Formulation Development and Evaluation of Orodispersible Tablet of Omeprazole by Using
Co-Processed Superdisintegrant.
Sharad A. More, Shrinivas K. Mohite
Department of Quality
Assurance, Rajarambapu College of Pharmacy,
Kasegaon, Sangli, India.
ABSTRACT:
In the present study, novel
co-processed superdisintegrants were developed by
solvent evaporation method using crospovidone and crosscarmellose sodium in different ratios (1:1, 1:3 and
3:1) for use in the fast dissolving tablet formulations. The developed
excipients were evaluated for angle of repose, Carr’s index and Hausner’s ratio in comparison with physical mixture of superdisintegrants. The angle of repose of the developed
excipients was found to be <23o, Carr’s index in the range of
11-21% and Hausner’s ratio in the range of 1.13-1.6. ordispersible tablets of omeprazole were prepared using the above co-processed superdisintegrants and evaluated for pre-compression and
post-compression parameters. Based on in vitro dispersion time (approximately
21sec), promising formulation CP1 was tested for in vitro drug release pattern
in pH 6.8 Phosphate buffer, drug excipient
interaction (IR spectroscopy). Among the designed formulations, the formulation
(CP1) containing 6% w/w of co processed superdisintegrant
(1:1 mixture of crospovidone and croscarmellose
sodium) emerged as the overall best formulation based on drug release
characteristics in pH 6.8 phosphate buffer compared to commercial conventional
tablet formulation.
KEYWORDS: co-processed super disintegrant, Omeprazole, Oro dispersible
tablet, crospovidone and croscarmellose
sodium..
INTRODUCTION:
Oral
drug delivery has been known for decades as the most widely utilized route of
administration among all the routes that have been explored for the systemic
delivery of drugs via various pharmaceutical products of different dosage
forms.1 The reason that the oral route achieved such popularity may be
attributed to its ease of administration as well as the traditional belief that
by oral administration the drug is well absorbed as the food stuffs ingested
daily1. In fact, the development of pharmaceutical products for oral
delivery, irrespective of physical form involves varying extents of
optimization of dosage form within the inherent constraints of GI physiology.
Therefore, a fundamental understanding of various disciplines, including GI
physiology, pharmacokinetics, pharmacodynamics and
formulation design are essential to achieve a systemic approach to the
successful development of an oral dosage form. The more sophisticated a
delivery system, the greater is the complexity of these various disciplines
involved in the design and optimization of the system. Drug Delivery Systems
(DDS) are a strategic tool for expanding markets/indications, extending product
life cycles and generating opportunities2. DDS make a significant
contribution to global pharmaceutical sales through market segmentation, and
are moving rapidly. Drug delivery systems are becoming increasingly
sophisticated as pharmaceutical scientists acquire a better understanding of
the physicochemical and biochemical parameters pertinent to their performance.2
Recent advances in Novel Drug Delivery Systems (NDDS)
aim for the same by formulating a dosage form, convenient to be administered so
as to achieve better patient compliance
Pharmaceutical
technologists have put in their best efforts to develop a Fast Dissolving Drug
Delivery System, i.e Mouth Dissolving Tablet. Fast
dissolving tablets are also called as mouth-dissolving tablets, melt-in mouth
tablets, Orodispersible tablets, rapimelts,
porous tablets, quick dissolving etc. Fast dissolving tablets are those when
put on tongue disintegrate instantaneously releasing the drug which dissolve or
disperses in the saliva. The faster the drug into solution,
quicker the absorption and onset of clinical effect. Some drugs are
absorbed from the mouth, pharynx and esophagus as the saliva passes down into
the stomach. In such cases, bioavailability of drug is significantly greater
than those observed from conventional tablets dosage form. The advantage of
mouth dissolving dosage forms are increasingly being recognized in both,
industry and academics3. Their growing importance was underlined
recently when European pharmacopoeia adopted the term “Orodispersible
tablet” as a tablet that to be placed in the mouth where it disperses rapidly before
swallowing. According to European pharmacopoeia, the ODT should
disperse/disintegrate in less than three minutes. The basic approach in
development of FDT is the use of superdisintegrants
like cross linked carboxymethyl cellulose (croscarmellose), sodium starch glycolate
(primogel, explotab), polyvinylpyrollidone (polyplasdone)
etc, which provide instantaneous disintegration of tablet after putting on
tongue, their by release the drug in saliva. Co-processing is based on the
novel concept of two or more excipients interacting at the sub particle level,
the objective of which is to provide a synergy of functionality improvement as
well as masking the undesirable properties of individual. Co-processing
excipients leads to the formulation of excipient granules
with superior properties compared with physical mixtures of components or
individual components4-6.Omeprazole belongs to the drugs called
proton pump inhibitor (PPIs). The proton pump is the site within the stomach
cell where the hydrochloric acid is actually made and pumped out into the
stomach. the PPI
inhibits the formation of acid in the stomach 80 to 90 % if enough of
the drug has taken. omeprazole
is used in any condition where stomach acid is causing problem and tissue
injury. these include peptic ulcer in stomach and
duodenum ulcer and specially gastro esophageal reflux disease. In present work The concept of formulating fast dissolving tablets (FDT) of omeprazole using co-processed superdisintegrants
which increase the water uptake with shortest wetting time and thereby decrease
the disintegration time of the tablets by simple and cost effective direct
compression technique6-13.
MATERIALS
AND METHODS:
Materials:
Omeprazole active drug obtained
from gift sample from DR. Reddys lab. Hyderabad. The crospovidone and croscarmellose
sodium obtiained gift sample from Alkem
laboraties. And the mannitol,
talc, sodium lauryl sulphate,
avicel102, and aspartame obtained from Research lab fine chemical industries,
Mumbai.
Methods:
1. Preparation of Co-processed Superdisintegrants:
The
co-processed superdisintegrants were prepared by
solvent evaporation method. A blend of crospovidone
and croscarmellose sodium (in the ratio of 1:1, 1:3
and 3:1) was added to 10 ml of ethanol. The contents of the beaker (250 ml
capacity) were mixed thoroughly and stirring was continued till most of ethanol
evaporated. The wet coherent mass was granulated through # 44-mesh sieve. The
wet granules were dried in a hot air oven at 60º C for 20 minutes. The dried
granules were sifted through # 44- mesh sieve and
stored in airtight container till further use15-17.
2. Preparation of fast
dissolving tablets by direct compression method:
Fast
dissolving tablets of omeprazole were prepared by
direct compression. All the ingredients (except granular directly compressible
excipients) were passed through # 60-mesh separately. Then the ingredients were
weighed and mixed in geometrical order such as first the sodium lauryl sulphate, avicel (102), talc, mannitol
mixed properly then superdisintegrant(CP+CCS),
aspartame and Omeprazole added and compressed into
tablets of 200mg by direct compression method using 8 mm bi concave punches on
a ‘Rimek mini press 1’ a 10 station rotary
compression machine18-23.
Table No.:1.
Preparation Of Orodispersible
Tablet Of Omeprazole:
|
Ingredients
Mg/tablet |
Formulation
Code |
||||||
|
CP0 |
PM1 |
PM2 |
PM3 |
CP1 |
CP2 |
CP3 |
|
|
Omeprazole |
40 |
40 |
40 |
40 |
40 |
40 |
40 |
|
Superdisintegrant (CP+CCS) |
- |
6 |
6 |
6 |
6 |
6 |
6 |
|
Aspartame |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
|
Sodium lauryl sulphate (SLS) |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
|
Microcrystalline
cellulose (avicle 102) |
40 |
40 |
40 |
40 |
40 |
40 |
40 |
|
Talc |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
|
Mannitol |
112.5 |
106.5 |
106.5 |
106.5 |
106.5 |
106.5 |
106.5 |
|
Total wt (mg) |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
PM - Physical Mixture of crospovidone and croscarmellose sodium in different ratios (1:1, 1:3, 3:1),
CP – Coprocessed Superdisintegrants of crospovidone and
croscarmellose sodium in different ratios (1:1, 1:2, 1:3),
CP0 - Control formulation (without superdisintegrants),
CP - Crospovidone, CCS- Croscarmellose
sodium.
Evaluation of Orodispersible Tablet of Omeprazole24-28
1. Hardness:
A significant strength of ODT
is difficult to achieve due to the specialized processes and ingredients used
in the manufacturing. The limit of hardness for the ODT is usually kept in a
lower range to facilitate early disintegration in the mouth. The hardness of
the tablet may be measured using conventional hardness testers.
2. Friability:
To
achieve % friability within limits for an ODT is a challenge for a formulator
since all methods of manufacturing of ODT are responsible for increasing the %
friability values. Thus, it is necessary that this parameter should be
evaluated and the results are within bound limits (0.1-0.9%).
3. Wetting time and
water absorption ratio:
Wetting
time of dosage form is related to with the contact angle. Wetting time of the
ODT is another important parameter, which needs to be assessed to give an
insight into the disintegration properties of the tablet. Lower wetting time
implies a quicker disintegration of the tablet. The wetting time of the tablets
can be measured by using the simple procedure29. Five circular tissue papers of
10cm diameter are placed in a petridish. Ten
milliliters of water soluble dye solution is added to petridish.
A tablet is carefully placed on the surface of the tissue paper. The time
required for water to reach upper surface of the tablet is noted as the wetting
time. For measuring water absorption ration the weight of the tablet before
keeping in the petridish is noted (Wb). The wetted tablet from the petridish
is taken and reweighed (Wa).
The water absorption ratio, R can be the determined according to the following
equation.
R = 100 (Wa-Wb) / Wb
4. Moisture uptake
studies:
Moisture
uptake studies for ODT should be conducted to assess the stability of the
formulation. Ten tablets from each formulation were kept in a dessicator over calcium chloride at 370C for 24h. The
tablets were then weighed and exposed to 75% relative humidity, at room
temperature for 2 weeks. Required humidity was achieved by keeping saturated
sodium chloride solution at the bottom of the dessicator
for 3 days. One tablet as control (without super disintegrants)
was kept to assess the moisture uptake due to other excipients. Tablets were
weighed and the percentage increase in weight was recorded.
5. Disintegration test:
The
time for disintegration of ODTs is generally <1min and actual disintegration
time that patience can experience ranges from 5 to 30s. The standard procedure
of performing disintegration test for these dosage forms has several
limitations and they do not suffice the measurement of very short
disintegration times. The disintegration test for ODT should mimic
disintegration in mouth with in salivary contents.
6. Dissolution test:
The
development of dissolution methods for ODT is comparable to approach taken for
conventional tablets and is practically identical when ODT does not utilize
taste masking. Commonly the drugs may have dissolution conditions as in USP
monograph. Other media such as 0.1 N Hcl, pH 4.5 and
pH 6.8 buffers should be used for evaluation of ODT in the same way as their
ordinary tablet counterparts. Experience has indicated that USP 2 paddle
apparatus is most suitable and common choice for dissolution test of ODT
tablets, where a paddle speed of 50 rpm is commonly used. Typically the
dissolution of ODTs is very fast when using USP monograph conditions. Hence
slower paddle speeds may be utilized to obtain a comparative profile. Large
tablets approaching or exceeding one gram and containing relatively dense
particles may produce a mound in the dissolution vessel, which can be prevented
by using higher paddle speeds. These two situations expand the suitable range
of stirring to 25-75 rpm. The USP 1 (basket) apparatus may have certain
applications for ODT but is used less frequently due to specific physical
properties of tablets. Specifically tablet fragments or disintegration tablet
masses may become trapped on the inside top of the basket at the spindle where
little or no effective stirring occurs, yielding irreproducible results in
dissolution profile.
7. In-vitro dispersion
time:
Tablet
was added to 10 ml of phosphate buffer solution, pH 6.8 at 37+0.5ºc, Time
required for complete dispersion of a Tablet was measured.
Table
No.2. Evaluation of Powder Blend:
|
Formulation code |
Bulk density(g/cm3) (± SD), n=3 |
Tapped density(g/cm3) (± SD), n=3 |
Compressibility (%) (± SD),
n=3 |
Hausner’s ratio (±SD),n=3 |
Angle repose (θ) (±SD),n=3 |
|
CP0 |
0.42 (0.015) |
0.46 (0.005) |
13.11 (0.74) |
1.64 (0.62) |
26.26 (0.3) |
|
PM1 |
0.42 (0.02) |
0.47 (0.015) |
11.58 (0.912) |
1.51 (0.66) |
27.67 (1.4) |
|
PM2 |
0.45 (0.025) |
0.50 (0.020) |
13.48 (1.014) |
1.54 (0.68) |
25.92 (0.8) |
|
PM3 |
0.43 (0.015) |
0.48 (0.005) |
18.83 (1.448) |
1.13 (0.01) |
27.86 (0.7) |
|
CP1 |
0.43 (0.020) |
0.42 (0.020) |
12.48 (1.640) |
1.20 (0.02) |
23.99 (0.2) |
|
CP2 |
0.46 (0.026) |
0.43 (0.017) |
13.85 (0.741) |
1.48 (0.54) |
25.59 (0.6) |
|
CP3 |
0.42 (0.020) |
0.45 (0.015) |
21.29 (1.787) |
1.30 (0.03) |
27.8 (0.31) |
Table No. 3 Evaluation Of Post Compression Parameter
|
Formulation code |
Hardness test(kg/cm2) (± SD), n=5 |
Friability (%) (±SD), n=3 |
Thickness (mm) (±SD), n=5 |
Weight variation test(mg)(±SD), n=3 |
Drug content (%) (±SD),n=3 |
|
CP0 |
2.87
(0.017) |
0.31(0.030) |
3.68
(0.14) |
200
(1.73) |
97.48(0.998) |
|
PM1 |
2.96
(0.025) |
0.63
(0.045) |
3.69(0.093) |
202 (1.15) |
100.77(1.31) |
|
PM2 |
2.94
(0.043) |
0.40
(0.030) |
3.58
(0.078) |
198 (2) |
98.27(0.847) |
|
PM3 |
2.95
(0.022) |
0.55
(0.036) |
3.69
(0.092) |
199 (
2.08) |
99.70(1.55) |
|
CP1 |
3.04
(0.15) |
0.34
(0.047) |
3.72
(0.084) |
201
(0.56) |
99.21(0.847) |
|
CP2 |
2.91
(0.085) |
0.55
(0.109) |
3.71 (0.11) |
202 (1.73) |
98.74(1.160) |
|
CP3 |
3.24
(0.25) |
0.45
(0.035) |
3.71
(0.097) |
200
(1.52) |
100.48(0.960) |
RESULT AND DISCUSSION:
Co-processed
superdisintegrants were prepared by solvent
evaporation using crospovidone and croscarmellose sodium in different ratios (1:1, 1:3. and
3:1). The co-processed superdisintegrants were
evaluated for their flow and compression properties in comparison with physical
mixture of superdisintegrants. The angle of repose of
coprocessed superdisintegrants
was found to be <23o which indicate excellent flow in comparison to physical
mixture of superdisintegrants (<30o) due to
granule formation, Carr’s index in the range of 11- 21% and Hausner’s
ratio in the range of 1.13-1.6 shown in table no. 2
Orodispersible tablets of omeprazole obtained were of uniform weight (due to uniform
die fill), with acceptable variation as per IP specification i.e., below 7.5%.
Drug content was found to be in the range of 97 to 100%, which is within
acceptable limits. Hardness of the tablets was found to be in the range of
2.91-3.04 kg/cm2. Friability below 1% was an indication of good mechanical
resistance of the tablets. wetting time, which are important criteria for understanding
the capacity of disintegrants to swell in presence of
little amount of water were found to be in the range of 27-77 sec respectively. Among all the
designed formulations, formulation CP1 was found to be promising and displayed
an in vitro dispersion time of 21 sec, which facilitates its faster dispersion
in the mouth. Overall, the formulation CP1 containing 6% w/w of co-processed superdisintegrant (1:1 mixture of crospovidone
and croscarmellose sodium) was found to be promising
and has shown an in vitro dispersion time of 21 sec, wetting time of 27 sec and
when compared to the formulation PM1 containing 4% w/w of physical mixture of superdisintegrants (1:1 mixture of crospovidone
and croscarmellose sodium) which shows 34 sec, 36 sec
wetting time and 66% values respectively and control formulation (CPO) which
shows 99 sec, 105 sec and 45% values respectively for the above parameters 63%
drug release for control formulation and 85% drug release for physical mixture
of superdisintegrant is 94% within 15 minute. Shown in table no. 3.
All the formulations were evaluated for wetting time described in the
methodology. The average wetting time of all the formulation in the range 27-77second. The wetting time of batch CP1 is 27sec. and
is the lowest wetting time in all formulation batches. The wetting time of
physical mixture in the range
36-53sec. All the formulations were evaluated for the in vitro
dispersion time described in methodology. The average
dispersion time for all the batches in the range 21-64sec. The
dispersion time for all the co-processed superdisintegrant
batches in the range 21-36sec. in that the CP1 batch having the wetting time
21sec. The dispersion time for all physical mixture batches in the range
34-49sec.
In vitro dissolution test for Omeprazole Orodispersible tablet:
The drug release studies were performed by USP type 2 dissolution test
apparatus. The phosphate buffer pH 6.8 was used as dissolution medium. The
temperature and speed of apparatus were maintained at 37±0.50 and 50
rpm respectively. The sample were withdrawn at predetermined time interval and
analyzed for drug concentration at 302nm by using UV- visible spectrophotometer
after filtrations were taken triplicate.
Table no.:4. Result of evaluation of wetting time and dispersion time
of orodispersible table
|
Formulation Code |
Wetting time(sec.)
(±SD), n=3 |
In vitro dispersion Time(sec.) (±SD), n=3 |
|
CP0 |
77(1.52) |
64 (2.64) |
|
PM1 |
36 (1.0) |
34 (2.0) |
|
PM2 |
42 (0.57) |
44 (1.52) |
|
PM3 |
53 (1.52) |
49 (1.0) |
|
CP1 |
27 (1.0) |
21 (0.57) |
|
CP2 |
34 (0.57) |
28 (1.0) |
|
CP3 |
41 (2.0) |
36 (0.57) |
Figure No.:1.Dissolution profiles of Orodispersible
tablet of Omeprazole formulation (CP0-CP3)
Table No.:5. In vitro dissolution data:
|
Time (min) |
Percent Cumulative
Drug Release |
||||||
|
Batch Code |
C0 |
PM1 |
PM2 |
PM3 |
CP1 |
CP2 |
CP3 |
|
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
32.125±1.34 |
56.62±0.48 |
52.87±0.710 |
52.65±1.09 |
60.75±1.39 |
52.72±1.2 |
52.72±1.05 |
|
4 |
45.056±0.74 |
67.88±0.285 |
55.56±0.732 |
58.12±0.994 |
67.43±1.76 |
57.59±0.9 |
58.49±0.99 |
|
6 |
49.880±1.29 |
75.39±0.935 |
60±1.03 |
62.93±0.767 |
73.72±1.24 |
60.46±0.7 |
62.64±1.32 |
|
8 |
53.38±1.10 |
79.40±1.06 |
62.50±1.27 |
66.89±1.21 |
82.670±1.27 |
62.75±1.1 |
65.05±0.98 |
|
10 |
60.197±1.83 |
82.84±0.71 |
67.12±0.399 |
69.43±1.33 |
91.22±0.33 |
68.11±1.1 |
67.95±1.25 |
|
15 |
63.376±1.10 |
85.54±1.10 |
70.71±0.675 |
72.061±1.00 |
99.21±0.178 |
70.58±1.0 |
71.28±0.39 |
|
20 |
71.40±0.995 |
86.89±1.47 |
73.26±1.28 |
73.561±1.30 |
101.78±1.14 |
75±1.46 |
74.85±1.41 |
|
25 |
74.520±1.12 |
87.65±1.17 |
76.72±1.28 |
76.87±1.52 |
- |
76.21±1.0 |
77.47±1.24 |
|
30 |
78.014±1.96 |
94.15±0.59 |
78.43±1.03 |
78.59±0.59 |
- |
81.40±0.8 |
80.25±1.22 |
The % drug release for the batch CP0 (without superdisintegrant)
within 15 minutes is 63.37%, the percent drug release for the physical mixture
batches PM1, PM2 and PM3 within 15 minutes are 85.54%, 70.71%, and 72.06 and
the percent drug release for the co-processed superdisintegrant
batches CP1, CP2, CP3 are 99.21%, 70.58%, 71.28%.
From above results the co-processed superdisintegrant
shows maximum release of drug. CP1 is the optimized batch showing 99.21%
release within 15 minutes. So CP1 batch shows maximum release of drug.
CONCLUSION:
Co-processed superdisintegrants
consisting
of crospovidone and croscarmellose
sodium exhibit good flow and compression characteristics. Orodispersible tablets of Omeprazole containing co-processed superdisintegrants exhibit quick disintegration and
improved drug dissolution. It can be concluded from the present work that
co-processed superdisintegrants of crospovidone and croscarmellose sodium are superior to
physical mixtures of crospovidone and croscarmellose sodium.
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and Bhagwati ST. Orodispersible
tablets: New fangled drug delivery system: A review. Indian J Pharm Educ 2005; 39(4):177.
Received on 23.06.2012
Accepted
on 20.07.2012
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A&V Publication all right reserved
Research Journal of Pharmaceutical Dosage Forms and
Technology. 4(4): July-Aug. 2012,
216-220