RESEARCH ARTICLE TITLE FORMULATION DEVELOPMENT AND EVALUATION OF GASTRORETENTIVE
RAMIPRIL MICROBEADS.
AUTHORS –
SURAJ S. MULAJE*1, SHIVPRASAD M. BIRAJDAR2, ANILKUMAR CHINCHOLE3
(*1, 2, 3 –Department of Quality Assurance, Maharashtra college of pharmacy, Nilanga.
Dist.-Latur (M.S.) India)
ADDRESS FOR CORRESPONDENCEDepartment Of Quality Assurance, Maharashtra College of Pharmacy, Nilanga. Pin413521 Dist.- Latur (M.S.) India.
E-mail address- surajmulje24@gmail.com, Contact No.- 9730371957
ABSTRACTNew era of Novel Drug Delivery System oriented towards increasing safety &
efficacy of existing drug molecule through novel concepts like oral drug delivery system. The
focus of current investigation was to formulate & evaluate for gastroretentive Ramipril
microbeads for better patient compliance & quality. Ramipril is antihypertensive agent &
angiotensin converting enzyme (ACE) inhibiter. It was selected as a model drug for
investigation because of its suitable properties like Elimination half- life- 9 to18 (hr.) &
Tmax 0.53 to 1(hr.). As a part of preformulation, different aspects like determination of
melting point, pH and solubility. λmax ( in 0.1N HCL & in phosphate buffer pH 7.4) &
calibration curve of Ramipril determined using UV- Visible spectroscopy. The infrared
spectrum of pure drug was also recorded & Model drug was assessed by carrying out
differential scanning calorimetry (DSC). The calcium alginate floating microbeads were
formulated by ionotropic gelation method. Calcium alginate microbeads formed as alginate
undergoes ionotropic gelation by calcium ions and carbon dioxide gas developed from the
reaction of carbonate salt and acetic acid which is permeated through the alginate matrix,
leaving gas bubbles or pores which provide the buoyancy followed by dispersing (1%) of
Ramipril into polymeric solution. Ramipril loaded calcium alginate floating microbeads of
different size were prepared for different batches(F1 to F6). Floating microbeads were
evaluated for different evaluation parameters & results were determined. stability study was
also carried out for Present study as per the ICH(Q1) guideline.
Keywords- gastroretentive , microbeads, Ramipril, stability, ionotropic gelation
INTRODUCTION Historically, the oral route of administration has been used the most for both
conventional and novel drug delivery systems. There are a variety of both physicochemical
and biological factors that come into play in the design of sustained release systems.
Sustained release systems include any drug delivery system that "achieves slow release of
drug over an extended period of time". If the system can provide some control, whether this
is a temporal or spatial nature, in other words, if the system is successful in maintaining
constant drug levels in the target tissue or cells, it is considered a controlled release
system.[1-5]
Dosage forms that can be retained in stomach are called gastroretentive drug delivery
systems (GRDDS). GRDDS can improve the controlled delivery of drugs that have an
absorption window by continuously releasing the drug for a prolonged period of time before
it reaches its absorption site thus ensuring its optimal bioavailability.[6,7] The approaches
that have been pursued to increase the retention of an oral dosage form in the stomach include
bioadhesive systems, swelling and expanding systems, High density systems and Low density
(Floating) systems. Floating drug delivery systems (FDDS) have a bulk density less than
gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying
rate for a prolonged period of time. .[8] While the system is floating on the gastric contents,
the drug is released slowly at the desired rate from the system. After release of drug, the
residual system is emptied from the stomach. This results in an increased GRT and a better
control of the fluctuations in plasma drug concentration. The main aim of gastric floating
drug delivery system is to achieve better bioavailability by releasing of the drug from specific
system to its absorption window and the high level of patient compliance due to the ease of
administration and handling of these forms. Oral route has been the commonly adopted and
the most convenient route for the drug administration [9,10]
Ionotropic gelation is based on the ability of polyelectrolyte’s to cross link in the
presence of counter ions to form gelispheres. Since, the use of Alginates, Gellan gum,
Chitosan and Carboxymethyl cellulose are widely used for the encapsulation of drug and
even cells. In this method cationic or anionic polymer forms meshwork structure due to by
combining with the polyvalent cations or anions. The gelispheres are produced by dropping a
drug-loaded polymeric solution into the aqueous solution of polyvalent cations or anions.
Biomolecules can also be loaded into these gelispheres under mild conditions to retain their
three dimensional structure.
Ramipril is antihypertensive agent & angiotensin converting enzyme (ACE) inhibiter
which prevents the formation of angiotensin II from angiotensin I and exhibits pharmacologic
effects that are similar to Captopril. It competitively inhibits angiotensin-converting enzyme
(ACE) from converting angiotensin I to angiotensin II resulting in increased plasma renin
activity and reduced aldosterone secretion. It also increases bradykinin levels. By these
mechanisms, ramipril produces a hypotensive effect and a beneficial effect in Cardiac heart
failure. The present study aimed to formulation development and evaluation of
gastroretentive Ramipril microbeads by using sodium alginate as natural biodegradable
polymer & evaluation of microbeads for various properties. [11-14]
MATERIALS AND METHODS –
MaterialsRamipril & HPMC K100M were obtained as a gift sample from Glenmark Pvt. Ltd,
Mumbai, India. Other excipients like Sodium alginate, Calcium carbonate, Calcium chloride
& acetic acid were purchased from Vishal-chem, Mumbai.
Methods –

Melting point:
The melting point of Ramipril was determined by melting point apparatus
(Chemiline).

Determination of pH and solubility:
The pH of Ramipril in distilled water checked by using digital pH meter and the
reading was noted. Solubility study of Ramipril was determined by adding excessive
dug in solvent. The solubility study was carried out in distilled water, 0.1N HCl and
pH 7.4 phosphate buffers and absorbance taken at room temperature and after 24 hrs.
Equilibrium solubility was determined by taking supernatant and analyzing it by using
UV-Visible double beam spectrophotometer.

Determination of λ-Max:
UV spectrum of Ramipril was carried out in 0.1N HCL and pH 7.4 Phosphate buffer
& Wavelength for maximum absorbance was recorded.

Calibration curve by UV spectroscopy:
A stock solution containing 100 μg/ml of Ramipril in 0.1N HCl was prepared. Then
suitable aliquots of stock solution (0.2-2ml) of Ramipril were transferred into 10 ml
volumetric flask and diluted with 10 ml 0.1 N HCl to get solution of different
concentration of 2-20 μg/ml. The absorbance of all solutions was measured against 0.1N
HCl as a blank at 210 nm. Using this concentration-absorbance data, Beers-Lambert
graph was plotted. This standard curve was used to estimate Ramipril release from
floating hydrogel microbeads formulations in the dissolution fluid. Same process was
respectively used to prepare calibration curve of Ramipril in phosphate buffer pH 7.4

Determination of IR spectrum
The infrared spectrum of Ramipril (pure drug) was recorded by potassium bromide
dispersion technique in which mixture of drug and potassium bromide was placed in
sample holder and an infrared spectrum was recorded using FTIR Spectrophotometer
(Jasco-4100, Japan). The identified peaks were compared with the principle peaks of
reported IR spectrum of Ramipril and the sample was authenticated.

Determination of thermal behaviour by differential scanning calorimetry (DSC):
Ramipril was assessed by carrying out thermal analysis. The inert atmosphere was
maintained by purging nitrogen gas throughout the experiment. The samples (5mg)
were carefully transferred and heated in a crimped aluminium pan for accurate results.
The samples were heated from 30°C-250°C at the rate of 10°C/min.

Fourier transform infrared spectroscopy (FTIR):
The infrared spectrum of physical mixture of sodium alginate: Ramipril (1:1), HPMC
K100M: Ramipril (1:1), Calcium carbonate: Ramipril (1:1) and mixtures were
recorded by potassium bromide dispersion technique. The identified peaks were
compared with the principle peaks of reported IR spectrum of Ramipril and respective
polymers.

Formulation of calcium alginate floating microbeads:
The calcium alginate floating microbeads were formulated by ionotropic gelation
method. Calcium alginate microbeads formed as alginate undergoes ionotropic
gelation by calcium ions and carbon dioxide gas developed from the reaction of
carbonate salt and acetic acid which is permeated through the alginate matrix, leaving
gas bubbles or pores which provide the buoyancy

formulation of drug loaded calcium alginate microbeads:
The weighed amount (0.5%) of HPMC K100M was dissolved in water. The solution
was heated to 80˚C to dissolve HPMC K100M. After cooling, weighed amount(0.53%) of sodium alginate was added, stirred for 1 hr. using mechanical stirrer (Remi).
The weighed amount (1%) of Ramipril was dispersed into polymeric solution and
stirred for 30 min. Weighed amount (0.5-1%) of Calcium carbonate was added to the
solution and then allowed to stand in sonicator till the removal of entrapped air
bubbles. After sonication, this solution was added drop wise from the distance 2.5 cm
using syringe fitted with needle (23G) into 50 ml calcium chloride solution containing
10 % acetic acid at room temperature. Microbeads were left for curing for specified
time (15 min) and after curing, microbeads were collected by filtration and washed
twice with distilled water and allowed to dry at room temperature for 24 hrs.[27,
28,32,37,38,39]. Ramipril loaded calcium alginate microbeads were evaluated for
microbeads size, sphericity, percent entrapment efficiency, floating lag time, floating
duration, percent swelling index and percent cumulative drug release for 12 hrs.
Ingredient(%)
F1
F2
F3
F4
F5
F6
RAMIPRIL
1
1
1
1
1
1
Sodium Alginate
0.5
1
1.5
2
2.5
3
Calcium carbonate
0.5
0.5
0.5
1
1
1
HPMC
0.5
0.5
0.5
0.5
0.5
0.5
Calcium carbonate
1
1
1
1
1
1
Acetic acid
10
10
10
10
10
10
Table No. 1 : Formulation batches
Evaluation of floating microbeads

Microbeads size and sphericity: [15]
The microbeads size was measured by randomly picked 10 microbeads on a glass slide
under polarized light. The size of microbeads was calculated by measuring the number of
divisions of theocular micrometer covering the length and width of microspheres. The
stage micrometer was previously used to standardize the ocular micrometer. Microbeads
sphericity was observed through optical microscope

Floating lag time and floating duration: [16,17]
Floating properties of dry microbeads were evaluated in a USPXXIII dissolution test
apparatus II (paddle type) filled with 900ml of 0.1N HCl (pH1.2). Paddle rotation speed
of 100 rpm was kept constant. Temperature was maintained at 37 ± 0.2°. Hundred
microbeads were placed in the media and floating lag time and floating duration of
microbeads was measured by visual observation

Percent drug content and Percent entrapment efficiency for calcium alginate
floating microbeads: [18]
An accurately weighed quantity of 2.5 mg microbeads were taken and crushed in
mortar with pestle and added to 2.5 ml pH 7.4 phosphate buffers. Solution was
sonicated for 1-2 hrs using sonicator. Then in to this solution 7.5 ml 10 % acetic acid
was added and further sonicated for 1 hr. The resultant dispersion was filtered through
Whatman filter paper of 0.45 μ size to obtain clear solution and analysed for drug
content at 210 nm using UV spectrophotometry (LabIndia3000+). The experiments
were done in triplicate and results were calculated

Percent entrapment efficiency: [19]
The encapsulation efficiency was calculated according to the following relationship.
%Entrapment efficiency= AQ/TQ × 100
Where,
AQ - Actual amount of drug found in the microbeads.
TQ- Theoretical amount of drug found in the microbeads.

Equilibrium Swelling Studies: [20,21,22]
The accurately weighed (0.25 gm) dried microbeads were placed in USP dissolution
apparatus II containing 900 ml, 0.1 N HCl (pH 1.2) maintained at 37±20C and allowed to
swell up to constant weight i.e. 12 hr. The microbeads were removed, blotted with filter
paper, and changes in weight were measured. The experiments were carried out in
triplicate. The degree of swelling (Swelling index) was then calculated from the formula,
Swelling index= (Wg−Wo)Wo×100
Where,
o Wo- Initial weight of microbeads
o Wg- Weight of swelled microbeads in the medium after 12hrs

In- vitro Dissolution Studies: [23]
In-vitro dissolution studies were performed for all the formulation using USP
dissolution test apparatus I (basket type). The dissolution study performed in
replicates and results expressed were the mean of three experiments. Analysis of data
was done by using 'PCP Disso V-3' software, India.

Stability studies as per ICH guidelines for 3 months [24,25]
Present study was carried out as per the ICH guidelines for the stability study of the new
drug substances and products. Stability of a drug has been defined as the ability of a
particular formulation, in a specific container, to remain within its physical, chemical,
therapeutic and toxicological specifications. The tablets from the selected were studied
for stability and kept under the three months. After one month, the formulation was
observed for changes in physical appearance and chemical analyses were done after every
one month up to three months. The results were illustrated.
RESULTS:
Melting point:
Table No.2: standard and practical melting point of Ramipril
Sample Name
Standard
Practical
106-1100C
Ramipril
108-1100C
pH study:
Table No. 3: pH of Ramipril in distilled water
Sample
Name
Ramipril
pH
3.5-5
Solubility study:
Table No. 4: Solubility study of Ramipril at room temperature
Ramipril
Solubility (mg/ml)
Distilled Water
3.5
Solubility after
24Hrs.(mg/ml)
4.1
0.1N HCl
4.0
4.5
PH 7.4 Phosphate buffer
1.5
2.5
Ultraviolet absorbance spectroscopy:
Table No. 5: λ maxvalues of Ramipril in 0.1N HCl and Phosphate buffer (pH 7.4)
λmax in nm
Sr. No
Solvent
1
0.1N HCl
210
2
Phosphate buffer (pH 7.4)
211
Figure No.1: U.V. absorption spectrum of Ramipril in 0.1N HCl
Figure No.2: U.V. absorption spectrum of Ramipril in Phosphate buffer 7.4
Calibration curves of Ramipril :
Figure No.3: Calibration curve of Ramipril in phosphate buffer pH 7.4
Figure No.4: IR spectrum of Ramipril
Differential Scanning Calorimetry
Figure No. 5 : Differential scanning colorimetry of Ramipril
Compatibility studies –
Figure No.6: FTIR Spectra for compatibility study: Ramipril and mixture
Size and Sphericity:
Table No. 6: Size and sphericity of batches of Ramipril loaded calcium alginate floating
microbeads
Microbeads size (μm)*
Batch Code
Sphericity
F1
683.25±4.56
Spherical with porous
F2
F3
F4
F5
F6
667.59±9.61
630.65±6.48
865.54±4.56
850.21±8.12
871.45±4.36
Spherical with porous
Spherical with porous
Spherical but without porous
Slightly irregular with porous
Spherical but without porous
Floating lag time and floating duration:
Table No. 7: In-vitro buoyancy study
Floating lag time (Sec)
Batch Code
Floating duration (hrs.)
F1
<5
8-12
F2
F3
F4
F5
<5
8-12
>12
F6
<5
<5
>12
>12
F5 <5 >12
>12
F6 <5 >12
>12
>12
<5
<5
>12
Percent entrapment efficiency:
Table No. 8: Percent entrapment efficiency study
Batch Code
F1
% Entrapment Efficiency*
67.93±0.21
F2
71.98±0.60
F3
75.29±0.27
F4
66.78±0.20
F5
71.12±0.18
F6
73.14±0.17
*All values are expressed as Mean ±SD, n = 3
>12
Percent Swelling Index:
Table No. 9: Swelling index study
Batch Code
% swelling index
(After 12 hr.)*
F1
1.50±0.09
F2
1.65±0.07
F3
1.35±0.06
F4
2.55±0.19
F5
2.18±0.16
F6
2.05±0.01
*All values are expressed as Mean ±SD, n = 3
In-vitro percent Cumulative Drug release:
Table No. 10: In-vitro percent cumulative drug release study
Batch Code
Percent Cumulative Drug
release (after 12 hrs.)*
F1
85.14±0.22
F2
82.97±0.33
F3
81.1±0.56
F4
99.24±0.33
F5
95.66±0.35
F6
90.05±0.12
*All values are expressed as Mean ±SD, n = 3
Dissolution study:
Table No. 11: Average*(± SD) cumulative percent drug release from calcium alginate
floating microbeads (F1 to F6)
Time (hr)
F1
0
0
1
2.21±0.61
2±0.12
1.92±0.21
3.77±0.32
3.28±0.12
2.57±0.00
2
8.72±0.11
8.15±0.21
8.15±0.21
11.57±0.23
10.67±0.33
9.15±0.44
3
15.36±0.21
14.4±0.42
14.55±0.32
19.74±0.22
18.43±0.33
16.2±0.54
4
22.59±0.33
20.91±0.20
21.13±0.21
27.15±0.24
25.89±0.43
23.87±0.32
5
28.85±0.3
27.53±0.24
27.59±0.68
35.37±0.38
33.53±0.44
31.07±0.53
6
35.37±0.55
34.47±0.21
33.37±0.53
42.97±0.75
41.44±0.98
37.88±0.54
7
42.78±0.95
40.73±0.11
40.48±0.72
50.93±0.61
49.01±1.19
45.42±0.22
8
49.59±0.42
47.68±0.33
47.92±0.84
59.28±0.55
57.14±0.58
53.13±0.45
9
56.49±0.22
54.66±0.43
54.39±0.84
67.14±0.48
64.81±0.82
60.27±0.55
10
63.37±0.19
60.44±0.30
61.8±0.77
76.01±0.25
73.14±0.87
67.53±0.38
11
77.86±0.19
70.02±0.26
71.5±1.17
85.29±0.74
84.31±1.07
79.96±0.26
12
85.14±0.22
82.97±0.33
81.1±0.56
99.24±0.33
95.66±0.35
90.05±0.12
F2
F3
0
F4
0
F5
0
F6
0
0
*All values are expressed as Mean ±SD, n = 3
Figure No.7: Dissolution profiles of Ramipril loaded calcium alginate floating microbeads
(F1 to F6)
Stability study of selected batch of microbeads
Table No. 12: Effect of temperature and humidity on selected batch of microbeads
Formulation
Initial
F4
F4
Colour
Light
Yellow
Odour
No
% Entrapment 66.78±0.20
efficiency
% cumulative
99.24±0.33
drug release
% Swelling
2.55±0.19
index
40ºC ± 2 ºC at 75% ± 5% RH
1 Month
2Month
3 Month
Light Yellow Light
Light
Yellow
Yellow
No
No
No
66.80±0.12
66.85±0.22
66.85±0.56
Compatibility
Complies
Complies
Complies
99.29±0.24
99.35±0.12
99.39±0.11
Complies
2.51±0.15
2.50±0.56
2.51±0.45
Complies
Here no any significance difference was found to be in initials and after three
month in stability data, so it can be concluded that microbeads showed good stability after
three months.
DISCUSSION
The identity of Ramipril was confirmed by carrying out pH study in distilled water &
solubility at room temperature.(Table no.3 &4) Analytical study such as λ
max
values of
Ramipril in 0.1N HCl and Phosphate buffer (pH 7.4) was also carried out.(Table no.5, Fig.1&2
respectively) Calibration curve of Ramipril in phosphate buffer pH 7.4 followed Beer-Lamberts
law.(Fig.3) FTIR spectrum of pure drug was also carried out.(Fig.4)
Differential scanning colorimetry of Ramipril also showed satisfied results.(Fig.5)
Drug-polymer interactions were studied by FTIR spectrophotometer and no interaction was
found.(Fig.6) Ramipril loaded microbeads were formulated by using ionotropic gelation
technique for 6 batches(Table no.1).The formulated microbeads were evaluated for
microbeads size & sphericity, (Table no. 6), Floating lag time and floating duration (Table
no.7), and percent entrapment efficiency (Table no.8), percent swelling index, (Table no.9)
and in-vitro percent cumulative drug release(Table no.10). The concentration of sodium
alginate had significant impact on drug particle size was observed. 3.5 % w/v sodium alginate
polymeric solution was too viscous to pass through needle therefore microbeads could not
form. Hence sodium alginate concentration from 0.5 to 3 % w/v which forms desired
viscosity to obtain desired microbeads. HPMCK100M was selected in combination with
sodium alginate to decreases the burst release and to sustain the release. Also good floating
properties i.e. increased floating duration more than 12 hrs as seen in formulation F4. F5 and
F6 respectively.(Table no.11 & Fig. no.7) CaCO3:polymer ratio, fulfilled maximum
requisites because of better drug entrapment efficiency and % cumulative sustained release of
the drug therefore-F4formulation was selected as best batch. Here no any significance
difference was found to be in initials and after three month in stability data, (Table no.12) so
microbeads showed good stability after three month results of selected batch & proved the
porous nature of microbeads.
CONCLUSION:
Ionotropic gelation can be promising method to formulate floating microbeads of
calcium alginate containing Ramipril. Percent entrapment efficiency of selected batch found
66.78 % also the percent cumulative drug release was found to be 99.24 % and good floating
>12 hrs. In-vitro drug release study of F4 indicated that Ramipril was released in controlled
and sustained manner up to 12 hours. No significance difference was found to be in initials
and after one two and three months in stability data, so it can be concluded that microbeads
showed good stability after three months.
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