The elusive structure of the antihistamine Levocetirizine determined by electron diffraction
For pharmaceuticals, knowing the chemical composition is not
enough—molecular geometry and crystal structure also play an important
role in a drug’s activity. By using a method based on electron
diffraction, it has now been possible for a research team to determine
the structure of Levocetirizine, as reported in the journal Angewandte Chemie. The advantage of this technique is that, unlike for X-ray crystallography, nanoscale crystals are sufficient.
© Wiley-VCH, re-use with credit to 'Angewandte Chemie' and a link to the original article.
Despite being chemically identical, many pharmaceutical substances
may adopt different crystal structures or form cocrystals with an
additive. This can significantly influence the properties of a drug,
such as bioavailability, solubility, stability, and tabletability.
Structural determinations are correspondingly important in the
development of advanced solid pharmaceuticals.
Today, the standard and routine method for determining the
three-dimensional structures of crystalline molecules and biological
macromolecules with atomic resolution is single-crystal X-ray
diffraction structure analysis (SCXRD). The atoms within the crystal
diffract the X-ray radiation, forming a diffraction pattern from which
the positions of the individual atoms in the structure of the crystal
can be calculated. This requires sufficiently large, well-diffracting
single crystals. However, many compounds are difficult or impossible to
crystallize. An alternative method is powder X-ray diffraction (PXRD),
which can analyze a sample in the form of a powder. However, the data
analysis is not straightforward and if the sample is a mixture of
several phases of the same or different compounds, it is very difficult
and often ambiguous.
A more recent technique is 3D-electron diffraction/micro-crystal
diffraction (3D ED/MicroED). Instead of X-rays, electron beams from an
electron microscope are diffracted. Because the interaction of matter
with electrons is significantly stronger than interactions with X-rays,
sub-micro to nanometer-sized crystals produce diffraction patterns that
can be evaluated and direct analysis of components in microcrystalline
mixtures becomes possible.
A team led by Durga Prasad Karothu and Panče Naumov has used 3D
ED/MicroED to determine the structure of Levocetirizine dihydrochloride.
Levocetirizine is an over-the-counter oral antihistamine used to treat
allergy symptoms such as hay fever and hives. Although it has been in
broad use, its crystal structure has remained unknown because no
crystals good enough for X-ray crystallographic analysis could been
grown. Recently, the structure of this medication was studied using
powder X-ray diffraction and computer calculations—but uncertainty and
ambiguity remained.
The team at New York University Abu Dhabi (United Arab Emirates),
Rigaku Europe SE (Neu-Isenburg, Germany), and New York University (New
York, USA) worked with crystals obtained by grinding commercially
available tablets. In addition to determining the drug’s crystal
structure, they were able to use a special evaluation process (dynamical
refinement) to unambiguously determine the absolute configuration (the
exact spatial arrangement of all atoms within the molecule) of
Levocetirizine.
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About the Author
Dr. Durga Prasad
Karothu is a Senior Research Scientist in the Center for Smart
Engineering Materials (CSEM) working with Professor Panče Naumov
(Director) at New York University Abu Dhabi. His research focuses on the
development of organic-based smart materials, organic solid-state
chemistry, (photo)crystallography, and electron diffraction. He is the
recipient of the Rising Star Award from the Asian Crystallographic
Association (AsCA) for the year 2022.