African Journal of Pharmacy and Pharmacology Vol. 5(1), pp.

31-41, January 2011

Available online http://www.academicjournals.org/ajpp
DOI: 10.5897/AJPP10.274
ISSN 1996-0816 ©2011 Academic Journals

Full Length Research Paper

Formulation and evaluation of immediate release

tablets with different types of paracetamol powders
prepared by direct compression
Biljana Govedarica1*, Rade Injac2, Rok Dreu1 and Stane Srcic1
1
Faculty of Pharmacy, Institute of Pharmaceutical Technology, University of Ljubljana, Askerceva 7, 1000 Ljubljana,
Slovenia.
2
Faculty of Pharmacy, Institute of Pharmaceutical Biology, University of Ljubljana, Askerceva 7, 1000 Ljubljana,
Slovenia.
Accepted 13 January, 2011

Paracetamol (PAR) crystals exhibit poor compressibility, poor flowability and its tablets show a
tendency to cap. To improve the mechanical strength of tablets several kinds of “Paracetamol for direct
compression” are present on the market. Current research demonstrated the best tablet properties with
coated paracetamol (mass of tablets, diameter, height and mechanical strength, friability RSD<2%).
Furthermore, coated paracetamol in combination with both investigated superdisintegrants such as
® ®
Vivasol and Polyplasdone XL-10 shows faster disintegration time and dissolution rate in comparison
to paracetamol for direct compression. Eventually, the major advantages of the formulation with coated
paracetamol for industrial production are decrease of friability and superiority in terms of flowability,
compressibility, quick disintegration and dissolution. Regarding the results, coating of PAR particles is
beneficial for the manufacturing of tablets with immediate release.

Key words: Paracetamol, powder, direct compression, immediate release, superdisintegrants.

INTRODUCTION

Acetaminophen (paracetamol) is one of the most widely utilized to improve tablet strength, especially when the
used over the counter medication. It has analgesic and interparticulate bonds between the compound crystals
antipyretic properties, but low antiinflammatory activity are weak (Eichie and Amalime, 2007; Ngwuluka et al.,
(Quellet and Percival, 2001). PAR is usually formulated in 2010). PAR crystals exhibit poor compression ability, low
tablets containing 300 to 500 mg of drug (Martinello et al., flowability and its tablets show great tendency to cap.
2006). The most appropriate technology for industrial The poor compaction behavior of PAR and its elastic
production of tablets is direct compression. In practice, deformation has been related to different PAR poly-
direct compression has been limited mainly to formulation morphic forms.
containing small proportions of the active ingredient and Even though they are chemically iden-tical, the different
appropriate compressibility. The advantages of the direct polymorphic forms show different free energies, and
compression are primary reduced production cost, better different physical properties that can signi-ficantly
product stability and faster dissolution of API when influence product performance. These include differences
compare to process of granulation (Aulton, 2007). In in solubility and dissolution rate (affecting bioavailability),
terms of inadequate compressibility, powder properties solid-state stability (affecting potency), deformation
can be improved by the addition of binders (Nyström et characteristics (affecting compressibility), and particle
al., 1982; Kolter and Flick, 2000). Dry binders can be size and shape (affecting powder density and flow
properties) (Martinello et al., 2006). There are several
methods for modification of the crystalline structure of
PAR, in order to manufacture tablets via direct
*Corresponding author. E-mail: [email protected]. compression.
Tel: +386 40 248010. Fax: +386 1 425803. Examples include spherical crystallization, crystallization
32 Afr. J. Pharm. Pharmacol.

from different solvents to produce different crystal habits, Finally, we wanted to elaborate, whether the coating of
incorporation of additives by co-precipitation, develop- PAR particles has a beneficial effect for manufacturing of
ment of sintered-like crystals and co-extrusion with tablets with immediate release.
isomalt (Di Martino et al., 1996; Fachaux et al., 1995;
Garekani et al., 2000; Ndindayino et al., 2001). Untreated
PAR particles show massive elastic deformation under MATERIALS AND METHODS
pressure which results in axial expansion of tablet in the
PAR (monoclinic form, Huzhou Konch Pharmaceuticals Co. Ltd.),
phase of decompression. As a consequence, tablets PAR D.C. (Mallinckrodt inc. St.Louis, USA) and PAR coated
often express different types of mechanical strength (Ethypharm SA, France) were chosen as active ingredients; (Figure
problems such as capping, chipping, lamination, stress 1) Kolidon® VA 64 (BASF, Germany) and Klucel® - EXF (Aqualon,
cracking, and sticking as well as picking (Wu et al., Germany) were used as binders; Polyplasdone® XL-10 (ISP,
2007). Switzerland) and Vivasol® (JRS Pharma, Rosenberg, Germany)
To improve the mechanical strength of tablets with were used as superdisintegrants; Avicl® PH 200 (FMC, USA) was
used as a filler, Mg-stearate (Pharmachemic, Belgium) and Aerosil®
PAR, several PARs for direct compression (D.C.) are 200 (Degussa, Germany) were utilized as glidants. Febricet®
present in the market. These materials provide sufficient (Hemopharm concern, Stada, Germany) was chosen as reference
flowability and compactability. PAR for D.C. is modified tablet.
with different binders, but it still shows optimal dissolution
rate, which is necessary for development of tablets with
Powder properties
immediate release profile (Fachaux et al., 1995; Kulkarni
and Amin, 2008; Okoye et al., 2009). Despite the True, bulk, and tapped density
increasing interest in controlled release drug delivery
systems, the most desired forms of tablets are those The true densities of the powder mixtures were determined by
intended to be swallowed whole. They subsequently helium picnometry (Accupyc 1330, Microneritics, Norcross, Ga.,
disintegrate and release their active ingredient rapidly in USA). Three samples of each mixture were analyzed, each sample
was read three times, and the overall means were calculated.
the gastrointestinal tract (GIT) (Zhao and Augsburger, Bulk density measurements were carried out using flat – ground
2005a). measuring cylinder with a volume of 250 ml. The cylinder was filled
Tablets for immediate release often consist of filler, a with the specified mass of powder mixture and unsettled apparent
binder, lubricants and disintegrants (Fukami et al., 2006). volume V0 was read to the nearest millilitre. After 10, 250, 500,
In many cases, the disintegration time of solid dosage 1250 taps the corresponding volume was read to the nearest
forms is too long to provide appropriate therapeutic millilitre. The tapped volume was recorded when the difference
between the two volumes was smaller than 1 ml For PAR D.C.,
effect. To improve the disintegration time, so-called disin- PAR coated, and tablet powder mixtures, V1250 was used. The
tegrants are used. The most accepted mechanisms of tapped density was determined on a tapped volume determination
their action are wicking, swelling, deformation recovery apparatus (Vankel apparatus, Van Kel Technology Group, Edison,
and particle repulsion. Together, these phenomena NJ, USA).
create a disintegrating force within the matrix (Zhao and
Apparent density before settling or density of bulk product:
Augsburger, 2005b). In the past, non-modified disin-
tegrants were used to accelerate disintegration, that is, = m/V0 [g/ml] (1)
alginates, starches, ambrelite resins, cellulosic materials,
pectines and others. Today, a fast working superdisin- Apparent density after settling or density of settled product:
tegrant is chemically modified, typically by crosslinking
the organic chains of a polymeric molecules. Three = m/V1250 or [g/ml] (2)
classes of superdisintegrants are commonly used:
®
modified cellulose (croscarmellose sodium - Ac-Di-Sol , Flowability
®
Vivasol ), crosslinked polyvinyl-lpyrrolidone
®
(Polyplasdone XL-10) and modified starch (Sodium Flowability was defined according to Hausner ratio:
® ®
Starch Glycolate – Primojel , Explotab ).
Hausner ratio = (Tapped density)/ (Bulk density) (3)
The basic objective of this study was to produce
immediate release tablets containing different types of Flow of powder was measured using a standard funnel as
PAR via direct compression, to compare their properties, described in Ph. Eur. VI (European Pharmacopeia, 2008). Into a dry
disintegration and dissolution profiles. PAR was used as funnel, whose bottom opening has been blocked by suitable
a model drug for immediate release tablets because of its means, a test sample was introduced without compacting. After
primary indication in treatment of pain where the effect of unblocking the bottom opening of the funnel, the time needed for
the entire sample to flow out thought the funnel was measured.
drug should be rapid. To reach this goal, it is necessary
to find a suitable disintegrants having excellent com-
pactability and disintegrating properties. Furthe-rmore, Angle of repose
we were focus on establishing differences between PAR
powders and to examine how their characteristics Angle of repose was determined by measuring the height of the
influence the tablet manufacture and dissolution profiles. cone of powder and calculating the angle of repose - , from the
 Govedarica et al. 33

Figure3. Disintegration test of tablet formulations

.

a b c
Figure 1. Scanning electron micrographs of different paracetamol powders (a - monocrystalline paracetamol; b - paracetamol D.C; c - coated paracetamol).

given equation (Equation 4). The end of a funnel was ( ) was determined. Compressibility index
placed 2 cm above a flat base. The funnel was filled with
the powder (the used mass depended on the bulk density Compressibility index was determined according to Carr’s
of the material, around 2.5 g), therefore after releasing the Height index:
powder out of the funnel the top of the resulting cone
tan ( ) = (4) (Tapped density) - (Bulk density)
reached the end of the funnel. From the height of the cone
(h) and the diameter at the base (d), the angle of repose, 0.5 x base (Tapped density x 100
Carr’s index =
34 Afr. J. Pharm. Pharmacol.

Table 1. Direct compression formulation.

Ingredients Formulation I Formulation II Formulation III Formulation IV

PAR D.C. 75 75 - -
PAR coated - - 80.85 80.85
Kolidon VA 64 4 4 2 2
©
Vivasol - 5 - 5
Polyplasdone® XL-10 4 - 4 -
Avicel PH 200 12.5 11.5 8.64 7.64
Klucel EXF 2 2 2 2
Peg 4000 1 1 1 1
Mg-stearate 1 1 1 1
Aerosil 200 0.5 0.5 0.5 0.5

Dry sieve analysis Measurement of tablet porosity

Particle size distributions of PAR bulk powders, and powder Tablet porosity ( ) is calculated using Equation 7
mixtures were determined using a stack of metal sieve plates from
the largest to the finest aperture in the following order: 500, 355
ρa
(Der Shuenn, Taiwan), 250, 180, 125, 63 and 45 m (Cole-Palmer, ε =1− (7)
Illinois). Retsch apparatus type AS 200 basic was used for the
analysis (F.Kurt Retsch GmbH and Co KG, Germany). The weight
ρt
of the powders retained on the surface of each sieve plate was
divided by the total sample weight to obtain the corresponding And
weight percentage oversize for each sieve fraction.
m
ρa =
2π r 2 h
Morphology of powder

The scanning electron microscope (Supra 32 VP, Zeiss, Germany)

was used to observe the morphology of the PAR powders. where is the porosity, a is the apparent density, t is the true
density, m is the mass, r the radius, and h the height of the tablet.
The diameter and thickness were determined with a thickness
Preparation of tablets meter (Digitale Schiebelehre, Mister Tool, Walter Werkzeuge
Salzburg GmbH, Austria).
The formulations of PAR tablets are presented in Table 1. Drug and
excipients without the lubricants were first mixed for 30 min.
Magnesium stearate and Aerosil® 200 are sieved through a sieve Wetting time
(180 m) and after adding them into the mixture, the mixing was
continued for 5 min. Finally, the powder mixture was sieved (sieve The wetting time of tablet was measured by the method described
500 m). Tablets of 700 mg in weight and 12 mm in diameter were by Bi et al. (1996). The method is as follows. A piece of tissue
prepared by direct compression using a single-punch tableting paper (12 × 10.75 cm) folded twice was placed in a small culture
machine, Kilian SP 300 (Kilian and Co GmbH, Germany). Tablets dish, and the time for complete wetting was measured at 25ºC. The
were compressed with force of 9 kN and compression speed of 25 wetted tablet was then weighed. Water absorption ratio, R was
tbl/min. Finally, the weight and diameter of tablets were measured. determined according to the following equation:

Wb −Wa
Tablet properties R= (8)
Wa
Uniformity of mass, tablet hardness and friability
where, Wa and Wb are the weight before and after water absorption,
The average tablet weight was determined by weighing 20 tablets respectively.
individually using an analytical balance (European Pharmacopeia, Disintegration time
2008).
Hardness was determined using tablet hardness tester Disintegration time was measured with Erweka apparatus Type ZT4
(Vanderkamp VK 200, VanKel Industries, Inc., Edison, NJ, USA). -1, disintegration tester (ERWEKA GmbH, Heusnstamm, Germany).
Ten tablets of each formulation were tested. Friability was Tests were carried out in 800 ml of distilled water at 37 ± 0.5°C. All
determined by placing 10 tablets of each formulation in a TAR 10 tests were run using six tablets of each formulation.
friabilator (Erweka GmbH, Heusnstamm, Germany) and operating
the drum for 4 min and 25 rpm. Friability was determined using the
following formula: Friability = [(Initial weight-Final weight) / Initial Dissolution study

weight)] x100 [%] (6) Dissolution profiles were determined using the paddle method
 Govedarica et al. 35

Table 2. Bulk powder properties.

Ingredients Mean particle size Bulk density (g/ml) Flow (s) Angle of repose Hausner ratio Carr’s index
PAR Cryst >355 0.382 59.9 1.90 47.44
PAR D.C. >45 0.679 35 41.63 1.39 28.12
PAR coated >250 0.469 30 39.52 1.14 12.36

Table 3. Properties of powder mixtures.

Mean particle Bulk density Angle of Hausner

Ingredients Flow (s) Carr’s index
size (µm) (g/ml) repose ratio
PAR D.C.+Polyplasdone XL-10 >45 0.479 7.5 40.20 1.31 23.56
PAR D.C.+Vivasol >45 0.483 8.5 41.63 1.29 22.94
PAR coated+Polyplasdone XL-10 >250 0.609 8.5 39.34 1.29 18.75
PAR coated+Vivasol >250 0.608 5.2 39.36 1.25 20.00

Table 4. Tablet properties.

Porosity Crushing Friabilit Wetting time Water/absorption

Ingredients Weight (g)
(%) strength (N) y (%) (s) ratio
PAR D.C.+Polyplasdone XL-10 0.709±1.84 15.45 153.19 0.52 742 0.285
PAR D.C.+Vivasol 0.705±0.43 59.43 150.46 0.51 195 0.402
PAR coated + Polyplasdone XL-10 0.702±0.03 59.23 71.99 0.24 140 0.479
PAR coated + Vivasol 0.702±0.52 59.42 65.30 0.24 158 0.755
Reference 0.604±0.10 - 61.30 0.91 178 0.897

described in USP XXX (United States Pharmacopeia 30th ed., compressibility, according to the results presented in
2007), and the paddle speed of 50 rpm/min (VanKel VK 7000; Table 3.
VanKel industries Inc, Edison, NJ, USA). Dissolution was tested in
buffer solutions pH = 1.0 (0.1 N HCl), pH = 4.5 (phosphate buffer),
pH = 5.8 (phosphate buffer) and pH = 6.8 (phosphate buffer). The Tablet properties
volume of the dissolution medium was 900 ml at 37.0 ± 0.5 C and
was prepared according to the Eur. Ph VI. Samples of 10 Ml were The results of tablet properties are summarized in Table
withdrawn from the dissolution medium at appropriate time intervals
4. It is apparent that the best tablet characteristics have
and filtered through a membrane filter (pore size 0.45 m). Each
experiment was carried out using six tablets. The samples were formulations with coated PAR when compared to
appropriately diluted (50×) in a fresh quantity of the dissolution formulation with PAR D.C. The maximum official weight
medium. The absorbance was measured by a spectrophotometer variation for tablets heavier than 250 mg is 5%, therefore,
(UV-Visible Spectrophotometer 8643, Agilent, France) at 243 nm. all formulations met criteria of the Eur. Ph VI specification
(European Pharmacopeia, 2008). Furthermore, all
formulations met the specification of Eur. Ph VI (Euro-
RESULTS pean Pharmacopeia, 2008) for friability of uncoated
tablets. Regarding the results, investigated formulations
Bulk powder properties
demonstrated a statistically significant decrease of
The active ingredients tested in this paper exhibited friability in comparison to the reference (p < 0.05) (Table 4).
considerable differences in their powder properties. As
Disintegration time and dissolution profiles
shown in Table 2, Hausner ratio, Carr’s index and flow
were significantly higher for monocrystalline PAR in The times required for complete disintegration in water
comparison to PAR D.C. and coated PAR. (37ºC, 800 ml) are acceptable according to Eur. Ph VI for
uncoated tablets (European Pharmacopeia, 2008) for all
Properties of powder mixtures investigated formulations. Dissolution experiments
performed on six samples from each formulation are
Modifications of PAR powder improved the flowability and summarized in Figure 2 (a, b, c, d). According to the
36 Afr. J. Pharm. Pharmacol.

! " #$
% &' !
! " #$
% &' !

Figure 2a. Dissolution profiles from paracetamol tablets in pH = 1.0.

! " #$
% &' !
! " #$
% &' !

Figure 2b. Dissolution profiles from paracetamol tablets in pH = 4.5.

! " #$

% &' !

! " #$

% &' !

Figure 2c. Dissolution profiles from paracetamol tablets in pH = 5.8.

results, all formulations met the BCS specification for shape and surface characteristics of the particles
immediate release dosage forms. integrating a powder (Holgado et al., 1996). The para-
meters of flowability clearly show that monocrystalline
PAR is absolutely inappropriate for direct compression.
DISCUSSION Angle of repose could not be determined for unmodified
PAR because its rheological characteristics were very
The behaviour of the bulk solids is clearly influenced by poor. Prismatic shape of PAR crystals and high surface
 Govedarica et al. 37

! " #$

% &' !

( ! " #$

% &' !

Figure 2d. Dissolution profiles from paracetamol tablets in pH = 6.8.

to mass ratio results in extremely poor flowability and because of very high elastic relaxation and capping of the
compression characteristics. In the case of PAR D.C and resulting tablets. Furthermore, it was infeasible to make
®
coated PAR, smaller values of Hausner ratio and Carr’s tablets with lactose superdisintegrants (Starlac ,
® ®
index theoretically predict better flowability and Microcellac , Ludipress ) and crystalline PAR due to the
compressibility. The particle size determination (Table 2) fact that in these kinds of formulations lactose has limited
shows that PAR D.C. has the finest particles, which ability to form strong tablets and it has low dilution
should therefore be able to rearrange in phase of potential.
compression and create new surfaces. As a
consequence, the tablets will have increased mechanical
strength. Furthermore, PAR D.C. has needle shape Tablet properties
particles, which increases the specific contact surface
area and therefore, compressibility. The mechanical strength of tablets is often defined as the
The best flow properties were found for coated PAR, force required fracturing a tablet across its diameter
which is related to its spherical shape (Figure 1). (Martinello et al., 2006). Mechanical strength is directly
Particles of coated PAR are very porous and crystals of related to porosity and disintegration time. The packaging
the active ingredient are implemented inside of the process and transportation of the final product requires
particles. Minimal contact of PAR crystals between appropriate tablet strength. Properties of powder mixtures
coated PAR particles significantly improves flowability show that PAR D.C. provides greater crushing strength
and compressibility. which is in correlation with smaller particle size and
Because of the high content of PAR in the mixture, higher specific surface area that assures new contact
PAR’s physical characteristics will have an essential surfaces and bonding between particles. Furthermore,
®
influence on the compression properties and elastic crushing strength of formulations with Polyplasdone XL-
relaxation of the tablets. This could be explained with 10 is increased in comparison to formulations containing
®
dominant PAR-PAR interactions, which are responsible Vivasol . The reasons for this are higher compressibility
®
for more cohesive properties of the mixture and of Polyplasdone XL-10 (Desai et al., 1994), (unique
consequently poor flowability. Also, these interactions particle morphology) and the greater content of
®
have an influence on elastic recovery, which has been microcrystalline cellulose - MCC (Avicel PH 200). Avicel
®
associated with the storage of elastic energy during PH 200 has a nominal mean particle size of 180 m and
compression, as deformation energy under stress, and because of increased surface area, enables direct
subsequent release of this energy after removal of axial compression of mixtures with higher content of PAR than
®
pressure. On the other hand, spherical structure and Avicel PH 101 (Martinello et al., 2006, Rowe et al.,
®
protection of PAR crystals inside of coated particles 2004). In addition, highly compactable Avicel PH 200
provided compression of higher percentage of active contributes to greater crushing strength of tablets, which
ingredients in comparison to PAR D.C. It was impossible could be explained with the increase in number of
to compress the powder mixture of unmodified PAR with mechanical interlocking between MCC particles. Small
the automatic method on single punch tableting machine crushing strength of tablets with coated PAR is
38 Afr. J. Pharm. Pharmacol.

%&' !
D isin te g ratio n tim e (s)

! "#$
%&' !
! "#$

Reference tablet

Figure 3. Disintegration test of tablet formulations.

associated with particle size, shape and coating of PAR Disintegration and dissolution profiles
particles. The larger granules with smaller surface area
and higher percentage of voids inside of such tablets with One of the aims of this paper was also to produce
consequently weaker inter-particulate bonding requiring immediate release tablets, which is especially important
the lower crushing strength for diameter fracture (Eichie for treatment of pain. As an analgesic we used PAR,
and Kudehinbu, 2009). which is classified in Class II, according to the BCS (high
When pharmaceutical powders are compacted into permeability, low solubility) (FDA guidelines, 1995). For
tablets, elastic recovery is responsible for capping, drugs in Class II, the principal limitation of its oral
lamination or chipping phenomena. There are different absorption is its dissolution rate. Because of that, it is
theories to explain capping tendencies, such as entrap- necessary to use more than one dissolution medium as a
ment of air, elastic characteristics of materials, radial prognostic tool in the assessment of both drug potential
relaxation of tablets and non-uniform density distribution for oral absorption and the bioequivalence of its formu-
(Wu et al., 2007). lation (Dressman et al., 1998). A tablet is considered to
As mentioned previously, it was not possible to be rapidly dissolving when more than 85% of the labelled
manufacture tablets with unmodified PAR because of the amount of drug substance (Q + 5%) dissolves within 30
high degree of axial relaxation and tendency for capping. min in a volume of < 900 ml buffer solution using USP
th
Furthermore, tablets containing modified PAR also Apparatus I or II (United States Pharmacopeia 30 ed.,
showed tendency to cap. Solution for this was usage of 2007).
®
Klucell EXF (hydroxypropylcellulose – HPC) binding To improve disintegration we used superdisintegrants
®
agent for direct compression, in concentration of 2% in crosscaramellose sodium (Vivasol ) and cros-spovidone
®
each formulation. HPC is nonionic, water-soluble cellu- (Polyplasdone XL-10). Effect of disintegrants and PAR
lose ether with remarkable thermoplastic characteristics, powders on disintegration time of tablets was investi-
and it has a very high degree of plastic flow. Low gated. Obtained results are shown in Figure 3. However,
molecular weight, low viscosity grades of HPC (EXF) are tablets formulated with coated PAR show faster disin-
recommended as immediate release binders. Therefore, tegration time than those prepared with PAR D.C. In the
when HPC was utilized, it provided toughness, absorbed case of coated PAR, present superdisintegrants provided
the compression energy, and finally decreased the approximately the same disintegration time. On the other
ejection force. hand, different results were obtained in case of tablets
Recently, newer classes of natural binders with with PAR D.C. Tablets formulated from PAR D.C. and
®
excellent properties regarding tabletability (stronger Polyplasdone XL-10 are less porous (Table 4) in
®
interparticulate cohesive bonds) that are also related for comparison to tablets from PAR D.C. and Vivasol . As a
manufacturing of tablets with immediate release have consequence, wicking, which is assumed to be the
®
been involved (Eichie and Amalime 2007; Ngwuluka et mechanism of action of Polyplasdone XL -10 is limited
al., 2010; Martins et al., 2007). by low porosity of tablets. Possible explanation for
 Govedarica et al. 39

Wetting time (s)

" #$ !
% &' !
" #$ !
% &' !

Disintegration time (s)

Figure 4. Relationship between wetting time and disintegration time of tablets with D.C. and coated paracetamol.

Table 5. Fit Factors, I-Paracetamol D.C. + Polyplasdone XL-10®; II-Paracetamol D.C. + Vivasol®; III -Paracetamol coated + Polyplasdone
XL-10®; IV- Paracetamol coated + Vivasol®; V-Reference.

Fit factors pH 1.0; t = 5, 10, 15, 20, 25, 30 pH 4.5; t = 5, 10, 15, 20, 25, 30 pH 6.8; t = 5, 10, 15, 20, 25, 30
I/V II/V III/V IV/V I/V II/V III/V IV/V I/V II/V III/V IV/V
f1 44.2 3.30 7.10 4.9 39.9 2,.9 9.8 8.1 42.3 7.2 10.8 10.4
f2 17.3 64.7 56.9 50.9 19.7 71.3 44.0 50.5 18.7 54.0 41.1 46.3

decreased disintegration and dissolution of tablets with independent approach that uses difference factor (f1) and
®
PAR D.C. and Polyplasdone XL-10 is the very high similarity factor (f2) was determined to compare dissolu-
packaging fraction which obstructs the penetration of fluid tion profiles. Results of fit factors were summarized in
into the tablet that would cause the matrix of the tablet to Table 5. Generally, f1 values up to 15 (0 to 15) and f2
break. values greater than 50 (50 to 100) guarantied equiva-
The relationship between the wetting time and lence of the two dissolution curves and furthermore test
disintegration time of tablets is shown in Figure 4. and reference similarity (Costa et al., 2003). According to
®
According to this relationship, as soon as the water fit factors, formulation with PAR D.C. and Polyplasdone
penetrates the tablet, it disrupts the interparticulate matrix XL-10 is different in comparison to the reference, while
bonds causing the tablet to fall apart. It has also been other formulations exhibited similarity in dissolution
reported that crosscaramellose absorbs large amount of profiles.
water and swells (Table 4). It has been reported that Elaboration of how pH affects the efficiency of the
®
disintegration mechanism of Polyplasdone XL-10 is superdisintegrants in terms of dissolution is completely
wicking, and because of this, tablets containing this different among scientists. It was reported that, when the
superdisintegrant expressed delayed disintegration superdisintegrant was incorporated into the tablet,
resulting in filling up the tablet voids (Zhao and dissolution within 15 min was slower in the acidic medium
Augsburger, 2005b). The dissolution study of the market than that in the neutral medium regardless of whether
formulation of PAR (500 mg) demonstrated complete crosspovidone or crosscaramellose was used (Gordon et
drug release within 30 min. All prepared tablets, except al., 1993). Also it was pointed out that in a capsule
®
the formulation of PAR D.C. and Polyplasdone XL-10 formula (PAR + dibasic calcium phosphate + magnesium
showed complete drug release within 30 min. According stearate) the dissolution was faster in 0.1 N HCl than in
to results obtained by ANOVA, all formulations show deionized water due to the dibasic calcium phosphate
statistically significant differences in dissolution profiles excipients (Dahl et al., 1991). Furthermore, Chen et al.
for the first 15 min (data not shown). Also, model (1997) reported that interaction between ingredients in
40 Afr. J. Pharm. Pharmacol.

100

90
80

*
.(

70 %&' !
60 *
* * %&' !
'

50
%&' !
+,- &

40
%&' !
30

20
10

0
) * pH * 4.5

Figure 5. Percentage of dissolved drug from tablets with Vivasol® after 5 minutes in pH = 4.5 and pH = 6.8.
*Significance level (p < 0.05).

tablets with PAR may lead to different dissolution rates, However, this result is desired in case of immediate
especially in the acidic medium (Chen et al., 1997). release tablets, which are intended to disintegrate in the
Moreover, Zhao and Augsburger (2005a) demonstrated stomach, and provide a fast effect. Statistically different
different dissolution rates from lactose and dicalcium percentage of dissolved PAR between tablets with
®
phosphate tablets where croscarmellose was used as Vivasol is evident only in the first 5 min in pH = 4.5 and
superdisintegrant in acidic and neutral media. They also pH = 6.8 (Figure 2b, 2d). It is obvious that dissolution of
®
established the same behaviour of Polyplasdone XL-10 drug in pH = 6.8 is delayed. This is in correlation with
in both media. In our experiment, dissolution data from greater swelling and gelling capacity of crosscaramellose
®
tablets containing PAR D.C. and Polyplasdone XL-10 in neutral pH (Figure 2d).
were significantly different in all investigated dissolution Considering the results, best disintegration time and
media and in all time points when compare to other dissolution profile were obtained for coated PAR.
formulations. This result is in correlation with the small Production of tablets with coated PAR is less variable,
porosity of tablets and longer wetting and disintegration which is confirmed by appropriate flow of its powder,
time (Murkesh et al., 2007). uniform mass of tablets, improved friability, and disinter-
Percentage of dissolved active principle from tablets gration time. Furthermore, presented superdisintegrants
®
with PAR D.C. and Polyplasdone XL-10 did not vary provide approximately the same disintergration of
significantly in acidic and neutral media in all time points. prepared tablets. These results confirm positive effect of
This was also confirmed for formulation with coated PAR coating of PAR particles on manufacturing of tablets with
®
and Polyplasdone XL-10, which also verify that immediate release.
®
behaviour of Polyplasdone XL-10 is not dependent of pH
(Buckton, 1990). Mild agitation force exerted by
dissolution paddles (50 rpm) was not strong enough to Conclusion
cause complete breakdown of the larger fragments of
tablet that resulted in smaller percentage of dissolved The best tablet properties were obtained with coated
®
drug in comparison to tablets with Vivasol . Na Zhao and PAR (mass of tablets, diameter, height and mechanical
L. L. Augsburger also confirmed this fact (Zhao and strength, friability RSD< 2%). Coated PAR is not pure,
Augsburger, 2005a). but exhibits improved flowability and adequate com-
On the other hand, percentage of dissolved active pressibility which are essential for direct compression.
®
principle from tablets with Vivasol was greater in acidic Furthermore, coated PAR in combination with both
medium than in neutral (Figure 5). This result was not investigated superdisintegrants shows faster disinter-
expected, because of the decrease swelling capacity of gration times and dissolution rates in comparison to PAR
®
Vivasol in acidic medium (Zhao and Augsburger, D.C. The advantages of the formulation with coated PAR
2005b). Possible explanation for this is the formation of a for industrial production are decrease of friability and
gel layer in neutral pH, which presents a depot of PAR. superiority in terms of flowability, compressibility, quick
 Govedarica et al. 41

disintegration and dissolution. With regards to results, Fukami J, Yonemoshi E, Youshihashi Y, Terada K (2006). Evaluation of
rapidly disintegrating tablets containing glycine and
coating of PAR particles has a positive effect on
carboxymethylcellulose. Int. J. Pharm., 310: 101-109.
manufacturing of tablets with immediate release. Garekani HA, Ford JL, Rubinstein MH, Rajabi-Siahboomi AR (2000).
Highly compressible paracetamol - II. Compression properties. Int. J.
Pharm., 208: 101-110.
Gordon MS, Ruddararaju VS, Dani K, Chowhan ZT (1993). The effect of
ACKNOWLEDGEMENTS
aging on the dissolution of wet granulated tablets containing super
disintegrants. Int. J. Pharm., 97: 119-131.
The authors would like to thank prof. Odon Planinsek for Kolter K, Flick D (2000). Structure and dry binding activity of different
SEM analysis of samples. polymers, including Kollidon® VA 64. Drug. Dev. Ind. Pharm., 26(11):
1159-1165.
Kulkarni RB, Amin PD (2008). Masking of unpleasant gustatory
sensation by cross-linking of dehydrated paracetamol alginate pellets
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