Adhyapak A A et al.

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INTERNATIONAL RESEARCH JOURNAL OF PHARMACY

Available online http://www.irjponline.com
Research Article

FORMULATION AND CHARACTERIZATION OF FLOATING SODIUM

ALGINATE BEADS OF AMOXICILLIN FOR PROLONGED GASTRIC
RETENTION
Adhyapak Anjana A1*, Naduvinamani Suma N2, Tikare Vijay P2
1
KLE University’s College of Pharmacy, JNMC Campus, Belgaum, Karnataka, India
2
Maratha Mandal’s college of Pharmacy, Mal Maruti Extension, Belguam, Karnataka, India

*Adhyapak Anjana A., Asst. professor, Dept. of pharmaceutics, KLE University’s College of Pharmacy,
JNMC Campus, Belgaum 590010 E mail: anju_aaa@yahoo.com
Article Received on: 12/11/10 Revised on: 28/11/10 Approved for publication: 09/12/10

ABSTRACT
Sodium alginate (SA) floating beads containing amoxicillin were prepared by dripping method
using calcium carbonate as gas generating agent. Hydroxyl propyl methyl cellulose (HPMC) was used in
all the four formulations (A1, A2, A3 and A4) as swelling agent to control the release of the drug. Gas
generating agent forms pores on the surface of the bead because of the rapid escape of CO2 during the
curing process in precipitating media. Scanning electron microscopy (SEM) confirmed their porous and
grossly spherical structure and size of the beads in the range of 800-1000μm. The drug entrapment
efficiency was found to be 72.97-91.60%. A1 showed maximum drug entrapment efficiency and A4
showed least entrapment efficiency. The percentage porosity of beads was 78.99-96.03%. The porosity
depends on the concentration of gas forming agent. The mechanical strength of the beads was 391-729
gm. All the formulations showed good floating time. The in- vitro release study was performed according
to USP for 12 h. The cumulative percentage drug release was found to be 70.81 – 88.48%. The In-vitro
dissolution study reveals that the concentration of gas generating agent affects the release rate.

KEYWORDS: Floating Alginate Beads, Sodium Alginate, HPMC, scanning electron microscopy

INTRODUCTION
Over the years there has been available a variety of drug modification and dosage forms, with
which we have attempted to control the time course and specificity of drugs in the body. To maximize the
utilization, it is necessary to deliver the drug to its target tissue in the correct amount at the proper time to
elicit the desired response. Moreover, drug delivery must be continued at a rate such that the condition in
question is cured or controlled in a minimum time with the fewest side effects1.
Oral control release drug delivery formulations using biocompatible polymers have limited
utilization if the system cannot remain in the vicinity of the absorption site for a longer time. Thus, site
and time specific drug delivery have recently been of great interest in the pharmaceutical field to achieve
overall therapeutic efficacy. A problem encountered with the conventional oral controlled release dosage
forms is the inability to increase their residence time in the stomach and the proximal portion of the small
intestine. The most convenient route for the drug delivery has historically has been by oral ingestion.
However, oral controlled drug delivery system is complicated by gastric residence time which leads to
incomplete drug release in the absorption zone and reduce the efficacy of the administered dose2, 3.
To overcome these problems, several methods have been developed recently to extend
gastrointestinal transit time of the dosage forms. One such method is floating drug delivery systems. Such
systems have a bulk density lower than gastric fluids and thus remain buoyant in stomach for a prolonged
period of time, without affecting the gastric emptying rate. Although, the system floats on gastric
contents, the drug is released slowly at a desired rate from the system. After the release of drug, the

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residual system is emptied from the stomach. This results in an increase in gastric retention time and a
better control of fluctuations in the plasma drug concentrations4, 5.
In this investigation, it is intended to formulate and evaluate the floating sodium alginate beads
for increasing the bioavailability of amoxicillin. They are also used as hydrophilic polymers in the
development of controlled release formulation for the delivery of drugs.
Amoxicillin was chosen as the suitable drug candidate as it is stable in gastric acidic medium and
has a low absorption window in gastrointestinal tract, it is also highly soluble at acidic pH and has no
effect on food absorption. It has higher eradication rate in-vivo to H. pylori. Hence, increase in the gastric
retention time of the drug in the stomach may improve its bioavailability and therapeutic efficacy6.

MATERIALS AND METHODS

Amoxicillin was procured from Cipla Ltd Goa, Hydroxy propyl methyl cellulose K4M was
procured from Colorcon Asia. Sodium alginate was procured from Snap Naturals and alginates Ltd
Mumbai, India. All other chemicals were of analytical grade.
Preparation of Floating Sodium Alginate Beads
Floating SA beads of amoxicillin were prepared as shown in Table 1, using different proportions
of SA, HPMC and CaCo3. The weighed quantity of SA and HPMC were mixed with water to form a gel,
and then drug was incorporated by triturating. The gas forming agent was added to the gel form. The
resulting gel was dropped through a 26G syringe needle into 50ml of CaCl2 solution (1%w/v) containing
10%v/v acetic acid. The solution containing beads were stirred using magnetic stirrer for about 10min.
The beads were allowed to remain in the same solution for 2h to improve their mechanical strength. The
thus formed beads were separated, washed initially with alcohol and subsequently with distilled water
and then air dried7.
Characterization of Beads
Size analysis and morphology of the beads
The size of sodium alginate beads was measured by taking 5-10 beads on glass slide under
polarized light. The mean diameter was calculated by measuring the number of divisions covered by
beads. The stage micrometer was previously calibrated using ocular micrometer. The surface
morphological study was carried out using SEM8, 9.
Drug entrapment efficiency of SA beads
Beads 10mg were dissolved in 100ml acidic buffer pH 1.2 and sonicated. The solution was
filtered after sufficient dilution with acidic buffer (pH 1.2)10, 11. The solution was analysed
spectrophotometrically at 272 nm and drug entrapment efficiency was calculated using the following
equation,
EE = (actual drug content in the beads/ theoretical drug content) X 100
Bead porosity and mean pore diameter
The bead porosity was measured using porosimeter. The pressure was applied from 0 – 6000psi.
The mercury intrusion data were recorded. Standard values for the contact angle and surface tension of
mercury were used for calculations7, 12.
Mechanical strength of beads
Ten beads of identical size were selected from each batch, and the crushing strength of each bead
was determined using mercury load cell method7.
In-vitro floating behaviour
The time taken for dosage form to emerge on the surface of the medium is called the buoyancy
lag time, and the duration of time by which the dosage form constantly emerges on the surface of the
medium is called total floating time. Weighed amount of beads from each batch was placed in USP XXIII
type II dissolution apparatus containing 900ml of acidic buffer pH 1.2, using paddle at a rotational speed
of 75rpm. The temperature of medium was maintained at 370C ± 20C. Initially all the beads start floating
with zero floating lag time. Then, total floating time was determined 11, 13.

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In-vitro drug release study

Dissolution of the SA beads of each batch was carried out using USP type II apparatus using
paddle. 900 ml of acidic buffer pH 1.2 was filled in a dissolution vessel and the temperature of the
medium was set at 370C ± 20C. SA beads equivalent to 50mg drug were placed in each dissolution vessel
and the rotational speed of paddle was set at 75rpm. Then, 5ml of sample was withdrawn at
predetermined time interval for 12h and the same volume of fresh medium was replaced. The samples
were analysed for drug content against acidic buffer pH 1.2 as blank at 272 nm using double beam UV
spectrophotometer. The content of drug was calculated using the equation generated from standard curve.
The cumulative percentage drug release was calculated13, 14.
The matrix systems were reported to follow the zero order and diffusion mechanism for the
release of drug. To analyse the mechanism for the release and release rate kinetics of the dosage form, the
data obtained were fitted into zero order, first order, Higuchi matrix, Peppas and Hixson Crowell model15.
Stability study
The accelerated stability studies were conducted for selected formulations as per the ICH
guidelines. The selected formulations were analysed for physical appearance, entrapment efficiency, in
vitro floating ability and in vitro release study16, 17.

RESULTS
Preparation of Floating Sodium Alginate Beads
Floating SA beads were successfully prepared for the delivery of amoxicillin to enhance
absorption and bioavailability by increasing the gastric retention time. In concern to this approach, the
primary necessity is to float the beads in gastric environment. In this study four formulations were
prepared. In each formulation gas forming agent concentration was varied. The detailed composition of
each formulation is given in Table 1.
Characterization of Sa Beads
Size Analysis and Morphology of Beads
Scanning electron microscopy of the formulation is shown in Fig I. The beads of the drug of all
batches are almost grossly spherical. The SEM images illustrate the spherical shape with thin and
incomplete calcium surface coating. Beads with higher gas forming agent concentration for A3 and A4
were more porous, rough and grossly spherical.
The size of SA beads is shown in Table I. The size of the beads was found to be in the range of
842.86, 938.17, 966.33 and 988.67μm for formulations A1, A2, A3 and A4. The bead size was found to
increase with increase in the concentration of the gas forming agent which may be due to pore formation.
Drug Entrapment Efficiency of SA beads
The results of % drug entrapment efficiency are shown in the Table II. The high entrapment
efficiencies are seen with lower concentration of gas forming agent as in A1 and A2 than A3 and A4.
This may be due to increased porosity and pore diameter which is unable to retain the drug more
effectively as seen with the formulations A3 and A4.
Mechanical strength of beads
Mechanical strength testing was performed to study the effect of gas forming agent. The high
proportion of gas forming agent made the beads highly fragile and porous as seen in A3 and A4 and
hence showed lower crushing strength than A1and A2. Higher mechanical strength of beads is important
for avoiding breaking and distortion of beads during normal handling. The results of mechanical strength
are given in Table II.
Percentage porosity and mean pore diameter of beads
Porosity and mean pore diameter was studied to determine the effects of gas forming agent on
pore structure of the beads. The percentage porosity for the formulations A1, A2, A3 and A4 was
78.99%, 88.10%, 90.12% and 96.12% respectively. By increasing the ratio of gas forming agent as in A3
and A4, percentage porosity and mean pore diameter were increased. The results are shown in Table II.

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In-vitro buoyancy behaviour

The floating ability of the prepared beads was evaluated in acidic buffer pH 1.2. The wet beads
had better floating ability than dry beads. The floating ability of sodium alginate beads is directly related
to the gas content of the polymer matrix, which depends on the concentration of the gas forming agent.
As the concentration of gas forming agent increases, the number of air trapped pores in the beads
increases, which makes the beads to float. Wet beads contain greater proportion of CO2 gas than the dry
ones and are thus more buoyant. Results of in vitro buoyancy studies are given in Table III.
In-vitro drug release studies
Dissolution studies of all the four formulations of SA beads of amoxicillin were carried out using
USP XXIII type II paddle dissolution apparatus for 12h. The cumulative percentage drug release for 12
hrs was found to be 70.81, 76.47, 82.83 and 88.48% for the formulation A1 to A4 respectively. The
cumulative percentage drug release vs. time graph for all the formulation is shown in the Fig II. A1 is the
best formulation selected among all on the basis of drug entrapment efficiency, drug release study,
floating behaviour and mechanical strength.
The curve fitting results of the release rate profile of the designed formulations gave an idea on
the release rate profile and the mechanism of the drug release. Fitting of the release rate data to the
various models revealed that formulations A1 and A2 follows Peppa’s model and A3 and A4 follow
Higuchi matrix.
Stability studies
A stability study was conducted for the formulation A1 at 25oC±2oC with relative humidity 60%
for a period of 30days. Stability testing results showed that there was no change in the physical
appearance, entrapment efficiency, drug release pattern and floating behaviour of the SA beads at the end
of 30days.

DISCUSSION
There were two principle objectives to this study. Firstly, use of CaCO3 for the production of
floating alginate beads by simple dripping method. The data presented here has established that the gas
forming agent is highly effective for floating bead formation. The second objective was to assess the
effects of gas forming agent on bead characteristics. The study has clearly shown that the amount of gas
forming agent has a profound effect on bead size, morphology, floating ability, drug entrapment
efficiency, pore diameter and % porosity, mechanical strength and release pattern.
SA beads were prepared by dripping method using 26G needle. HPMC K4 M was used as a
swellable polymer for sustained release of the drug form the beads. The beads were formed due to the
cross linking of sodium alginate with divalent calcium ions of the CaCl2 solution. This mechanism is
called ionotropic gelation.
The surface topography reveals that the beads were highly porous because of the rapid escape of
the carbon dioxide during curing process. The number of observed pores appears to be directly related to
the amount of gas forming agent.
The high entrapment efficiencies are seen with lower concentration of gas forming agent. This
may be due to increased porosity and pore diameter which is unable to retain the drug more effectively.
The high concentration of gas forming agent made the beads highly fragile and porous and showed lower
mechanical strength.
The floating results were not affected by stirring speed of the paddle. The floating abilities
persisted until disintegration of the beads began. Buoyancy of the beads is directly related to
concentration of the gas forming agent. Instantaneous in vitro floating behaviour was observed for all
batches which may be due to low apparent density provided by the porous nature of beads.
The maximum release of the drug may be due to higher concentration of the gas forming agent
which increases the pore formation from which drug releases easily from the alginate matrix. A1 is the
best formulation selected among all on the basis of drug entrapment efficiency, drug release study,
floating behaviour and mechanical strength.

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ACKNOWLEDGEMENTS
This study was supported by KLES’s university’s college of pharmacy Belgaum and Maratha
mandal’s college of pharmacy Belgaum. The authors wish to thank Cipla limited Goa for supplying
Amoxicillin. We also wish to thank snap naturals and alginates limited Mumbai.

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System: Effects Of Co2 Gas-Forming Agents. Int. J. Pharm, 2002; 239: 81-91.
8. Edith Madithowitz. Encyclopedia of Controlled Drug Delivery. 1st ed. NY, John Wiley and Sons.
1999 p.242.
9. Kulkarni AR, Soppimath KS, Aminbhavi TM. In-vitro Kinetics of cefadroxil loaded sodium
alginate interpenetrating network beads. Eur J Pharn and Biopharm. 2001;51: 127-33.
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beads with factorial design based studies. Eur J. Pharm Sci.1998;6:241-46.
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controlled drug delivery in stomach. J Pharm sci. 1992;81:135-40.
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15. Lachman L, Partic D. Kinetic Principles and Stability. Theory and Practice of Industrial
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Table I: Formulation Of Alginate Beads Of Amoxicillin And Their Sizes

Formulation SA HPMC CaCO3 Amoxicillin Bead size Bead size
Code (%w/v) (%w/v) (%w/v) (%w/v) average (wet) average (dry)
mm ± S.D. mm ± S.D.
A1 3 0.3 1.5 1.5 234 ± .007 842.86 ± 005

A2 3 0.3 2.0 1.5 293 ± .005 938.17 ± 008

A3 3 0.3 3.0 1.5 367± .008 966.33 ±001

A4 3 0.3 3.0 1.5 388± .003 988.67 ± 004

Table II: Effect Of Gas Forming Agent On Drug Entrapment Efficiency And Various Physical
Properties Of Beads
Drug Average mean Porosity average Mechanical strength of
Formulation entrapment Pore diameter (%) ± S.D. beads (g)
efficiency (%) mm ± S.D.

A1 91.60 0.31± 0.003 78.99 ± 0.32 729 ± 0.83

A2 88.12 0.49 ± 0.14 88.10 ± 0.99 497 ± 0.38

A3 83.30 0.69 ± 0.38 90.12 ± 1.79 465 ± 0.1

A4 72.97 0.82 ± 0.33 96.03 ± 0.95 391 ± 0.03

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Table III: Results Of Floating Property Of Formulations A1-A4

Formulation code Floatation property Duration of floatation (h)

A1
- + More than 12 h

A2 -+ More than 12 h

A3 ++ More than 12 h

A4 ++ More than 12 h

- + partially floating, + + completely floating

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Figure I: Scanning Electron Microphotographs Of Floating Alginate Beads Of Amoxicillin

100
Cum % drug release for F1-F4

90

80

70
Series1
60
Series2
50
Series3
40
Series4
30

20

10

0
0 2 4 6 8 10 12 14

Time (h)

Series1- A1, Series2- A2, Series3-A3, Series4-A4.

Figure II: Comparison Of In Vitro Drug Release For Alginate Beads Of Amoxicillin F1-F4

Source of support: Nil, Conflict of interest: None Declared

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