3744
VARUGHESE, AZIM, AND DESIRAJU
formed by less basic heterocyclics. For the 1421 hits
for 1,2,4-triazoles in the Cambridge Structural
Database (CSD), only a very few neutral co-crystals
are reported.21 A detailed analysis of the supramo-
lecular synthons present in the crystal structures of
triazoles (with the number of chemical units >1) was
carried out. The molecular complexation of 1,2,4-
triazoles with carboxylic acids and phenols is
infrequent. However, hydrated forms of triazole with
various hydrogen bond patterns are numerous.a One
of the best examples of a pharmaceutical co-crystal
involving a 1,2,4-triazole and a carboxylic acid is the
2:1 molecular complex of the antifungal drug
itraconazole with succinic acid (SA); this complex
reportedly achieves a higher solubility when com-
pared to the crystalline drug.22 Thus, a systematic
evaluation of heterosynthons present in the co-
crystals of 1,2,4-triazoles is interesting from both
academic and commercial viewpoints. This is the aim
of the present work.
The present study focuses on synthon preferences
of the 1,2,4-triazole ring by examining the hydrogen
bonds in co-crystals of a 1,2,4-triazole containing
drug, alprazolam (ALP). This drug belongs to the
benzodiazepine class and is used to treat moderate to
severe anxiety disorders, panic attacks, and depres-
sion.23,24 ALP works by slowing down the movement
of chemicals in the brain that may become unba-
lanced, which in turn results in a reduction in nervous
tension (anxiety). Alprazolam is marketed under the
trade names Xanax, Xanor, Alprax, and Niravam and
these are among the most marketed drugs in the
United States and Europe. To develop a better
understanding of the supramolecular synthons invol-
ving the triazole fragment, we carried out several co-
crystallization experiments of ALP with carboxylic
acids, boric acid, boronic acids, sulfonic acids, and
phenols. Of the several combinations tried we were
successful in obtaining single crystals of molecular
complexes in 20% of the cases. These complexes have
been analyzed to identify novel and robust hetero-
synthons between the 1,2,4-triazole moiety and
various complementary functional groups. In this
article, we report the recognition patterns in co-
crystals of alprazolam with the following coformers:
benzoic acid (BA), 4-aminobenzoic acid (ABA), 2,6-
dihydroxybenzoic acid (26DHB), 3,5-dihydroxyben-
zoic acid (35DHB), 2,6-difluorobenzoic acid (26DFB),
3,5-difluorobenzoic acid (35DFB), oxalic acid (OA),
fumaric acid (FA), succinic acid (SA), boric acid
(BORA), 1,4-benzenediboronic acid (BDBA), 4-hydro-
xyphenylboronic acid (HPBA), hydroquinone (HQ),
and 2,4,6-trichlorophenol (TCP). Some of the binary
compounds isolated crystallized as neutral molecules.
These are referred to here as ‘‘co-crystals.’’ In some
cases, proton transfer occurs across a hydrogen bond.
These compounds are referred to as ‘‘salts.’’ Taken
together, the co-crystals and salts are referred to as
‘‘molecular complexes.’’
The motivation of the present work is structural. It
is hoped that with the information obtained in this
work, further studies can be undertaken with the aim
of using co-crystal forms of alprazolam in formulation
technologies.
EXPERIMENTAL
Materials
Alprazolam was obtained from Lupin Ltd., Pune,
India and was used without further purification.
All the coformers were obtained from either Aldrich,
Bangalore or SD Fine Chem. (India). Reagent grade
solvents were used for the co-crystallization experi-
ments. Equimolar mixtures were ground, using a
mortar and pestle, for 15 min followed by the addition
of two drops of methanol. The resulting mixture was
ground further for another 10 min. The mixture was
analyzed using powder X-ray diffraction for the
possible formation of new phases. The mixtures were
dissolved in various solvents and solvent mixtures
and the clear solution was kept for slow evaporation.
Crystals formed over a period of a fortnight were
analyzed using single crystal X-ray diffraction.
Powder X-Ray Diffraction (PXRD)
X-ray powder diffraction data were collected in the
Indian Institute of Science on a Philips X’pert Pro
X-ray powder diffractometer equipped with X’cellera-
tor detector. The scan range, step size, and time
per step were 2u ¼ 5.00 to 408, 0.028, and 25 s,
respectively.
Single Crystal Diffraction (SXRD)
Single crystals were carefully chosen after viewing
through an Olympus microscope supported by a
rotatable polarizing stage and a CCD camera. The
crystals were cleaned thoroughly and glued to a thin
glass fiber using an adhesive (cyanoacrylate) and
mounted on a diffractometer equipped with an APEX
CCD area detector. Data were collected both in the
University of Hyderabad and in the Indian Institute
of Science. Normal methods were employed for crystal
handling and data collection, except that the crystals
were smeared in cyanoacrylate to protect them from
ambient laboratory conditions. The intensity data
were processed using the Bruker suite of data
processing programs (SAINT), and absorption correc-
tions were applied using SADABS.25 The structure
solution was carried out by direct methods,
aORTEP diagram of molecular complexes, experimental details,
crystallographic information, hydrogen bond table, the synthons
present in various 1,2,4-triazole rings and additional information
are given in the supplementary information.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
DOI 10.1002/jps