The Pfizer Institute

Changing the Materials Landscape

Changing the Materials Landscape was the theme of the Cambridge University Symposium held November 14th at Sandwich. The event brought together two dozen Cambridge University researchers and many Pfizer colleagues to talk about progress in computational approaches to pharmaceutical sciences.

“That’s just what we’re doing – changing the landscape,” explains Pfizer Research Fellow Tony Auffret, who organised the event. “The Pfizer Institute of Pharmaceutical Materials Science, based at the University of Cambridge, is leading the way. We’re setting the standard for the entire industry.”

Many R&D companies these days are partnering with academia; the Pfizer Institute is years ahead of the curve: “Back in 2000, when we first began to plan the Pfizer Institute, we took a much more pro-active approach,” says Tony. It wasn't the University who came to us, telling us what they could do. We went to them and said “this is the cutting edge science you should be doing.”

Cambridge embraced the challenge, and six years on, says Tony: “Pfizer colleagues have access to a range of high quality research and scientific tools that no one else has, and in all likelihood still wouldn’t exist if we hadn’t taken this initiative.”

The Pfizer Institute’s research encompasses all aspects of the structure, manufacture and behaviour of solid dosage forms, such as tablets, which should be applicable at all scales of operation and use. “Their research efforts are very broad-ranging,” explains Tony: “They model molecular crystallisation, they look at the best ways to achieve powder compaction, tabletting, diffusion and release. The Institute provides a focus for strategic research, and complements the on-going work of Pfizer colleagues.”

“Because we have access to both the tools and the tool makers, we’ve been able to achieve great results, particularly in developing computational modelling tools. In Materials Science, we are now using these computational tools routinely as part of our ‘day job.’ There are other tools as well, specifically in the area of computational powder handling, that we will be integrating into drug product design groups of both MatSci and OPCoE during 2008.”

The Big Issues: Stable Forms
One of the main issues for Materials Science is finding stable crystal forms – polymorphs -- that won’t change with time and conditions. Finding a stable polymorph is important because a drug’s polymorph affects the solubility of the drug and the bioavailability of the API (the active pharmaceutical ingredient). It’s also important because regulatory approval is usually given only for a particular polymorph; if the polymorph changes as a result of time or conditions, the drug may become commercially unviable, as happened a few years ago with Abbott Lab’s drug Ritonavir.

Crystal polymorphs are very challenging: they can change their form, or in some cases disappear completely; in other cases, they can be made once, but they can’t be re-created. Aurora Cruz-Cabeza, Graeme Day and Peter Galek presented the results of their research demonstrating how computer modelling can help identify stable polymorphs, reduce randomness and ensure better quality formulations. “We can make many different polymorphs for a compound,” explains Aurora. “Our challenge is to find the low-energy forms – these are the most stable; if we don’t find the most stable polymorph, nature is very likely to find it for us – it’s the element of uncertainty we want to avoid.”

“Our main challenge is to develop a methodology that can be trusted to find all possible polymorphs and get their relative stabilities right,” explains Graeme Day. “The energy differences between crystal structures are much smaller than the accuracy of common methods of calculating energies. Also, pharmaceutical molecules are larger than the molecules for which crystal structure prediction methods have been developed, so we have had to deal with the complexities involved with modelling large, flexible molecules.”

“We’ve made big advances,” continues Graeme. “We can now use crystal structure prediction on moderately sized drug-like molecules, which was far beyond what could be done a few years ago. By using computational studies to explore and understand the polymorphism of APIs, we can be much more confident in choosing a crystal form for development, as well as saving time and money on experimentation. Doing it this way has great potential for lowering the cost of pharmaceuticals and shortening development times.”

Colleagues were also fascinated to hear from Dr. Tomislav Friscic about his work concerning cocrystals, a recently recognised class of API solid forms, an alternative to polymorphs, hydrates and salts. “In principle, the formation of cocrystals allows the manipulation of physicochemical properties of solid API forms,” explains Dr. Friscic. “This may enable the construction of viable products from drug candidates that may initially seem inadequate. The resulting access to a large number of APIs with tunable properties would greatly cut production costs and improve drug properties.”

Big Issue Two: Designing a ‘Commercialisable’ Drug Product
Making a drug for market, or even for the more limited demands of clinical trials, means producing the compound in quantity. Making fifty grams of an API is a challenge; producing hundreds of kilos is a challenge on quite another scale, and involves very different considerations. Every aspect of tablet design is subject to meticulous and rigorous analysis, and computational modelling is being used at many stages of the process: “We have developed an experimental method to control tablet quality and predict failure,” explains Linghao Han. “By reducing the time and cost to make the dosage form, our research will mean quicker delivery of new drug to patients.

Professor of Materials Science Alan Windle poses the provocative question: “Why can computer modelling be used to design an Airbus A380, but not to describe a humble tablet?” The answer, he explains is resources: “If we commit the resources, computational approaches can indeed be successful in describing the tabletting process, and will yield real value to patients and the pharmaceutical industry. A typical tablet consists of around a million powder particles, about the same number of individual components as a jet aeroplane. Understanding how these particles interact and behave together is a challenge, and it becomes much more complex when one considers molecular structure and interactions as well.”

Yuen Sin Cheong’s research aims at improving inhalation devices technology. “Two years ago the most difficult part of developing a new inhalation device was knowing how the formulation would flow into the device on filling, and out of the device on actuation,” he explains. “The computational models we have developed allow us to design powders that are optimised for inhalers. That means that patients will get the maximum benefit from their medicines.”

“Judging by the feedback, this year’s symposium has been a great success, ” says Tony. “We’re all part of a process here – a process that brings life-saving medicines to patients. The Pfizer Institute at Cambridge is breaking new ground, finding new ways to do things better. Their work is something we can all be proud of.“

Original article by Geoff Kieley, TA Communications.

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