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Business

Solid-State Services

Specialized companies help drug developers find crystalline forms with the right properties

by Ann M. Thayer
June 18, 2007 | A version of this story appeared in Volume 85, Issue 25

 

Crystal Clear
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Credit: Pharmorphix
SAFC's Pharmorphix business offers solid-state chemistry services.
Credit: Pharmorphix
SAFC's Pharmorphix business offers solid-state chemistry services.

MOST MAJOR DRUG FIRMS have a horror story in which a crystalline form, or polymorph, of a drug candidate suddenly appears or disappears, to the detriment of the development process. A polymorphic change in a commercial product can be even worse news if the change affects a drug's performance and safety. "In the world of polymorphs, confusing results are standard," Novartis research manager Piotr H. Karpinski has observed (Chem. Eng. Technol. 2006, 29, 233).

The majority of drugs are sold as solids. But before a pharmaceutical company develops a finished product, it first has a compound with chemical and physical properties. These properties affect the compound's synthesis, handling, stability, formulation, and, most critically, behavior as a medicine. Which one of many possible polymorphs takes shape has a significant effect as well. Consequently, determining and controlling the solid form of drugs is a growing area of science and business.

Pharmaceutical developers want to find forms with optimal properties for therapeutic use that they can make reliably and consistently. And, because they may be able to patent each form, crystal forms have become critical factors in intellectual property (IP), generic drug competition, and litigation. Over the past decade, events on these fronts along with a regulatory obligation to screen for polymorphs have heightened the drug industry's need to understand solid forms.

Pharmaceutical forms can range from pure crystalline or noncrystalline compounds to multicomponent systems, which include salts, solvates, hydrates, and other types of cocrystals. An estimated 80% or more of pharmaceuticals exhibit polymorphism. Choosing an appropriate form requires a thorough and systematic approach to screening and characterization, Karpinski suggests.

The major drug companies possess these capabilities. Having in-house access was important enough to Johnson & Johnson that it paid $230 million in 2005 to acquire the solid-state chemistry services firm TransForm Pharmaceuticals. Founded in 1999, the Lexington, Mass., company had technology licensed from Millennium Pharmaceuticals and employed about 80 people when it was acquired. Today, it works only for J&J.

TransForm has developed high-throughput crystallization and formulation methods to discover and make new drug forms. "Whereas a generic developer tries to match the profile of an existing drug, we look to improve products," says Julius F. Remenar, principal investigator at TransForm. This process can entail, for example, finding more soluble forms to allow for smaller dosages or more stable forms for better storage.

When the need arises, drug companies can turn to outside providers, although only a handful of companies are really focused on solid-state chemistry. It is an area of expertise at Solvias, which has its origins in Ciba-Geigy's central research unit and was spun out of Novartis in 1999.

Rolf Hilfiker, head of solid-state development at Solvias, says drug company clients have two primary goals. "In early development, the primary aim is to find a stable nonsolvated form or hydrate with good properties, and at a later stage, it is finding as many forms as possible in order to cover the IP situation very well." Getting the solid form right early in the process shortens development times, he explains, although it means spending money on some compounds that will fail.

Typical searches start by looking for polymorphs and hydrates; solvates are rarely used, Hilfiker says. Next on the list may be salts, which are common drug forms, and cocrystals, which are gaining interest, especially for compounds that don't form salts or are difficult to crystallize as single ingredients. Preliminary screens, company managers say, may cost from $25,000 to $50,000, and more extensive ones cost $100,000 or more.

Many custom manufacturing firms offer polymorph and salt screening services, but these are cursory relative to the resources and expertise at dedicated providers, according to people in the solid-state chemistry business community. From both scientific and business perspectives, the field is very specialized, which is a barrier to new fully committed entrants, explains Chris Frampton, chief scientific officer at U.K.-based Pharmorphix.

Sigma-Aldrich acquired Pharmorphix last year in a bid to broaden its SAFC Pharma custom manufacturing business. Since then, SAFC has added Pharmorphix's solid-form research capabilities to its high-potency compound manufacturing operations in Madison, Wis. For Pharmorphix, the acquisition broadens its reach into new geographic markets, such as Asia.

Frampton believes one of Pharmorphix's strengths is that its founders and most of its scientific team have pharmaceutical industry experience. The four-year-old company has been expanding its lab space and hopes to grow 25% to about 40 people by year-end. "But the scientists we need to recruit are from a very small sector of chemistry and physics," he acknowledges. Experienced people may already be ensconced in large companies.

Regulatory drivers, IP concerns, and issues with unstable polymorphs have contributed to the growth of the solid-state chemistry services business. Combinatorial synthesis and high-throughput screening in drug discovery, meanwhile, are yielding numerous compounds, many of which don't meet the usual criteria for being good candidates. "So you really have to push the physiochemical characteristics in order to make them developable," Frampton says.

Business is proportional to the number of compounds in development. Large companies are trying to keep compounds moving into the clinic and may pursue alternative solid forms to do so. All these drivers, coupled with a desire to explore various solid forms of these compounds earlier in development, can lead to overflow work for outside providers. Business is also coming from small drug discovery companies that don't have in-house capabilities.

"When they want to move a compound to the clinic, many small companies have no experience in what to do next," says G. Patrick Stahly, former chief operating officer of SSCI, West Lafayette, Ind., who has started his own consulting firm, Chemfocus. "In addition, their compounds may be much better candidates for licensing if they can provide a potential partner with information on developability that would aid in selecting clinical candidates."

SSCI was founded in 1991 and acquired by the drug development services firm Aptuit last year. With about 100 employees, SSCI's unique capabilities come from its R&D work on crystallization methods and analytical technologies, Stahly says. Among these are a new software approach to analyzing spectra to determine amorphous or noncrystalline content, solid-form screening in capillaries, and a high-throughput ultrasonification method particularly applicable to making cocrystals.

Another player is Pharmaterials, which was spun out of the London School of Pharmacy in 2000. The firm's work is based on the technical expertise of professor of pharmaceutics Graham Buckton, who had pioneered a number of thermal analysis and spectroscopic methods, particularly for studying the amorphous content of drug materials. Although often unstable, amorphous forms can be advantageous because they may be the most soluble form.

Buckton says companies have become more receptive to marketing amorphous forms because approaches to stabilizing them against crystallization have matured. "The first choice might be a form that's thermodynamically stable, because thermodynamics is a very comforting thing if it's on your side," he says. "The reality is that many drug candidates are so poorly soluble that you either discard them or you produce a form that will allow some kind of bioavailability."

Multitasking
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Credit: Avantium
Avantium develops high-throughput crystallization methods.
Credit: Avantium
Avantium develops high-throughput crystallization methods.

SINCE ITS INCEPTION, Pharmaterials has expanded its ability to work with different crystal forms and in drug formulation. With a staff of just 13 today, its intent is to double in size every few years, Buckton says. It has projects under way with two of the top five international drug companies, as well as a new sales office in Japan. Like its competitors, the company sees a huge potential market among small drug firms.

Solid-state chemistry capabilities typically include multiple techniques for making crystal forms and methods for analysis and characterization, company managers say. Back in 1997, the founders of Pharmorphix collaborated with Pfizer to build the first automated salt and polymorph screening system, Frampton says. Today, several laboratory equipment companies make units for conducting multiple parallel crystallization experiments.

Avantium Technologies in Amsterdam sells a unit called the Crystal16 that has 16 1-mL reactors for crystallization and solubility measurements. Internally, Avantium has more extensive and sophisticated capabilities for conducting systematic high-throughput crystallization studies for drug company clients. The firm's efforts in this area began in 2000 via a collaboration with Leiden University, the Netherlands.

Solid-state chemistry is "a field where it is good to have a second opinion," says Avantium's chief business officer, Guus Scheefhals. There are no guarantees that all crystal forms can be found and that problems won't appear down the road, but customers want confidence that a search is thorough and well-planned and covers most of the options. The number of possible experiments can quickly become unwieldy when trying to cover a variety of reaction conditions and polymorph, salt, or cocrystal forms.

"To keep up the pace with experimentation, you also need high-throughput analytics and data reporting," Scheefhals says. For example, his company has developed an efficient X-ray powder diffraction method to quickly characterize crystal forms. With interest in cocrystals expanding, and in keeping with its experimental design skills, Avantium is working with the Delft University of Technology, in the Netherlands, to develop a rational cocrystal component selection approach and a library of component compounds to use routinely in high-throughput screening.

One problem with studying solid forms early in development is the limited amounts of material that are usually available. Solid-state chemistry companies have different views on what approach to take; some prefer to do focused and limited screens, and others attempt broader screens by using small volumes and high-throughput methods. Avantium, for example, says it can conduct more than 1,000 crystallizations under different conditions on about 3 to 5 g of material.

Similarly, Symyx Technologies in Santa Clara, Calif., has developed automated high-throughput parallel crystallization systems with 96-well arrays that can perform 384 crystallizations using as little as 1 mg of compound each, explains Eric Carlson, director for Symyx Tools product development. Crystals can be made via evaporation, precipitation, controlled cooling, and slurry methods. They can then be isolated without manipulation on a substrate for in situ microscopy, XPRD, and Raman studies, followed by other spectroscopic, thermal, and physicochemical measurements. The company has sold its systems to both large and small drug companies, as well as contract research and manufacturing firms.

Solid-state specialists use the data they gather in screening and characterization studies to make recommendations to drug developers about how to move ahead. But having an optimal and well-defined crystal form is just the start. Further steps are required to develop robust, large-scale crystallization processes that can reproducibly yield the desired form. Collaborations with drug development firms often continue through production scale-up and into formulation, where the form must survive further processing.

Solid-state chemistry companies also typically offer services across the lifetime of a drug by helping with patent filings, providing litigation support, and solving problems. Some solid-state specialists work only with innovator companies, whereas others say they'll work with generic drug firms so long as conflicts can be avoided.

Innovator firms will often protect a product by finding and patenting as many crystal forms as possible; they may then consider trying to extend a product's life by launching new forms over time. In contrast, generic drug developers will seek forms the innovator didn't manage to secure; some, for example, often target an amorphous form.

"When an innovator company sees that a compound is progressing in the clinic, they are willing to invest significantly," Scheefhals says. "A pharmaceutical company may spend $1 million on getting full understanding of a compound's solid-state behavior, but the return can be significant."

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