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Optimizing the solid form of a drug reaps scientific and technical awards.
Solid-form characterization and research are important for improving the understanding of and modifying the physical properties of active pharmaceutical ingredients (APIs) to ensure therapeutic benefit, optimize product development, and protect intellectual property. Early in drug development, the primary goal is to find a stable form of the drug, but the potential patentability of other solid forms offers further opportunities in maintaining product exclusivity or for product extension. Solid-state chemistry is of growing importance not only for pharmaceutical companies in their drug development, but also for contract manufacturers and specialists serving the pharmaceutical industry.
Patricia Van Arnum (GLOW IMAGES/GETTY IMAGES)
Polymorphs: key considerations
Screening for and identifying polymorphs when developing and manufacturing APIs is an ongoing challenge for pharmaceutical manufacturers. Polymorphism is the ability of a compound to exist in more than one crystalline structure. Polymorphs or other solid forms are identified using a polymorph study or screen (1). Different solid forms can possess different properties, including solubility, which, in turn, can affect the bioavailability of the drug.
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One of the more well-chronicled examples of polymorphism occurred in ritonavir, the API in "Norvir," a protease inhibitor developed by Abbott Laboratories (Abbott Park, IL). The drug was approved in 1996, and in mid-1998, Abbott encountered manufacturing difficulties with the capsule formulation, according to the company's 1998 annual report. Ritonavir exhibited conformational polymorphism of two unique crystal lattices that had significantly different solubility properties (2). The formation of the polymorph caused Abbott to pull the drug from the market and reformulate.
A recent analysis by SSCI, the solid-state chemistry business of Aptuit (Greenwich, CT), showed that of 245 compounds it screened, 89% had multiple solid forms. Approximately 50% of the compounds showed polymorphism, 37% were hydrates, and 31% were solvates (2). Other research conducted by Professor Ulrich Griesser at the University of Innsbruck shows a lower incidence of multiple solid forms in organic molecules: polymorphism (36%), hydrates (28%), and solvates (10%) (1, 3).
CMOs launch solid-state services
The prevalence of polymorphism and the challenge in screening and detecting them has led several contract manufacturing organizations (CMOs) to launch solid-state chemistry services. Almac Sciences (Craigavon, Northern Ireland) is the latest to do so. The company announced the launch of its solid-state chemistry business at CPhI Worldwide, which was held in Frankfurt last month. Almac's solid-state chemistry team, housed at the company's Craigavon, facility, specializes in solid-form characterization, screening and selection, and crystallization process development.
"By exploring polymorphs, salts, cocrystals, and amorphous materials, Almac can dramatically improve the characteristics of APIs," said Linda McCausland, group leader of physical sciences at Almac Sciences, in a Oct. 1, 2008 company press release. "A variety of screening methods are employed to discover new solid forms. These may provide improvement in properties such as increased solubility, bioavailability, and stability."
SAFC (St. Louis, MO), which acquired the solid-state services firm Pharmorphix in 2006, announced the second phase of a $600,000 expansion of the Pharmorphix facility in Cambridge, England, earlier this year. The company added 7500 ft2 of laboratory capacity to augment the existing 12,500-ft2 facility. The multiphase development program includes office reorganization and the installation of additional spectroscopic and diffraction equipment.
Xcelience (Tampa, FL), a provider of early drug-development services, announced in May 2008 that it added X-ray diffraction (XRD) services to its preformulation- and formulation-
development capabilities. "At the urging of several of our clients, we have committed to the purchase of an XRD instrument to enhance our overall capabilities in formulation analysis, polymorph identification, salt screen and selection, and crystallinity determination," said Mark Cappucci, team leader for preformulation and formulation of Xcelience, in a May 6, 2008 company press release.
Pharmaterials (Reading, England) is another specialist in solid-state chemistry that was the recent acquisition target by a CMO. Pharmaterials was founded in January 2000 by Professor Graham Buckton as a spinout company from the London School of Pharmacy. In January 2008, the CMO Pharmaceutics International (PII, Hunt Valley, MD) acquired Pharmaterials, which later this year added to its capabilities in polymorph screening. In August 2008, the company announced it had commissioned and tested additional XRD equipment. Pharmaterials worked with the analytical instrumentation company PANAlytical (Lelyweg, The Netherlands) to develop a 96-well plate transmission system that allows for rapid reading of its screening plates as a primary screen for polymorphism. Working alongside the previous capability for powder diffraction and single crystal X-ray studies, this new instrument provides rapid and sensitive sample handling, according to the company. Data can be generated with a small sample mass and the instrument can detect and quantify 1% amorphous content in crystalline samples.
Adding solid-state services was also an objective of Aptuit (Greenwich, CT), which acquired the solid-state chemistry company SSCI in 2007. With the acquisition, Aptuit gained SSCI's 100 employees and facilities in West Lafayette, Indiana; Atlanta, Georgia and Oxford, England.
With CMOs interested in adding solid-state services to their toolboxes, certain specialists have made their commitment to stay independent be known. For example, in June 2008, Tom van Aken, CEO of Avantium Technologies (Amsterdam) affirmed the company's commitment to offering solid-state services following the company's withdrawal of an initial public offering in November 2007. Avantium specializes in high-throughput screening, combinatorial catalysis, and solid-state chemistry.
"In 2006 and 2007, most of our competitors became part of large contract service organizations with a 'one-stop-shop' philosophy," van Aken said in a June 20, 2008 company press release. "We have been and remain a true specialist in the area of crystallization research. Moving forward, we expect to expand our business with biotech companies and midsize pharmaceutical companies while continuing to augment the capabilities of large pharma companies, especially for comprehensive solid-form screens."
Academia is also getting involved. In July 2008, the Solid State Pharmaceuticals Cluster (SSPC) was launched at the University of Limerick in Ireland. The research group supports pharmaceutical companies in Ireland. "The combined expertise and background knowledge of the cluster enables the development of a research area in Ireland which supports the pharmaceutical industry by developing the expertise, research, and capacity to understand, generate, design and optimize processes to manufacture solid-state pharmaceuticals to meet the demands of advanced formulation and drug delivery systems," said Professor Kieran Hodnett, dean of the faculty of science and engineering at the University of Limerick and project leader of SSPC, in a July 2008 university press release. "Researchers will study, in a fundamental manner, properties of pharmaceutical solids that have a definite impact on performance characteristics, e.g., random variability of flow characteristics from batch to batch leading to handling failures at the formulation stage."
SSPC is providing training to the PhD level in pharmaceutical solids. "The training will come from the best academic and industrial laboratories in this country and overseas and will provide an exciting mixture of academic and industrial experience as a preparation for a career in this industry," said Hodnett. "It will address the severe and growing shortage of PhD graduates in the areas of physical chemistry, chemical and mechanical engineering, and pharmaceutics. Industry sources point to the lack of skilled graduates in all the technical areas dealing with pharmaceutical solids, and this shortfall is a definite impediment to the Irish industry in its collective ambition to move back along the value chain within their companies and increase competitiveness," he said.
Analytical methods for polymorphs
X-ray powder diffraction (XRPD) is the most common analytical method used in polymorph screening. In a typical study, a crystallographer places a compound in a range of solvents and subjects them to a range of crystallization conditions in hopes of obtaining single crystals. The number of solvents used in the screening varies. A small polymorph screen should include 8–10 solvents, but a more complete screen may involve more than 50 solvents (2). In recent research, Xu and Redman-Furey outlined an approach to narrow their selection of 57 solvents to 20 (2, 4). In a related study, Miller suggested an approach of finding the most stable polymorphs by slurring compounds in a variety of solvents (2, 5).
Although XRPD is the most common technique used in the overall solid-state characterization of pharmaceutical materials, other techniques are needed to understand the form, determine how it behaves under stress conditions, discern the relationship between forms, and decide which form is suitable for development. Although a powder pattern can indicate if the compound is crystalline, it may not provide critical information such as solvation state, melting point, water uptake, solubility, and physical stability. Thermal data such as differential scanning calorimetry, thermogravimetry, and hot-stage microscopy are used to determine melting temperature, solvation state, desolvation, and form changes upon drying (2).
Gravimetric vapor sorption is used to measure water sorption and desorption, which can lead to environmental handling guidelines to prevent hydrate formation or dehydration upon exposure to various relative humidity conditions. Other methods such as infrared, Raman, and nuclear magnetic resonance (NMR) spectroscopies can often show specificity between forms that may be more difficult to see with XRPD (2).
Intellectual property concerns
Aside from the technical and scientific considerations in developing solid forms, legal issues are also important. Recent research by Andrew Trask, PhD, and intellectual property legal intern with the law firm Jones Day offered a perspective on how the developing field of cocrystallization may affect the intellectual property landscape of the pharmaceutical industry (6). In his research, Trask explains that cocrystals may present unique scientific and regulatory advantages and, therefore, distinct intellectual property challenges and opportunities. He defines a cocrystal as "a distinct solid-state material with, in general, a unique and unpredictable structure and physical property profile" (6). A broad definition of cocrystals or "crystalline molecular complexes" encompasses hydrates and solvents. The patentability of cocrystals, or any patent for that matter, depends on three criteria: novelty, utility, and nonobviousness (6).
In his research, Trask points out that as new and distinct solid-state structures, cocrystals should satisfy the novelty requirement for patentability equally as well as salts. The prevalence of patents relating to salts (estimated at more than 24,000 issued US patents) far exceeds the number of patents for cocrystals, but this should not affect patentability.
In terms of utility, a cocrystal of an API generally shares the patentable therapeutic utility of its parent API. The cocrystal, many in fact, offer better utility by offering improved performance in solubility, bioavailability, and physical stability and may enhance other properties such as hygroscopicity, chemical stability, compressability, and flowability. Also, given current challenges of cocrystal prediction, Trask points out that cocrystals are likely to be regarded as nonobvious from a general patentability perspective (6).
By offering a framework for patentability, pharmaceutical cocrystals can offer certain commercial advantages. Trask points out in his research that patent claims concerning the chemical structure of an API represent the primary patent protection for a commercialized drug product, but in certain cases, additional patent protection can be obtained by patenting novel solid forms of the API (6). Solid-form screening, therefore, becomes an important element in the patent strategy for a given API not only in development but also possibly in product-life extension. Trask notes that pharmaceutical cocrystals have not been officially addressed in terms of generic drug approvals, but that the issue of whether a new cocrystal of a commercial API may have a pathway for regulatory approval as an abbreviated new drug application would impact the value of cocrystal technology to the generic drug industry (6).
Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, firstname.lastname@example.org
1. S. Byrn, K. Morris, and S. Comelia, "Reducing Time to Market with A Science-Based Product Management Strategy," Pharm. Technol. 29 (8) supp. "Outsourcing Resources," s46–s56 (2005).
2. P. Van Arnum, "Advancing Approaches in Polymorphism," Pharm. Technol. 31 (9) supp. "Pharmaceutical Ingredients," s18–s23 (2007).
3. U. Griesser, "Relevance and Analysis of Polymorphism in Drug Development," presented at the British Association of Crystal Growth Spring Meeting, Lancaster, UK, Apr. 4–6, 2006.
4 D. Xu and N. Redman-Furey, "Statistical Cluster Analysis of Pharmaceutical Solvents," Intl. J. of Pharm. 339 (1–2), 175–188 (2007).
5. J.M. Miller et al., "Identifying the Stable Polymorph Early in the Drug Discovery-Development Process," Pharm. Dev. Technol. 10 (2), 291–297 (2005).
6. A.V. Trask, "An Overview of Pharmaceutical Cocrystals as Intellectual Property," Mol. Pharmaceutics 4 (3), 301–309 (2007).