Pankaj Vaghasiya, Dhara Amitkumar Chavda*, Malaykumar Bhavanbhai Chotaliya, Anjali Pratik Sangani, Reena Govindbhai Korat, Mina Jaysukhbhai Sinhar
Shree H. N. Shukla Institute of Pharmaceutical Education & Research, Rajkot
B/H lalpari lake, Marketing Yard (Bhichri), Rajkot360005 Gujarat (India)
*Address for Corresponding Author
Dr. Dhara Amitkumar Chavda
Head, Shree H. N. Shukla Institute of Pharmaceutical Education and ResearchRajkot
B/H lalpari lake, Marketing Yard (Bhichri), Rajkot360005, Gujarat, India
Abstract
Objective: The current study involves the development of oral effervescent floating bed of Lafutidine and the optimization of their invitro drug release. Materials and methods: A 3^{2} Full factorial design was employed to systematically optimize the drug delivery containing two polymers. Inotropic gelation method was utilized to prepare floating beads. The proportions of Sodium Alginate and Sodium Bicarbonate were varied to be fitted in 3^{2} full factorial design. Percent entrapment efficiency (M), drug release at 24h were taken as responses. Response surface plots were drawn and the optimum formulation was selected by desirability function. Results: Invitro drug release study was carried out using simulated gastric fluid (SGF) pH 1.2. The experimental values of M, % Entrapment efficiency and % drug release at 1hr for check point batch were found to be 84.33%, and 22.05% respectively. The release profile indicated anomalous (nonFickian) transport mechanism. Conclusion: The developed formulation was stable and provided sustained release of the drug over a period 12 hr. The optimized batch was passed stability test. It is concluded that the method attempted to formulate effervescent floating beads of lafutidine being simple and acceptable.
Keywords: 3^{2 }full factorial design, floating bed, ionotropic gelation, sweling index, entrapment efficiency
Introduction
The formulated multiparticulate increases the gastric residence time and provide the sustained release of drug. The formulated dosage forms will release the drug at the site of absorption i.e., Upper GI tract, to optimize formulation by applying statistical design, to formulate sustain release multiparticulate system by using gas forming agent by ionotropic gelation method. Lafutidine is a H_{2} receptor antagonist which used in to hyperacidity condition. The main drawback of lafutidine conventional dosage forms is short biological halflife, frequent administration and it has low water solubility. These criteria’s makes lafutidine an ideal candidate for the development of multiparticulate formulation to release the drug at a sustain manner as well as reduce the dosage frequency. Lafutidine is least absorbed from lower part of gastrointestinal tract and better absorbed from the stomach (Vasava and Jha, 2011; Jassal et al., 2015).
By studying of Effervescent drug delivery for oral administration W0066089 (Pather et al., 2000) patent, we found that there is certain disease which require drug release after lag time and total floating from the time of administration. Lafutidine has low solubility and short halflife. It is available in form of sustained release dosage form release over long time. So, there is need to develop multiparticulate effervescent floating drug delivery. The aim of the present study is an evaluation of effervescent floating bed of Lafutidine in treatment of hyperacidity condition: Statistical design and invitro studies.
Materials and methods
Materials: Lafutidine was procured from Pure chem, Ankleshwar, Sodium alginate was obtained from Molychem, Mumbai, Pectin was procured from ACS chemicals, Ahmedabad, Calcium chloride, Hydrochloric acid and Sodium bicarbonate were procured from Finar Limited, Ahmedabad.
Methods of preparation of beads
Ionotropic gelation method
All the ingredients like drug, polymer and gas forming agent were accurately weighed and prepared by ionotropic gelation method. Required amount of sodium alginate, pectin and sodium bicarbonate were dissolved in 10 mL double distilled water with constant stirring at 250 rpm on magnetic stirrer. Accurately weighed amount of drug was than added. The resultant mixture was extruded drop by drop from 18G needle into 1% to 4% calcium chloride as crosslinking agent (100 mL) under magnetic stirrer at 300 rpm and the droplets were retained for 10 min in the crosslinking solution to complete the reaction. Then the prepared beads were filtered and dried at room temperature for 24 hrs (Malakar and Nayak, 2012; Singh and Kim, 2000).
Optimization of variables using full factorial design
From the preliminary studies it was concluded that Sodium bicarbonate and sodium alginate have the significant effect on entrapment efficiency as well as drug release also. A 3^{2 }randomized full factorial design was used in present research work. In this design 2 factors were evaluated, each at 3 levels and experimental trials were performed. The concentration of both the polymers Sodium alginate/ pectin (X_{1}) and Sodium bicarbonate concentration (X_{2}) were selected as independent variables, while entrapment efficiency (Y_{1}) and %drug release (Y_{2}) were selected as dependent variables (Fatima and Kakatum, 2015; Chinta et al., 2014; Elmashad and Ashmony, 2012).
The polynomial terms were used to evaluate the responses. Where, Y is the dependent variable. b_{0} is the arithmetic mean response of 9 runs and b is estimated coefficient for the factor (Table 1).
Y= b_{0}+b_{1}X_{1}+b_{2}X_{2}+b_{11}X_{1}X_{1}+b_{22}X_{2}X_{2}+b_{12}X_{1}X_{2}
Evaluation parameters
Micromeritics Properties (Vishami and Laxmi, 2015; Reddy et al., 2012; Sayeh et al., 2014)
Angle of repose (θ)
The angle of repose of prepared beads will determine by glass funnel method, weigh required quantity of the prepared products using following equation:
θ = Tan^{1 }h / r
Where, θ = angle of repose h = height of the pile and r = radius of the powder cone
Bulk density
The bulk density of prepared beads will be measured by using following equation:
Bulk density = Weight of products in gram / Bulk volume of products in cm^{3}
Tapped density
The tapped density of prepared beads will be measured by using following equation Tapped density = Mass of products / Volume of micro products after tapping.
Carr’s compressibility index
This is an important property in maintaining uniform weight. It is calculated using following equation.
% Compressibility Index = Tapped density – Bulk density X100 / Tapped density
Hausner’s ratio
Hausner’s ratio of prepared beads will calculated using following equation.
Hausner’s ratio=Tapped Density X 100 / Bulk Density
Particle size determination
The size of micron sized multiparticulate is measured by compound microscope and optical microscopy, while larger size of multiparticulate is measured by digital vernier callipers e.g., beads.
Percentage yield
The yield of prepared beads was calculated using the following equation:
% Yield = (mass of prepared formulation)/(mass of drug+ mass of polymer)] × 100
Drug entrapment efficiency
Accurately weighed 100 mg of prepared beads from each batch were taken separately. Then beads were crushed using mortar and pestle. The crushed powder was placed in 50 ml 0.1 N Hydrochloric acid with pH 1.2. The polymer debris formed after disintegration of bead was removed filtering through 0.22 μm pore size Whatman filter paper. The drug content in the filtrate was determined spectrophotometrically using a UV–Visible spectrophotometer (Shimadzu, Japan) at 282 nm. The drug entrapment efficiency of beads was calculated by using this following formula:
% Entrapment efficiency = experiment drug content/ theoretical drug content x100
Swelling study
The swelling study of prepared beads was determined by water uptake study. An accurately weighed mass of beads was immersed in acidic media (0.1 N HCl, pH 1.2) for 2 hr. After removal of samples, the excess fluid was carefully removed from the surface with a filter paper. The swollen beads were weighted, dried until constant weight, and weighted again. Swelling index was calculated by the formula:
Swelling Index = W_{t }– W 0 X 100 / W
Where,
W_{t }= Weight of products after water uptake. W_{0}= The initial weight of products.
In vitro floating study
The invitro floating time of prepared beads was measured using 0.1 N HCl, pH 1.2. These beads were floated after being placed in the acidic medium. Here, Sodium bicarbonate in the beads was responsible for floating. Lowdensity bicarbonate can lower the density of the polymeric systems with incorporation.
Floating lag time and total floating time
The floating lag time is defined as the time taken by the beads to reach the top from the bottom of the dissolution flask. The floating lag time of beads was measured by visual inspection. The time for which the formulation float constantly on the surface of the medium is known as the duration of floating. Total floating time of beads was determined by visual inspection.
In vitro drug release studies
In vitro drug release of beads was carried out using USP II dissolution test apparatus in 0.1 N HCl (pH 1.2) as dissolution medium. The temperature was maintained at 37±0.5 °C with 50 rpm agitation speed. At appropriate time intervals 5 ml samples were collected and replaced with 5mL of fresh solution. The samples were assayed spectrophotometrically at 282 nm.
Kinetics analysis of drug release
The mechanism of drug release was analysed by fitting the dissolution data with different mathematical models (Korsemeyer–Peppas, Higuchi, Firstorder, Hixson– Crowell and Baker–Lonsdale). To analyze the mechanism of drug release from the formulations, the in vitro dissolution data was fitted to Zeroorder, Firstorder, Higuchi, and Korsmeyer and Peppas release models (Dandang, 2013; Ashra, 2014; Kumar et al., 2011). In this by comparing the obtained r values, the best fit model (r value nearest to 1) was selected.
Zero order kinetics
Drug dissolution from pharmaceutical dosage forms that do not disaggregate and release the drug slowly, if the area does not change and no equilibrium conditions are obtained can be represented by the following equation.
Q_{t} = Q_{o} + K_{ot}
Where, Q_{t }= Amount of drug dissolved in time t, Q_{o} = Initial amount of drug in the solution and K_{o}= Zero order release constant.
First order kinetics: To study the first order release rate kinetics the release rate data were fitted to the following equation.
Log Q_{t }= log Q_{o} + K_{1t }/ 2.303
Where, Q_{t} = Amount of drug released in time t, Q_{o} = Initial amount of drug in the solution and K_{1} = First order release constant.
Higuchi model: Higuchi developed several theoretical models to study the release of water soluble and lowsoluble drugs incorporated in semisolids and or solid matrices. Mathematical expressions were obtained for drug particles dispersed in a uniform matrix behaving as the diffusion media (Ashra, 2014).
The Higuchi equation is Q_{t }= K_{H }x t 1/2 Where, Q_{t }= Amount of drug released in time t and K_{H} = Higuchi dissolution constant
Accelerated Stability study
The accelerated stability study was conducted as per ICH guideline. Accelerated stability was carried out under the condition 40º C ± 2º C 75%RH ± 5% for 1 month (Ashra, 2014).
Results and discussion
Optimization of 3^{2} full factorial design
All factorial batches were studied for its floating lag time, there were no lag time for all formulations because of gas forming agent such as NaHCO_{3} provide immediate floating of beads. The total floating time was >12 hr. for all floating beads formulation. They were remaining float still after complete drug release. The percentage entrapment efficiency of floating beads was carried out for all the batches. It was found that as increase in concentration of pectin and NaHCO_{3} entrapment efficiency was increase. The highest entrapment was found in batch B9 (Table 1 and 2).
Table 1. Formulation Batches using 3^{2 }Full Factorial Design
Ingredients (mg) 
B1 
B2 
B3 
B4 
B5 
B6 
B7 
B8 
B9 

Lafutidine 
10 
10 
10 
10 
10 
10 
10 
10 
10 

Sodium Alginate 
300 
400 
500 
300 
400 
500 
300 
400 
500 

Pectin 
500 
600 
700 
500 
600 
700 
500 
600 
700 

NaHCO_{3} 
600 
700 
800 
600 
700 
800 
600 
700 
800 

CaCl2 
2% 
3% 
4% 
2% 
3% 
4% 
2% 
3% 
4% 

Water (ml) 
10 
10 
10 
10 
10 
10 
10 
10 
10 

Coded Value 
Actual Value 

Sodium Alginate:Pectin 
NaHCO_{3} 

1 
3:5 
6 

0 
4:6 
7 

+1 
5:7 
8 
Table 2. Composition of various Factorial Batches and Actual vs Coded Value
Ingredients 
F1 
F2 
F3 
F4 
F5 
F6 
F7 
F8 
F9 
Drug 
10 
10 
10 
10 
10 
10 
10 
10 
10 
Sodium Alginate 
300 
400 
500 
300 
400 
500 
300 
400 
500 
Pectin 
500 
600 
700 
500 
600 
700 
500 
600 
700 
NaHCO_{3} 
600 
700 
800 
600 
700 
800 
600 
700 
800 
CaCl_{2} 
2 
3 
4 
2 
3 
4 
2 
3 
4 
Distill Water 
10 
10 
10 
10 
10 
10 
10 
10 
10 
The invitro drugrelease studies were carried out for all formulated Sodium bicarbonate entrapped sodium alginate/ pectin floating beads containing lafutidine (Figure 1).
Figure 1 (a) Invitro drug release of full factorial design batches, (b) Contour plot depicting effect of polymer ratio and NaHCO_{3} on % Entrapment efficiency
From the results it was concluded that polymer concentration and amount of gas forming agent such as NaHCO_{3} added can control the release behaviour of floating beads. It showed delay in drug release when increase in polymer concentration and NaHCO_{3} concentration. It also showed reduction in amount of drug which was release at absorption site. The initial burst release was also reduced when increase in Sodium alginate/pectin proportion and concentration of Sodium bicarbonate. The batch B1 and B2 showed 97.16 and 97.38% drug release in after 6 hr. The batch B7, B8 and B9 showed drug release 97.40, 95.79 and 92.31% respectively up to 12 hr (Table 3 and 4).
Table 3. Evaluation of factorial batches
Code 
B_{d} (g/cm^{3}) 
T_{d} (gm/cm^{3}) 
Angle of Repose 
%Yield 
%Swelling Index at 2 (hr) 
Particle Size (mm) 
B1 
0.455±0.004 
0.498±0.009 
30.43 
73.55 
11.33±1.2 
1.37±0.06 
B2 
0.462±0.005 
0.508±0.006 
29.75 
75.38 
15.46±0.3 
1.51±0.08 
B3 
0.466±0.006 
0.555±0.007 
27.58 
79.80 
12.41±0.2 
1.58±1.67 
B4 
0.357±0.007 
0.384±0.009 
28.29 
81.81 
10.35±0.1 
1.34±1.9 
B5 
0.358±0.005 
0.382±0.046 
30.04 
82.6 
7.73±0.5 
1.40±0.09 
B6 
0.416±0.004 
0.454±0.011 
27.49 
73.58 
8.61±0.3 
1.82±0.14 
B7 
0.454±0.006 
0.5±0.006 
28.78 
79.98 
7.74±0.1 
1.40±0.15 
B8 
0.398±0.008 
0.443±0.007 
26.55 
80.91 
8.61±0.3 
1.9±0.0075 
B9 
0.384±0.004 
0.454±0.005 
28.56 
82.20 
9.84±0.2 
1.84±0.15 
Results are (Mean±SD), n=3
Table 4. Observed dependent variable of full factorial design
Code 
Y_{1} (%Entrapment efficiency) 
Y_{2 }(%Drug Release at 2 hr) 
B1 
76.5±1.00 
42.52 
B2 
76.88±1.54 
30.21 
B3 
75.46±1.04 
36.20 
B4 
78.45±1.09 
33.57 
B5 
83.54±1.21 
29.48 
B6 
84.15±1.06 
27.30 
B7 
83.34±0.93 
27.70 
B8 
86.26±0.97 
22.18 
B9 
87.68±0.94 
20.11 
Results are (Mean±SD), n=3
Statistical analysis
The statistical model was incorporated and polynomial terms were used to evaluate the various responses (Ashra, 2014: Patel and Patel, 2015).
Y = b0 + b_{1}X_{1}+ b_{2} X_{2} + b_{11} X_{1}X_{1}+ b_{22 }X_{2}X_{2} + b_{12} X_{1}X_{2}
The polynomial terms were used to considering the magnitude coefficients. The data were analyzed using Microsoft excel 2007.
The obtained results of ANOVA suggested that F calculated value of each dependent variable like %entrapment efficiency, % drug release at 12 hr as given in table 5 and 6. Tabulated F (5, 3) value was found to be 9.01 at a= 0.05. Calculated F values were greater than tabulated for all dependent variables therefore selected factors have significant effect on all dependent variables. From the results of regression analysis, it was found that both independent variables had statistically significant influence on all dependent variables as significance F value < 0.05.
Table 5. Summary of results of full model regression analysis
Y_{1 }% Entrapment Efficiency 

(Y_{1}) 
B_{0} 
B_{1} 
B_{2} 
B_{11} 
B_{22} 
B_{12} 
R^{2} 
Coefficient 
82.91 
1.5 
4.74 
1.296 
1.0266 
1.345 
0.961 
p Value 
4.94E07 
0.0859 
0.0041 
0.297 
0.3923 
0.161 

Y_{2 }Drug Release at 12 hr 

(Y_{2}) 
B_{0} 
B_{1} 
B_{2} 
B_{11} 
B_{22} 
B_{12} 
R^{2} 
Coefficient 
29.71 
3.031 
8.32 
0.38 
0.61 
0.87 
0.998 
p Value 
9.01E07 
0.00013 
6.72E06 
0.061 
0.3049 
0.0255 
Table 6. Results of ANOVA
Parameters 
D_{f} 
SS 
MS 
F Calculated 
pValue 
Y_{1}%Entrapment Efficiency 

Regression 
5 
161.01 
32.20 
15.17 
0.0024 
Residual 
3 
6.36 
2.12 


Total 
8 
473.40 



Y2 % Drug release at 12 hr. 

Regression 
5 
473.14 
94.628 
1082.86 
4.42 
Residual 
3 
0.2623 
0.0874 


Total 
8 
474.40 



Statistical analysis for % Entrapment efficiency (Y1)
The polynomial equation was generated from Microsoft Excel 2007.
Y = 82.91 +1.53X_{1}+ 4.74X_{2} 1.0296X_{1}X_{1}1.0266 X_{2}X_{2}+1.345X_{1} X_{2}
For %entrapment efficiency as, seen from the equation and graph indicated that the concentration of Sodium bicarbonate increases the drug entrapment also increased. The pectin/ Sodium alginate also influenced the entrapment of drug. So, both factors have significant effect on entrapment of drug (Figure 2 and 3).
Figure 2. Surface response plot showing effect of NaHCO_{3} and polymer ratio on % Entrapment efficiency
Figure 3. Contour plot depicting effect of polymer ratio and NaHCO_{3} concentration on % drug release at 2 hr
As seen from equation the coefficient of X_{2} (NaHCO_{3} concentration %) variable was lower than coefficient of X_{1 }(Ratio of sodium alginate/pectin) variable indicated that effect of X_{1} variable was more significant than effect of X_{2} variable. The positive sign of both the coefficient indicated that there was increase in the response Y_{1} with increase in either of variables. It was observed that X_{1}, X_{2}, X_{1}X_{1} were significant variables with p value less than 0.05, while X_{1}X_{2} variable was not significant.
Statistical analysis for % drug release at 2 hr (Y_{2})
The polynomial equation was generated from Microsoft Excel 2007
Y = 29.71 – 0.03X_{1} – 8.32X_{2 }– 0.61X_{1}X_{1}+ 0.87 X_{2}X_{2} +0.1825X_{1}X_{2}
For the drug release at 12 hr, as seen from the equation and graphs the decrease in drug release initially when increase in Sodium alginate/ pectin and concentration of NaHCO_{3}. The negative sign indicates decrease the response with increase in level of independent variables. The coefficient of X_{1} was higher than coefficient of X_{2} which indicated that the effect X_{21}variable was more significant as compare to X_{2 }variable. From the equation it was concluded that only X_{1 }and X_{2 }variables were significant, while polynomial terms X_{1}X_{1} and X_{2}X_{2} were not significant because of higher pvalue (> 0.05). The contour plot and surface response plot showed effect of sodium alginate/pectin ratio and concentration of NaHCO_{3} on the drug release at 12 hr (Figure 4).
Figure 4. Surface response plot indicating effect of polymer ratio and NaHCO_{3} concentration on %drug release at 2 hr
Optimization of batch from desirability function using Design expert version 10
The optimum formulation was selected based on the criteria of attaining value with the minimum and the maximum limit of formulation variables. An overall desirability function dependent on all the investigated formulation variables was used to predict the ranges of variables where the optimum formulation might occur. The desirable ranges are from zero to one (least to most desirable, respectively). The maximum value for entrapment of drug was selected 87.68 % for optimization, the value of drug release at 2 hr kept minimum 20.11 for selection of optimized batch.
From the graph (Figure 1 and 2), it was concluded that the F9 batch was selected as optimized batch which has composite desirability 0.997 as per given table 7. The predicted value of Y1, Y2 was 87.602 and 20.017 respectively. Optimized batch is given table 8 and figure 5.
Figure 5. Optimization of batch from desirability function using design expert10
Table 7. Solution obtained from design expert Version 10
Batch 
Polymer Ratio 
NaHCO3 Concentration 
%Entrapment efficiency 
%Drug Release 
Desirability 
S1 
1 
1 
87.602 
20.17 
0.997 
S2 
0.983 
1 
87.577 
20.045 
0.996 
S3 
1 
0.983 
87.520 
20.129 
0.993 
S4 
0.794 
1 
87.293 
20.381 
0.978 
S5 
0.779 
1 
87.271 
20.408 
0.997 
Table 8. Formulation composition of optimized batch
Ingredients 
Quantity 
Lafutidine 
10 mg 
Sodium alginate 
500 mg 
Pectin 
700 mg 
Sodium bicarbonate 
800 mg 
Double distilled water 
10 mL 
Prediction of release mechanism for optimized batch
The dissolution profile of optimized batch was analyzed using kinetic model such as korsemeyer and Pappas to ascertain the kinetic drug release (Fule and Amin, 2014; Dween and Chimta, 2015). The diffusion coefficient n is the indicative the mechanism of drug release. The n value is used to characterize different release mechanisms, concluding for values for a slab, of n < 0.5 for Fickian diffusion mechanism, 0. 5 < n < 0.85 to nonFiction (Anamolous) transport, values of n is 0.851.0 to CaseII transport (zero order), and n > 1.0 to super case II transport as per given in table 9.
Table 9. Model fitting for release profile of optimized batch
Code 
Zero order 
First Order 
Higuchi 
Korsemeyer Peppas 
Hixon Model 
Optimized Formulation 
R^{2} 
R^{2} 
R^{2} 
R^{2} 
R^{2} 
0.9982 
0.9750 
0.9737 
0.9789 
0.9982 
Stability study
The stability study indicated that the formulation was physically and chemically stable with no significant changes in any of the evaluated parameters when stored at the 40 ± 2°C and 75 ± 5% RH conditions for 1 month. It was observed that there was a slight change in all parameters which have > ±5 % bias which was insignificance. Negligible difference was observed in results obtained from optimized batch and after the stability study (Table 10).
From the stability study f1 was found to be 2.99 and f2 was found to be 85.80 which ensured that the dissolution data for before stability and after stability of optimized batch was equivalent. Thus, from the f1 and f2 data it could be concluded that both dissolution profiles were similar and no significant changes observed in dissolution profile. From the stability study, it was concluded that the effervescent floating beads of Lafutidine was stable after 1month stability period.
Table 10. Effect of stability testing on various parameters of optimized batch
Parameters 
Before Stability Period 
After Stability Period 
%Bias 
% Yield 
82.20 
80.54 
2.061 
% Swelling Index 
9.48±0.199 
9.52±0.212 
0.421 
Particle size 
1.48±0.15 
1.80±0.23 
2.173 
%Entrapment efficiency 
87.68±0.94 
86.45±0.124 
1.402 
Floating Lag time 
No Lag Time 
No Lag time 
 
Total Floating time 
> 12 hr 
> 12 hr 
 
Conclusion
In this study of effervescent floating bead containing multiparticulate drug delivery system, the effervescent floating beads of Lafutidine was successfully formulated using Sodium alginate, pectin, and Sodium bicarbonate for the treatment of hyperacidity condition. The formulated dosage forms float over the 0.1 N HCl and provide the drug release for prolonged period (up to 12 hr). Among various batches of full factorial design, the batch F9 (5%:7% Sodium alginate/ pectin ratio) and (8% Concentration of sodium bicarbonate) was selected as optimized batch with 0.997 overall desirability, high entrapment efficiency and remain for extended period. The developed formulation was stable and provided sustained release of the drug over a period 12 hr. The optimized batch was passed stability test as there were no significant change in all parameters after storage. It is concluded that the method attempted to formulate effervescent floating beads of Lafutidine being simple and acceptable.
References
Asra PH. 2014. Formulation and Invitro evaluation of gastroretentive bilayer floating tablets of clarithromycin and lafutidine. International Journal of Pharmacy and Technology 6(2): 665170.
Chinta B, Nannapaneni M, Tata S. 2014. Evaluation of floating drug delivery system of famotidine study of effervescent granules and floating beads. Indo American Journal of Pharmaceutical Research 4(2):108391.
Dandang PM. 2013. Formulation and evaluation of Itropride hydrochloride floatingbeads for gastroretentive delivery. International Journal Pharmaceutical Science and Nano Technology 6(2): 15678.
Dwean B, Chimta R. 2015. An open label randomized, cross over bioequivalence study of lafutidine 10mg under fasting condition. World Journal of Gastro Intestinal Pharmacology and Therapeutics 2(2): 5061.
ElMeshad A, ElAshmoony M. 2012. Floating furosemide gel beads: in vitro and in vivo evaluation. Journal of Drug Delivery Science and Technology 22(4):31725.
Fatima F, Katakum P. 2015. Formulation and characterization of lafutidine floating matrix tablet employing three grades of HPMC Polymers. Pharmacreations 2(2): 5061.
Fule R, Amin P. 2014. Development and evaluation of lafutidine solid dispersion via Hot melt extrusion investigating drug polymer miscibility with advance characterization. Asian Journal of Pharmaceutical Science 9(2):106.
Jassal M, Nautiyal U, Kundlas S, Singh D. 2015. A Review Gastro retentive drug delivery system (GRDDS). Indian Journal of Pharmaceutical and Biological Research 3(1): 8292.
Kumar D, Saini S, Seth N, Khullar R, Sharma R. 2011. Approaches, Techniques, and evaluation of Gastroretentive drug delivery system: An overview. International Journal of Research in Ayurveda and Pharmacy 2(3): 76774.
Lohithasu D, Kumar D, Rao H. 2014. Design and evaluation of lafutidine floating tablets for controlled release by using semi synthetic and natural polymer. Journal of Drug Discovery and Therapeutics 2(24): 18.
Malakar J, Nayak AK. 2012. Development of cloxacillin loaded multipleunit alginatebased floating system by emulsiongelation method. International Journal of Biological Macromolecule 50(1):13847.
Patel DM, Patel N. 2015. Formulation and optimization of raft chewable tablet containing of lafutidine. International Journal of Pharmaceutical Science and Drug Research 7(3): 22934.
Pather S, Robinson J, Jonathan E. 2000. Effervescent drug delivery system for oral administration US patent PCT/WO00/66089, 2000.
Reddy RB, Prasanna D. Prasad M. 2012. Preparation and Invitro evaluation of Lamivudine floating Sodium alginate beads. International Journal of Pharmaceutical and Clinical Research 9(4): 8188.
Rowe Rand Sheskey P. 2009. Handbook of Pharmaceutical Excipients: Pharmaceutical Press, pp.1917.
Sayeh A, Abu ELA, Maha A. 2014. Ketorolac tromethamine floating beads for oral application: characterization and in vitro/ in vivo evaluation. Saudi Pharmaceutical Journal 2(2):34959.
Singh B, Kim K. 2000. Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. Journal of Controlled Release 6(3): 23559.
Vasava K, Jha LL. 2011. A review on gastro retentive drug delivery (GRDDS) system with special emphasis on formulation and development of floating microspheres. International Journal of Pharmaceutical Sciences Review and Research 11(2):7681.
Vishami K, Laxmi VM. 2015. Evaluation of gastro retentive floating calcium alginate microbeads of ranitidine HCl prepare by using NaHCO_{3} olive oil effervescent vs/oil/ entrapment. Indo American Journal of Pharmaceutical Research 5(5): 163340.