An elusive polymorph of Paracetamol

What does it look like?

Image generated by the Mercury crystal structure visualisation software http://www.ccdc.cam.ac.uk/Solutions/CSDSystem/Pages/Mercury.aspx

Image generated by the Mercury crystal structure visualisation software http://www.ccdc.cam.ac.uk/Solutions/CSDSystem/Pages/Mercury.aspx

What is it?

All of this blogging is starting to cause a few headaches! Luckily we have paracetamol on hand to help out. Understanding crystal structure is a vital part of every aspect of drug design, from finding out how they interact in our bodies to how they pack into the pills we need to take.

Hence it’s a requirement that before a drug goes onto our shelves that its crystal structure is fully understood.   Crystal structure can help us understand many physical properties of a material, and one very relevant to the drug industry is solubility. An insoluble drug is useless as our bodies can’t break it down and use it.

This can get a bit complicated if the drug in question can form more than one type of crystal structure, and paracetamol is no exception to this. There are, in fact, three forms (or polymorphs) of paracetamol. Forms I and II have been known about for quite a long time, but Form III was only fully understood in 2008 and is the structure featured here. To found this out the researchers had to combine powder diffraction with state-of-the-art crystal structure prediction. In this structure the paracetamol molecule layer up, but are tilted slightly compared to the other forms.

Where did the structure come from?

Form III of paracetamol was worked out by Perrin et al. in 2008.

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Crystals you can grow at home – Nickel Sulphate hexahydrate

What does it look like?

niso46h2o_62051

Spot the helix! Drawn using Jmol.

What is it?

Nickel sulphate hexahydrate (NiSO4.6H2O) forms large, perfect crystals
that can easily be grown at home – just dissolve plenty of NiSO4 in
water and let the water evaporate. You can see a beautiful example here . As an extra bonus, by choosing the appropriate
temperature you can get slightly different coloured crystals – up to
53C the crystals will be dark blue-green, and above 53C they will be
clear green. These colours correspond to slightly different
structures, and this is an apparently unique situation, as similar
sulphate compounds are only stable as a single structure type. As
might be expected for something so easily grown, it is found in nature
as the mineral retgersite.

 

NiSO4.6H20 is also interesting because of its ability to rotate the
direction of polarisation of light – and the strength of this rotation
depends on the wavelength of the light, even switching rotation
direction at 0.5um. In a fascinating paper, Stadnicka, Glazer and
Koralewski [1] were able to relate the direction and strength of the
optical rotation to the properties of the structural helix formed by
the O atoms. The helix goes from top to bottom on the structural
diagram above.

Where did the structure come from?

The structure of the lower-temperature phase was first determined in
1932 by Beevers and Lipson [2]. It was sufficient to classify X-ray
reflections into 8 intensity classes ranging from “very strong” to
“absent” in order to derive and verify their model. Both forms have
since been extensively studied by X-ray and neutron diffraction.

[1] Stadnicka, K., Glazer, A.M. and Koralewski, M. (1987), Acta Cryst.B43, 319-325
http://dx.doi.org/10.1107/S0108768187097787
[2] Beevers, C. A. and Lipson, H. (1932) Z. Kristallogr. 83, 123-135
(http://rruff.info/doclib/zk/vol83/ZK83_123.pdf)

Further reading

Angel, R. J. and Finger, L. W. (1988) “Polymorphism of Nickel Sulfate Hexahydrate”,
Acta Cryst. C44, 1869-1873 http://dx.doi.org/10.1107/S0108270188006717

Getting in a Twist – A Polyrotaxane

Dave Turner, tells us about some of the crystal structure’s he’s been working on.

What does it look like?

Polyrotaxane

What is it?

My imagination for finding vaguely amusing molecules, or ones with an amusing back story, has temporarily deserted me. In times of need there is only one truly reliable person to turn to. That’s right, today I’m posting my own work for the first time!

My group has recently been interested in using dicarboxylates to make polymeric structures by forming bridges between metal atoms, giving a type of material known as a coordination polymer. In this specific example, we form chains that contain rings which are bridged by another organic group, bipyridine (see picture, left). The size of the ring is ideal for a bipyridine to pass through and the chemical nature of these groups means that it is favourable for it to do so. The structure is able to satisfy this inclusion by having chains that run at angles to each other and pass through each other. The middle picture shows four chains, with the bipyridine of one passing through the ring of another. As these chains run the length of the crystal, overall we see a complicated arrangement with each chain passing through, or being threaded by, many others (see picture, right). An arrangement where a molecular thread passes through a molecular ring is known as a rotaxane, with this example being a polyrotaxane.

We make these types of structures to try and control the manner in which molecules assemble in the solid state. Unbelievably we were actually trying to get something similar to this when we carried out the reaction.

These structures always make me think about crystal formation. For crystals made from simple molecules it is easy to envisage the identical molecules packing on top of each other, like playing Tetris with only one type of block (and yes, that’s a time-wasting hyperlink for you). In these complicated structures that have rings being threaded through each other, the process is much harder to imagine and it is impressive that such arrangements can form.

Where did the structure come from?

We published this structure earlier this year, alongside related examples of interlocked chains that form polycatenated structures. The work appeared in Chemical Communications, and was the work of a final year undergraduate in my research group.

Selenite – Crystal Cathedrals

What is it?

It is the dream of all crystallographers to develop a technique which can grow the largest and highest quality crystals possible. Often this is extremely difficult to do due to all of the competing factors which can drive crystal growth, and so it is often considered an art form. The rarity of large single crystals is what makes the Naica crystal caves truly extraordinary.

The great crystal cavern of NAICA mines.

The great crystal cavern of NAICA mines.

Buried 300 meters below the surface, and discovered at a time when we people believed that they had seen every spectacular sight the earth had to offer, are the selenite crystal caves (Figure 1). No, this is not a carefully constructed Photoshop; those are real people climbing over pure gypsum crystals, otherwise known as selenite. In fact these are the largest of any naturally occurring crystals measuring up to 12 m in length, 4 m in diameter and 55 tons in weight. However, before you rush to pull out your passport and start booking flights, know that these caves are not open to the public. The caves are restricted partially for preservation purposes (instigated by a mining company of all things) but also because conditions within the cave are oppressive. Due to their location above an underground magma chamber and the presence of a large quantity of ground water, temperatures can sit at a constant 58 °C and 90 to 99 % humidity. Without special protection humans can only survive in these conditions for a few minutes. Incidentally, these are ideal conditions for crystal growth. Prior to their discovery, the caves were filled with hot, mineral rich water for 500,000 years. During this time the temperature hardly varied and the crystals were allowed to slowly grow to the size they are today.[1]

Researcher in protective gear among the crystals.

Researcher in protective gear among the crystals.

So if the caves are closed to public access, what are people doing there? A huge research project is being undertaken covering fields from medical research to regional geology. Some examples of the research being performed include, investigating how the crystals became so large and how old they are, studying pollen and microorganisms trapped inside the crystals, developing technology which enables humans to work in extreme conditions for long periods of time and building an understanding of the physiological effects of exposure to these extreme conditions over a long period of time. However, the longer the crystals are exposed to the air the more faded and brittle they become, eventually cracking under their own weight. As a result there are constant discussions on whether research should continue in order to understand this unique natural resource or whether the caves should be re-flooded with water in order to preserve their current form.

What does it look like?

Structure was generated in VESTA

Structure was generated in VESTA

As mentioned, the crystals are a pure form of gypsum known as selenite. The crystal structure of selenite/gypsum (CaSO4•2(H2O)) has been featured before on this blog in its “desert rose form”. The main difference between the desert rose crystals and selenite is the presence of sand impurities in desert rose. Another view of the structure is provided below where calcium is shown in blue, SO4 tetrahedra are yellow, oxygen is red and hydrogen is white.

Where did the structure come from?

The image was generated from a structure in the paper Schofield P. F., Knight K. S., Stretton I. C. American Mineralogist 81 (1996) 847-851 and can be found on the American Mineralogical database.

Images from:

Cave of Crystal Giants – National Geographic Magazine, Available from: <http://ngm.nationalgeographic.com/2008/11/crystal-giants/shea-text&gt; [November 2008]

[1]          NAICA PROJECT/CRYSTALS’ CAVE, Available from: <http://www.naica.com.mx/english/internas/interna4_1.htm&gt; [Accessed May 2014]

A protein structure that is a β-barrel of laughs

What does it look like?

Outer membrane protein F (OmpF) from Escherichia coli

Outer membrane protein F (OmpF) from Escherichia coli

 

What is it?

A membrane is the biological structure that forms the barrier between a cell and its outside environment. Gram-negative bacteria (so called because they don’t respond to the Gram stain) have a double membrane and include bacteria such as Escherichia coli (the microbiologist’s lab rat), Yersinia pestis (bubonic plague), and Pseudomonas aeruginosa (lung infections in cystic fibrosis patients). The outer membrane of Gram-negative bacteria forms a barrier that protects the cell from toxins and other harmful agents however vital nutrients still need to cross the outer membrane to get to the cell. The membrane proteins that facilitate nutrient transport across the outer membrane are known as porins. Shown here is the porin called outer membrane protein F (OmpF) from E. coli.

OmpF is a general porin that will allow small (generally under 600 Da) water-soluble molecules to passively cross the outer membrane. Typically an E. coli will have about 100 000 OmpF molecules per cell. OmpF is a homotrimer with each monomer consisting of 16 β-strands that form a hollow cylindrical structure called a β-barrel (hence todays title). Molecules travel down the centre of each β-barrel where there is also a constriction loop (parts coloured orange) which reduces the size of the pore to 1.7 nm in diameter.

Where does it come from?

The crystal structure of OmpF was first determined by S. Cowen and colleagues in 1992 [1] and the structure shown is OmpF in the tetragonal crystal form [2] and has the PBD number 1OPF in the protein data bank.

[1] S.W. Cowen, T. Schirmer, G. Rummel, M. Steiert, R. Ghosh, R.A. Pauptit, J.N. Jansonius, J.P. Rosenbush (1992) Crystal structures explain functional properties of two E. coli porins. Nature 358: 727-733.

[2] S.W. Cowen, R.M. Garavito, J.N. Jansonius, J.A. Jenkins, R. Karlsson, N. Konig, E.F. Pai, R.A. Pauptit, P.J. Rizkallah, J.P. Rosenbush, G. Rummel, T. Schirmer (1995) The structure of OmpF porin in a tetragonal crystal form. Structure 3: 1041-1050.

MIL-143 or the big-brother (ir)regular beta-cristobalite

What does it look like?

Crystallographic representation generated with Diamond.

Crystallographic representation generated with Diamond.

What is it?

When transition metals meet organic linkers (carboxylates, N-donors such as pyrazine, phosphonates, sulfonates), they can give rise to a 1D-, 2D- ou 3D- framework, namely MOFs for Metal Organic Frameworks or PCPs for Porous Coordination Polymers. Indeed, some Coordination Polymers don’t exhibit porosity.

MOFs are crystalline materials and X-ray diffraction is a suitable tool to determine their structure. A majority of MOFs are based on divalent metal (M2+= Zn2+, Cu2+, Co2+, Ni2+, Mg2+, etc…) which gives rise to crystals big enough (from 0.1 to 0.2 millimetres) to be measured on single crystals X-ray diffractometer, a well-known and successful technique for structure determination. Nevertheless, growing single crystals from trivalent (M3+= Fe3+, Cr3+, Al3+, V3+, Ga3+, In3+, etc…) or tetravalent metals (M4+= Zr4+, Ti4+, Hf4+) is more challenging and scarce and lead often to a powder; Crystallographers must thus solve the structure from a powder diffraction pattern which contains much more less information than a single crystal diffractogramme. In addition, MOFs crystallinity can be really “bad” and synchrotron measurements are often needed for this technique.

The MOF we’re talking about today MIL-143(Fe3+) (or Fe3O(Cl)(H2O)2(bdc)3/2(btb).nsolv) was solved from powder diffraction data and crystallizes in the cubic F23 (n°196) space group (a=40.8635(1) Å). MIL stands for ‘Materials of Institute Lavoisier’ and this was the 143rd MOF they made. As there is no classification for MOFs, each lab names its baby after the lab’s name so we got some nice name such as HKUST (for instance HKUST-1), CAU, UMCM, UiO, STA, PCN, POST, MOM and so on.

The particularity of MIL-143 is that it is built up from two types of linkers whilst a majority of MOFs contains only one type of linker. Regarding its structure, oxo-centered trimers of iron (III) octahedra (see Figure (a)) constitute the primary building unit. They assemble with the ligands to give rise to two types of super-tetrahedra (ST) (see Figure (b) and (c)). The edges of these ST are 11.7 Å and 16.9 Å (vs 2.5 Å for the b-cristobalite), thus the term “big brother” and there are two types of tetrahedral (vs a unique tetrahedral in the b-cristobalite) creating an irregularity but the whole structure being regular. The first ST (see Figure (b)) is similar to those being identical to those observed in MIL-101,1 i.e. with terephthalate on the edges and the second ST (see Figure (c)) are similar to those of MIL-100,2 but with the 1,3,5-benzenetrisbenzoate linker instead of 1,3,5-benzenetriscarboxylate on the faces. Indeed, the structure of the MIL-143 can be considered as a succession of extended ST of MIL-100 and ST of MIL-101. Similarly to the MIL-100 and MIL-101, this leads to the formation of two sets of mesoporous cages with free diameters of 20 Å and 24 Å

What is it for?

MOFs have attracted attention due to their high porosity and their promising properties for several potential applications such as gas storage, separation, nano-applications, catalysis, energy storage and more recently biomedicine.3,4

Nevertheless, one of the main issues with MOFs is their low chemical and thermal stability. A large amount of MOFs based on M2+ metals are not even stable to air moisture and must be kept in solvent or under inert atmosphere, making their industrial application difficult. By increasing the valence of the metal, one can increase their stability5 but it is not an absolute rule as others parameters can interfere such as the mesoporosity, i.e. containing pores with diameters above 20 Å (N.B: most of the MOF are microporous, i.e. below 20 Å). Indeed, MOFs exhibiting a mesoporosity tend to be more fragile, MIL-143 is one of them as its mesoporosity is only partially accessible.

Where did the structure come from?

The structure comes from “Me” et al. and was published in 2013 in Angewandte Chemie, Internationale Edition.6

References

(1) Férey, G.; Mellot-Draznieks, C.; Serre, C.; Millange, F.; Dutour, J.; Surblé, S.; Margiolaki, I. Science 2005, 309, 2040.

(2) Férey, G.; Serre, C.; Mellot-Draznieks, C.; Millange, F.; Surblé, S.; Dutour, J.; Margiolaki, I. Angew. Chem., Int. Ed. Engl. 2004, 43, 6296.

(3) Chem. Soc. Rev. 2009, 38, 1203.

(4) Chem. Rev. 2012, 112, 673.

(5) Low, J. J.; Benin, A. I.; Jakubczak, P.; Abrahamian, J. F.; Faheem, S. A.; Willis, R. R. J. Am. Chem. Soc. 2009, 131, 15834.

(6) Chevreau, H.; Devic, T.; Salles, F.; Maurin, G.; Stock, N.; Serre, C. Angew. Chem., Int. Ed. 2013, 52, 5056.

Same… but different. The structure of beta – cristobalite.

What does it look like?

Crystallographic representation generated with Diamond.

Crystallographic representation generated with Diamond.

What is it?

Basically, the a-cristobalite is stable at temperature below 270°C then above this temperature, the atoms re-arrange to give rise to the b-cristobalite, the symmetry of the solid changing from tetragonal to cubic. And the silica family does not stop here; there are 11 crystalline polymorphs, plus 2 amorphous (non-crystalline) polymorphs. One of them is particularly interesting: is Keatite, which does not exist in the nature, a pure synthetic SiO2 polymorphs.

You can learn more at SiO2 polymorphs at http://www.quartzpage.de/gen_mod.html.

Where did the structure come from?

The structure comes from a paper of Wyckoff Ralph W.G. published in the german journal for Crystallography, namely “Zeitschrift für Kristallographie”, in 1925.