“DESIGN AND EVALUATION OF BILAYER TABLETS OF CAPECITABINE

AND ONDANSETRON”

Register number: 261311006

DEPARTMENT OF PHARMACEUTICS Under the guidance of CHERRAAN’S COLLEGE OF PHARMACY Dr. N. THIRUMOORTHY, COIMBATORE-641039 M. PHARM, PH.D.,

  It comprises of two layers, one of which is sustained release of

Capacetabine and another one is immediate release of Ondansetron. Hence, it uses Dual Release Drug Absorption System(DUREDAS)

technology.

  To provide once a day dosage form for the treatment of nausea and

vomiting . As Capacetabine having shorter half life, bilayer tablet provide

extended release of Capacetabine . Hence reduce dose frequency. Also, Ondansetron formulated as an

immediate release part provides initial relief as is the case with loading dose in an extended release formulation.

Give additive effect of used both the drugs. Hence reduce dose dependent side -effects. Also, Ondansetron is able

to overcome the some side effects of Capacetabine. The process involves reduced manufacturing steps and manufacturing

time and finally makes a cost effective formulation 

1. AIM OF PRESENT WORK

2. BILAYER TABLET Bi-layer tablet which is made up of two Distinct layers.

compressed together with the individual layers lying one on top of Another.

The administration of sustained release preparation as one layer with the immediate release preparation as the second layer is possible. The separation of two incompatible substances with addition of any barrier layer between them is possible.

DUal RElease Drug Absorption System  (DUREDAS technology) is a bilayer tablet which can

provide immediate or sustained release of two drugs or different release rates of the same drug in one dosage form.

3. LITERATURE REVIEWResearcher Research Title

M.Sowmya, M.SarithaHas developed and optimized bilayered sustained release matrix tablets of Valsartan.

Pandey H developed sustained release bilayer tablet of domperidone using hydrophilic matrix material such as HPMC, carbapol and poly-ethylene oxide.

Shirwaikar A. formulated sustained release of Diltiazem hydrochloride tablets by utilizing the bilayer concept using matrix material rosin and ethyl cellulose.

Bhavesh Shiyani et al.

The aim of this study was to prepare bi-layer tablet of Metoclopramide Hydrochloride (MTH) and Ibuprofen (IB) for the effective treatment of migraine.

Jayabalan Nirmal et al

formulated bilayer tablets consisting of atorvastatin calcium (AT) as an immediate release layer and nicotinic acid (NA) as an extended release layer.

4. PLAN OF WORKPre-formulation studies

Calibration curve. Flow properties. Drug excipient compatibilities.

Preparation Of Tablets By Direct Compression Method ( IR tablets). Preparation Of Tablets By Direct Compression Method (SR tablets). Evaluation of the prepared tablets for various physico-chemical

parameters such as. Appearance. Hardness. Weight variation. Friability. Thickness. In vitro drug release. Kinetic studies.

4.DRUG PROFILEName Capacetabine

Brand names XelodaCategories

Antineoplastic

Antimetabolites

Indication For the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen.

Plasma Half life Capacetabine having shorter half life, 45-60 minutes and its metabolites.

Mechanism of action Folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2'-deaxyuridylate.

Absorption Readily absorbed through the GI tract (~70%).Properties:

Statemelting point

Solid110-121 °C

polarizability 35.81Dosage forms Tablet oral

4.DRUG PROFILEName Ondansetron

Description A competitive serotonin type 3 receptor antagonist. It is effective in the treatment of nausea and vomiting caused by cytotoxic chemotherapy drugs.

Category AntiemeticsIndication For the prevention of nausea and vomiting associated with

emetogenic cancer chemotherapy, postoperation, and radiation.

Mechanism of action

Ondansetron is a selective serotonin 5-HT3 receptor antagonist. The antiemetic activity of the drug is brought about through the inhibition of 5-HT3 receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract).

Absorption Ondansetron is well absorbed after oral administration and undergoes limited first-pass metabolism.

Protein binding 70%-76% (Plasma protein binding)Half life 5.7 hours

State solid

EXCIPIENTSPOVIDONE Enhancer; tablet Disintegrant;

dissolution binder.MAGNESIUM STEARATE Tablet and capsule lubricant .CROSS POVIDONE (CP) Tablet disintegrant. and dissolution

agent.

SODIUM STARCH GLYCOLATE

(SSG)

Tablet and capsule disintegrant.

Microcrystalline cellulose (MCC) Adsorbent; suspending agent; tablet and capsule diluent; tablet

disintegrant.

Hydroxy Propyl Methyl Cellelose (HPMC) Minimize interaction problems when

used in acidic, basic,

Polyvinyle pyrrolydine (PVP) Binder in wet granulation

Ethyl Cellelose (EC)Coating agent,

Sodium Lauryl Sulphate (SLS) Excipient in dissolvable dosage forms.Talc Lubricant

5.PREFORMULATION & FORMULATIONS STUDY 

.PREFORMULATION STUDY: 

◦ Organoleptic properties◦ Solubility◦ Density◦ Carr’s compressibility index & Hausner’s ratio◦ Angle of repose(ɵ)◦ Compatibility studies◦ F.T.I.R

  FORMULATIONS  The bilayer tablet was prepared by direct compression method. As shown in Table powder mixtures of Capacetabine,

microcrystalline cellulose, polymers and binder were dry blended for 20 min followed by addition of Magnesium Stearate and Talc.

The mixtures were then further blended for 10 min., 400mg of resultant powder blend was manually compressed using KBr hydraulic press at a pressure of 1 ton, with a 12mm punch and die to obtain the tablet.

a) First layer fill ; b) First layer tamping; c) Upper punch withdrawal; d) second layer fill; e) main compression; f) Ejection;

Ingredients

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10

Capacetabine (mg)

150 150 150 150 150 150 150 150 150 150

HPMC K4M(%)

10 -- -- -- -- -- 5 -- -- --

HPMC K100M(%)

-- 10 -- -- 15 20 15 15 15 20

HPMC E15(%)

-- -- 10 -- -- -- -- 5 -- --

EC(%) -- -- -- 10 -- -- -- -- 5 5

PVP K30 (%)

5 5 5 5 5 5 5 5 5 5

Talc (%) 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5

Magnesium stearate(%)

2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5

MCC(mg) Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S

Total weight (mg)

400 400 400 400 400 400 400 400 400 400

COMPOSITION OF SUSTAINED RELEASE LAYERTable no 1 formulation table for sustained release

layer

5.PREFORMULATION & FORMULATIONS STUDY

DIRECT COMPRESSION FOR IMMEDIATE LAYER

All the ingredients were passed through sieve and mixed in a motor and pestle for 30min for uniform mixing. The addition of ingredients was done in a geometrical manner. Then the ondansetron layer was compressed using 8mm round punch. COMPOSITION OF IMMEDIATE RELEASE LAYER

Table no2: formulation table for immediate release layerIngredi

ents (mg)

F1 F2 F3 F4 F5 F6 F7 F8 F9

Ondansetron

8 8 8 8 8 8 8 8 8

HPC (%) 5 5 5 5 5 5 5 5 5

SSG(%) 5 -- -- -- -- -- -- -- --

CCS(%) -- 5 -- 7.5 10 12.5 10 10 10

CP(%) -- -- 5 -- -- -- -- -- --

Lactose monohy

drate

Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S

Magnesium

stearate(%)

2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5

Talc (%) 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5

SLS(%) -- -- -- -- -- -- 0.5 1 1.5

Total weight

150 150 150 150 150 150 150 150 150

BILAYERED TABLET PUNCHAfter the batch was optimized in both immediate release layer ( F8) and sustained release layer (F7).The optimized batch in both was

compressed by using same ingredientsFlow PropertiesAngle of Repose

Bulk density:Tapped density

Compressibility index and Hausner ratio

TABLE NO 3 : ACCEPTANCE CRITERIA OF FLOW PROPERTIES Flow properties Angle of repose(θ) Compressibility

Index (%)Hausner ratio

Excellent 25-30 <10 1.00-1.11

Good 31-35 11-15 1.12-1.18

Fair 36-40 16-20 1.19-1.25

Passable 41-45 21-25 1.26-1.34

Poor 46-55 26-31 1.35-1.45

Very poor 56-65 32-37 1.46-1.59

Very very poor > 66 >38 >1.6

EVALUATION’S PARAMETERSAppearanceWeight variation testThickness testHardness testFriability testDevelopment of analytical methods In-vitro studiesSwelling indexDrug content(assay of tablet)Release of kineticsStability study

6. RESULT & DISCUSSION  Pre-compression parameters:

Preformulation studies: Capacetabine(API)

Physical characterization: physical characterization of Capacetabine was

studied. Density and flow properties of drug: the drug having the excellent flow properties. Evaluation of Formulated blend: Bulk density, Tapped

density, Carr’s compressibility index , Hausner’s ratio and Angle of repose are studied .the values are within the limits. And the Formulation blend was good flow property

 

6. RESULT & DISCUSSIONPreparation of standard calibration curve of

Ondansetron: in 0.1N HCl calibration curve of Ondansetron in 0.1N HCl

Standard Graph of Capacetabine (0.1 N Hcl): calibration curve for Capacetabine in 0.1N HCl at

303nm Standard Graph of Capacetabine in 6.8pH

phosphate buffer : calibration curve for capacetabine in 6.8pH

phosphate buffer at 304nm 

COMPATIBILITY STUDIES  

(FTIR) was used for infrared analysis of samples to intercept the interactions of drug with polymers and other ingredients. The powder sample along with KBr was used for FTIR studies. The samples were analyzed between the wave numbers 4000 and 400 cm2.

Fig no 1: FTIR spectra of Capecitabine pure drug

Fig no 2: FTIR spectra of Ondansetron pure drug

Fig no 3: FTIR spectra of bilayered tablet

EVALUATION OF PRE COMPRESSION PARAMETERS FOR SUSTAINED RELAESE LAYER OF CAPACETABINE

FormulationsAngle of Repose (θ)Loose BulkDensity (g/ml)Tapped BulkDensity (g/ml) %CompressibilityHausner’s ratio

INVITRO DISSOLUTION STUDIES FOR SR TABLETS - DISSOLUTION STUDY ( SR TABLETS) :

Acidic Stage: Medium : 0.1N HCL Type of apparatus : USP - II (paddle type) RPM : 50 Volume : 900ml Temperature : 37ºC± 0.5 Time : 2hrs Buffer Stage: Medium : 6.8pH phosphate buffer Type of apparatus : USP - II (paddle type) RPM : 50 Volume : 900ml Time : 24hrs

In vitro dissolution for SR tablets were done initially in 0.1N HCL for 2hrs and next in 6.8 phosphate buffer for 12hrs

 

In-Vitro Drug Release Studies for SR tablets:Table no 4. Cumulative Percentage Drug Release of Sustained Layer

Time(hrs) F1 F2 F3 F4 F5 F6 F7 F8 F9 F10

Dissolution medium 0.1N HCL

1 38.5 45.9 80.4 32.4 25.5 19.6 25.5 34.5 35.6 26.3

2 45.7 72.2 95.6 45.5 39.9 24.3 39.2 42.1 40 33.2

6.8pH phosphate buffer

3 53.8 80.7 -- 67.4 43.4 31.4 46.5 52.7 49.7 40.1

4 70.4 92.4 -- 72.6 59.4 45.9 55.2 60.3 53.9 45.6

5 84.9 -- -- 85.4 78.2 57.3 68.5 72.4 63.8 55.2

6 93.6 -- -- 95.8 94.2 80.7 75.9 78.3 70.4 63.8

8 -- -- -- -- -- 94.9 81.3 80.1 75.8 73.6

12 -- -- -- -- -- -- 96.5 -- 84.9 80.4

 Dissolution Medium for SR tablets

Table no 5: Dissolution profile of bilayered tabletS.NO Sampling time

Percentage drug released (%)ONDANSETRAN CAPACETABINE

1 15mins 80.7 4.22 30 mins 99.8 6.63 1hr -- 20.64 2hr -- 37.75 3hr -- 45.46 4hr -- 53.87 5hr -- 69.78 6hr -- 77.99 8hr -- 89.0

10 12hr -- 97.3 Discussion for in-vitro release of Capacetabine layer SR

From the table, it was confirmed that the F1, F2, F3, F4, F5, F6 and F8 of SR layer does not fulfill the sustained release theory up to 12 hrs. And also from the table, it was also confirmed that the formulation made with combination of HPMC K100 and HPMC K4M (F7) showed maximum drug release up to 12hrs.

KINETIC RELEASE MODELS:Drug release kinetics and mechanism:

To analyze the mechanism of drug releasefrom the formulation, the dissolution profile of all the batches were fitted to zero order, first order, Higuchi and Peppas models to ascertain the kinetic modeling of drug release.

• Zero Order: Q = K0 t • First order: Log Qt = Log Qo+ K1t / 2.303• Peppas model: Mt/M∞ = ktn Higuichi model: Q = K2 t1/2

 

0 0.2 0.4 0.6 0.8 1 1.20

0.5

1

1.5

2

2.5f(x) = 1.52302339651559 x + 0.664893877455113R² = 0.634123199116763

PEPPAS

LOG TIME

LOG % C D R

0 2 4 6 8 10 12 140

20

40

60

80

100

120f(x) = 8.15309396485867 x + 15.4323147440794R² = 0.879081254001317

ZERO ORDER

TIME IN HRS

% C D R

Fig no 5 - kinetic release graph for F7 sustained release formulation

 Table no 6: EVALUATION PARAMETERS FOR IMMEDIATE RELEASE

LAYER OF ONDANSETRANPRE COMPRESSION PARAMETERS

 Formulation

sAngle of

Repose (θ)Loose Bulk

Density (g/ml)

Tapped BulkDensity (g/ml)

%Compressibi

lity

Hausner’s ratio

F1 23.90 0.3 0.35 14.29 1.17

F2 24.20 0.38 0.45 15.56 1.18

F3 27.20 0.53 0.62 14.52 1.17

F4 25.50 0.57 0.68 16.18 1.19

F5 23.80 0.43 0.49 12.24 1.14

F6 24.10 0.37 0.45 17.78 1.22

F7 29.40 0.43 0.5 14.00 1.16

F8 22.100 0.44 0.51 13.73 1.16

F9 26.40 0.4 0.47 14.89 1.18From the above pre-compression parameters it was clear evidence that drug and excipients has good flow properties and suitable for direct compression.

Post-compression parameters:Post compression evaluation parameters for immediate release formulation

The results of the uniformity of weight, hardness, thickness and friability of the tablets are given in Table.

All the tablets of different batches complied with the official requirements of uniformity of weight as their weights varied between 147 to 152mg.

The hardness of the tablets ranged from 3.1 to 3.6kg/cm2 and the friability values were less than 0.5% indicating that the matrix tablets were compact and hard.

The thickness of the tablets ranged from to 2.1 to 2.5mm. Thus all the physical attributes of the prepared tablets were found be practically within control.

Table no 7. Post compression parameters for immediate release tablets

Formulations

Average weight (mg)

HardnessKg/cm2

Thickness (mm) Friability (%)

F1 149 3.4 2.1 0.29

F2 147 3.5 2.3 0.25

F3 150 3.1 2.5 0.30

F4 152 3.3 2.2 0.41

F5 150 3.6 2.4 0.52

F6 150 3.2 2.2 0.49

F7 148 3.1 2.5 0.44

F8 149 3.4 2.4 0.43

F9 150 3.3 2.3 0.42

Table No 8. Dissolution for immediate release tablet of OndansetranTime

in mins

F1 F2 F3 F4 F5 F6 F7 F8 F9

5 25 22 14 22 36 31 40 65 48

10 37 38 26 42 57 59 67 70 63

15 45 49 40 56 65 65 79 84 80

30 50 56 54 63 72 72 86 96 94

45 48 72 63 78 88 86 94 -- --

6062 80 75 89 93 95

---- --

BILAYERED TABLET COMPRESSION After the batch was optimized in both immediate release layer (F8) and sustained release

layer (F7).The optimized batch in both was compressed by using same ingredients. DISSOLUTION STUDY (BILAYERED TABLETS) : Dissolution Medium for IR tablets Acidic Stage: Medium : 0.1N HCL Type of apparatus : USP - II (paddle type) RPM : 50 Volume : 900ml Temperature : 37ºC± 0.5 Time : 30min In vitro dissolution for IR tablets were done in 0.1N HCL for 30 minutes.

Dissolution Medium for SR tablets Acidic Stage: Medium : 0.1N HCL Type of apparatus : USP - II (paddle type) RPM : 50 Volume : 900ml Temperature : 37ºC± 0.5 Time : 2hrs In vitro dissolution for SR tablets were done in 6.8 pH for 12hrs.

Table no 9 : Dissolution profile of bilayered tablet

S.NO Sampling timePercentage drug released (%)

ONDANSETRAN CAPACETABINE

1 15mins 80.7 4.2

2 30 mins 99.8 6.6

5 1hr -- 20.6

6 2hr -- 37.7

7 3hr -- 45.4

8 4hr -- 53.8

9 5hr -- 69.7

10 6hr -- 77.9

11 8hr -- 89.0

12 12hr -- 97.3

Stability Studies Stability of a drug has been defined as the ability of a particular formulation,

in a specific container, to remain within its physical, chemical, therapeutic and toxicological specifications.

The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under

the influence of a variety of environmental factors such as temperature, humidity, light, and enables recommendedstorage conditions. Overall observations from different evaluation studies such as drug-polymer

interactions, evaluation of prepared formulations and drug release studies were carried out.

Based on the obtained results best formulation was subjected for further stability study.

The stability study was conducted as per ICH guidelines for the period of six months at various accelerated temperature and humidity conditions of 25°C/65%RH, 40°C/75%RH.

The accelerated stability study of the best formulations was carried out as per the ICH guidelines

Table 10 :STABILITY DATA OF OPTIMIZED FORMULATION

S.No Time points (min) Initial

Cumulative % Drug Release (mean SD) (n=3)

25C/60%RH 40C/75%RH

1st Month 3rd Month 1stMonth 3rd

Month

10.5 99.8

99.4 98.2 98.0 97.7

2 1 20.6 20.1 19.8 20.5 19.1

3 2 37.7 35.1 35.0 34.8 34.2

4 3 45.4 45.2 44.7 45.0 44.6

5 4 53.8 52.1 51.9 50.5 50.7

6 5 69.7 67.2 67.1 66.7 66.2

7 6 77.9 77.1 76.3 77.2 76.1

8 8 89.0 88.8 87.4 88.4 86.4

9 Assay 99.7 99.3 99.4 99.2 98.7

SUMMARY & CONCLUSION The Bilayered tablets containing Capacetabine SR and

Ondansetron IR were successfully prepared by direct compression method respectively.

Various formulations were prepared and evaluated with an aim of presenting Capacetabine as sustained release and Ondansetron as immediate release for improving the patient’s compliance.

The physiochemical evaluation results for the granules of all trials pass the official limits in angle of repose, compressibility index.

The prepared blend for IR layer tablets and SR layer tablets were also maintained the physiochemical properties of tablets such as thickness, hardness, weight variation, friability.

The optimized formulation F8 in IR formulations contains the average thickness of 2.4mm, average hardness of 3.4 kg/cm2, average weight of 149mg, friability of 0.43%.

SUMMARY & CONCLUSION The optimized formulation F7 in SR formulations contains the average

thickness of 2.3mm, average hardness of 7.3 kg/cm2, friability of 0.41%.

The F7 formulation which releases the capacetabine in sustained manner in 1st hour it releases 25.5% but the remaining drug release was sustained up to 12 hours and ondansetron immediate release F7 formulation showed 96 % drug release with in 30 min.

With the data of kinetic analysis, F7 formulation showed best linearity in Higuchi’s Equation plot indicating that the release of drug from matrix tablet follows Non Fickian diffusion.

The dissolution study was carried out for optimized bilayer tablet and it correlates with the drug release of individual release layer formulations.

“Hence it may be summarized that the tablets prepared by direct compression method for sustained release layer and immediate release layer might be a perfect and effective formulation to prevent the side effects in treating cancer”.

 

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Thank you

Reg.261311006