research papers

Journal of
Applied
Structure determination of diclofenac in a
Crystallography diclofenac-containing chitosan matrix using
ISSN 0021-8898
conventional X-ray powder diffraction data
Received 16 December 2003
Accepted 29 January 2004 Nongnuj Muangsin,a* Malee Prajuabsook,a Pitiporn Chimsook,a Nuanphun
Chantarasiri,a Krisana Siraleartmukul,b Narongsak Chaichitc and Supot
Hannongbuaa

a
Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330,
Thailand, bMetallurgy and Materials Science Research Institute, Chulalongkorn University,
Thailand, and cDepartment of Physics, Faculty of Science and Technology, Thammasart University,
Thailand. Correspondence e-mail: nongnuj.j@chula.ac.th

The structure determination of diclofenac embedded in a diclofenac-containing

# 2004 International Union of Crystallography
Printed in Great Britain ± all rights reserved
chitosan matrix using conventional X-ray powder diffraction data is demon-
strated. It reveals that sodium diclofenac, the starting material in the
preparation of a controlled-release diclofenac-containing chitosan matrix,
changes to diclofenac acid in space group C2/c in the matrix. Simple methods
were employed for handling the sample to obtain X-ray powder diffraction data
of suf®ciently high quality for the determination of the crystal structure of
diclofenac embedded in chitosan. These involved grinding and sieving several
times through a micro-mesh sieve to obtain a suitable particle size and a
uniformly spherical particle shape. A traditional technique for structure solution
from X-ray powder diffraction data was applied. The X-ray diffraction
intensities were extracted using Le Bail's method. The structure was solved
by direct methods from the extracted powder data and re®ned using the
Rietveld method. For comparison, the single-crystal structure of the same drug
was also determined. The result shows that the crystal structure solved from
conventional X-ray powder diffraction data is in good agreement with that of
the single crystal. The deviations of the differences in bond lengths and angles
are of the order of 0.030 AÊ and 0.639 , respectively.

1. Introduction In order to produce conventional XRPD data of suf®ciently

1.1. Structure determination from X-ray powder diffraction
data
X-ray single-crystal diffraction (XRSC) is the most
powerful technique for crystal structure determination. By
contrast, the crystal structure determination of organic
compounds from X-ray powder diffraction (XRPD) data
continues to be a challenging task (Harris & Tremayne, 1996;
Kariuki et al., 1999). Most pharmaceutical substances or drugs
are small organic molecules consisting of light atoms such as C,
H, O or N. Their powder diffraction data often have many
overlapping peaks, especially at high scattering angles, and the
quality is often not good enough for structure determination.
Despite such problems, a third-generation source of
synchrotron radiation combined with highly optimized
powder diffraction instrumentation is able to produce high-
quality XRPD patterns. However, synchrotron time is very
expensive and not easily available, whereas conventional
X-ray powder diffractometers are widely available in labora-
tories.
high quality for determining crystal structure, the organic
compounds must be pure and highly crystalline. However,
many drugs are prepared in a controlled-release or sustained-
release formulation using a polymer as the controlled-release
material. Although XRPD determination of the amount of a
crystalline drug in a powder mixture with an amorphous
material has been reported (Villiers et al., 1998), a structure
determination of a drug embedded in a polymer matrix, such
as is used for the controlled release or sustained release of a
drug, has not been reported to date. In this paper, we present
the structure determination of diclofenac embedded in a
chitosan matrix, from conventional X-ray powder diffraction
data.
1.2. Diclofenac and its crystalline forms
Different solid forms of a pharmaceutical substance may
display different physical and chemical properties. Pharma-
ceutical substances may change to different polymorphs,
solvates (pseudo-polymorphism), desolvates or amorphous

288 DOI: 10.1107/S0021889804002353 J. Appl. Cryst. (2004). 37, 288±294


Figure 1
The chemical structure of diclofenac.
materials after standard pharmaceutical processes such as
crystallization, milling, freeze drying, spray drying and solid
dispersion, which may change their pharmaceutical activities.
The pharmaceutical industry requires a strategy to char-
acterize polymorphic drugs and produce drugs of consistent
quality (Yu et al., 1998). Therefore, it is important to char-
acterize pharmaceutical solids in their formulations, especially
those substances dispersed or embedded in a polymer matrix,
to ascertain that they still retain the required pharmacological
properties, including their chemical and physical properties
and biological activities.
Diclofenac, 2-[(2,6-dichlorophenyl)amino]phenylacetic acid
(Fig. 1), is an excellent nonsteroidal anti-in¯ammatory drug
(NSAID) (Skoutakis et al., 1988) and is mainly used in the
treatment of rheumatoid arthritis and other rheumatoid
disorders. It is a good example of a drug that is often prepared
as a controlled-release formulation. Diclofenac has numerous
solid forms, including the acid and various diclofenac salts. The
exemplary diclofenac acid crystal forms include its monoclinic
forms, in space group P21/c, which is recrystallized from
research papers
Figure 2
The intramolecular cyclization reaction of diclofenac in acidic solution
(Racz, 1990).
Palomo and coworkers studied sodium diclofenac treated
with acidic, neutral and basic solutions using UV±vis spec-
trophotometry, differential scanning calorimetry, SEM and
X-ray powder diffraction. They found that diclofenac changed
its physical and chemical properties and the X-ray powder
diffraction pattern changed, depending on the pH conditions
(Palomo et al., 1999).
No report to date has explained what happens to diclofenac
under acidic conditions.
1.4. Chitosan±diclofenac controlled-release drug
It has been reported that the half-life of diclofenac in
plasma is 1±2 h. Diclofenac can also cause gastrointestinal side
effects such as bleeding, ulceration or perforation. In order to
increase its biological half-life and reduce its associated
adverse effects, diclofenac is often used in the form of a
polymer±diclofenac controlled-release drug.
methanol by slow evaporation, and in C2/c, which is recrys-
tallized from acetone (Castellari & Ottani, 1997). Diclofenac
acid also exists in an orthorhombic form in space group Pcan,
which is recrystallized from hot methanol by slow evaporation
(Jaiboon et al., 2001). Examples of diclofenac salts include
potassium diclofenac dihydrate (Fini et al., 2001), sodium
diclofenac tetrahydrate (Fini et al., 2001), and sodium diclo-
fenac pentahydrate (Muangsin et al., 2002). The above-
mentioned polymorphism of diclofenac depends on the
recrystallization conditions. The study of polymorphism in
pharmaceutical substances is important because of possible
changes in their solubility, dissolution and shelf life (Yu et al.,
1998).
1.3. Diclofenac in acidic conditions
There have been reports that the physical and chemical
properties of diclofenac depend on the acidity of the condi-
tions to which it is exposed. The solubility of diclofenac
depends substantially on the pH of the surrounding solution,
being lower than 1 mg mlÿ1 in acidic conditions and increasing
for pH values above 6.5 (Palomo et al., 1999; Fini et al., 1995,
1992).
In addition, diclofenac can undergo chemical reactions
under acidic conditions to give biologically inactive products.
For example, it can undergo an intramolecular cyclization
(Fig. 2) under the acidic conditions found in gastric juices
(Racz, 1990).
J. Appl. Cryst. (2004). 37, 288±294 Nongnuj Muangsin et al.
Chitosan is poly[-(1,4)-linked-2-amino-2-deoxy-o-
glucose], produced from chitin. It is a non-toxic biodegradable
natural polymer that is widely used for controlled-release
drugs (Machida et al., 1989; Yao et al., 1995).
Usually, in the preparation of a diclofenac-containing chit-
osan matrix, diclofenac is dissolved in a solution of chitosan in
1%(w/v) acetic acid, and then the chitosan±diclofenac ®lms
are neutralized by 0.1 M NaOH (Orienti et al., 2002; Gupta &
Kumar, 2000; Fernandez-Hervas et al., 1998; Al-Angary et al.,
1998). Moreover, to decrease the release rate of diclofenac
from chitosan, glutaraldehyde is added into the chitosan±
diclofenac mixture to cross-link the chitosan matrix (Jameela
& Jayakrishnan, 1995; Kumbar et al., 2002).
Since chitosan dissolves only in certain dilute acids, it is
inevitable that the diclofenac will be exposed to an acidic
solution. The diclofenac may degrade or undergo chemical
reactions and produce biologically inactive products, or
undergo polymorphic changes which may alter its physico-
chemical properties and biological activities. Therefore, it is
very important to determine the nature of the solid form of
diclofenac in the diclofenac-containing chitosan matrix in
order to produce a pharmaceutical formulation with consis-
tent pharmaceutical qualities. Unfortunately, the chitosan±
diclofenac mixture cannot be prepared as single crystals and
so X-ray powder diffraction has to be used to investigate the
solid crystalline forms of diclofenac in the matrix. However,
the XRPD pattern in the presence of chitosan, which is an
amorphous material, is usually of poor quality. This paper
 Diclofenac±chitosan by X-ray powder diffraction 289
research papers
presents a technique for the preparation of the powder and its Table 1
characterization using conventional X-ray powder diffraction. Comparison of crystal data and structure re®nements of diclofenac acid,
as determined from single-crystal and powder data.
Single-crystal data Powder data
2. Experimental Wavelength 0.71073 AÊ 1.54059 AÊ
Crystal system and space group Monoclinic, C2/c Monoclinic, C2/c
The diclofenac-containing chitosan matrix employed in this Unit-cell dimensions a = 20.2906 (4) A Ê a = 20.298 (4) A Ê
study was prepared in the form of a ®lm. Diclofenac and b = 6.9952 (1) AÊ b = 6.993 (4) AÊ
chitosan were dissolved in 1% acetic acid and the solvent was c = 20.1137 (4) A Ê c = 20.107 (4) A Ê
then evaporated. This gave a chitosan±diclofenac ®lm in which
the diclofenac was dispersed in a chitosan matrix. The ®lm was
then pulverized and the resulting powder sieved to obtain a
sample suitable for structure determination from XRPD data.
2.1. Sample preparations
2.1.1. Recrystallization of a single crystal of diclofenac
acid (C2/c) for X-ray single-crystal diffraction. Sodium
diclofenac (2 g) was dissolved in water. The solution was
acidi®ed with concentrated HCl until a white precipitate of
diclofenac acid was observed. The precipitate was ®ltered,
washed with distilled water and dried in vacuo, and then
recrystallized from ethanol by slow evaporation.
2.1.2. Preparation of chitosan±diclofenac powder sample
for X-ray powder diffraction. Chitosan. Chitosan (1 g,
purchased from Fluka) was dissolved in 100 ml of 1% (w/v)
acetic acid solution and stirred at room temperature until the
solution was clear. The solution was then poured onto plastic
plates and left to dry at room temperature. The chitosan ®lms
were pulverized with a Retch ZM 1000 mill and the resulting
powder was screened through a testing sieve, Mesh No. 200,
75 mm.
The chitosan±diclofenac matrix. For the preparation of the
diclofenac-containing chitosan matrix at a weight ratio of 1:1,
1 g of chitosan was dissolved in 100 ml of 1% acetic acid
solution, and then 1 g of sodium diclofenac (purchased from
Amoli Organics Limited) was added and the mixture stirred at
room temperature until the solution was clear. The solution
was poured onto plastic plates and, after drying at room
temperature for 3 d, a pale-yellow ®lm was obtained. This
chitosan±diclofenac ®lm was immersed in 0.1 M NaOH over-
night, and then dried overnight under reduced pressure. The
®lm was pulverized with a Retch ZM 1000 mill and the
resulting diclofenac±chitosan powder was screened through a
sieve with a nominal mesh size of 75 mm. To avoid changing
the polymorphic form of the diclofenac, the chitosan±diclo-
fenac powder was subsequently ground using a mortar instead
of a high-speed mill, and screened through a sieve again. This
procedure was carried out repeatedly until a powder sample
suitable for XRPD analysis was obtained.
The diclofenac-containing chitosan matrix at a weight ratio
of 5:1 was prepared in the same manner as described above,
except that 5 g of sodium diclofenac was used.
Amount of diclofenac in the diclofenac-containing chitosan
matrix. A small quantity (0.2076 g) of the diclofenac±chitosan
(5:1) powder sample after the ®nal sieving, as used for XRPD
analysis, was stirred in 40 ml of methanol for 3 d to dissolve
the diclofenac from the chitosan matrix. The suspension was
290 Nongnuj Muangsin et al.  Diclofenac±chitosan by X-ray powder diffraction
 = 109.663 (1)  = 109.60 (2)
V = 2688.40 (8) A Ê3 V = 2689 (1) A Ê3
Z and calculated density 8, 1.463 Mg mÿ3 8, 1.463 Mg mÿ3
Re¯ections collected 6188 1378
Data / parameters 2197 / 216 1378 / 177
R1 = 0.0338 Rp = 0.155
wR2 = 0.0904 Rwp = 0.165
Bragg R
factor = 6.10
®ltered to obtain chitosan as a powdery yellow solid, which
was then washed with methanol and dried overnight under
reduced pressure to give dried chitosan (0.0315 g). The ®ltrate
was evaporated to obtain diclofenac as a white solid and then
dried under reduced pressure to give diclofenac (0.1668 g).
Calculated amount: 0.1723 g of diclofenac, 0.0353 g of chit-
osan; found: 0.1668 g of diclofenac, 0.0315 g of chitosan.
2.2. X-ray diffraction analysis
2.2.1. Single-crystal X-ray diffraction. Diclofenac acid
(DFNH) was recrystallized from ethanol with a crystal size of
0.40  0.45  0.45 mm. The diffraction data were collected on
a Bruker SMART CCD diffractometer equipped with a
graphite monochromator crystal and an Mo K radiation
source ( = 0.71073 A Ê ). The program SMART (Sheldrick,
1997) was used for diffractometer control, frame scans,
indexing, orientation matrix calculations, least-squares
re®nement of cell parameters, crystal-face measurements and
the actual data collection. Raw data frames were read by the
program SAINT (Sheldrick, 1997) and integrated using three-
dimensional pro®ling algorithms. The resulting data were
reduced to produce hkl indices, intensities and estimated
standard deviations. The data were corrected for Lorentz and
polarization effects. Absorption corrections were applied by
integration based on indexed measured faces. Data prepara-
tion was carried out using the program XPREP (Sheldrick,
1997). The structure was solved by direct methods. All non-H
atoms were found from electron-density maps and included in
the anisotropic re®nement. The H atoms were found from
difference Fourier maps and re®ned without any constraints.
The molecular structure of diclofenac acid from the single-
crystal data (represented by dashed lines) is shown in Fig. 3.
Crystal and experimental data are given in Table 1.
2.2.2. X-ray powder diffraction. The samples were `front
loaded' into a sample holder. The step-scanned diffraction
data were measured on a Rigaku diffractometer using
graphite-monochromated Cu K radiation ( = 1.5406 A Ê)
operating at 40 kV and 30 mA. The divergence slit size was
1 mm and the receiving slit was 0.1 mm. The pattern was
collected in the 2 < 2 < 100 range with a step size of 0.02 and
J. Appl. Cryst. (2004). 37, 288±294

Figure 3
A comparison of the molecular structures of diclofenac acid as re®ned
from powder data using the Rietveld method (dashed lines) and as
re®ned from single-crystal data (solid lines).
a counting time of 5 s per step. The K2 contribution was
mathematically removed from the data.
3. Results and discussion
3.1. Sample preparation for XRPD data collection
Initially, XRPD data were collected from the diclofenac-
containing chitosan matrix with the weight ratio of 1:1. The
XRPD pattern showed high background and noise, leading to
a very low signal-to-noise ratio. Since the quality of the data
can deteriorate with the amount of chitosan, the next attempt
was to increase the amount of crystalline diclofenac in the
matrix using a chitosan:diclofenac ratio of 1:5. However, the
result still gave high background and noise (low signal-to-
noise ratio). The XRPD diffraction data were still of low
quality, which made it dif®cult even for a solid-phase identi-
®cation of diclofenac in the chitosan matrix.
Figure 4
X-ray powder diffraction patterns of the diclofenac-containing chitosan
matrix at the weight ratio of 1:1, (a) before sieving and (b) after sieving
through a screen with a nominal mesh size of 75 mm.
J. Appl. Cryst. (2004). 37, 288±294
research papers
Figure 5
SEM photographs of the diclofenac-containing chitosan matrix at the
weight ratio of 5:1, (a) before sieving and (b) the ®nal sieved powder
sample, as used for collecting the XRPD data for structure determination.
Particle size and shape have an effect on the quality of the
data. Fine spherical particles pack more densely than needle-
shaped or large particles, so ef®cient sample packing can
increase the quantity of crystalline material in the X-ray beam.
However, reducing the particle size in pharmaceutical
processes by pulverizing the sample using a high-speed mill
may cause a change in polymorphic forms and degrade the
sample. Thus, to improve the quality of the present XRPD
data, the powder was ground using a glass mortar and put
through a sieve with a nominal mesh size of 75 mm until the
background and noise were minimized. This is achieved by
removing bulky and needle-shaped particles from the sample,
and by splitting aggregated particles. Fig. 4 shows the XRPD
patterns of the diclofenac-containing chitosan matrix at the
weight ratio of 1:1 before and after sieving several times. The
XRPD pattern of the sample before sieving shows a lower
signal-to-noise ratio than the sample after grinding and
sieving. The improvement in Fig. 4(b) is due to more ef®cient
sample packing.
Fig. 5 shows SEM photographs of the diclofenac-containing
chitosan matrix at the ratio of 5:1, of the sample before sieving
and of that used for the ®nal XRPD data collection for the
present structure determination. The lumps in the photo-
graphs are the chitosan matrix and the small bright particles
Nongnuj Muangsin et al.  Diclofenac±chitosan by X-ray powder diffraction 291
research papers
are diclofenac. The diclofenac particles are embedded inside
the chitosan matrix and some are deposited on the surfaces of
the chitosan lumps. As seen in Fig. 5(a), the particle shapes of
the diclofenac-containing chitosan matrix before sieving are
non-uniform and some particles are larger than 50 mm. In Fig.
5(b), the particles of the matrix are uniformly spherical and
the particle sizes are in the range of 10±20 mm.
To determine the amounts of diclofenac and chitosan in the
diclofenac-containing chitosan matrix used for the ®nal XRPD
data collection, the matrix was stirred in methanol for at least
3 d to dissolve the diclofenac dispersed inside the chitosan
matrix (x2.1.2). The amount of chitosan used to prepare the
diclofenac-containing chitosan matrix at the ratio 5:1 was
about 17% by weight. The amount of chitosan that remained
in the matrix used for the ®nal XRPD data collection was
about 15% by weight [as seen in Fig. 5(b), the sample powder
still contained chitosan matrix lumps]. This indicates that the
sieving procedure did not remove chitosan.
Therefore, in this work, it was possible to prepare samples
by the procedure described above to obtain XRPD data of
suf®ciently high quality for structure determination.
Fig. 6 shows the XRPD patterns of chitosan, sodium
diclofenac and the diclofenac-containing chitosan matrix at
the weight ratios of chitosan:diclofenac of 1:1 and 1:5. Chit-
osan gives an amorphous pattern. The XRD pattern of sodium
diclofenac corresponds to the JCPDS powder diffraction ®les
39-1684 and 36-1525. The XRPD patterns of the diclofenac-
containing chitosan matrix at the weight ratios of 1:1 and 5:1
are different from the pattern of sodium diclofenac before it is
added into the chitosan solution. These XRPD patterns of the
diclofenac contained in the chitosan matrix did not match any
JCPDS powder diffraction ®les. In the ®rst attempt to deter-
mine the crystal structure of diclofenac in the chitosan matrix, Figure 6
the diclofenac-containing chitosan matrix was dissolved in X-ray powder diffraction patterns of (a) chitosan, (b) sodium diclofenac,
(c) the diclofenac-containing chitosan matrix at the weight ratio 1:1, (d)
ethanol and the diclofenac recrystallized from ethyl acetate. the diclofenac-containing chitosan matrix at the weight ratio 5:1 and (e)
The crystal structure obtained for diclofenac recrystallized diclofenac sodium pentahydrate generated from single-crystal data
from the matrix is sodium diclofenac pentahydrate (Muangsin (Muangsin et al., 2002).
et al., 2002). The XRPD pattern of sodium diclofenac penta-
hydrate generated from its single-crystal data using the
PCW10 program is different from the XRPD pattern of the
diclofenac-containing chitosan matrix. This means that the
solid crystalline form of sodium diclofenac is different in the
diclofenac-containing chitosan matrix from that obtained after
recrystallization. The XRPD pattern of this diclofenac-
20.107 (4) AÊ and  = 109.60 (2) . The systematic absences
were consistent with the space group C2/c. This unit-cell
information is very close to the crystal structure of diclofenac
acid, which crystallizes in monoclinic space group C2/c with
unit-cell parameters of a = 20.2906 (4) AÊ , b = 6.9952 (1) A
Ê ,c=
Ê 
containing chitosan matrix was the same as that for diclofenac
precipitated from phosphate buffer (Palomo et al., 1999).
3.2. Structural analysis and discussion
Once XRPD data of suf®ciently good quality had been
collected, the pattern of the diclofenac-containing chitosan
matrix was indexed using the DICVOL91 program (Boultif &
Louer, 1991) on the basis of the 20 highest observed lines. The
best solution indexed all the lines, indicating a monoclinic cell.
The unit-cell parameters of diclofenac in the polymer mixture
were re®ned using CELREF (Laugier, 1999). The re®ned unit-
cell parameters are a = 20.298 (4) A Ê , b = 6.993 (4) A
Ê, c =
292 Nongnuj Muangsin et al.  Diclofenac±chitosan by X-ray powder diffraction
20.1137 (4) A,  = 109.663 (1) and V = 2688.40 (8) A Ê3
(Castellari & Ottani, 1997). In an attempt to solve the struc-
ture of crystalline diclofenac dispersed in the chitosan matrix
using the powder method, we disregarded the previously
reported structure. For our further studies, we recrystallized
diclofenac acid from ethanol and solved the structure.
Therefore, in this work we used our single-crystal data for
comparison with the powder solution.
The raw data were transferred to the FULLPROF98
program package (Rodriguez-Carvajal, 1990) and the powder
pattern was initially ®tted by re®ning the following para-
meters: zero point, background (polynomial function), pro®le
peak shape (pseudo-Voigt function) and unit-cell parameters
from powder data.
J. Appl. Cryst. (2004). 37, 288±294

Figure 7
Observed (circles) and calculated (solid line) pro®les for the Rietveld
re®nement of the chitosan±diclofenac mixture. The difference plot is on
the same intensity scale.
Integrated intensities were extracted from the pro®les using
Le Bail's method (Le Bail et al., 1988) over the range of 9.0 <
2 < 100 for 1378 re¯ections. A direct-methods calculation
was then carried out. All non-H-atom positions were located
and then re®ned using this data set in the SHELX97/PC
package (Sheldrick, 1997) and the FULLPROF 98 program.
The benzene rings obtained from the extracted data were
distorted. The Rietveld method was then used to re®ne all
non-H-atom positions without any constraints and with
isotropic displacement parameters, except for the benzene
rings, which were constrained. To complete the re®nement, all
H atoms were constrained to idealized positions and assigned
isotropic displacement parameters which were 20% greater
than the equivalent B values of the atoms to which they were
bonded. The ®nal cycle of re®nement was based on 117
parameters, and the resulting R values were Rp = 15.5, Rwp =
16.5 and Bragg R factor = 6.10. The residual R factors were
high, probably due to the presence of another crystalline
phase as an impurity. The difference plot (Fig. 7, comparing
the experimental powder diffraction pattern and the
computed pattern) shows peaks at about 2 = 13 and 21 .
These peaks correspond to the characteristic peaks of diclo-
fenac sodium pentahydrate (Fig. 6e) (Muangsin et al., 2002),
indicating its existence in the matrix.
The crystal structure of diclofenac acid from the chitosan±
diclofenac matrix was compared with the crystal structure of
diclofenac acid from single-crystal diffraction data. The
comparison parameters include the molecular structure,
atomic coordinates and bond lengths and angles.
In Fig. 3, the molecular structure of diclofenac acid obtained
from powder diffraction data, represented by solid lines, is
compared with that from the single-crystal data, represented
by dashed lines. The overall molecular structure from the
powder data is essentially the same as the molecular structure
from the single-crystal data. The positions of the Cl and N
atoms were relatively accurate compared with the single-
J. Appl. Cryst. (2004). 37, 288±294 Nongnuj Muangsin et al.
research papers
crystal structure. The H atom of the amine group is involved in
a bifurcated hydrogen bond, to the Cl atom and the carbonyl
O atom of the carboxylic group, giving rigidity. However, the
orientations of the carboxylic group and benzene ring are
slightly different from the single-crystal structure. The differ-
ences in orientation are probably due to the presence of
chitosan adversely affecting the quality of the data.
A comparison of the crystallographic data from the single-
crystal and powder samples is shown in Table 1. Table 2,
comparing the atomic coordinates, Table 3, comparing the
bond distances and angles, and other structural data have been
deposited.1 The deviation, de®ned as D* = (XRSC ÿ XRPD)/
2
(XRSC 2
ÿ XRPD )1/2, is used for comparison of ®nal atomic
positions and bond lengths and angles. The atomic coordinates
obtained from both XRPD and XRSC are comparable, with
the deviations of the atomic positions in the range ÿ0.0169±
0.0312.
The comparison shown in Fig. 3 reveals that the present
structural determination of diclofenac acid in the diclofenac-
containing chitosan matrix from conventional XRPD data is in
good agreement with the single-crystal structure. In particular,
both structures are comparable in all bond lengths and angles.
The average differences in the bond lengths and angles are
0.042 AÊ and 5.03 , respectively, and the deviations of the bond
lengths and angles are in the ranges ÿ0.028±0.036 A Ê and

ÿ0.639±0.710 , respectively.
4. Conclusion
In this paper, we have identi®ed that sodium diclofenac, the
starting material in the preparation of a controlled-release
diclofenac-containing chitosan matrix, changes in the matrix
to diclofenac acid with space group C2/c. In its acid form, the
solubility of diclofenac is lower than in its salt form (Fini et al.,
1992, 1995). This may cause the release rate of diclofenac from
the chitosan matrix to be lower than expected. The crystal
structure of diclofenac in the chitosan matrix was determined
using conventional powder diffraction techniques. This paper
presents simple techniques for handling a powder sample of
diclofenac embedded in a chitosan matrix for characterization
of the solid crystalline forms and structure determination of
diclofenac. The quality of the powder diffraction data was
improved by obtaining a powder sample with a suitable
particle size and uniformly spherical shape in order to reduce
the preferred orientation and increase the signal-to-noise
ratio. This can be achieved simply by grinding and sieving the
powder samples through a micro-mesh sieve several times
until the signal-to-noise ratio is satisfactory. The structure
solution of diclofenac embedded in a chitosan matrix from
conventional powder diffraction data is relatively accurate,
compared with the single-crystal structure. The unit-cell
parameters, molecular structure and bond lengths and angles
1
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: KS0188). Services for accessing these data are described
at the back of the journal.
 Diclofenac±chitosan by X-ray powder diffraction 293
research papers
are in good agreement. The average differences of the bond
Ê and 5.03 , respectively.
lengths and angles are 0.042 A
Financial support was provided by the National Science and
Technology Development Agency (NSTDA), Thailand e-
Science and Chulalongkorn University, Thailand. Mr P.
Mikasana (TISTR, Thailand) is thanked for research colla-
boration.
References
Al-Angary, A. A., Al-Helw, A. A. M., Al-Dardiri, M. M. & Mahrous,
G. M. (1998). Pharm. Ind. 60, 629±634.
Boultif, A. & Louer, D. (1991). J. Appl. Cryst. 24, 987±993.
Castellari, C. & Ottani, S. (1997). Acta Cryst. C53, 794±797.
Fernandez-Hervas, M. J., Holgado, M. A., Fini, A. & Fell, J. T. (1998).
Int. J. Pharm. 163, 23±34.
Fini, A., Fazio, G. & Feroci, G. (1995). Int. J. Pharm. 126, 95±102.
Fini, A., Fazio, G., Orienti, V., Bertasi, V., Zecchi, V. & Rapaport, I.
(1992). Eur. J. Pharm. Biopharm. 38, 66±70.
Fini, A., Garuti, M., Fazio, G., Alvarez-Fuentes, J. & Holgado, M. A.
(2001). J. Pharm. Sci. 90, 2049±2057.
Gupta, K. C. & Kumar, M. N. V. R. (2000). Biomaterials, 21, 1115±
1119.
Harris, K. D. M. & Tremayne, M. (1996). Chem. Mater. 8, 2554±2570.
Jaiboon, N., Yos-in, K., Ruangchaithaweesook, S., Chaichit, N.,
Thutivoranath, R., Siritaedmukul, K. & Hannongbua, S. (2001).
Anal. Sci. 17, 1465±1466.
Jameela, S. R. & Jayakrishnan, A. (1995). Biomaterials, 16, 769±775.
294 Nongnuj Muangsin et al.  Diclofenac±chitosan by X-ray powder diffraction
Kariuki, B. M., Psallidas, K., Harris, K. D. M., Johnston R. L.,
Lancaster, W. R., Staniforth, S. E. & Cooper, S. M. (1999). Chem.
Commun. pp. 1677±1678.
Kumbar, S. G., Kulkarni, A. R. & Aminabhavi, T. M. (2002). J.
Microencapsul. 19, 173±180.
Laugier, J. (1999). CELREF. Domaine University, France.
Le Bail, A., Duroy, H. & Fourqueet, J. L. (1988). Mater. Res. Bull. 23,
447.
Machida, Y., Nagai, T., Inouye, K. & Sannan, T. (1989). Chitin and
Chitosan, edited by G. Skjak-Brack, T. Anthonson & P. Sandford,
pp. 693±702. Amsterdam: Elsevier.
Muangsin, N., Prajaubsook, M., Chaichit, N., Siritaedmukul, K. &
Hannongbua, S. (2002). Anal. Sci. 18, 967±968.
Orienti, I., Cerchiara, T., Luppi, B., Bigucci, F., Zuccari, G. & Zecchi,
V. (2002). Int. J. Pharm. 238, 51±59.
Palomo, M. E., Ballesteros, M. P. & Frutos, P. (1999). J. Pharm.
Biomed. Anal. 21, 83±94.
Racz, I. (1990). Drug Formulation, pp. 352±386. Budapest: Wiley
Rodriguez-Carvajal, J. (1990). FULLPROF. A Program for Rietveld
Re®nement and Pattern Matching Analysis. Abstracts of the
Satellite Meeting on Powder Diffraction of the XV Congress of
the IUCr, Toulouse, France, p. 127.
Sheldrick, G. M. (1997). SMART and SAINT (Versions 4.0), and
XPREP and SHELX97/PC, both in SHELXTL (Version 5.10).
Bruker AXS Inc., Madison, Wisconsin, USA.
Skoutakis, V. A., Carter, Ch. A., Mickle, T. R., Smith, V. H., Arkin,
Ch. R., Alissantros, J. & Petty, D. A. (1988). Drug Intell. Clin.
Pharm. 22, 850±859.
Villiers, M. M. de, Wurster, D. E., Van der Watt, J. G. & Ketkar, A.
(1998). Int. J. Pharm. 613, 219±224.
Yao, K. D., Peng, T., Yin, Y. J., Xu, M. X. & Goosen, M. F. A. (1995). J.
Macromol. Sci. Rev. Macromol. Chem. 35, 155±180.
Yu, L., Reutzel, S. M. & Stephenson, G. A. (1998). Pharm. Sci.
Technol. Today, 1, 118±127.
J. Appl. Cryst. (2004). 37, 288±294