Crystal engineering of multiple-component organic solids: Pharmaceutical cocrystals of tadalafil with persistent hydrogen bonding motifs

Article abstract of DOI:10.1039/c2ce06574f

Pharmaceutical cocrystals of tadalafil with methylparaben, propylparaben and hydrocinnamic acid have been prepared and characterized. The crystal packing observed in the three resulting cocrystals reveals that tadalafil molecules form persistent hydrogen-

Full text of DOI:10.1039/c2ce06574f

View Article Online / Journal Homepage / Table of Contents for this issue

Dynamic Article Links <
C
CrystEngComm
Cite this: CrystEngComm, 2012, 14, 2377
www.rsc.org/crystengcomm
COMMUNICATION
Crystal engineering of multiple-component organic solids: Pharmaceutical
cocrystals of tadalafil with persistent hydrogen bonding motifs†
a
a
a
David R. Weyna, Miranda L. Cheney, Ning Shan, Mazen Hanna,a qukasz Wojtasb
*
b
*
and Michael J. Zaworotko
Received 23rd November 2011, Accepted 15th December 2011
DOI: 10.1039/c2ce06574f
become evident that crystal engineering facilitates the discovery of
pharmaceutical cocrystals and that resulting property enhancements
can be significant enough to be clinically relevant. In this contribu-
tion, we report the application of crystal engineering to the synthesis
of tadalafil cocrystals and address the crystal packing in the resulting
cocrystals.
Pharmaceutical cocrystals of tadalafil with methylparaben, pro-
pylparaben and hydrocinnamic acid have been prepared and char-
acterized. The crystal packing observed in the three resulting
cocrystals reveals that tadalafil molecules form persistent hydrogen-
bonded chains which accept additional hydrogen bonds from the OH
moieties of the respective coformers.
Tadalafil (TDF, Fig. 1) is currently used for the treatment of
erectile dysfunction (ED) under the brand name Cialisꢀ. TDF is
a cGMP (cyclic gaunosine monophosphate) specific phosphodies-
terase 5 (PDE5) inhibitor.17,18 This medication stops the breakdown
of cGMP in endothelial cells in the corpus cavernosum of the penis by
inhibiting PDE5. This effect results in vasodilation and a subsequent
increase of blood flow into the corporus cavernosum leading to penile
erection upon sexual stimulation.19 TDF is also currently being
investigated as a treatment for pulmonary arterial hypertension.20,21
For ED treatment, TDF is manufactured as a tablet for daily use (2.5
and 5 mg) with doses ranging from 5 up to 20 mg as needed. Among
the PDE5 inhibitors that have been approved and marketed, TDF
exhibits a longer half life22 but possibly a slower onset of action.23 The
slower onset could be caused by its low aqueous solubility. TDF,
It is well recognised that the supramolecular interactions in crystalline
organic solids can profoundly impact the physicochemical properties
of a particular crystal form.1,2 Crystal engineering has been employed
as a useful tool for the synthesis of crystal structures with desired
supramolecular arrangements.3,4 However, the ultimate goal of
crystal engineering is to synthesize pre-designed crystal structures
with desirable properties that are based solely on the knowledge of
the molecular components.3 In this context, the ‘‘supramolecular
synthon approach’’, in which structure and composition of multiple
component crystals are controlled using previously identified robust
intermolecular interactions, has proven to be a particularly reliable
strategy.5–7 In the context of pharmaceutical science, crystal engi-
neering has been successfully employed for the discovery of phar-
maceutical salts8 and cocrystals9–12 of active pharmaceutical
ingredients (APIs), thereby creating opportunities to fine tune the
physicochemical and pharmacokinetic properties of the APIs. Car-
bamazepine, for example, forms cocrystals with a variety of
carboxylic acids and amides because of the self-complementary
nature of amide-carboxylic acid and amide-amide functional
groups.13 As a result, a series of carbamazepine cocrystals were
synthesized and characterized.14 Among those novel crystal forms,
the cocrystal of carbamazepine and saccharin exhibited significantly
improved physical stability and favourable pharmacokinetics in dogs
compared to the original API.15 The cocrystal of carbamazepine and
nicotinamide also exhibited superior physical properties.16 It has now
aThar Pharmaceuticals Inc, 3802 Spectrum Boulevard, Suite 120, Tampa,
Florida, 33612, USA. E-mail: nshan@tharpharma.com; Tel:
+1-813-978-3980
bDepartment of Chemistry, University of South Florida, 4202 East Fowler
Avenue, CHE205, Tampa, Florida, 33620, USA. E-mail: xtal@usf.edu
† Electronic supplementary information (ESI) available: Experimental
methods for synthesis, characterization and CSD analysis. CCDC
reference numbers 855598–855600. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c2ce06574f
Fig. 1 Molecular structures of TDF and its coformers.
CrystEngComm, 2012, 14, 2377–2380 | 2377
This journal is ª The Royal Society of Chemistry 2012

a white powder at ambient conditions, is practically insoluble in water
(2 mg mLꢀ1),24 and is considered a class II drug22 by the Bio-
pharmaceutics Classification System.25 In consequence, TDF takes
approximately 0.5 to 6 h (Tmax) to achieve mean peak plasma
concentration (Cmax) in the body, regardless of food intake.22 Various
formulation techniques have been used to improve the solubility and
onset of TDF with limited success reported.26,27 It is believed that
modification of the TDF crystal form could offer a promising
alternative to enhance the solubility of this API and improve the oral
drug absorption, thus enabling faster clinical performance of the
drug.
alcohol-alcohol interaction). Specifically, the alcohol and carboxylic
acid moieties were approximately five and two times more likely,
respectively, to form a supramolecular heterosynthon with the lactam
moiety, when compared to the occurrence of the corresponding
supramolecular homosynthons, which were found to occur less than
15% of the time. A similar trend was found upon examination of the
indole moiety where the tendency for supramolecular heterosynthon
formation was ca. 50% greater than supramolecular homosynthon
formation in the presence of an alcohol or a carboxylic acid.
Methylparaben (MPB, Fig. 1), a pharmaceutically acceptable
alcohol, was selected as a potential coformer for cocrystallization
with TDF. Thin plate-like single cocrystals of TDF and MPB (1)
were obtained from an acetonitrile solution with equaimolar amounts
of TDF and MPB. The crystal structure of 1 was determined by
single crystal X-ray diffraction.‡ 1 crystallizes in the space group P21
and there is one TDF and one MP molecule in the asymmetric unit.
The structure of 1 reveals that adjacent TDF molecules are hydrogen-
bonded via N–H/O]C interactions [N3-H3A/O6: N/O 2.981(2)
A recent literature search showed that at least eight crystal forms of
TDF, including polymorphs and solvates, have been reported,28 while
only one crystal structure of TDF has been deposited (refcode:
IQUMAI)18 in the Cambridge Structural Database29 (CSD) to date.
Due to the existence of lactam and indole moieties in the molecular
structure of TDF, it is predisposed to form hydrogen bonds with
a second molecule (coformer) in the crystal lattice and it was therefore
considered appropriate for cocrystal screening.
ꢁ
ꢀ
ꢀ
A, H/O 2.12 A, N–H/O 164.4 ] that are similar to those seen in
pure TDF. As a result, hydrogen bonded chains of TDF extend along
the b-axis. The MPB molecules are linked to the supramolecular
chains as pendant components via O–H/O]C interactions [O7-
To better understand the potential intermolecular interactions of
TDF cocrystals, the crystal structure of TDF was analysed. The
crystal packing in TDF reveals that adjacent TDF molecules are
hydrogen-bonded via N–H/O]C interactions [N3-H9/O2: N/O
ꢁ
ꢀ
ꢀ
H1O/O1: O/O 2.746(3) A, O/H 1.83 A, O–H/O 166.3 ]. The
resulting TDF supramolecular chains with additional MPB mole-
cules are interdigitated and thereby form supramolecular sheets as
shown in Fig. 3. The interdigitation is supported by C–Hester/p
interactions between the methyl group on one MPB molecule and an
aromatic ring of another MPB molecule associated with the neigh-
bouring chain. Preparation of 1 was also achieved by solvent-drop
grinding30 and slurry methods. This cocrystal form was also charac-
terized by powder X-ray diffraction (PXRD), Fourier transform
infrared spectroscopy (FT-IR), and differential scanning calorimetry
(DSC) analyses.
ꢁ
ꢀ
ꢀ
2.985 A, H/O 2.09 A, N–H/O 167.06 ] between the indole group
of one molecule and the lactam carbonyl group of a neighbouring
molecule. The result shows that TDF molecules form supramolecular
chains in the crystal lattice along a 21 screw axis parallel to the b-axis
(Fig. 2).18 In addition, the lactam carbonyl group that is not involved
in the supramolecular chain formation interacts with the indole ring
of another TDF molecule in an adjacent chain via weaker C–Harom
/
O]C hydrogen bonding. A CSD survey of lactam and indole
molecules was also performed. Certain restrictions were placed upon
the CSD survey to include relevant crystal structures with atomic
coordinates determined, R-factor # 0.075, only organic molecules
and no ions involved. The result indicated that TDF would be
amenable to form cocrystals with coformers that contain alcohol or
carboxylic acid moieties, due to the greater propensity for supra-
molecular heterosynthon versus supramolecular homosynthon
formation (i.e., formation of carboxylic acid-carboxylic acid or
The presence of TDF hydrogen bonded chains in both pure TDF
and 1 prompted us to study how persistent this arrangement might
be. Therefore, propylparaben (PPB), another pharmaceutically
acceptable alcohol, was crystallized in the presence of TDF. Col-
ourless block single crystals of TDF and PPB (2) were collected via
slow evaporation of an acetonitrile solution containing equimolar
quantities of TDF and PPB. 2 was also characterized by single crystal
Fig. 2 (a) Hydrogen bonding in crystal structure of TDF (IQUMAI).
(b) Supramolecular chains of TDF extended along the b-axis.
Fig. 3 Crystal packing of 1.
2378 | CrystEngComm, 2012, 14, 2377–2380
This journal is ª The Royal Society of Chemistry 2012

X-ray diffraction. 2 adopts a similar supramolecular structure to that
of 1 and even exhibits similar unit cell parameters. 2 also crystallizes
in P21 with one molecule of TDF and one molecule of PPB in the
asymmetric unit. The structure of 2 also exhibits TDF supramolec-
ular chains via N–H/O]C hydrogen bonds [N1-H1A/O5: N/O
ꢁ
ꢀ
ꢀ
2.965(3) A, H/O 2.10 A, N–H/O 168.3 ] between neighbouring
TDF molecules. Additionally, PPB molecules are found to be
hydrogen-bonded to the TDF chains through O–H/O]C inter-
ꢀ
ꢀ
actions [O1-H1/O4: O/O 2.748(3) A, O/H 1.91 A, O/H–O
175.4ꢁ]. The resulting assembly adopts the same type of interdigitated
close packing seen for 1 (Fig. 4). However, in contrast to 1, the
interdigitation is supported by C–Harom/O]C interactions between
adjacent PPB molecules. Synthesis of 2 was also achieved using
solvent-drop grinding and slurry methods.
A TDF cocrystal screen using pharmaceutically acceptable
carboxylic acids was also performed given that alcohols and
carboxylic acids are both capable of serving as hydrogen bond
donors.31 TDF and hydrocinnamic acid (HCA) were cocrystallized
from an acetonitrile solution in a 1 : 1 molar ratio. Successful prep-
aration of TDF:HCA cocrystals (3) were also obtained through
solvent-drop grinding and slurry methods. The crystal structure of 3
was determined by single crystal X-ray diffraction. 3 adopts a similar
supramolecular arrangement compared to that of 1 and 2 and is
found to exhibit similar unit cell parameters in P21. The asymmetric
unit of 3 comprises one TDF and one HCA molecule and no proton
transfer is evident from the bond lengths. TDF supramolecular
chains linked via N–H/O]C hydrogen bonds [N3-H3/O5: N/O
Fig. 5 Crystal packing of 3.
suitable crystals of 4 for single crystal X-ray diffraction analysis to
date. In the absence of a single crystal structure of 4, its PXRD
profile was compared against that of 1–3. As presented in Fig. 6,
the PXRD profile of 4 was found to be distinctly different from
that of the other TDF cocrystals. However, this is by no means
sufficient to draw any conclusions about the nature of the supra-
molecular interactions that occur in 4. The unit cell parameters of
4, obtained from indexing the PXRD data,32 were also found to be
different from that of 1, 2 and 3.
ꢁ
ꢀ
ꢀ
2.918(3) A, H/O 2.05 A, N–H/O 168.3 ] are reminiscent of 1 and
2. HCA molecules are linked to the TDF chains through OH/O]C
In conclusion, TDF was successfully cocrystallized with three
pharmaceutically acceptable coformers, MPB, PPB and HCA,
through both solution and grinding methods. The structures of
three resulting cocrystals (1, 2 and 3) were determined by X-ray
diffraction techniques. In all three cocrystals, TDF molecules are
observed to be linked by N–H/O hydrogen bonds that form the
same supramolecular chains seen in pure TDF. However, when
a coformer with higher molecular complexity, HBA, was cocrys-
tallized with TDF, there are significant changes in the PXRD
profile. Future work will focus upon determination of the crystal
structure of 4 and cocrystal screening with a broader range of
coformers. The resulting series of TDF cocrystals will be evaluated
using in vitro and in vivo studies.
ꢀ
ꢀ
hydrogen bonds [O1-H1/O6: O/O 2.748(3) A, O H/1.94 A, O–
H/O 160.3ꢁ]. The assemblies of the TDF chains with pendant HA
molecules are once again interdigitated as presented in Fig. 5. The
interdgitation is supported by the edge-to-face C–Harom/p interac-
tions between HA and TDF molecules.
We further investigated the generality of these hydrogen bonding
patterns by looking at cocrystals of 4-hydroxybenzoic acid (HBA)
and TDF. From
a crystal engineering viewpoint, HBA is
a coformer with higher molecular complexity because both its
hydroxyl and carboxylic acid groups can act as hydrogen bond
donors. Cocrystals of TDF and HBA (4) were obtained from both
solution and grinding. However, we have been unable to obtain
Fig. 4 Crystal packing of 2.
Fig. 6 PXRD profiles for 1–4.
This journal is ª The Royal Society of Chemistry 2012
CrystEngComm, 2012, 14, 2377–2380 | 2379

12 W. Jones, S. Motherwell and A. V. Trask, MRS Bull., 2006, 31, 875–
879.
Acknowledgements
13 S. G. Fleischman, S. S. Kuduva, J. A. McMahon, B. Moulton,
R. D. B. Walsh, N. Rodriguez-Hornedo and M. J. Zaworotko,
Cryst. Growth Des., 2003, 3, 909–919.
We thank Mr. Raymond K. Houck for stimulating discussions and
valuable input to the project.
14 P. Vishweshwar, J. A. McMahon, J. A. Bis and M. J. Zaworotko, J.
Pharm. Sci., 2006, 95, 499–516.
15 M. B. Hickey, M. L. Peterson, L. A. Scoppettuolo, S. L. Morrisette,
A. Vetter, H. Guzman, J. F. Remenar, Z. Zhang, M. D. Tawa,
S. Haley, M. J. Zaworotko and O. Almarsson, Eur. J. Pharm.
Biopharm., 2007, 67, 112–119.
16 Z. Rahman, C. Agarabi, A. Zidan, S. Khan and M. Khan, AAPS
PharmSciTech, 12, pp. 693–704.
17 A. Daugan, P. Grondin, C. Ruault, A. C. L. de Gouville, H. Coste,
J. Kirilovsky, F. Hyafil and R. Labaudiniere, J. Med. Chem., 2003,
46, 4525–4532.
18 A. Daugan, P. Grondin, C. Ruault, A. C. L. de Gouville, H. Coste,
J. M. Linget, J. Kirilovsky, F. Hyafil and R. Labaudiniere, J. Med.
Chem., 2003, 46, 4533–4542.
19 J. D. Corbin and S. H. Francis, Int. J. Clin. Pract., 2002, 56, 453–
459.
20 T. Reffelmann and R. A. Kloner, Circulation, 2003, 108, 239–244.
21 N. Galie, B. H. Brundage, H. A. Ghofrani, R. J. Oudiz,
G. Simonneau, Z. Safdar, S. Shapiro, R. J. White, M. Chan,
A. Beardsworth, L. Frumkin, R. J. Barst, H. Pulm Arterial and
Resp, Circulation, 2009, 119, 2894–U2865.
Notes and references
‡ Crystal data for 1–3:
ꢀ
1: C30H27N3O7, M ¼ 541.55, monoclinic, a ¼ 9.4455(3) A, b ¼ 7.8767(2)
ꢁ
3
ꢀ
ꢀ
ꢀ
A, c ¼ 17.2532(5) A, b ¼ 98.352(2) , U ¼ 1270.01(6) A , T ¼ 100(2)K,
space group P21, Z ¼ 2, Dc ¼ 1.416 gcmꢀ3, m ¼ 0.844 mmꢀ1, F(000) ¼ 568,
3531 unique (Rint ¼ 0.0292), Final R1 (wR2) ¼ 0.0349 (0.0864) [I > 2.0 s
(I)].
ꢀ
2: C32H31N3O7, M ¼ 569.60, monoclinic, a ¼ 9.3357(2) A, b ¼ 8.3056(2)
ꢁ
3
ꢀ
ꢀ
ꢀ
A, c ¼ 17.3542(5) A, b ¼ 90.854(2) , U ¼ 1345.47(6) A , T ¼ 100(2)K,
space group P21, Z ¼ 2, Dc ¼ 1.406 gcmꢀ3, m ¼ 0.824 mmꢀ1, F(000) ¼ 600,
6565 reflections measured, 3487 unique (Rint ¼ 0.0358), Final R1 (wR2) ¼
0.0410 (0.0963) [I > 2.0 s(I)].
ꢀ
ꢀ
3: C31H29N3O6, M ¼ 539.57, monoclinic, a ¼ 9.548(1) A, b ¼ 8.188(1) A,
ꢁ
3
ꢀ
ꢀ
c ¼ 16.673(2) A, b ¼ 96.305(9) , U ¼ 1295.5(3) A , T ¼ 100(2)K, space
group P21, Z ¼ 2, Dc ¼ 1.383 gcmꢀ3, m ¼ 0.795 mmꢀ1, F(000) ¼ 568, 8513
reflections measured, 3654 unique (Rint ¼ 0.0439), Final R1 (wR2) ¼
0.0420 (0.0957) [I > 2.0 s(I)].
1 J.-M. Lehn, Supramolecular Chemistry: Concepts and Perspectives,
VCH, Weinheim, 1995.
22 M. Gupta, A. Kovar and B. Meibohm, J. Clin. Pharmacol., 2005, 45,
987–1003.
2 J. W. Steed and J. L. Atwood, Supramolecular Chemistry, 2nd edn,
John Wiley & Sons, Ltd., Chichester, UK, 2009.
3 G. R. Desiraju, Crystal Engineering: The Design of Organic Solids,
Elsevier, 1989.
4 G. R. Desiraju, Angew. Chem., Int. Ed. Engl., 1995, 34, 2311–2327.
5 M. L. Cheney, N. Shan, E. R. Healey, M. Hanna, L. Wojtas,
M. J. Zaworotko, V. Sava, S. J. Song and J. R. Sanchez-Ramos,
Cryst. Growth Des., 2010, 10, 394–405.
23 M. Limin, N. Johnsen and W. J. G. Hellstrom, Expert Opin. Invest.
Drugs, 2010, 19, 1427–1437.
24 US Pat., 2008/0009502A1, 2009.
25 G. L. Amidon, H. Lennernas, V. P. Shah and J. R. Crison, Pharm.
Res., 1995, 12, 413–420.
26 US Pat., 20080009502 A1, 2008.
27 US Pat., 20070104792 A1, 2007.
28 US Pat., 20060111571 Al, 2006.
6 M. L. Cheney, D. R. Weyna, N. Shan, M. Hanna, L. Wojtas and
M. J. Zaworotko, Cryst. Growth Des., 2010, 10, 4401–4413.
7 L. R. MacGillivray, J. L. Reid and J. A. Ripmeester, J. Am. Chem.
Soc., 2000, 122, 7817–7818.
8 R. Banerjee, P. M. Bhatt and G. R. Desiraju, Cryst. Growth Des.,
2006, 6, 1468–1478.
29 F. H. Allen, Acta Crystallogr., Sect. B: Struct. Sci., 2002, 58, 380–
388.
30 N. Shan, A. D. Bond and W. Jones, Cryst. Eng., 2002, 5, 9–24.
31 D. K. Bucar, R. F. Henry, X. C. Lou, R. W. Duerst,
L. R. MacGillivray and G. G. Z. Zhang, Cryst. Growth Des., 2009,
9, 1932–1943.
9 N. Shan and M. J. Zaworotko, Drug Discovery Today, 2008, 13, 440–446.
10 M. L. Cheney, D. R. Weyna, N. Shan, M. Hanna, L. Wojtas and
M. J. Zaworotko, J. Pharm. Sci., 2011, 100, 2172–2181.
11 N. Shan, M. Zaworotko, in Burger’s Medicinal Chemistry and Drug
Discovery, 2010pp. 187–218 .
32 The indexing of the laboratory PXRD data of 4 was performed by the
DICVOL04 program (Boultif et al., J. Appl. Cryst., 2004, 37, 724–
731). The structure of 4 was determined in the monoclinic crystal
ꢀ
system with unit cell parameters reported as a ¼ 16.223(18) A, b ¼
ꢁ
ꢀ
ꢀ
6.117(7) A, c ¼ 11.085(12) A and b ¼ 94.39(12) .
2380 | CrystEngComm, 2012, 14, 2377–2380
This journal is ª The Royal Society of Chemistry 2012