Coordination polymers as potential solid forms of drugs: Three zinc(ii) coordination polymers of theophylline with biocompatible organic acids

Article abstract of DOI:10.1039/c2nj40625j

The biocompatible organic acids such as acetic acid (Hac), benzoic acid (Hbz) and nicotinic acid (Hnit), have been employed as second ligands to assemble biocompatible coordination polymers of theophylline (Hthp), respectively. As a result, three coordination polymers [Zn₂(thp) ₂(ac)(OH)]_n (1), [Zn₂(thp)₂(bz)(OH)] _n (2) and [Zn(thp)(nit)]_∞ (3) have been synthesized through hydrothermal and mechanochemical reactions. Theophylline could be released rapidly in simulated gastroenteric fluid (phosphate-buffered solution, PBS) and slow release of theophylline could be achieved from the three polymers in pure water at 37 °C with continuous stirring.

Full text of DOI:10.1039/c2nj40625j

NJC
View Article Online
View Journal | View Issue
PAPER
Coordination polymers as potential solid forms of
drugs: three zinc(II) coordination polymers of
theophylline with biocompatible organic acids†
Cite this: NewJ.Chem., 2013,
37, 309
Benyong Lou*ab and Fengdan Hea
The biocompatible organic acids such as acetic acid (Hac), benzoic acid (Hbz) and nicotinic acid (Hnit),
have been employed as second ligands to assemble biocompatible coordination polymers of
theophylline (Hthp), respectively. As a result, three coordination polymers [Zn2(thp)2(ac)(OH)]n (1),
[Zn2(thp)2(bz)(OH)]n (2) and [Zn(thp)(nit)]N (3) have been synthesized through hydrothermal and
mechanochemical reactions. Theophylline could be released rapidly in simulated gastroenteric fluid
(phosphate-buffered solution, PBS) and slow release of theophylline could be achieved from the three
polymers in pure water at 37 1C with continuous stirring.
Received (in Montpellier, France)
19th July 2012,
Accepted 3rd October 2012
DOI: 10.1039/c2nj40625j
www.rsc.org/njc
In fact, many APIs have been employed as good building blocks for
constructing functional coordination polymers.9 Recently, Serre and
Introduction
Coordination polymers, known as an emerging class of mole-
cular materials, have been successfully exploited in biomedical
applications such as drug delivery.1,2 Especially, several porous
coordination polymers showed a remarkable capacity for drug
loading and controlled delivery.3 However, pharmaceutical
applications would clearly require the biocompatibility of metal
ions and organic building blocks. Although there exist many
biocompatible molecules that could bridge metal ions, it is
usually difficult to generate large accessible pores enough to
accommodate drug molecules by these biomolecules alone.4
In the past decade, crystal engineering has emerged into
pharmaceutical material science and developed cocrystallization
as a useful means of generating new solid forms of active
pharmaceutical ingredients (APIs).5 The tailored pharmaceutical
properties can be obtained by introducing suitable cocrystal
formers which are generally regarded as safe (GRAS) by the
principle of crystal engineering.6 On the other hand, metal
coordination has been attempted to construct novel solid-state
forms of APIs since many APIs contain functional groups which
could coordinate to metal ions.7 Some discrete metal complexes
of APIs have been investigated as potential solid forms of drugs.8
co-workers reported the first biodegradable active coordination
polymer based on non-toxic iron and therapeutically active nicotinic
acid.10 In fact, many cocrystal formers such as carboxylic acids are
likewise good linkers for bridging metal cations into specific
coordination polymers.11 Therefore, various biocompatible coordi-
nation polymers of APIs could result from microelement cations as
nodes linking APIs and specific cocrystal formers together into a
new class of crystalline solid-state forms. The cocrystal formers as
second ligands could be expected to tailor the properties of APIs as
they do likewise in pharmaceutical cocrystals.
Theophylline is a methylxanthine drug used in the treatment of
asthma and chronic obstructive pulmonary disease.12 Although
theophylline is a BCS class I drug, the strong side effects limit its
use. The slow-release forms of theophylline, which could decrease its
side effects, have been extensively developed.13 According to crystal
engineering strategies, physical stability enhancement of theophyl-
line had been achieved through cocrystallization with dicarboxylic
acids.14 In this paper, we chose theophylline (Hthp) as the drug
model and microelement zinc(II) as the metal center. The N-contain-
ing ring of theophylline is capable of chelating Zn(II) ions and a
mononuclear Zn(II) complex was investigated as a potential solid
form of theophylline.15 For this study, we chose three organic acids,
acetic acid (Hac), benzoic acid (Hbz) and nicotinic acid (Hnit), as
second ligands to assemble coordination polymers of theophylline
(Fig. 1). All of the three organic acids are generally regarded as safe by
FDA.16 As a result, three coordination polymers [Zn2(thp)2(ac)(OH)]n
(1), [Zn2(thp)2(bz)(OH)]n (2) and [Zn(thp)(nit)]N (3) have been synthe-
sized, respectively. Theophylline could be released rapidly in
a Department of Chemistry and Chemical Engineering, Minjiang University, Fuzhou,
350108, China. E-mail: lby@mju.edu.cn
b State Key Laboratory of Structural Chemistry, Fuzhou, 350002, China
† Electronic supplementary information (ESI) available: Calibration plot of theo-
phylline by the HPLC method. CCDC reference numbers 879623–879625 (1–3).
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2nj40625j
c
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013
New J. Chem., 2013, 37, 309--316 309

View Article Online
Paper
NJC
(55 mg, 0.25 mmol) in 10 mL water was placed in a 23 mL
Teflon-lined autoclave and 0.1 mL triethylamine were added.
Then, the sealed autoclave was placed in a furnace at 130 1C for
2 days. Colorless block crystals were isolated and about 50 mg
product was collected (67% yield based on theophylline).
Element analysis for C16H18N8O7Zn2 (%), calcd: C 33.97, H
3.21,
N 19.82; found: C 33.55, H 3.12, N 20.07. IR
(KBr, cmÀ1): 3420 b, 2925 w, 1702 s, 1656 s, 1570 m, 1545 m,
1425 w, 1228 w, 885 w.
Mechanosynthesis: A mixture of theophylline (180 mg,
1 mmol) and Zn(OH)2 (99 mg,1 mmol) with 0.2 mL acetic acid
added was ground with a LAB WIZZ 320 ball mill in a 25 mL
steel vessel with a 15 mm steel ball at 30 Hz for 30 min. The
powder was then dried and collected for XRD.
Fig. 1 The structures of theophylline and organic acids employed.
[Zn2(thp)2(bz)(OH)]n (2). Hydrothermal synthesis: A mixture
of theophylline (45 mg, 0.25 mmol), Zn(NO3)2Á6H2O (74 mg,
0.25 mmol) and benzoic acid (30 mg, 0.25 mmol) in 10 mL
water was placed in a 23 mL Teflon-lined autoclave and 0.1 mL
triethylamine were added. Then, the sealed autoclave was
placed in a furnace at 130 1C for 2 days. Colorless block crystals
were isolated and about 45 mg product was collected (57% yield
based on theophylline). Element analysis for C21H20N8O7Zn2
(%), calcd: C 40.18, H 3.21, N 17.86; found: C 39.87, H 3.11, N
17.17. IR (KBr, cmÀ1): 3421 b, 2925 w, 1705 s, 1660 s, 1536 m,
1536 m, 1410 w, 1223 w, 891 w.
Mechanosynthesis: A mixture of theophylline (180 mg,
1 mmol), Zn(OH)2 (99 mg, 1 mmol) and benzoic acid (60 mg,
0.5 mmol) with 0.1 mL water added was ground with a LAB
WIZZ 320 ball mill in a 25 mL steel vessel with a 15 mm steel
ball at 30 Hz for 30 min. The powder was then dried and
collected for XRD.
simulated gastroenteric fluid (phosphate-buffered solution, PBS)
and slow release of theophylline could be achieved from the three
polymers in pure water at 37 1C with continuous stirring.
Experimental
General remarks
All reagents were purchased as analytical grade and used with-
out further purification. The IR spectra of the KBr disk were
recorded on a Magna 750 FT-IR spectrophotometer. C, H and N
elemental analyses were determined on an Elementary Vario
ELIII elemental analyzer. X-ray powder diffractions were per-
formed on Philips X’Pert Pro MPD. The dissolution studies
were carried out on a 78X-6A Dissolution apparatus. The
concentrations were determined in a Waters HPLC system.
Syntheses
[Zn(thp)(nit)]N (3). Hydrothermal synthesis: A mixture of
[Zn2(thp)2(ac)(OH)]n (1). Hydrothermal synthesis: A mixture theophylline (45 mg, 0.25 mmol), Zn(NO3)2Á6H2O (74 mg,
of theophylline (45 mg, 0.25 mmol) and Zn(CH3COO)2Á2H2O 0.25 mmol) and nicotinic acid (31 mg, 0.25 mmol) in 10 mL
Table 1 Crystal data and structure refinement for complexes 1–3
1
2
3
Formula
FW
Crystal size/mm
Crystal system
C16H18N8O7Zn2
565.12
0.45 Â 0.15 Â 0.10
Monoclinic
C2/c
C21H20N8O7Zn2
627.19
0.45 Â 0.15 Â 0.15
Monoclinic
C2/c
C13H11N5O4Zn
366.64
0.35 Â 0.30 Â 0.15
Orthorhombic
Pbca
Space group
a/Å
b/Å
c/Å
a/1
17.083(2)
11.2862(9)
11.2092(15)
90
16.023(2)
13.4229(16)
11.4932(19)
90
11.8565(11)
11.0480(8)
20.2252(16)
90
b/1
106.755(7)
90
2069.4(4)
4
1.814
1144
103.331(9)
90
2405.3(6)
4
1.732
1272
90
90
2649.3(4)
8
1.838
g/1
V/Å3
Z
Dc/g cmÀ3
F000
1488
2ymax/1
55.0
7664
2311
0.0278
155
1.088
0.0316
0.1180
55.0
9148
2752
0.0344
176
1.096
0.0386
0.0805
55.0
19341
3024
0.0266
210
1.109
0.0283
0.0666
Reflections collected
Unique reflections
Rint
Parameters
Final GooF
R1 (I 4 2s(I))
wR (all data)
c
310 New J. Chem., 2013, 37, 309--316
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013

View Article Online
NJC
Paper
water was placed in a 23 mL Teflon-lined autoclave and 0.2 mL
triethylamine were added. Then, the sealed autoclave was
placed in a furnace at 130 1C for 2 days. Colorless block crystals
were isolated and about 50 mg product was collected (55% yield
based on theophylline). Element analysis for C13H11N5O4Zn
(%), calcd: C 42.55, H 3.02, N 19.09; found: C 42.78, H 3.02,
N 19.71. IR (KBr, cmÀ1): 3420 b, 2925 w, 1704 s, 1663 s, 1645 s,
1594 m, 1535 m, 1445 w, 1349 s, 1193 w, 870 w.
Mechanosynthesis: A mixture of theophylline (180 mg,
1 mmol), Zn(OH)2 (99 mg, 1 mmol) and nicotinic acid
(123 mg, 1 mmol) with 0.1 mL water added was ground with
a LAB WIZZ 320 ball mill in a 25 mL steel vessel with a 15 mm
steel ball at 30 Hz for 30 min. The powder was then dried and
collected for XRD.
X-ray structure determination
The data were collected on a Rigaku Mercury-CCD diffracto-
meter at 293 K, using graphite-monochromated Mo-Ka radia-
tion (l = 0.7107 Å). The empirical absorption corrections were
applied by using the CrystalClear program.17 The structures
were solved by direct methods and refined on F2 by full-matrix
least-squares methods using the SHELXTL-97 program pack-
Fig. 3 XRD patterns of complex 2; (a) simulated; (b) hydrothermally-synthesized;
(c) mechanically-synthesized (thp: Zn(OH)2 : bz = 1 : 1 : 0.5); (d) mechanically-
age.18 Non-hydrogen atoms were refined anisotropically and synthesized (thp: Zn(OH)2 : bz = 1 : 1 : 1).
organic hydrogen atoms were generated geometrically. In 1 and
2, the hydrogen atoms of OHÀ were located by difference maps
and constrained to ride on their parent O atoms. (CCDC 879623
for 1, 879624 for 2 and 879625 for 3). Crystal data of 1–3 are
listed in Table 1.
experiment, three 1000 mL round-bottomed flasks containing
900 mL solvent were equilibrated at 37.0 1C. The powdered
samples containing 100 mg of theophylline were added to
the flasks, and the resulting slurry was stirred at 100 rpm.
Theophylline release studies
The samples of complexes 1–3 were micronized and sieved
using standard-mesh sieves (mesh size 150 mm). In each
Fig. 2 XRD patterns of complex 1; (a) simulated; (b) hydrothermally-synthesized;
Fig. 4 XRD patterns of complex 3; (a) simulated; (b) hydrothermally-synthesized;
(c) mechanically-synthesized (thp: Zn(OH)2 : nit = 1 : 1 : 1); (d) mechanically-synthe-
sized (thp: Zn(OH)2 : nit = 1 : 1 : 0.5).
(c) mechanically-synthesized (thp: Zn(OH)2 : ac
synthesized (thp: Zn(OH)2 : ac = 1 : 1 : 1).
= 1 : 1 : 0.5); (d) mechanically-
c
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013
New J. Chem., 2013, 37, 309--316 311

View Article Online
Paper
NJC
Fig. 5 The 1D polymeric chain in complex 1.
Fig. 6 The 3D hydrogen-bonded framework of complex 1.
At specific time intervals over 3 days, 2 mL of the slurry was of water. The flow rate was 0.8 mL minÀ1 and the column
withdrawn from the three flasks and filtered through a 0.2 mm temperature was 25 1C. The effluent was monitored at 271 nm
syringe filter. Additional 2 mL fresh solvent was added into the and the injection volume was 20 mL. The retention time for
flasks after sampling. A 20 mL filtered sample was then injected theophylline was 5.3 min. Several theophylline solutions at
directly into the HPLC column. The concentration of theophyl- concentrations of 0, 10, 20, 40 and 60 mg LÀ1 in pure water
line in each sample was calculated from the standard graph.
were used as standards. The calibrated plot showed a good
correlation coefficient 40.99 (Fig. S1, ESI†).
HPLC determination
The HPLC method was used to determine the concentrations of
theophylline. A Waters HPLC system, including a solvent
delivery pump, a controller and a UV detector, was used in this
Results and discussion
Syntheses of complexes 1–3
study. A 25 cm C-18 column containing particles with a All three complexes could be synthesized under hydrothermal
diameter of 5 mm and a pore size of 4.6 Â 150 mm was used. conditions in desirable yields. The purity was confirmed by powder
The mobile phase consisted of 35 vol. of methanol and 65 vol. X-ray diffraction. We have also carried out mechanochemical
c
312 New J. Chem., 2013, 37, 309--316
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013

View Article Online
NJC
Paper
Fig. 7 The dimer structure of complex 2.
reactions for preparing complexes 1–3 by liquid-assisted grind-
ing (LAG) which has proved to be very efficient for preparing
supramolecular compounds of APIs.19 These three complexes
could be obtained easily by the same stoichiometries obtained
in the hydrothermal reactions. Complex 1 was prepared by
grinding theophylline with Zn(OH)2 in a ball mill in the
presence of a small amount of added acetic acid for 30 min.
Complexes 2 and 3 were prepared by grinding theophylline and
Zn(OH)2 with benzoic acid (1 : 1 : 0.5) or nicotinic acid (1 : 1 : 1)
in the presence of added water for 30 min. The facile prepara-
tion of the coordination polymers makes it possible to develop
them as practical solid forms of APIs. Since the additional
presence of OHÀ in 1 and 2 is the unexpected results from
hydrothermal syntheses, we have attempted to replace OHÀ by
ac or bz anions through mechanochemical reactions in which
the ratio of 1 : 1 : 1 was employed for theophylline, Zn(OH)2 and
acetate (benzoic acid). As a result, excessive ac anions failed to
replace bridging OHÀ and still resulted in complex 1 (Fig. 2).
However, excessive benzoic acid resulted in a new phase
different from complex 2 (Fig. 3). The failure of obtaining
Fig. 8 The 3D hydrogen-bonded framework of complex 2.
Fig. 9 The structural unit in complex 3. A = 1/2 À x, y À 1/2, z; B = 1/2 + x, y, 1/2 À z.
c
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013
New J. Chem., 2013, 37, 309--316 313

View Article Online
Paper
NJC
Fig. 10 The 2D coordination network of 3 viewed along the b axis (top) and the a axis (bottom).
single crystals makes it difficult to characterize the structure lost the proton of its imidazole ring acting as a bidentate anion (thp)
accurately. The ratio of 1 : 1 : 0.5 for theophylline, Zn(OH)2 and bridging two different Zn(II) centers through two N atoms of the
nicotinic acid was attempted to obtain a new coordination imidazole ring. In complex 1, the Zn(II) center is coordinated by two
polymer. The results indicate that complex 3 is still the main N atoms of the thp anion, carboxylic O atom of acetate and O atom
product and it is difficult to remove completely the byproduct of the hydroxyl ion. The complex has crystallographically-imposed
of excessive theophylline and Zn(OH)2 (Fig. 4).
twofold symmetry, with the bridging acetate carbon atoms
(C8 and C9) and the hydroxy group O4–H4 on the twofold axis.
Acetate and hydroxyl anions bridge two Zn(II) centers at a
distance of 3.345 Å. The thp anions connect Zn(II) centers at a
distance of 5.759 Å along the c axis into a 1D polymeric Zn(II)–thp
Crystal structures of complexes 1–3
Single crystal X-ray diffractions show that Zn(II) centers in each
complex are in a four-coordinated environment and theophylline
c
314 New J. Chem., 2013, 37, 309--316
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013

View Article Online
NJC
Paper
Fig. 11 The release profiles of 1–3 in pure water at 37 1C.
chain which is linked into a 1D double-chain polymeric structure by delivered theophylline concentration was determined by HPLC. In
bridging acetate and hydroxyl anions (Fig. 5). The hydrogen-bonding a PBS buffer (pH = 2) similar to gastric fluid, each polymer powder
interactions [O4ÁÁÁO2#1 = 2.881(4) Å, O4ÁÁÁÁO2#2 = 2.881(4) Å, #1: could dissolve rapidly and theophylline could be completely
1/2 À x, 3/2 À y, Àz; #2: 1/2 + x, 3/2 À y, 1/2 + z] between hydroxyl ion released. It indicates that coordination polymers are rapidly decom-
and –CQO of thp link 1D coordination chains into a 3D hydrogen- posed in such acidic environments. In a PBS buffer (pH = 6.8)
bonded framework (Fig. 6).
similar to intestinal fluid, theophylline could be completely
In complex 2, there are similar interactions between metal released within 1 hour for 1–3 though the powder samples of 1–3
centers and ligands with complex 1, resulting in the bridged dimer remain undissolved in the PBS buffer (pH = 6.8). This indicatesÀthat
structure (Fig. 7). There also exists similar twofold symmetry, with theophylline anions in 1–3 might be easily replaced by H2PO4 or
2À
the bridging benzoate carbon atoms (C8, C9 and C12) and the HPO4 in the PBS buffer. The quick release of theophylline is
hydroxy group O2–H2 on the twofold axis. The bz anion instead of similar to the one observed for the iron–nicotinic acid coordination
acetate results in a similar 1D coordination chain and similar polymer.10
hydrogen-bonding interactions result in a similar 3D hydrogen-
To exclude the influence of anions of PBS buffers, we have
bonded framework with complex 1 (Fig. 8). The thp anions bridge studied the release profiles of 1–3 in pure water (Fig. 11). The results
Zn(II) centers at a distance of 5.756 Å and bz and hydroxyl anions show that theophylline could be slowly released from 1–3 in pure
bridge Zn(II) centers at a distance of 3.307 Å. The crystal density of 2 water. For 1, 36.5% of theophylline could be released during the first
(1.7318 g cmÀ3) is smaller than 1 (1.8136 g cmÀ3) due to the extra 10 hours and maximal release (68%) was realized after 60 h. For 2,
benzyl ring of the bz anion.
the release rate of theophylline was higher than in 1 during the first
In 3, the nit anion acts as a bridging ligand through pyridyl 10 hours. 55.5% of theophylline was released at 10 h and maximal
N and carboxylic O atoms and the Zn(II) center is coordinated release (70%) was realized after 48 h. For 3, 36.5% of theophylline
by two N atoms of thp, carboxylic O atom and pyridyl N atom of could be released during the first 10 hours and maximal release was
the nit anion (Fig. 9). The thp anions link Zn(II) centers at a only up to 50% after 60 h. This indicates that theophylline in a 2D
distance of 5.878 Å along the b axis into a 1D polymeric chain coordination network of 3 is more difficult to escape than theophyl-
which is further connected into a 2D coordination network line in the 1D polymeric chain of 1 and 2. The theophylline release
through metal coordination between the Zn(II) center and in pure water might be regarded as a gradual hydrolysis process of
pyridyl N and carboxylic O atoms of the nit anion (Fig. 10).
coordination polymers. Different second ligands could result in
In 1 and 2, acetate (or benzoate) and hydroxyl anions bridge two different coordination frameworks which have different hydrolysis
Zn(II) centers to form a binuclear unit which connects theophylline rates. Although complexes 1 and 2 have similar polymeric struc-
anions into a 1D polymeric framework through Zn(II)–thp coordina- tures, the benzoate anion in 2 results in a faster release of theophyl-
tion. In 3, nit anions link Zn(II) centers into a 1D polymeric chain line than the acetate anion in 1. In 3, the nit anion results in a 2D
which connects theophylline anions into a 2D coordination layer. In coordination network, which makes it more difficult to release
these cases, Zn(II) binuclear units or polymeric chains act as drug theophylline. Besides, the additional presence of OHÀ in 1 and 2
carriers anchoring theophylline through coordination interactions might accelerate the hydrolysis process of the two complexes.
between carriers and drugs. The contents of theophylline anions are
up to 63.40% for 1, 57.13% for 2 and 48.87% for 3.
Actually, the three coordination polymers are very instable
in PBS buffers, indicated by their rapid decompositions. How-
ever, we have successfully demonstrated that different biocom-
patible organic molecules could result in different coordination
Theophylline release studies
The release behaviors of theophylline to simulated gastroenteric polymers with different release behavior of theophylline in pure
fluid at 37 1C with continuous stirring have been investigated. The water. The diversity of biocompatible organic molecules could
c
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013
New J. Chem., 2013, 37, 309--316 315

View Article Online
Paper
NJC
´
´
4 I. Imaz, M. Rubio-Martınez, J. An, I. Sole-Font, N. L. Rosi
offer various coordination polymers with different release charac-
ters of APIs. Therefore, the controlled release of drugs could be
achieved by employing specific second ligands which could adjust
structures and release behaviors of resulting coordination poly-
mers. The multicomponent systems would have the advantage of
porous coordination polymers in which guest APIs are loaded and
released. The hard drug-loading process could be avoided since
drug-containing polymers are directly synthesized.10 Moreover,
mechanochemical synthesis provides an efficient and convenient
pathway for preparing the multicomponent crystals. This can make
it practical to develop multicomponent coordination polymers as
potential forms of APIs. Of course, the major challenge is to
synthesize stable coordination polymers of APIs in PBS buffers.
and D. Maspoch, Chem. Commun., 2011, 47, 7287.
5 O. Almarsson and M. J. Zaworotko, Chem. Commun., 2004,
¨
1889.
6 A. V. Trask, W. D. S. Motherwell and W. Jones, Cryst. Growth
ˇˇ´
´ ´
Des., 2005, 5, 1013; S. Karki, T. Friscic, L. Fabian, P. R. Laiti,
G. M. Day and W. Jones, Adv. Mater., 2009, 21, 3905; S. Chattoraj,
L. Shi and C. C. Sun, CrystEngComm, 2010, 12, 2466.
ˇˇ ´
7 E. H. H. Chow, F. C. Strobridge and T. Friscic, Chem.
Commun., 2010, 46, 6368; V. Andre, A. Hardeman,
´
I. Halasz, R. S. Stein, G. J. Jackson, D. G. Reid, M. J. Duer,
C. Curfs, M. T. Duarte and T. Friscic, Angew. Chem., Int. Ed.,
ˇˇ ´
2011, 50, 7858.
8 P. Ochsenbein, M. Bonin, O. Masson, D. Loyaux, G. Chapuis
and K. J. Schenk, Angew. Chem., Int. Ed., 2004, 43, 2694;
Z. Ma and B. Moulton, Mol. Pharmaceutics, 2007, 4, 373;
Z. Ma and B. Moulton, Cryst. Growth Des., 2007, 7, 196;
D. Braga, F. Grepioni, V. Andre and M. T. Duarte, CrystEng-
Comm, 2009, 11, 2618; D. Braga, F. Grepioni, L. Maini,
R. Brescello and L. Cotarca, CrystEngComm, 2008, 10, 469.
9 R. G. Xiong, X. Z. You, B. F. Abrahams, Z. Xue and C. M. Che,
Angew. Chem., Int. Ed., 2001, 40, 4422; J. Zhao, L. Mi, J. Hu,
H. Hou and Y. Fan, J. Am. Chem. Soc., 2008, 130, 15222;
D. R. Xiao, E. B. Wang, H. Y. An, Z. M. Su, Y. G. Li, L. Gao,
C. Y. Sun and L. Xu, Chem.–Eur. J., 2005, 11, 6673.
Conclusions
Three
coordination
polymers
[Zn2(thp)2(ac)(OH)]n
(1),
[Zn2(thp)2(bz)(OH)]n (2) and [Zn(thp)(nit)]N (3) have been synthe-
sized through hydrothermal and mechanochemical reactions by
the use of acetic acid (Hac), benzoic acid (Hbz) and nicotinic acid
(Hnit), as second ligands reacting with theophylline (Hthp) and
Zn(II). Theophylline could be released rapidly in simulated gastro-
enteric fluid. Slow release of theophylline could be achieved from
the three polymers in pure water at 37 1C with continuous stirring.
The maximal release (68%) was realized after 60 h for 1 and
maximal release is up to 70% after 48 h for 2. For 3, maximal
release was up to 50% after 60 h. The studies in this paper provide a
new strategy for developing multicomponent coordination poly-
mers as potential solid forms of APIs which could be expected to
release drug molecules in a controlled way.
10 S. R. Miller, D. Heurtaux, T. Baati, P. Horcajada,
`
J. M. Greneche and C. Serre, Chem. Commun., 2010,
46, 4526.
11 P. Jain, V. Ramachandran, R. J. Clark, H. D. Zhou,
B. H. Toby, N. S. Dalal, H. W. Kroto and A. K. Cheetham,
J. Am. Chem. Soc., 2009, 131, 13625; P. M. Forster and
A. K. Cheetham, Angew. Chem., Int. Ed., 2002, 41, 457;
Acknowledgements
´
C. Serre, F. Millange, S. Surble and G. Ferey, Angew. Chem.,
Int. Ed., 2004, 43, 6285; S. Thushari, J. A. K. Cha, H. H.
Y. Sung, S. S. Y. Chui, A. L. F. Leung, Y. F. Yen and
I. D. Williams, Chem. Commun., 2005, 5515.
The authors are grateful to the grants from the National Natural
Science Foundation of China (20901037), Program for New
Century Excellent Talents in Fujian Province University
(JK2010043) and the Undergraduate Innovative Research Pro-
gram of Fujian Province (mjcx1102).
12 C. P. Page, J. Clin. Pharmacol., 1999, 39, 237; P. J. Barnes, Am.
J. Respir. Crit. Care Med., 2003, 167, 813.
13 K. J. Simons, F. Estelle, R. Simons, K. D. Plett and C. Scerbo,
J. Pharm. Sci., 1984, 73, 939; A. R. Fassihi and D. L. Munday,
J. Pharm. Sci., 1989, 41, 369; K. Asare-Addo, M. Levina,
A. R. Rajabi-Siahboomi and A. Nokhodchi, Carbohydr.
Polym., 2011, 86, 85.
References
1 Z. Ma and B. Moulton, Coord. Chem. Rev., 2011, 255, 1623;
P. Horcajada, R. Gref, T. Baati, P. K. Allan, G. Maurin,
´
P. Couvreur, G. Ferey, R. E. Morris and C. Serre, Chem. 14 A. V. Trask, W. D. S. Motherwell and W. Jones, Int. J. Pharm.,
ˇˇ ´
´ ´
Rev., 2012, 112, 1232.
2006, 320, 114; T. Friscic, L. Fabian, J. C. Burley, D. G. Reid,
2 K. M. L. Taylor-Pashow, J. D. Rocca, Z. Xie, S. Tran and
M. J. Duer and W. Jones, Chem. Commun., 2008, 1644.
W. Lin, J. Am. Chem. Soc., 2009, 131, 14261; W. J. Rieter, 15 M. J. Gardner, F. X. Smith and E. Shefter, J. Pharm. Sci.,
K. M. Pott, K. M. L. Taylor and W. Lin, J. Am. Chem. Soc., 1983, 72, 348.
2008, 130, 11584; W. J. Rieter, K. M. L. Taylor and W. Lin, 16 FDA GRAS substances can be found at http://www.fda.gov/
J. Am. Chem. Soc., 2007, 129, 9852.
3 P. Horcajada, C. Serre, M. Vallet-Regı, M. Sebban, F. Taulelle
Food/FoodIngredientsPackaging/FoodAdditives/FoodAdditi
veListings/ucm091048.htm.
´
´
and G. Ferey, Angew. Chem., Int. Ed., 2006, 45, 5974; 17 Rigaku, CrystalClear Programs for data collection, cell refine-
P. Horcajada, C. Serre, G. Maurin, N. A. Ramsahye, ment and structure solution, Rigaku Corp, Japan, 2000.
F. Balas, M. Vallet-Regı, M. Sebban, F. Taulelle and 18 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr.,
´
´
G. Ferey, J. Am. Chem. Soc., 2008, 130, 6774; J. An,
2008, 64, 112.
ˇˇ ´
S. J. Geib and N. L. Rosi, J. Am. Chem. Soc., 2009, 131, 8376. 19 T. Friscic, Chem. Soc. Rev., 2012, 41, 3493.
c
316 New J. Chem., 2013, 37, 309--316
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013