48 East and Central African Journal of Pharmaceutical Sciences

Vol. 17 (2014) 48-53

Simplex Lattice Optimization of Superdisintegrants in the Formulation of Fast Oral Dissolving

Tablets of Ibuprofen

SYLVESTER OKHUELEGBE ERAGA*, MATTHEW IKHUORIA ARHEWOH AND PRECIOUS

CHUKWUFUMNAYA UKWADIAMO

Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, University of

Benin, Benin City 300001, Nigeria

Optimization of different superdisintegrants using the simplex lattice design in

the formulation of fast disintegrating tablets of ibuprofen was studied. Seven
formulations (F1 to F7) were prepared by direct compression of ibuprofen as the
model drug and a combination of superdisintegrants–pre-gelatinized starch,
croscarmellose sodium and crospovidone–utilizing the simplex lattice design.
FTIR analysis of drug and excipients was carried out. Granules and tablets
formulated were evaluated for pre- and post-compression parameters. The
granules were fairly free flowing with angles of repose ranging from 42 - 49°,
Carr’s index < 24 %, and a Hausner’s quotient < 1.3. The tablet hardness and
friability were 4.00 - 5.99 kgF and < 1 %, respectively, while wetting and
disintegration times were < 160 and < 76 s, respectively. Dissolution profiles
showed all the tablets released over 60 % of drug within 5 min. FTIR analysis
showed no interactions between ibuprofen and excipients. The simplex lattice
design revealed that combination of superdisintegrants significantly affects the
wetting and disintegration times as well as drug release.

Key words: Simplex lattice, fast disintegrating tablets, superdisintegrants.

INTRODUCTION developed to improve the ease of

administration, the FDTs are the most widely
Fast disintegrating tablets (FDTs) or oral preferred commercial products [4].
dissolving tablets are advantageous
particularly for pediatric, geriatric and FDTs are a new generation of formulations
mentally ill patients as well as for persons which combine the advantages of both liquid
experiencing difficulty in swallowing and conventional tablet formulations and, at
conventional tablets and capsules [1]. These the same time, offer added advantages over
dosage forms are placed in the mouth and both the traditional dosage forms. They
allowed to disperse or dissolve in the saliva. provide the handling convenience of a tablet
They release the drug as soon as they come in formulation and also afford the ease of
contact with the saliva, thus obviating the need swallowing provided by a liquid formulation
for water during administration. Water plays [5]. Currently, FDTs are available in the
an important lubricating role when swallowing market for the treatment of many disease
oral dosage forms and people usually conditions including hypertension, migraine,
experience discomfort when swallowing dysphagia, nausea, vomiting, Parkinson’s
conventional solid dosage forms without water disease, schizophrenia and pediatric
[2]. emergencies [6-9].

The United States Food and Drug Ibuprofen, a propionic acid derivative, is one
Administration (FDA) has defined an FDT as of the most commonly used non-steroidal anti-
“A solid dosage form containing medicinal inflammatory drug (NSAID) for its analgesic,
substances or active ingredients which anti-inflammatory and anti-pyretic properties
disintegrates rapidly within a few seconds [10,11]. It is used in the management of mild
when placed on the tongue”. FDTs release to moderate pain [12] and in acute or chronic
medicament in the mouth allowing for pain [13] especially in dental practice.
absorption throughout the gastro-intestinal Ibuprofen is absorbed throughout the
tract [3]. Among the various dosage forms gastrointestinal tract [14]. Hence an FDT

* Author to whom correspondence may be addressed. E-mail: [email protected]

49 Eraga et al. East Cent. Afr. J. Pharm. Sci. 17 (2014)

formulation of the drug will enhance ibuprofen containing the three

absorption right from the mouth, especially superdisintegrants croscarmellose sodium,
when fast onset of action is needed. crospovidone and pre-gelatinized starch in
The objective of the present investigation was different proportions were prepared using
to explore the feasibility of preparing a fast anhydrous dicalcium phosphate as diluent.
dissolving tablet brand of ibuprofen using Amounts of the ingredients calculated to
different superdisintegrants and optimizing produce 100 tablets per batch were mixed
their concentrations when used together as a together. The powder blend was passed
blend. through a 710 μm mesh screen (Endecotts,
London, UK) and the resulting blend evaluated
EXPERIMENTAL for pre-compression parameters prior to
compression into tablets using a single punch
Materials tableting machine (Manesty Machines,
Liverpool, UK) at a pressure of 35 arbitrary
Ibuprofen powder and magnesium stearate units (AU).
were gift samples from Edo Pharmaceuticals
Ltd, Benin City, Edo State, Nigeria. Excipients Table 1: Composition of Superdisintegrants
employed in the formulation included in Formulation
croscarmellose sodium (BDH Chemicals, Transformed Fraction
Poole, UK), crospovidone (ISP Technologies Batch of Independent Variables
Inc., Wayne, NJ, USA), pre-gelatinised starch Code
X1 X2 X3
and dicalcium phosphate anhydrous (Innophos
Inc., Cranbury, NJ, USA). F1 1* 0 0
F2 0.5 0.5 0
Preparation of tablets
F3 0 1 0
Simplex lattice design F4 0 0.5 0.5
F5 0 0 1
The simplex lattice design was developed by
Scheffe [15] using the theory of statistics and F6 0.5 0 0.5
experiments to obtain models that can be used F7 0.33 0.33 0.33
to determine mix proportions for a specified X1: amount of croscarmellose sodium (mg), X2:
criterion. In our design experiment, one amount of crospovidone (mg), X3: amount of pre-
criterion (disintegration) was evaluated by gelatinized starch (mg). *A value of 1, 0.5 and 0.33
changing the concentrations of three represents 20, 10 and 6.67 mg respectively of the
superdisintegrants simultaneously while superdisintegrant. All batches contained 200 mg of
keeping their total concentration constant. A ibuprofen, 176 mg of anhydrous dicalcium
phosphate and 1% w/w of magnesium stearate.
three-superdisintegrant system design will be
Average tablet weight = 400 mg.
represented by a two dimensional equilateral
triangle with its three vertices representing a
Evaluation of powder blend
formulation containing the maximum amount
of one superdisintegrant, with the other two The granule bulk and tapped densities as well
superdisintegrants at a minimum level. The as the angle of repose were evaluated
three midpoints between vertices represent a according to compendial specifications.
formulation containing the average of the Compressibility (Carr’s) index and Hausner
minimum and maximum amounts of the other factor were thereafter calculated.
two superdisintegrants and a center point
representing a formulation containing one
Compatibility studies
third of each superdisintegrant.
Drug-excipient interactions were studied using
Using this design, with our independent a Spectrum BX Fourier Transform Infrared
variables being the concentrations of each Spectrophotometer (Perkin-Elmer,
superdisintegrant, the various batches of Beaconsfield, England). The drug, excipients
tablets were prepared using the formula in and powdered tablet formulations were
Table 1. Seven formulations (batches) of
50 Eraga et al. East Cent. Afr. J. Pharm. Sci. 17 (2014)

separately pressed into KBr pellets and between mean were determined using
scanned at a range of 4000 - 350 cm-1. ANOVA and p ˂ 0.05 was considered
significant.
Evaluation of tablets
RESULTS AND DISCUSSION
The tablet dimensions, weight uniformity,
hardness and friability of the compressed The FTIR spectra of drug, excipients and
tablets were evaluated as per standard formulated tablets are shown in Figure 1. The
procedures [16]. IR absorption spectra of the individual
excipients and pure ibuprofen were found to
Wetting time: A piece of double-folded tissue be similar with that of the formulated tablet
paper was placed in a Petri dish containing 6 granules containing ibuprofen and the
ml of water. The tablet was placed on the wet excipients, with no extra bands observed in the
tissue paper and the time in seconds for spectra. This finding confirmed that ibuprofen
complete wetting of the tablet surface was did not interact with any of the excipients used
measured and recorded [17]. in this study, an indication that the drug and
excipients were compatible with each other.
Disintegration test: The disintegration time
for all formulations was measured using a Pre-compression parameters
tablet disintegration test apparatus (Manesty
Machines Ltd, Liverpool, UK). A tablet was The flow properties of powder mixtures are
placed in each of the six tubes of the important for the uniformity of the mass of the
apparatus. Distilled water at 37 ± 0.5 ºC was tablet. The angle of repose was between
used as the disintegration medium. The time in 42.93°-49.09º, indicating poor powder flow.
seconds taken for the tablet to disintegrate However, other parameters put together gave a
completely was measured and recorded. Hausner’s ratio ranging from 1.170 to 1.319 as
seen in Table 2, which is within the acceptable
Dissolution studies: The dissolution tests range. Consequently, flow still occurred
were carried out using a BP dissolution test despite the high angle of repose.
apparatus (GB Caleva Ltd, Sturminster
Newton, UK) fitted with a basket rotated at
100 rpm. The dissolution medium was 900 ml
of phosphate buffer pH 6.8 maintained at 37 ±
0.5 ºC. Six (6) tablets selected at random from
each batch were used simultaneously for the
study. A 5 ml aliquot of leaching fluid was
withdrawn at 5 min intervals for 30 min. The
withdrawn fluid was replaced with an
equivalent volume of phosphate buffer
maintained at 37 ± 0.5 ºC. The aliquot was
filtered and diluted with an equal volume of
phosphate buffer. The absorbances of the
resulting solutions were measured at λ max 266
nm, using a UV/Visible spectrophotometer.
The percentage of drug released was
calculated from the absorbance. The
dissolution profiles of two commercially
available ibuprofen tablets were evaluated for
comparison.
Figure 1: FTIR Spectra of ibuprofen,
Statistical analysis excipients and formulations
Key: A = croscarmellose sodium, B =
Descriptive statistics was performed for all crospovidone, C = anhydrous dicalcium phosphate,
data using Microsoft Excel (2007). Means and D = pre-gelatinized starch, E = magnesium stearate,
standard deviations of triplicate determinations F = ibuprofen, G = ibuprofen + excipients
were computed and reported. Differences
51 Eraga et al. East Cent. Afr. J. Pharm. Sci. 17 (2014)

Table 2: Pre-compression parameters of the powder blends of the various batches

Bulk Tapped Angle of Carr’s
Hausner
Batch Density Density Repose Index
3 3 Ratio
(g/cm ) (g/cm ) (º) (%)
F1 0.500 ± 0.29 0.588 ± 0.18 43.95 ± 0.03 14.97 ± 0.56 1.176 ± 0.13
F2 0.435 ± 0.25 0.526 ± 0.27 45.64 ± 0.65 17.30 ± 0.67 1.209 ± 0.25
F3 0.488 ± 0.17 0.571 ± 0.13 49.09 ± 0.21 14.54 ± 0.45 1.170 ± 0.10
F4 0.490 ± 0.32 0.625 ± 0.22 45.00 ± 0.32 21.60 ± 0.33 1.275 ± 0.18
F5 0.481 ± 0.14 0.600 ± 0.10 43.60 ± 0.67 19.83 ± 0.56 1.247 ± 0.65
F6 0.496 ± 0.23 0.615 ± 0.23 47.94 ± 0.33 20.64 ± 0.54 1.240 ± 0.18
F7 0.444 ± 0.19 0.586 ± 0.42 42.93 ± 0.65 24.23 ± 0.43 1.319 ± 0.56

Post-compression parameters 4.0 kgF is considered to be the minimum for a

satisfactory tablet [18]. These values were
The weight of the prepared tablets ranged observed to be highest in F3 (5.0) and lowest
between 390.22 and 409.34 mg. The weights in F5 (4.0). This finding is in agreement with
did not vary significantly (p > 0.05) among Lachman et al. [19] who, in a similar study,
themselves. The percentage friability of all the observed a relative drop in the tensile strength
tablets was less than 1.0 % (Table 3) of FDTs formulated with pre-gelatinized
indicating the ability of the tablets to withstand starch compared to those formulated with
abrasion in handling, packaging and shipment. crospovidone and croscarmellose sodium as
The hardness of prepared tablets was between superdisintegrants.
4.0 to 5.0 kgF (Table 3). Tablet hardness of

Table 3: Post-compression parameters of the tablets formulated (Mean ± SD)

Weight Wetting Disintegration
Hardness Friability
Batch Variation Time Time
(kgF) (%w/w)
(mg) (sec) (sec)
F1 1.520 ± 0.01 4.25 ± 0.14 0.70 ± 0.22 78 ± 0.34 20.34 ± 0.04
F2 0.756 ± 0.02 4.75 ± 0.09 0.80 ± 0.16 50 ± 0.14 12.05 ± 0.34
F3 2.439 ± 0.16 5.00 ± 0.33 0.90 ± 0.06 145 ± 0.25 60.05 ± 0.05
F4 1.234 ± 0.02 4.50 ± 0.45 0.80 ± 0.02 102 ± 0.45 32.25 ± 0.65
F5 0.982 ± 0.17 4.00 ± 0.66 0.96 ± 0.42 160 ± 0.82 75.45 ± 0.78
F6 1.112 ± 0.02 4.50 ± 0.12 0.88 ± 0.56 130 ± 0.90 39.45 ± 0.09
F7 0.789 ± 0.23 4.75 ± 0.33 0.62 ± 0.09 93 ± 0.56 26.18 ± 0.67

The wetting time of formulation F2 containing The most important parameter that needs to be
crospovidone and croscarmellose sodium in optimized in the development of FDTs is the
equal proportions was 50 sec (Table 3) and disintegrating time of the tablet (FDA
was lower than that of the other formulations. approved value ≤ 3 min) [22]. In our study, it
Deepali [20] achieved a similar result in his was observed that with increased
study on naproxen tablet formulations. Zhao concentration of pre-gelatinized starch, there
and Augsburger [21] in their study showed was a relative increase in the disintegrating
that wetting time in addition to disintegration time of the formulated tablets: F5 (75.45 sec)
time affects dissolution time of drugs. The compared to F6 (39.45 sec) and F4 (32.25
authors reported that increasing concentrations sec). This may have been due to the formation
of crospovidone will decrease the wetting time of a viscous gel layer by the swelling of pre-
of tablets (via its wicking action) while pre- gelatinized starch at higher concentrations.
gelatinized starch on the other hand will The gel layer can be a barrier to the
increase the wetting time but croscarmellose penetration of the disintegrating medium and
will have no observable effect on wetting time. possibly hinder disintegration or leakage of the
tablet content.
52 Eraga et al. East Cent. Afr. J. Pharm. Sci. 17 (2014)

In a similar work, Bolhuis et al. [23] release occurred from the F5 batch with longer
concluded that disintegration time can be wetting and disintegration times. This slow
effectively reduced by using a combination of release of the batch F5 tablets may be due to
wick-type and swelling-dependent rapid swelling into primary particles of the
superdisintegrants with an even blend of pre-gelatinized starch forming a viscous gel
croscarmellose and crospovidone (wick and layer that slowly releases the drug. Thus the
swell type) giving the least disintegration time. differences in drug release profiles may be
attributed to the difference in surface area
The optimum formulation which showed rapid exposed to the dissolving medium rather than
disintegration was formulation F2 containing the speed of tablet disintegration. Furthermore,
equal proportions of crospovidone and the dissolution profile of batch F3 tablets
croscarmellose sodium. This rapid containing crospovidone alone is dependent on
disintegration was due to the penetration of the volume of the dissolution medium and
liquid into the pores of the tablets, leading to surface area of the granules exposed to the
the swelling and wicking of superdisintegrants medium.
to create enough hydrodynamic pressure for
quick and complete tablet disintegration. Both CONCLUSION
superdisintegrants exhibit good water uptake
with high capillary action and rapid swelling. The formulation containing crospovidone and
This combination of properties leads to fast croscarmellose sodium in equal proportions
tablet disintegration as was also observed in a showed the fastest disintegration time when
similar work carried out by Seong et al. [24]. compared to the other formulations. Tablets
with fast disintegration can be produced by
Wetting and disintegration times are critical to selecting the proper amounts and combinations
the dissolution profiles of FDTs. There is a of disintegrants in tablet formulation.
correlation between wetting time, Although differences existed between
disintegration time and the drug release superdisintegrants, FDTs of ibuprofen could
profiles of the formulated tablets (Figure 2). be prepared using any of the
superdisintegrants used here to achieve over
90 % drug release within 30 min.

ACKNOWLEDGEMENTS

We acknowledge the support of our

departmental resources and staff. The work
was self-financed by the authors.

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