Crystals – A Pain in The Neck

Let’s take a break between serious stories. I think I am going to write a short essay on crystals.

What Is A Crystal?

Let’s begin with the definition of a crystal. Technically, it refers to a solid substance in which the ions or molecules are arranged regularly. The common crystals that are familiar to us include table salt (sodium chloride), sugar, and diamond. An example of solids that aren’t crystalline is glass. When you look closely at table salt, each grain of it should appear cube-shaped (Figure 1). This is the result of sodium and chloride ions being regularly arranged much like a jungle gym. A single grain of table salt contains roughly one quintillion (1,000,000,000,000,000,000) of tightly packed ions.

Fig 1 crystal of sodium chloride

Most organic molecules have more complex shapes than salt, so they don’t typically make simple cubic crystals. They often form plate- and needle-shaped crystals, but these are no different from salt in that the constituents of the crystal are organized in perfect order.

For us chemists who work with a variety of compounds, getting a compound to crystallize has a number of merits. Since a crystal is composed of a single compound, it means that it’s in a state of absolute purity free of any external debris. If you dissolve a sample of impure solid compound in an appropriate solvent and grow a crystal carefully from the solution, you can purify the compound by leaving the impurities in the solution. This is the process of recrystallization, a basic technique of compound purification.
By hitting the obtained crystal with X-ray beam and analyzing the data, it can provide detailed information about the structure of the molecule. Among the many highly advanced analytical instruments available today, this X-ray diffraction analysis is still the most direct and reliable method.

Also, it’s usually difficult to develop drug compounds if they don’t form good crystals. Non-crystalline compounds tend to be inconsistent among batches in the properties like solubility and absorption, which affects the efficacy of the drug. Crystalline compounds are important in terms of stability as well. Working with crystals, however, can be a big pain and a source of struggle for us chemists in pharmaceutical industry. There is even an episode where one day a water-soluble compound suddenly stopped dissolving and that halted a clinical trial. It happened because of the change in crystal packing pattern, but it must’ve been a heartbreaking experience for the researchers if their effort was ruined by such a strange accident.

Seed Crystal

Dissolve a chemical called sodium thiosulfate in boiling water as much as it dissolves, and then cool the solution slowly. You might expect that a crystal will start coming out as the temperature and solubility drop, but it won’t. Sodium thiosulfate makes good orderly crystal, but once it dissolves in water to become individual ions, it “forgets” the original crystal lattice structure. So, what you need to do is to “remind” it its original structure by throwing in a tiny piece of crystal into the cooled solution. This is called the “seed crystal.” The ions of sodium thiosulfate that have been flowing randomly in solution will begin to align themselves to follow the arrangement of the seed crystal and will soon grow into a big crystal. A seed crystal works essentially as a role model.
Newly synthesized compounds or natural products isolated for the first time don’t have their seed crystal yet. Sometimes a crystal can be obtained right away, but many compounds (especially complex molecules) don’t crystallize easily and can be obtained only as sticky oil or as an amorphous powder. In these cases, you wish you had a grain of seed crystal to produce a lot more, but getting this first piece of crystal is sometimes a big challenge.
There is no guideline you can follow to be always successful in growing a crystal, because the condition of growing a crystal is influenced by molecular structures and many other subtle factors. Sometimes a chemist has to just try different solvents and temperatures and keep scratching the wall of his flask for weeks and months. When you finally get tire of it after so much effort without luck, you might find a shiny crystal on the mouth of a bottle on the lab bench. It takes the art and experience of an expert, but it’s also a simple matter of luck. Crystallization is an important technique needed in purification and structural analysis as I mentioned earlier, so a Nobel Prize will be a guarantee if you can find a way to crystallize anything.

The Synchronicity of Crystals?

When it comes to the discussion of crystals, there’s a famous legend about glycerin. The story that’s frequently found in occult books goes like the following:

……Glycerin is an important compound used as lubricant, food additive, and various industrial ingredients. However, no one has ever been able to crystallize it, leading to the belief that the solid state of glycerin does not exist.” (Figure 2.15)
But one day, a barrel-full of glycerin on a British cargo ship was found completely crystallized. When the news spread and the laboratories everywhere rushed to ask for a sample as seed crystal, and something strange happened. Shortly after the discovery, the glycerins in factories and laboratories around the world began to crystallize all together even without seed crystals. That puzzled the chemists in all fields, because nothing had been changed in both production and storage conditions. A speculation that a seed crystal might have gotten in from someone’s clothing or skin was unlikely because carefully controlled experiments showed the same result. Today, glycerin can be crystallized easily by anyone by simply cooling it to seventeen degrees Celsius……

Well, this is the legend which has become famous recently and has even been on a cartoon. Professor Makoto Kikuchi of Osaka University in Japan has done an investigation on this case, and he arrived at an article published on the Journal of American Chemical Society in 1923. The article said:

“After the seed crystals had arrived it was found that crystallization practically always occurred when amounts of 100 g. of any laboratory sample were slowly warmed over a period of a day, after cooling to liquid-air temperatures. This occurred even when great precautions were taken to exclude the presence of seeds. However, it was found readily possible, by temperature manipulation alone, to produce crystalline or supercooled glycerol at will.” J. Am. Chem. Soc. 1923, 45, 93.

So, the legend is probably based on this article, but with some extra exaggerations attached. It is quite possible that the original report became more and more farfetched as it was told among the researchers who had experienced unpredictable things while having hard times crystallizing compounds.
By the way, even today glycerin can be crystallized only by adding a seed crystal at zero degree Celsius or warming it slowly from very low temperature. Unlike what many books say, crystallizing glycerin is still not an easy thing to do. Let’s just remember to be careful about believing these kinds of story.

Fig 2 glycerin

Crystals are causing headaches for chemists around the world and their stories are endless. The hottest genre in current science is life science, and more specifically it is the understanding of protein functions. The preparation and purification of proteins have become easier with the advancement of biotechnology, but protein crystallization needed for its analysis is far more challenging than that of simple molecules. Unfortunately crystallization is remaining as the bottleneck of many researches, and the best we can do after all is to try as many experimental conditions as possible like carpet bombing. The fact that cutting-edge science relies on art and luck reminds me that science will always be a human practice.

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