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FORMULATION AND EVALUATION OF PRESS COATED TABLETS
OF ESOMEPRAZOLE
Naseeb Basha Shaik*1, Gundogiwar Pooja Rani
1, Latha Kukati
1 and Pallavi Kanagala
1
1G. Pulla Reddy College of Pharmacy, Mehdipatnam, Hyderabad, Telangana-500028, India.
ABSTRACT
The objective of the present study is to prepare and evaluate press
coated tablets of esomeprazole by using press coating technique.
Esomeprazole magnesium trihydrate is a proton pump inhibitor,
degrades in acidic environment, hence protection of drug is done by
coating the drug with retardant coating polymers. Presscoated tablets
contains two layers esomeprazole core tablets prepared by direct
compression and core tablets were coated by using different weight
ratios and combinations of hydrophobilc polymer like ethyl cellulose
and hydrophilic polymers such as HPMC E15 and HPMC K4M as a
coating layer. Among the various formulations, F5 formulation
containing ethyl cellulose: HPMC E15 (10:90) and F9 formulation containing ethyl cellulose:
HPMC K4M (20:80) were optimized based on their better drug release within 8 hrs. The
optimized formulation complied with the ICH stability testing guidelines, it showed that the
formulations were stable. Based on the results, the developed esomeprazole press coated
tablets delivered the drug in the intestine and protected the drug from degradation in acid
media.
KEYWORDS: Esomeprazole magnesium trihydrate, retardant materials, press coating &
direct compression.
INTRODUCTION
One of the challenges in pharmaceutical research is site targeted dosage form design for acid
liable drugs. These formulation can release active substance in the intestine through the press
coating to treat peptic diseases by improving the systemic absorption of the drugs, Which are
unstable in gastric juice or low pH conditions, thus must be protected from the gastric acid by
the coating with high pH soluble polymers or aqueous soluble polymers (press coated
World Journal of Pharmaceutical Research SJIF Impact Factor 8.074
Volume 7, Issue 9, 1711-1741. Research Article ISSN 2277– 7105
Article Received on
18 March 2018,
Revised on 08 April 2018,
Accepted on 28 April 2018
DOI: 10.20959/wjpr20189-12224
*Corresponding Author
Naseeb Basha Shaik
G. Pulla Reddy College of
Pharmacy, Mehdipatnam,
Hyderabad, Telangana-
500028, India.
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Naseeb et al. World Journal of Pharmaceutical Research
polymers) when given orally. These formulations can administer in the form of press coated
dosage form. It does not release the active substance until it reaches to the proximal part of
small intestine.[1,3]
Esomeprazole is s-isomer of omeprazole. It is benzimidazole derivative H2 receptor blocker.
Generally proton pump inhibitors are administered as an inactive prodrug form because these
are acid labile drugs. When present in the gastric fluids, the drugs will be degraded so, by
enteric-coating to avoid the acid degradation. When the press coating formulations are
passing through the stomach into the proximal intestine the drug will release immediately in
duodenum part of intestine by this formulation. Esomeprazole site of targeting is intestine for
treatment of peptic ulcer. Its half-life is 1.2 hours, so when conventional dosage form reaches
to the gastric fluids it will degrade by the gastric enzymes that problem is avoiding by the
press coated formulation.[4,6]
Press-coating technology
Press-coating, also referred to as double compression coating, compression coating, or dry
coating, is an old technique first proposed by Noyes in an 1896. An industrial application of
this technique was introduced during the period 1950–1960 to allow the formulation of
incompatible drugs.[7]
Press coating is a novel technology for the formulation of new DDS
systems have several advantages like to protect hygroscopic, light-sensitive, oxygen labile or
acid-labile drugs, this process does not require solvents, has a relatively short manufacturing
process and achieves a greater increase in mass of core tablet than solvent-based methods, to
separate incompatible drugs from each other and achieve sustained release, to modify drug
release pattern (delayed, pulsatile and programmable release for different drugs in one tablet),
it is also possible to produce combination dosage forms, in which two active substances
target different areas of the gastrointestinal tract.[7,8]
MATERIALS AND METHODS
Materials
Esomeprazole magnesium trihydrate was obtained as gift sample from Finosa Pharma Pvt.
Ltd., Hyderabad, India. HPMC K4M, Micro Crystalline Cellulose, Croscarmellose Sodium,
Polyvinyl Pyrrolidone were obtained from Yarrow chem industries, Mumbai, India. Sodium
Starch Glycolate, Potassium di-hydrogen ortho phosphate, di-sodium hydrogen ortho
phosphate, concentrated HCl, magnesium stearate and methanol were obtained from S.D fine
chemicals, Mumbai, India.
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METHODOLOGY[9,56]
Drug-Excipient compatibility studies by FTIR
Fourier Transforms Infrared Spectroscopy: This study was performed to ensure the
compatability between excipient and drug. Fourier transform infrared (FT-IR 8400s,
Shimadzu, Japan) spectra were obtained for pure drug esomeprazole and liquid FT-IR studies
were carried out to the prepared formulations with different excipients and their
compatability was checked. Spectrum of drug was obtained using the potassium bromide disc
method. The pellet was prepared with the dry samples by applying 10 tons/inch2 pressure for
10 min.
DSC studies
DSC studies were carried out to investigate and predict any physiochemical interactions
between the drug and the excipients. DSC was performed using Shimadzu, DSC- 60
(Shimadzu, Japan). 2 mg of sample was placed in a 50 µL perforated aluminium pan and
sealed. Samples were allowed to equilibrate for 1 min and then heated in an atmosphere of
nitrogen over a temperature range from 5ºC to 300ºC. Nitrogen was used as a purge gas, at
the flow rate of 20 ml/min for all the studies.
Preparation of Esomeprazole presscoated tablets[9,21]
The preparation of esomeprazole presscoated tabletsinclude two steps 1) Preparation of inner
core tablets prepared by using direct compression method 2) Preparation of press coated
tablets by using various polymers.
I) Preparation of Esomeprazole core tablets
The inner core tablets were prepared by using direct compression method and the
composition as shown in Table 1. Powder mixtures of esomeprazole, microcrystalline
cellulose (MCC), poly vinyl pyrrolidine (PVP) and sodium starch glycolyte (SSG) were dry
blended for 20 min, followed by addition of magnesium stearate and talc as lubricant.[48]
The
mixtures were then further blended for 10 min., 50 mg of resultant powder blend was
manually compressed using compression machine with 4.76 mm punch to obtain core tablets.
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Table 1: Composition of Esomeprazole core tablets.
S.No. Ingredients
(mg)
CT1
(mg)
CT2
(mg)
CT3
(mg)
CT4
(mg)
CT5
(mg)
CT6
(mg)
CT7
(mg)
CT8
(mg)
CT9
(mg)
1 Drug 20 20 20 20 20 20 20 20 20
2 MCC 26.5 26 25.5 26.5 26 25.5 26.5 26 25.5
3 CCS _ _ _ 1.5 1.5 1.5 _ _ _
4 PVP K30 1.5 1.5 1.5 _ _ _ _ _ _
5 STARCH _ _ _ _ _ _ 1.5 1.5 1.5
6 SSG 1.75 2.25 2.75 1.75 2.25 2.75 1.75 2.25 2.75
7 Mg stearate 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25
8 Total tablet weight (mg) 50 50 50 50 50 50 50 50 50
Table 2: Different coating combinations of core tablets.
S.No. Formulation Ethyl cellulose (mg) HPMC E15 (mg) HPMC K4M (mg)
1 F1 100 - -
2 F2 50 50 -
3 F3 30 70 -
4 F4 20 80 -
5 F5 10 90 -
6 F6 - 100 -
7 F7 - - 100
8 F8 10 - 90
9 F9 20 - 80
10 F10 50 - 50
11 F11 70 - 30
12 F12 80 - 20
Pre compression Studies[56]
The powder mixture was evaluated for various parameters like bulk density, tapped density,
angle of repose, carr’s compressibility index and Hausner ratio.
Post compression studies
The prepared core and press coated tablets were evaluated for weight variation test, hardness,
friability, thickness whereas disintegration time and drug content were evaluated only for the
core tablet.
Pre compression parameters
Bulk density (*b)
Accurately weighed quantity of powder was carefully poured into the graduated cylinder and
volume was measured as which is called bulk density. The bulk density was calculated by
using below mentioned formula, The increase in bulk density of a powder is related to its
cohesiveness.
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*b=M/V* ---------------- Equation 1
Where, M is Mass of the blend, V* is Untapped volume
Tapped density (*t)
10 grams of powder was introduced into a clean, dry 100ml measuring cylinder. The cylinder
was then tapped 50 times from a constant weight in a tap density tester and tapped volume
was read. The tapped density was calculated using the following formula,
*t = M / V ---------------- Equation 2
Where, M is Mass of the blend, V is Tapped volume
Angle of Repose (θ)
It is defined as the maximum angle possible between the surface of pile of the powder and the
horizontal plane. Open ended cylinder method was used. Angles less than 30 are usually
indicative of good flow, while powders with angles greater than 40 are likely to be
problematic.
Tan θ = h / r (or) θ = tan -1
(h / r) ---------------- Equation 3
Where, θ is Angle of repose h is Height of pile r is Radius of the base of the pile.
Table 3: Flow properties and corresponding angle of repose.
Flow Property Angle of Repose „θ‟(degrees)
Excellent 25–30
Good 31–35
Fair - aid not needed 36–40
Passable - may hang up 41–45
Poor - must agitate, vibrate 46–55
Very poor 56–65
Very very poor >66
Carr‟s compressibility Index and Hausner‟s Ratio: Compressibility indices are a measure
of the tendency for arch formation and the ease with which the arches will fall and, as such, is
a useful measure of flow. Hausner’s ratio is an indirect index of ease of powder flow Carr’s
index is calculated as follows,
I = (Dt – Db) /Dt X 100 ---------------- Equation 4
Where Dt Where, Dt is Tapped density Db is Bulk density
Hausner‟s ratio = tapped density/ bulk density
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Table 4: Relation of flow property with Carr‟s compressibility index & Hausner‟s ratio.
Carr‟s compressibility
Index (%) Flow Character Hauser‟s Ratio
10 Excellent 1.00–1.11
11–15 Good 1.12–1.18
16–20 Fair 1.19–1.25
21–25 Passable 1.26–1.34
26–31 Poor 1.35–1.45
32–37 Very poor 1.46–1.59
>38 Very very poor >1.60
Post-compression parameters
Weight variation test
Twenty tablets were randomly selected and average weight was determined. Then individual
tablets were weighed and percent deviation from the average was calculated (Table 5).
Thickness
The thickness of tablet is measured by screw gauge. The thickness of the tablet is related to
the tablet hardness. Tablet thickness should be controlled within a ± 5% variation of a
standard value. In addition, thickness must be controlled to facilitate packaging. The
thickness measure in milli meters.
Hardness
The strength of tablet is expressed as tensile strength (Kg/ cm2). The tablet crushing load,
which is the force required to break a tablet into pieces by compression.[50]
It was measured
using a tablet hardness tester (Monsanto hardness tester). Three tablets from each formulation
batch were tested randomly and the average reading noted.
Table 5: Percentage deviation allowed for the tablets (USP).
Pharmaceutical Form Avg. Weight % Deviation
Tablets
130 mg or less ±10
>130 mg to 324 mg ±7.5
>324 mg ±5
Friability
Friability of the tablets was determined using Roche Friabilator. This device consists of a
plastic chamber that is set to revolve around 25 rpm for 4 minutes dropping the tablets at a
distance of 6 inches with each revolution. Pre weighed sample of 20 tablets was placed in the
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friabilator and were subjected to 100 revolutions. Tablets were dusted using a soft muslin
cloth and reweighed. The friability (F %) is given by the formula.
F % = (1-W0 /W)×100 ---------------- Equation 5
Where, W0 is weight of the tablets before the test And W is the weight of the tablets after
test.
Disintegration time
Disintegration time was measured using a disintegration apparatus. Randomly six tablets
were selected from each batch for disintegration test. Disintegration test was performed in
900 ml 6.8 pH phosphate buffer at 37±0.5 0C temperature and at the rate of 30±2 cycles/min.
Assay
Twenty tablets were randomly selected and average weight was calculated. Tablets were
powdered in a glass mortar. Powder equivalent to 5 mg was weighed and dissolved in 100 ml
of 6.8 pH phosphate buffer in volumetric flask. This dispersion was filtered and 1.2 ml of the
above solutions were taken and diluted to 10 ml with distilled water.[50]
The absorbance of
this solution was determined at 278 nm against the blank. The percentage assay was
calculated.
Dissolution study
The release rate of Esomeprazole was determined using USP dissolution testing apparatus-2
(paddle method). The dissolution medium was 0.1 N HCl and 6.8 pH phosphate buffer. The
dissolution was performed at 37±0.50C temperature with 75 rpm. A sample (5ml) of the
solution was withdrawn from the dissolution apparatus hourly and the samples were replaced
with fresh dissolution medium. The samples were filtered and absorbance of these solutions
was measured at 276 nm and 278 nm using a UV- spectrophotometer.
Dissolution study
Acidic stage - Dissolution parameters
Medium : 0.1N HCl
Type of apparatus : USP –II (paddle type)
RPM : 75
Temperature : 37 ºC ± 0.5 ºC
Volume : 900ml
Time : 2 hrs
λmax :276 nm
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Buffer stage - Dissolution parameters
Medium : 6.8 pH phosphate buffer
Type of apparatus : USP –II (paddle type)
RPM : 75
Temperature : 37 ºC ± 0.5 ºC
Volume : 900ml
Time : 8 hrs
λmax : 278nm
Sem (Scanning Electron Microscopy)
The effect of coating on the morphology of the core tablet was observed using SEM. The
main objective of scanning electron microscopy is to study the different coating layers on
core tablet.[37]
Surface morphology
Surface Morphology and cross-sectional view of coated tablets were evaluated by SEM. The
surface should be uniform and the core tablet should be completely surrounded by the coat.
Kinetic Analysis of Dissolution Data (Model Dependent Method)
To analyze the in vitro release data various kinetic models were used to describe the release
kinetics. The zero order rate Equation 6 describes the systems where the drug release rate is
independent of its concentration.
C = K0 t ---------------- Equation 6
Where, K0 is zero-order rate constant expressed in units of concentration/time and t is the
time. In this graph is plotted between Cumulative % drug release vs. time (Zero order kinetic
model).
The first order equation 7 describes the release from system where release rate is
concentration dependent (Bourne, 2002).[53]
In this graph is plotted between log cumulative
of % drug remaining vs. time (First order kinetic model).
Log C = logC0 - K1 t / 2.303 ---------------- Equation 7
Where, C0 is the initial concentration of drug and K1 is first order constant.
Higuchi (1963) described the release of drugs from insoluble matrix as a square root of time
dependent process based on Fickian diffusion equation 8. In this graph is plotted between
Cumulative % drug release vs square root of time (Higuchi model).
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Q = KH t1/2
---------------- Equation 8
Where, KH is the constant reflecting the design variables of the system.
Korsmeyer and Peppas model
Korsmeyeret al (1983) derived a simple relationship which described drug release from a
polymeric system. To find out the mechanism of drug release, drug release data was fitted in
Korsmeyer Peppas model.
Mt / M∞= Ktn ---------------- Equation 9
Where Mt/M∞is fraction of drug released at time t, K is the release rate constant incorporating
structural and geometric characteristics of the tablet, and n is the release exponent. The n
value is used to characterize different release mechanisms which are given in Table 6.
A plot of log cumulative % drug release vs. log time was made. Slope of the line was n. The
n value is used to characterize different release mechanisms for the cylindrical shaped
matrices. In fickian diffusion drug release follows ficks law, anomalous transport (Non-
Fickian) refers to a combination of both diffusion and erosion controlled-drug release and
super case-II transport generally refers to the release by erosion of the polymeric chain
(Peppas, 1985).[53]
Table 6: Mathematical model or model dependent kinetics.
Model Equation Plot of graph parameters
Zero order Qt=Q0+K0t % drug release vs time K0-release rate constant
First order In Qt=InQ0+K1t Log % drug remaining vs time K1-release rate constant
Higuchi release Qt=KHt1/2
% drug release vs square root of time KH- Higuchi constant
Korsemeyer-peppas Qt/Q8=Kktn Log % drug release vs log time n- release exponent
Table 7: Interpretation of diffusion release mechanism from “n” values.
Release Exponent (n) Drug transport mechanism Rate as a function of time
<0.5 Fichian diffusion t-0.5
0.5<n<1.0 Anomalous transport tn-1
1.0 Case-II transport Zero order release
Higher than 1.0 Super case-II transport tn-1
Kinetic Analysis of Dissolution Data (Model Independent Kinetics[53]
A model independent approach was used to estimate the difference factor (f1) and similarity
factor (f2) to compare the dissolution profile of optimized formulation with the marketed
formulation. The marketed formulation RACIPER®20 (20 mg of Esomeprazole magnesium
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trihydrate (IP) was manufactured by Ranbaxy Laboratory limited (Mfg Lic.No.:2698458,
Mfg. date: 05/2015, Exp. date: 04/2017).
The difference factor calculates the percent difference between the two curves at each time
point and is a measurement of the relative error between the two curves. It is expressed as:
---------------- Equation 10
The similarity factor (f2) is used to compare the dissolution profile of each formulation with
that of the marketed formulation. In this approach, recommended by the FDA guidance for
the industry, when the value is between 50 and 100, the two profiles are nearly identical.
In dissolution profile, comparisons are made especially to assure similarity in product
performances. The regulatory interest is in knowing how similar the two curves are and to
have measure which is more sensitive to large differences at any particular time point.
10011log502
5.0
1
2n
t
tt TRn
f
---------------- Equation 11
Where, n = Number of time points, Rt =dissolution value of the reference batch at time t,
Tt=dissolution value of the test batch at same time point
Table 8: Comparison of dissolution profile.
Difference factor f1 Similarity factor f2 Inference
0 100 Dissolution profiles are identical
15 50 Similarity or equivalence of two profiles
A specific procedure to determine difference and similarity factors is as follows
1. Determine the dissolution profile of two products (12 units each) of the test (postchange)
and reference (prechange) products.
2. Using the mean dissolution values from both curves at each time interval, calculate the
difference factor (f1) and similarity factor (f2) using the above 12 equations.
3. For curves to be considered similar, f1 values should be close to 0, and f2 values should be
close to 100. Generally, f1values up to 15 (0-15) and f2values greater than 50 (50-100) ensure
sameness or equivalence of the two curves and, thus, of the performance of the test
(postchange) and reference (prechange) products.[50]
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This model independent method is most suitable for dissolution profile comparison when
three to four or more dissolution time points are available.
Significance and applications of similarity factor
The wide application of similarity factor signifies it as an efficient tool for comparison of
dissolution profiles. Similarity factor finds its main application as
Response or dependent variable usually for optimization purposes, e.g. to compare
manufacturing processes for establishing experimental conditions maximizing similarity
between formulations.
Part of a decision criterion to establish similarity of two formulations. The regulatory
suggestion ―decide similarity if (the sample) f2 exceeds 50‖ is applied in a literal sense.
Stability Study
The stability studies of prepared formulations were carried out at accelerated stability
condition (40°C±2ºC/ 75% ± 5% RH) as per ICH guidelines over a period of 3 months. The
changes in their physical appearance, average weight of tablets hardness, release profile and
the drug content were observed. If there are no significant changes in the physical as well as
chemical characteristics of the formulation. Then, it can be concluded from the results that
the developed tablets are stable.
RESULTS AND DISCUSSIONS[9,56]
Characterization of API
The description of the drug was observed visually. The solubility data reveals that the drug is
freely soluble and is a member of class III drugs according to the BCS classification. The
LOD data was observed indicating that the API is non-hygroscopic. The melting point of the
API was performed using Melting point apparatus (Table 9).
Table 9: Characterization of API.
S.No Test Specification Results
1
Organoleptic properties
Colour White to off-white White to off-white
Odour Odourless Odourless
Nature Amorphous Amorphous
2 Solubility slightly soluble in water slightly soluble in water
3 LOD NMT 0.5% of its weight 0.25%
4 Melting Point 155 0C 155
0C
5 Assay NLT 98.0% and NMT 102.0% 99.86%
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Determination of absorption maxima (λmax) of esomeprazole in 0.1N HCl
The analytical method development for Esomeprazole was performed for the determination
of absorption maxima using 30 µg/ml of standard solution on a double beam
spectrophotometer against 0.1N HCl as the blank.
Figure 1: Absorption spectra of Esomeprazole in 0.1 N HCl.
An absorption maximum (λmax) of 276 nm was observed as shown in the Figure 1.
Figure 2: Standard graph of Esomeprazole in 0.1 N HCl.
Determination of absorption maxima (λmax) of Esomeprazole in 6.8 pH phosphate buffer
The analytical method development for Esomeprazole was performed for the determination
of absorption maxima using 30 µg/ml of standard solution on a double beam
spectrophotometer against 6.8 pH phosphate buffer.
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Figure 3: Absorption spectrum of Esomeprazole in 6.8 pH phosphate buffer.
An absorption maximum (λmax) of 278 nm was observed as shown in the Figure 3.
Figure 4: Standard graph of Esomeprazole in 6.8 pH phosphate buffer.
Drug-excipient compatibility studies
Compatibility studies were carried out to study the possible interactions between
Esomeprazole and other inactive ingredients.
FT-IR spectrophotometric method
Esomeprazole compatibility with excipients was studied by FTIR. The IR spectroscopy was
obtained by a FTIR spectrophotometer (Shimadzu, Japan) using KBR pellets.[50]
The FTIR
spectra of pure drug with different excipients indicated that there was no drug – polymer
interactions.
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Figure 5: FTIR spectra obtained for pure drug.
Table 12: Interpretation of Esomeprazole IR graph.
S.No. Functional group Region in cm-1
1 C=C 1610
2 O-H 3220
3 C-H 2933
4 C-H 1477
5 C-N 1611
From Figure 5 and Table 12 characteristic peaks at 3220 cm-1 indicates O-H stretching
presence of amide group.
DSC (Differential Scanning Calorimetry)
To study drug-excipient compaibility between esomeprazole and excipients, DSC study was
conducted. Different samples such as esomeprazole, HPMC E15, HPMC K4M, ethyl
cellulose, optimized formulation F5 and F9 were examined by DSC.
100.00 200.00Temp [C]
-4.00
-3.00
-2.00
-1.00
0.00
mWDSC
77.30x100COnset
99.79x100CEndset
93.03x100CPeak
-63.68x100mJ
-10.61x100J/g
-15.21x100mcal
-2.54x100cal/g
Heat
117.78x100COnset
125.00x100CEndset
122.58x100CPeak
-5.01x100mJ
-0.84x100J/g
-1.20x100mcal
-0.20x100cal/g
Heat
136.55x100COnset
140.79x100CEndset
137.29x100CPeak
-2.35x100mJ
-0.39x100J/g
-0.56x100mcal
-0.09x100cal/g
Heat
142.02x100COnset
158.84x100CEndset
151.96x100CPeak
-14.50x100mJ
-2.42x100J/g
-3.46x100mcal
-0.58x100cal/g
Heat
198.05x100COnset
214.03x100CEndset
207.84x100CPeak
204.44x100mJ
34.07x100J/g
48.84x100mcal
8.14x100cal/g
Heat
Esomeprazole 2016-07-06.tadDSC
Figure 6: DSC peaks of Esomeprazole.
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Figure 7: DSC peaks of HPMC E15.
100.00 200.00 300.00Temp [C]
-10.00
-5.00
0.00
mWDSC
165.42x100COnset
192.62x100CEndset
160.89x100CPeak
-29.20x100mJ
-4.87x100J/g
-6.98x100mcal
-1.16x100cal/g
Heat
Ethyl Cellulose 2016-07-06.tadDSC
Figure 8: DSC peaks of ethyl cellulose.
Figure 9: DSC peaks of HPMC K4M.
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100.00 200.00Temp [C]
-5.00
-4.00
-3.00
-2.00
-1.00
0.00
mWDSC
70.86x100COnset
91.35x100CEndset
88.18x100CPeak
-11.02x100mJ
-1.84x100J/g
-2.63x100mcal
-0.44x100cal/g
Heat
Esomeprazole+HPMCE15+EC 2016-07-06.tadDSC
Figure 10: DSC peaks of formulation F5.
100.00 200.00Temp [C]
-6.00
-5.00
-4.00
-3.00
-2.00
-1.00
0.00
mWDSC
68.70x100COnset
86.29x100CEndset
82.06x100CPeak
-19.45x100mJ
-3.24x100J/g
-4.65x100mcal
-0.77x100cal/g
Heat
133.45x100COnset
151.47x100CEndset
127.31x100CPeak
-10.84x100mJ
-1.81x100J/g
-2.59x100mcal
-0.43x100cal/g
Heat
Esomeprazole+HPMCK4M+EC 2016-07-06.tadDSC
Figure 11: DSC peaks of formulation F9.
Thermal behaviour of pure esomeprazole, ethyl cellulose, HPMC E15, HPMC K4M and their
physical mixture (formulation F5 and F9) are depicted in figure 6-11. The pure esomeprazole
showed melting endothermic peak at 177.30C which is also been reported by Achin Jain
et.al., in spray-dried esomeprazole magnesium microspheres.
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The endothermic peak for the drug in physical mixture, showed minor changes in the melting
endotherm of drug could be due to the mixing of drug and excipients, which lower the purity
of each component in the mixture and may not necessarily indicates potential incompatibility.
Evaluation of Core Tablet
Pre compression parameters of core tablets
The physical properties like bulk density, tapped density, Carr’s compressibility index,
Hausner’s ratio and angle of repose for esomeprazole and mixture of excipients and
esomeprazole blend are shown in table.
Figure 12: Cross section of press coated tablet.
(a) T.S. view of press coated tablet (b) L.S. view of press coated tablet.
Table 13: Pre compression parameters of core tablets.
Formulation
Bulk
density
(gm/cc)
Tapped
density
(gm/cc)
Carr‟s
Compressibility
Index (%)
Hausner's
ratio
Angle of
repose (θ)
CT1 0.260±0.54 0.343±0.13 24.19±0.99 1.31±0.23 25.4±0.36
CT2 0.308±0.02 0.378±0.48 18.5±0.28 1.22±0.34 27.74±0.8
CT3 0.327±0.76 0.401±0.06 18.4±0.28 1.22±0.34 30.1±0.17
CT4 0.289±0.54 0.366±0.17 21.0±0.32 1.26±0.36 28.8±0.68
CT5 0.309±0.43 0.389±0.59 20.5±0.44 1.25±0.09 27.4±0.14
CT6 0.322±0.29 0.425±0.93 24.2±0.9 1.3±019 26.5±0.43
CT7 0.326±0.21 0.398±0.25 18.0±0.20 1.22±0.84 33.4±0.24
CT8 0.289±0.19 0.344±0.93 15.9±0.07 1.19±0.41 37.2±0.44
CT9 0.312±0.12 0.408±0.03 23.5±0.03 1.30±0.44 24.2±0.76
All the values expressed as Mean±SD, n=3
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Table 14: Cumulative percentage release of core tablets.
Time (min) CT1 (%) CT2 (%) CT3 (%) CT4 (%) CT5 (%) CT6 (%) CT7 (%) CT8 (%) CT9 (%)
1 11.1±0.6 29.52±0.04 36.65±0.5 57.25±1.0 65.25±0.2 12.46±0.6 15.2±0.25 28.01±0.11 41.53±0.01
3 31.28±0.5 54.09±0.2 77.25±0.3 72.03±0.1 83.24±0.4 31.18±0.5 34.25±0.31 47.96±0.02 82.08±0.16
5 56.03±0.9 83.75±0.1 92.68±0.2 101.3±0.3 92.53±0.2 46.96±0.3 61.08±0.19 79.62±0.31 96.20±0.56
10 78.59±0.7 102.37±0.3 - - 101.56±0.6 61.68±0.1 84.03±0.04 101.23±0.13 -
15 98.7±0.4 - - - - 83.43±0.5 98.21±0.29 - -
20 - - - - - 99.4±0.8 - - -
All the values expressed as Mean±SD, n=3
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Figure 13: Dissolution profile of core tablets.
Table 15: Pre compression parameters of press coated tablets.
Formulation Bulk density
(gm/cc)
Tapped
density
(gm/cc)
Compressibility
Index
(%)
Hausner's
ratio
Angle of
repose
Drug+EC+ HPMC E15 0.32±0.12 0.37±0.3 11.89±0.2 1.13±0.1 250±0.5
Drug+EC+ HPMC K4M 0.31±0.05 0.36±0.2 11.87±0.1 1.13±0.5 260±0.6
Drug +Ethyl cellulose 0.35±0.01 0.40±0.1 14.21±0.5 1.16±0.6 250±0.3
All the values expressed as Mean±SD, n=3
Table 16: Post compression parameters of press coated tablets.
Formulation Weight variation
a
(%) Assay
b (%)
Hardnessc
(kg/cm2)
Thicknessd
(mm)
Friabilitye
(%)
F1 2.5±0.08 90.4±0.45 5.0±0.01 4.53±0.05 0.71±0.01
F2 2.6±0.07 94.86±0.57 4.9±0.04 4.32±0.01 0.80±0.02
F3 3.8±-0.06 87.6±0.90 4.8±0.02 4.50±0.04 0.68±0.07
F4 3.9±0.06 92.06±0.91 5.3±0.02 4.26±0.04 0.54±0.04
F5 4.2±0.07 95.14±0.22 4.9±0.02 4.2±0.05 0.86±0.06
F6 3.82±0.05 98.45±0.55 5.4±0.04 4.32±0.04 0.82±0.04
F7 3.86±0.06 99.13±0.56 4.9±0.02 4.34±0.03 0.87±0.07
F8 4.9±0.05 101.06±0.42 5.1±0.02 4.22±0.04 0.63±0.07
F9 3.9±0.05 87.8±0.51 4.5±0.02 4.16±0.03 0.69±0.02
F10 4.04±0.07 84.8±0.4 5.0±0.03 4.1±0.01 0.82±0.04
F11 3.98±0.06 90.96±0.6 4.7±0.02 4.26±0.04 0.96±0.04
F12 3.87±0.05 88.4±0.7 4.9±0.02 4.30±0.04 0.78±0.07
All the values are expressed as Mean ±SD. a: n=20, b, e: n=10, c, d: n=5.
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Table 17: Cumulative percentage release of F1-F6.
Time (hrs) F1 (%) F2 (%) F3 (%) F4 (%) F5 (%) F6 (%)
Dissolution in 0.1 N HCl
2 0.4±0.06 0.32±0.03 0.43±0.06 0.52±0.06 0.25±0.09 0.18±0.14
Dissolution in 6.8 pH buffer
3 10±0.08 5.7±0.12 15±0.06 24.4±0.09 14.7±0.03 36.5±0.09
4 17.6±0.06 12.3±0.06 23.7±0.12 55.2±0.07 20.4±0.15 64±0.06
5 21.8±0.04 23.2±0.09 33.7±0.07 76.3±0.15 32.1±0.12 88.6±0.1
6 43.4±0.11 42.9±0.07 45.7±0.03 79.8±0.09 64.7±0.06 102.6±0.2
7 52.8±0.06 53.1±0.15 60±0.08 83.6±0.14 78.9±0.03 -
8 64.7±0.09 64.0±0.13 74.2±0.05 95.5±0.11 98.6±0.11 -
9 69.4±0.04 73.9±0.11 95.5±0.15 102.01±0.16 - -
10 71.8±0.07 84.6±0.04 - - - -
All Values are expressed as Mean ± SD, n=3
Table 18: Cumulative percentage release of F7-F12.
Time (hrs) F7 (%) F8 (%) F9 (%) F10 (%) F11 (%) F12 (%)
Dissolution in 0.1 N HCl
2 0.21±0.05 0.4±0.06 0.29±0.05 0.37±0.03 0.4±0.10 0.43±0.15
Dissolution in 6.8 pH buffer
3 19.9±0.06 15±0.07 12.3±0.09 9.3±0.14 24.4±0.13 6.3±0.05
4 32.4±0.05 22.4±0.15 18.5±0.13 17.8±0.11 38.4±0.11 11.9±0.03
5 48.5±0.02 35.12±0.13 38.6±0.07 33.2±0.16 46.5±0.03 16.6±0.07
6 66.3±0.03 64±0.04 69.4±0.05 47.6±0.09 51.7±0.06 24.9±0.11
7 82.4±0.11 82.06±0.06 88.4±0.08 56.2±0.12 58.5±0.13 35.1±0.05
8 105.09±0.04 105.09±0.09 100.2±0.03 78.7±0.14 67.3±0.04 47.6±0.03
9 - 86±0.03 72±0.12 60.9±0.09 - -
10 - - 95.5±0.08 81.7±0.09 76.3±0.10 -
All Values are expressed as Mean ± SD, n=3
Figure 14: Dissolution profile of F1-F6.
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Figure 15: Dissolution profile of F7-F12.
Scanning Electron Microscopy
Obtained SEM photographs of optimized formulations F5 & F9 are shown in below Figure
16 and Figure 17.
Figure 16. SEM of formulation F5. Figure 17. SEM of formulation F9.
The effect of coating on the morphology of the core tablets was observed using SEM. The
main objective of scanning electron microscopy is to study the different coating layers on the
core tablet. Obtained SEM photographs of tablets coated with ethyl cellulose and HPMC E15
i.e. F5 and tablets coated with ethyl cellulose and HPMC K4M i.e. F9 are shown in Figure
16 and Figure 17. Form this we can observe that coating is uniform for both the optimized
formulations.
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Kinetic analysis of dissolution data (Model dependent method)[32,53]
The data obtained from in-vitro release studies of the entire formulations F1-F12 were fitted
to various kinetic equations such as zero order, first order, Higuchi's model and Korsemeyer -
peppas. The results are shown in Table 21.
Table 21: Drug release kinetics.
Batch Zero order first order Higuchi Korsemeyer-Peppas
Release mechanism R
2 R
2 R
2 R
2 n
F1 0.9692 0.851 0.9602 0.9643 1.075 Super case II
F2 0.9833 0.893 0.9568 0.9849 1.759 Super case II
F3 0.9823 0.863 0.9894 0.9625 1.430 Super case II
F4 0.8996 0.672 0.9464 0.8432 1.340 Super case II
F5 0.937 0.706 0.79 0.993 1.449 Super case II
F6 0.981 0.768 0.9956 0.884 1.26 Super case II
F7 0.9921 0.610 0.9674 0.9844 1.32 Super case II
F8 0.9631 0.724 0.9219 0.9853 1.752 Super case II
F9 0.8935 0.942 0.7569 0.9752 1.245 Super case II
F10 0.986 0.906 0.963 0.9882 1.61 Super case II
F11 0.928 0.712 0.9588 0.8318 1.32 Super case II
F12 0.953 0.9465 0.8989 0.9918 1.328 Super case II
Figure 18: Model dependent kinetic analysis for the dissolution profile of optimized
formulation F5.
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From the above table it was observed that the optimized formulation F5, ―n‖ value was found
to be 1.4497. The drug release was found to follow super case 2 transport. This value
indicates erosion mechanism. Also, the drug release mechanism was best explained by zero
order equation, as the plots showed the highest linearity (r2 =0.937), followed by korsemeyer
peppas equation (r2= 0.99). As the drug release was best fitted in zero order kinetics, it
indicated that the rate of drug release is concentration independent.
i
Figure 19: Model dependent kinetic analysis for the dissolution profile of optimized
formulation F9.
From the above table it was observed that the ―n‖ value of 1.245 obtained for F9 formulation,
the drug release was found to follow super case 2 transport. This value indicates erosion
mechanism. Also, the drug release mechanism was best explained by first order equation, as
the plots showed the highest linearity (r2 = 0.942), followed by korsemeyer peppas equation
(r2= 0.975). As the drug release was best fitted in first order kinetics, it indicated that the rate
of drug release is concentration dependent
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Kinetic analysis of dissolution data (Model independent kinetics)
Table 21: Calculation of similarity and dissimilarity factors for F5.
Time (hrs) n Marketed (%)(Rt) F5(Tt) (Rt-Tt) (Rt-Tt)²
2 0.3 0.25 0.5 1
3 12.7 14.7 -2 4
4 37.3 20.4 16.9 285.61
5 49.8 32.1 17.7 313.29
6 68.7 64.1 4.6 21.16
7 86 78.9 7.1 50.41
8 101.4 98.6 2.8 7.84
Table 22: Calculation of similarity and dissimilarity factors for F9.
Time (hrs) n Marketed (%)(Rt) F9(Tt) (Rt-Tt) (Rt-Tt)²
2 0.3 0.29 0.1 0.01
3 12.7 12.3 0.4 0.16
4 37.3 18.5 18.8 353.44
5 49.8 38.6 11.2 125.44
6 68.7 69.4 -0.7 0.49
7 86 88.4 2.4 5.76
8 101.4 100.2 1.2 1.44
Table 23: Similarity & Dissimilarity Factors.
Formulations F1 value F2 value
F5 12.4 73
F9 9.6 53
Table 24: Comparative dissolution studies of marketed tablet (Raciper-20) with
optimized formulations F5 and F9.
Time (hrs) Marketed (%) F5 (%) F9 (%)
Dissolution in 0.1 N HCl
2 0.3 0.25±0.09 0.29±0.05
Dissolution in 6.8 pH buffer
3 12.7 14.7±0.03 12.3±0.09
4 37.3 20.4±0.15 18.5±0.13
5 49.8 32.1±0.12 38.6±0.07
6 68.7 64.7±0.06 69.4±0.05
7 86 78.9±0.03 88.4±0.08
8 101.4 98.6±0.11 100.2±0.03
All Values are expressed as Mean ± SD, n=3
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Figure 20: Comparative dissolution studies of marketed tablet (Raciper-20) with
optimized formulations F5 and F9.
Stability Studies for Opimized Formulations
Table 25: Stability study (40°C±2ºc/75% ± 5% RH) of optimized F5 formulation.
Parameters Optimized F5 formulation Optimized F9 formulation
Initial 30 days Initial 30 days
Physical appearance white white white white
Weight variation (%) 4.2±0.07 4.2±0.07 3.9±0.05 3.9±0.05
Hardness (kg/cm2) 4.9±0.02 4.9±0.02 4.5±0.02 4.5±0.02
Friability (%) 0.86±0.06 0.86±0.06 0.69±0.02 0.67±0.01
In-vitro release (%) 98.6% 96.7% 102.2% 98.9%
All Values are expressed as Mean ± SD, n=3.
The stability studies of optimized formulation F5 and F9 was carried out at 40°C±2ºC/75% ±
5% RH as per ICH guidelines over a period of one month.[48]
There is no significant change
in their physical appearance, average weight of tablets and hardness. The release profile and
the drug content also not showed any significant changes indicating that there were no
changes in the physical as well as chemical characteristics of the formulation. Hence, it can
be concluded from the results that the developed tablets were stable and retain their
pharmaceutical properties over a period of one month. The results are shown in Table 25.
CONCLUSION
Esomeprazole is an acid liable drug which degrades at acidic pH of stomach. In order to
delay the release in the stomach and promote the drug release in the intestine, enteric coating
of the drug was attempted. An enteric coated delayed release formulation was successfully
formulated by press coating technique. FTIR characterization of drug with different
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excipients indicated that there was no drug-polymer interaction. DSC studies revealed that
the pure esomeprazole showed melting endothermic peak at 177.3ºC. Core tablets were
prepared by direct compression of a homogenous mixture of esomeprazole, PVP K30, SSG,
MCC, magnesium stearate and talc. Among them 3.5% SSG core tablet formulation was
optimized. Drug release was sustained by using ethyl cellulose. As the amount of ethyl
cellulose content increases drug release retardation occurs. Among the various formulations
F5 containing ethyl cellulose: HPMC E15(10:90) and F9 containing ethyl cellulose: HPMC
K4M (20:80) were optimized based on the better drug release within 8 hrs. For the optimized
formulations the drug release in 0.1 N HCl is 0.25% (F5) and 0.29% (F9), where as in 6.8 pH
buffer the percentage drug release was 98.6% (F5) and 100.2%(F9) which is obtained
according to USP limit-NMT 10% in 0.1N HCl and NLT 75% in 6.8 pH buffer. These both
formulations gave delayed release for 8 hrs. F5 followed zero order kinetics with super case-2
transport mechanism whereas; F9 followed first order kinetics with super case-2 transport
mechanism. Stability studies showed that the formulations were stable. Obtained SEM
photographs of tablets showed that core tablet is uniformly coated by coating layer by press
coating. The formulations are stable for one month in physically, chemically & potentially.
These formulations to be checked with two more months of stability studies & in-vivo studies
are required. The press coated tablets of esomeprazole is promosing dosage form for the
treatment of peptic ulcer, H.pylori eradication, Zollinger- Ellison syndrome etc.
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