Exploring Solid-State Chemistry

Optimizing the solid form of a drug reaps scientific and technical awards.
Nov 02, 2008
Volume 32, Issue 11

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.

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.

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.

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