Research Papers

JPP 2004, 56: 429̄–436

ß 2004 The Authors
Received September 24, 2003
Accepted December 22, 2003
DOI 10.1211/0022357023015 Application of poly(acrylic acid) superporous
ISSN 0022-3573
hydrogel microparticles as a super-disintegrant
in fast-disintegrating tablets

Shicheng Yang, Yurong Fu, Seong Hoon Jeong and Kinam Park

Abstract
Poly(acrylic acid) superporous hydrogel (SPH) microparticles possessing a unique porous structure
were used as a wicking agent to decrease disintegration time of fast-disintegrating tablets (FDTs).
The compression behaviour of poly(acrylic acid) SPH microparticles was evaluated using the
Kawakita equation. Effects of various SPH microparticle sizes and a 19-run fractional factorial design
were evaluated. The factorial design was based on four factors consisting of ketoprofen, SPH
microparticle, filler, and tableting pressure, and each factor contained three levels on the disinte-
gration time and tensile strength of the prepared FDTs. The poly(acrylic acid) SPH microparticles
existed in an amorphous state and swelled approximately 80-times in distilled water and 50-times in
pH 6.8 0.2 M phosphate buffer. The compressibility of SPH microparticles increased significantly as the
microparticle size increased. The FDTs made of SPH microparticles in the range of 75Å –106 ·m showed
the fastest disintegration time and higher tensile strength. SPH microparticle, tableting pressure and
ketoprofen had significant effects on disintegration time and tensile strength of ketoprofen FDTs.
The FDTs that were prepared with 2.5% w/w SPH microparticles of 75Å –106 ·m at 63 MPa pressure
possessed a tensile strength of 84.4 ± 4.1 N cm¡2 and disintegrated in 15.0 ± 2.0 s. It was concluded
that the poly(acrylic acid) SPH microparticles could serve as a good super-disintegrant decreasing the
disintegration time of FDTs.

Introduction

Drug delivery using fast-disintegrating tablets (FDTs) is rapidly gaining interest in the
pharmaceutical industry since the tablets either disintegrate or dissolve in the mouth
rapidly, without requiring any water to aid in swallowing. This novel dosage form is
suitable for all age groups, particularly for children, the elderly and schizophrenic
patients who have difficulty in swallowing conventional tablets and capsules (Lindgren
& Janzon 1993). To ensure the tablet’s fast-disintegrating property, water must be
Purdue University, Departments quickly absorbed into the tablet matrix causing rapid disintegration of the tablet. The
of Industrial and Physical current approaches of making fast-disintegrating tablets are maximizing the porous
Pharmacy, West Lafayette,
structure of the tablet matrix and incorporating appropriate disintegrating agents and/
Indiana, 47907, USA
or highly water-soluble excipients in the tablet formulation (Chang et al 2000; Habib
Shicheng Yang, Yurong Fu, et al 2000; Sastry et al 2000; Dobetti 2000).
Seong Hoon Jeong, Kinam Park
Direct compression is the easiest way of manufacturing tablets. The biggest advan-
tages are the low manufacturing cost and high mechanical property of the tablets
Correspondence: K. Park, Purdue (Takao et al 1996). Disintegration and solubilization of direct-compression tablets are
University, School of Pharmacy, based on single or combined actions of disintegrants, water-soluble excipients, and
575 Stadium Mall Drive,
Room G22, West Lafayette,
effervescent agents (Shangraw et al 1980). In many cases, the disintegrants play a major
IN 47907-2051, USA. role in the disintegration and dissolution process of FDTs made by direct compression.
E-mail: [email protected] The choice of a suitable type and an optimal amount of disintegrant is critical for
ensuring fast disintegration (Dobetti 2000). The super-disintegrants, such as sodium
Funding: This study was starch glycolate and sodium croscarmellose, have been used as wicking agents in the
supported in part by NSF
Industry/University Center for
FDT formulations (Bi et al 1999; Khankari et al 2001; Mattsson et al 2001).
Pharmaceutical Processing Recently, superporous hydrogel (SPH) blocks with fast swelling and super-
Research and Samyang Corp. absorbent properties have been developed (Park et al 2001b) for developing a gastric

429
430 Shicheng Yang et al

retention device (Chen et al 1999; Chen & Park 2000). SPHs 1.25 £ 10¡1 M (10.5 g) NaHCO3. The whole solution was
are hydrogels with numerous pores connected together to stirred vigorously by magnetic stirring to accelerate foam-
form open channel structures. Water is absorbed into the ing and to evenly distribute the gas bubbles. The gelling
dried SPHs by capillary wetting rather than by diffusion. started within 30 s. Synthesis process was carried out under
The dried SPH hydrogels swell extremely fast with the a nitrogen atmosphere.
swelling ratio easily reaching more than 100-times within Synthesis of the poly(acrylic acid) hydrogel and poly
minutes (Chen et al 1999; Park et al 2001a). (acrylic acid) was similar to the synthesis of poly(acrylic
SPH microparticles, having a unique porous structure acid) SPH, but the foaming agent NaHCO3 was omit-
for fast transport of water through capillary forces, are ted in the synthesis of poly(acrylic acid) hydrogel; and
expected to result in an extremely fast wicking effect into NaHCO3 and crosslinker PEGDA were deleted in the
the tablet core. Tablets prepared by direct compression in synthesis of poly(acrylic acid). The synthesized poly(acrylic
the presence of SPH microparticles are thought to dis- acid), SPH and hydrogel were purified with absolute ethyl
integrate very quickly due to the fast uptake of water into alcohol and dried in an oven at 50 ¯ C. The dried samples
the core of the tablets (Park 2002). To evaluate the effect were milled using IKA A11 BASIC (IKA Works, INC;
of SPH microparticles on the disintegration and tensile Wilmington, NC) and the resultant microparticles were
strength of FDTs prepared by direct compression, FDTs screened using different sieves to get various particle size
containing sugar-based excipients and ketoprofen, a model ranges.
drug, were prepared using SPH microparticles as a dis-
integrant. A SPH based on poly(acrylic acid), sodium salt,
was synthesized and characterized. The fast disintegrating Swelling of SPH microparticles
tablets composed of various amounts of SPH microparti- Samples of SPH microparticles (0.10 g) were placed in a
cles were prepared using a fractional factorial design. The series of graduated cylinders (50 mL). Deionized water or
formulation and process were optimized according to the 0.2 M phosphate buffer (25 mL) was added into the cylin-
disintegration time and tensile strength of resultant tablets. der. The system was mixed and left to stand at 37 ¯ C. After
60 min, the volumes of the swollen samples at equilibrium
were measured and the swelling value calculated using the
Materials and Methods following equation (Edge et al 2002):

Materials Swelling value ˆ volume of sample/

0 0
Acrylic acid, ammonium persulfate, N,N,N ,N -tetrameth- weight of a dry sample …1†
ylethylenediamine (TMED), and poly(ethylene glycol) dia-
crylate (PEGDA) were purchased from Aldrich Chemical
Company, Inc. (Milwaukee, WI). Sodium hydroxide, X-ray SPH microparticle diffraction
sodium bicarbonate and citric acid were bought from Analysis of poly(acrylic acid) SPH microparticles was
Mallinckrodt Baker, Inc. (Paris, KY). Mannitol was a gift carried out on a Shimadzu XRD-6000 X-ray microparticle
from SPI Pharma Inc. (New Castle, DE). Ketoprofen was diffractometer (Kratos Analytical, Inc., Chestnut Ridge,
purchased from Nordic Synthesis (Karlskoga, Sweden). NY) equipped with a fine-focus X-ray tube using Cu
Dextrates (EMDEX, NF) was a gift from Penwest radiation (1.5406 AÊ). The tube voltage and amperage
Pharmaceuticals Co. (Patterson, NJ). Fumed silica (CAB- were set at 30 kV and 30 mA, respectively. The divergence
O-SIL) was bought from CABOT corporation Cab-O-Sil and scattering slits were set at 1, and the receiving slit was
division (Tuscola, IL). Magnesium stearate was obtained set at 0.15 mm. A sodium iodide scintillation detector was
from Mallinckrodt Specialty Chemicals Company (St Louis, used to detect diffracted radiation. Theta-two-theta con-
MO). Aspartame was purchased from Spectrum Chemical tinuous scans at 5¯ min¡1 (with a step size of 0.02 ¯ ) from
Mfg. Corp. (Gardena, CA). 3 to 40¯ 2y were used. The instrument was calibrated using
silicon standard.

Synthesis of poly(acrylic acid) SPH

Vapour sorption gravimetry
Synthesis of the SPH was based on the methods described
previously (Chen et al 1999; Chen & Park 2000). Briefly, the Moisture sorption isotherm of the SPH microparticles
monomer solution was prepared by neutralizing acrylic was determined using a Symmetric Gravimetric Analyzer
acid with NaOH solution to make a final pH of 6.0 and the Model 100 (SGA-100, VTI corporation, Hialeah, FL).
final monomer solution equivalent to 6.0 M of total acrylic SPH microparticles (5.0 mg) ranging from 44 to 106 ·m
acid and sodium acrylate. The following components were placed in the sample holder and dried at 60 ¯ C for
were added sequentially to a beaker at ambient tempera- 3 h. The relative humidity was then set to zero until stable
ture: 1.25 M (208.0 mL) of the 6.0 M sodium acrylate solu- mass was recorded and the balance was zeroed. The sorp-
tion; 6.25 £ 10¡3 M (21.9 mL) 20% w/w PEGDA; 11.56 M tion balance was programmed to generate relative humid-
(208.0 mL) distilled water; 1.25 £ 10¡2 M (9.0 mL) acrylic ity steps in an absorption/desorption cycle. The target
acid; 1.25 £ 10¡2 M (14.25 mL) 20% w/w ammonium per- relative humidity, under a continuous nitrogen flow of
sulfate; 1.25 £ 10¡2 M (7.25 mL) 20% w/w TMED; and 200 cm3 min¡1 , used during absorption of the sample was
 Superporous hydrogel microparticles for fast-disintegrating tablets 431

in the range of 10±90% relative humidity. The relative Table 1 Factors and levels in the fractional factorial experimental
humidity was held at each 5% relative humidity increment design.
until equilibrium occurred. During the desorption period
the same steps were taken in the reverse order, starting Factor Label Level
from 90% relative humidity. The temperature in the incu-
1 2 3
bator was controlled at 25 ¯ C. Sample mass was repre-
sented as a percentage of the dried mass. A Ketoprofen (% w/w) 0 10 20
B SPH* (% w/w) 0 2.5 5
Tablet preparation C Dextrates:mannitol 1:0 4:1 3:2
D Pressure (MPa) 42 63 84
Tablets of 500 mg were compressed on a single punch
Carver Laboratory Press (Carver Inc. Wabash, IN) at *SPH microparticles of 75±106 ·m.
different compression pressures using plane-face punches
with a diameter of 0.5 inch.

Compression data analysis Hardness Tester (Vankel, 36 Meridan Road, Edison, NJ).
The tablet tensile strength (¼x ) of FDTs was calculated
Poly(acrylic acid) SPH microparticles in the range from the following equation (Fell & Newton 1970):
25±250 ·m were dried at 60 ¯ C for 12 h. The pure SPH
microparticle tablets were compressed at pressure ranging ¼x ˆ 2F/ºDT …4†
from 7 to 615 MPa. Changes in density or porosity of
SPH tablets were obtained by measuring the thickness of
resultant tablets at zero pressure. The densification behav- Disintegration time
iour of SPH microparticles was evaluated by means of
the Kawakita equation (Kawakita & Ludde 1971; Denny The disintegration time of the resultant tablets was meas-
2002) as follows: ured using a Basket-rack assembly according to the
USP24/NF19 method.
P/C ˆ P/a ‡ 1/ab …2†

where C is the relative volume decrease i.e. Results and Discussion

C ˆ …V0 ¡V†/ V0 …3† Synthesis of SPH
where V0 is the initial volume and V is the volume of the SPH was synthesized by crosslinking polymerization of
particle under the applied pressure P. A plot of P/C sodium acrylate using PEGDA as a crosslinker in the
against P should give a straight line for deriving a and b presence of carbon dioxide bubbles that were generated
as the constant characteristics to particles being com- by the reaction of sodium bicarbonate with acrylic acid
pressed. The constant a is equal to the value of the initial (Chen et al 1999). In the synthesis of SPH, the molar ratio
porosity, and the constant b has the dimension of the of acrylic acid to PEGDA was 200:1, and the molar ratio
reciprocal of stress. of acrylic acid to ammonium persulfate (initiator) and to
TMED was 100:1. After being milled and screened by a
Experimental design series of sieves, SPH microparticles of various size ranges
were obtained.
As a result of preliminary experiments on variables that
have effects on the disintegration time and tensile strength
of ketoprofen FDTs, four variable factors were chosen for Swelling of SPH microparticles
our experiment, ketoprofen, SPH microparticles, filler
(dextrates and granular mannitol) and tableting pressure, Poly(acrylic acid) SPH microparticles swelled to approx-
and each factor had three levels (Table 1). All other imately 80-times of their dried state in distilled water
factors that might influence the responses were kept the and approximately 50-times in pH 6.8 phosphate buffer
same in all runs. (Table 2). The swelling values increased slightly as the
A 19-run experiment created by fractional factorial microparticle size increased. However, the swelling values
design using a SAS 8.2 program was performed. Analysis of various microparticle sizes were not significantly differ-
of variance of the factors on the disintegration time and ent (P > 0.05). For SPH in large blocks, it has been
tensile strength of ketoprofen FDTs were analysed using reported that the swelling ratio was up to 300-times. The
the SAS program. pores inside the SPH were connected to each other to form
extensive capillary channels; this helped the dried gel swell
in water to near equilibrium in a matter of minutes (Chen
Tensile strength of tablets
et al 1999). The superpores were destroyed during ground-
The crushing force F (N), thickness T (cm) and diameter ing of the SPH blocks into microparticles. Thus, the swel-
D (cm) of tablets were determined using a VK 200 Tablet ling value of SPH microparticles was lower compared with
432 Shicheng Yang et al

Table 2 Swelling values of poly(acrylic acid) superporous hydrogel Moisture sorption isotherm curve of poly
microparticles with various sizes. (acrylic acid) SPH microparticles

Size (mm) Swelling value (cm3 g¡1) Absorption and desorption of moisture by poly(acrylic
acid) SPH microparticles were measured with the sorption
Distilled water Phosphate buffer balance at 25 ¯ C as shown in Figure 2. The moisture
absorption increased with the increase of relative humidity.
25±44 77.5 § 2.5 47.5 § 2.5
Absorption of water was as high as 150% of the dry mass
44±106 78.0 § 2.0 48.0 § 2.0
106±150 80.0 § 2.5 50.0 § 2.5 at the relative humidity 90%, which may have been due to
150±250 82.5 § 2.5 52.5 § 2.5 the high hygroscopic property and high porosity of the
SPH. Absorption and desorption behaviour of the SPH
Swelling data represent mean § s.d. (n ˆ 3). microparticles were similar in the range of 35±90% relative
humidity. However, the water content at desorption was
higher than the corresponding values at absorption when
the relative humidity was below 35%. The difference may
the same SPH in blocks. The swelling values of sodium have been due to the fact that desorption of moisture from
starch glycolate were approximately 20-times (Ferrari et al SPH needed a longer time than the predetermined time of
2000; Edge et al 2002) and croscarmellose sodium rapidly 3 h at 25 ¯ C.
swelled to approximately 10-times on contact with distilled
water (Ferrari et al 2000). Compared with these commer-
Compressibility and compactability study of SPH
cially available super-disintegrants, the SPH microparticles
microparticles
showed the highest swelling values for a better disintegrant
efficiency in tablets. The compressibility and compactability has a direct rela-
tionship with the tableting performance of the particulate
Crystallinity of poly(acrylic acid) SPH solids. The compactability of SPH microparticles was mea-
sured by plotting the SPH tablet tensile strength as a func-
microparticles
tion of compaction pressure. The tablet tensile strength
The X-ray diffraction diagrams of microparticles of poly increased in a sigmoid shape following the pressure in-
(acrylic acid) SPH, poly(acrylic acid) hydrogel and poly crease. As the pressure increased higher than 400 MPa, the
(acrylic acid) are shown in Figure 1. There was no sharp tablet tensile strength did not increase any further.
peak in the X-ray diffraction diagrams, indicating that the The compressibility behaviour of poly(acrylic acid) SPH
three polymers existed in an amorphous state. Poly(acrylic microparticles was analysed by measuring the relationship
acid) SPH was different from poly(acrylic acid) hydrogel between compression pressure and the relative volume
and poly(acrylic acid) in the diagrams. This difference decrease of the microparticles using the Kawakita equation
may have been due to the existence of sodium in the (Figure 3). When the pressure was lower than 63 MPa, a
crosslinked amorphous network of poly(acrylic acid) curvature appeared for various ranges of microparticle
SPH, since SPH particles were not washed with water to sizes. Straight lines (r2 > 0.9900) were observed at the pres-
remove the salts. sure higher than 63 MPa for various particle sizes. In the

180
Mass in percent of dry sample (%)

Poly(acrylic acid) SPH

160 Absorption
Intensity, arbitrary units

Desorption
140
120
Poly(acrylic acid) 100
80
Poly(acrylic acid) hydrogel 60
40
20

0
5 10 15 20 25 30 35 40 0 10 20 30 40 50 60 70 80 90
2q, degrees Relative humidity (%)

Figure 1 X-ray diffraction diagrams of poly(acrylic acid), poly Figure 2 The absorption and desorption of moisture by poly
(acrylic acid) hydrogel, and poly(acrylic acid) superporous hydrogel (acrylic acid) superporous hydrogel microparticles as measured by a
microparticles. sorption balance at 25 ¯ C. Mean value § s.d. (n ˆ 3).
 Superporous hydrogel microparticles for fast-disintegrating tablets 433

1600 350 A
150–250 mm Magnesium stearate
1400 106–150 mm 300
Fumed silica
44–106 mm

Disintegration time (s)

1200 25–44 mm 250

1000 200
P/ C

800 150
600
100
400
50
200
0
0 0–25 25–44 44–75 75– 106– 150– 180–
0 100 200 300 400 500 600 106 150 180 250
Pressure (MPa) SPH particle size (mm)

100 Magnesium stearate

Figure 3 Kawakita plots for poly(acrylic acid) superporous hydro- B
gel microparticles. Fumed silica
90

Tensile strength (N cmŠ 2)

Kawakita equation, the constant, a, gives an indication of 80
the maximum volume reduction available and is considered
to describe the compressibility of the particle. The constant
70
a for poly(acrylic acid) SPH microparticles decreased
significantly from 0.59 § 0.04 (n ˆ 3) for 25±44 ·m to
0.53 § 0.03 (n ˆ 3) for 150±250 ·m. The constant b is con- 60
sidered to describe an inclination toward volume reduc-
tion, and has the dimension of the reciprocal of stress. The 50
stress of SPH microparticles increased significantly from
65.3 § 2.5 (n ˆ 3) for 25±44 ·m to 236.1 § 6.8 (n ˆ 3) for 40
150±250 ·m. Kawakita & Ludde (1971) stated that this 0–25 25–44 44–75 75– 106– 150– 180–
equation holds best for soft fluffy pharmaceutical parti- 106 150 180 250
cles. It is now generally accepted that the Kawakita equa- SPH particle size (mm)
tion is best used for low pressure and high porosities
Figure 4 The effects of poly(acrylic acid) superporous hydrogel
(Kawakita & Ludde 1971; Denny 2002). The SPH micro-
microparticle sizes on the disintegration time (A) and tensile strength
particles possessed a high porosity, and so the Kawakita (B) of ketoprofen fast disintegration tablets. Mean value § s.d. (n ˆ 3).
equation was suitable to evaluate the compressibility of
SPH microparticles.

Fast disintegrating tablets the SPH microparticle sizes decreased from 180±250 ·m
to 25±44 ·m. However, when the microparticle size was
The FDTs containing SPH microparticles and water solu- smaller than 25 ·m, the tensile strength of resultant tablets
ble carbohydrates were evaluated using ketoprofen as a increased as the size decreased. According to the results,
model drug. Ketoprofen is a hydrophobic drug and has the optimal microparticle size should be in the range of
poor compaction properties. If ketoprofen could be suc- 75±106 ·m. From Figure 4, the glidants and/or lubricants
cessfully formulated in FDTs containing SPH microparti- had a significant effect on the disintegration time of the
cles, this study could be easily extended to other drugs. To tablets. The disintegration time of ketoprofen FDTs sig-
mask the unpleasant taste of ketoprofen, all the formula- nificantly increased after the addition of hydrophobic
tions contained 1.5% w/w citric acid, 2.0% w/w aspartame. magnesium stearate as compared with the addition of
silicon dioxide. For the tablets containing a swelling dis-
Effect of SPH microparticle size on the disintegration integrant, a negative effect of magnesium stearate on the
time and tensile strength disintegration time was observed (Smallenbroek et al
The ketoprofen FDT formulations containing 2.5% w/w 1981). Different particle sizes of disintegrants might result
SPH microparticles with different sizes were prepared at in different swelling pressure in the process of tablet
63 MPa pressure. Figure 4 shows the effect of microparti- disintegration (List & Mauzzam 1979). The effect of
cle size on the disintegration time and tensile strength of disintegrants on tablet disintegration time and hard-
ketoprofen FDTs. The minimum disintegration time was ness depends on the physicochemical properties of the
observed when the microparticle size was in the range of disintegrants themselves and formulation composition
75±106 ·m. Tensile strength of the tablets decreased as (Asker et al 1975).
434 Shicheng Yang et al

Experimental design of ketoprofen FDTs porosity. Penetration of water into the tablet was hin-
The disintegration time and tensile strength of ketoprofen dered, and thus the disintegration time increased. Fast
FDTs prepared according to the fractional factorial design dispersible ibuprofen tablets with the optimal porosity of
are shown in Table 3. The analysis of variance results of approximately 13% had the shortest disintegration time
disintegration time indicated that the three factors SPH of 36 s (Schiermeier & Schmidt 2002). Ketoprofen is a
(P < 0.01), pressure (P < 0.05) and ketoprofen content hydrophobic drug that can increase the wetting time of
(P < 0.05) had significant effects on the disintegration tablets as the content in the formulation increases, and
time of ketoprofen FDTs. The proportion of dextrates to thus increase the disintegration time of ketoprofen FDTs.
mannitol had little effect on the disintegration time of The analysis of variance results for tensile strength of
ketoprofen FDTs. ketoprofen FDTs showed that the three factors tableting
SPH microparticles, which acted as a super-disintegrant pressure (P < 0.01), SPH microparticles (P < 0.01) and
in the tablets, was a key factor to tablet disintegration time. ketoprofen (P < 0.05) had significant effect on the tensile
With 2.5% w/w of SPH microparticles (75±106 ·m), the strength of ketoprofen FDTs. The filler had little effect on
disintegration time of ketoprofen FDTs decreased with the the tensile strength of resultant tablets. The tensile
increase of SPH content in tablet formulation. However, the strength of the FDTs greatly increased as the pressure
disintegration time did not decrease with the increase of increased. The tensile strength of tablets or compacts is
SPH content when it was higher than 2.5% w/w. The max- governed by the sum of the bonding forces of all indivi-
imum disintegration force developed in a tablet depended dual interparticulate bonds in the failure plane of the
on the quality and quantity of the disintegrating agent and compact, and the sum increases with the compaction
was related to the amount of water absorbed by the tablet. pressure through rearrangement of particles, particle de-
Water penetration rate, rather than the amount of water formation and fragmentation (Eriksson & Alderborn
absorbed, influenced the disintegration time (Colombo et al 1995; Rankell & Higuchi 1968). However, the tensile
1981). The swelling materials make pore walls hydrophilic, strength of tablets decreased as the amount of SPH micro-
providing enough swelling force to produce interparticle particles increased in the formulation, which may have
bond disruption (Caramella et al 1984). The time taken for been due to the high stress of SPH microparticles.
the tablets to disintegrate was generally reduced by the
addition of a super-disintegrant; the effectiveness of the Selection of the optimum setting
super-disintegrant was dependent on the nature of the An ideal FDT should possess both short disintegration time
compound and excipients used (Mattsson et al 2001). and high mechanical strength. The mechanical strength of a
Porosity depended on the pressure at which tablets tablet is of great importance with regard to the subsequent
were compressed as well as on the nature of the materials packaging process and transportation. The optimal keto-
used. A high compression force led to tablets with a lower profen FDT should have a disintegration time of less than

Table 3 Factors and responses of the 19-run fractional factorial design.

Run Ketoprofen SPH (B) Dextrates: Pressure Disintegration Tensile

(A) (% w/w) (% w/w) mannitol (C) (D) (MPa) time (s) strength
(N cm¡2)

1 10 5 3:2 84 96.8 § 19.0 110.6§ 9.9

2 10 5 4:1 42 16.0 § 1.2 36.5 § 2.0
3 10 5 1:0 63 15.0 § 0.5 66.4 § 4.6
4 10 2.5 3:2 84 99.8 § 17.3 120.1§ 10.9
5 10 2.5 4:1 42 14.0 § 0.4 39.7 § 4.4
6 10 0 4:1 84 308.5§ 19.5 152.5§ 4.9
7 10 0 1:0 63 207.5§ 18.6 119.1§ 9.8
8 20 5 4:1 84 219.5§ 7.9 110.1§ 9.4
9 20 5 4:1 63 44.8 § 8.8 70.3 § 12.8
10 20 2.5 1:0 84 145.0§ 16.3 104.0§ 14.7
11 20 2.5 1:0 42 18.3 § 1.8 36.4 § 0.8
12 20 0 3:2 63 339.5§ 36.4 90.6 § 5.3
13 20 0 3:2 42 101.3§ 13.6 37.4 § 4.5
14 0 5 3:2 42 11.5 § 1.5 30.2 § 2.3
15 0 5 1:0 84 25.0 § 1.2 99.9 § 8.9
16 0 2.5 3:2 63 18.0 § 1.2 86.6 § 18.3
17 0 2.5 4:1 63 20.5 § 1.9 87.8 § 21.5
18 0 0 4:1 84 82.0 § 12.4 146.1§ 16.0
19 0 0 1:0 42 52.5 § 2.1 58.7 § 3.6

Response data represent mean § s.d. (n ˆ 4).

 Superporous hydrogel microparticles for fast-disintegrating tablets 435

30 s with a tensile strength of the tablet no less than

References
75 N cm¡2. Ketoprofen could increase the disintegration
time and decrease the tensile strength of tablets. For the
Asker, A. F., Saied, K. M., Abdel-Khalek, M. M. (1975)
formulation ketoprofen was chosen as 10% w/w. From the Materials as dry binders for direct compression in tablet man-
analysis of variance results of disintegration time and tensile ufacture. 4. Effect of disintegrants. Pharmazie 30: 377±378
strength, the SPH microparticle and tableting pressure had Bi, Y. X., Sunada, H., Yonezawa, Y., Danjo, K. (1999)
significant effects on the resultant FDTs. When the amount Evaluation of rapidly disintegrating tablets prepared by a
of SPH microparticles in the formulations increased from direct compression method. Drug Dev. Ind. Pharm. 25:
2.5 to 5.0% w/w, the disintegration time did not decrease 571±581
any further. On the other hand, the microparticles had an Caramella, C., Colombo, P., Conte, U., Gazzaniga, A.,
adverse effect on the resultant tablet tensile strength. The La Manna, A. (1984) The role of swelling in the disintegration
amount of SPH microparticles in the formulation was cho- process. Int. J. Pharm. Tech. Pro. Manuf. 5: 1±5
Chang, R.-K., Guo, X., Burnside, B. A., Couch, R. A. (2000)
sen as 2.5% w/w, which was high enough to decrease the
Fast-dissolving tablets. Pharm. Technol. 24: 52, 54, 56, 58
disintegration time but did not result in a great decrease in Chen, J., Park, K. (2000) Synthesis and characterization of
the tensile strength of the tablets. High pressure can increase superporous hydrogel composites. J. Control. Release 65:
the tensile strength, but significantly prolong the disintegra- 73±82
tion time of the resulting tablets. When the pressure was Chen, J., Park, H., Park, K. (1999) Synthesis of superporous
higher than 63 MPa, the disintegration time was too long to hydrogels. Hydrogels with fast swelling and superabsorbent
be acceptable for FDTs. However, when the pressure was properties. J. Biomed. Mater. Res. 44: 53±62
lower than 63 MPa, the resultant tablets were too weak to Colombo, P., Caramella, C., Conte, U., La Manna, A., Guyot-
be packaged as conventional tablets. Optimum pressure Herman, A. M., Ringard, J. (1981) Disintegrating force and
was considered to be 63 MPa. The filler had no significant tablet properties. Drug Dev. Ind. Pharm. 7: 135±153
Denny, P. J. (2002) Compaction equations: a comparison of
effect on either disintegration or tensile strength of resultant
the Heckel and Kawakita equations. Powder Technol. 127:
tablets. Dextrates is sweeter and cheaper than mannitol, 162±172
and thus dextrates was selected as a water soluble filler in Dobetti, L. (2000) Fast-melting tablets: developments and tech-
the ketoprofen FDTs. The optimum setting of ketoprofen nologies. Pharm. Technol. Europe 12: 32±42
FDTs was: A2 (ketoprofen, 10% w/w), B2 (SPH micro- Edge, S., Steele, D. F., Staniforth, J. N., Chen, A., Woodcock, P. M.
particles, 2.5% w/w), C1 (dextrates:mannitol ˆ 1:0) and (2002) Particle compaction properties of sodium starch glyco-
D2 (pressure, 63 MPa). The optimum formulation con- late disintegrants. Drug Dev. Ind. Pharm. 28: 989±999
tained 10% w/w ketoprofen, 2.5% w/w SPH microparticles Eriksson, M., Alderborn, G. (1995) The effect of particle frag-
(75±106 ·m), 83.5% w/w dextrates, 1.5% w/w citric acid, mentation and deformation on the interparticulate bond
2.0% w/w aspartame, and 0.5% w/w fumed silica. The opti- formation process during powder compaction. Pharm. Res.
12: 1031±1039
mal setting was performed six times, and the disintegration
Fell, J. T., Newton, J. M. (1970) Determination of tablet strength
time and tensile strength of optimal FDTs were 15.0 § 2.0 s by the diametral-compression tests. J. Pharm. Sci. 59: 688±691
and 84.4 § 4.1 N cm¡2 , respectively. The results indicated Ferrari, F., Rossi, S., Bonferoni, M. C., Canevari, S., Dobetti, L.,
that the ketoprofen FDTs produced according to these Caramella, C. (2000) The influence of product brand and
optimal settings had an excellent response of the disintegra- batch-to-batch variability on super-disintegrant performance.
tion time and tensile strength. S.T.P. Pharma Sci. 10: 459±465
Habib, W., Khankari, R., Hontz, J. (2000) Fast-dissolve drug
delivery systems. Crit. Rev. Ther. Drug Carrier Syst. 17: 61±72
Kawakita, K., Ludde, K. (1971) Some considerations on powder
Conclusions compression equations. Powder Technol. 4: 61±68
Poly(acrylic acid) SPH was synthesized using PEGDA as a Khankari, R. K., Hontz, J., Chastain, S. J., Katzner, L. (2001)
Rapidly dissolving tablet dosage form. US Patent 6,221,392
crosslinker. Poly(acrylic acid) SPH microparticles showed a
Lindgren, S., Janzon, L. (1993) Dysphagia: prevalence of swal-
high swelling property in various aqueous media, and had a lowing complaints and clinical finding. Med. Clin. North Am.
high compressibility and good compactability. The micro- 77: 3±5
particle size of SPH had a great effect on the disintegration List, P. H., Mauzzam, U. A. (1979) Swelling ± the driving force
time of FDTs. The optimal microparticle size for disinte- in tablet disintegration. Part 2. Pharmazeutische Industrie
gration time was in the range 75±106 ·m. A fractional 41: 1075±1077
factorial experiment with 19 runs was conducted to evaluate Mattsson, S., Bredenberg, S., Nystrom, C. (2001) Formulation of
the effects of ketoprofen, SPH, filler and tableting pressure high tensile strength rapidly disintegrating tablets. Evaluation
on disintegration time and tensile strength of FDTs. The of the effect of some binder properties. S.T.P. Pharma Sci. 11:
addition of SPH microparticles significantly decreased the 211±220
Park, K. (2002) Superporous hydrogels for pharmaceutical &
disintegration time of FDTs, but had a negative impact on
other applications. Drug Deliv. Technol. 2: 38, 40±44
tensile strength. The optimum ketoprofen FDT consisting
Park, K., Chen, J., Park, H. (2001a) Hydrogel composites and
of 2.5% w/w SPH microparticles, 10% w/w ketoprofen pre- superporous hydrogel composites having fast swelling, high
pared under 63 MPa pressure, demonstrated 15 s dis- mechanical strength and superabsorbent properties and pre-
integration time and 85 N cm¡2 tensile strength. The results paration thereof. US Patent 6,271,278
indicated that poly(acrylic acid) SPH microparticles were a Park, K., Chen, J., Park, H. (2001b) Superporous hydrogel com-
promising super-disintegrant for making FDTs. posites: a new generation of hydrogels with fast swelling
436 Shicheng Yang et al

kinetics, high swelling ratio and high mechanical strength. In: Schiermeier, S., Schmidt, P. C. (2002) Fast dispersible ibuprofen
Ottenbrite, R. M., Kim, S. W. (eds) Polymeric drugs & drug tablets. Eur. J. Pharm. Sci. 15: 295±305
delivery systems. Technomic Publishing Co., Lancaster, PA, Shangraw, R., Mitrevej, A., Shah, M. (1980) A new era of tablet
pp 145±156 disintegrants. Pharm. Technol. 4: 49±57
Rankell, A. S., Higuchi, T. (1968) Physics of tablet compression. Smallenbroek, A. J., Bolhuis, G. K., Lerk, C. F. (1981) The effect
XV. Thermodynamic and kinetic aspects of adhesion under of particle size of disintegrants on the disintegration of tablets.
pressure. J. Pharm. Sci. 57: 574±577 Pharm. Weekbl. [Sci]. 3: 172±175
Sastry, S. V., Nyshadham, J. R., Fix, J. A. (2000) Recent tech- Takao, M., Yoshinori, M., Muneo, F. (1996) Intrabuccally dis-
nological advances in oral drug delivery. A review. Pharma. solving compressed moldings and production process thereof.
Sci. .Technol. Today 3: 138±145 US patent 5,576,014