Everett Collection /
28 November 2014Big Pharma

Crystallics: crystal clear

Crystallics is a company based in Amsterdam that evaluates drug ingredients for the pharmaceutical industry. It is one of a handful of companies globally that underpins pharmaceutical research and development by investigating the crystalline structures of drugs and potential drug compounds to find their optimum form. Such research can be crucial to effective patent protection when a drug comes to market.

Marcel Hoffmann, chief scientific officer at Crystallics, recommends that his firm gets involved in IP early in the research chain. Even if a pharma company has existing IP, it may not be well covered, he says.

For example, if a company already has its own prior art, it may leave gaps and make it more difficult to secure patent protection.

“Ideally, companies would come to this earlier in the process,” Hoffmann says. “Often we get involved when it’s too late.”

The company began life under the name Avantium Pharma, a subsidiary of Avantium Holding, which in turn was founded in February 2000 as a spin-off from Shell. A consortium of shareholders joined as strategic partners to invest in Avantium, including pharma heavyweights Pfizer and GlaxoSmithKline, the Eastman Chemical Company, chemical conglomerate WR Grace, and Akzo Nobel, a Dutch multinational specialising in decorative paints and performance coatings. In 2011 a management buy-out of Avantium Pharma created Crystallics.

Solid state research

Crystallics’s core business is to carry out solid state research on a fee-for-service basis that can involve virtually all phases of drug development. Obviously, the active ingredient of a drug is crucial to its action and efficacy, but this is far from the only consideration in the development and formulation of a therapeutic agent.

Most pharmaceutically active ingredients exist in a crystalline form that gives the molecule stability, but for many drugs there is more than one crystalline form that the active molecule can take. These different forms of a pharmaceutical solid are known as polymorphs: compounds with the same chemical formula but different crystalline structures that may affect the physical and chemical properties of the compound.

This in turn can lead to differing pharmaceutical properties, such as varying therapeutic activity, solubility, stability or bioavailability, and can also affect manufacturing techniques and costs. Methods of tablet production, excipients added, and storage conditions may also influence the properties and stability of the final drug form. Other delivery routes, such as intravenous or transdermal formulations, may have specific requirements that differ from those of a drug in oral form.

"Around 95% of contracts are with innovative pharma companies investing in a drug development pipeline, and about 5% with generic manufacturers producing their own versions of established drug formulations."

Solid state research to analyse these characteristics initially aims to produce the solid forms of an active pharmaceutical ingredient (API), understand their physicochemical characteristics and use this knowledge to optimise the structure of the chemical substance of a candidate API. For example, it might yield the most bioactive or bioavailable form, or one with optimum stability for shelf life or storage in different conditions.

Such analysis can be vital to drug development, enabling researchers to predict the safety and efficacy of a candidate drug, select the most stable solid form of the API, forecast how it may behave in different temperatures or humidity levels, and determine the optimum formulation of the API for different applications.

Various techniques enable researchers to control the formation of different polymorphs during crystallisation, including the use of different solvents to dissolve the API, the rate of cooling and degree of super-saturation of the solution. It’s important that the techniques used to analyse the crystalline structures do not themselves promote any changes or reactions in the drug molecule, for example by heat or radiation.

IP assets

Hoffmann says that the technology underlying many processes used in the company’s investigations is non-proprietary, for example techniques for dissolving drugs in various organic solvents, evaporating and cooling the resultant solutions to produce crystalline forms. The company holds just a single piece of IP itself, an exclusive licence for a process known as high throughput X-ray powder diffraction (XRPD).

The reason this is so important to the company’s work is that it can be difficult to obtain single crystals of a drug of sufficient quality to analyse the API in the solid state by the standard technique of single crystal X-ray diffraction (SC-XRD). As an affordable alternative, XRPD enables scientists to determine the crystal structure from a finely ground powder prepared in a way that doesn’t affect the crystallinity of the sample.

The high throughput XRPD technology was originally licensed from Crystallics’s parent company, Avantium Holding, which held the patent on the process. In 2012 Avantium sold this and other patents to Vertical Analytics, a subsidiary of Acacia Research Corporation, a US company specialising in “partnering with inventors and patent owners and enforcing … intellectual property consisting primarily of patents, patent rights, and patented technologies”, according to Crystallics.

Vertical Analytics subsequently filed various complaints for patent infringement against other companies, which Hoffmann says were settled out of court for relatively small sums and did not affect Crystallics’s position, as the company has held a continuous licence for its XRPD technique. Crystallics is now the only contract research organisation to hold a perpetual licence for the technologies involved in high throughput XRPD, he says.

According to Hoffmann, Crystallics’s client drug companies have included almost all the large pharma manufacturers. Around 95% of contracts are with innovative pharma companies investing in a drug development pipeline, and about 5% with generic manufacturers producing their own versions of established drug formulations. While the vast majority of its work is for pharma companies, it also performs analyses of agrichemicals, flavours and fragrances, and has in the past been involved in research on pigments.

In pharma development, the company may be involved in all stages, from candidate drug selection to successful marketing and IP protection, he says. Once the optimum form of a drug crystal is determined, the pharma company would typically incorporate Crystallics’s findings into its own IP. He says that proper application of solid state knowledge can reduce the time to market of a new drug and ensure a well-protected drug substance and product by strong composition of matter IP.

In the past, Hoffmann says, Crystallics did consider patenting new crystalline forms of drugs itself, but this did not prove commercially profitable so was dropped. Instead, he sees the future of the company as a commodity, developing the technology and expertise in research products that fit the needs of pharma companies. Solid state research can better enable drug companies to protect their own IP against generic competitors, he says.

To this end, Crystallics recommends that clients formulate early a strategy for maintaining powerful IP protection for their investment. Only a tiny proportion of potential drug candidates ultimately succeed, in a highly competitive market.

“Many of the drugs we work on will unfortunately never make it to the market”, Hoffmann explains. “We usually start working on a drug molecule in early stages of development. The compound needs to pass the animal testing (pre-clinical) phase and three clinical phases before obtaining market approval. Many drugs in development fail for reasons of toxicity, poor pharmacokinetics and lack of efficacy. Overall about 1% of the compounds entering the pre-clinical phase will make it to the market.”

It is usually a long development time. “The average time between our doing our research on the compound and the compound reaching the market is between eight and five years,” he says. In early stages, Crystallics aims to provide services in line with the development state of the compound it is investigating, in terms of both cost and effort invested.

At later stages, when the chances of success increase, the company offers more in-depth investigations to mitigate risks. Finally, when marketing of a successful compound is imminent, Crystallics undertakes comprehensive investigations of all possible crystalline forms of the drug. The aim is to provide sufficient ammunition to keep early generic equivalents off the market before patent expiration. Hoffman’s advice to smaller companies especially is to invest in an up-front IP strategy so that solid state research can be patent-driven.

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