Sudhakarrao Naik Institute of Pharmacy, Pusad, Maharashtra, India 445204
The present study focuses on the formulation and evaluation of sustained release pellets of Rabeprazole Sodium using the extrusion-spheronization technique. Rabeprazole, a proton pump inhibitor, is acid-labile and requires protection from gastric degradation. To address this, a multiparticulate sustained release dosage form was developed using various polymers such as microcrystalline cellulose (MCC), hydroxypropyl methylcellulose (HPMC K4M and E5), ethyl cellulose, and polyvinylpyrrolidone (PVP K30). The pellets were prepared by wet massing the drug and excipients, extruding through a suitable die, and spheronizing under optimized conditions. Enteric coating was applied using suitable pH-dependent polymers to ensure drug release in the intestinal environment. The prepared pellets were evaluated for micromeritic properties, drug content, in vitro drug release, and stability. Drug release data were fitted to various kinetic models to understand the release mechanism. The optimized batch showed a controlled drug release profile over 12 hours with good stability. The extrusion-spheronization technique proved to be effective in achieving sustained release and uniform pellet size, providing a promising approach for improved patient compliance and therapeutic efficacy.
Oral drug delivery is the most preferred route for systemic administration of drugs due to its convenience, non-invasiveness, and high patient compliance. Among the various oral dosage forms, sustained release (SR) formulations offer multiple therapeutic benefits such as prolonged drug release, reduced dosing frequency, and minimization of side effects by maintaining consistent plasma drug levels over time. 4,5
Rabeprazole Sodium, a proton pump inhibitor (PPI), is widely prescribed for the treatment of acid-related gastrointestinal disorders such as gastroesophageal reflux disease (GERD), duodenal ulcers, and Zollinger-Ellison syndrome. However, Rabeprazole is highly sensitive to acidic environments, leading to degradation in gastric pH and reduced oral bioavailability. This necessitates its protection via enteric coating and the development of formulations that can prolong its release in a controlled manner within the intestinal environment. 6, 7
Multiparticulate dosage forms, particularly pellets, have gained attention in controlled drug delivery systems due to their multiple advantages over single-unit systems. Pellets exhibit better flow properties, uniform distribution in the gastrointestinal tract (GIT), and reduced inter- and intra-subject variability in drug absorption. Among various pelletization techniques, extrusion-spherizations a preferred method for the preparation of spherical, uniform-sized pellets. This technique allows for high drug loading, excellent mechanical strength, and ease of coating. 8, 9
Various polymers and excipients are employed to modify the release profile of Rabeprazole in pellet formulations. Hydrophilic and hydrophobic polymers like hydroxypropyl methylcellulose (HPMC), ethyl cellulose (EC), and polyvinylpyrrolidone (PVP) serve as matrix formers or release retardants, while microcrystalline cellulose (MCC) acts as a spheronization aid and binding agent. The selection and combination of these excipients play a critical role in controlling the drug release and ensuring formulation stability. 10, 11
The rationale of this study was to develop a robust and reproducible sustained release pellet formulation of Rabeprazole using extrusion-spheronization technology. By selecting appropriate polymers and process parameters, the goal was to achieve uniform pellet morphology, effective enteric coating, and desirable release kinetics. 12
This research not only aims to overcome Rabeprazole’s acid sensitivity but also to enhance its therapeutic efficacy by minimizing dosing frequency and maximizing patient adherence. The formulation was systematically evaluated for physicochemical properties, micromeritic characteristics, drug content, in vitro release, kinetic modeling, and stability, in accordance with regulatory expectations for pharmaceutical development.13
2. MATERIALS AND METHODS
1. Materials
Active Pharmaceutical Ingredient (API): Rabeprazole Sodium was used as the model drug due to its acid-labile nature and requirement for intestinal absorption.
2. Polymers and Excipients:
All chemicals and reagents used were of pharmaceutical grade and procured from certified suppliers. 14, 15, 16
3. METHODOLOGY
A) Preparation of Sustained Release Pellets
a. Wet Massing and Extrusion:
The weighed quantities of Rabeprazole Sodium, MCC, HPMC, and other excipients were dry-blended uniformly. PVP K30 solution in isopropyl alcohol was added gradually to form a wet mass with appropriate consistency. The wet mass was passed through a twin screw extruder using a die with uniform pore size (typically 1.0 mm diameter). 17
b. Spheronization:
The extrudates were transferred to a spheronizer fitted with a cross-hatch friction plate. The spheronization process was optimized for speed (1000–1400 rpm) and duration (3–5 minutes) to obtain spherical, uniform pellets.18
c. Drying and Sieving:
The pellets were dried at 45–50?°C in a hot air oven until constant weight was achieved. The dried pellets were sieved through a mesh 20 to 40 to achieve size uniformity. 19, 20
B) Enteric Coating of Pellets
a. Seal Coating:
A protective sub-coating of ethyl cellulose (2%) was applied to avoid interaction between Rabeprazole and enteric coating. 21, 22
b. Enteric Coating:
An enteric coating solution comprising ethyl cellulose N10, HPMC phthalate, methylene dichloride, diethyl phthalate, and sunset yellow was applied using a fluidized bed coater under controlled spray rate, atomization pressure, and bed temperature (40–45°C). Coating weight gain was optimized between 8–10%. 23
Table no. 1 Formulation table of sustain release Pellets 24
|
INGREDIENT(gm) |
F1(1:1) |
F2(1:2) |
F3(1:3) |
F4(1:1) |
F5((1:2) |
F6(1:3) |
|
Rabeprazole |
2 |
2 |
2 |
2 |
2 |
2 |
|
HPMC K4M |
2 |
4 |
6 |
- |
- |
- |
|
Ethyl Cellulose |
- |
- |
- |
2 |
4 |
6 |
|
MCC |
5.5 |
3.5 |
2.5 |
5.5 |
3.5 |
2.5 |
|
Magnesium Stearate |
0.5 |
0.5 |
0.5 |
0.5 |
0.5 |
0.5 |
|
PVP K30(1%) |
QS |
QS |
QS |
QS |
QS |
QS |
|
Water |
- |
- |
- |
- |
- |
- |
|
Barrier coating(mg)(weight gain 3%) |
||||||
|
|
|
|
|
|
|
|
|
HPMC E5 |
200 |
200 |
200 |
200 |
200 |
200 |
|
PVP K30 |
25 |
25 |
25 |
25 |
25 |
25 |
|
Light magnesium oxide |
25 |
25 |
25 |
25 |
25 |
25 |
|
Enteric coating(mg)(weight gain 27%) |
||||||
|
Eudragit L100 |
630 |
630 |
630 |
630 |
630 |
630 |
|
Triethyl citrate |
70 |
70 |
70 |
70 |
70 |
70 |
|
Talc |
190 |
190 |
190 |
190 |
190 |
190 |
|
Isopropyl alcohol |
QS |
QS |
QS |
QS |
QS |
QS |
4. EVALUATION OF PELLETS
a. Micromeritic Properties 25
Angle of repose, Bulk density and tapped density, Carr’s Index and Hausner’s Ratio
b. Particle Size Distribution 26
Sieve analysis was carried out using a sieve shaker and standard mesh sizes.
c. Surface Morphology 27
The morphology and uniformity of coated pellets were examined under a scanning electron microscope (SEM).
d. Drug Content Uniformity 28
Accurately weighed pellets equivalent to 20 mg Rabeprazole were crushed, dissolved, and analyzed by UV-visible spectrophotometry at 284 nm.
e. In Vitro Drug Release 29
Drug release was studied using a USP Type I dissolution apparatus:
Samples were analyzed at regular intervals to determine cumulative % drug release.
f. Drug Release Kinetics 30
The in vitro drug release data were fitted to various kinetic models (Zero-order, First-order, Higuchi, Korsmeyer-Peppas, and Hixson-Crowell) to determine the mechanism of drug release.
g. Stability Studies 31
Accelerated stability testing of the optimized formulation was conducted at 40?±?2?°C / 75?±?5% RH for 1 month. Samples were tested for appearance, drug content, and dissolution at predetermined intervals.
5. RESULTS AND DISCUSSION
a) Preformulation Studies 32
Nature Solid, White or yellowish white Coloured Crystalline Powder, Tasteless, Odourless, Solubility 100 µg/ml, Melting point 138-141°C
b) Analytical Method
1. Drug-Excipient Compatibility 33
FTIR spectra of Rabeprazole and physical mixtures with excipients (HPMC K4M, HPMC E5, MCC, PVP K30, Ethyl Cellulose) showed no significant shifting or disappearance of characteristic peaks, confirming the absence of chemical interaction. The characteristic absorption peaks of Rabeprazole were retained (notably at \~2960 cm^-1 for C-H stretching and 1270 cm^-1 for S=O stretching).
Fig.1- FTIR of Rabeprazole Sodium
Fig.2- FTIR spectrum of PVP K30
Fig. 3-FTIR Spectrum of HPMC K4M
Fig 4: FTIR Spectrum of Ethyl cellulose
Fig 5-FTIR Spectrum of Rabeprazole sodium +PVP K-30+HPMC K4M+MCC
Fig. 6- FTIR Spectrum of Rabeprazole sodium +PVP K-30+Ethyl Cellulose+MCC
2) Determination of λ max of Rabeprazole sodium 34
Rabeprazole showed the maximum wavelength at 284 nm, which matches with the Standard. Hence drug used in formulation was found to be pure according to I.P specification.
Fig. 7- λ max of Rabeprazole sodium
c) Micromeritic Properties
All pellet batches showed excellent flow properties: 35
Table No. 2- Micromeritic Properties of pellets
|
Parameter |
Optimised Batch Results |
|
Angel of Repose |
23.8° ± 0.5 |
|
Bulk density (g/cm³ |
0.45 ± 0.02 |
|
Tapped density (g/cm³) |
0.52 ± 0.01 |
|
Carr’s index (%) |
13.4 ± 0.7 |
|
Hausner’s ratio |
1.15 ± 0.02 |
Low Carr’s index and Hausner’s ratio indicate excellent flow, critical for uniform capsule filling and coating. 36
d) Particle Size Distribution
Sieve analysis showed 85% of pellets within 710–1000 µm, confirming uniformity. Controlled spheronization speed (1200 rpm) and time (4 min) contributed to narrow size distribution. 39
e) Surface Morphology
SEM images revealed smooth, spherical pellets with uniform enteric coating. No visible cracks or defects were observed, confirming process optimization. 40
f) Drug Content Uniformity
Drug content across batches ranged from 98.2% to 101.1%, indicating consistent distribution of Rabeprazole. 41
g) In Vitro Drug Release
Acid Stage (0.1 N HCl, 2 h): Negligible drug release (<5%) was observed, confirming effective enteric protection.
Buffer Stage (pH 6.8, up to 12 h): The optimized batch (F5) showed sustained drug release:
This profile demonstrates extended drug release suitable for once-daily dosing. Time (Hrs.) 42, 43
Table No. 3-In vitro Drug Release
|
Time (Hrs) |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
1 |
4.032±0.3 |
10.836±0.3 |
8.46±0.15 |
4.604±0.35 |
3.636±0.35 |
1.944±0.35 |
|
2 |
13.392±0.35 |
19.044±0.22 |
15.336±0.35 |
10.944±0.35 |
13.068±0.22 |
13.176±0.35 |
|
3 |
25.992±0.37 |
25.848±0.35 |
19.26±0.31 |
16.848±0.37 |
20.16±0.35 |
19.26±0.22 |
|
4 |
27.144±0.35 |
40.428±0.37 |
27.216±0.344 |
27.036±0.22 |
29.736±0.22 |
25.848±0.33 |
|
5 |
40.248±0.45 |
47.628±0.22 |
36.432± 0.37 |
36.864±0.35 |
38.088±0.30 |
35.064±0.37 |
|
6 |
56.448±0.25 |
59.436±0.35 |
56.124±0.35 |
48.276±0.32 |
55.584±0.33 |
47.88±0.33 |
|
7 |
57.24±0.22 |
71.352±0.45 |
64.08±0.35 |
58.536±0.33 |
70.524±0.37 |
57.204±0.32 |
|
8 |
62.64±0.19 |
76.968±0.35 |
67.68±0.35 |
64.08±0.31 |
73.044±0.30 |
66.168±0.22 |
|
9 |
71.82±0.55 |
83.88±0.25 |
72.36±0.22 |
67.248±0.37 |
80.136±0.35 |
69.228±0.35 |
|
10 |
75.24±0.15 |
88.38±0.3 |
75.708±0.35 |
72.36±0.24 |
84.528±0.33 |
72.72±0.33 |
|
11 |
77.436±0.35 |
90.432±0.3 |
77.976±0.3 |
83.772±0.22 |
85.248±0.22 |
75.96±0.32 |
|
12 |
88.272±0.25 |
92.952±0.37 |
81.144±0.22 |
89.532±0.32 |
95.472±0.32 |
82.836±0.37 |
h. Release Kinetics
Regression coefficients (R²) for the optimized batch: 44
Table No. 4-Release Kinetics
|
R² Value |
||||
|
Zero-order |
First-order |
Higuchi |
Korsmeyer-Peppas |
Hixson-Crowell |
|
0.976 |
0.947 |
0.983 |
0.987 |
0.942 |
i. Stability Study
After 1 month of accelerated conditions:
This demonstrates excellent stability of the formulation. 45
6. DISCUSSION
The study successfully demonstrated: Extrusion-spheronization produces uniform, spherical sustained release pellets. A combination of hydrophilic (HPMC) and hydrophobic (EC) polymers effectively modulated drug release. The enteric coating prevented acid degradation and ensured site-specific release in the intestine. The process yielded reproducible results with excellent stability. Overall, the formulation meets the objectives of sustained delivery, acid protection, and improved patient compliance. 46, 47
7. CONCLUSION
The present study successfully demonstrated the formulation and evaluation of sustained release pellets of Rabeprazole Sodium using the extrusion-spheronization technique. The formulation approach effectively addressed the acid-labile nature of Rabeprazole by employing an enteric coating strategy, thereby enhancing its stability and ensuring targeted release in the intestinal region. 48
Optimization of polymer concentrations (HPMC K4M, ethyl cellulose, and PVP K30) and process parameters (spheronization speed and duration) resulted in pellets with excellent flow properties, uniform size distribution, and desirable surface morphology. In vitro drug release studies confirmed a sustained and controlled release profile extending up to 12 hours, with minimal release in acidic conditions, demonstrating the efficiency of the enteric coating.
Kinetic modeling indicated that the drug release followed non-Fickian (anomalous) diffusion, governed by both polymer erosion and diffusion mechanisms. Stability studies confirmed that the optimized formulation maintained its physicochemical and release characteristics under accelerated conditions. 49
Overall, the sustained release pellet formulation developed in this study offers a promising platform for improving therapeutic efficacy, enhancing patient compliance, and reducing dosing frequency for Rabeprazole Sodium. The extrusion-spheronization technique proved to be a robust and scalable method for manufacturing multiparticulate dosage forms for acid-labile drugs.
8. FUTURE SCOPE 50
The sustained release pellets of Rabeprazole Sodium developed through extrusion-spheronization present a strong foundation for further pharmaceutical development. Future research could focus on the following aspects:
REFERENCES
Jayshri Kawale, Dr. A. M. Mahale, Formulation, Optimization, and Characterization of Rabeprazole Sodium Pellets for Sustained and Targeted Intestinal Drug Release, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 8, 1127-1137. https://doi.org/10.5281/zenodo.16798605
10.5281/zenodo.16798605
