Frustration with recrystallization

13 Oct
Published by RyanPakula

Subject 

Request for Help

Last Wednesday I began some simple tests to try to find a good solvent for recrystallization, and here's some details and thoughts on what I've found so far.
I started with PZQ from Merck, fresh stuff from the container.  Just to see if any of these would work, I added a few crystals of PZQ to less than or up to 1 mL of the following solvents: acetone, hexanes, EtOAc, ether, and THF.  The only one lacking real solubility was the hexanes.  This was just a simple and not-supposed-to-be-conclusive test to see if it was worth using any of these.  I might come back to them later, but, besides hexanes, I don't think any of these will be terribly useful for me.
 
Thursday I dissolved 243.7 mg PZQ in 0.4 mL methylene chloride and added hexanes dropwise to try to crash out the hexanes.  White ppt formed where the drops of hexanes hit, but dissolved again as the solvents mixed.  With 2.6 mL of hexanes, the ppt persisted.  After heating to try to dissolve the ppt, I believe the methylene chloride simply evaporated, so I added 0.6 mL methylene chloride to redissolve, then put on ice to try to ppt.  After an hour though, no ppt had formed.  I might come back to this...
 
I tried a similar experiment but with ether and hexanes.  Dissolving 286.2 mg PZQ in 3 mL hexanes, I added ether to dissolve, but even with 33.8 mL ether, it didn't go in.  I rotovapped off the solvents, thinking that ether might not be a good enough solvent to pull the PZQ into solution, but that also means I might be able to use it to crash it out of solution.  We'll see.
 
With 3 mL hexanes on the 286.2 mg PZQ from above, I added methylene chloride (1.2 mL) to dissolve, then started adding hexanes to try to crash the PZQ back out.  After 30 mL, still no PZQ crashed out, but after sitting for a few hours, little white specks formed all over the outside of the flask, though not connected.  This might be helpful in the future, but it was kinda funky, so I'm not so inclined to pursue it.
 
With the dried 243.7 mg from before, I added EtOH (as suggested by a labmate) and heated slightly (to ~40ºC) to dissolve.  It went in nicely, and formed pretty sweet crystals upon cooling to RT.  I tried doing the same with the 286.2 mg from above, but I heated with a heatgun.  After apparently a bit too long of heating, the solution turned brown and oily.  A labmate mentioned that we store PZQ at -20ºC, so I'm not sure if this is a reaction betwen EtOH and PZQ or just a decomposition of PZQ with heat.  I kept this oil to study in the days to come.
 
Today I studied the PZQ recrystallization from EtOH.  In 2 mL EtOH, I was able to dissolve 707.1 mg of PZQ easily, so I tried it with a slightly different set-up:  I put 1.4992 g PZQ in a 20 mL sieve vial and added EtOH, heating after additions, until the PZQ dissolved upon heating.  With 1.2 mL, all the PZQ went in.  I thought I might have overshot the volume needed, so I added PZQ until it wouldn't dissolve anymore.  I was able to get just less than 3.4276 g PZQ in 1.2 mL EtOH, and I can confidently say 2.8305 g PZQ is a lower limit (i.e., I weighed the container from which I was adding PZQ at this point, but not again until the 3.4276 g point was reached, so the solubility is somewhere in this range).  I felt comfortable saying 3.2 g PZQ will go into 1.2 mL EtOH when heated.  So, I decided to try to quantitate this a little more accurately on a large scale.  I put 8.6065 g PZQ in a 100 mL Erlenmeyer flask and added EtOH, heating, until it all dissolved.  It took 3.2 mL, but I noticed that the solution was yellowing.  I think the undesired reaction was occurring.  I let this cool, and lots of white powder/crystal formed, but the problem with taking advantage of the huge solubility at high temps is apparent: there's no visible solvent upon cooling.  I mean, I know it's there, but the mixture won't flow because there's just not enough liquid.  It reminds me of supersaturated solutions of sodium acetate in water: when bumped, they just form a whole ton of precipitate, but you can't even tell there's water there because the solid takes up so much space.  I think I'll have to avoid this...
 
So, I'm wondering a few things: should I try dissolving the PZQ in hot (but not too hot) EtOH, then add hexanes to crash it out, thus allowing me enough liquid afterwards to actually pour the suspension out onto a Buchner funnel.  Or maybe I should not push it all the way to the limit with EtOH, but rather use a little more EtOH and heat less, but this will at least allow me to isolate the crystals afterwards while also avoiding the decomposition reaction or whatever it is since I didn't notice the browning when heated to lower temperatures (e.g., 40ºC).  I think I'll try these two tomorrow, as well as begin to isolate and study the brown/yellow/whatever products of the heating or heating with EtOH reaction.
 
Does anyone have input on recrystallizations?

Comments

MatTodd's picture

 Ryan,
The ethanol's 95%, not 100%, right?
The 40 degree heating things sounds like a good idea, and we certainly need TLC and NMR for whatever the brown fraction is - awkward if PZQ is decomposing under these pretty mild conditions. It'd be useful to know the temperature this starts at.
3 mL EtOH for 8 g PZQ is too conc, yes. We need a solvent system that's a little less effective at dissolving PZQ. 
Were you thinking of trying toluene and/or benzene? Do these dissolve PZQ when at room temp?
Does water work as a recryst solvent?
Mat