Polymorphism and Crystallisation in Modern Pharmaceuticals



Pharma IQ
11/02/2011

Polymorphism and crystallisation are among the most important and challenging areas of pharmaceuticals today, with new polymorph discoveries harbouring the potential to dramatically change the properties of a drug.

With rapid improvements in technology and drug development, keeping up to date with the latest pharmaceutical research and best practice approaches is an essential part of improving drug efficacy, safety and quality.

Polymorphism also provides pharmaceutical firms with the means to gain a market share in drugs that are already under patent, however, the process is a double-edged sword and just as it can be incredibly beneficial to discover new polymorphs, their emergence can have incredibly damaging repercussions.

How polymorphism plays a part in drug development

When compounds adopt more than one crystal structure during their solid state, the variations are known as polymorphs and while chemically identical different polymorphs can have dramatically altered properties, a fact evident in the gross disparity between graphite and diamonds.

Researchers can use this process to develop new drugs with the same properties as those already on the shelves, if the patent only covers the one polymorph, rather than the chemical makeup, with an estimated 30 to 50 per cent of pharma compounds thought to show signs of polymorphism.
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This was illustrated by GlaxoSmithKline in 1998 when it started legal proceedings against TorPharm for alleged breach of the patent of the active ingredient in Zantac, on the grounds that, while its main patent had expired, it had a further patent on a second polymorph of the compound.

The case was found in favour of TorPharm when it was discovered they were using the polymorph described in the expired patent rather than any other forms.

Situations similar to this have led to intense litigation over drug patents.

"The polymorph issue is so important to the pharmaceutical industry," Jerry Atwood of the University of Missouri-Columbia, told Science Service.

"We're talking about multibillion-dollar drugs. Ultimately, it comes down to a hard legal battle."

Indeed, the crystalline form of compounds in medicine is very important to how effective they are, especially those which are administered orally, as it can have an effect on how they dissolve and therefore how quickly they are able to act.

Introducing different polymorphs has also enhanced the production of paracetamol tablets, as paracetamol powder has naturally poor compression qualities which originally made manufacturing pills a challenge.

Polymorphism in genetics

Similarly, polymorphism has been seen to make the same genes behave very differently.

According to a recent study published in the Translational Psychiatry journal, participants in the research, in this instance experienced aeroplane pilots, with one version of a single gene had a decline in mental performance which was nearly double that of those with a different coding of the gene.[inlinead]  
"This gene-associated difference may apply not only to pilots but also to the general public, for example in the ability to operate complex machinery," said the study's senior author Dr Ahmad Salehi.

The polymorphism studied has also been linked to depression, stroke, anorexia nervosa, anxiety-related disorders, suicidal behaviour and schizophrenia.

However, the emergence of a new polymorph is not always a welcome event for those in the pharmaceutical and medical industry.

When good drugs go bad

"The worst that can happen for a pharmaceutical company is if a new polymorph suddenly appears in the temperature and humidity conditions of a blister pack when a compound is actually on the market."

This is the opinion of Chris Frampton, chief scientific officer of SAFC- Pharmorphix, in an interview with Chemistry World.

He explained that in this instance, polymorphism is a "saboteur" which can dramatically alter the characteristics of a drug overnight, with the potential for it to become less soluble and less bioavailable.

For this reason, compounds are now routinely screened to explore the solid state of drugs at an early stage of development, as well as suggest any storage specifications that may be necessary to avoid the development of new polymorphs in transit.

Whether beneficial or detrimental, polymorphs play an incredibly important role in pharmaceuticals and will continue to do so for the foreseeable future.

The Polymorphism and Crystallisation 2012 event will be hosted from 27th - 29th February in Amsterdam, The Netherlands.

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