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My Intellectual Expectations

Intuitively, I would expect strong stirring to improve crystal purity during the process of crystalization. My rationale is that strong stirring would increase contact between each crystal and the variety of ions present in solution at each given level of solubility, and thus minimize the gap between reality and the equilibrium that would be reached if the conditions at each instant (solvent volume and temperature) would be kept equal for a very long time.

Information I have Read

I've read that as a general rule, the size of the crystals that form correlates well with the purity inside the crystals (i.e. that crystal size in general is a good indicator of purity).

My Conflicting Observations

My observations are that under strong stirring the crystals that form are much smaller than if the crystalization is carried out in still water (at equal rate of cooling / solvent evaporation). This indicates that either crystal size is not a great indicator of purity, or that my rationale is wrong and by counterintuitive mechanisms which I ignore, crystals of greater purity would be formed without stirring.

My Question

Does anyone know 1) Wether stirring the solution during the crystalization process positively or negatively affects crystal purity? 2) What is the physical explanation of the answer?

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  • $\begingroup$ Comments are not for extended discussion; this conversation has been moved to chat. $\endgroup$ – andselisk Nov 21 '20 at 13:52
  • $\begingroup$ Perhaps the solution relates to the impact of the speed of stirring on a solution's cooling rate. Basis: see this article in Journal of Physical Chemistry Chemical Physics here pubs.rsc.org/en/content/articlelanding/2019/cp/… . $\endgroup$ – AJKOER Nov 22 '20 at 18:44
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"Strong stirring" is a rather imprecise term. There is such a thing as too much speed. Rule of thumb for APIs, if you're working with a magnetic stirrer in a round bottomed flask in a lab (rather than in some industrial vessel or pilot plant setup) 350 rpm is too fast (and no, I can't quote a reference on that, it's one of those things you get told and then confirm by experiece - usually by being a wise-arse and bucking the "established wisdom" and ending up with a product that doesn't make medical grade).

Agitation for different crystallisation processes are generally kept in certain narrow bands to avoid inclusions as wel as a number of other reasons.

An example is described in Chow et.al [1] where when crystallizing paracetamol from water in a 500 mL round-bottom flask with p-acetoxyacetanilide present, increasing the stirring speed from 200 to 320 rpm increased product purity, but increasing further to 400 rpm lead to decline in product purity.

According to Meedara et.al. [2] stirrer-particle and interparticle collisions can facilitate crystal attrition in suspensions with high energy agitation, leading to attrition-induced inclusions.

Urwin et.al. [3] did a reasonably thorough job testing various methods and reasons for presence of impurities in crystals, and is worth a read.

Another good reference is The Handbook of Continuous Crystallization, start with chapter 1 [4]

That said, in crystallisation especially of APIs, mechanisms can be compex and are still not completely understood. All kinds of workarounds have been developed, such as e.g. ultrasonics to help prevent agglomeration when crystallizing paracetamol from certain solutions.

If you have no literature on the process you are attempting, finding the "sweet spot" where you get the greatest purity of product, is only going to happen with a lot of experimentation.

[1] Chow, A. H. L.; Chow, P. K. K.; Zhongshan, W.; Grant, D. J. W. Modification of Acetaminophen Crystals: Influence of Growth in Aqueous Solutions Containing P-Acetoxyacetanilide on Crystal Properties Int. J. Pharm. 1985, 24 (2–3), 239– 258, DOI: 10.1016/0378-5173(85)90024-9

[2] Meadhra, R.; Kramer, H. J. M.; Van Rosmalen, G. M. Model for Secondary Nucleation in a Suspension Crystallizer AIChE J. 1996, 42 (4), 973– 982, DOI: 10.1002/aic.690420410

[3] Urwin, SJ, Levilain, G, Marziano, I, Merritt, JM, Houson, I and Ter Horst, JP A Structured Approach To Cope with Impurities during Industrial Crystallization Development Organic Process Research & Development 2020 24 (8), 1443-1456, DOI: 10.1021/acs.oprd.0c00166

[4] McGinty, J, Yazdanpanah, N, Price, C, ter Horst, JH and Sefcik, J Nucleation and Crystal Growth in Continuous Crystallization , in The Handbook of Continuous Crystallization, 2020, pp. 1-50 DOI: 10.1039/9781788013581-00001

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  • $\begingroup$ Thanks a lot for this answer Gwyn! I think that the truth may be in that direction. I think that to properly answer the question we need to identify all the major factors that affect crystal purity, and that some factors that favour purity are increased with stirring (e.g. homogeneity of the solution), as are as well some factors that disfavour purity (e.g. crystal collision & inclusions, as you mention), such that crystal purity is maximized at the agitation level at which the net influence of all factors is maximized (the intermediate level which you mention is observed). $\endgroup$ – Hans Nov 21 '20 at 9:03
  • $\begingroup$ Thanks a lot for your contribution! $\endgroup$ – Hans Nov 21 '20 at 9:03
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  1. Stirring during crystallization is positive for the purity of the crystals.

  2. The explanation is that with stirring, your liquid phase will be homogeneous.

Then, there are some other details. Many times, especially in research labs, the target of crystallizing is to get a crystal for XR. What you need then is a crystal big enough to put it into the instrument. Stirring accelerates the crystallization and nucleation rate, so you get smaller crystals. That means, if you want a big crystal, don't stir and wait. But if you are producing some chemical and you have a constraint on purity, and on batch time, stir as efficiently as you can. Then, if the crystal size is too small, the filtration time will be longer so, do some optimization.

If you don't stir, the crystals grow slower. The liquid phase can be very supersaturated without nucleation. But, at the same time, your liquid phase is not homogeneous, so the surface of the crystal is not in equilibrium with the bulk of the liquid. At that point, the less soluble compound, the one that is crystallizing, might not be locally supersaturated and some other impurity can start crystallizing on the growing crystal, yielding a final product of bigger crystals with lower purity.

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    $\begingroup$ It would be good if you explained from where you are generalising here. $\endgroup$ – Karl Nov 20 '20 at 23:39
  • $\begingroup$ I would say that in general it goes the other way around. Unless one is trying to precipitate / crystallize by-products or traces, which is rather non sense. $\endgroup$ – Alchimista Nov 21 '20 at 7:32
  • $\begingroup$ Thanks for your answer Raoul! I think, as Gwyn identifies, that more stirring is not necessarily always better, but that in general some level of stirring is necessary to maximize purity (because, at least in part, as you write, it increases the homogeneity of the solution). $\endgroup$ – Hans Nov 21 '20 at 9:08

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