Two different crystalline forms of aspirin in
intergrown domains.
When you get a headache, you probably reach for
aspirin. What is giving researchers a headache is the question of the
crystal structure of aspirin. Is there another form on top of the
long-known one? A team of scientists from Denmark, Germany, and India
seems to have solved this controversial puzzle: yes, there is a second
structure - but it does not exist as a pure form. "The two crystalline
forms of aspirin are so closely related," explains the research team
of Andrew D. Bond, Roland Boese and Gautam R. Desiraju in Angewandte
Chemie, "that they form structures containing domains of both crystal
types."
In 2004, computer calculations had indicated that
while the long-known crystal structure of aspirin (form I) is
definitely one of the most stable forms, another version might exist
that is just as stable, though it had not yet been discovered - a
clear challenge to researchers in the field. The difference between
the proposed structures is slight: both have identical layers
containing molecules grouped into pairs, but these layers are arranged
differently in the two different structures. In 2005, researchers in
the USA announced the discovery of the predicted structure (form II).
But was this merely an artifact?
"We can now clear this matter up," say Bond, Boese
and Desiraju, after very careful examination of aspirin crystals.
"Aspirin has a tendency to crystallize with an
unusual intergrown structure. The same single crystal contains domains
with both arrangements lying side by side." The distribution and ratio
of the domains are variable but limited. Whereas a pure form I exists,
it has so far only been possible to obtain crystals containing a
maximum of 85 % form II. The ratio of the two domains within crystals
produced under identical conditions seems to be roughly constant.
This discovery upends fundamental principles and
requires new concepts: chemists previously understood "polymorphism"
to mean that a molecule can take on one or another packing arrangement
in the crystalline state; a single crystal of a specific chemical
substance is either one polymorph or the other. Aspirin is the first
case in which two different "polymorphic" structures exist in one
single crystal. So is aspirin polymorphic or not? Should the
definition of polymorphism be updated? Such questions are not just
philosophical in nature, but could have tangible implications in
patent law, because each polymorph of a compound is viewed as a
separate patentable substance.
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