Wednesday, September 5, 2012

Process Wednesday: the details of crystallization

In Organic Process Research and Development, a request for exactness in speech and writing in process chemistry from John Knight:
First, take precipitation and crystallisation. This is not as straightforward as it might at first appear. Tung, Paul, Midler, and McCauley indicate that the process of reactive crystallisation is also known as precipitation but then go on to say that the term reactive crystallisation is generally applied only when the product is crystalline. If the product is amorphous or a mixture of amorphous and crystalline forms, then the term precipitation applies. Davey and Garside, on the other hand, discuss particle size, commenting that crystals can be almost any size from a few nanometres to several millimetres; traditionally, when crystals are less than a few micrometres in size, the term precipitation is used. For most of us, I suspect that we think in terms of the speed with which a solid was formed and deposited from solution, with precipitation usually being ‘fast’ but what is fast, and so it goes on. 
I ask that chemists and engineers aim to be more precise in the terms applied and suggest that, unless it is obvious or the process is known to provide crystalline product, then the term precipitation is universally adopted for a reactive crystallisation such as salt formations that result in essentially immediate depositions of solids, and for all other cases simply state that solid was deposited, harvested, etc. Adopting this simple distinction can avoid the forward progression of what may have been a ‘throw-away’ comment in a laboratory book about the ‘isolation of crystalline solid’ into a legal battle in 15 years’ time over solid state and patent validity! 
So what about an amorphous solid versus a crystalline solid? Much as above, unless you know the solid product to be crystalline either by analysis or by virtue of the known process of isolation, avoid using either term simply state ‘solid product’ was isolated etc. From a patent viewpoint, only factual data should be recorded; unless there is analytical data to confirm crystallinity, this is conjecture only, albeit educated conjecture.
I suspect that people like to use the terms "crystals" and "crystallize" rather than "solid" and "deposited" because it sounds more scientific. I certainly do not haul out the microscope to look at every solid product that I make (maybe I should?)

Well, time for me to go harvest some solid...


  1. As part of the lab work up we routinely got x-ray powder data in the search for polymorphs. This was always accompanied by a report on the crystallinity of the drug substance.
    In some cases it was written into the specs. and used as part of the QA release.

  2. p.s.
    It may be my eyes but I have a really hard time getting the "human verification" correct. It usually takes me about 5 goes. Help:))
    p.p.s. I'm not a robot either, no mechanical parts, yet.

  3. Do people not run Melting Points any more as standard test? Or even possibly a DSC? Those would allow solid to be classified in majority of cases. As Quintus suggests handling in the lab typically is enough define nature of material dealing with, often even without XRPD, trusting translates to scale if done properly.

  4. The exact terminology used can have impacts on the IP...a CoM patent said a compound of interest was "crystallized" with a specific m.p. reported, and the IP protection for a form that melts at that same m.p. was challenged by a generic company in later litigation to prove that the form had already been disclosed by the m.p. Bad form on the part of the generics, but perfectly legal. Also, there was quite a legal tangle for some patent (Wyeth, I think) that stated the compound of interest was "recrystallized" from some solvent or other, which was read by the patent office as prior art....So, be careful of your working...language usage is important.

  5. "For most of us, I suspect that we think in terms of the speed with which a solid was formed and deposited from solution, with precipitation usually being ‘fast’ but what is fast, and so it goes on."

    I never think about the kinetics of "solid deposition" as defining the process as a crystallization or a precipitation. Seems counterintuitive to me, as kinetics could be vastly different for even the same system. I've run across several systems where the rate of the product coming out of solution was incredibly sensitive to what was in solution (impurities, water, etc.). In one instance the same compound when chromatographed took minutes to reach full destauration but when isolated from the crude mixture took several days to reach full desaturation.

    I was always under the impression that crystallization meant you got a crystalline product and precipitation meant you got an amorphous product.

    In the process group where I work we all routinely look at newly generated solid product samples under the microscope for birefringence (rotate the stage, look for particles "winking" in and out) and particle shape. That's usually followed up by XRD, which we process chemists have learned how to run ourselves. When we run across a new XRD pattern, then DSC/TGA get run by the solid state group. While this has been standard practice for isolated API's for quite a while, more and more we're doing it on isolated intermediates as well. Never a good day when you run into a new polymorph at any stage of the process which forces you to redesign the isolation.