User talk:Simonjohns

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Proposed deletion of Drug development: Ignore polymorphism at your peril


The article Drug development: Ignore polymorphism at your peril has been proposed for deletion&#32; because of the following concern:
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Drug development: Ignore polymorphism at your peril
The consequences of Abbott Laboratories’ antiretroviral drug Ritonavir, used to treat HIV infection and AIDS and problems with polymorphism has yet to be universally understood. Avoiding action has not yet widely been taken on polymorphism by the global pharmaceutical industry, so it is worth repeating the story.

In 1996 Abbott launched on the market an effective protease inhibitor Norvir® that had cost the company in excess of $200 million to develop. The drug was formulated as an encapsulated ethanol/water solution. In the summer of 1998, supplies of the drug were interrupted by the appearance of a new crystal form (polymorphism) at a plant in the USA and then later at a plant in Italy. This new, more thermodynamically stable polymorphic form had very different physical properties than the earlier material and Abbott was forced to withdraw the drug from sale. The new form failed dissolution tests and precipitated out within the capsules. The company lost an estimated $250 million in sales as well as hundreds of millions of dollars trying to recover the original polymorph while the product was off the market. No doubt many AIDS sufferers were not helped by the product’s absence. What appeared to have happened was that a degradation product obtained during manufacturing had initiated the appearance of a second crystalline form, a second polymorph.

So what is polymorphism? It is simply a different arrangement a molecule might adopt in a crystal. Most drug molecules are crystalline. That is, the molecules pack together in a particular regular way. Some molecules, perhaps most, are able to pack together in more than one way and thus give rise to different polymorphs. A pair of polymorphs might have very different physical properties. Over 50% of all Active Pharmaceutical Ingredients (APIs) exist in at least 2 polymorphic forms.

During drug development, an initial scouting polymorphism screen is designed to find a stable non-solvated form with good properties. A later comprehensive polymorphism screen is to find as many forms as possible in order to exhaustively cover the Intellectual Property space. Continuous monitoring is needed throughout development in order to ensure continued control of polymorphism.

What can cause polymorphism changes? Crystallisation from different solvents may give rise to different crystal forms or solvates. Extremes of humidity or heat are among the more obvious factors affecting polymorphism. Changes in polymorphism can also be induced as a consequence of several common stages of API processing such as granulation, melting, spray drying, compression and milling that are required to produce the final dosage form.

X-Ray Powder diffraction and Raman spectroscopy are the two workhorse methods used to evaluate the presence and amount of different polymorphic forms found during screening. Differential Scanning Calorimetry (DSC), Differential Thermal Analysis (DTA), Dynamic Vapour Sorption (DVS) and hot stage microscopy are additional specialised techniques used to characterise different polymorphic forms.

All is not doom and gloom as the polymorphism properties of a chemical substance are patentable. A new polymorphic form therefore may be used to extend the patent life of a drug. A counter to this is that a new polymorphic form with advantageous properties may be able to supersede an existing drug and effectively ‘bust’ the original patent.

It’s not surprising to learn that manufacturers & developers of generic drugs actively pursue new polymorphic forms of patented drug substances. This can be a highly litigious area.

National regulatory authorities require that all companies register the precise polymorph of any new drug. Moreover, manufacturers need to demonstrate that each polymorph is stable and can be reliably reproduced

Many small pharmaceutical companies do not intend taking their drug candidates all the way to commercialisation themselves but to seek to license at an earlier stage. This arises because of the considerable increase in costs as a drug moves through the clinic. If a polymorph screen is also included then the package is certainly stronger and the licensor can expect a further premium.

During pre-clinical development the quantity of an API that is available for studies is usually very low. Screening a wide variety of solvents and conditions needs to be conducted for that reason on a very small scale. Systems that can handle multiple experiments at the milligram scale are best. At some labs automated systems can handle up to 96 well plate formats and conduct experiments at 0.5-2mg scale. Thus the total amount of API used for an initial screen can be a modest 50-200mg.

Typically, a salt selection project will precede a polymorphism study: once a salt is found that has the most promising properties, it will be further developed, characterised and might be the subject of a further polymorphism screen during the normal course of pre-clinical development.

Polymorphism, in addition to complicating drug development also aids drug efficacy and can ensure that any hard earned work is justifiably rewarded.

May 2010
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