August 2022

Polymorph Screening - Motivation and Theory - Solid Form Screening


It is unusual for a sponsor to require a polymorph screen before investigating salts and cocrystals first. All crystalline materials, whether parent API, salt or cocrystal may exist in multiple polymorphic forms usually identified by the Roman numerals I, II, III, IV etc.

Dissolution rate and solubility
Polymorphs will exhibit different physical properties such as melting point, dissolution rate and solubility. This leads to polymorphs having different bioavailability, a key parameter in early drug development.

Running a polymorph screen may identify crystalline forms even where an API has not been observed crystalline before.

A new polymorph is patentable if it has some demonstrable advantage over the prior art and the inventor has a proven method of preparation, i.e. reduction to practice. Competitors may seek new polymorphs of existing compounds to find advantage, and new discoveries require knowledge of the polymorphs available to safeguard the invention. The FDA mandates such studies during development.

Other processability
Polymorphs may vary in crystal shape, needles and plates can be very difficult to filter and handle in further processes, so a new polymorph with a more convenient block-like shape could be the goal.


Polymorphs are (strictly speaking) defined as the same chemical substance existing in two or more crystalline states.

The definition used by the FDA, however, includes hydrates and solvates so it is important to be absolutely clear what the sponsor understands by polymorphism before screening begins. Solvates and hydrates are often discovered during polymorph screening. Amorphous materials are sometimes referred to as an amorphous polymorph, preferable is to use the term amorphous form.

Selection of solvents for polymorph screening

Selection of coformers uses two criteria

  1. Solubility
    There are 4 main methods for screening for novel polymorphs; evaporation of solutions under ambient conditions, extended slurrying at 80% dissolved, (theory suggests that polymorph transition often occurs at the surface of undissolved material), thermal cycling in and out of solution and antisolvent addition at ambient temperature. In all cases the recommended concentration to work at is in the range 10-100mg/mL and solvents should be selected to achieve such concentrations taking into account that slurrying should be carried out at elevated temperature and thermal cycling is limited by the boiling point of the solvent. Suitable antisolvents are usually the less polar examples (heptane, TBME, toluene etc).
  2. Reactivity
    Polymorph screening involves extended slurrying or thermal cycling and therefore due regard should be given to the reactivity of the solvent choices. In general drug molecules are sufficiently robust to survive such conditions but beware examples that are deliberately designed to be reactive such as ester prodrugs. These may suffer ester exchange with alcohols or be hydrolysed by water in polar solvents.

Ostwald Theory of Stages

This theory suggests that polymorph transformation takes place through a series of stages where each stage has a small energy barrier rather than a spontaneous one-step drop into a much more stable form.

In the diagram we see stepwise transformation through a series of polymorphs A, B and C to a stable crystal.

This supports the use of elevated temperatures in slurrying and thermal cycling, overcoming kinetic barriers to transformation and making it more likely to avoid the isolation of metastable forms.

Ostwald ripening

Should not be confused with theory of stages and is not really about polymorphs, but suggests that over time high energy smaller particles will tend to re-dissolve and that larger crystals will grow. This process will be particularly important under thermal cycling conditions and is used in process chemistry to generate larger, more easily filtered crystals. Crystallisations are often given ‘ripening’ times to obtain material with a lower content of fines that can block filters.
This phenomenon is observed widely in many fields from gas bubbles to emulsions to gold nano-particles.

Most stable polymorph?

A polymorph screen attempts to identify all readily achievable polymorphs of a substance, but no guarantee can be made that a new form will not appear over time. Confidence in the stability of a polymorph is given by 2 factors. Firstly a diligent screening regime, allowing time for any transformations to occur. This can be an issue with rapid, small scale high throughput screens. Secondly comparison with the prior art (SCXRD structures in the CCDB) using part structures to look for common H-bonding and lipophilic interactions in related crystals. This requires a full molecular structure derived from SCXRD or Rietveld analysis of high quality PXRD data (usually capillary PXRD). If the intermolecular interactions look unusual compared with related compounds then the recommendation is to keep looking for new polymorphs with a more highly precedented structure.

Polymorph characterisation

The following methods are useful in confirming polymorph formation and excluding hydrate and solvate formation:

  • PXRD to confirm crystallinity and polymorph identity
  • DSC for a sharp melting point, stability and hydration status
  • NMR (1H) to exclude solvate formation

In addition the sponsor may be interested in further properties:

  • TGA for stability and hydration status
  • DVS for affinity for water
  • Dissolution/solubility
  • Chemical stability

Learn more about our Polymorph Screening Services


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Download the Polymorph Screening and Selection Theory Sheet PDF

Polymorph Screening - Motivation and Theory PDF






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