AAPS PharmSciTech 2004; 5 (2) Article 34 (http://www.aapspharmscitech.org).

Gastroretentive Drug Delivery System of Ranitidine Hydrochloride:

Formulation and In Vitro Evaluation
Submitted: February 25, 2004; Accepted: April 8, 2004.
Brijesh S. Dave,1 Avani F. Amin,1 and Madhabhai M. Patel1
1Shree S. K. Patel College of Pharmaceutical Education & Research, Ganpat Vidyanagar, India

ABSTRACT reflux disease, and erosive esophagitis. The recommended

adult oral dosage of ranitidine is 150 mg twice daily or 300
The purpose of this research was to prepare a gastroretentive
mg once daily. The effective treatment of erosive esophagitis
drug delivery system of ranitidine hydrochloride. Guar gum,
requires administration of 150 mg of ranitidine 4 times a
xanthan gum, and hydroxypropyl methylcellulose were eval-
uated for gel-forming properties. Sodium bicarbonate was day.1 A conventional dose of 150 mg can inhibit gastric acid
secretion up to 5 hours but not up to 10 hours. An alternative
incorporated as a gas-generating agent. The effects of citric
dose of 300 mg leads to plasma fluctuations; thus a sustained
acid and stearic acid on drug release profile and floating
properties were investigated. The addition of stearic acid release dosage form of RHCl is desirable.2 The short biolog-
reduces the drug dissolution due to its hydrophobic nature. A ical half-life of drug (~2.5-3 hours) also favors development
of a sustained release formulation.
32 full factorial design was applied to systemically optimize
the drug release profile. The amounts of citric acid anhydrous A traditional oral sustained release formulation releases most
(X1) and stearic acid (X2) were selected as independent vari- of the drug at the colon, thus the drug should have absorption
ables. The times required for 50% (t50) and 80% drug disso- window either in the colon or throughout the gastrointestinal
lution (t80), and the similarity factor f2 were selected as tract. Ranitidine is absorbed only in the initial part of the
dependent variables. The results of the full factorial design small intestine and has 50% absolute bioavailability.3,4
indicated that a low amount of citric acid and a high amount Moreover, colonic metabolism of ranitidine is partly respon-
of stearic acid favors sustained release of ranitidine sible for the poor bioavailability of ranitidine from the
hydrochloride from a gastroretentive formulation. A theoret- colon.5 These properties of RHCl do not favor the tradition-
ical dissolution profile was generated using pharmacokinetic al approach to sustained release delivery. Hence, clinically
parameters of ranitidine hydrochloride. The similarity factor acceptable sustained release dosage forms of RHCl prepared
f2 was applied between the factorial design batches and the with conventional technology may not be successful.
theoretical dissolution profile. No significant difference was The gastroretentive drug delivery systems can be retained in
observed between the desired release profile and batches F2, the stomach and assist in improving the oral sustained deliv-
F3, F6, and F9. Batch F9 showed the highest f2 (f2 = 75) ery of drugs that have an absorption window in a particular
among all the batches, and this similarity is also reflected in region of the gastrointestinal tract. These systems help in
t50 (~214 minutes) and t80 (~537 minutes) values. These stud- continuously releasing the drug before it reaches the absorp-
ies indicate that the proper balance between a release rate tion window, thus ensuring optimal bioavailability.
enhancer and a release rate retardant can produce a drug dis- It is also reported that oral treatment of gastric disorders with
solution profile similar to a theoretical dissolution profile. an H2-receptor antagonist like ranitidine or famotidine used
in combination with antacids promotes local delivery of
these drugs to the receptor of the parietal cell wall. Local
KEYWORDS: ranitidine hydrochloride, gastroretentive,
delivery also increases the stomach wall receptor site
floating drug delivery, sustained release.
bioavailability and increases the efficacy of drugs to reduce
acid secretion.6 This principle may be applied for improving
INTRODUCTION systemic as well as local delivery of RHCl, which would effi-
ciently reduce gastric acid secretion.
Ranitidine hydrochloride (RHCl) is a histamine H2-receptor
Several approaches are currently used to prolong gastric
antagonist. It is widely prescribed in active duodenal ulcers,
retention time. These include floating drug delivery systems,
gastric ulcers, Zollinger-Ellison syndrome, gastroesophageal
also known as hydrodynamically balanced systems, swelling
Corresponding Author: Brijesh S. Dave, Shree S. K. and expanding systems, polymeric bioadhesive systems,
Patel College of Pharmaceutical Education & Research, modified-shape systems, high-density systems, and other
Ganpat Vidyanagar, India. Tel: +91-2762-286082. Fax: delayed gastric emptying devices.7,8 The principle of buoyant
+91-2762-286082. Email: brijesh_dave@yahoo.com. preparation offers a simple and practical approach to achieve

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 AAPS PharmSciTech 2004; 5 (2) Article 34 (http://www.aapspharmscitech.org).

Table 1. Tablet Formulations for Preliminary Trials*

Ingredients A1 A2 A3 A4 A5 A6 A7 A8
HPMC K4 M, milligrams - - 90 90 90 90 90 90
Guar gum, milligrams 90 - - - - - - -
Xanthan gum, milligrams - 90 - - - - - -
NaHCO3, milligrams 50 50 50 25 50 50 50 50
Stearic acid, milligrams - - - - 50 20 5 5
Citric acid, milligrams - - - - 10 10 10 20
Floating lag time, seconds No floating 695 106 460 121 77 106 65
t50, minutes - - 104 134 430 381 200 7
*HPMC K4 M indicates hydroxypropyl methylcellulose. All batches contained 336 milligrams ranitidine hydrochloride, 1% wt/wt talc
and 1% wt/wt magnesium stearate.
increased gastric residence time for the dosage form and sus- The tablets were round and flat with an average diameter of
tained drug release. 12 ± 0.1 mm and a thickness of 4 ± 0.2 mm. The formula-
In context of the above principles, a strong need was recog- tions of the preliminary trial batches (A1 to A8) are shown in
nized for the development of a dosage form to deliver RHCl Table 1. The formulations of the factorial design batches (F1
in the stomach and to increase the efficiency of the drug, pro- to F9) are shown in Table 2.
viding sustained action. The present investigation applied a
systematic approach to the development of gastroretentive
RHCl dosage forms. In Vitro Buoyancy Studies
The in vitro buoyancy was determined by floating lag time,
per the method described by Rosa et al9 The tablets were
MATERIALS AND METHODS
placed in a 100-mL beaker containing 0.1N HCl. The time
Materials required for the tablet to rise to the surface and float was
Ranitidine hydrochloride was received as a gift sample from determined as floating lag time.
Cadila Pharmaceuticals Ltd, Ahmedabad, India. Hydroxy-
propyl methylcellulose (HPMC K4 M), guar gum, and xan-
than gum were received as gift samples from Zydus-Cadila In Vitro Dissolution Studies
Healthcare Ltd, Ahmedabad, India. Sodium bicarbonate, The release rate of RHCl from floating tablets (n = 3) was
stearic acid, and citric acid anhydrous (hereafter referred to
determined using United States Pharmacopeia (USP) 24.
as citric acid) were purchased from S.D. Fine-Chem Ltd,
Dissolution Testing Apparatus 2 (paddle method). The disso-
Ahmedabad, India. All other ingredients were of laboratory
lution test was performed using 900 mL of 0.1N HCl, at 37 ±
grade.
0.5°C and 75 rpm. A sample (10 mL) of the solution was
withdrawn from the dissolution apparatus hourly for 12 hours,
Methods and the samples were replaced with fresh dissolution medium.
The samples were filtered through a 0.45-µ membrane filter
Preparation of Ranitidine Hydrochloride Floating Tablets
and diluted to a suitable concentration with 0.1N HCl.
(Preliminary Trials)
Absorbance of these solutions was measured at 315 nm using
RHCl (336 mg equivalent to 300 mg of ranitidine) was a Shimadzu UV-1601 UV/Vis double-beam spectrophotome-
mixed with the required quantities of HPMC K4 M/guar ter (Kyoto, Japan). Cumulative percentage drug release was
gum/xanthan gum, sodium bicarbonate, and citric acid by calculated using an equation obtained from a standard curve.
geometric mixing. In batches A5 to A8 and factorial design The times for 50% and 80% drug release were calculated
batches (F1 to F9), RHCl was dispersed in chloroformic based on the Korsemeyer and Peppas model.10
solution of the required quantity of stearic acid. The disper-
sion was stirred and chloroform was evaporated to form an
RHCl-stearic acid mixture. This mixture was then blended
Full Factorial Design
with other ingredients as described previously. The powder
blend was then lubricated with magnesium stearate (1% A 32 randomized full factorial design was used in this study.
wt/wt) and purified talc (1% wt/wt) and compressed on sin- In this design 2 factors were evaluated, each at 3 levels, and
gle punch tablet machine (Cadmach, Ahmedabad, India). experimental trials were performed at all 9 possible combi-

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 AAPS PharmSciTech 2004; 5 (2) Article 34 (http://www.aapspharmscitech.org).

Table 2. Formulation and Dissolution Characteristics of Batches in a 32 Full Factorial Design*

Variable Level in Coded Form†
Batch Code X1 X2 t50 (minutes) ± SD t80 (minutes) ± SD Similarity Factor f2
F1 -1 -1 86 ± 1.2 392 ± 3.1 45
F2 -1 0 139 ± 1.8 625 ± 4.6 52
F3 -1 1 190 ± 2.3 631 ± 2.5 52
F4 0 -1 79 ± 0.8 392 ± 5.1 45
F5 0 0 121 ± 2.3 391 ± 4.6 46
F6 0 1 160 ± 2.1 429 ± 1.6 51
F7 1 -1 38 ± 0.7 297 ± 4.9 37
F8 1 0 96 ± 2.6 431 ± 6.4 47
F9 1 1 214 ± 0.8 537 ± 5.9 75
Theoretical 221 523 -
Actual values†
Coded values X1 X2
-1 0 0
0 5 5
1 10 15
*All batches contained 336 mg ranitidine hydrochloride, 50 mg sodium bicarbonate, 1% wt/wt talc, and 1% wt/wt magnesium stearate.
†X is amount of citric acid in milligrams; X is amount of stearic acid in milligrams
1 2

nations. The amounts of citric acid anhydrous (X1) and floating dosage forms.24 Batches A1 and A2, containing guar
stearic acid (X2) were selected as independent variables. The gum and xanthan gum, failed to form a gel with sufficient
times required for 50% and 80% drug dissolution, and the strength, while A3 with HPMC K4 M produced tablets with
similarity factor f2 were selected as dependent variables. good gel strength, entrapping CO2 gas and imparting stable
and persistent buoyancy. To study the effect of sodium bicar-
bonate concentration on floating lag time, batch A4 was for-
Kinetic Modeling of Drug Release mulated. The results, shown in Table 1, demonstrate that as the
The dissolution profile of all the batches was fitted to zero- amount of sodium bicarbonate decreases, the floating lag time
order, first-order,11,12 Higuchi,13-15 Hixon-Crowell,16 Korse- increases. Thus, sodium bicarbonate (50 mg per tablet) was
meyer and Peppas,10,17,18 and Weibull models19-22 to ascertain essential to achieve optimum in vitro buoyancy.
the kinetic modeling of drug release. The method of Bamba
et al was adopted for deciding the most appropriate model.23
In Vitro Dissolution Studies
Since the pH of stomach is elevated under fed condition
RESULTS AND DISCUSSION (~3.5), citric acid was incorporated in the formulation to pro-
In Vitro Buoyancy Studies vide an acidic medium for sodium bicarbonate. Moreover,
citric acid has a stabilizing effect on RHCl formulations.25
Noneffervescent floating drug delivery was used to achieve in
However, because adding citric acid to the formulation might
vitro buoyancy. In the initial batches, RHCl tablets prepared
using polymers such as HPMC K4 M, guar gum, and xanthan enhance dissolution, stearic acid was incorporated in the for-
gum did not exhibit sufficient swelling to provide in vitro mulations to sustain drug release. Batches A5 to A7 were for-
buoyancy. An effervescent approach was then adopted. Three mulated to study the effect of stearic acid concentration on
batches (A1 to A3) were prepared using guar gum, xanthan release profile. In batch A8, the concentration of citric acid
gum, and HPMC K4 M, respectively; sodium bicarbonate was was increased. The pharmacokinetic parameters1,3,4 of RHCl
added as a gas-generating agent. Sodium bicarbonate induced were used to calculate a theoretical drug release profile for a
CO2 generation in the presence of dissolution medium (0.1N 12-hour dosage form. The immediate release part for sus-
HCl). The gas generated is trapped and protected within the tained-release RHCl was calculated using Equation 1 and
gel, formed by hydration of polymer, thus decreasing the den- was found to be 96.53 mg.
sity of the tablet. As the density of the tablet falls below 1, the
tablet becomes buoyant. Whitehead et al have demonstrated Immediate release part = (Css × Vd) / F, (1)
good correlation between in vitro and in vivo buoyancy of

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 AAPS PharmSciTech 2004; 5 (2) Article 34 (http://www.aapspharmscitech.org).

where Css is steady-state plasma concentration (Average The values of the correlation coefficient indicate a good fit.
Cmax), Vd is volume of distribution, and F is fraction The polynomial equation can be used to draw conclusions
bioavailable. after considering the magnitude of coefficient and the math-
ematical sign it carries, (ie, positive or negative).
Hence, the formulation should release 96.53 mg (32.17%) of
drug in 1 hour like conventional tablets and 18.5 mg (6.16%) Figures 1 and 2 show the plot of the amount of citric acid (X1)
per hour up to 12 hours thereafter. The t50 of the theoretical and amount of stearic acid (X2) versus t50 and t80, respective-
dissolution profile is 221 minutes. The t50 of batches A5 to ly. The plot was drawn using Sigma Plot software (Jandel
A8 varied from the theoretical t50 (Table 1). Incorporation of Scientific Software, San Rafael, CA). The data demonstrate
citric acid reduced floating lag time but caused tablet erosion. that both X1 and X2 affect the drug release (t50 and t80). It may
also be concluded that the low level of X1 (amount of citric
acid) and the higher level of X2 (amount of stearic acid) favor
Factorial Design the preparation of gastroretentive sustained release RHCl
A 32 full factorial design was constructed to study the effect tablets. The high value of X1X2 coefficient also suggests that
of the amount of citric acid (X1) and the amount of stearic the interaction between X1 and X2 has a significant effect on
acid (X2) on the drug release from gastroretentive RHCl t50. It can be concluded that the drug release pattern may be
tablets. The dependent variables chosen were times required
for 50% and 80% drug dissolution, and similarity factor f2
(average dissolution profile with theoretical release profile).
A statistical model incorporating interactive and polynomial
terms was utilized to evaluate the response.

Y = b0 + b1X1 + b2X2 + b12X1X2 + b11X12 + b22X22, (2)

where Y is the dependent variable, b0 is the arithmetic mean

response of the 9 runs, and bi is the estimated coefficient for
the factor Xi. The main effects (X1 and X2) represent the aver-
age result of changing one factor at a time from its low to
high value. The interaction terms (X1 X2) show how the
response changes when 2 factors are changed simultaneous-
ly. The polynomial terms (X12 and X22) are included to inves-
tigate nonlinearity. The statistical analysis of the factorial
design batches was performed by multiple linear regression
analysis using Microsoft Excel. The t50, t80, and f2 values for Figure 1. Response surface plot for t50.
the 9 batches (F1 to F9) showed a wide variation; the results
are shown in Table 2. The data clearly indicate that the val-
ues of t50, t80, and f2 are strongly dependent on the independ-
ent variables. The fitted equations relating the response t50,
t80, and f2 to the transformed factor are shown in Equation 3,
Equation 4, and Equation 5, respectively.
t50 = 114.189 -11.231 X1 + 60.333 X2 +
17.940 X1X2 + 6.96X12+9.054X22 (3)
2
(R = 0.9391)

t80 = 428.145 -63.728 X1 + 85.991 X2 +

0.173 X1X2 + 81.404 X12 - 36.128 X22 (4)
2
(R = 0.8094)

f2 =45.666 + 1.666 X1 + 8.5 X2 + 7.75

X1X2 + 4 X12 + 2.5 X22 (5)
2
(R = 0.8370) Figure 2. Response surface plot for t80.

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changed by appropriate selection of the X1 and X2 levels. The Kinetics of Drug Release
results in Table 2 reveal that batches F3 and F9 were close to The dissolution data of batches F1 to F9 was fitted to zero-
theoretical t50, while F9 was the only batch that was similar order, first-order, Higuchi, Hixson-Crowell, Korsemeyer and
to theoretical t80. Peppas, and Weibull models. The method of Bamba et al was
The similarity factor, f2, given by Scale Up and Pose adopted for deciding the most appropriate model.23 The
Approval Changes (SUPAC) guidelines for modified release results of F-statistics were used to select the most appropri-
dosage form was used as a basis to compare dissolution pro- ate model. The release profile of the best batch, F9, fitted best
files.26 The dissolution profiles are considered to be similar to the Korsemeyer and Peppas model (F = 1.65). This supe-
when f2 is between 50 and 100. The method was first report- riority is statistically insignificant with the Higuchi model
ed by Moore and Flanner.27 (F = 1.86), but significant with the Weibull model (F = 17.4)
as shown by the goodness-of-fit test (F ratio test). But prior-
The results in Table 2 indicate that batches F2, F3, F6, and ity should be given to the model with the lowest F value.
F9 fulfill the above criteria. But batch F9 showed the high- Thus, it may be concluded that drug release from gastroreten-
est f2 among all the batches, and this similarity is also tive RHCl tablets is best explained by the Korsemeyer and
reflected in t50 and t80 values. The f2 value of 75 of batch F9 Peppas model. The values of slope and intercept for the
indicates less than 5% difference in dissolution profiles. Korsemeyer and Peppas model are 0.5105 and -1.4906,
The similarity between the theoretical dissolution profile respectively. The value of the slope indicates that the drug
and the dissolution profile of F9 is clearly demonstrated in released by diffusion of an anomalous type. However, batch-
Figure 3. es F1 to F8 followed the Korsemeyer and Peppas model for
drug release but showed nonanomalous diffusion.

Figure 3. Comparison of in vitro dissolution profiles of

batch F9 and theoretical dissolution profile: ♦ indicates
theoretical dissolution profile; „ indicates F9.

In Vitro Buoyancy of Factorial Design Batches

All the factorial design batches showed good in vitro buoyan-
cy. The results of the in vitro buoyancy study of batch F9 are
shown in Figure 4. The figure clearly indicates the floating lag
time (2 minutes) of the RHCl tablets and the floating and
swelling tendency of the formulation. The tablet swelled radi-
ally and axially. The average radial diameter after 8 hours was
15 ± 0.3 mm, while the thickness was 7.5 ± 0.4 mm. The fig-
ure also indicates that the tablet remained buoyant for 8 hours,
but the tablet actually floated throughout the entire study. The
in vitro buoyancy study was also conducted at an elevated pH
condition (~4.5). The floating tendency remained unaltered at
higher pH. Figure 4. In vitro buoyancy study of batch F9.

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CONCLUSION 11. Wagner JG. Interpretation of percent dissolved-time plots derived

from in vitro testing of conventional tablets and capsules. J Pharm Sci.
This study discusses the preparation of gastroretentive tablets 1969;58:1253-1257.
of RHCl. The effervescent-based floating drug delivery was 12. Gibaldi M, Feldman S. Establishment of sink conditions in dissolu-
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ment in drug release that was retarded by incorporation of
Pharm Sci. 1963;52:1145-1149.
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15. Cobby J, Mayersohn M, Walker GC. Influence of shape factors on
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and stearic acid had a significant effect on t50, t80, and f2. Sci. 1974;63:732-737.
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