Indo American Journal of Pharmaceutical Research, 2014
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ISSN NO: 2231-6876
INDO AMERICAN
JOURNAL OF
PHARMACEUTICAL
RESEARCH
EXTRUSION-SPHERONIZATION
VS
SOLUTION
/
SUSPENSION
LAYERING
TECHNIQUE FOR FORMULATION OF ITOPRIDE HYDROCHLORIDE PELLETS: A
TRUCE
Prateek Kulshrestha 1*, Arun Kumar Das1, R. Raja Reddy1, A.Pavani1, N. Srilakshmi1
1
Department of Pharmaceutics, Malla Reddy Pharmacy College, Maisammaguda, Dhulapally (Post-Via Hakimpet), Secunderabad500014, Andhra Pradesh, India.
ARTICLE INFO
Article history
Received 22/03/2014
Available online
30/03/2014
Keywords
Pellets,
Sustained Release
Formulation, ExtrusionSpheronization,
Solution/Suspension Layering,
HPMC, FBP,
Sugar Spheres And
Itopridehcl.
ABSTRACT
The purpose of this study is to formulate itopride hydrochloride sustained release pellets by
Extrusion–Spheronization and Solution/ Suspension layering technique and to compare the
pellet characteristics prepared from both the techniques. In the Extrusion-Spheronization
technique, the drug pellets were prepared by mixing the drug with excipients along with a
binder solution, the resultant mass was extruded through extruder followed by spheronizer.
In Solution/suspension layering technology the pellets were prepared by coating the drug
solution/suspension on the sugar spheres in a fluidized bed processor (FBP). The prepared
drug pellets from both the techniques were seal coated with HPMC 5cps followed by
sustained release coating of Ethyl cellulose 7cps in the FBP. Formulation F3, F4 prepared
using Extrusion-Spheronization and formulation F7, F8 prepared using Solution/suspension
layering technique were selected for comparison. The formulations F4 & F8 showed good
reproducible dissolution profiles. Pellets of formulation F4 showed better drug content
whereas pellets of F8 had good surface morphology. From the results obtained it can be
concluded that the Sustained release ItoprideHCl pellets prepared by Solution/Suspension
layering technique had good surface quality but compromises uniform drug distribution over
the pellet whereas the pellets prepared from Extrusion-Spheronization technique had uniform
drug content but had poor surface quality and requires continuous monitoring of every
processing parameters viz. granulation, extrusion.
Copy right © 2014 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical
Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Please cite this article in press as Prateek Kulshrestha, et al. Extrusion-Spheronization Vs Solution / Suspension Layering
Technique for Formulation of Itopride Hydrochloride Pellets: A Truce. Indo American Journal of Pharm Research.2014:4(03).
1544
Corresponding author
Prateek Kulshrestha,
Malla Reddy Pharmacy College,
Maisammaguda, Dhulapally,
Secunderabad– 500014
[email protected]
-8801225517
Vol 4, Issue 03, 2014.
Prateek Kulshrestha,et. al.
ISSN NO: 2231-6876
INTRODUCTION
The main aim of formulation development is to deliver the drug at the desired site while lowering the side effects and
improving patient compliance. The modified release drug delivery systems are one of the most promising delivery systems to achieve
this goal but the main disadvantage of these systems are that there is always a risk of dose dumping. This can be reduced by
formulating the drug as multi-particulate drug delivery systems. They reduce the dose dumping, have a flexibility of achieving
combination of different release patterns with reproducible and little gastric residence (1). Multi-particulate drug delivery systems are
oral dosage forms which have multiple small units of the drug delivery systems and each having desired characteristics. Thus in multiparticulate drug delivery systems the active ingredient is present in multiple number of small independent units (2). Some examples of
multi-particulate drug delivery systems are microcapsules, beads, pellets and granules (3).
Pellets are one of the most promising multi-particulate drug delivery systems but the main challenge lies in selecting the
manufacturing technique suitable to formulate pellets with desired characteristics. Various techniques used to manufacture pellets are
Solution/Suspension layering, Powder layering technique, Extrusion-Spheronization technique, Spray drying and spray congealing,
Melt-spheronization and Cryopelletization.
In this research article an attempt was made to compare two techniques, Solution/Suspension layering and ExtrusionSpheronization, to manufacture Sustained release pellets of ItoprideHCl pellets. The pellets were prepared by both the methods and
the pellet characteristics were compared to know which technique is more suitable to formulate ItoprideHCl pellets.
MATERIALS AND METHODS
Materials:
ItoprideHCl was obtained from Vasudhapharma chemicals, Hyderabad, AP. Microcrystailline cellulose (Avicel PH 101) was
obtained from FMC Biopolymers, Bangalore. Sugar Spheres (#25/30 and #30/40) and Talc were obtained from Signet Chemicals,
Mumbai. Povidone K-30 was obtained from BASF, Maharashtra. HPMC and EC were obtained from Colorcon, Verna, Goa. IPA,
Methylene Chloride and Acetone were obtained from Deepak Fertilizers and Chemicals, Hyderabad, Andhra Pradesh. Purified water
used was In-house.
Methods:
The preparation of SR pellets of ItoprideHCl was done in three steps.
1.
Preparation of Core drug pellets
2.
Preparation of Seal coated pellets
3.
Preparation of Sustained release pellets
The core drug pellets were prepared by the following methods: Extrusion-Spheronization and Solution/Suspension layering technique.
Extrusion–Spheronization method[4, 5]:
This technique was optimized with respect to the proportion of diluents, spheronization speed, spheronization residence time
(dwell time) and concentration of binder.Pellets were prepared using Itopride hydrochloride with microcrystalline cellulose as
diluents, povidone in purified water and/or iso-propyl alcohol solution as binder. Initially the excipients were weighed accurately and
microcrystalline cellulose and ItoprideHCl were mixed uniformly and simultaneously the binder solution was prepared using
Povidone as binder in water and/or isopropyl alcohol. Then the dry blend was granulated using the binder solution in the rapid mixer
granulator until the granulation end point was reached. Then the granules were transferred into the extruder to obtain uniform
extrudes, followed by Spheronization leading to formation of uniform spherical pellets. The obtained pellets were dried in a rapid drier
and used for further coating.
Table 1:Composition for Extrusion-Spheronization technique
Ingredients
ItoprideHCl
Avicel PH 101
Povidone K-30
Solvent
( IPA or Purified Water)
F-1
150.00mg
59.64mg
11.00mg
Purified water
F-2
150.00mg
64.46mg
6.00mg
Purified water
F-4
150.00mg
59.64mg
11.00mg
IPA
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1545
Process Parameters:
Dry blending:
Time: 2 min.
Impeller speed: 120 rpm.
Chopper speed: Off.
Granulation and Kneading:
Time: 1 min 20 sec.
Impeller speed: 120 rpm.
Chopper speed: 2500 rpm.
F-3
150.00mg
64.46mg
6.00mg
IPA
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Vol 4, Issue 03, 2014.
Prateek Kulshrestha,et. al.
ISSN NO: 2231-6876
Extruder:
Mesh size: 0.8mm
Speed: 50-60 rpm
Spherodizer:
Plate specifications: 3.25mm checkered plate
Speed: 300-600 rpm
Solution / Suspension layering technique[4,7 and 11]:
In this method the drug was coated on the inert non-pareil seeds using the fluidized bed coater. Initially the drug
coating solution was prepared by dissolving povidone K-30 in a mixture of purified water and isopropyl alcohol (50:50)
using a mechanical stirrer until complete povidone has been dissolved. Then ItoprideHCl was dispersed in the povidone
solution followed by talc to obtain a homogenous dispersion. For the coating of the drug solution the required quantity of the
non-pareil seeds were taken in the fluidized bed processor bottom spray equipment and coated with the prepared drug coating
solution until required amount of drug loading has been achieved.
Table 2: Composition for Solution/ Suspension layering technique
Ingredients
F-5
F-6
ItoprideHCl
150.00mg
150.00mg
Sugar Spheres
(#25/30) 55.46mg (#25/30) 55.46mg
Povidone K-30
7.50mg
5.00mg
Talc
7.50mg
10.00mg
Purified water
q.s
q.s
Isopropyl Alcohol q.s
q.s
Coating parameters:
Inlet temperature: 30-34°C
Bed temperature: 25-30°C
Blower speed: 1500 – 1800 rpm
Atomization air pressure: 1.5 – 2 psi
Spray rpm: 1 – 2
The Core drug pellets were then seal coated using HPMC 5cps.
F-7
150.00mg
(#30/40) 37.46mg
23.00mg
10.00mg
q.s
q.s
F-8
150.00mg
(#30/40) 37.46mg
30.00mg
3.00mg
q.s
q.s
Coating of the core pellets with Seal coating polymer:
The seal coating of the core pellets was done to prevent any contact between the core pellets and the sustained release
polymer. The polymer used for the seal coating is HPMC 5cps. Initially the coating solution was prepared by dissolving HPMC in a
mixture of IPA and methylene chloride (50:50) using a mechanical stirrer. Then the core pellets were prepared by the prepared
solution using the fluidized bed coater bottom spray equipment. The core pellets were coated until the desired coating was achieved.
The seal coated pellets so obtained were weighed and used for SR coating.
Table 3:Composition for Seal coating
Qty
11.00mg
q.s.
q.s
Seal coating parameters:
Inlet temperature: 40-44°C
Bed temperature: 30-35°C
Blower speed: 1600 – 1800 rpm
Atomization air pressure: 1.5 – 2 psi
Spray rpm: 3 – 4
Coating time: 1-2 hours
The Seal coated pellets were then coated with different concentrations of sustained release polymer (Ethyl cellulose 7 cps).
Coating of the Seal coated pellets with SR coating polymer [6]:
The sustained release polymer used to prepare ItoprideHCl pellets is Ethyl cellulose 7cps. The SR coating solution was
prepared by dissolving the Diethyl Phthalate in a mixture of acetone and water (95:5) with a mechanical stirred and then ethyl
cellulose was added slowly with continuous stirring. The seal coated pellets were taken in the Fluidized bed coated bottom spray
equipment and then coated with SR polymer until required amount of coating was achieved.
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Ingredient
HPMC 5 cps
IPA
Methylene Chloride
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S.No.
1
2
3
Vol 4, Issue 03, 2014.
Prateek Kulshrestha,et. al.
ISSN NO: 2231-6876
Table 4:Composition for Sustained release coating
Ingredient
Ethyl cellulose 7cps
Diethyl phthalate
Acetone
Purified water
Table 5:Chromatographic conditions for dissolution
Column name
Flow rate
Mobile phase
Injection volume
Detection
Retention time
Phenomenexluna
(c18(2), 250*4.6mm, 5µm)
1.0ml/min
Methanol: water (80:20)
20µl
258nm
15mins
Table 6:Dissolution Parameters
Medium
Volume
Apparatus
Rotary speed
Temperature
Sampling points
Water
900ml
USP apparatus II (paddle)
50rpm
37±0.50C
60, 120, 240, 480, 720 mins
Procedure:
Inject 10µl of blank and sample separately into chromatographic column. Record and measure the peaks. Calculate the
percentage of ItoprideHCl released from the pellets by using the formula.
Content of Itopride (in %w/w) =
Where,
AT = Area of peak of Itopride in Chromatogram of the sample solution.
AS = Average area of Itopride peak in chromatogram of standard solution.
WS = Weight of Itopride working standard taken in mg.
P = Purity of Itopride working standard used.
T = Average weight of ItoprideHCl pellets.
L = Label claim of ItoprideHCl in %w/w.
358.43 = Molecular weight of Itopride.
394.93 = Molecular weight of ItoprideHCl.
Stability Studies [10]:
The selected formulations were packed in HDPE bottles and capped properly. They were then stored at 40±2°C and 75±5% RH
and Room temperature for 6 months and evaluated for their physical appearance, drug content and dissolution profile.
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3.
Characterization of SR Pellets:
Pellet size:The diameter of the final pellets was determined by using vernier calipers.
Assay: The prepared pellets were assayed for the drug content. The assay was done using UV-Visible
Spectrophotometer. The pellets were dissolved in water completely and then diluted appropriately. The absorptions for the
diluted samples were then measured at 258nm and the percentage drug content was calculated.
Dissolution[8, 9]: The dissolution of the prepared pellets was carried out using the HPLC apparatus using water as the
medium. USP apparatus II (paddle) was used to perform the dissolution. Periodically samples were taken and diluted
appropriately and 10µl of the diluted sample was injected into the column. The peaks were evaluated at 258nm.
Page
1.
2.
3%SR coating
5.7393 mg
1.205 mg
q.s.
q.s.
Vol 4, Issue 03, 2014.
Prateek Kulshrestha,et. al.
ISSN NO: 2231-6876
RESULTS
The SR pellets of ItoprideHCl were prepared by using the Extrusion-Spheronization and Solution/Suspension layering
technique. The prepared core pellets were then coated with HPMC 5 Cps and then finally coated with 3%Ethylcellulose 7 cps, as a
sustained release polymer.Formulation F3, F4 prepared using Extrusion-Spheronization and formulation F7, F8 prepared using
Solution/suspension layering technique were selected for comparison to decide which is a better method for formulation of
ItoprideHCl pellets.
Pellet size: The diameter of the final pellets was found to be in the range 0.95-1.05mm.
Table 7: Assay of the selected formulations
S.No.
Formulation
1
2
3
4
F3
F4
F7
F8
Percentage
Drug content (%)
100.2
101.2
98.8
99.6
Table 8: Dissolution of the selected formulations
Time (Hrs)
0
1
4
8
12
F3
0
17.3
38.7
51.2
60.4
F4
0
25.9
54.0
79.6
87.8
F7
0
20
43.2
56.4
62.3
F8
0
29.0
61.3
76.2
85.6
Table 9: Stability data of the finalized formulations
Dissolution
F4
F8
F4
F8
180 days
100.3%
99.1%
99.5%
100.7%
40±2oC/75%±5 RH
30 days 90 days
100.5% 100.1%
100.3% 99.4%
99.6%
99.8%
100.8% 100.2%
180 days
99.98%
98.9%
99.79%
99.4%
Figure 1: FTIR Graph of ItoprideHCl
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Assay
Room Temperature
30 days 90 days
100.5% 100.3%
100.1% 99.8%
99.8%
99.5%
101%
100.8%
Page
Time point
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Prateek Kulshrestha,et. al.
ISSN NO: 2231-6876
Figure 2:FTIR Graph of Placebo (mixture of excipients)
Figure3: Cumulative Drug release of selected formulations
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CONCLUSION
The SR pellets of ItoprideHCl can be prepared by using both Extrusion-Spheronization and Solution/suspension layering
technique. Formulation F4 prepared using Extrusion-Spheronization and formulation F8 prepared using Solution/suspension layering
technique showed good pellet characteristics. The pellets prepared from Extrusion-Spheronization had uniform drug content but had
poor surface quality and requires continuous monitoring of every processing parameters viz. granulation, extrusion, Spheronization
whereas the pellets prepared using solution/suspension layering technique had good surface quality but compromises uniform drug
distribution over the pellet and this technique is comparatively simpler requiring less monitoring over the processing parameters.
Each pelletization technique has their own advantages and limitations therefore the technique to be used has to be chosen very
carefully considering all the variables of that particular technique that may affect the product. A person skilled in the art may choose
the Extrusion-Spheronization technique over Solution/suspension layering because of its robustness.
The Extrusion-Spheronization technique should further be explored to so as to produce pellets with uniform drug content and good
surface qualities.
1549
DISCUSSION
The drug-excipient compatibility studies done by using FTIR, from the Fig 1 and 2 we can see that there is no interaction
between the drug and the selected excipients.
During comparison of the pellets prepared by two methods the pellets were compared for Assay and dissolution.
From the above results in the Table 7 we can see that the formulations F3 and F4 prepared from Extrusion-Spheronization have good
drug content and the Formulation F7 and F8 prepared from Solution/Suspension layering have poor drug content.
From the dissolution profile in Table 8 and Fig 3 it can be clearly seen that Formulation F4 and F8 gave better sustained release profile
when compared to other formulations.
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Prateek Kulshrestha,et. al.
ISSN NO: 2231-6876
ACKNOWLEDGEMENT
I sincerely thank to Mr. Arun Kumar Das ,Mrs. Mitali Dutta and Mrs. N. Srilakshmi for their constant support, encouragement
and flexible regarding my project study and also for providing the facilities to carry out the research work in Malla Reddy Pharmacy
College.
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