Technology focus The shape shifters A sudden change in the properties of a drug as a new polymorph appears can be highly damaging for pharma firms. The industry now appears to be in control of the situation and is even reaping financial rewards from new polymorphs, as Susan Aldridge discovers

The pharmaceutical industry solid state properties for the – a crucial consideration when faces a deadly and swift saboteur. In short pharmaceutical and biotechnology shipping a pharmaceutical or food This attacker hits unexpectedly  Polymorphism, when industries. ‘The worst that can product. The US Food and Drug and comes under the title compounds adopt happen for a pharmaceutical Administration (FDA) thinks ‘polymorphism’: when compounds more than one crystal company is if a new polymorph these issues important enough to adopt more than one crystal structure, is taken very suddenly appears in the temperature require companies to register the structure or polymorph in the seriously by the pharma and humidity conditions of a blister polymorphic forms of any new drug solid state. A new polymorph industry pack when a compound is actually they make. can be catastrophic; overnight a  A new polymorph on the market.’ It is likely that all small organic drug manufactured for market can appear suddenly in Polymorphism was first molecules have the potential for can become less soluble and less a manufactured drug, discovered in 1821 by the German polymorphism, because there are bioavailable. Although a compound’s with devastating results. chemist Eilhard Mitscherlich and so many ways in which molecules polymorphs are chemically Although chemically is a widespread phenomenon in the can be packed within a crystal, identical, their physical properties identical, the new chemical world. Polymorphs differ mainly through different ways of can be tremendously different. polymorph can have in their outer form (habit) as well arranging hydrogen bonds between ‘Polymorphism is completely very different physical as their inner structure (form). For neighbouring molecules. unpredictable,’ says Chris Frampton, properties example, polymorphs of the amino ‘It is a matter of finding the right chief scientific officer of SAFC-  It is estimated that acid glycine exist either as prisms or conditions for a polymorph to form,’ Pharmorphix, a Cambridge, UK- 30–50 per cent of as a pencil shape, while paracetamol explains Frampton. Sometimes these based company which investigates pharma compounds crystals may appear as prisms or conditions may be so extreme – very exhibit polymorphism monoliths (see fig, p68). Polymorphs high pressure, for instance – that the  Polymorphs are may differ in melting point, polymorph’s existence is likely to patentable and can be solubility, density, hardness, and in remain undiscovered indefinitely. A used to extend the life of optical and electrical properties. In drug or food product is made many a drug industrial terms, these differences times over; any changes in synthesis may affect manufacturing and conditions, however subtle, may processing properties, shelf life, encourage the emergence of new texture, stability against air and light, polymorphic forms. ‘We want to ability to be compressed into a tablet, ensure the crystallisation step yields and so on. the same polymorph each time,’ says The first polymorph to form may Frampton. be metastable and liable to convert Roland Boese, of the University of to a different, more stable, form over Duisberg-Essen, Germany, quotes time or under different conditions estimates that 30 to 50 per cent of re-synthesis. Or the most stable of pharmaceutically important polymorph at room temperature compounds exhibit polymorphism. may become metastable at another If hydrates and solvates are included, Chemist Eilhard temperature; transitions between then perhaps as many as 90 per cent Mitscherlich discovered polymorphs may occur as the of compounds will exist in more than polymorphism in 1821 temperature is raised or lowered one crystalline form. 64 | Chemistry World | April 2007 www.chemistryworld.org

CW.04.07.polymorphs.indd 64 21/03/2007 08:25:41 PHARMORPHIX

www.chemistryworld.org Chemistry World | April 2007 | 65

CW.04.07.polymorphs.indd 65 21/03/2007 08:26:13 Technology focus

Now polymorph screening is a common procedure, using robots to carry out hundreds or thousands PHARMORPHIX of crystallisation experiments using different solvents or solvent mixtures and different cooling and evaporation rates. Boese, one of the international team that analysed aspirin’s form II, adds that some scientists still discover polymorphs using a more empirical approach. ‘There is no general rule, but some more or less intuitive guidelines do exist, sometimes kept secret by experimentalists.’ A stable polymorph is obviously a potentially good choice for a pharmaceutical company to take into further development. But stability is not the only consideration. ‘A metastable form may have better dissolution properties, which then improves the bioavailability,’ says Boese. ‘But the metastable form may then transform into the stable form, which is then less soluble. This was the case with ritonavir.’ On the other hand, as Frampton points out, a compound can be too soluble – it may take in water during storage. Once a desired polymorph has been discovered, the next step is to learn how to obtain it reliably – and stop less desired polymorphs from forming. The crystallisation process is not well understood Industrial cost form II exclusively. This involved X-ray crystallography but involves nuclei forming In industry, the existence of a carefully controlled reflux and is crucial in the hunt for within a supersaturated solution polymorphs is best discovered cooling cycle, keeping the solutions new polymorphs of the compound. The nuclei act sooner rather than later, as US and reactor as free as possible from as templates for the formation pharmaceutical firm Abbott form II contamination. of further crystals within the Laboratories learnt to its cost. In Even long-established drugs can solution. Without nucleation, the 1998 the company found that it be hit by polymorphism. In 2005, a supersaturated solution may not could no longer make the original team of researchers led by Michael crystallise for a long time, which form of its HIV drug ritonavir Zaworotko of the University of is why chemists sometimes try to because a second polymorph had South Florida, US, claimed to form nuclei by scratching the side taken the place of the first during have discovered and made a new of the vessel containing the solution manufacture. Abbott scientists polymorph of aspirin: form II (see with a glass rod. Tiny crystals of had discovered that the drug was fig, p70). Then, last year, a team from the desired polymorph – if they starting to fail dissolution tests Denmark, Germany and India, led exist – can act as nuclei or seeds for and precipitating out of capsules. by Boese, claimed to show that the crystallising that polymorph. But Investigation showed the existence crystals analysed by the US team seeding doesn’t always work as of polymorph II (needles), which were in fact an intergrowth of two planned – if seeds of an undesired was more soluble and less stable polymorphs: form I and form II. polymorph are present, even in a than polymorph I (rods). Form II Pure form II is elusive, they say. very small amount, they will tend soon spread and form I could no ‘It is the worst to seed that polymorph, instead of longer be synthesised. Form II’s Structure screening the wanted one. Impurities can also decreased solubility could have Ritonavir served as a wake-up call that can happen act as seeds. ‘The purer a compound affected the drug’s bioavailability for the pharmaceutical industry, for a pharma is the less likely templating is. As and Abbott was forced to withdraw which became more interested in a compound becomes purer, there ritonavir from the market for a time exploring the solid state of drug company if a could be a switch to a different while it figured out how to get the candidates at an earlier stage. new polymorph polymorph,’ says Bill Jones, head original polymorph back; its loss Previously, companies had been of the chemistry department at in sales was compounded by extra reluctant to part with precious suddenly Cambridge University, UK. development costs. Abbott scientists milligrams of a new compound for appears when Crystallisation need not be so finally found a way to get back, these studies – especially when unpredictable. Recent research from consistently, to form I while also they might not even go ahead with a drug is on the Mike Ward’s group at the University discovering a way to manufacture developing the compound. market’ of Minnesota, US, suggests that the 66 | Chemistry World | April 2007 www.chemistryworld.org

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CW Adverts_Display.indd 67 20/03/2007 15:37:52 Technology focus How many polymorphs? Many compounds such as sucrose polymorphism was discovered and naphthalene appear to have by Lian Yu, now of the University only one polymorphic form. At the of Wisconsin-Madison, US, other end of the spectrum is 5- and coworkers in 2000. Two methyl-2-[(2-nitrophenyl)amino]- other forms of ROY, both yellow 3-thiophenecarbonitrile – also crystals, were discovered in known as ROY (red orange yellow) 2005. ROY holds the Cambridge because of its seven solvent-free Structural Database record for polymorphs. These occur as red the most polymorphs of any or yellow prisms, orange plates or solved crystal structure. A survey needles, yellow needles, orange- carried out by Yu in 2000 found red plates, and red plates. 321 polymorphic systems of ROY is an intermediate in the which 291 had two polymorphs,

synthesis of the antipsychotic 27 had three, three had four, and US WISCONSIN-MADISON, of UNIVERSITY YU, LIAN drug olanzapine and its ROY (red, orange, yellow) has several polymorphs none had five or more.

process can sometimes be controlled to several lengthy court battles. For ‘Lengthy court Predicting the unpredictable using synthetic porous polymers as instance, ranitidine hydrochloride – In future, computational methods a crystallisation surface. The pores the anti-ulcer drug Zantac – has long battles have may be able to take some of may limit the size of nucleus that enjoyed blockbuster status. Glaxo been waged the unpredictability out of can form and therefore drive the (now GlaxoSmithKline or GSK) polymorphism. Jones’s Cambridge formation of a particular polymorph. discovered a second polymorph of over polymorph group has already made important Working with the compound ROY, ranitidine hydrochloride early in ownership’ computational steps. Maleic acid, which has several polymorphs (see the drug’s development and took an important salt-forming agent box, above), the Minnesota team out a patent. The second form in the pharmaceutical industry, is found that only one of them formed proved easier to manufacture a key example. Since maleic acid’s within the pores. and became the drug’s active crystallisation in 1881, it had been ingredient. believed that there was just one Patentable polymorphs When the patent on the first form polymorphic form but Jones recently Although polymorphism may expired, generic companies were discovered a second, in the form of sound like a trying challenge for the naturally keen to make their own colourless plate-like crystals, after pharmaceutical industry, it does versions. But the very existence of co-crystallisation with caffeine. His have its positive side. Polymorphs the second form, still under patent, team was able to use a computational are patentable. If an early screen made it hard for competitors to make approach to predict the existence of reveals the existence of two or more the first form without contamination. this second form – and others. polymorphs, a company can patent This scientific problem bought Meanwhile, a team from them all, choose to develop one and GSK valuable time by delaying the University College London (UCL), then, when it comes to the end of appearance of generic versions of under its e-Materials project and led its patent life, go back and develop Zantac. by Sally Price, used computational one of the others to extend the life of Lengthy court battles have techniques to predict a new the drug – a process that Frampton also been waged over polymorph polymorph of the Alzheimer’s drug calls ‘evergreening’ or life cycle ownership for the antidepressant piracetam – polymorph IV. Colin extension. paroxetine hydrochloride (Seroxat), Pulham from Edinburgh University’s The issue of the ownership, the antibiotic cefadroxil, and Paracetamol can convert high-pressure group had already identity and characterisation of terazosin hydrochloride, a drug for from form I I (below, left) discovered a new form of the drug in pharmaceutical polymorphs has led prostate problems. to form I (below, right) the lab and challenged Price to tell PHARMORPHIX

68 | Chemistry World | April 2007 www.chemistryworld.org

CW.04.07.polymorphs.indd 68 21/03/2007 08:57:53 Industry and Technology Forum – Speciality Chemicals Sector

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CW Adverts_Display.indd 69 21/03/2007 16:21:47 Technology focus Companies  Pharmorphix is based in Cambridge, UK, and provides solid-form research services to the international pharmaceutical and biotechnology industries. It uses a range of techniques to predict polymorphs. www.pharmorphix.com

 TeraView, Cambridge, UK, provides terahertz spectroscopic systems for polymorphism analysis. Terahertz spectroscopy can, for example, differentiate between different hydrate forms. www.teraview.com

 Bruker, US, sells a range of US FLORIDA, SOUTH OF UNIVERSITY ZAWOROTKO, MICHAEL machines that can be used to hunt for polymorphs. Bruker AXS, for him its structure. ‘We were correct in In 2005, US researchers Abbott from the ritonavir crisis; the example, offers x-ray solutions, the prediction we sent him,’ she says. from the University of molecule is too big and contains lots while Bruker Optics sells Fourier Early work as part of the e-Materials Florida claimed to have of unusual functional groups. ‘But in transform infrared, near infrared project had also predicted aspirin’s formed a new crystal a few years I think we could tackle a and Raman spectrometers. Bruker form II. ‘It’s exciting to see a new form of aspirin: form II molecule like this,’ she predicts. has developed a one-off prototype polymorph appear,’ says Price. ‘This It would seem that a multi- hybrid x-ray and Raman machine is such a fun area to be in – when pronged approach to spotting new for Pharmorphix (above). we calculate that more polymorphs polymorphs is the key, combining www.bruker.com are feasible than are already known, computational chemistry with either new polymorphs are found, or analytical lab techniques (see box,  Anachem, Luton, UK, sells we need to work out why not.’ below). Given polymorphism’s a ‘parallel chemistry product’ The UCL work is part of a potential to destroy pharmaceutical (ReactArraySolo) which contains polymorphism project, Control and sales targets, it is well worth a series of mini reaction vessels prediction of the organic solid state, companies staying or becoming with different temperature zones. funded by the Research Councils UK. vigilant. After all, it’s not all negative These allow temperature profiles Computational methods are still – discovering a new polymorph can to be set up to drive the formation in relative infancy. ‘They cannot be the key to scientific and financial of polymorphic forms. be applied to very complex active success. www.anachem.co.uk pharmaceutical ingredients at present, says Frampton. ‘But we Susan Aldridge is a freelance science  PANalytical, the Netherlands, are aware of the possibility and are writer based in London, UK supplies analytical working towards it with various Further reading instrumentation and software academic groups. Ideally, you would  A D Bond et al, Angew. Chem. Int. Ed., 2007, for x-ray diffraction and x-ray be able to take a two dimensional 46, 615 fluorescence spectrometry. The structure and predict a molecule’s  P Vishweshwat et al, J. Am. Chem. Soc., 2005, company is part of Spectris, physical and chemical properties 127, 16802  Ed: Rolf Hilfiker.Polymorphism in the pharma- Egham, UK. in the solid state. We are nowhere ceutical industry, Wiley VCH, 2006 www.panalytical .com close to this.’ Price agrees that  S Chen et al, J. Am. Chem. Soc., 2005, 127, computation could not have saved 9881  Zinsser Analytic, Germany, sells an automated liquid and powder handling platform for How to spot a polymorph polymorphism screening studies. Single-crystal and powder x-ray is a good way of finding new which will further refine the The platform, Crissy, can be used diffraction are the gold standard polymorphic forms,’ comments characterisation of polymorphs. to analyse a series of crystals for determining how molecules Chris Frampton, chief scientific Meanwhile, gravimetric vapour using x-ray powder diffraction. are packed in the crystal; officer of SAFC-Pharmorphix, sorption determines how much www.zinsser-analytic .com advances in this technology UK. Infrared, Raman, and water a compound absorbs mean that ever smaller crystals nuclear magnetic resonance and whether it forms hydrates.  Solvias, Switzerland, offers can be used. Differential spectroscopy (NMR) are used Finally, a compound may be a polymorphism service which scanning calorimetry (DSC) because the different hydrogen exposed to what Frampton covers polymorphism screening, allows the detailed study of bonding patterns in polymorphs calls the ‘tanning salon’ which crystal purity and kinetic stability, the crystal’s behaviour as give rise to different spectra; simulates the effect of long crystallisation optimisation and it is heated and cooled, to added to these are solid periods of sunlight exposure monitoring, and a controlled determine the stability range state NMR and terahertz (far on a crystal form. These data scale-up of the crystallisation of different polymorphs and to infrared) spectroscopy (see are important for determining a process. identify any changes from one Chemistry World, March 2007, polymorph’s possible behaviour www.solvias .com polymorph to another. ‘DSC p52), emerging technologies during shipping and storage.

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