APIs
Polymorph detection and quantification – a novel method A novel method of detecting very low levels of different polymorphs using high-resolution X-ray powder diffraction with a synchrotron light source has been developed by Zach-Zambon Chemicals of Italy. Key to the project has been development of software to enable appropriate data presentation. he issue of polymorphism in pharmaceuticals has attracted increasing attention over the past 20 years and is something to which development scientists and the regulatory authorities pay considerable attention. But why? Consider first a couple of very high profile examples from the 1990s and 2000s to see why polymorphism attracts so much attention: The case in the 1990s of Ranitidine Hydrochloride, one of the first blockbuster drugs on the market. Originally discovered and subsequently patented by (the then) Allen and Hanburys in 1978, development continued and Glaxo serendipitously discovered a new polymorph in 1980, designated Form 2, and was granted a patent in 1981 based on improved filtration and drying characteristics of Form 2 over Form 1. In 1992 the sales of Ranitidine Hydrochloride (Zantac) reached $3.44 billion so clearly an attractive proposition for the generic drugs manufacturers, especially if they could manufacture Form 1 as this came off patent
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three years earlier than Form 2. There were the inevitable infringement claims by Glaxo and patent invalidity counter-claims by the challengers. This brief example serves to demonstrate the importance of polymorphism and its understanding from the point of view of protecting intellectual property. A slightly more recent case is that of Ritonavir (Norvir) (see S R Chemburkar et al, Organic process Research and Development, 2000, 4, (5), 413) when in 1998 Abbott started to suffer many final batch lots failing specification due to lack of solubility. In short, a new thermodynamically more stable and consequently far less soluble polymorph had been generated. The failure of the lots was having a serious commercial impact as the supply of one of the formulations was depleting very rapidly. Abbott was able to recover from the situation but only after considerable effort. This very short example serves to illustrate the importance of polymorph understanding and control from the technical manufacturing point of view, which of course can impact the business.
The Sincrotrone Elettra facility at Trieste, Italy. Zach-Zambon Chemicals worked with this company to measure down to as low as 500ppm of one polymorph in another in the solid crystalline product.
So, polymorphism is important and of course can often form the basis for a generics company to attack an innovator’s patent or indeed find ways around existing patents through identification and manufacture of alternative physical forms. A report by RBC Capital Markets dated 15 January 2010, entitled Pharmaceuticals, Analyzing Litigation Success Rates comments that patent challenges remain on the rise, with 65 first-tofile lawsuits in 2009, up from 51 in 2008 and more than double the number in 2006. Not all will centre around the polymorph, but it is clearly an area of sensitivity and innovators need to be vigilant in both their scientific work and the quality of the patent itself.
What is polymorphism? Polymorphism is the tendency of a solid substance to crystallise into more than one crystalline structure. These crystalline forms, although chemically identical, result from a different ordered arrangement of the molecules within the crystal lattice – a common example being two forms of carbon; graphite and diamond. Different crystal forms can have different properties, a number of which are crucial in the pharmaceuticals arena such as solubility, stability, dissolution and ultimately bioavailability. Is polymorphism common? Yes. In a survey by Stahly and co-workers, 89% of compounds screened resulted in multiple forms (based on 245 screens, see Stahly et al, Crystal Growth and Design. 2007, 7, 1007-1026). So what’s the problem? The increasing complexity of pharmaceutical molecules presents a challenge for the process chemist and engineer not only in the synthesis, but also in control of crystal form and the physical properties of the solid that are important for consistent formulation and drug delivery. In more recent years, the quest for increasingly selective (and potent) new chemical entities (NCEs) has often seen discovery chemists introducing relatively large organic sidechains, such as aromatic rings or long alkyl chains to tap into the very specific protein environment of interest, but at the expense of
January/February 2012 sp2 Inter-Active