Formulation and Optimization of Sustained Release Floating, Bioadhesive and Swellable Matrix Tablets of Ranitidine Hydrochloride
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Date
2018-03
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Abstract
Ranitidine HCl is an ideal candidate for gastrortentive drug delivery system (GRDDS) because of
its short biological half-life (~2.5-3.0 h), low bioavailability (50 % absolute bioavailability), site
specific absorption (in the proximal part of small intestine), and susceptibility to colonic
degradation. Designing the drug as an immediate release dosage form may result in bioavailability
variation due to factors associated with GIT. The conventional controlled delivery approach may
not improve its bioavailability because of the inherent characteristics of the drug and shorter gastric
emptying nature of this delivery approach. Furthermore, designing the drug using any single
GRDDS (e.g. floating or bioadhesive or swelling, etc) may not be effective due to the limitations
associated with each system (for example, floating systems need sufficient gastric fluid,
bioadhesive systems may not be effective due to high mucus turnover, and swelling systems may
not have the desired mechanical strength); and this may lead to variation in bioavailability among
individuals. Recently, use of combination systems have been effective strategies to overcome the
limitations associated with the individual systems.
The aim of the present study was therefore, to prepare and optimize floating, bioadhesive, and
swellable matrix tablets of ranitidine HCl (150mg) using hydroxypropylmethylcellulose (HPMC)
and sodium carboxymethylcellulose (NaCMC) (as release retarding polymers) and sodium
bicarbonate (NaHCO3) (as gas generating agent) to increase the mean residence time in the
stomach, thereby increasing bioavailability and reducing in vivo variability among individuals.
The polymer powder blends were evaluated for density and related properties. The matrix tablets
were prepared by direct compression method (EK0 Korsch, 8410- 68, Berlin, Germany) and their
physicochemcial properties were evaluated. Compatibility study was done using FTIR. Origin 8
software and one way analysis of variance (ANOVA) were applied for analysis and comparison
of results. Response surface methodology (RSM) based on central composite design (CCD)
(design expert version 10.0.7.0) was employed to optimize the formulation.
Results from preliminary studies indicated that viscosity grade of HPMC, concentration of
polymer, HPMC/NaCMC ratio and the concentration of NaHCO3 significantly affect the floating,
bioadhesive, swelling and drug release characteristics of the matrix tablets. Hardness of tablets
significantly affected the floating lag time, while its effect on the other properties was not
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significant. The two polymers exhibited synergistic effect on prolonging the drug release; and the
polymer blend containing HPMC/NaCMC (3:1) showed better matrix characteristics.
From preliminary studies, concentration of HPMC/NaCMC (3:1) (X1) and NaHCO3 (X2) were
selected as independent variables; and floating lag time (Y1), bioadhesive strength (Y2), swelling
index (Y3), cumulative drug release at 1 h (Y4), time to 50% drug release (t50%) (Y5) and cumulative
drug release at 12 h (Y6) were taken as the response variables during optimization.
By comparing several statistical parameters, linear model was selected as best fit for bioadhesive
strength, swelling index, cumulative drug release at 1 h and 12 h; and the quadratic model was
selected as best fit for floating lag time and t50%. The adequacy of the models as per ANOVA
revealed that both models have significant values indicating the terms in the models have
significant effect (P < 0.05) on the responses.
An optimum region of 5.12 sec, 29.27 g, 313.37 %, 23.48%, 3.89 h and 90.00% was obtained for
floating lag time, bioadhesive strength, maximum swelling index, cumulative drug release in the
first 1 h, t50% and cumulative release at 12 h, respectively at corresponding level of 214.55 mg/tab
(45.65 %) of HPMC/NaCMC and 61.22 mg/tab (13.02 %) of NaHCO3 with desirability of 0.856.
Analysis of three batches formulated at the optimum region confirmed the effectiveness of
optimization. The experimental values were found to be in close agreement with the predicted
values confirming the predictability and validity of the model. The kinetic study of the optimized
formulation followed Higuchi square root model with non Fickian diffusion release mechanism.
The FT-IR spectra showed no incompatibility between ranitidine HCl and the excipients.
In conclusion, this study has come up with an optimum formulation of floating, bioadhesive and
swellable matrix tablets of ranitidine HCl that could remain buoyant for > 12 h with shorter lag
time, swellable with sufficient matrix integrity, bioadhesive to gastric mucus with ex vivo retention time of > 12 h, and that release the drug over a period of 12 h in a sustained manner. Hence, from in vitro perspective, this formulation may overcome the low bioavailability of oral ranitidine HCl and the associated variability among individuals.
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Keywords
Ranitidine hydrochloride, gastroretentive drug delivery systems, floating, bioadhesive, swelling, HPMC, NaCMC, central composite design