Formulation development and evalution of matrix tablet of

FORMULATION DEVELOPMENT AND EVALUTION

OF MATRIX TABLET OF AN ANTIHYPERTENSIVE

DRUG USING COMBINATION OF pH DEPENDENT

AND INDEPENDENT POLYMER

Presented By Guided By

Mr. Gajanan S. Ingole Mr. K.B. Charhate

ANURADHA COLLEGE OF PHARMACY, CHIKHLI.

2

CONTENTS

1. Introduction

2. Literature review

3. Drug and excipients profile

4. Aim and objective

5. Rational and plan of work

6. Materials and equpiments

7. Experimental work

8. Results

9. Discussion

10. Conclusion

11. References

3

INTRODUCTION

Oral delivery of drugs is the most convenient route of Drug delivery systems due to

Ease of administration Patient compliance Flexibility in formulation

Tablets ingested

orallyTablets used in

oral cavity

Tablets administered by

other route

Tablets administered by

other route

Tablets used to prepare solution

Matrix Tablets Type of controlled drug delivery systems, which release the drug in continuous manner.a matrix is defined as a well-mixed composite of one or more drugs with gelling agent i.e. hydrophilic. release the drug by both controlled and diffusion controlled mechanisms.

4

ADVANTAGES & DISAVDANTAGES OF MATRIX TABLET

Easy to manufacture,effe

ctive and low cost .avoids the high blood

concentration.maintain

therapeutic concentrations over prolonged

periods. Reduce the toxicity.Minimize the local and

systemic side effects. Increase the stability.

The remaining matrix must be removed after the drug has

been released.

The release rates are affected by various factors such as, food and the rate transit through the gut.

Release rate continuously diminishes due to an increase in

diffusional resistance

5

CLASSIFICATION OF MATRIX TABLETS

A)On the Basis of Retardant Material Used

• Hydrophobic Matrices • Lipid Matrices• Hydrophilic Matrices• Biodegradable Matrices• Mineral Matrices

B)On the Basis of Porosity of Matrix

• Macroporous Systems• Microporous System• Non-porous System

6

POLYMERS USED IN MATRIX TABLETS

POLYMERS EXAMPLE

i) Hydrogels Polyhydroxyethyl methylacrylate.

ii) Soluble polymers Polyethylene glycol (PEG)

iii)Biodegradable polymers Polylaceticacid (PLA)

iv)Non biodegradable polymers Polyethylene vinyl acetate.(PVA)

v)Mucoadhesivepolymers Sodium carboxymethyl cellulose.

7

PH DEPENDENT AND INDEPENDENT POLYMER

Specific polymers have been designed to release drugs into specific regions of the gastrointestinal tract.

A)pH dependent polymer:

EudragitE,EudragitL,EudragitS,Hydroxyproylmethylcellulose phthalate.

B)pH independent polymer:

Hydroxy propyl methyl cellulose, Kollidon.

8

2. LITERATURE SURVEY

Kumar et al; in their review “Oral Extended Release Drug Delivery System” providing the recent literature regarding development and design of extended release tablets.

Patel et al; in their Overview “Extended Release Matrix Technology” This article contains the basic information regarding extended-release formulation and also the different types of the same.

Patel et al; in their review “Matrix Type Drug Delivery System: A Review” Focused on to formulate tablets in order to avoid the first pass metabolism and increase the bioavailability. Hence in this work an attempt was made to formulate sustain release. system for in order to achieve even plasma concentration profile up to 24 hrs. it can be easily concluded that sustained-release formulation are helpful in increasing the efficiency of the dose as well as they are also improving the patient’s compatibility.

Mulani H et al, in their research work pH independent sustained release matrix tablet was formulated. It was found that Kollidon® SR is suitable for pH-independent extended release matrix tablets.

Pao-Chu Wu et al; their study was to develop and optimize the propranolol once-daily extended release formulations containing HPMC,Microcrystalline cellulose (MCC) and lactose.

9

3. DRUG AND EXCIPIENTS PROFILE

Drug Profile

Name: NSL

Assay:101.4 %w/w (By

HPLC, on dried base).

Solubility: soluble in

ethanol and insoluble in

water.

Half-life: Plasma half-life

is 7-12 hrs

Description: yellow crystalline

powder

Category: calcium channel

blockers

Loss on drying: 0.15% (By Karl

Fisher)

10

Clinical Pharmacology

Mechanism of Action

Distribution

Metabolism

Elimination

Uses

Contraindication

11

Excipients Profile

Lactose Monohydrate

Sodium Lauryl Sulfate

Cellulose Microcrystalline

Magnesium Stearate

Colloidal Silicon Dioxide

Instacoat Universal Brown

12

Polymer Profile

Hydroxypropylmethylcellulose

Polymethacrylates

13

4) AIM AND OBJECTIVE

Aim: The aim of present study is to develop & characterized matrix

tablet of antihypertensive drug using pH dependent and independent polymer.

Objectives: To deliver the dosage form at the site of absorption their by

enhancing the bioavailability. To delay and control the release of drug through the formulation. To match the invitro dissolution profile of marketed reference

product. To formulate Site specific drug delivery. To formulate Stable formulation. To formulate Cost effective dosages form with respect to

marketed reference product.

14

5. RATIONAL AND PLAN OF WORK

RATIONAL Antihypertensive therapy has a well established place to prevent the

complications of high blood pressure. Amongst the existing agents NSL is effective ones. formulation of matrix tablet provides an increase in the bioavailability of

calcium channel blocker. Manufacturing of Antihypertensive drug is easy. reduces the frequency of administration improves patient compliance, better selectivity and longer duration of

action.

15

PLAN OF WORK

Literature survey.

Selection of material

Preformulation studies.

Drug excipients compatibility

studies

Preparation of various

formulations

Evaluation of tablet

Stability Studies

Result and Discussion

Conclusion

16

INNOVATOR PRODUCT CHARACTERISTIC

Sr. No. Parameters Observations

1 Dosage form Solid Oral

2 Brand name of the product Sular

3Generic name of the

productNSL tablet

4 Manufactured by Skye pharma production SAS

5 Label claim Each tablet contain 34 mg of NSL

6 DescriptionOrange oval tablet with SC1503 marking one side

&plain other side

7Excipients

Hypromellose,Lactose, Hypromellose phthalate,

Glyceryl behenate, Silicon dioxide,SLS,Povidone,

Magnesium sterate, Methacrylic acid copolymer.

8 Thickness(nm) 6.76-6.88

9 Hardness(N) 160

10 Container HDPE

11 Storage 20-250C Protect from light & moisture

17

7. EXPERIMENTAL WORK

Preformulation Study

Formulation of matrix tablet

Optimization Study

Stability Studies

18

A)Preformulation Study

a)Characterstics of the Bulk Drug and Powder

Blend Properties

1)Bulk density

2)Tapped density

3)Compressibility index

4)Hausner’s ratio

5) Loss on drying (LOD)

b)Drug Excipient Compatibility Study

19

B)FORMULATION OF MATRIX TABLET

Sr. NoIngredients

Trial Batches in mg

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10

Intragranular

1 NSL 34 34 34 34 34 34 34 34 34 34

2Hypromellose (Methocel prem K100LV) 50 50 - - - - - - - -

3Lactose monohydrate (pharmatose 200M) 30 30 30 30 46.6 38.3 38.3 38.3 76.6

4Methacrylic Acid Copolymer Eudragit L10055 - - 50 36 56 46 46 46 46 46

5Microcrystalline cellulose (Avicel PH101)

140.4 136.8 136.8 136.8 231.8 184.2 214.9 168.9 253.2 176.6

6Sodium lauryl sulphate(Texaponk12pPH) - 3.6 3.6 3.6 5.6 4.6 4.6 4.6 4.6 4.6

Binder

7 IPA q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s

8 Purified water q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s

Extragranular

9Hypromellose(Methocel K100CR) 100 100 100 114 177.3 145.7 115 161 115 115

10Colloidal silicon dioxide(Aerosil200) 2 2 2 2 3.1 2.6 2.6 2.6 2.6 2.6

11 Magnesium stearate 3.6 3.6 3.6 3.6 5.6 4.6 4.6 4.6 4.6 4.6

Total wt of core tablet 360 360 360 360 560 460 460 460 460 460

Coating solution

12Instacoat Universal brown A0G11058IHS 10.8 10.8 10.8 10.8 16.8 13.8 13.8 13.8 13.8 13.8

13 Purified water q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s

Total wt of coated tablet370.

8 370.8 370.8 370.8 576.8 473.8 473.8 473.8 473.8 473.8

20

Sifting Dry MixingBinder

Preparation

Granulation

DryingSifting Pre-

Lubrication

Lubrication

Compression Coating

a)MANUFACTURING PROCESS

21

b) In-Process Evaluations of Tablet

1)Tablet appearance

2)Weight Variation

3)Hardness

4)Thickness5)Friability

6)Dissolution

7) Assay

22

C) OPTIMIZATION STUDY

D) STABILITY STUDIES

on the basis

presence of pH depend

ent polyme

r

Formulation were modified

with subject to pH

independent

polymer

concentration of polymer

and surfactant were change

d

the capacity of a drug substance to maintain its identity, quality and purity

Definition

• quality of the drug substance

• shelf life for drug substance

Objective

• 1st and 2nd month Stability testing

• assay and% drug release of optimized batch was compared

Method

23

8. RESULTS Preformulation

Sr.No.

Tests Specification Results

1 DescriptionYellow crystalline

powderYellow crystalline

powder

2 SolubilitySoluble in ethanol and

insoluble in water.Complies

3 Water content(%w/w) Not more than 0.50 0.15%

5 Assay (%w/w)Not less than 99.0 & Not more than101.0

96.9

6 Bulk Density (gm/ml) - 0.19

7 Tapped Density (gm/ml) - 0.334

8Compressibility Index

(%)- 42.42

9 Hausner ratio - 1.7

24

Sr. No. Contents

Physical Description Initial

Condition – Dry 40C/75% RH

15days 1months

1 APIYellow crystalline powder

No Change No Change

2API+ Hypromellose (Methocel prem K100LV)

Light yellow crystalline powder

No Change No Change

3API+ Lactose monohydrate(pharmatose 200M)


No Change No Change

4API+ Methacrylic Acid Copolymer (Eudragit L10055)


No Change No Change

5API+ Microcrystalline cellulose(Avicel PH101)


No Change No Change

6API+ Sodium lauryl sulphate(Texaponk12pPH)


No Change No Change

7API+ Hypromellose(Methocel K100CR)


No Change No Change

8API+ Colloidal silicon dioxide(Aerosil 200)


No Change No Change

9 API+ Magnesium stearateLight yellow crystalline powder

No Change No Change

10API+ Instacoat Universal brown A0G11058IHS

Dark yellow crystalline powder

No Change No Change

11 API+ All ExcipientsLight yellow yellow crystalline powder

No Change No Change

Drug –Excipient Compatibility study

25

Trial

Evaluation Parameters

LOD at105ºC (%) BD(gm/cm3) TD(gm/cm3) CI (%)

HR

F13.34 0.503 0.711 29.231 1.413

F 23.99 0.407 0.550 26.0 1.351

F 33.10 0.315 0.530 26.80 1.355

F42.55 0.350 0.533 25.23 1.315

F 53.75 0.295 0.404 26.923 1.368

F63.25 0.326 0.439 25.714 1.346

F 73.41 0.321 0.411 21.875 1.280

F 83.48 0.406 0.515 21.212 1.269

F93.45 0.340 0.451 24.59 1.326

F103.46 0.320 0.423 25.21 1.319

Characteristics of Lubricated Blend

26

Formula optimization

Trial without pH dependent

polymer

Trials with pH dependent polymer.

Optimization of effective drug

release surface area.

Optimization of HPMC

Optimization of MCC and

Lactose ratio.

Final optimized formula

27

Trials

Evaluation Parameters of Uncoated Matrix tablet(without pH dependant )

Av.w (Mg) Thick (mm.) Hardness (N) Friability (%)

F1 360 5.45 138 0.04

F 2 361 5.28 142 0.06

Dissolution in (0.1 N HCL+0.5% SLS), paddle 50 rpm, 900ml

Time (Hrs)

% Drug Release

Sular F1 F2

1 2 1 4

2 7 1 9

4 20 2 20

6 32 22 32

8 39 40 43

10 57 45 57

12 74 59 68

15 78 75 80

16 87 83 89

18 90 86 90

20 91 88 98

24 95 92 97

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

% D

rug

Rel

ease

Time(Hrs)

% Drug Release inHCL+0.5%SLS

Sular F1 F2

28

Time (Hrs)

% Drug Release

Sular F2

1 4 42 12 10

4 30 21

6 47 29

8 62 42

10 80 53

12 90 62

15 92 73

16 94 80

18 93 85

20 93 90

24 95 94

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

%Dr

ug R

eleas

e

Time(Hrs)

% Drug Release in pH6.8 +0.5 % SLS

Sular F2

Dissolution in ph 6.8 +0.5 % SLS, paddle, 50 rpm, 900 ml

29

Trials

Evaluation Parameters of Uncoated Matrix tablet ( pH dependant )

Av.wt(Mg) Thickness(mm.)

Hardness (N)

Friability (%)

F3 360 5.10 138 0.03

F4 361 5.07 145 0.04

% Drug Release in HCl+0.5%SLS.

Time (Hrs)% Drug Release

Sular F3 F4

1 2 4 1

2 7 12 3

4 20 23 13

6 32 38 22

8 39 46 32

10 57 62 49

12 74 80 64

15 78 89 72

16 87 95 79

18 90 97 84

20 91 98 88

24 95 98 92

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

%Dr

ug R

rele

ase

Time(Hrs)

% Drug Release inHCL+0.5%SLS

Sular F3 F4

30

% Drug Release in pH 6.8+0.5%SLS

Time (Hrs)

%Drug Relesase

Sular F3 F4

1 4 5 5

2 12 21 12

4 30 40 28

6 47 52 45

8 62 73 60

10 80 94 74

12 90 94 83

15 92 96 91

16 94 98 93

18 93 100 96

20 93 100 96

24 95 100 97

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

%Dr

ug R

elea

se

Time(Hrs)

% Drug Release in pH 6.8+%0.5%SLS

Sular F3 F4

31

Trials

Evaluation Parameters of Uncoated Matrix tablet

(Optimization of effective drug release surface area.)

Av.wt. (Mg)Thickness(m

m.)

Hardness

(N)

Friability

(%)

F4 361 5.07 145 0.04

F5 560 6.54 175 0.11

F6 460 5.50 178 0.20

Time (Hrs)

% Drug Release

Sular F4 F5 F61 2 1 3 32 7 3 8 94 20 13 18 226 32 22 29 358 39 32 38 43

10 57 49 47 5312 74 64 56 7115 78 72 68 8216 87 79 74 9118 90 84 79 9520 91 88 84 9724 95 92 92 100

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

%D

rug

Rel

ease

Time(Hrs)

% Dug Release in HCL+0.5% SLS

Sular F4 F5 F6

% Drug Release in HCl+0.5%SLS.

32

Time (Hrs)

% Drug Release

Sular F4 F5 F61 4 5 7 62 12 12 14 154 30 28 31 356 47 45 52 538 62 60 59 68

10 80 74 73 8212 90 83 79 9315 92 91 88 9516 94 93 92 9518 93 96 93 9620 93 96 95 9724 95 97 95 98

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

%D

rug

Rel

ease

Time(Hrs)

% Drug Release in pH 6.8+%0.5%SLS

Sular F4 F5 F6

%Drug Release in pH 6.8 +0.5 %SLS

33

Trials

Evaluation Parameters of Uncoated Matrix tablet)

(Optimization of HPMC)

Av.wt. (Mg)Thickness(m

m.)

Hardness

(N)

Friability

(%)

F6 460 5.50 178 0.20

F7 460 5.45 179 Nil

F8 460 5.51 175 0.22

% Drug Release in 0.1N HCL+0.5% SLS.

Time (Hrs)

% Drug Release

Sular F6 F7 F81 2 3 4 32 7 9 11 84 20 22 23 176 32 35 35 288 39 43 44 35

10 57 53 57 5312 74 71 75 6215 78 82 83 7216 87 91 92 7618 90 95 94 8120 91 97 96 8524 95 100 98 88

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

%D

rug

Rel

ease

Time(Hrs)

% Drug Release in HCL+0.5% SLS

Sular F6 F7 F8

34

%Drug Release in pH 6.8 +0.5 % SLS

Time (Hrs)

% Drug Release

Sular F6 F7 F81 4 6 6 22 12 15 15 84 30 35 32 266 47 53 50 398 62 68 66 57

10 80 82 85 7212 90 93 93 8015 92 95 96 8316 94 95 96 8518 93 96 95 8220 93 97 94 8224 95 98 97 86 0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

%D

rug

Rel

ease

Time(Hrs)

Dissolution in pH 6.8 +0.5 % SLS

Sular F6 F7 F8

35

Trials

Evaluation Parameters of Uncoated Matrix tablet

(Optimization of MCC and Lactose ratio)

Av.wt. (Mg)Thickness

(mm.)

Hardness

(N)

Friability

(%)

F7 460 5.45 179 Nil

F9 460 5.49 175 0.04

F10 460 5.51 169 Nil% Drug Release in HCL+0.5% SLS

Time (Hrs)% Drug Release

Sular F7 F9 F10

1 2 4 8 2

2 7 11 15 8

4 20 23 29 21

6 32 35 42 33

8 39 44 52 40

10 57 57 64 55

12 74 75 83 74

15 78 83 90 80

16 87 92 95 88

18 90 94 99 90

20 91 96 100 93

24 95 98 100 99

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

%D

rug

Rel

ease

Time(Hrs)

% Drug Release in(HCL+0.5% SLS)

Sular F7 F9 F10

36

% Drug Release in pH 6.8 +0.5 % SLS

Time (Hrs)

% Drug Release

Sular F7 F9 F101 4 6 8 62 12 15 20 144 30 32 36 316 47 50 55 468 62 66 70 62

10 80 85 86 7912 90 93 95 8915 92 96 98 9216 94 96 98 9418 93 95 99 9720 93 94 100 9824 95 97 100 99

Evaluation

Parameters High Hardness Low Hardness Optimum Hardness

Av.wt. (Mg) 461 460 460

Thickness (nm.) 5.40 5.61 5.59

Hardness (N) 181 120 169

Friability (%) 0.02 0.30 NilAssay of Formulation

% Labeled amount

Drugs Innovat

or

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10

NSL 99.8 98.0 99.2 98.3 98.2 97.3 99.1 99.1 98.0 99.23 99.5

Stability study results

Parameter Initial 40°C / 75%RH

After 1 monthAfter2 month

Description

Orange colored round shape biconvex film coated tablet plain on both side.

Complies Complies

Average Weight (mg) 460.0 459.9 459.9

Assay (%) 99.50 99.55 99.51

Evaluation of finally optimized formula

38

STABILITY STUDY RESULT OF DISSOLUTION

% Drug Release in 0.1 N HCL

Time (Hrs)

% drug releaseInitial 1month 2 months

1 2 2 22 8 7 84 21 21 216 33 34 348 40 41 41

10 55 56 5612 74 75 7515 80 81 8116 88 88 8918 90 90 9020 93 94 9324 99 98 99

39

Time (Hrs)

% drug releaseInitial 1month 2 months

1 6 6 62 14 14 144 31 32 316 46 47 468 62 63 6310 79 79 7912 89 89 9015 92 93 9216 94 94 9418 97 97 9720 98 98 9824 99 98 99

% Drug Release in pH 6.8+0.5% SLS

40

9. DISCUSSION

1)Compatibility studies

2)Evaluation of Blend

3)In Process

Evaluation Tests for Tablets

4)InVitro Release Study

5)Stability Study of

Optimized Batch

41

10. CONCLUSION

Relatively well absorbed into the systemic circulation with 87% of the radiolabeled

drug recovered in urine and feces

Suitable candidate for delayed/controlled release matrix tablet

Market reference product explorted trilayer tablet approach with inactive layer

sandwiching drug layer Similar profile was achieved in trial

mention by using monolayer tableting approach

Delayed release matrix tablet s best promising option for drug get metabolized in

gut wall.

The role of ph dependent and independent polymer enhance the flexibility and efficacy

of dosage form.

42

11. REFERENCE Robinson, J.R., Lee, V.H.L., In, Controlled Drug Delivery: Fundamentals and Applications

(Robinson, J.R., Lee, V.H.L, ed.), 2nd edition. Marcel Dekker, New York, 1987, pag16.

Lachman L, Lieberman H. A, Kanig J. L, The Theory and Practice of Industrial Pharmacy,

3rd ed., Varghese publishing house, Bombay. 1987: Pag294, 336, 413.

Kumar .S, Oral Extended Release Drug Delivery System Asian J. Pharm. Tech. 2012; Vol. 2: Issue 2, Pag 38-43.

Jain N K, Controlled and novel drug delivery system, in progress in controlled and novel

drug delivery system, C B S publishers and distributors, New delhi, 2004, pag419-35.

Bramhankar DM, Jaiswal S B, “Biopharmaceutics and pharmacokinetics”, 1st ed, Vallabh

Prakashan; 2008, Pag335-371.

Patel K, An Overview: Extended Release Matrix Technology international Journal Of

Pharmaceutical And Chemical Sciences Apr – Jun 2012, vol. 1 (2). Chien Y. W., Novel drug delivery systems, volume-50, Marcel Dekker, Inc. New York

2002, pag.1-43.

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Alford N Martin, Patrick J. Sinko, Martin’s Physical pharmacy and pharmaceutical sciences, 2006.

Patel H.,Matrix Type Drug Delivery System: A Review JPSBR,Volume 1, Dec 2011,pag143-151.

Vyas S.P, Khar R.K,Controlled Drug Delivery: Concepts and Advances, Ist

ed,vallabh prakashan, 2002, pag 156-189

Aulton ME,Pharmaceutics: The Science of Dosage Form Design Wadher.J, Formulation and Evaluation of Sustained Release Matrix Tablets of

Metformin Hydrochloride Using pH Dependent and pH Independent Methacrylate Polymer, British Journal of Pharmaceutical Research2011 1(2),pag29-45.

Mulani H, Development of pH-independent matrix type sustained release drug

delivery system of propranolol hydrochloride Journal of Applied Pharmaceutical Science2011 01 (03), Pag83-92.

Mohd Azharuddin, Krishnananda Kamath, T. Panneerselvam, Subash S. Pillai, A.R. Shabaraya,Formulation and evaluation of controlled release matrix tablets Of antihypertensive drug using natural and synthetic Hydrophilic polymers research in Biotechnology, 2011 2(4),pag26-32

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Thank You

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