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INTERNATIONAL JOURNAL OF ADVANCES IN PHARMACY,
BIOLOGY AND CHEMISTRY
Research Article
Formulation and Evaluation of Rabeprazole Sodium
Enteric Coated Pellets
KL. Senthilkumar*, M. Muthukumaran and B. Chenchuratnam
Padmavathi College of Pharmacy & Research Institute, Dharmapuri, Tamilnadu, India.
ABSTRACT
The aim of the present investigation was to prepare delayed release i.e., enteric coated pel ets of Rabeprazole
sodium by using hydroxyproply methyl cel ulose based sub coating and methacrylic acid copolymer based enteric coating. The different batches of pel ets were prepared by drug suspension layering method. Comparatrive study of dissolution profile of final batch with market preparations was conducted and it was concluded that final batch shown good similarity with market products. The results of the accelerated stability of final formulation revealed that storage conditions were excel ent.
Keywords: Rabeprazole sodium, sub coating, enteric coating.

INTRODUCTION
The first aim of present work was to prepare Delayed Proton Pump Inhibitors (PPIs) are used in the release i.e., enteric coated pellets of Rabeprazole treatment of acid – related gastro – duodenal sodium by using Methacrylic acid copolymer in disorders by reducing gastric acid secretion. Proton Fluid bed processor to prevent degradation in the pump inhibitors are substituted benzimidazoles and stomach due to the acidic environment or gastric all share a similar core structure and mode of action, enzymes and compare with the market sample but differ in substituent groups. The type of substituents affects the chemical properties of the MATERIALS
compounds that directly influence their rates of Rabeprazole Sodium (I.H.S) Mannitol (Pearlitol reactions and therefore their stability in different SD200), Sodium Carbonate (I.P), Polyplasdone XL, media. The stability of PPIs in aqueous media is a XL-10 (ISP), Talc (I.P), Opadry clears (Colorcon), function of PH with an increased rate of degradation as the PH decreases. Degradation of the Rabeprazole leads to a yellow or purple discoloration of the EXPERIMENTAL
pellets, film layer or dissolution medium. Stability of Preformulation studies
Rabeprazole sodium also decreases under moisture Preformulation studies were carried out for conditions. Exposure of Rabeprazole sodium to the appropriate selection of excipients in view of acidic content of the stomach would lead to Rabeprazole Sodium modified release pellets. significant degradation of the drug and hence, Micromeritic properties of Rabeprazole Sodium
Delayed release dosage form is best formulations 1. Angle of repose
which are used for drugs that are destroyed in the The angle of repose of Rabeprazoe powder were gastric fluids, or cause gastric irritation or are determined by the funnel method. The accurately absorbed preferentially in the intestine. Such weight powder blend were taken in the funnel. The preparations contain an alkaline core material height of the funnel was adjusted in such a way the comprising the active substance, a separating layer tip of the funnel just touched the apex of the powder blend. The powder blend was allowed to flow through the funnel freely on to the surface. The www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012
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diameter of the powder cone was measured and angle
Table 1: Compatibility study of Rabeprazole
of repose was calculated using the following sodium with excipients
tan θ = h/r
Diluents
Excipients
/75%RH±5%
Where h and r are the height and radius of the powder 2. Bulk Density and tapped Density
Both Bulk density (BD) and tapped density (TD) was determined. A quantity of 2 gm of Rabeprazole sodium powder from each formula, previously shaken to break any agglomerates formed, was introduced in to 10 ml measuring cylinder. After that Estimation of Rabeprazole sodium
the initial volume was noted and the cylinder was Two different solutions of Rabeprazole sodium were allowed to fall under its own weight on to a hard prepared in 0.1 N HCl and 6.8 pH phosphate buffer surface from the height of 2.5cm at second intervals. respectively. The UV spectras were taken using Tapping was continued until no further change in spectrophotometer. The UV maxima of Rabeprazole volume was noted. Bulk density and Tapped density sodium in 0.1 N HCl and 6.8 pH phosphate buffer were calculated using the following equations. were found to be 260 nm and 284 nm respectively. Bulk density = weight of the powder blend/untapped Formulation development of core pellets of
Tapped density = weight of the blend/Tapped volume Rabeprazole sodium
The drug suspension was prepared by mixing 3. Compressibility Index
crosspovidone and Hydroxypropylmethyl cellulose in The compressibility Index of the powder blend was purified water. The suspension was then placed into determined by Carr’s compressibility index. The the spray gun system of Glatt fluid bed processor machine and sprayed onto the sugar core pellets while the Glatt machine was set in running condition. Carr’s Index (%) = {(TD – BD) x 100} / TD
This would allow the drug to be evenly coated onto the core pellets to form drug – coated spherical 4. Hausner’s ratio
pellets. The drug – coated pellets were dried under Hausner’s ratio is a number that is correlated to the flowability of a powder or granular material. The ratio of tapped density to bulk density of the powders is called the Hausner’s ratio. It is calculated by the Table 2: Formulation of different batches of
Rabeprazole sodium core pellets
Ingredients
Formulations (quantities in gms)
Hausner’s ratio (H) = TD / BD
Where TD = tapped density, BD = bulk density. Drug excipients compatibility study
Drug excipients compatibility studies were carried out by mixing the drug with various excipients in different proportions. Studies were carried out in flint vials at Accelerated conditions, 40±2oC /75%RH±5% RH. The studies were conducted for 4 Table 3: composition of Subcoating solution
weeks and compared with control at 2 - 8 oC. Material
Quantity (%)
Physical observations of the blend were recorded at www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012
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Preparation of Coating solution of Color coat
atomizing air pressure (1 to 3 bars), % fluidization (10 to 30%) and percent solids content (7%) were To prevent interaction between Rabeprazole sodium adjusted and optimized. After finishing of the and Colorcoat EC4S, seal coating of core pellets of coating pellets were dried at 40o C and at 10% Rabeprazole sodium was done by Colorcoat FC4S fluidization. The coated pellets were removed and until weight gain 8-10%. Coating solution was prepared by dissolving Colorcoat FC4S in mixture of Iso Propyl Alcohol (IPA) and Mehtylene Dichloride Evaluation of Parameters
(MDC) under constant stirring for 15-20 minutes by Description: Examine visually and record the
Table 4: Composition of enteric coating solution
Identification: The Retention time of the major peak
in the chromatogram of the sample preparation corresponds to that of the standard preparation as Material
Quantity (%)
Moisture content: Take about 35ml of Methanol in
titration flask of Karl Fischer titrator and titrate with Preparation of Coating solution of enteric coating
Karl Fischer reagent to end point. Grind the pellets solution
to fine powder in a dry mortar, weigh accurately Required quantities of solvents were weight in the about 0.5mg of the sample, transfer quickly to the beaker or other suitable vessel. Propeller stirrer was titration flask, dissolve by stirring and titrate with used for preparation of coating solution. Propeller was kept in the center and as close to the bottom of the vessel as possible, stir the mixture of solvents to Bulk density:
form a vortex without entrapment of air in to the the sample into a 100 ml measuring cylinder, tap the liquid. After that required quantity of Eudragit L100- measuring cylinder 10 to 15 times and record the 55 (for 30% weight gain) was added in the water and volume occupied by the sample. Calculate the bulk kept continuous stirring for 15-20 minutes. Coating of core pellets
Bulk density = Weight of the sample (g)
A protective coating solution was prepared by mixing Volume occupied by sample (ml)
Opadry clear slowly in the solvent mixture of IPA and MDC (60:40). This coating was then placed into Gastric Resistance
the spray gun of the Glatt machine and sprayed onto Chromatographic conditions
Buffer: Dissolve 2.72 g of Potassium dihydrogen
the drug – coated pellets while the Glatt machine was ortho phosphate and 0.525 g of Dipotassium set in running condition. After the coating was hydrogen ortho phosphate in 1000 ml of water completed, the protective coating-covered pellets were again dried under warm air within the Glatt
Mobile phase: Prepare a mixture of Buffer and
Acetonitrile in the ratio of 60:40, and adjust pH to 7.4 Finally, an enteric coating agent was prepared by with Potassium hydroxide solution, filter and degas. mixing Eudragit L100-55 in a mixture of Isopropyl alcohol and Methylen dichloride. This coating agent
Preparation of 0.1 M NaOH: Dissolve 4 g of
was placed into the spray gun of the Glatt machine and sprayed onto the protective coating-covered pellets to form the pharmaceutical pellets before final
Standard Preparation: Weigh about 80.0 mg
drying of the granules to complete the process of Rabeprazole sodium working standard in to a 100 ml making the enteric coating-covered pellets. volumetric flask dissolve and dilute to volume with Coating of pellets was done using Glatt fluid bed 0.1 M NaOH and mix. Transfer 2.0 ml of this processor machine. First fixed quantity (1Kg) pellets solution in to a 50 ml volumetric flask and dilute to were put in the product chamber which was readjusted at 50oC temperature for 5 – 10 minutes. Various parameters like spraying rate (8 to 25 gm/min), inlet air temperature (20 to 50oC), www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012
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Sample Preparation: Weigh and transfer the pellets
apparatus and run for 2 hrs at 100 rpm. After 2 hrs equivalent to 20 mg of Rabeprazole sodium lift the paddles completely and drain out the acid individually in each of the 6 dissolution jars, carefully without loss of pellets. Then add 900 ml of containing 900 ml of 0.1 M Hydrochloric acid which pH 8.0 Phosphate buffer the temperature of which has been equilibrated to the temperature of 37±0.50C. has been equilibrated to 37±0.50C and run the Immediately start the apparatus and run for 2 hours. apparatus. After specified interval withdraw sample After 2 hours lift the paddles. Drain the medium about 10 ml from a zone midway between the surface completely with out losing any pellet. Carefully of the medium and top of the rotating blade and not transfer the pellets in to a 50 ml volumetric flask less than 1 cm from the vessel wall and filter through individually with the aid of a funnel. Add about 25 0.45 micron membrane filter. Immediately transfer 5 ml of 0.1 M Sodium hydroxide and sonicate for 15 ml of filtrate into a 10 ml of volumetric flask already minutes and shake for 15 minutes. Dilute to volume containing 2 ml of 0.2 M sodium hydroxide solution. with 0.1 M Sodium hydroxide and mix. Centrifuge a Mix well immediately and dilute to volume with portion of the preparation at about 3000 RPM for 15 minutes. Transfer 2.0 ml of the clear supernatant liquid in to a 25 ml volumetric flask and dilute to Procedure: Inject separately Standard and test
samples into Liquid chromatograph port and record Procedure:
Preparation and the Sample Preparation into the liquid chromatograph and record the area due to Standard Preparation: Weigh accurately about
80.0 mg of Rabeprazole sodium working standard in to a 100 ml volumetric flask. Dissolve and dilute to Dissolution in buffer
volume with 0.1 N NaOH and mix. Transfer 2.0 ml Dissolution Parameters
of this solution in to a 50 ml volumetric flask and Medium : Initially run in 900ml of 0.1 N
dilute to volume with mobile phase and mix. Sample Preparation: Grind about 10g of pellets to
fine powder in a dry mortar and weigh accurately the Volume : 1000ml
quantity of powder equivalent to 20 mg of Apparatus : USP-II (paddle)
Rabeprazole sodium in to a 50 ml volumetric flask. Speed : 100 rpm
Add 25 ml of 0.1N NaOH and dissolve the content by Temp : 37±0.50C
sonicating for 15 min followed by shaking for 10 Sampling points : 2hr in acid and 10, 20 and
min, dilute to volume with 0.1N NaOH and mix. Centrifuge a portion of the sample at 3000 RPM for Standard Preparation: Weigh accurately 80.0 mg
10 min. Transfer 2 ml of the clear supernatant in to a of Rabeprazole Sodium working standard into a 100 25 ml volumetric flask and dilute to volume with ml volumetric flask, dissolve in 10 ml of 0.1 M NaOH and dilute to volume with 0.1M NaOH. Pipette out 2.0 ml above stock solution into a 100 ml RESULTS AND DISCUSSION
of volumetric flask, which contains 20 ml of 0.2 M Preformulation studies
sodium hydroxide mix immediately, and dilute to 100 From the results of Micromeritic studies of the Rabeprazole sodium has poor flow property and Sample preparation: Transfer 900 ml of 0.1 N Hcl
compressibility property. From the physical into each of six dissolution jars the temperature of which has been equilibrated to 37±0.50C. Transfer interaction was notified. So it was concluded that the weighed pellets equivalent to 20 mg of drug and other excipients were compatible with each Rabeprazole Sodium in to each of six jars. Start the Table 5: Micromeritic properties of API
Angle of repose (o)
Compressibility Index
Hausner’s ratio
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Table 6: Drug Excipient compatibility study (Physical observation)
Batch no.
Drug-Excipients combination
D:E Ratio
Final description
observation
1M/ (400C / 75%RH
Evaluation parameters of the optimized batch of
storage conditions were not found any significant Rabeprazole sodium
changes in final formulation dissolution profile with From the results of comparative study of dissolution profile of final batch with market preparations. It was concluded that final formulation was shown EVALUATION OF MARKET SAMPLE
The assay of the Market sample was found to be Accelerated stability study of the optimized batch
From the results of the accelerated stability of the final formulation for 3 months, it was concluded that ACID RESISTANCE
Amount of the drug resisted after 2 hr in acid was DISSOLUTION
Table 7: Dissolution comparison of F2 sample (capsule) with Market sample in pH 8.0 buffer
Time (min)
Market sample
InVitro dissolution profile
Time (min)
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Table 8: Acid resistance test
% S.C+ % E.C
Dissolution
time(2 hrs)

DISCUSSION
were conducted with increasing sub coat and In coating process the enteric coating was done with the percentage build ups of 22, 24, 26, and 28 with 8% sub coating. Acid resistance test failed up to 26% EVALUATION OF RABEPRAZOLE SODIUM
but at 28% build up acid resistance test passed. But COATED PELLETS (CAPSULE)
for safer side, we coated up to 30% with 8% sub The following results were compared with Market coating. For optimizing coating process further trails Table 9: Comparison of Assay, Drug release and Acid resistance of
coated Pellets (capsule) with market sample
Market sample
dissolution
resistance
Assay - % labeled amount of Rabeprazole sodium
Dissolution - % labeled amount of Rabeprazole sodium released in Buffer
Acid resistance test - % labeled amount of Rabeprazole sodium retained in acid Dissolution
Table 10: Comparison of Dissolution profiles of
Market sample and coated tablets in pH8.0 buffer
Dissolution profile
In - Vitro drug dissolution profile
Time (mins)
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From the above results, we found that F1, F2 , F3 and
dissolution profile. So finally F2 was found to be F4 batches passed in assay and acid resistance tests. best formula for formulation of Rabeprazole sodium In sub coating process, the pellets were coated to 8% and enteric build up was given upto 30 percentages. Even though acid resistance test passed at 28 % STABILITY
SELECTED
enteric build up for safer side we coated up to 30% of FORMULATION (F2)
Stability studies were conducted at 40ºC / 75% RH Based on results, F2 formulation was found to be for about 3 months in stability chamber (thermo lab). satisfactory as it matched with the market sample Samples were collected at 1, 2 and 3 months. Table 11: Stability data
Temperature
40ºC / 75% RH
Dissolution profile of selected stability sample
T ime (mins)

Selected formulation F2 was kept for stability studies and observed that assay, acid resistance and drug release at
the end of 1, 2 and 3 months. There was no significant change in in-vitro release profile. It shows that formulation
F2 was stable.

SUMMARY AND CONCLUSION
The aim of the present study was to formulate and evaluate delayed release pellets of Rabeprazole sodium by enteric
coating. It is an acid labile drug so it is degraded at acidic pH of stomach so an attempt was made to stabilize the
drug with super disintegrant with different particle size and alkaline agent Sodium carbonate. Finally enteric coating
was given to bypass the stomach. The enteric coating was carried out by using enteric polymer Methacrylic acid
copolymer Eudragit L 30D-55. The study includes preformulation of drug and excipients, formulation, evaluation
and stability studies of delayed release pellets.
The core pellets were prepared using suspension layering technique in fluid bed process. Sub coating was given to core pellets to avoid direct contact of drug with enteric coating materials. Sub coating was given with Opadry clear which contains HPMC, diethyl phthalate which was dispersed in isopropyl alcohol & methylene-di-chloride acting as a solvents system. An average weight build up of 8%w/w was given to core pellets. www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012
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Enteric coating was given to sub coated pellets using Eudragit L 30D-55 at an average weight build up of 30% w/w
of sub coated tablets and the drug release profile, acid resistance and assay compared with market product (Razo).
13
Stability studies were conducted at 40ºC / 75% RH (accelerated stability testing) for 3 months. Assay, acid
resistance, drug release profiles were compared between market sample and selected formulation (F2). Based on the
above data it was concluded that drug release from F2 formulation was similar to that of market product.
REFERENCES
7. Ojantakanen S. Effect of viscosity grade of polymer additive and compression force on Schatzlein. Polymers in Drug Delivery: 235. Pharmaceutical Sciences. 1993;1(2):109-14 3. Thomas WYL and Robinson J. The Science Lippinkette, William and Willins: 903-911. release dosage forms. STP Pharma Sciences. 9. Release Vial-Bernasconi AC, Doelker E and Banker G.S. Tablet Formulation Design. In: Schwartz BJ. (ed.) Pharmaceutical Dosage 10. Leon Lachman, Herbert A. Lieberman and Forms: Tablets. Marcel Decker, New York: Joseph L. Kanig. The Theory and Practice of 11. Olsen K. Fluid bed equipment. In: Ghebre- Delivery Systems, 6th ed. New Delhi: B.I. Sellassie I. Pharmaceutical Pelletization Technology. New York: Marcel and Dekker. 39-69.

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