FORMULATION AND EVALUATION OF PRESS COATED TABLETS …

www.wjpr.net Vol 7, Issue 9, 2018.

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Naseeb et al. World Journal of Pharmaceutical Research

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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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 - - -



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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


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 (%)


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


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 -


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 (%)


2 0.3 0.25±0.09 0.29±0.05


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



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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


1736


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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