JPRHC
Research Article
SUSTAINED RELEASE ITOPRIDE HYDROCHLORIDE MATRIX TABLET
BHUPENDRA G.PRAJAPATI, NIKLESH PATEL, HITESH K. PATEL
For author affiliations, see end of text
This paper is available online at www.jprhc.com
ABSTRACT of the Sustained release formulation. 32 factorial designs
were applied to the polymer concentration that affects the
Oral route gets the highest priority for the drug release profile. Reduced equation for drug release at
delivery of the drug as well as better patient compliance in 2hr,6hr,and10hrwere
case of self delivery dosage formulation. The aim of 2
Q2 37.644 5.41X1 3.25X 2 2.017X1 ,
present investigation was undertaken with the objective of
2
formulating sustain release formulation of Itopride Q6 72.367 8.05 X 1 4.4 X 2 3.75 X 1 ,and
hydrochloride for oral drug delivery. Itopride hydrochloride
Q10 90.844 5.8 X1 2.633X 2 2.8 X1 X 2
is highly water soluble prokinetic drug.
respectively. Optimized batch F019 shows good tablet
Hydroxypropylmethylcellulose K4M (lower viscosity
properties like hardness(7-9kg/cm2), thickness(4.48mm),
grade) and K100M (higher viscosity grade) were used as a
friability(0.024%),assay(99.3%) and nearly similar drug
matrix forming agents to control the release of drug. HPMC
release profile to the targeted reference drug release profile
K4M and HPMC K100M were used individually as well as
and it was indicated by similarity factor (f2=86.04).
in combination with different proportion in the preparation
KEY WORDS: Itopride hydrochloride,
Hydroxypropylmethylcellulose (HPMC), Sustained release,
Prokinetic drug
JPRHC January 2010 Volume 2 Issue 1 75-83
JPRHC
Research Article
INTRODUCTION Microcrystalline Cellulose (pH 102) was purchased from
FMC Biopolymer, Shangai, China. Lactose (DCL 21) was
Oral route of drug administration is perhaps the purchased from DMV International, Veghel, Netherlands.
most appealing route for the delivery of drugs. Of the Pregelatinize Starch was purchased from Colorcon Asia
various dosage forms administered orally, the tablet is one Pvt. Ltd, Mumbai, India. Colloidal silicon dioxide was
of the most preferred dosage forms because of its ease of purchased from Cabot sanmar Ltd., Chennai, India.
manufacturing, convenience in administration, accurate Magnesium Stearate was purchased from Amishi drugs &
dosing, stability compared with oral liquids, and because it Chemicals, Ahmedabad, India.
[1-4]
is more tamperproof than capsules. Sustained release
drug system is “any drug or dosage form modification that Methods:
prolongs the therapeutic activity of the drug.”5 Ideally a
Drug excipients compatibility study
sustained release oral dosage form is designed to release
rapidly some pre determined fraction of the total dose in to
GI tract. This fraction (loading dose) is an amount of drug, API and excipients were been thoroughly mixed in
which will produce the desired pharmacological response predetermined ratio and passed through the 40# sieve. The
as promptly as possible and the remaining fraction of the blend was to be filled in transparent glass vials and were
total dose (maintenance dose) is then release at a constant closed with gray coloured rubber stoppers and further
[5-6]
rate. Hypromellose (Hydroxypropylmethylcellulose) is sealed with aluminum seal and charged into stress
widely used in oral, ophthalmic and topical pharmaceutical condition at 25ºCº±2°C / 60%RH± 5 % RH and 40ºC±2°C /
formulations.7 Itopride hydrochloride, a novel prokinetic 75%RH± 5 % RH. Similarly API was also kept at same
agent is best candidate for Gastro esophageal reflux disease condition as for the samples. Samples were withdrawn for
(GERD). Itopride 50mg is given thrice in a day along with analysis within two days of sampling date as per the
Proton pump inhibitor.8 By developing the sustain release compatibility study plan. Physical observation should be
formulation of Itopride hydrochloride, the frequency of done at every week up to 1 month and DSC studies were
drug administration can be reduce to once only to obtain carried out to determine the compatibility of excipients
good therapeutic response. The prepared formulation is with the drug.9
usually taken on an empty stomach about an hour before
Full Factorial Design:
meals and efficient to overcome GERD for 24 hr. Sustain
release formulation of Itopride hydrochloride gives better
After studying results from preliminary batches,
patient compliance by reducing dosage frequency.
2
3 full factorial designs were prepared as shown in table 1.
In this design 2 factors are evaluated, each at 3 levels, and
MATERIALS AND METHODS:
experimental trials are performed at all 9 possible
Material
Combinations. The amounts of matrixing agent, HPMC
K4M (X1), HPMC K100M (X2) were selected as
Itopride hydrochloride was received as a gift
independent variables. The Q2, Q6 and Q10 were selected as
sample from Cadila Healthcare ltd, Ankleshvar, India.
dependent variables.[10-12]
Hydroxypropylmethylcellulose (HPMC) K4M and K100M
were purchased from Dow Chemicals, India.
JPRHC January 2010 Volume 2 Issue 1 75-83
JPRHC
Research Article
Preparation of Itopride HCl SR Tablets: In-vitro dissolution profile of prepared Itopride HCl SR
Tablets
Itopride HCl SR Tablets were prepared by direct
compression technique as follow. Drug was passed through The release rate of Itopride HCl from SR tablets
40# sieve. HPMC K4M & HPMC K100M was passed was determined using United State Pharmacopoeia (USP)
through 30# sieve. All the other ingredients were passed XXIV dissolution testing apparatus II (paddle method). The
through 40 # sieve accept Mg Stearate which was passed dissolution test was performed using 900 ml of 0.1 N HCl
through 60# sieve. Itopride HCl, Lactose DCL 21 & MCC (PH=1.2), at 37°C ± 0.5°C at 50rpm. A sample (10 ml) of
Avicel pH102 were mixed in double cone blender for the solution was withdrawn from the dissolution apparatus
10minute at 18 RPM. Add polymer and colloidal silicon at different time interval. The samples were replaced with
dioxide into above mixture and again mixed for 10minute fresh dissolution medium of same quantity. Drug released
at 18 RPM. Add Mg Stearate into above mixture and mixed were analyzed at 258 nm wavelength using 0.1N HCl as a
it for 3minute at 18 RPM. The prepared blend was reference standard by Shimadzu UV1700 Double beam
compressed (14/32 diameter, flat punches) using 16 station Spectrophotometer, Shimadzu (Kyoto, Japan.). 14
tablet compression machine (Cadmach, Ahmedabad, India).
Evaluation of SR Tablets Comparison of dissolution profiles by statistical analysis
with marketed product
The tablet geometry was determined by a means
of Digital vernier calipers. Five tablets were used, and The similarity factor (f2) was defined by CDER,
average values were calculated. While the breaking FDA and EMEA as the “logarithmic reciprocal square root
strength (hardness) of five tablets was determined using the transformation of one plus the mean squared difference in
Benchsavertm Series type hardness tester and the average percent dissolved between the test and the reference
values were calculated. Twenty tablets of each formulation products”. Moore and Flanner give the model independent
were checked visually for any discoloration or surface mathematical approach for calculating a similarity factor f2
roughness in the tablet formulation. To study weight for comparison between dissolution profiles of different
variation test, twenty tablets of the formulation were samples. The similarity factor (f2) given by SUPAC
weighed using a Mettler Toledo electronic balance and the guidelines for modified release dosage form was used as a
test was performed according to the official method. The basis to compare dissolution profile. The dissolution
friability of twenty tablets was measured by Roche profiles of products were compared using f2. The similarity
friabilator for 4 minute at 25rpm for 100 revolutions. factor is calculated by following formula. 15
Accurately weigh twenty tablets placed into Roche
friabilator for 100 revolutions than dedust the tablets and
2 0.5
weigh.13 n
f2 50X log 1 1 wt Rt Tt X 100
n t 1
(2)
W0 W
% Friability 100
W0 Where, n is the number of dissolution time points
(1)
Rt – The reference profile at the time point t
JPRHC January 2010 Volume 2 Issue 1 75-83
JPRHC
Research Article
Tt - The test profile at the same point. Reproduce large scale batch F019 in blister pack
(PVDC – Alu blister packing), was placed for stability
A value of 100% for the similarity factor suggests that the
study at 40˚C/75% RH for 3 months. Sample was collected
test and reference profiles are identical. Values between 50
at every 1 month interval and evaluated for dissolution in
and 100 indicate that the dissolution profiles are similar
0.1N HCl, USP- II paddle apparatus, 50rpm. F2 value was
whilst smaller values imply an increase in dissimilarity
applied to stability study to show the effect of storage on
between release profiles. 16
in-vitro drug release of formulation.17
Accelerated Stability study
RESULT AND DISCUSSION: required quantity of lactose as a diluent, as it is well known
fact that the drug release is also dependent on the size and
Drug excipients compatibility study:
surface area of matrix tablets.
From the DSC Study and physical observation it
was concluded that there was no significant Drug- In-Vitro Drug release study
Excipient interaction found. There was no change in drug’s
The drug release profiles were characterized by
melting peak after the preparation of tablet. So we can
an initial burst effect Q2 i.e. initial 30-35% drug release
conclude that drug and other excipients were compatible
required in 2 hrs. The biphasic release is often observed
with each other in tablet dosage form.
from hydrophilic matrix systems. As the release rate
limiting polymer like HPMC changes from a glassy state to
Evaluation of SR Tablets
rubbery state, a gel structure is formed around the tablet
matrix, which considerably decreases the release rate of
The prepared tablet formulations as shown in
table.1 were evaluated for different parameters like drug since the drug has to diffuse through this gel barrier
hardness, friability, assay, weight variation. Results of into bulk phase. The strength of the gel depends on the
chemical structure and molecular size of the polymer. It is
these parameters were shown in table 2. Hardness of the
prepared tablets was found in range of 6-8 KP. All the known that higher viscosity grade polymer i.e. HPMC
tablet formulations showed acceptable pharmacotechnical K100M hydrates at faster rate and therefore, it is capable of
properties and complied with the in-house specifications forming gel structure quickly than a low viscosity grade
HPMC K4M polymer.
for weight variation, drug content, hardness, and friability.
The size and surface area were kept constant by adding
JPRHC January 2010 Volume 2 Issue 1 75-83
JPRHC
Research Article
Table 1. Formula of Factorial batches
Table 1. Formula of Factorial batches
Ingredients (%w/w)
MCC HPMC HPMC
Trials Lactose Colloidal
Itopride (Avicel K4M K100M Magnesium
Anhydrous Silicon Total
HCl PH DC DC Stearate
(DCL 21) Dioxide
102) Grade Grade
F01 47.29 20.71 10.00 5.00 15.00 1.00 1.00 100.00
F02 47.29 15.71 10.00 5.00 20.00 1.00 1.00 100.00
F03 47.29 10.71 10.00 5.00 25.00 1.00 1.00 100.00
F04 47.29 18.21 10.00 7.50 15.00 1.00 1.00 100.00
F05 47.29 13.21 10.00 7.50 20.00 1.00 1.00 100.00
F06 47.29 8.21 10.00 7.50 25.00 1.00 1.00 100.00
F07 47.29 15.71 10.00 10.00 15.00 1.00 1.00 100.00
F08 47.29 10.71 10.00 10.00 20.00 1.00 1.00 100.00
F09 47.29 5.71 10.00 10.00 25.00 1.00 1.00 100.00
Table 2. Evaluation of tablets of Factorial batches
Table 2. Evaluation of tablets of Factorial batches
Factorial Batches Hardness (kP) Thickness Friability (%) Avg. Wt. Assay (%)
(mm) (mg)
F01 7-8 4.66 0.045 351.3 99.8
F02 7-9 4.47 0.104 352.1 100.2
F03 6.5-8 4.43 0.128 350.1 100.1
F04 7-8 4.57 0.059 349.9 98.8
F05 7-8 4.58 0.002 350.4 98.7
F06 7-9 4.48 0.029 350.3 99.3
F07 7-9 4.41 0.019 351.2 99.4
F08 7-8 4.64 0.019 350.2 98.4
F09 7-8 4.62 0.052 350.4 99.3
JPRHC January 2010 Volume 2 Issue 1 75-83
JPRHC
Research Article
Table 3 Effect of independent variables on dependent variables by 3 2 full factorial of Itopride HCl Sustained release matrix tablet
Table 3. Effect of Independent variable on dependent variable by 3 2 full
factorial design of Itopride HCl Sustained release matrix tablet
Independent variable Dependent variable
Batch No.
X1 X2 Q2 (%) Q6 (%) Q10 (%)
F01 -1 -1 43.2 79.4 94.3
F02 -1 0 40.1 76.9 96.4
F03 -1 +1 38.2 73.5 93.5
F04 0 -1 40.1 75.2 90.4
F05 0 0 37.8 72.0 89.8
F06 0 +1 33.4 69.7 87.4
F07 +1 -1 32.9 67.9 87.8
F08 +1 0 31.0 60.7 85.8
F09 +1 +1 25.1 52.9 75.8
Real Value
Independent Variables
Low (-1) Medium (0) High (+1)
HPMC K4 M (X1) 5.0% 7.5 % 10.0 %
HPMC K100 M(X2) 15.0% 20.0 % 25.0 %
JPRHC January 2010 Volume 2 Issue 1 75-83
JPRHC
Research Article
Fig. 1 Comparative dissolution profile of Factorial batches of F01 to F09 and innovator
Fig. 2 Comparative dissolution profile of Accelerated stability study
JPRHC January 2010 Volume 2 Issue 1 75-83
JPRHC
Research Article
The drug release is significantly dependent on the Accelerated Stability study
proportion and type of the polymer used. HPMC K4M was Reproduce large scale batch F06 in blister pack (PVDC –
responsible for initial burst effect and HPMC K100M was Alu blister packing), was placed for stability study at
used to sustained drug release. Factorial batches formulated 40˚C/75% RH for 3 months. Sample was collected at every
using combination of HPMC K4M and HPMC K100M of 1 month interval and evaluated for dissolution in 0.1N HCl,
Itopride HCl SR tablet were evaluated for dissolution USP- II paddle apparatus, 50rpm. f2 value was applied to
study. Data of drug release are graphically represented in stability study to show the effect of storage on in-vitro drug
figure 1. f2 value of F01 to F09 batches are 50.89, 57.53, release of formulation. The results of accelerated stability
67.45, 64.87, 75.85, 86.04, 82.81, 74.71, 46.18. F06 batch studies were shown figure 2.
showing very good similarity to the innovator batch release
CONCLUSION
profile. (86.04)
Results of present study suggested that Itopride HCl
Effect of Independent variable on dependent variable
Sustained release matrix tablet can be successfully
The factorial batches were prepared by using independent formulated using combination of HPMC K4M (7.5%) and
variable, concentration of HPMC K4M(X1 )and HPMC HPMC K100M (25%). F06 Batch of Itopride HCL SR
K100M(X2) and its effect were check on dependent tablets were good in terms of tablet physical properties,
variable like Q2, Q6, and Q10.Factorial batches of Itopride minimum drug excipients incompatibility and nearly
HCl sustained release matrix tablets were evaluated for the similar drug release profile to that targeted release profile.
in-vitro drug release (table 3), the effect of the individual
polymer and combination of the polymers were studied.
JPRHC January 2010 Volume 2 Issue 1 75-83
JPRHC
Research Article
REFERENCES: 12) Box GEP, Behnken DW. Some new three level
designs for the study of quantitative variables,
1) Swamy PA, Areefulla SH, Shrisand SB, Gandra
Technometrics.1960; 2: 455–475.
S, Prashanth B. Orodispersible tablets of
13) The Indian Pharmacopoeia, 4th Edition, Ministry
meloxicam using superdisintegrant blends for
of Health and Family Welfare, Govt. of India.
improved efficiency. Ind J Pharm Sci. 2007;
The controller of publications, New
69(6):836-840.
Delhi.1996;:Volume II
2) Malke S, Shidhaye S, Kadam VJ. Formulation
14) The United States Pharmacopeia, 24th ed.; by
and evaluation of oxcarbazepine fast dissolving
authority of the United States Pharmacopeial
tablets. Ind J Pharm Sci. 2007; 69(2):211-214.
Convention, Inc.; printed by National Publishing:
3) Patel MM, Patel DM. Fast dissolving valdecoxib
Philadelphia, PA, 2000
tablets containing solid dispersion of valdecoxib.
15) Moore JW., Flanner HH., Mathematical
Ind J Pharm Sci. 2006; 68 (2): 222-226.
comparison of curves with an emphasis on in-
4) Khan S, Kataria P, Nakhat P, Yeole P. Taste
vitro dissolution profiles; Pharmaceutical
masking of ondansetrone hydrochloride by
Technology; 1996; 20(6); 64-74.
polymer carrier system and formulation of rapid
16) Paulo C, Manuel J, Sousa L. Modeling and
disintegrating tablets. AAPS Pharm.Sci.Tech.
comparison of dissolution profiles; European
2007; 8(2):E1-E7.
Journal of Pharmaceutical Science. 2001; 13:123-
5) Swarbrick J, Boylan JC. Encyclopedia of
133.
Pharmaceutical Technology.1990; 3:281-286.
17) ICH GUIDELINES Q1A (R2), Guidance for
6) Lee TW, Robinson JR, Remington: The science
industry, stability testing of new drug substance
and practice of pharmacy; Gennaro, Ed.;
and products (Available on: http://
Lippincott Williams and Wilkins: Baltimore;
http://www.ich.org).
2000; (2):903-929.
7) Sheskey Paul J, Rowe Raymond C, Owen Siaˆn AUTHOR AFFILIATIONS:
C,Handbook of pharmaceutical excipient, 5th ed;
S.K.Patel College of Pharmaceutical Education and
346-349.
8) Gupta S, Kapoor V, Kapoor B. Itopride: A Novel Research, Ganpat University, Kherva-382711, Mehsana,
Prokinetic agent; JK Science. A drug Review; Gujarat State, INDIA.
2004; 6(2): 106-108.
ADDRESS FOR COMMUNICATION:
9) Baertschi SW. Pharmaceutical stress testing,
predicting drug degradation. Taylor and Francis Bhupendra G Prajapati,
group. 2005: 344-350.
S.K.Patel College of Pharmaceutical Education and
10) Rekub K, Shaikh M. Statistical design of
experiments with engineering application. 172- Research, Ganpat University, Kherva-382711, Mehsana,
180. Gujarat State, INDIA.E-mail: bhupen_27@yahoo.co.in
11) William MK. Research methods knowledge base,
Phone: (O) 91-02762-286080, (R) 91-9925043272.
factorial design.2006.
JPRHC January 2010 Volume 2 Issue 1 75-83
