chemrox
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crystallizationof organic cmpds
I would like to suggest a sub-forum in cryx techniques. I just learned one I didn't know or rather hadn't paid attention to. I have an intermediate
that is very soluble in methanol and not very soluble in ether. But pouring ether into a warm methanol solution makes a gooey mess that clogs filter
paper, frits, etc. One way to resolve this is to boil off the methanol until the stuff will cryx. A better technique is to put the methanol
solution in a small beaker and place that in a larger beaker that has some ether in it. After a few hours vapor exchange causes cryx from the
MeOH/ether solution that results. The enrichment of the ether is slow enough that I got cryx instead of goo.
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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Crowfjord
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Mood: Ever so slowly crystallizing...
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That is really neat! Don't know why I hadn't thought/heard of it before, either. I'll have to give it a try some time.
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DJF90
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The vapor diffusion technique is common practice when it comes to growing x-ray quality crystals as relatively large, well-formed specimens are
required. It only works well if the antisolvent (in this case ether) is more volatile than the solvent. MeOH-DCM is another fairly common mixture that
works well like this. EtOAc and pentanes would probably work well too.
Another decent technique is layering the solvent and antisolvent. This generally also works well, so long as the antisolvent is added carefully. The
two layers formed then slowly diffuse together, allowing the formation of quality crystals.
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chemrox
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Outstanding DJF! I think I did this by accident once.
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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DJF90
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Generally as a chemist, we don't grow nice crystals for single crystral xray diffraction. Determining a solvent system for purification is fairly
simple and can be done with small amounts of (pre-purified) material. If the suspected/identified impurities are also available then this is
simplified further (i.e. it is applicable to home chemistry). Solvents and antisolvents can be found from the same screening conditions. Here we go...
Ideally the reaction is run through on a test scale to generate 1-2 g of material, which is purified (typically by column chromatography). This
material will be used to screen the solvents for a system that can be used to purify your compound and avoid the column. It is also worth flushing the
column and combining all the product free/mixed fractions. This (when concentrated) will comprise of the impurities your crystallisation process will
need to remove.
Lets start with the screen. Determine the (number of) solvents you wish to screen for the process. A usual list will be about 20 strong:
> Heptanes
> Cyclohexane
> Toluene
> Methanol
> Ethanol
> Isopropanol
> n-Butanol
> Ethyl acetate
> Butyl acetate
> Acetone
> MEK
> MIBK
> Diethyl ether
> Diisopropyl ether
> TBME
> THF
> 1,4-Dioxane
> Acetonitrile
> Dichloromethane
> Chloroform
Limitations on the choice of solvent depend on what the desired product would be used for, e.g. in the API business, solvents are limited to those in
ICH class 3. Other solvents (e.g. benzene, carbon tetrachloride) may be used if appropriate. Solvents like ethylene glycol, DMF, DMSO and NMP are
often also avoided due to the high boiling points.
Take a suitable number of (7 mL) vials and fill each with ca. 50 mg of the product (1 g will allow the screening of 20 solvents!). Perform the
following protocol for each of the vials, using a different solvent in each one:
> Define 1 volume of solvent as 50 microliters (uL) Solvent will be added in portions using a Gilson micropipette as specified, and inbetween
additions the mixture is checked for full solution. Create a table, with the solvents in the far left column, and the "total volume added" as the
headings for the remaining columns.
> "Total volume added" will be 2, 5, 10, 15, 20, 25, 30, 40, 50, 75 and 100 volumes.
> Make observations after every addition of solvent. When it gives a full solution, put a tick in the box. If its not all in solution, put a cross.
Do this for all the solvents. You'll get an indication of how soluble your material is and in which solvents. Solvents that the product is very
insoluble in (requires 50, 75 or 100 volumes of solvent) are ideal candidates for antisolvent. Solvents where solubility is acheived in <25 volumes
are often ideal solvents for the crystallisation process).
Repeat this process for the combined impurities if you have them. All together, the data collected will allow you to choose a solvent/antisolvent
system suitable for an "antisolvent crystallisation" as opposed to a "cooling crystallisation". In order to be effective, the solvent/antisolvent
system has to perform two jobs:
> The product will crystallise on addition of the antisolvent
> The impurities will remain in solution (i.e. the solvent and antisolvent for the product will both be good solvents for the impurities).
Once the solvent system is decided upon, another screen should be performed. Take 50-100mg of product in several vials again. Add the required amount
of solvent to each vial, to give a clear solution (look up the volume required from the previous screen). Then, to each of the vials, add an amount of
antisolvent (different amount in each vial, see below). The purpose of this screen is to determine how much antisolvent will be required to give the
highest recovery, without requiring excess solvent. To determine the recovery of solids, you'll need to filter each with a hirsch funnel. I suggest
adding the antisolvent in amounts relative the amount of solvent used (defined as 1 volume now), e.g. 0.5, 1, 2, 5, 10, 15 volumes relative to volume
of solvent used.
And thats it! Its just a general guide but its a good start if you're having trouble. I hope this helps someone.
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watson.fawkes
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Quote: Originally posted by DJF90  | | Limitations on the choice of solvent depend on what the desired product would be used for, e.g. in the API business, solvents are limited to those in
ICH class 3. |
For those, like me, unfamiliar with these acronyms, I looked them up. ICH is, yes, it's a
mouthful, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. The term "class 3" refers
to Impurities: Guideline for Residual Solvents; complete lists are available in the guideline document in PDF on that page. API is "Active
Pharmaceutical Ingredient".
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DJF90
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Sorry Watson, I should have defined the acronyms before using them. They're important in my line of work, but I should appreciate that most may never
have heard of them before.
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watson.fawkes
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Not a problem. It gave me the
opportunity to see first-hand the single most bureaucratic name I've seen in years.
I posted because I'm a bit surprised I had never heard of this before.
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Dr.Bob
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Just take a GMP (good manufacturing practices) or GLP (good laboratory practices), class (requrement for making pharm ingredates, at least in the US)
or even better an FDA training course. The acronyms just hurt my brain, there are so many of them. And the FDA types love to call everything by the
CFR number (Code of Federal Regulations), so they will say things like "CFR 92.34.12.7 requires a SOP for the GLP assay on the API before the the MBF
can be filed with the ATR for your GGRA".
DJF, Nice Xtal SOP, BTW.
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DraconicAcid
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| Quote: Originally posted by DJF90 | | The vapor diffusion technique is common practice when it comes to growing x-ray quality crystals as relatively large, well-formed specimens are
required. It only works well if the antisolvent (in this case ether) is more volatile than the solvent. MeOH-DCM is another fairly common mixture that
works well like this. EtOAc and pentanes would probably work well too. |
It works fine even if they are of similar volatilities. I grew a number of nice xtals in my grad studies days by placing my NMR tube (with
d-dichloromethane) into a Schlenck tube filled with ether and removing the NMR tube cap.
If your antisolvent is significantly less volatile, you can mix them, and let the solvent slowly evaporate.
Please remember: "Filtrate" is not a verb.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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DJF90
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@Draconic acid: Yes, I've heard of this method also, but I've never had to dry it. Good to hear it works as described.
@Dr.Bob: Sounds like you're more familiar with GMP than I am (at the moment). Kudos to you, and cheers.
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