Exploring Solid-State Chemistry - Pharmaceutical Technology

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PharmTech Europe

Exploring Solid-State Chemistry
Optimizing the solid form of a drug reaps scientific and technical awards.

Pharmaceutical Technology
Volume 32, Issue 11, pp. 58-64

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,


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).


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