What are Polymorphs?

Polymorphs are compounds that can exist in two or more crystalline structures; the chemical composition remains the same, but the arrangement of the molecules is changed. Crystalline compounds exhibit a repeating structure (the unit cell), forming the crystal lattice. There are seven known types of lattices.


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Different polymorphs can have considerable effects on the physical and chemical properties of the compound. Polymorphs pose a considerable headache for the pharmaceutical industry as more than 50% of Active Pharmaceutical Ingredients (APIs) can generate polymorphs. This can have considerable implications for the compound itself, but more importantly, pharmacokinetics, especially bioavailability and motility.

Why are they formed?

There are several theories about why polymorphs are formed. Systems tend to move towards the most thermodynamically stable state. This, however, is seldom a direct route, resulting in the formation of metastable compounds that exist in thermodynamic troughs. The kinetic nucleation theory describes factors such as the degree of supersaturation, the temperature of crystallization, and interfacial tension (energy at the surface between the compound (solid) and the solvent (liquid)). It is proposed that the stable form exhibits higher nucleation at lower temperatures (supercooling to induce supersaturation) than the metastable form.

Cross-nucleation occurs when one polymorph nucleates on another polymorph. The polymorph with the fastest growth rate will be observed. Many factors influence cross-nucleation: the initial polymorphs formed, the growth rate, the nucleation rate, thermodynamic stability, defects, lattice matching, crystallographic orientation, and formation of interfacial transition layers. Manipulation of factors such as temperature and supersaturation can modulate the final polymorph. Interestingly, cross-nucleation can only occur when the polymorphs have comparable free energies.

How are they formed?

There are two forms of polymorphs: conformational and packing. Conformational polymorphs relate to the arrangement of the atoms in the molecules. This is influenced by the energy constraints posed on the lattice (intramolecularly or intermolecularly). Organic molecules which exhibit greater torsion (less steric constraint) are more likely to exhibit polymorphic behavior.

Packing polymorphs are formed due to the orientation of the individual molecules, generating different permutations. Polymorphs can exist as monotropic or enantiotropic. Monotropic polymorphs are stable across a temperature range, while enantiotropic polymorphs possess a transition temperature at which polymorphs change stability.

How are they detected?

The method used to detect the polymorphs depends on the sample abundance, whether it can be destroyed, time, and if the sample is wet or dry. Powder X-ray diffraction (PXRD) is the most common means to detect polymorphs, often used for high-throughput screens. It does, however, require reference powder patterns. These are obtained from single-crystal X-ray analysis; this requires a single crystal of sufficient quality. Raman and mid-FT-Infrared spectroscopy can also be utilized. Both provide defined spectral readouts to determine polymorphs. Raman can be used with wet samples.

How are they regulated?

It is critical to monitor the parameters that influence polymorph formation. Physiochemical factors such as the temperature of crystallization, agitation, supersaturation, pH, and solvent choice all play a role. In drug development, it is critical to conduct screens to monitor these parameters to evaluate polymorphism.

High-throughput screening has improved the detection of polymorphs. This, coupled with computer software that can accurately model the potential arrangement of atoms to determine the most stable polymorph, has increased understanding of polymorphism. It has detected five different polymorphs of ritonavir (an HIV protease inhibitor drug).

There are numerous ways to modulate the generation of polymorphs. Crystallization from the melt involves cooling the compound to below the melting point of the metastable form to produce the unstructured form (amorphous). It is cooled so rapidly it prevents crystallization from occurring. Similarly, removing solvents or hydrates can collapse the crystalline structure and generate an amorphous form. Desolvation in solvents with poor solubility at low to medium temperatures has generated polymorphs of interest to the pharmaceutical industry.

Polymorph investigations are often conducted on the nano-scale due to the different size-based properties, such as increased surface-to-volume ratio. These changes affect temperature and crystal pore size, which modulate the polymorphs' relative stability. This has been manipulated to modify the stability of metastable form III of acetaminophen and to crystallize the stable form of mefenamic acid (anti-inflammatory analgesic).

Seeding is another useful technique to regulate polymorph formation. A seed of the desired polymorph or a "pseudo-seed" is used only to encourage the solution to crystallize the polymorph of interest. Understanding the nucleation processes of the polymorphs is essential as seeds can often function as sites for undesired polymorphs.


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Why are they relevant to the pharmaceutical industry?

Polymorphs present a serious challenge to the pharmaceutical industry and contribute significantly to drug attrition. The most stable form of the drug is not always the most biologically active one. The compound will intrinsically want to seek the most thermostable. The pharmaceutical industry utilizes an understanding of polymorphism and pharmacology to provide the best outcome in terms of processing and bioavailability.

One classic example is the antibiotic chloramphenicol. It exists in three forms: the stable form A (biologically inactive), the metastable form B (biologically active), and unstable form C. The relative differences in solubility and subsequent bioavailability between the first two forms have resulted in the metastable form being formulated. Atorvastatin calcium is a popular cholesterol-reducing drug (Lipitor®). It is unstable and possesses very low bioavailability. It has sixty polymorphs: many drug companies are now interested in patenting these to provide more efficacious alternatives.


Polymorphs pose a Janus-faced scenario in the pharmaceutical industry: polymorphs can offer differential therapeutic benefits but also present challenges in the manufacturing and processing APIs. Numerous popular drugs possess polymorphs that balance therapeutic efficacy and bioavailability. The advent of high-throughput screening and computer modeling has improved understanding and detection of polymorphism, limiting drug attrition.

Click here to read more about the modern challenges of drug discovery!


  • Censi, R. and Di Martino, P. (2015) 'Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs', Molecules (Basel, Switzerland), 20(10), pp. 18759–18776. doi: 10.3390/molecules201018759.
  • Florence, A.J. (2010) 'Polymorph screening in pharmaceutical development.' European Pharmaceutical Review, pp.28-33.
  • Lee, E. H. (2014) 'A practical guide to pharmaceutical polymorph screening & selection', Asian Journal of Pharmaceutical Sciences, 9(4), pp. 163–175. doi: https://doi.org/10.1016/j.ajps.2014.05.002.

Further Reading

Last Updated: Jul 18, 2022

Bryan Savage

Written by

Bryan Savage

Bryan has a strong interest in science communication and dissemination. He presented his research at the American Society for Cell Biology symposium in Washington D.C. in 2019. He worked as a demonstrator and tutor for undergraduate students; motivating them through the practical and theoretical elements of biochemistry (a very misunderstood aspect of the life sciences!).


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