Advances in Solid-State Chemistry - Pharmaceutical Technology

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PharmTech Europe

Advances in Solid-State Chemistry
Industrial and academic partnerships forge new territory in solid-state chemistry.

Pharmaceutical Technology
pp. 60-64

In October 2010, Avantium Pharma (Amsterdam) announced its participation in a consortium consisting of the Institute of Process Research & Development (iPRD) and pharmaceutical and fine-chemical companies. The consortium is supported by a grant from the British government-backed Technology Strategy Board. Avantium, which specializes in high throughput crystal screening, is contributing the use of a medium-throughput crystallizer (i.e., Crystal16) for use at the University of Leeds in Scotland for a research program focused on process integration and product enhancement using crystal-growth modifiers. The Crystal16 covers a wide range of heating and cooling rates, is good for solubility and dissolution studies, and can operate using as little as 0.5 mg of sample per reaction. Avantium developed the instrument to meet a need to secure crystallization information on small amounts of sample. The company is also using the Crystalline PV to measure the real-time effect of crystal-growth modifiers.

In November 2009, Avantium and Avant-garde Materials Simulations (AMS, Freiburg, Germany) formed a collaboration to develop and commercialize crystal-structure prediction services. Under the agreement, AMS develops software to accelerate the calculations and broaden the range of compounds that can be studied. AMS also performs the predictions for third parties. Avantium develops experimental strategies to physically generate predicted crystal forms and commercialize the crystal structure prediction service.

These offerings include computational polymorph prediction services. The computational results can be used for various purposes: a confirmation of experimental results, as a guide during experimental screening, and to understand the crystal structures of the polymorphic forms generated. Multiple component crystals (hydrates, solvates, and cocrystals) can be handled as well (1).

Crystal-structure prediction is an important aspect of drug analysis. It allows a researcher to search through crystal structures and evaluate their free energies accurately as a function of temperature and pressure to obtain the global minimum energies of optimal crystal structures. The crystal-structure prediction process starts with the generation of millions of trial crystal structures, followed by the optimization of these structures, and their ranking according to their lattice energy as a first approximation to the lattice free energy. The crystal structure with the lowest lattice energy is expected to correspond to the most stable polymorph that can be found experimentally. The differences between the stable and metastable forms is typically on the order of only a few kJ/mol (1).

Generally, lattice-energy ranking is based on molecular mechanics and generic forcefields. Under this approach, molecules are modeled as balls and springs, representing the atoms and bonds. The forcefield is a large table that describes the balls' and springs' intramolecular behavior during bond stretching, bond bending, out-of-plane bending, and torsional rotation. The intermolecular interactions are described as charge–charge interactions and induced dipole–dipole interactions (van der Waals interactions). These forcefields are based on empirical data with fitted parameters. Forcefields are meant to be generic and describe a lot of different situations. Because the problem of crystal-structure prediction requires very accurate energy rankings, it turns out that the precision and accuracy of these forcefields is not sufficient (1).

The approach forward by AMS and Avantium, however, does not use generic forcefields. Advanced quantum-mechanical calculations (dispersion-corrected density functional theory or d-DFT) are used instead to develop a forcefield that is customized specifically for the molecule at hand (1–3). This forcefield is then used in the geometry optimization of the thousands of crystal structures generated. The most promising structures with the lowest lattice energy are reranked with d-DFT, which results in an energy ranking to provide the computational results.

A blind test of crystal-structure prediction technology is organized every two to three years by the Cambridge Crystallographic Data Center. The results of the 2007 blind test showed that the approach developed by Marcus Neumann with AMS in cooperation with F. Leusen and J. Kendrick from the Institute of Pharmaceutical Innovation at the University of Bradford in the United Kingdom generated and optimized the crystal structures using the quantum mechanics-derived forcefields followed by final energy ranking using the d-DFT calculations, allows for the accuracy required (1, 4, 5).

Earlier this year, Aptuit (Greenwich, CT) announced that it had developed a proprietary production screen for use in solid-state chemistry applications to enable a better understanding of the AP and drug formulations earlier in the product life cycle. The production screen examines and measures the effects of temperature, humidity, and other physical stresses on the solid form of a drug—the API, excipients, or the API–excipient form. It can be tailored to small or large molecules. "Scale-up, in particular, introduces mechanical stresses to a compound which can create issues related to the stability and integrity of the drug," said Jan-Olav Henck, senior director of scientific operations and site director at Aptuit's facility in West Lafayette, Indiana, in a Feb. 17, 2010 press release.

Researchers at Aptuit recently reported on research that describes the solid-state characterization of three forms of finasteride. The study outlined a systematic approach to characterizing a set of solvated APIs and evaluated the solid-state behavior of each. The researchers' initial efforts were to determine the approximate solubility for subsequent solid-form screens on finasteride. In researching this, they observed recrystallization properties that prompted the study and proceeded to generate, characterize, and investigate the solid-state behavior of three finasteride solvates. The study found that the newly observed finasteride forms were isostructural members to an already existing family of isostructural, finasteride solvates. The study determined how each of the solvated forms could be converted to other forms through standard manufacturing processes, according to a December 2009 press release.

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. P. Van Arnum, Pharm. Technol. 33 (12), 34–35 (2009).

2. M.A. Neumann and M.A. Perrin, J. Phys. Chem. B, 109 (32), 15531–15541 (2005).

3. M.A. Neumann, J. Phys. Chem. B, 112 (32), 9810–9829 (2008).

4. M.A. Neumann, F.J.J. Leusen, and J. Kendrick, Angew. Chem. Int. Ed. 47 (13), 2427–2430 (2008).

5. G.M. Day et al., Acta Cryst. B 65 (2) 107–125 (2009).


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