Crystallization in thermodynamic conditions, however, afforded the same product when a proper amount of water was present,
points out von Raumer. This product was not hygroscopic, was stable, and its water content determined by KF was about 20%.
Crystallization under kinetic conditions, especially when the water activity in the medium was poor, afforded a hygroscopic
product with KF lower than 20%. This product was not stable and converted under appropriate conditions into a stable product
with KF of approximately 20% and XRPD and Raman results identical with the precipitated product. All the products obtained
from crystallization trials that gave KF around 20% displayed the same XRPD spectrum.
"According to the above experiments, it was proven that andolast disodium crystallized in only one preferred hydrated form:
the penthaydrate. All other hydrated forms were not stable and converted under appropriate conditions into the pentahydrate,"
notes von Raumer. "The single-crystal structure was resolved, and molecular-mechanics simulation showed that, upon water removal,
a certain degree of distortion was introduced within the crystal structure, with the distortion being proportional to the
number of water molecules removed."
From this solid-state study, a new crystalline form, andolast pentahydrate, was revealed, which displayed certain superior
properties, says von Raumer. Andolast pentahydrate is not a hygroscopic solid, is stable to mechanical milling, and is stable
to as much as 85% relative humidity. It also can consistently be prepared according to a standard process, has constant mechanical
properties such as flowability, and has advantages in formulation in comparison with previous material because of a better
performance in delivered dose, fine particles delivered, and fine-particle fraction. Aside from improved performance, the
new crystalline form of andolast also led to patent applications in the United States and Europe (13, 14). The European patent
application calls for an expiration date of 2026 compared with the original expiration date of 2010 that is specified in an
earlier patent (15).
"While the development of the andolast drug product was hampered due to inconsistencies and was slowed down by a non-negligible
factor, the actual situation allows for a rapid continuation with a possibly much longer time horizon of exclusivity," says
von Raumer. "This situation once again demonstrates the utility and opportunities that are created by carefully investigating
the solid-state aspects of drug candidates."
Analytical methods for polymorphs
XRPD is the most common analytical method used in polymorph screening, although certain researchers use Raman spectroscopy
as their primary screening method. "Each method has its value, and more recently SAFC-Pharmorphix has been experimenting on
the use of both methods in combination for polymorph and cocrystal screening using a combined X-ray powder diffractometer
with a Raman attachment," says Frampton. "This instrument has been developed in collaboration with Bruker AXS, and a patent
covering this technology has recently been published (16). This technology has been further enhanced by a new release of the
clustering program, Polysnap2, which can cluster any two-dimensional data and produce weighted combinations." SAFC-Pharmorphix
has an active collaboration with Professor Chris Gilmore and his group at the University of Glasgow (Glasgow, UK).
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, Aptuit's Byrn explains. He points out that the number of solvents used in
the screening varies. A small polymorph screen should include 8–10 solvents (17). "A more complete screen would require more
than 50 solvents," he adds. In recent research, Xu and Redman-Furey outlined an approach to narrow their selection of 57 solvents
to 20 (18). Byrn points out that in a related study, Miller suggested an approach of finding the most stable polymorphs by
slurring compounds in a variety of solvents (19).
"We now know that solvent-based crystallizations alone do not find all of the forms. In several cases, solvent-based polymorph
screens have missed very important solid forms," explains Byrn. In another example, Yu discovered the second most stable form
of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) using a melt-recrystallization technique (20). "It is
well established that ROY had previously been screened by all of the best-known high-throughput techniques, and this form
had not been found," explains Byrn, adding, solvent-free techniques such as drying, sublimation, and amorphous crystallization
can produce new forms not discovered by solvent-based crystallization.