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Compatibility Study of Ibuprofen with Some

Excipients Employed for Solid Dosage Forms

Article in Revista de Chimie -Bucharest- Original Edition- · February 2015

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 Compatibility Study of Ibuprofen with Some Excipients
Employed for Solid Dosage Forms

FELICIA DRAGAN1, IRINA KACSO2*, SIMINA DREVE2, FLAVIA MARTIN2, GHEORGHE BORODI2, IOAN BRATU2, KAMEL EARAR3*
1
Oradea University, Faculty of Medicine and Pharmacy, 1 Armatei Romane Str., 410087, Oradea, Romania
2
National Institute for Research and Development of Isotopic and Molecular Technologies, 67-103 Donat Str., 400293, Cluj-
Napoca, Romania
3
Dunarea de Jos University of Galati, Faculty of Medicine and Farmacy, 35 Al. I. Cuza Str., 800010, Galati, Romania

The present work evaluates the compatibility of the commercial form of Ibuprofen (IBU), a non-steroidal
anti-inflammatory drug with a range of pharmaceutical excipients of common use. The study was performed
on drug and excipients mixtures in a 1:1 (w:w) ratio, mixed by grinding at room temperature. In order to
prove the compatibility/incompatibility of IBU with the selected excipients the most frequently analytical
methods were employed: differential scanning calorimetry (DSC), Fourier transformed Infrared Spectroscopy
(FT-IR) and X-ray powder diffraction technique (XRPD). The calorimetric results, confirmed by FT-IR and
XRPD analysis, suggest interactions between IBU and two excipients, magnesium stearate (Mg stearate)
and Macrogol 6000.
Keywords: Ibuprofen, Excipients, Thermal analysis, FT-IR spectroscopy, X-ray powder diffraction

The pharmaceutical formulation of a drug active
substance involves blending with different excipients to
maximize the physico-chemical stability of the drug and
to ensure the drug bioavailability and the dosage form
manufacturability, respectively.
Preformulation is the first step in the active
pharmaceutical ingredients (API) formulation. The
adequate excipient selection improves both the
manufacturing and the ability of the product to be
administrated in most efficient doses [1, 2]. The
preformulation stage is mandatory associated with quick
and accurate test methods, in order to find the most
appropriate relation between drug-excipient or excipient-
excipient interactions and delivery/desorption phenomena
[3, 4]. New dosage forms are meant to increase therapeutic
efficacy and safety of drugs. Potential physical and
chemical interactions between drugs and excipients may
lead to changes of API’s bioavailability and stability in new
formulations [5-7]. The specific excipient selection for a
new formulation of a drug depends on its physico-chemical
compatibility/interaction, taking into account that even
excipients thought as being inert have shown possible
interactions with the drug [8, 9]. The gastric depletion rate
of drugs determines their absorption; through an adequate
formulation one can improve the drug solubility and
dissolution rate and consequently their absorption is faster
[10].
Drug-excipient chemical compatibility can be predicted
by computational methods which offer a rapid analysis
without requiring substance quantities, but its use as unique
information source presents an inherent risk. The binary
mixture compatibility testing is the commonly used
method, when 1:1 (w/w) or customized binary mixtures
of drug and excipient are blended with or without water
addition, stored under stressed conditions and analyzed
using stability-indicating methods (e.g. high performance
liquid chromatography, FTIR and thermal methods) [1, 9-
14]. The compatibility with excipients can be influenced
also by the polymorphic form of the active pharmaceutical
chemical ingredients used in formulation process [4, 11-
16].
Ibuprofen (IBU) (C13H18O2, (RS)-2-(4-(2-methylpropyl)
phenyl)propanoic acid) is a non-steroidal anti-
inflammatory drug (NSAID) with antipyretic and analgesic
effects being an inhibitor of cyclooxygenase, the enzyme
responsible for the conversion of arachidonic acid to
prostaglandins [5, 15-18]. IBU was widely prescribed by
physicians, despite its side effects as irritating agent for
gastro-intestinal tract [19, 20]. IBU, like other disperse
systems, which require mixing compatibility exhibit low
solubility in water, bad powder flow, compressibility and
compactibility [13, 14, 21, 22]. Moreover, from its
hydrophobicity the bioactive substance IBU tends to stick
and to agglomerate, dosage being more difficult. The
structural formula of IBU is represented in figure 1.
Fig. 1. Structural formula
of Ibuprofen (IBU)
There are several reports in the literature concerning the
interactions and incompatibilities of IBU with the most used
pharmaceutical excipients in solid dosage forms [2, 5, 10,
22-25]. The reports showed some incompatibilities with
polyvinylpyrrolidone and stearates [1, 5, 26], PEG 8000 [22],
Eudragit RL100 [27], magnesium oxide and sodium
bicarbonate [28], cellulose ether derivatives [29],
highlighted by different techniques, such as differential
scanning calorimetry (DSC), Fourier transform infrared (FT-
IR) spectroscopy or X-ray powder diffraction (XRPD) .
The aim of the present study was to evaluate the
compatibility between IBU and some of the commonly
employed pharmaceutical excipients: microcrystalline
cellulose, corn starch, lactose monohydrate, starch sodium
glycolate, macrogol 6000 (PEG 6000), magnesium
stearate, titanium dioxide and talcum. Using differential
scanning calorimetry with the support of Fourier transform
infrared spectroscopy and X-ray powder diffraction we were

* email: irina.kacso@itim-cj.ro; earar_dr.kamel@yahoo.com

REV. CHIM. (Bucharest) ♦ 66 ♦ No. 2 ♦ 2015 http://www.revistadechimie.ro 191

able to evaluate the compatibility/incompatibility of IBU
with these excipients.
The sample of IBU used in this study corresponds to the
solid form reported by McConnell in 1974 [30] in the
Cambridge Structural Database [31] and confirmed by
Stone in 2009 [32], being different to that used in the
compatibility studies performed by Tita [5, 23].
Experimental part
Materials
The non-steroidal anti-inflammatory drug IBU (ShaSun
Chemicals and Drugs LTD, India) and the pharmaceutical
excipients: microcrystalline cellulose, corn starch, lactose
monohydrate, starch sodium glycolate, Macrogol 6000
(PEG 6000), magnesium stearate, titanium dioxide and
talcum, were supplied royalty free by the Faculty of Fig. 2. Thermoanalytical curves of IBU with Macrogol 6000
Medicine and Pharmacy, Oradea University, Romania. The
chemicals were used as received without further
purification.
Sample preparation.
The excipients were blended and sieved on a 0.2 mm
sieve, the granulometric fraction of 200μm being retained.
For compatibility testing of the IBU with excipients, the
components were accurately weighed and physically
mixed by grinding in an agate mortar in a proportion of 1:1
(w:w) approximately for 5 min at room temperature.
Equipment
The DSC thermograms were obtained with a DSC-60
Shimadzu differential scanning calorimeter. The heating
of the samples was done with a rate of 10oC/min in the 20-
Fig. 3. Thermoanalytical curves of IBU with Mg stearate.
500oC interval by using sealed aluminium cells under
nitrogen atmosphere. A crimped cell containing alumina Thermal behaviour of IBU to controlled heating presents
was taken as reference. FT-IR measurements were a sharp endothermic melting peak at Tonset = 73.6°C with
performed with a JASCO 6100 FT-IR spectrometer in the ΔHfus = -160.7 J . g-1, the compound being stable up to 170oC
4000-400 cm 1 spectral domain with a resolution of 4 cm-1 and above this temperature it decompose.
by using the KBr pellet technique. X-ray diffractograms The DSC curve of Macrogol 6000 (fig. 2) has shown a
were obtained with a Bruker D8 Advance diffractometer in sharp endothermic peak with Tonset = 55.8°C and ΔHfus = -
the 2θ (°) = 3-43 angular domain using Cu Kα1 radiation. 238 J . g-1 corresponding to the melting point.
In order to increase the resolution a monochromator was The physical mixture IBU-Macrogol 6000 presents a
used to eliminate the Kα2 radiation. single sharp endothermic peak at Tonset = 46.4°C and Tpeak
= 49.8°C with ΔHfus = -186.3 J . g-1, in this case the melting
Results and discussions temperature of the mixture is lower than of the pure
Differential Scanning Calorimetry components.
One of the most frequently used instrumental technique Magnesium stearate presents on DSC curve (fig. 3) a
on pharmaceutical researches in the pre-formulation broad endothermic peak between 50 and 77°C with Tpeak =
stages is the thermal analysis, in particular DSC [2, 8, 33, 66.3°C representing dehydration of the sample, while the
34]. It is a rapid method for evaluating the physico-chemical IBU-Mg stearate mixture shows an endothermic signal at
interactions between the components and to determine a lower temperature with Tonset = 46.4°C and Tpeak = 50.9°C
the thermal stability of drugs - an important property and ΔHfus = -177.6 J . g-1.
concerning the adequate drug formulation technology and In both mixtures one can observe that the melting peak
the storage conditions. Shifting or disappearance of of IBU disappears and the melting temperatures of the
characteristic melting signals and/or ΔH enthalpy variations mixtures are lower than of the components indicating
are indications of the chemical incompatibility between interactions between them in the 40 - 50°C temperature
the drug-excipient mixture components [35, 36]. range, in agreement with the literature data [1, 5, 23, 37].
In the 1:1 mixtures of IBU with microcrystalline
cellulose, corn starch, lactose monohydrate, starch sodium FT-IR Spectroscopy
glycolate, titanium dioxide and talcum the DSC analysis FT-IR spectroscopy is used as a supplementar y
shows no interaction between drug and excipient. The technique to investigate possible drug-excipient chemical
values of thermal events for both components of the tested interactions, by detecting the involved atoms/groups and
mixtures remain practically unchanged, the DSC curves to support the results obtained by the thermal analysis [24].
reflects the physical mixtures IBU- excipient. In the case The appearances of new absorption band(s), broadening
of mixtures with Macrogol 6000 and magnesium stearate of band(s), and alteration in intensity are the main
the DSC traces show differences in the thermal behavior characteristics to evidence interactions between the
of the IBU, in terms of the melting temperature values (fig. components [38, 39].
2 and fig. 3). For a physical mixture with no chemical interactions
the FT-IR spectra can be considered as the superposition
192 http://www.revistadechimie.ro REV. CHIM. (Bucharest) ♦ 66 ♦ No. 2 ♦ 2015

A
A
of the individual ones without any shift or broadening in the
vibration bands of the components.
For all physical mixtures of IBU with excipients the FT-
IR spectra were recorded. Further, only the spectra for the
cases where the thermal analysis indicates a possible
interaction will be presented: the mixtures of IBU with
Macrogol 6000 (fig. 4A and B) and Mg stearate (fig. 5A and
B), respectively.
In the 2400–3100 cm-1 spectral region the spectrum of
pure IBU shows the bands corresponding to the stretching
vibrations of the methylene and methyl groups at 2941,
2914 and 2862 cm-1 and to the stretching vibration of the
O-H group. In the 1800-1000 cm-1 spectral domain the
intense band at 1721 cm -1 represents the stretching
vibration of the carboxylic -C=O group. The C-C stretching
vibrations of the aromatic ring are present at 1507 cm-1
and the region 1450-1300 cm -1 shows bands which
correspond to the symmetric and asymmetric bending
vibrations of the –CH3 group [25].
The FT-IR spectrum for Macrogol 6000 presents the
characteristic stretching vibrations bands for –CH2 groups
at 2888, 1468, 1341 and 1280 cm-1 and for C-O-C bond at
1108 cm-1, respectively [24].
The IBU-Macrogol 6000 mixture spectrum (fig. 4A and
B) shows a split of the stretching vibrations band of the
methylene groups located at 2888 cm-1 on the Macrogol
6000 spectrum. However, there are no spectral changes in
the 1800-1000 cm-1 region concerning this sample.
Magnesium stearate presents strong C-H vibrations in
the region of 2950 - 2850 cm -1. In the 1700–1400 cm-1
spectral domain, the asymmetric and symmetric
stretching vibrations corresponding to –COO - and the
bending vibrations of the aliphatic C-H bonds are observed.
As concerning IBU-Mg stearate mixture (fig. 5A and B),
whereas the C=O vibrational frequency remains
unmodified, the -COO- vibration of Mg stearate is shifted to
a lower value, at 1561 cm-1, perhaps due to the hydrogen
bonding. Also, one can observe some intensity changes
appearing in the FT-IR spectrum of the physical mixture as
compared to the starting compounds spectra.
REV. CHIM. (Bucharest) ♦ 66 ♦ No. 2 ♦ 2015 http://www.revistadechimie.ro
Fig. 4. FT-IR spectra of IBU with
Macrogol 6000:
A. 3600-2400 cm-1 spectral domain;
B. 1800-1000 cm-1 spectral domain
B
Fig. 5. FT-IR spectra of IBU with
Mg stearate:
A. 3100-2700 cm-1 spectral domain;
B. 1800-1100 cm-1 spectral domain
B
X-Ray Powder Diffraction
X-ray powder diffraction is a useful analysis in
determining incompatibilities that occur during
preformulation or formulation processes causing
modifications of the cr ystallinity/amorphicity or
polymorphic form of the drug in the presence of excipients
[40, 41]. This is possible by comparison of the physical
mixture powder pattern with those of its individual
components. The disappearance of some peaks present
in the individual components, along with the change in the
intensity of peaks proves the interactions between
components.
The incompatibility of IBU-Macrogol 6000 and IBU-Mg
stearate physical mixtures, resulted from our DSC
measurements, and investigated by X-ray diffraction is
illustrated in figure 6 and 7, respectively. For the other used
excipients the XRPD method confirms the compatibility
since the diffraction peaks of IBU remained unaltered
within the physical mixtures.
The powder diffraction pattern of the binary mixture
formed by IBU with Macrogol 6000 (fig. 6) shows a good
crystallinity compared to its physical mixture with Mg
stearate. IBU-Mg stearate (fig. 7) has a distorted crystalline
network, due to the excipient which is amorphous, but
IBU keeps its crystallinity in the mixture.
Fig. 6. X-ray diffraction patterns of IBU and of the binary mixture
with Macrogol 6000
193

X-ray DIFFRACTION DATA FOR IBU, MACROGOL 6000 AND IBU-MACROGOL 6000
θ θ
Fig. 7. X-ray diffraction patterns of IBU and of the
binary mixture with Mg stearate
θ θ
X-ray diffraction data for IBU, Macrogol 6000, Mg stearate
and their physical mixtures (1:1 w/w) are illustrated in
table 1 and table 2.
Comparing the diffraction pattern of IBU with those of
mixtures with the two excipients, Macrogol 6000 and Mg
stearate, one can observe the appearance of new peaks
or disappearance of some from diffraction patterns of the
pure components. The more intense peaks of IBU appear
at the following value of the 2…(°): 6.076, 12.183, 16.562,
17.620, 19.464 and 20.132.
The characteristic peaks of IBU are slightly shifted in
the IBU-Macrogol 6000 mixture, as shown in table 1. As
well some peaks corresponding to Macrogol 6000 are not
present in the diffraction pattern of the physical mixture.
The differences which appear in the diffraction pattern
of IBU-Mg stearate mixture compared with the
components patterns are presented in table 2. We can
observe the appearance of new diffraction lines at 2…(°)
194 http://www.revistadechimie.ro
Table 1
(1:1 w/w)
θ
θ
Table 2
X-ray DIFFRACTION DATA FOR IBU,
MG STEARATE AND IBU-MG STEARATE
(1:1 w/w)
= 3.394; 5.218; 12.718; 23.389 and a small shift of the
more intense peaks of the IBU.
All these data obtained from XRPD indicate the physical/
chemical interactions between IBU and these two
excipients, supporting the results of DSC analysis.
Conclusions
DSC, FT-IR and powder X-ray diffraction were used to
study the drug-excipient physical mixtures compatibility
(1:1 w/w) of Ibuprofen, as active pharmaceutical
ingredient, with a range of eight commonly used excipients
in pharmaceutical formulations: microcrystalline cellulose,
corn starch, lactose monohydrate, starch sodium glycolate,
Macrogol 6000 (PEG 6000), magnesium stearate, titanium
dioxide and talcum.
Thermal analysis revealed the shift to lower melting
temperatures of the characteristic peaks for the
preformulations of IBU with only two excipients, Macrogol
6000 and Mg stearate. FT-IR spectroscopic data and XRPD
REV. CHIM. (Bucharest) ♦ 66 ♦ No. 2 ♦ 2015
patterns support the results obtained by the thermo
analytical method, offering complementary information
about the functional moieties involved in such drug-
excipient interactions.
In both cases, a weak intermolecular hydrogen-bonding
type interaction between IBU and the two excipients is
incriminated. As a result of these interactions, the FT-IR
spectra and X-ray diffraction patterns of the physical
mixtures are different compared to those of individual
components. Our preformulation studies proved the
incompatibility between IBU and Macrogol 6000 and Mg
stearate, respectively. This finding is of major importance
in formulation process, in order to avoid problems during
long-term stability testing of drug products.
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