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Physical aspects of dexibuprofen and racemic ibuprofen

Article  in  The Journal of Clinical Pharmacology · January 1997

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 Physical Aspects of Dexibuprofen and
Racemic Ibuprofen
Günther Leising, Roland Resel, Franz Stelzer, Stefan Tasch, Arthur Lanziner,
and Gerhard Hantich

This article presents a comparative study of ibuprofen materials in their solid state.
Ibuprofen crystallizes into tirn different structures for the S(-r·) enantiomer (dexibupro·
fon) and racemic ibuprofen. The cTFstal structure of ibuprofen. its optical absorption
and photoluminescence. and the thermodynamic results {melting point and heat of
fusion} are discussed. From these physicochemical properties, the authors conclude
that dexibuprofen. \\·hich is the most active species pharmaceutically. and racemic
ibuprofen are inherently different solid-state materials.

T knowledge
he aims of this research \Yere to provide the
necessary to produce a stable, effec-
tive, safe, and reproducible dosage form of drug sub-
stances. Dexibuprofen, the pure S(-:-) enantiomer of
ibuprofen, shows appreciably high er solubility,
higher dissolution rates. a lower melting tempera-
ture. and a different crystal structure compared with
the racemic form. 1 - 6 Same physical properties of de-
xibuprofen and racemic ibuprofen are investigated
and discussed in the framevvork of their physico-
chemical properties. This article reports on the crys-
tal structures of the two enantiomers. their optical
and thermodynamic properties, and their solubility.
Dexibuprofen and racemic ibuprofen are fundamen-
R(- )-ibuprofen. Racemic ibuprofen contains both
S( + )-ibuprofen and R(- )-ibuprofen molecules, gen-
erally in equal amounts. lt is e\·ident that dexibupro-
fen should have a different crYstal structure than the
racemic form. The x-ray diffraction technique is a
pmverful tool for studying the crystal structure of
solid materials. The ibuprofens and their different
crystalline forms have been studied using this tech-
nique. 2 ·"- 7
In the present work, the authors also studied the
crystal structure of the pure S( - ) enantiomer of ibu-
profen and ofracemic ibuprofen in their polycrystal-
line powder form. The x-ray diffraction powder spec-
tra for Cu-K radiation for dexibuprofen and the race-
0

tally different materials in terms of their physical
properties. These differences rna\· have irnplications
regarding their physiologic ax-ailabili ty and their
ph~·sical and chemical stabilit\. The physiologic
arnilability appears tobe higher for the dexibuprofen
enantiomer.
CRYSTAL STRUCTURE
mic form are shown in Figure 2. The different crystal
structures of the l\rn enantiomers are manifested in
their completely different diffraction patterns. The
crvstal structure data of the two enantiomers are
gi~1 en in Table 1. There are the same number of ibu-
profen molecules in the unit cell of each enantiorner.
but the size oftheir unit cells (a. b, c) are significantly
different and they have other space groups.

Figure 1 depicts the chernical structure of the two

OPTICAL PROPERTIES
enantiomers S( + )-ibuprofen (dexibuprofen) and

The optical absorption of atoms. molecules, and sol-

From the Institut für Festkörperphysik {Univ Prof. Dr. Leising and Dr.
Resel) and the Institut für Chemische Technologie Organischer Stoffe
:Dr. Stelzer), Technische Universität Graz, Graz. Austria. and Gebro Fieb-
erbrunn. Broschek GmbH, Fieberbrunn, Austria iDrs. Lanziner and Han-
t1ch). Address for reprints: Günther Leising, Institut für Festkörperphysik,
Technische Universität Graz, Petersgasse 16. A-8010 Graz, Austria.
ids is caused by dipole-allowed transitions of elec-
trons from a ground state to an excited state. If the
transition of this excited system to the grounded state
is also dipole allowed, light emission (i.e„ photolu-
minescence) is observed. The ultraYiolet absorption
spectrum of dexibuprofen in an n-heptane solution

J Clin Pharmacol 1996;36:3S-6S 3S

 LEISING ET AL

TABLE 1
H,C ~OH Crystal Structure Data for ( + )-lbuprofen and (:.t )-
H,~ ~ lbuprofen (after Ref. 3)
(+)- (=)-
(S)( +)-Ibuprofen (R)(-)-lbuprofen lbuprofen lbuprofen

Formula C13H1a02 C13H1aÜ2

Figure 1. The chemical structure of the S( 7) and R(-) enantiomers Molecular weight 206.3
of ibuprofen.
206.3
Crystal system monoclinic monoclinic
Space group P211c P21
a [Al 12.46 12.67
is presented in Figure 3. The main feature is a broad b [Al 8.03 7.88
c [Al 13.53 10.73
absorption peak at approximately 221 nm, which Cl' [o]
changes its position as a function of the refractive ß [o] 112.95 99.3
index and the polarity of the solvent used. Hs The No. of molecules in the cell 4 4
transition from ground state (r.) to excited state (ri*) Density [g/cm- 3] 1.098 1.110 7
in the 1,4-substituted benzene ring of the ibuprofen
molecule is responsible for this absorption peak. The
ibuprofen enantiomers and the racemate cannot be
distinguished when the optical absorption experi- 220-nm ultraviolet light are shown in Figure 4. and
ments are performed with unpolarized light. This is the dexibuprofen and the racemate material can be
also true for the photoluminescence emission of the clearly distinguished. The structure in the photolu-
molecules in solution. The situation is completely minescence emission spectra is created from the in-
different for ibuprofen in the solid state. Because of teraction of the C=C/C-C vibrations in the benzene
the different crvstal structure and, therefore, the dif- ring with the electronic transitions of the ibuprofen
ferent molecul~r packing of the enantiomers and the molecules.
racemate 5 in the solid state, the conditions for the
radiative transitions of the excited ibuprofen mole-
cules (i.e„ the photoluminescence spectra) are ex- THERMODYNAMIC PROPERTIES
pected to depend an the local structural environ-
ment. There is a pronounced difference between the ther-
The photoluminescence spectra of dexibuprofen modynamic properties of the two materials, dexibu-
powder and racemate powder under excitation with profen and the racemate. Because of the different

i ": µLv~ 1~ U~~

A 1
L ~~~'---~~--'-~~--'~~~~~~........J B
5 10 15 20 25 30 5 10 15 20 25 30
20 [deg) 20 [deg)

F'igure 2. X-mv diffraction spectra from ibuprofen poivders. A. dexibuprofen: B. racemic ibuprofen.

4S • J Clin Pharmacol 1996;36:35-65

 DEXIBUPROFEN AND RACEMIC IBUPROFEN

1.6
,........ 1.4
·I
/·
:::;
~ 1.2 ·I I.
<ll 1.0
(.) . 1
~ 0.8
.0
I.
. 1
0 0.6
I .
C/)
.0
<( 0.4 __ ___, . \
0.2
40 45 50 55 60 65 70 75 80 85
0. 0 '-"-'-'--'-'-"~---'-'-~_J_._...._,__._L_......._~:...............__,__J

200 210 220 230 240 250 260 Temperature (°C)

Wavelength (nm)
Fig~re5. Differential Scanning Calorimeter traces for powders of
dex1buprofen (solid line) and racemic ibuprofen (dashed line).
Fi~ure 3. Ultraviolet absorption spectrum of dexibuprofen in an
n-lleptane solution.

0.3°C and 75.3 ::!::: 0.3°C, respectively. The heat of fu-

crystal packing and crystal binding energy, they have
significantly different melting points and values for
the heat of fusion. 1 - 9 The authors measured the melt-
ing point and the heat of fusion for a series ofpowder
samples of dexibuprofen and the racemate with the
Differential Scanning Calorimeter (DSC4; Perkin El-
mer. Übeulingeu, Germany) and plotted a typical re-
sult for each series (Figure 5). The melting points
of dexibuprofen and racemic ibuprofen were 52.1 :±:
::;
sion was calculated from the integration of the Differ-
ential Scanning Calorimeter trace, and the values
were 91 :±: 1 J/g for dexibuprofen and 125 :::':: 2 J/g
for racemic ibuprofen, a significantly higher value.
These figures agree with the data in the literature
concerning different types of ibuprofen. 1 - 9
SOLUBILITY
The solubility and dissolution rates of the ibuprofen
enantiomers and the racemate depend strongly on
the temperature and the pH value of the sokent. 1 - 2 -9
The authors performed solubility experiments on a
series of powder samples of S( + )-ibuprofen. R( - )-
ibuprofen, and the racemate in a buffer solution (pH
= 1.5; 37.3 g of potassium chloride and 35 mL of

-CO
(J)
(.)
hydrochloric acid concentration in 10 L of water,
with the hydrochloride adjusted to pH = 1.5) at a
temperature of 37 = 0.5°C. For dexibuprofen. the sol-
c
CO
_o '\J ubility was 9.61 mg/100 mL; for R(- )-ibuprofen. a
._
similar value of 9.51 mg/100 mL was obtained. For
0
Cl)
_o
<
V the racemic ibuprofen, however, the solubilitv was
only 4.65 mg/100 mL, which is less than half of the

! values of the pure enantiomers. Even after a storaoe

time of more than 100 hours, the dexibuprofen sol~­
tion still had a concentration of 9.50 mg/100 mL (rep-
260 280 300 320 340 360 resenting a change of approximately 1 % over 100
Wavelength (nm) hours). In contrast, the concentration of the racemate
decreased by approximately 4% to a value of 4.47
mg/100 mL. Therefore, the dexibuprofen had a solu-
Fi_gure 4. Solid-state powder photoluminescence emission spectra bility twice as high as that of the racemate, and the
o_t dexibuprofen (solid line} and racemic ibuprofen (dashed line). solution was very stable over a few days.

DECEMBER SUPPLEMENT 5$

DISCUSSION
From the available physicochemical data, the au-
thors conclude that S( + )-ibuprofen and racemic ibu-
profen are two inherently different solid-state mate-
rials. Thev have different crvstal structures, which
poses se\;ere consequences · for their behavior in
terms of their drug-relevant properties. The high sol-
ubility and the high dissolution rate of the pharma-
ceutically active S( +) enantiomer of ibuprofen (dexi-
buprofen) seem to guarantee a high physiologic avail-
ability of this new drug material.
The ibu profen materials were provided b\· Gebro Broschek
GmbH. Fieberbrunn ..\ustria.
REFERENCES
1. Udupa '.\: Characterization of different crvstal forms of ibupro-
fen. tinidazole and lorazepam. Drug De11
1990: 16:1591-1596.
65 • J Clin Pharmacol 1996;36:35-65
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LEISING ET AL
2. Romero AJ: PhD Thesis. Providence: Uni\·ersitv of Rhode Is-
land. 1991. ·
3. Romero AJ, Rhodes CT: Approaches to stereospecific preformu-
lation of ibuprofen. Drug Dev· Ind Pharm 1991:17:777-792.
4. Dwivedi SK, Sattari S, Jamali F. !v!itchell .\G: Ibuprofen race-
mate and enantiomers: phase diagram. solubility and thermody-
namic studies. Int f Pharmaceutics 1992:87:95-104.
5. Romero .\J, Rhodes CT: Stereochemical aspects of the molecu-
lar pharmaceutics of ibuprofen. f Ph arm Pharmacol l 993; 45:258-
262.
6. Romero .\), Savastano L. Rhodes CT: Monitoring crvstal modi-
fications in systems containing ibuprofen. Int f Pharmaceutics
1993; 99:125-134.
7. Labhasetwar V. Deshmukh SV. Dorle .\K: Studies on some
crystalline forms of ibuprofen. Drug Dev Ind Pharm 1993: 19:631-
641.
8. Schiermeier W~!: Zur Löslichkeit rnn Ibuprofen-Racemat und
Enantiomeren (PhD Thesis). Innsbruck. ,\ustria: Cniversit\· of
Innsbruck. 1994. .
9. Burger .\.Koller KT, Schiermeier \V:Vl: Ibuprofen und dexipro-
Ind Pharm fen: binäres system und ungewöhnliches löslichkeitsverhalten.
Sei Pharm 1994;62:141.