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Abbott Laboratories, the US pharmaceutical company, in 1996 launched a protease inhibitor Norvir® that had cost the company during pharmaceutical development, in excess of $200 million to develop. Two years later, supplies of the drug were interrupted by the appearance of a new crystal form at a manufacturing plant. This more thermodynamically stable form had very different physical properties and Abbott withdrew the drug from the market. The new form failed dissolution tests and precipitated out within the capsules. The company lost $250 million in sales as well as hundreds of millions of dollars trying to recover the original form. Many AIDS sufferers were undoubtedly not helped by the product’s absence. A degradation product obtained during manufacturing had apparently initiated the appearance of a second crystalline form, a second polymorph.
Polymorphs are different crystalline forms of a chemical compound. That is the same chemical but packed differently. Up to 80% of all Active Pharmaceutical Ingredients (APIs aka drugs) exist in more than one polymorphic form. Each form can display distinctive physical and chemical properties and this can influence it’s bioavailability (solubility), manufacturability (compressibility) and stability (chemical stability and water absorbance) of the compound. These properties become more and more important as a drug moves through the development pipeline and onto the market.
The recommendation is clear: to each pharmaceutical or biotech company, conduct a thorough polymorph investigation. Many companies are either not aware of the ramifications or choose to ignore the costs of such work. A new polymorph is potentially patentable and if it is found to have some superior properties compared to an existing drug, it is possible to take the earlier drug’s market. As in the example above, make a mistake during development and it could come back to bite.
There are a number of companies that offer polymorph screening but fewer who can integrate this with the manufacturing during drug development to ensure consistent manufacture of a target polymorph. Onyx Scientific Ltd, based in the UK is one such company developing a strong reputation for this and process development. The company can do a rapid analysis of API salts and subject the preferred compound to a detailed polymorph screen. Candidates can then be evaluated in more detail including analysis by DSC, TGA, HSM, X-Ray PD, Raman spectroscopy DVS and other more conventional techniques such as HPLC, IR, UV-Vis, GC and so on. For the biotech company that is intending to licence the drug at an early stage this provides a more valuable package. For the pharmaceutical company this provides peace of mind that the optimum compound has been chosen for development and intellectual property has been protected.
