitartrate
First, some of the important chemical characteristics of tartaric acid:

Searching for information about whether tartaric acid can be washed out in solvents other than ethanol and water, in the case of excess use, I found this:

Quote:
TARTARIC ACID, also dihydroxy-succinic acid, organic acid of formula C4H6O6, found in many plants and known to the early Greeks and Romans as tartar, the acid potassium salt derived as a deposit from fermented grape juice. The acid was first isolated in 1769 by the Swedish chemist Carl Wilhelm Scheele, who boiled tartar with chalk and decomposed the product with sulfuric acid.


This information backs up the viability of much of the techniques used in this theoretical method, what it says is that tartaric acid was first made by taking the potassium bitartrate (which can be bought as cream of tartar incidentally), adding calcium sulphate, which forms potassium bisulphate (soluble) and calcium tartrate (presumably, insoluble), and then adding sulphuric acid to the calcium tartrate, calcium sulphate (chalk) is precipitated and the solution is 100% tartaric acid.

Here:

Quote:
.3 Other Properties

Solubility: Soluble in water ( 115g / 100ml at 0°C, 139g / 100ml at 20°C ).

Soluble in ethanol (27g / 100ml); Soluble in methanol, ether.

Soluble in glycerol.

Insoluble: Insoluble in chloroform.

Deposit Density: 950 kg/m3


Thus, the addition of an excess of tartaric acid to the initial boiling solution, should, theoretically, be able to be removed by toluene/naptha. Solubility in acetone was not mentioned, but given that it dissolves in ethanol, methanol, ether and water, ketones sit somewhere between alcohols and esters, and of lower polarity than esters is ethers, then hydrocarbons.

The cause of its insolubility in chloroform... I have no idea... Presumably this is something to do with the particular combination of acid and alcohol... After reading the hazardous reactivity section of a MSDS (tartaric acid reacts producing hydrogen gas when combined with tin, aluminium, or zinc, and says 'dangerous with silver and silver compounds' presumably meaning a strong exothermic reaction which frequently ignites the hydrogen produced, and probably the most relevant point, reactivity to strong oxidisers and strong bases/alkalis, the latter I presume to specifically mean in concentrated or dry form) I concluded that either one of two things, it wasn't specified which on the MSDS, that it reacts badly to chloroform (does not mention as such so I doubt that conclusion) or that because there is an oxidiser lurking attatched to a carbon, the reactivity with oxidisers is not invoked but instead creates a strong repulsion between itself and the chlorinated hydrocarbon, which is what causes insolubility in all cases.

Converting Pseudoephedrine to Bitartrate
So we add tartaric acid to the salty solution, which serves a double purpose, denaturing the salts, and displacing the sulphate from the pseudoephedrine. Tartaric acid conveniently, as the pure acid, washes out with toluene or ether and when combined with the contents of this tablet will cause changes to the salts that result in the dry mass after the boil/barrier separation which will facilitate this process.

First of all, like calcium sulphate, calcium tartrate is insoluble. Potassium bitartrate is insoluble too, however, sodium tartrate is soluble, as is the complex salt of potassium sodium tartrate (rochelle's salt). Magnesium tartrate is virtually insoluble too. So, as the salts we have present in the pill naturally tartaric acid forms insolubles with (magnesium, calcium), and sodium tartrate is moderately soluble. There is the possibility of conjugate salts, but it looks like this only occurs with group 1 elements (lithium sodium potassium etc), the two electron alkali earth metals (calcium, magnesium) pull both of it's bonds at once, we only have one group 1 element in this mixture, sodium.

So, being that the point of all this is to ensure that we end up at the end with pseudoephedrine converted to the acidic bitartrate salt, which should increase polarity and improve resistance to being washed out by anything other than alcohol and water.

The addition of a decent amount of tartaric acid will result in the conversion of the soaps to sodium tartrate and free fatty acids, the magnesium stearate to magnesium tartrate and free stearic acid (another fatty acid) and the pseudoephedrine to the bitartrate salt. It will not have significant reaction with anything else.

Calcium Hydroxide for Sulphate Sequestration
The sulphates who have nowhere to go... By adding calcium hydroxide (hydrated lime) to a degree lesser than the tartaric acid (we don't mind going decently overboard on the tartaric acid because we can clean it up later), we can give the sulphate somewhere further down the solubility ladder to slide down to, otherwise it may not come off everything we want it off.

Calcium sulphate, out of all of the salts in this solution is almost certainly the most insoluble salt in the solution, and even if it isn't, it's definitely below the solubility of the chemical we want most of all to take up the tartrate ion, the pseudoephedrine. Pseudoephedrine is definitely going to be more soluble than calcium sulphate or tartrate, hence the calcium addition followed by an excess of tartaric acid.

Calcium hydroxide, in a neutral or near neutral solution, would make the fatty acids insoluble, which is something we dont want. Thus, the simplest way to ensure this does not happen is with excess tartaric acid. The hydrated lime, saturated sodium chloride and tartaric acid mixture should be mixed preferably before adding them to the pills to cook them up, to ensure that the calcium is already formed into calcium tartrate, ready to take up sulphates if need be.

Microwave Safety with Salt Solutions
Be careful with concentrated solutions in a microwave by the way, they are much more rapidly heating than plain water and can quickly get to a state of superheating more readily than plain water can, so go easy. You only nead the pills to divest their contents and coatings, so stop it once you see the swelling cease, the sign that the barrier layer has burst. Don't let it go any further, with all those salts in there if it has a nasty bump that acid (and the salt) ends up all over your microwave, promoting corrosion.

Separating Barrier Layer from Chalky Pill Mass
Then, chop up the broken barrier shells so they fully expose themselves inside and out, and give the whole thing a good stir. The desired goal here is to dislodge all of the white powdery stuff into the salty water. Once this is done, pick up the spent barrier shell fragments, and place them in a small strainer and agitate them at the surface of the solution to wash the traces of the tablet contents fully off the shells.

Cooking
After this is done, the most evil part of the pill is now sitting in the disposal pile or in the bin or something, and not with the rest of the pill. That barrier layer is almost certainly the location of the PVP, as I speculated earlier, but of course I could be wrong, but the logic seems correct to me anyway.

So, in order to get all the reactions we want to happen, we have to heat it up, preferably to a simmer, and give it a good stir, for maybe 5-10 minutes. The purpose of this cooking is to ensure that all the ion switcheroo we want to occur, occurs, as the temperature gets to this sort of temperature the water has more ion holding capacity and thus there is plenty of room in the solution for the acid to attack all the soapy chemicals and for the free fatty acids thus liberated to, to some degree, help carry the other nonpolar substances in there.

Wet Wash
Before we get to the dry washes, due to the presence of the excess of tartaric acid in the solution, there is a skin of free fatty acids on the top of the solution, and the solution is pretty much just going to be decanted off, which will pour most of the nonpolars on the top anyway, no need to separate it except for disposal or recycling.

Thus, after the business with getting all the solid/powder stuff out of the barrier skins has been done, a small amount of a nonpolar such as toluene or naptha is added (toluene is the preferable choice). Mix the whole mixture thoroughly (I have a small battery powered gizmo which is for stirring lattes which is lovely for this, but by all means turn on the magstirrer if you got one).

The stirring will be best done on the solution while it is still warm, both increasing the solvation power of the solvent as it absorbs the heat, and because this will bring it into contact with the warmer nonpolars we are trying to ensure are removed here.

Once it settles down and all the solids are back at the bottom, and temperature is below 20 degrees C, you can now decant the supernatant solution, all there is in liquid form at this point is saturated sodium chloride solution, nonpolar solvent containing junk like free fatty acids, rosin, white wax and possibly a bit of carnauba wax (this wax is moderately water soluble).

At this point all the salts that we wanted to be formed from the tartaric acid will be fully formed, and excess tartaric acid will also be taken up by the toluene wash, to a significant degree. The rest will come out in the dry toluene wash.

Cooling
Since we chose 10g/100ml of water as our amount of NaCl solution, at 20 degrees C, the solution is exactly at the point where the sodium chloride is the 100% ionic solute and everything from the pill mass is precipitated. So you only have to let it cool to room temperature. Since one only cooked it for as long as it took for the pills to thoroughly burst and fall apart, they will probably not even have got much past 80 degrees.

We must cool it before we decant it, because the hot solution could be taking away something that we want (which is more than likely because it will be amongst the more soluble things in the solution). It won't hurt at all to cool it fast in the refrigerator, or freezer, just don't forget to come back to it if you put it in the freezer Wink

Then, presumably all the solids have fallen to the bottom, and you can now just pour the liquid off, carefully, ensuring you don't pour off anything solid, in the solids are the goods.

Then put the slurry on a steam bath and dry it down until fully free of water. As it gets close to the end, a bit of ethanol (some say acetone too, I don't know whether acetone loves water as much as ethanol tho), to azeotropically increase the rate of water loss from the solution. You want the solution as dry as possible.

Side note on microwave pill busting: The bursting is more of an effect from the microwave than from being immersed in water, and is a very handy feature indeed. Its effects on other types of pills should be investigated by interested parties. Especially in combination with a method adapted from this one, which works on a different vulnerability of denaturants than any previous method, that they are inert to salty water (compared to nonsalty water or alkaline water) because they are too nonpolar to interact with the salty water at all.

Side note on polymer slow release agents and acidity: The acidity should not be a cause of problems with these other plastics, as many of them are intentionally designed to only release their contents in an alkaline environment, in the stomach the pill material leaks out slowly as the water penetrates it, but only as the polymer/alkaloid/etc solution gets to the alkaline intestines does it release properly from the plastic. This is the key mechanism underlying most of the long release formulations polymer binders, and is not there to cause stress to methedrine cooks but for the exact reason they claim them, because it is resistant most especially to dissolving in an acidic solution.


Dry Washes
Dry acetone or MEK will remove the loratadine, trace PVP and much of the sugars, and some of the gums and waxes and soaps, while leaving the paydirt in solid state. Toluene will dissolve waxes and fatty acids, and the rosin and to a moderate degree the sugars as well. Dry chloroform/DCM/TCE will remove the antihistamine and waxes and sugars too. The trace sodium chloride that is present will work to your advantage here, any dissolved water in the solvents will preferentially absorb it. Use all the available solvents to hand that you can get. There is overlap in what they pull, and as a combination, pull everything you don't want.

It is my opinion that the most expedient and convenient way to do the washes is by adding the solvent, heating the solvent, if equipment permits doing this safely, until it boils, and give it a good stir to ensure full circulation throughout the solids. It may be worth grinding the dry mass before starting the wash process, if there has been clumping from the first boil in salty water, as this will ensure that everything is fully penetrated while washing.

There should be nothing causing clumping except maybe sugars, and because of this, it is most likely compulsory. But at the same time, a lot of sugar will have dissolved into the saturated salty water, because sugar's dissolution mechanism is different than salts (being made of cyclic polyalcohols). Likewise, a lot of the microcrystalline cellulose will have dissolved into the water, it too being pretty much like sugar but bigger molecules.

Extracting into Dry Alcohol
After a wash with these three solvents, all that will be left is calcium sulphate, calcium tartrate, magnesium magnesium tartrate, talc (magnesium silicate), titanium dioxide and pseudoephedrine tartrate. The use of excess tartrate was intended to displace the pseudoephedrine from sulphate. Only pseudoephedrine tartrate, out of all these salts, has the capacity to, as a dry salt, dissolve in dry alcohol - eg IPA or methanol that has been dried with baked magnesium sulphate.

So, if one adds the dry alcohol to this mixture after it has been washed, 99.9% of what is absorbed will be pseudoephedrine tartrate. Use minimal alcohol. I have not got exact numbers for it's solubility in IPA or methanol, so one way to be sure of getting it all is to do multiple small washes followed by evaporating it and scraping together to prepare for the next pass. Once nothing comes out of the alcohol, one is finished. There is nothing in the solids you want now, so move them to the disposal thing.

Conversion to Hydrochloride
The now re-dried 99% pseudoephedrine bitartrate crystals are redissolved in a minimal amount of water, and potassium chloride is added, which should prompt precipitation of potassium bitartrate (cream of tartar) and leave the now pseudoephedrine hydrochloride in the water. The amount of potassium chloride to add should be calculated to an equal molarity as the pseudoephedrine tartrate.

Side note: There is a method of making hydriodic acid which involves forming potassium bitartrate. Since tartaric acid is soluble in ether and hydrocarbons, one could use this to remove the excess tartaric acid, add the dry tartaric acid in excess of the approximate correct molar ratio required, in dry form, add the amount of water calculated to dilute the resultant hydriodic acid to a bit short of full concentration (~54%) and add the toluene to wash out the excess tartaric acid. settle and decant liquid from precipitate, then separate nonpolar from polar.

One can then evaporate it again and again dissolve into minimal (hot) dry alcohol and then add a 3-4x volume of dry acetone and put the solution in the freezer to precipitate. An insulated container will of course make bigger, purer crystals by slowing the process down.

Conclusion
The result of this process, according to my current thinking, should be a good 90-95% or better, yield of pseudoephedrine hydrochloride, from a pseudoephedrine pill with contents like the ones in the pill described at the top.

A better yield because there is no liquid/liquid steps in the process, which are a much more hit and miss affair than liquids dissolving solids and relative solubilities driven to the max, ensuring full transition from soluble to insoluble is caused.

Polymer Gaks
This method, as I noted somewhere above, could be applicable to the compounded continuous slow release (as opposed to delayed second release as the one described at the top is) pills which contain those funny and famous chemicals like orange II and eudragit et al as well.

The key to this method for any pill is utilising the microwave to cause the pill to expand due to the miniscule amount of water in it being heated up by the microwaves. This can only be done inside a liquid really, and the modification of saturated salty water with an excess of tartaric acid added should dramatically alter the way that these other pills can be treated.

The salty acidic water *should* make the polymers behave as though they were still dry, and the similarity to the environment in which they are intended to slowly absorb would tend to indicate that they are designed to be delivering the drug down inside an acidic enviromnent, which means that the polymers will mostly be ones which are formed in acids and decomposed in alkali.

Unlike inside the stomach, the pill will have already had its innards disgorged into a highly fragmented state thanks to the microwave, and thus, when the toluene wet wash is done, it should take up some of the polymers (some as in certain kinds, and certain degrees in each kind).

Measures probably need to be taken when drying the mass down, possibly one may wish to catch it in filter paper and press the moisture out of it rather than steaming it down, as the plastics may be adversely affected by heat. The chances that it cannot be washed out of with chlorinated hydrocarbons, aromatic hydrocarbons and ketones are pretty slim, and its almost certain that the pseudoephedrine bitartrate won't be.

There may possibly be higher solubility of this salt in aromatics than the neutral sulphate, because the free tartrate is soluble in them, but tartrate salts in general aren't so it shouldn't cause any significant problem between the bitartrate vs tartrate. This could be an incorrect idea, any initial study of this method should clearly establish the solubilities of the tartrate vs the bitartrate.

The proper salt form will greatly improve efficiency. The bitartrate is just easier to get to, because one can add excess tartaric acid and collect the excess tartaric acid in a nonpolar solvent such as toluene.

By the time it gets to the alcohol dissolution stage, all the gak should be gone. I would think that everything of the gak will come out in the chlorinated hydrocarbons or the ketone, and to a lesser degree the aromatics.

Concluding Conclusion
I cannot speculate any further on this subject really. The rest is practical tests. The theory is sound enough, at least to me, at this point, which is why I want to try it out on other people, see if it's has merit or not.

The key ideas I use in these methods come from many experiments I have done with extracting via the use of solid/liquid phases and solubility changes (the inspiration for these experiments started with the Manske syrian rue extraction method, which uses salting out).
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loki
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Mon May 16, 2005 6:03 am
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A few things will need to be tested before the extraction method detailed at the end of the above post can be used:

tartaric acid solubility in toluene - This is not specified in the MSDS which says it is soluble in ether, but it's very rare that something is soluble in ether and not toluene as well. Of course if you have ether, then it's guaranteed to work.

tartaric acid converting soaps into tartrate salts and free fatty acids - I know this works with hydrochloric acid, but I just haven't tried it with tartaric acid. This shall be tested too

pseudoephedrine bitartrate solubilities in solvents - It is virtually a foregone conclusion that it will definitely be insoluble in chlorinated hydrocarbons as this is specifically stated in the MSDS data, of the tartaric acid (which the bitartrate is at least 50% behaving like the tartaric acid), however the solubility in acetone and toluene are not known, neither type of solvent is mentioned in the MSDS data of either solubility or insolubility


a morning-after comment: i know this post lacks structure and flow. I apologise for this. As the full mechanisms are tested and properly understood a simpler set of instructions will be written. The post is full of theory and needs testing to enable it being useful. Tests of solubilities, for example, allows a much briefer statement about it rather than the waffling 'maybe, but i don't know, no refs' business.
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loki
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Mon May 16, 2005 8:04 am
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man, that post is so full of technical errors. Corrections are sorely needed

potassium tartrate, cream of tartar is 1:1 potassium hydroxide:tartaric acid

potassium bitartrate (di-potassium tartrate) is 2:1 potassium hydroxide:tartaric acid

pseudoephedrine tartrate is 1:1 pseudoephedrine:tartaric acid

pseudoephedrine bitartrate (di-pseudoephedrine tartrate) is 2:1 pseudoephedrine:tartaric acid

The convention which gives the synonym hydrogensulphate to me seems a more transparent and obvious way to name di-acids such as tartaric acid and sulphuric acid, thus one could also say pseudoephedrine hydrogentartrate to indicate the acidic 1:1 salt

Another correction, in the isolation of tartaric acid from potassium tartrate, i have incorrectly called chalk calcium sulphate, when in fact it is calcium carbonate, thus that section should read:

potassium tartrate is mixed with calcium carbonate (chalk), precipitating calcium tartrate and leaving potassium carbonate in solution. Calcium tartrate is treated with sulphuric acid to precipitate calcium sulphate (gypsum) and leaves free tartaric acid in solution.

Thus a solution for those who can't find tartaric acid is presented:

cream of tartar + chalk --> potassium carbonate (aq) + calcium tartrate (s)
calcium tartrate + sulphuric acid --> calcium sulphate (s) + tartaric acid (aq)

In this reaction it is most likely that sulphuric acid could be substituted with oxalic acid if the former is more difficult to find. And also, simply acidifying potassium tartrate with hydrochloric acid should result in a solution containing tartaric acid and potassium chloride, if done with the nonpolar that dissolves tartaric acid on top, and concentrated hydrochloric acid added carefully dropwise, the tartaric acid will go into the nonpolar solvent. The two step reaction via calcium tartrate is probably the more accessible, safe and and economic route though (water and salts are almost always cheaper than solvents).

But seriously folks, you WILL be able to find tartaric acid at a home brewing supply. Just as it is possible to get potassium hydroxide, and nitric acid, if one looks in the right places (hydroponics).

Ionic chemistry, the foundation of all this chicanery that I've invented here, is way cool, fast and quantitative in most cases, because it allows one to produce new arrangements of chemicals which are insoluble in water and near totally insoluble as solids to most other solvents as well.

The idea of deliberately forming the tartrate (acidic 1:1 salt) of the freebase amine, followed by addition of potassium chloride, resulting in the precipitation of potassium tartrate, means NO MORE HCl SOLUTIONS! w00t!

One can also ensure purity of the produced salt by diluting one's titrant (potassium chloride) to the degree that one can abort the addition of the titrant as soon as one sees that it is no longer causing precipitation. The precipitate is then filtered (might as well save it for regenerating into tartaric acid I suppose) and the solution evaporated, redissolved in minimal hot dry alcohol and then put in the freezer, the end result should be pure neutral alkaloid hydrochloride. There is almost inevitably going to be the slightest trace of potassium chloride but miniscule in the extreme.

Once I get started with this idea thing it just kinda starts to run by itself...

In a previous thread I talked about using ascorbic acid to reduce the intermediate iodide, and talked about an established method for high yield iodination of amino alcohols which uses sulphuric acid, kaolin (silica alumina hydroxide) and potassium iodide. This reaction follows the same type of scheme as these ionic jiggery pokery things does too. I think I'll pursue that whole thing at a later date, or at least shaddup for a bit Very Happy
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loki
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Fri May 20, 2005 3:01 pm
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due to the fact that sodium chloride is not exactly one of the most soluble salts that can form in that mixture (given time, i expect that sodium sulphate would form) Most especially of concern is that pseudoephedrine HCl would be one of those of greater solubility (probably the most soluble of all) it is unlikely that it would remain as a precipitate.

the first procedure mentioned at the top of the thread is known to work anyways
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loki
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Sun May 22, 2005 11:35 am
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Taking a different tack, but applying some similar ideas, some other ways to deal with these pills.

First idea is to do the initial step in a solvent in which the desired product is not soluble. As it is abundantly clear that these pills like to kinda puff up like popped corn when irradiated with microwaves, there is two solvents right off the bat that are probable suspects for this initial processing to be done in - a hydrocarbon solvent or a ketone.

After thinking about it for a while, the hydrocarbon solvent seems like the most desirable because it has the highest boiling point, most particularly xylene or toluene. I have safely heated these solvents in a microwave before, without incident, and in any case we only want to heat it in there as long as it takes to have the pills fall apart nicely for us. These pills are rock hard and hard to crush or otherwise grind, but in a microwave they just fall apart after about 30 seconds. In the microwave, the nonpolar solvent here, lacking significant amount of water in it, will be transparent to the microwaves and the pills will, having the only water content in this scenario, be the most direct targets for the heating and should theoretically burst even faster than they would normally in plain water.

In a hypothetical scenario then, one has popped all the pills one desires to extract into a quantity of toluene sufficient to cover the pills, and irradiated them in the microwave until they completely fall to bits. The inner core barrier layers have been discovered to be prone to splitting at the seams around the flattened side of the pill. In this solvent, they probably will somewhat dissolve... this is not a bad thing, however, better is to agitate and munce up the mass so that the powdery parts are fully separating from the barrier layer. The layer will not satisfactorily dissolve in toluene, as a goodly amount of it is cornstarch.

The reason for using toluene in the first step is that it won't boil as readily as naptha would and is somewhat less prone to going BOOM. In any case, unless one has left a metal fork in the solution it's unlikely any sparks will develop. We are just shooting for the pills to fall apart in the solvent without anything we want dissolving in the process. As a secondary bonus we get to remove a lot of the waxes and the fatty acid in there and that icky acacia gum.

So the next thing the hypothetical extractor would do is to remove all the shell bits from the barrier layer, let the whole thing settle down and decant the toluene off the pill mass. To further remove the toluene from the mass, it is then boiled in two or three quantities of naptha, on a sparkless heat source, decanted between boils, and by the end of this most of the residual toluene will have been replaced by hexane/pentane/heptanish stuff which will much more readily dry out - and smell less bad - a steam bath probably wouldn't hurt but just spreading it out thinly on a broad dish would allow it to dry pretty well clear of the solvents.

At this point, most everything that tends to want to dissolve in toluene and naptha is thoroughly gone. Next is a series of boils in dry acetone or MEK. Same procedure as the naptha boils, heat over a safe heat source until boiling thoroughly, then let it settle down, decant and repeat 2 more times. After all three boils are done, again spread it out on the broad dish and let all that yucky acetone evaporate off.

And now, possibly maybe one could do the same thing with DCM or similar, but it hardly seems worth it when acetone/mek and toluene/naptha pretty much overlaps in the same polarity region where you find chlorinated hydrocarbons, so we won't hypothetically do that.

All the waxes, gums, rosin, fatty acids, sugars, etc, are gone now. All that will be left is pseudo sulphate, talc, calcium sulphate, titanium dioxide, microcrystalline cellulose, magnesium stearate, medicinal soap. As i conjectured earlier, I am inclined to think that due to the relative ease that extracting these via conventional methods (a/b) goes, the povidone must be a component of the barrier layer to help bind the oils and starches together. Most of the rosin is in there too, judging by the smell of that layer.

So, next step is boil in strongly acidic water. 1 or 0.5 molar HCl solution is probably perfect for this (half to 1 moles HCl per litre, ie ~18-36g of HCl per litre, which is about 1/10-1/20 of standard concentrated pool acid). To this mixture one adds some proportion of grams of calcium carbonate - approximately equimolar to the expected yield of pseudoephedrine in the pills. The HCl solution will then be able to displace the sulphate on the pseudoephedrine, and the calcium carbonate will allow the sulphate to go to calcium sulphate which will then precipitate. In boiling conditions, most of the carbonic acid from the calcium carbonate will simply gas off as carbon dioxide as boiling solutions quickly lose dissolved gases.

The result will be a solution containing three components, a mostly calcium sulphate/magnesium silicate precipitate, an acidic solution containing pseudoephedrine, and at the top will be a layer of fatty acids.

The mixture would then be filtered, and then the clear (ish) acidic solution is defatted using toluene. This will remove insolubles and remove the oils liberated by the HCl solution.

Next, basify the solution, and extract in some quantity of toluene. Dry toluene/freebase solution with anhydrous epsom salts and then decolourise with a little activated carbon, mainly aimed at ensuring that we don't end up with trace rosin and other such things.

Since the ultimate purpose here is purity, at this point I add an optional step. According to http://designer-drugs.com/pte/12.162.180.114/dcd/chemistry/ephedrine.chou-jbc.html, the oxalic acid salt of ephedrine is only moderately soluble in alcohol. The same probably applies, although to a lesser degree, to the tartaric acid salt. So instead of titrating into dilute HCl solution, we use oxalic acid/tartaric acid. Once all of the pseudoephedrine is extracted to the acid, evaporate it down, and then redissolve in hot dry IPA or MeOH, and then place in a recrystallisation vessel and in an insulated container in the freezer. The result should be very pure pseudoephedrine bitartrate/bioxalate (i am assuming here that this is the 2:1 base:acid salt, as it specifies 'neutral to litmus'). Put these crystals into water adjusted to pH 13, and extract into toluene.

Finally, titrate into dilute HCl solution for super clean pseudo.HCl crystals.
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loki
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Mon Jun 13, 2005 10:35 pm
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swim is an idiot... pills which have PVP in them, being the only nasty crap in there... are EASY to extract from. acid base extraction into toluene/naptha is all that is required, the pvp doesn't follow the goods across, and then dry the hydrocarbon solvent and one can be sure that absolutely no pvp ends up in the end product. pills with povidone just can't be extracted via alcohol.

PEG is another story altogether. Although it looks suspiciously like it should be able to be largely frozen out of a wet alcohol solution, due to its high molecular weight, there's other solutions too:

from the wikipedia
Quote:
PEG is soluble in water, methanol, benzene, dichloromethane and is insoluble in diethyl ether and hexane. It is coupled to hydrophobic molecules to produce non-ionic surfactants.


<3 wikipedia

This means that if one followed a similar procedure as for povidone, but instead use naptha to extract, the PEG would not come across. To add to the effectiveness of such an extraction, a wash of the dry pill mass with a chlorinated hydrocarbon before extracting into water would also help. Or defatting the aqueous extraction with DCM perhaps.

The inactives listed for an internationally available 24 hour pill which is made by the same folks who make the one described at the top are as follows:

Quote:
The inactive ingredients for oval, biconvex **** 24 hour extended release tablets are calcium phosphate, carnauba wax, ethylcellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, povidone, silicon dioxide, sugar, titanium dioxide, and white wax.


these are not as economic as the 12 hour preparation though, and are usually available side by side so imho, go for the 12 hour.
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Sektor

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Tue Jun 14, 2005 1:39 pm
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so what about the pills that you get given via prescription from a doctor? they come in a little plastic container and are simply labeled 'pseudoephedrine 60mg', no brand, nothing , just simply put 'pseudoephedrine 60mg'? does one have to use the whole tetra trap extract or is it much simpler with these non-brand prescription pills? thanks heaps
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loki
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Tue Jun 14, 2005 4:06 pm
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povidone is now very common as a binding agent in pills, it's possible that even these generics have it in them. believe it or not, a simple, by the book, acid base extraction does the job (including drying the tolly/whatever before extracting into dilute hydrochloric acid). your mileage may vary, but you can't go wrong if you a/b the pills. as i said, PEG should be sorted out by extracting into naptha, or by doing a DCM/chloroform/tetra soak. The solvent should be dried first.

incidentally, i discovered recently that a microwave oven dries out epsom salts much more efficiently than the oven. about 6 minutes on high and you're done. stopping half way and giving it a stir helps.
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geezmeister
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Tue Jun 14, 2005 9:25 pm
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Loki-- On drying epsoms salts in the microwave--- experience suggests better drying occurs if the salt is heated in a series of three or four lower power sessions. The first one approximately five minutes at half power, then the salt is allowed to cool somewhat before being heated again for five minues at six on a ten power scale; allowed to cool somewhat again before being heated again for five minutes at eight on a ten power scale, and allowed to cool some again before being heated for three minutes at full power. This differs with the power of the microwave. Heating at full power can create hot spots in the epsom salt that will glow orange and will melt pyrex. The shorter, hotter cook does not, IMHO, assure dryness. Heating for at least fifteen minutes seems necessary IME. Oven drying generally gives smaller pieces, but IME even these need some crunching up to decrease the size of the particles.

Povidone can be removed by a soak in aromatic solvents. Give the soak four hours or so at room temperature, and povidone will not be a problem. PEGs show different solubilities at varying molecular weights. The lower weights used frequently in the pills can be removed by hot naptha; two or three soaks or boils in hot naptha will suffice. Microwave heating of the pill mass with the naptha over it, done until the naptha is hot, seems to work best for extracting the PEG. The PEGs as noted are watersoluble; they complex with the hygroscopic pseudo, however, and the surfactant properties make the a/b less effective against them. Washing the nonpolar solvent prior to titration is no guarantee you will not extract PEG with the pseudo. Gassing for the salt form of the pseudo limits the amount of PEG coming over more effectively than washing and titrating. The best method to avoid the PEG is to get it out prior to extracting the pseudo. Remember you may be dealing with differing weights of the polymer and at different molecular weights it has different characteristics.

A DCM wash of the pill mass prior to extraction will help remove more than a few of the problemmatic polymers. Be certain to dry the DCM very carefully, after washing it to remove any methanol. DCM is often derived from paint strippers which contain methanol and DCM forms an azetrope with methanol with the alcohol being about 6.5% of the azetrope. Water also forms an azetrope with DCM at about 1.5%. If these are present and not washed out and the DCM not dried, you will have substantial yield loss of the pseudo from the use of DCM. You will not have the yield loss if you dry the DCM. Save the DCM you use separately, and you may have pseudo crystallize out of it over a period of hours. The amount can surprise you.

The DCM/tetra combination seems to help prevent extracting pseudo with the DCM; the addition of some EGME, EGMEA, PGMEA, or PGME will help break down some of the polymers nothing else seems to affect.
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loki
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Wed Jun 15, 2005 3:41 am
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yeah the quantity of epsom salts that was dried was about 10 teaspoons full, a layer about half a centimetre thick in a jar. i figure there's no point in drying more than that at once, one uses at most 1 teaspoon in an average drying.

i'm not sure you are right about peg and naptha, from what i read about peg's they are insoluble in aliphatic hydrocarbons. but mildly soluble in aromatics. they are very soluble in chlorinated hydrocarbons... I'd say a xylene soak would deal with PEGs too. imho, if dcm is washing out the pseudo, it's because it's wet dcm. chlorinated hydrocarbons hold a lot more water than aromatics. TCE and PCE are worse than DCM in this respect.

povidone does not interfere with an acid base extraction, it just means one must dry the nonpolar at the end because it clings to the dissolved water and makes the solvent cloudy, or if you are unlucky, doesn't, and then you blissfully unaware extract into acid and wonder why you got goo... i'd say this would not be a problem if one used heptane, hexane or naptha (hexane would be the nicest), because of their greater non-polarity, but probably still worth drying at the end.
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geezmeister
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Wed Jun 15, 2005 6:47 am
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I am well aware that the Merck indicates that aliphatic solvents won't dissolve PEG. I was quite surprised to find that the PEGs in the 200-800 range were in fact quite soluble in hot naptha. This is from experience, not reference. Xylene soaks and boils did not do the job on the lower weight PEGs.

I have never known TCE to need drying.
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loki
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Wed Jun 15, 2005 8:29 am
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that's probably because of the amount of toluene in your local naptha geez.

true, it wouldn't have much in it, i presume you are talking about tetra/per chloroethylene from the spray can things. there will be a little water caught in the process of spraying it out, but yeah...

anyway, funny enough, for reasons of economics, swim gets the ones that only have povidone in them anyway. the ones that have peg in them are the 24 hour long acting type preparations and they cost more per yield of goodz. not even counting the extra expense having to get tetra etc and the extra work.
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geezmeister
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Wed Jun 15, 2005 10:11 pm
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If it were tolly in the VM&P naptha, tolly would have done the same job, or xylene. They didn't, but hot VM&P naptha did. Boils and soaks with both tolly and xylene left the lower weight PEGs in the mix, but the hot naptha took it out.
Dry basing those same pills, not using any water, alcohol, or even acetone to mobilize the base, and boiling the pill mass in VM&P naptha resulted in what at first was considered to be very high yields of freebase pseudo. It was quickly discovered that the yields were of freebase pseudo and the PEGs which populated the 120's at the time, before the advent of the methacrylate polymers. Realizing the PEG and pseudo would migrate together in the hot naptha under those circumstances led to the boiling in naptha prior to basing. The naptha would be decanted into a glass vessel and allowed to cool, and displayed density gradients not seen before. The pseudo extracted had minimal amount of PEG with it. The discovery of its effectiveness was inadvertent.

The pill mass was also boiled in that method with xylene or toluene twice before the naptha boils, and twice in acetone after the naptha boils. Skipping only the naptha boils resulted in PEG in the pseudo. Employing the boils prevented this. This comment is true for the PEGs in the 400-800 weight range which were used in the twelve hour pill formulations at the time as foilants to extraction. The naptha had no effect when the PEGs employed were in the higher weights.

Attrribute it as you wish; it was merely a observation born of experimentation.
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loki
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Thu Jun 16, 2005 3:52 am
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Ah, i see the rationale. the naptha doesn't dissolve the PEG very well, but moderately well when boiling, the 'laziness' (low solvation power) of the naptha counteracts the carry-across of the pfed.hcl.

PEGs are added to pills to reduce the dissolution of the pill in the gut so that the drug is delivered smoothly for a longer period of time than the drug itself is active. It may have the side effect of foiling extractions, but the primary motivation for the use of it would generally be to produce a slow release pill with nice low rate of dissolution of the matrix.

It is my opinion that the talk of 'foiling dem mef cooks' that goes on, which was started by the DEA, is more of an exercise in PR than anything else, both you and I know that the biggest producers (biker gangs etc) are diverting their precursors and reagents in lab grade, in hundreds of kilo batches and cooking up in 20L RBFs. The mom and pop cooks are a hard target for them so they use psychological warfare on them.

The reason why I say this? Because, next time SWIYou checks out the pharmacy, have a look for the one which is '12 hour' and contains a two-step release system, the barrier being composed mainly of rosin, fatty acids and cornstarch pressed very bloody hard so it takes a long time for water to breach it. This pill, as far as I know, is available in virtually every country in the world, and it's only gak is povidone. The extraction of this pill is a standard a/b, with drying of the nonpolar, followed by a two solvent recrystallisation in dry acetone and IPA/MeOH.

The presence of this pill on the market directly indicates that there is no directive or obligation to 'denature' pills. These excipients would not be appropriate in a short acting preparation at all. There is 6, 12 and 24 hour pills around, and it's the 24 hour ones which are gakloaded. I dunno what it's like where swiy lives but they are also more expensive per yield. And amusingly enough, while the pharmacists are being leaned on by the narcoswine to demand ID for pseudo.HCl containing pills, none is requested for these sulphate containing pills, and in some pharmacies one gets the distinct impression they would let you walk away with two 18 packs.

Just a minor aside/vent: they are unlikely to withdraw pseudoephedrine from the market any time soon. It is quite likely that sales of this drug, especially combined with antihistamines, are much greater for *ahem* 'legitimate' use than ...other uses. And despite the PR 'no to mef' stance they are projecting, when it comes down to it, they are in business, to make money. They just want to make things seem to the general public, who have been subjected to massive and recently, intensive villification of the drug, to both present the image of 'community concern', and so they can feel like they are not selling medicines to 'criminals'.

It boggles my mind the amnesia that the public and the medical establishment has been induced into by pharmaceutical companies aiming to capitalise on their fat portfolios of patents... Pseudoephedrine used to be regarded as an excellent preventative medication for bronchial asthma and quite helpful for full blown asthma, with many advantages over the shorter acting salbutamol and, going further back, adrenalin, inhalers. As a sufferer of this milder form of asthma, bronchial asthma, it is my opinion that I have a right to access this medication without prescription, as an alternative to steroidal preventative medications. For more intense asthma, the story may be different, but for the form of asthma that i have, which involves mucus buildup and bronchiconstriction, this drug is excellent.

I had almost forgotten that I had this type of asthma until i quit smoking cannabis regularly Very Happy (and that used to also be a recognised and effective medication for asthma too). In nearly 10 years of regular cannabis smoking, not a single incident of asthma (only the odd flu once or twice). I had to stop though because the anxiety increasing and IQ decreasing effects were making it not only uneconomic, but detrimental to my mental and financial health (damn stingy welfare bastids Smile )
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p2e3r4f5e6c7t8

Joined: 31 May 2005
Posts: 32
1088.66 Points

Mon Jun 27, 2005 11:31 am
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Has anyone tried festers KOH method on psuedo sulphate pills yet. ?????
And what were the results, yeilds work up methods all sorta thing.
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