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A Solid State NMR Investigation into Polymorphism in the Indomethacin Molecule. - Probing Inter-molecular Interactions between Spins


Over the summer (2009) I undertook an 8 week URSS research project investigating polymorphism in the Indomethacin molecule, supervised by Dr Steven Brown and Jonathan Bradley. Funding was provided by the University of Warwick Physics department. At the end of the project I was asked to present my findings to the solid state NMR department as well as produce an academic poster for the URSS student exhibition, which is available here.

What is Polymorphism?

Polymorphism arises when the unit cell of a molecule takes up different shapes, resulting in a different form of the 3D solid. The reasons for this change in shape are numerous and include changes in temperature and pressure as well as the presence of impurities. This environmental change is not drastic enough to alter the intramolecular forces, so the molecule remains the same, but the intermolecular forces are altered, so the way the molecules pack changes resulting in a new unit cell. The figure below should clear up the subject for anyone struggling with the concept.

Imagine the molecule of interest is a specifically shaped tile, the unit cell, a motif and the final solid, a pattern. The tile cannot change shape whereas the motif can. We will see that the choice of motif has a big impact on the final pattern. After selecting a tile (see the yellow shape at the top of the figure), a small number of tiles are positioned to form a motif (the red constructions). Many different motifs can be created but I have chosen two forthis demonstration. Each motif is reproduced and translated in a regular mannerto form a large final pattern. The final patterns (at the bottom of the figure) look nothing like each other, but both are made from the same original tile. The molecule/tile is held together by int ra-molecular forces whereas the unit cell/motif is determined by how these molecules stack together, in other words, the int er-molecular forces between molecules/tiles. It is these int ermolecular forces that are susceptible to change by variables already discussed such as temperature. If different unit cells/motifs exist then different solid forms of the molecule will exist and we call this polymorphism.

Why is polymorphism interesting from an NMR perspective?

As the intramolecular bonding in polymorphs remains the same (i.e. the molecular tile is the same), the difference in NMR sptra between two polymorphs must arise due to intermolecular interactions. By comparing the spectra of various polymorphs, an understanding of the way intermolecular bonding manifests itself in NMR experiments may be gained.

Polymorphism in the Pharmaceutical Industry

The physical and chemical (physicochemical) properties of an Active Pharmaceutical Ingredient (API) are often determined by its intermolecular structure. Different polymorphs of the same solid can have very different physicochemical properties. A good example of an API is Indomethacin which exists in two known polymorphic forms, Gamma and Alpha. The Gamma form of this molecule is the stable solid form, but has a low dissolution rate. The Alpha form, on the other hand, is meta stable, and has a high dissolution rate. It is possible to tailor the physicochemical properties of the API by introducing a benign former into the crystal structure, a process known as co-crystallisation. For Indomethacin, this has been achieved with the sweetener Saccharin to produce a new solid form of the API known as the IND-SAC co-crystal.

Aims of the Project

  • The three aforementioned solid forms of the API, Indomethacin (Alpha, Gamma and IND-SAC) have known crystal structures available from the Cambridge crystal database. It is the aim of this investigation to develop NMR structural identification techniques on the Indomethacin forms of known crystal structure, with the aim of applying the techniques to solid forms of unknown structure.

Just to make it clear, the structure of the Indomethacin molecule is known - this is not of interest. What is of interest, is how the molecule packs together and for this we must investigate the intermolecular interactions.

  • It is possible to simulate NMR experiments using computer programs. A comparison of simulated data versus experimental data will be made for each of the Indomethacin solid forms.
  • Finally, we shall look at Carbon-13 peak assignment for each of the solid forms at our disposal.

NMR Techniques

The techniques will be split into catogories depending on the observed chanel species.

  • Hydrogen-1
2D Double Quantum Coherence (DQC) CRAMPS Very useful experiment. Displays information on both inter and intra molecular dipolar coupling between protons.
  • Carbon-13 
CP MAS Cross polarisation MAS. The large gyromagnetic ratio of the Hydrogen nuclei are used to enhance the Carbon-13 signal via cross polarisation.
Refocused INEPT Same as the above, but J coupling mediated. Only Carbons directly bonded to hydrogen nuclei appear in the spectrum, often simplifying it considerably



The results can be viewed either via the links below, or with some background theory in a presentation (PDF Document) (sound to follow)

Hydrogen Experiments   Carbon Experiments



Main Supervisor:

Dr Steven Brown

s dot p dot brown at warwick dot ac dot uk




Jonathan Bradley

jonathan dot bradley at warwick dot ac dot uk


Undergraduate Research Scholarship Scheme