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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)
Light yellow crystalline powder
No Change No Change
4API+ Methacrylic Acid Copolymer (Eudragit L10055)
Light yellow crystalline powder
No Change No Change
5API+ Microcrystalline cellulose(Avicel PH101)
Light yellow crystalline powder
No Change No Change
6API+ Sodium lauryl sulphate(Texaponk12pPH)
Light yellow crystalline powder
No Change No Change
7API+ Hypromellose(Methocel K100CR)
Light yellow crystalline powder
No Change No Change
8API+ Colloidal silicon dioxide(Aerosil 200)
Light yellow crystalline powder
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.
43
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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