Mechanochemical synthesis and structural characterisation of a theophylline-benzoic acid cocrystal (1:1)

Article abstract of DOI:10.1039/c2ce25236h

The structure of a mechanochemically synthesised cocrystal containing theophylline (TP) and benzoic acid (BA) has been determined from powder X-ray diffraction data.

Full text of DOI:10.1039/c2ce25236h

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COMMUNICATION
Mechanochemical synthesis and structural characterisation of a
theophylline-benzoic acid cocrystal (1 : 1){
Sebastian Heiden, Lisa Tr o¨ bs, Klaus-J u¨ rgen Wenzel and Franziska Emmerling*
Received 17th February 2012, Accepted 31st May 2012
DOI: 10.1039/c2ce25236h
The structure of a mechanochemically synthesised cocrystal
containing theophylline (TP) and benzoic acid (BA) has been
determined from powder X-ray diffraction data.
assisted grinding are promising techniques for screening of new
16,18
cocrystals.
grinding at 30 Hz in a ball mill (MM400, Retsch, Germany) for
5 min. A 10 mL steel vessel was used with three steel balls
The title compound was synthesised by neat
2
Cocrystals are molecular complexes of two or more uncharged
1–4
solid organic compounds.
(10 mm) for a total load of 1 g. Theophylline (99%, Sigma Aldrich,
Germany) and benzoic acid (99,5%, Acros Organics, USA) were
purchased commercially and were used without further purifica-
tion. The completeness of the reaction was confirmed by X-ray
diffraction (XRD), no residues of the reagents were present in the
final powder (Fig. 2). Further experiments showed that reaction
was completed within 10 min. The XRD measurements were
performed on a D8 diffractometer (Bruker AXS, Karlsruhe,
In the context of pharmaceutical
research, cocrystallization is typically used with the intent to
enhance physicochemical properties of drugs. The resulting
compounds exhibit considerable advantages compared to salts
1,5
and solvates/hydrates. Cocrystallization can improve properties
of active pharmaceutical ingredients (APIs), i.e. their stability,
solubility, dissolution rate and bioavailability.
6
Theophylline (TP) is an API which is used in asthma-therapy
7
and the fight against chronic obstructive pulmonary disease. The
Germany) in transmission geometry (Cu-Ka
1
radiation, l =
˚
1.54056 A). Structure determination was carried out based on the
bioavailability of the amphoteric TP is limited by its low solubility.
Hence, the synthesis of its cocrystals with acids and bases can
increase its solubility. The structure of TP has great potential to
form stable cocrystals, assuming that the carbonyl groups and
aromatic nitrogen atoms participate in hydrogen bonds with the
cocrystal former (Fig. 1). Examples for cocrystals containing TP
powder XRD pattern. Indexing and structure calculation were
19
performed using the open source program FOX. .{ The unit cell
and space group were confirmed using CHEKCELL. FOX uses
20
global-optimization algorithms to solve the structure by perform-
ing trials in direct space. This search algorithm uses random
sampling coupled with simulated temperature annealing to locate
the global minimum of the figure-of-merit factor. To reduce the
total number of degrees of freedom, parts of the molecule were
refined as a rigid group. The whole theophylline molecule was set
rigid, while benzoic acid was set rigid with the exception of the
carboxyl oxygen and hydrogen atoms. The crystal structure of the
cocrystal was solved by the simulated annealing procedure on a
standard personal computer within 6 h, finding the deepest
minimum of the cost function several times during the procedure.
To complete the structure determination, the structural solution
obtained from MC/SA was subsequently subjected to a Rietveld
8–10
are discussed in the literature.
In this work, benzoic acid (BA) is
used to form a cocrystal. The DpK value serves as an indicator for
a
the possibility of cocrystallization. Formation of a cocrystal is
favoured whenever the difference of the pK values is lower than 0.
a
For a combination with DpK
a
. 0 the formation of salts is also
Since the measured pK value of BA is 4.19 and that
of the conjugated acid of TP is 0.5, the DpK value of TP:BA is
This indicates a strong tendency of the two compounds
11,12
possible.
a
a
12,13
23.69.
to form a cocrystal. This assumption was verified by Childs et al.
who identified the respective cocrystal based on IR measure-
1
2
ments. However, the crystal structure has not been reported yet.
This communication focuses on the structural determination of
the cocrystal TP:BA, which was synthesized mechanochemically.
Different crystallization methods are applied for cocrystallisation,
2
1
refinement employing the TOPAS software. Fig. 3 shows the
result of the Rietveld refinement illustrating the agreement of the
1
4
for example sonochemical approaches, as well as cocrysta-
16,17
1
5
llization from solution and mechanochemical
synthesis. In
mechanochemical experiments both neat grinding and liquid
BAM Federal Institute for Materials Research and Testing, Richard-
Willstaetter-Strasse 11, 12489, Berlin, Germany.
E-mail: franziska.emmerling@bam.de; Fax: +49 30/8104-1137;
Tel: +49 30/8104-1133
{
Electronic supplementary information (ESI) available. CCDC reference
number 868252. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2ce25236h
Fig. 1 Molecular diagram of theophylline (left) and benzoic acid (right).
This journal is ß The Royal Society of Chemistry 2012
5
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Fig. 2 Powder XRD patterns of the synthesised cocrystal TP:BA (green)
and educts TP (blue) and BA (black). Background contributions of the
sample holder were corrected.
Fig. 4 Dimer of TP and BA (top) and layered cocrystal structure of
TP:BA seen from the b–c plane (bottom). The hydrogen atoms not
involved in the hydrogen bonding were omitted for clarity. Dashed green
lines indicate hydrogen bonds.
References
{ Powder pattern were collected using a Bruker D8 Discover (Bruker AXS
GmbH, Germany) operated in transmission geometry and equipped with a
Lynxeye detector. The samples were measured over a range of 5–60u 2h
2
1
˚
(
2 kW; Cu-Ka, 1.54056 A, step width 0.009u, count time 20 s step ). Unit
˚
1
cell parameter for TP:BA: monoclinic, P2 /n, a = 6.98690(17) A, b =
3
˚ ˚ ˚
5.10944(84) A, c = 8.60685(30) A, b = 108.5597(18), V = 1431.431(78) A .
2
1
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2
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p
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TP:BA crystallizes in the monoclinic space group P2 /n. TP and
1
BA molecules form pairs connected via two strong hydrogen
bonds. One hydrogen bond is formed between the carbonyl group
…
˚
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…
˚
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along the a-axis (Fig. 4). The p–stacking of the phenyl ring of BA
and of the six membered ring of TP is collinear to a, with a
5
1
1
1
˚
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2
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In summary, the mechanochemical synthesis proved to be a fast
and successful approach towards the synthesis of cocrystals. It
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grinding for a few minutes. The crystal structure of the new
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