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Formulation And Evaluation of . Bi Layer Tablets of CANDESARTAN

By - Mohammed Zeeshan Saleem M.pharmacy Dept. of PHARMACEUTICS { Hltkt.No : 12FP1S0323 }

Guide : MNA.Riaz

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Contents :

1. Introduction

2. Drug and Excipient profile

3. Experimental work 4. Results and Discussions 5. Conclusion

6. References.

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Introduction :• Bilayer tablets have some key advantages compared to conventional

monolayer tablets. For instance, such tablets are commonly used to avoid chemical incompatibilities of formulation components by physical separation.

• In addition, bilayer tablets have enabled the development of controlled delivery of active pharmaceutical ingredients with pre-determined release profiles by combining layers with various release patterns, or by combining slow-release with immediate-release layers.

• Different approaches have been proposed to formulate sustained release tablets for retaining dosage form in stomach. These include bioadhesive or mucoadhesive systems, swelling and expanding systems and floating systems

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• Mucoadhesive bilayer tablet is new concept for successful development of sustained release formulation along with various features to provide a way of successful drug delivery system that include an Immediate release (IR) layer and an Sustained release (SR) layer.

• Immediate release (IR) layer provide therapeutically effective plasma drug concentration for a short period of time

• Sustained release (SR) layer maintain uniform drug levels over a sustained period to reduce dosing intervals and side effects, increase the safety margin for highly-potent drugs and thus offer better patient compliance.

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Need of Bilayer Tablets :• Controlling the delivery rate of either single or two different active

pharmaceutical ingredient(s)

• To modify the total surface area available for API layer either by sandwiching with one or two inactive layers in order to achieve swellable/erodible barriers for modified release.

• To separate incompatible Active pharmaceutical ingredient (APIs) from each other, to control the release of API from one layer by utilizing the functional property of the other layer (such as, osmotic property).

Quality and GMP-requirements :• Preventing capping and separation of the two individual layers that

constitute the bi-layer tablet

• Preventing cross-contamination between the two layers and Producing a clear visual separation between the two layers

• Accurate and individual weight control of the two layers.

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Drug Profile : Name of the Drug : Candesartan

Description: Candesartan is an angiotensin-II receptor antagonist used mainly for the treatment of hypertension

IUPAC.Name : 2-ethoxy-1-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-7-carboxylic acid

Molecular formula : C33H34N6O6

Molecular weight : 610.66 Dose : The recommended initial dose and usual maintenance dose is

8 mg once daily. Therapy should be adjusted according to blood pressure response.

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Mechanism of action : • Candesartan selectively blocks the binding of angiotensin II to AT1 in many tissues including vascular smooth muscle and the adrenal glands.

• This inhibits the AT1-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II and results in an overall decrease in blood pressure.

• It has a plasma half-life of 9hrs and peak plasma concentration reaches within 3 to 4 hrs.

• It produces toxicity like renal and hepatic impairment if given in higher doses resulting inconvenience to the patient and the possibility of reduced compliance with prescribed therapy.

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• Candesartan is a member of Angiotensin II Receptor Antagonist class of drugs and is an FDA approved drug for the treatment of hypertension, myocardial infarction and congestive heart failure.

• Candesartan reduces the blood pressure and is an effective antihypertensive agent in patients with mild to moderate hypertension.

• Candesartan is safer, more tolerable and as effective as other commonly used antihypertensive agents.

• It could be an attractive target for the generic industries.  

•  Compared with other ARBs, candesartan demonstrates the strongest binding affinity to the angiotensin II type 1 receptor. Clinical trials have demonstrated that candesartan is well tolerated in combination with diuretics or calcium channel blockers (CCBs)

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Excipient Profile :

• EUDRAGIT RS PO   EUDRAGIT RL PO

CROSPOVIDONE

DIBASIC CALCIUM PHOSPHATE DEHYDRATES

MAGNESIUM STEARATE

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Experimental work : Pre formulation Studies - Compatibility Study between Drug Substance and Excipients :S.No. Drug + Excipients Drug: Excipients (Ratio)

1. Drug -

2. Drug + DCP 1:5

3. Drug + RSPO 1:2

4. Drug + RLPO 1:2

5. Drug + Sod. starch glycolate 1:1

6. Drug + Mg.stearate 10:1

7. Drug + Talc 10:1

8. Drug + All excipients 5:5

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Estimation of Candesartan – UV visible spectrophotometric method Preparation of standard stock solution : 25 mg of Candesartan standard substance was weighed and transferred in to 25 ml volumetric flask separately, dissolved in methanol and made up to the volume with methanol. This solution contains 1mg/ml concentration.

Selection of wavelength for estimation and stability studies : The standard stock solution was further diluted with pH 6.8 Phosphate buffer to get the concentration of 10µg/ml and the solution was scanned between 200-400 nm using distilled water as blank. From the spectra, lamda max was found to be 224 nm and was selected as analytical wavelength.

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Preparation of calibration graph :

Working standard solution was prepared by pipetting 5 ml of the standard stock solution in to a 25 ml volumetric flask and made up to the volume with pH 6.8 Phosphate buffer to get the concentration of 200µg/ml. 0.5-5ml were transferred in to a series of 100ml volumetric flasks and made up to the volume with distilled water.

• The absorbance of different concentration solutions were measured at 224 nm. The calibration curve was constructed by plotting concentration Vs absorbance. Candesartan was linear with the concentration range of 1-10µg/ml at 224nm.

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Preparation of Bilayer tablets :

A 32full factorial design was utilized in the present investigation.

Two factors were evaluated, each at 3 levels, and experimental trials were performed at all 9 possible combinations.

The amount of Eudragit RSPO (X1) and the amount of Eudragit RLPO (X2) were selected as independent variables. The time required for 90% in vitro drug dissolution, was selected as dependent variable.

• This design resulted in 9 batches and it was summarized in below table.

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Table 4: Levels of Factors

Combination Factors

X1 X2(-1,-1) -1 -1(-1,0) -1 0

(-1,+1) -1 1(0,-1) 0 -1(0,0) 0 0

(0,+1) 0 1(+1,-1) 1 -1(+1,0) 1 0

(+1,+1) 1 1

Factor X1 X2High Level -1 -1

Middle Level 0 0Low Level 1 1

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Preparation of Bi-layer Tablets :

Formulation of Bilayered Sustained Release Matrix Tablets of Candesartan: Calculation of Loading and Maintenance Dose :

Calculation of steady state concentration: Css = Dm / Vd Css = 4 mg / 0.13 litre = 30.76 mg / litre

Calculation of immediate release dose ( IR ): IR = Css× Vd / F = 30.76 × 0.13 ×100 / 40 = 10 mg

Calculation of maintenance dose ( MD ): MD = IR (1+0.693× t / t1/2) = 10 (1+0.693× 12 / 9) = 10 (1.924) = 19.24 mg ≈ 22mg

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Preparation of immediate releasing (Loading dose) layer :• Immediate releasing layer containing 10 mg of Candesartan was prepared by direct compression method employing Polyplasdone XL-10 as super disintegrant.

•Finally mixed with weighed quantities of talc and magnesium stearate and directly punched over the sustaining layer. Formula for Immediate Release Layer

S.No Ingredients Quantity (mg)

1 Candesartan 102 Polyplasdone XL-10 143 Magnesium stearate 0.54 Talc 0.5

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Composition of different formulations :

S.No Formulation Code

Drug (mg)

Eudragit RSPO (X1)

Eudragit RLPO (X2)

Lactose DCL-22(mg)

Talc(mg) Magnesium stearate

(mg)1 F1 22 -1 -1 95.8 3.5 3.5

2 F2 22 -1 0 83.3 3.5 3.5

3 F3 22 -1 1 70.8 3.5 3.5

4 F4 22 0 -1 83.3 3.5 3

5 F5 22 0 0 70.8 3.5 3.5

6 F6 22 0 1 58.3 3.5 3.5

7 F7 22 1 -1 70.3 3.5 3.5

8 F8 22 1 0 58.3 3.5 3.5

9 F9 22 1 1 45.8 3.5 3.5

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Evaluation of Physical Properties of Tablets :

1. Thickness2. Weight variation3. Hardness4. Friability5. In vitro release studies: The release of Candesartan from the bilayered tablet was

studied in 900 ml of phosphate buffer pH 6.8 as dissolution medium using a USP dissolution paddle apparatus at 50 rpm and 37 ± 0.5o C. An aliquot (5 ml) was withdrawn at specific time intervals, filtered and diluted to 10 ml with phosphate buffer pH 6.8 and drug content was determined by UV-visible spectrophotometer at 224 nm.

• An equal volume of fresh dissolution medium was replaced to maintain the sink conditions. Dissolution studies were performed for a period of 12 hrs and percentage of drug release was calculated using an equation obtained from a standard curve.

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Results and Discussions :

Pre Formulation Study :

S.No API Characterisation Results1 Melting point 195 ºC

2 Bulk density 0.376 gm/ml

3 Tapped Density 0.421 gm/ml

4 Carr’s index 11.9

5 Hausner’s Ratio 1.119

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Solubility Studies :

Solvent Solubility ( mg/ml )

Water 0.185

Polyethylene Glycol-400 20.52

Propylene Glycol 2.253

Tween 80 9.65

Buffer pH (6.8) 0.194

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Drug-Polymer Interaction Study : IR spectra of Candesartan

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IR spectra of the Optimized Formulation :

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Standard Calibration Curve for Candesartan Cilexetil in 6.8 Phosphate Buffer :

Concentration (µg/ml) Absorbance

0 0

2 0.168

4 0.321

6 0.463

8 0.614

10 0.755

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0 1 2 3 4 5 6 7 8 9 100

0.2

0.4

0.6

0.8f(x) = 0.0750714285714288 x + 0.0114761904761907R² = 0.999203484357918

Standard Calibration Curve for Candesartan Cilexetil in 6.8 Phosphate Buffer

Concentration ( µg/ml )

Abs

orba

nce

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Formulation Code

Angle of Repose (°)

Bulk density (gm/ml)

Tapped Density (gm/ml)

Compressibility Index

Hausner's Ratio

F1 27.18±0.32 0.405 0.483 16.11 1.19

F2 28.57±0.20 0.416 0.481 13.54 1.16

F3 29.42±0.13 0.401 0.469 14.60 1.17

F4 28.37±0.37 0.398 0.472 15.59 1.18

F5 28.29±0.58 0.395 0.468 15.44 1.18

F6 29.19±0.33 0.396 0.463 14.61 1.17

F7 28.21±0.04 0.389 0.486 19.84 1.25

F8 26.00±0.28 0.405 0.468 13.42 1.15

F9 26.28±0.28 0.400 0.464 13.91 1.16

Blend Characteristics of Candesartan Granules :

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Formulation Thickness (mm)

Hardness (kg/cm2)

Friability (%)

Weight Variation (%)

Drug content Uniformity (%)

F1 2.53±0.07 5.60±0.08 0.52 2.98 99.92

F2 2.51±0.08 5.58±0.10 0.59 3.52 99.56

F3 2.56±0.09 5.60±0.10 0.42 2.46 99.56

F4 2.51±0.14 5.52±0.09 0.48 2.65 99.82

F5 2.53±0.18 5.58±0.07 0.53 3.2 99.89

F6 2.52±0.10 5.61±0.13 0.56 3.15 98.99

F7 2.49±0.13 5.59±0.08 0.49 3.58 99.29

F8 2.48±0.16 5.45±0.12 0.62 3.12 99.59

F9 2.58±0.18 5.42±0.16 0.42 3.58 98.96

Physical Evaluation of SR Tablets of Candesartan :

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Time(Hrs) Cumulative % Drug releasedF1 F2 F3 F4 F5 F6 F7 F8 F9

0 0 0 0 0 0 0 0 0 0

1 36 34 33 32 30 28 28 26 25

2 52 49 47 45 42 40 36 34 30

4 75 72 68 64 63 59 55 52 42

5 79 81 76 72 70 67 62 59 49

6 86 89 84 80 79 75 70 68 54

7 92 94 95 90 88 80 74 70 59

8 100 99 100 96 97 85 80 76 64

9       99 100 88 85 80 70

10           92 89 84 76

11           100 94 87 84

12             99 92 90

Dissolution Results :

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0 2 4 6 8 10 12 140

20

40

60

80

100

120Dissolution profiles

F1 F2 F3 F4 F5 F6 F7 F8 F9

Time (Hrs)

Cum

ulat

ive

% D

rug

Rel

ease

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Formulation code

Correlation coefficient ( R ) Release rate constant Exponential Coefficient

(n)

T90 (HRS)

Zero order First OrderZero order

First Order

Higuchi Peppas Rate constant K0 (mg.h-1)

Rate constant K1 (h-1)

F1 0.9030 0.8450 0.9970 0.9960 10.98 0.459 0.480 6.93

F2 0.9230 0.8860 0.9990 0.9980 11.42 0.486 0.524 7.7

F3 0.9416 0.8457 0.9976 0.9986 11.37 0.483 0.533 7.96

F4 0.9391 0.8678 0.9974 0.9978 10.12 0.437 0.525 8.62

F5 0.9518 0.8516 0.9944 0.9970 10.28 0.446 0.559 8.81

F6 0.9223 0.9961 0.9979 0.9976 7.98 0.229 0.527 10.7

F7 0.9364 0.9914 0.9983 0.9956 7.31 0.197 0.524 11.2

F8 0.9260 0.9936 0.9973 0.9948 6.82 0.171 0.525 11.45

F9 0.9670 0.9835 0.9778 0.9707 6.52 0.120 0.525 12.06

Kinetic model results :

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SCHEMATIC PRESENTATION FOR COMPRESSION OF BI-LAYER TABLET :

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Conclusion :• In present investigation, factorial batchesF1-F9 were prepared using

25mg to 50mg of Eudragit RSPO and 25mg to 50mg of Eudragit RLPO.

• Among the F1-F9 batches, F9batch containing Eudragit RSPO – 50mg

and Eudragit RLPO – 50 mg gives 25% drug release after 1 hr and 90 % drug release after 12 hrs which is nearer to theoretical release profile.

• Optimized batch F9 follows First order release kinetic and has R2 value 0.9835.

 

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References :

1. Shiyani B, Gattani S, Surana S. Formulation and evaluation of bi-layer tablet of Metoclopramide hydrochloride and Ibuprofen. AAPS Pharm Sci Tech 2008; 9(3):818-27.

  2. Pranjal Kumar Singh, Sanjoo Kumar Bilayer and Floating

Bioadhesive Tablets: Innovative approach to Gastroretention, Journal of Drug Delivery & Therapeutics; 2011, 1(1): 32-35

  3. Kulkarni A, Bhatia M. Development and evaluation of bilayer

floating tablets of atenolol and lovastatin for biphasic release profile. Iran. J. Pharm. Res. 2009; 8: 15–25. 

 

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Thank-u