Swellable/expandable systems for gastroretentive delivery/Asian Journal of Pharmaceutical Sciences 2008, 3 (1): 1-11

Development and characterization of swellable/expandable systems for

their potential application as a gastroretentive delivery (GRD) device
Shyr-Yi Lina, b, Wen Shian Siowc, Hsiu-O Hoc, Ming-Thau Sheuc, *
a
Department of Internal Medicine and Primary Care Medicine, Taipei Medical University and Hospital, Taiwan
b
Cancer and Chinese Herb Research Center, Taipei Medical University Hospital, Taiwan
c
College of Pharmacy, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan
Received 7 May 2007; Revised 3 September 2007; Accepted 29 October 2007
_____________________________________________________________________________________________________________

Abstract

Purpose: To obtain a synergy between the swelling indexes of swellable polymers with a combination of several swelling functionalities
in the unit, the investigation of different types of swellable polymers and addition of an ionic complex of polyelectrolytes with regard to
the swelling behavior was conducted in this study. Methods: Physical characterizations of the tablets, including a swelling index based
on weight variation and visual swelling observations, were carried out. Results: Of the four different grades of HEC 250 examined (H,
HX, HHX and M), HEC 250HHX exhibited the greatest swelling index. Lower molecular weight PEO, varying from Mw 100K to
Mw 900K, exhibited a low swelling index and dissolved almost completely after immersion for 2 to 4 h in the medium. However, the
swelling ability of PEO (Mw 8,000K) was found to be sustainable to an extent greater than that for HEC 250HHX. Combination of a
lower molecular weight PEO (Mw 900K) with HEC 250HHX resulted in a lower swelling index than that for HEC 250HHX alone,
whereas a high molecular weight PEO (Mw 8,000K) incorporated with HEC 250HHX resulted in a higher swelling rate. However, the
addition of an ionic complex of polyelectrolytes produced only a slight improvement in swelling index. Conclusion: HEC exhibited a
suitable swelling index apart from the higher molecular weight PEO (Mw 8,000K). The addition of 50% Carbopol in HEC would be
preferable to increase the swelling of the tablet. The swelling index obtained from the formulation with 10% to 50% of chitosan showed
a good swelling index in the pH 1.2 media, but the degree of swelling size was not high enough as required.

Keywords: Gastroretentive delivery device; Hydroxyethyl cellulose; Polyethylene oxide; Carbopol; Chitosan; Swelling
_____________________________________________________________________________________________________________

1. Introduction upper gastrointestinal (GI) tract, i.e. stomach and small

intestine. These limits promoted the development of
For the past three decades, oral controlled release gastroretentive drug delivery systems (GRDS). The
dosage forms have been developed because of their improvements offered by GRDS include achieving a
important therapeutic advantages compared with tradi- greater and more prolonged therapeutic effect, thereby
tional delivery systems. By the introduction of a variety reducing the frequency of the administrations, providing
of controlled delivery systems, the drug absorption from a more effective treatment of local stomach disorders
conventional tablets or capsules that resulted in a and minimizing both lower-tract inactivation of the drug
transient overdose, followed by a long period of under- and drug effects on the lower intestinal flora [1-2].
dosing, was overcome. The current controlled release Floating, swelling, and bioadhesive systems have
technology has made it possible to release drugs at a been developed to increase the gastric retention time of
constant rate for longer periods of time ranging from dosage forms. Although the physiological characteristics
days to even years. However, this benefit had not been of the upper GI tract play an important role in limiting
provided for a variety of important drugs with a narrow the development of such systems, many in vitro and in
absorption window that are mainly absorbed in the vivo studies of these systems have shown promising
__________ results. The various floating devices investigated have
*Corresponding author. Address: College of Pharmacy, Taipei included: hydrodynamically balanced systems [3-5],
Medical University, 250 Wu-Hsing Street, Taipei, Taiwan. Tel.:
+886-2-23771942; Fax: +886-2-23771942.
multiple unit systems with an air compartment [6], float-
E-mail: [email protected] ing systems based on gas-forming agents [7], floating

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systems using ion exchange resins [8-9] and floating 2. Materials and methods
microparticles based on low density foam powder [10].
Preda and Leucuta developed a biologically adhesive 2.1. Materials
delivery system based on bioadhesive polymers, i.e.,
poly(acrylic acid) (PAA) in gelatin microspheres [11]. Hydroxyethylcellulose 250H, 250HX, 250HHX,
Various attempts have been made to develop swelling 250M, and 250HHX (designated as HEC250H, HEC-
and expanding systems: hydrophilic natural gum mini- 250HX, HEC250HHX, HEC250M, and HEC250HHX,
matrix formulations [12], superporous hydrogel (SPH) respectively) were of pharmaceutical grade and supplied
composites [13-16], polymer based hydrocolloid tablets by Hercules (USA). Poly(ethylene oxide) Mw 100,000–
[17-18], rectangular shape unfolding gastroretentive 900,000 (PEO 100K–900K) and Mw 8,000,000 (PEO
dosage forms (GRDF) [19-20], and interpolymer 8,000K) were obtained from Acros Organics (USA) and
complexes from poly(acrylic acid) chitosan [21-23]. Dow (USA), respectively. Carbopol 940 and chitosan
Expandable GRDS based on unfolding resulting in a (Practical grade from crab shells) were purchased from
large configuration were first described by Laby in Sigma Aldrich Chemical Co. (USA). Colloidal silicon
1974 [24] while expandable GRDS based on expansion dioxide 200 (Aerosil 200) was provided by Degussa
(swelling) were first suggested by Johnson and Rowe (Germany).
in 1971 [25]. Sonobe et al. developed unfolding GRDF
having the shape, size and durability to be retained in 2.2. Evaluation of expandable tablets formulations
the stomach for a prolonged period [26]. Mamajek and
Moyer designed a swelling GRDF based on expansion 2.2.1. Fabrication of the expandable tablets
by osmotic pressure [27].
Many patents have been granted for GRDS during All excipients were passed separately through a No.
the past three decades. The important developments of 60 sieve. The polymer was then mixed according to the
expandable GRDS were highlighted by recently granted weight proportions listed in Table 1 and Table 2. The
patents, including the optimization of the polymer ratio, mixture was then compressed on a Carver Laboratory
tablet shapes to enhance gastric retention, extending the Press tabletting machine using flat-faced punches (diameter
drug release within the stomach and the controlled 8 mm) at a pressure of 1 ton for 6 s.
release of active substance in the GI tract [28-31]. We
have been interested in developing expandable gastro- 2.2.2. Determination of swelling index
retentive formulations based on different swelling
functionalities mainly classified into the following The swelling studies were carried out using testing
categories: (1) Combination of different swellable apparatus I (Vankel® dissolution apparatus) without any
polymers; (2) Addition of a chargeable polymer; rotation. The preweighed tablets were immersed in
(3) Addition of an ionic complex of polyelectrolytes; 500 ml of the medium (distilled water) and maintained
(4) Addition of osmogents, and (5) Addition of wicking for 8 h at 37.0 ± 0.5˚C. At predetermined time intervals (0,
agents. Swelling investigations of the fabricated hydro- 0.5, 2, 4, 6 and 8 h), the swollen tablets were removed
colloid tablets were carried out to obtain a comprehen- from the solution, immediately wiped with a paper towel
sive understanding of the swelling properties produced to remove droplets on the surface, and weighed.
by different swelling functionalities. The aim of this The swelling index (Sw) was calculated according the
study was to examine the influence of combining two following equation [32]:
Wt – W0
swellable polymers and addition of an ionic complex of Swelling index = _________
polyelectrolyte on the swelling behavior in an attempt W0
to develop a novel expandable gastroretentive drug where Wo and Wt represent the initial weight of the dry
delivery system. tablet and the weight of the swollen tablet at time t,

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Table 1
Formulation composition of the expandable tablets based on the combination of two swellable polymers.
HEC 250 PEO (K)
Rx Aerosil 200
H HX HHX M 100 200 300 600 900 8000
A1 100 — — — — — — — — — —
A2 — 100 — — — — — — — — —
A3 — — 100 — — — — — — — —
A4 — — — 100 — — — — — — —
B1 — — — — 100 — — — — — —
B2 — — — — — 100 — — — — —
B3 — — — — — — 100 — — — —
B4 — — — — — — — 100 — — —
B5 — — — — — — — — 100 — —
C1-1 — — 80 — — — — — 20 — —
C1-2 — — 60 — — — — — 40 — —
C1-3 — — 40 — — — — — 60 — —
C2-1 — — 80 — — — — — — 20 —
C2-2 — — 60 — — — — — — 40 —
C2-3 — — 0 — — — — — — 100 —
D1-1 — — 80 — — — — — 20 — 0.5
D1-2 — — 60 — — — — — 40 — 0.5
D1-3 — — 40 — — — — — 60 — 0.5
D2-1 — — 80 — — — — — — 20 0.5
D2-2 — — 60 — — — — — — 40 0.5
D2-3 — — 0 — — — — — — 100 0.5

Table 2
Formulation composition of the expandable tablets based on the addition of an ionic complex of polyelectrolytes.

Components (%)
Rx
HEC 250 HHX Carbopol 940 Chitosan
H1 30 70 0
H2 30 20 50
H3 30 0 70
I1 90 10 —
I2 70 30 —
I3 50 50 —
I4 30 70 —
J1 90 — 10
J2 70 — 30
J3 50 — 50
J4 30 — 70

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respectively. The data shown are the mean ± SD from tablets came into contact with water.
two samples per formulation. Polyethylene oxide (PEO) is widely used in the
pharmaceutical industry due to its non-toxicity, high
2.2.3. Photographic studies water-solubility and swellability, and it has been patented
as the major component for the preparation of gastric
After recording the weight of the swollen tablets, the retention systems. Accordingly, the swelling abilities of
tablets were then photographed using a digital camera different molecular weights of PEO were investigated
(Canon IXUS 400, Japan) at predetermined time inter- for comparison and the results are shown in Fig. 2. In
vals (0.5, 2, 4 and 6 h). The characterization of the formulation B, the lower molecular weight PEO, varying
swollen tablets included their thickness and appearance from Mw 100K to Mw 900K exhibited a low swelling
and these were recorded in detail. index, and dissolved almost completely after immersion
for 2 to 8 h in the medium. It was further found that
3. Results and discussion lower molecular weight PEO, varying from Mw 200K
to Mw 900K, formed a sticky, translucent and weak gel
All expandable tablets compressed weighed 160 mg layer after coming into contact with DDW for 0.5 h,
with a variation of ±1%. The swelling tests were then while no gel layer was formed in PEO with an Mw
carried out and the swelling weights were recorded and 100K. After being immersed in DDW for 2 h, PEO
used to calculate the swelling index. Photography was with a molecular weight varying from 100K to 300K
also used to study the swelling of the fabricated expand- completely dissolved. However, the size of PEO with
able tablets. The photographs provided information an Mw of 600K and 900K decreased gradually and the
necessary to explain the complex phenomenon of swell- dry core started to disappear after 6 h. This might be
ing. From the gel layer formed, the drug release mecha- due to the weaker chain entanglement within the lower
nism could also be predicted, either by diffusion from the molecular weight PEO, allowing water molecules to
swelling layer or by erosion from the polymer dissolution. diffuse through the matrix more easily and, hence, pro-
The effects of different types of swellable polymers mote the subsequent swelling erosion of the polymer [33].
and different combinations of swellable polymers were In formulation C1, combination of a lower molecular
investigated. The swelling index was obtained from weight PEO (Mw 900K) with HEC 250HHX resulted
different grades of hydroxyethylcellulose (HEC) as in a lower swelling index compared with HEC 250HHX
shown by formulation A series (Table 1). Among the alone (Fig. 3A). Only the formulation with a higher ratio
four different grades of HEC 250 (H, HX, HHX, and of HEC 250HHX (up to 80%) formed a thin and clear
M), the first three grades of HEC (250H, 250HX, and gel layer after 0.5 h. It was found that, in the formulation
250HHX) exhibited similar swelling profiles (Fig. 1A). with a higher ratio of lower molecular weight PEO, a
From the photographs (Fig. 1B), it was found that HEC translucent and weak gel layer was formed instead. How-
250H, HX and HHX formed a clear and rigid gel layer ever, when PEO 8,000K was incorporated with HEC
after swelling for 0.5 h in DDW but, in the case of the 250HHX, it resulted in a higher swelling rate compared
gel layer formed by HEC 250HHX, it was found to be with HEC 250HHX alone (Fig. 3B). In formulation C2,
the thickest after 6 h. This might be attributed to its containing higher molecular weight PEO (Mw 8,000K),
higher viscosity (3,500–5,000 MPa) compared with the the tablets swelled to a greater extent with the formation
others. On the other hand, HEC 250M formed a thinner of a translucent and rigid gel layer when the ratio of PEO
but cloudy gel layer and it was suspected that the pre- increased. This might be attributed to its high molecular
sence of insoluble components in the swelling zone weight of PEO 8,000K that made it possible to produce
would impede further swelling of the tablet [17-18]. a firm hydrogel in solution. On the other hand, the addi-
Tablets composed of polymeric matrices such as HEC tion of colloidal silicon dioxide (Aerosil 200) did not
would form a gel layer around the tablet core when the show any significant difference compared with those

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(A) (A-) HEC 250H

0 (A-2) HEC 250HX
(A-3) HEC 250HHX
(A-4) HEC 250M
8
Swelling Index

0
0 2 4 6 8
Time (h)

(B)

Fig. 1. Swelling profiles (A) and photographs (B) of different grades of HEC (Formulation A) in DDW. HEC grades: (●) HEC 250H; (■)
HEC 250HX; (◇) HEC 250HHX; (▲) HEC 250M.

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(A) (B) PEO 00K

0 (B2) PEO 200K
(B3) PEO 300K
(B4) PEO 600K
8 (B5) PEO 900K
PEO 8,000K
HEC 250HHX
Swelling Index

0
0 2 4 6 8
Time (h)

(B)

Fig. 2. Swelling profiles (A) and photographs (B) of PEO with different molecular weights (Formulation B) in DDW. PEO Mw: (●)
100K; (■) 200K; (◆) 300K; (▲) 600K; (▼) 900K; (○) 8000K; (◇) HEC 250HHX.

without added Aerosil 200. Carbopol 940 or chitosan, the combination of HEC
Since ionic complexes of polyelectrolytes exhibit a 250HHX with the former found to have a greater swell-
faster swelling compared with hydrogels with chemical ing ability compared with the latter. In formulation H,
crosslinks [21-23], they were incorporated with HEC the combination with a higher ratio of Carbopol 940
250HHX to observe their effect on swelling ability. showed a greater swelling index, while the combination
Following a comparison of the results obtained from with a higher ratio of chitosan (up to 70% of total)
the different combinations of HEC 250HHX with either immediately dissolved when it came into contact with

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(C-) HEC PEO-L (A)

0 (C-2) HEC PEO-L2
(C-3) HEC PEO-L3
(D-) HEC PEO-LA
8 (D-2) HEC PEO-LA2
(D-3) HEC PEO-LA3
HEC 250HHX
Swelling Index

0
0 2 4 6 8
Time (h)

(B)
(C2-) HEC PEO-H
0 (C2-2) HEC PEO-H2
(C2-3) HEC PEO-H3
(D2-) HEC PEO-HA
8 (D2-2) HEC PEO-HA2
(D2-3) HEC PEO-HA3
HEC 250HHX
Swelling Index

0
0 2 4 6 8
Time (h)

Fig. 3. Swelling index studies of a combination of HEC 250HHX and (A) lower or (B) higher molecular weight PEO (Mw 900K and
Mw 8,000K respectively) with (Formulation D1, D2) or without (Formulation C1, C2) addition of Aerosil in DDW. (A) H/P(L) ratio: (●/○)
80: 20; (■/□) 60: 40; (▲/△) 40: 60; (◇) HEC 250HHX. (B) H/P(H) ratio: (●/○) 80: 20; (■/□) 60: 40; (▲/△) 0: 100; (◇) HEC 250HHX.

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water (Fig. 4). In formulation I, the incorporation of This difference in the thickness of the gel layer was
Carbopol 940 slightly increased the swelling index of very apparent at 6 h. However, the degree of swelling
the tablets (Fig. 5). It was observed that a very thin, tur- was quite similar in the formulation with 50% and 70%
bid and rigid gel layer was formed in the combination of Carbopol 940. Therefore, it was concluded that the
HEC 250HHX and Carbopol 940 after being immersed addition of 50% Carbopol 940 was the ultimate amount
in DDW for 0.5 h. The gel layer formed was thicker in to obtain a higher swelling index with the incorporation
the formulation with higher amounts of Carbopol 940. of HEC 250HHX.

2 (H-) Car HEC CS-

(H-2) Car HEC CS-2
(H-3) Car HEC CS-3
0 HEC 250HHX

8
Swelling Index

0
0 2 4 6 8
Time (h)
Fig. 4. Swelling index studies of a combination of HEC 250HHX, Carbopol 940 and chitosan (formulation H) in DDW. Car/H/CS ratio: (●)
70: 30: 0; (■) 20: 30: 50; (▲) 0: 30: 70; (◇) HEC 250HHX.

2 (I-) HEC Car-

(I-2) HEC Car-2
(I-3) HEC Car-3
0 (I-4) HEC Car-4
HEC 250HHX

8
Swelling Index

0
0 2 4 6 8
Time (h)
Fig. 5. Swelling index studies of a combination of HEC 250HHX and Carbopol 940 (formulation I) in DDW. H/Car ratio: (●) 90: 10;
(■) 70: 30; (◆) 50: 50; (▲) 30: 70; (◇) HEC 250HHX.

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On the other hand, addition of 10% chitosan to HEC fact that chitosan is insoluble in water and, hence, hydra-
250HHX produced a slightly greater swelling index in tion is retarded despite the contribution to the swelling
DDW. A thin and unclear gel layer formed by the formu- index from HEC 250HHX. However, when the combina-
lation with addition of 10% chitosan might contribute tion of HEC 250HHX and chitosan was immersed in pH 1.2
to the swelling properties of HEC 250HHX itself in medium, with amounts of chitosan within the range 10%
DDW. Nevertheless, when the content of chitosan was to 50%, the swelling increased in proportion with the
more than 30%, the swelling index decreased (Fig. 6A). amount of chitosan. Nevertheless, 70% chitosan produced
No clear gel layer was formed but a turbid body was a reduction in the swelling index (Fig. 6B). The greater
observed in the formulation with more than 30% chito- swelling achieved in pH 1.2 was in agreement with the
san. The lack of formation of a gel layer is due to the high solubility of chitosan in an acidic environment.

2 (J1-1) HEC CS-1 (A)

(J1-2) HEC CS-2
(J1-3) HEC CS-3
0 (J1-4) HEC CS-4
HEC 250HHX

8
Swelling Index

0
0 2 4 6 8
Time (h)

(J2-1) HEC CS-1 (B)

2
(J2-2) HEC CS-2
(J2-3) HEC CS-3
0 (J2-4) HEC CS-4

8
Swelling Index

0
0 2 4 6 8
Time (h)
Fig. 6. Swelling index studies of a combination of HEC 250HHX and chitosan in (A) DDW (Formulation J-1) or (B) pH 1.2 medium
(formulation J-2). H/CS ratio: (●) 90: 10; (■) 70: 30; (◆) 50: 50; (▲) 30: 70; (◇) HEC 250HHX.

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4. Conclusion [12] J. Sujja-areeyath, D. L. Munday, P. J. Cox, et al.

Relationship between swelling, erosion and drug release in
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