Wednesday, September 28, 2011

Process Wednesday: the only recrystallization graph you need

Been thinking about recrystallization recently, so it's a good time to turn back to this graph:
Modified version of an graph
Seems to me that anytime people teach a course on recrystallization, people use this graph. Let's see what our mentor-by-literature Neal Anderson has to say about it (page 228):
Controlling the crystallization pressure is essential for both purification by crystallization and for efficient operations on scale. By adjusting solution conditions to decrease the solubility of the product within the metastable zone, the desired molecules can be pressured to come out of solution and crystallize. Gradual cooling without seeding leads to one nucleation event and the formation of relatively small crystals. Slowly applying the crystallization pressure can produce large crystals, depending on the size and number of seeds. If the crystallization pressure is too great, supersaturation occurs and molecules may be forced out of solution too quickly as small crystalline solids, noncrystalline precipitates, oil. 
There's a very tricky dance in a good crystallization -- you don't want a solution, you don't want a precipitate. You want a long residence in the metastable zone with not too many nucleations (too many nucleations = small crystals.) You want to slowly increase crystallization pressure by lowering the temperature or by adding an anti-solvent. Too fast, and you're going to precipitate and possibly oil out a great deal of product.

Nervous, nervous, nervous. 


  1. I was never very good at recrystallization but I can distill like a champion.

  2. Does some one actually teach courses on crystallization? Did some in undergrad and grad labs but wasn't till got into Process Development that learned, mostly empirically. Find interesting in the lab crystallization more often passive approach: non-stirred, limited heating, watch (or leave overnight/weekend) and wait, occasionally induction by add squirt of counter-solvent or cool in ice and then as last resort seed crystal (if lucky to have). At Scale stirring constant unless plan to dig out mass from reactors and must know before hand from lab profiling impacts of concentrator/solvent ratios and temperature ramps with seeding fairly common. Expect when confrontation with polymorph issues crystallization is probably the most rewarded aspect of processing IMO (especially if circumvents chromatography).