Formulation & Evaluation of floating microspheres of an antibiotic drug

PREPARED BY:

Keyur Vasava

Contents

Aim of present work Objectives Rationale Introduction Method Review of literature Drug profile Polymer profile Experimental work Evaluation conclusion References

AIM OF PRESENT WORK

Objectives Of Present Work

Prevent degradation in alkaline pH

To maintain constant level of drug in the blood plasma and minimize fluctuation

remain buoyant to improve bioavailability.

Prolonging gastric residence of a dosage form to improve therapeutic value

Rationale

oral route: Ease of administration Microspheres(multiparticulate system):uniform dosage form GRDDS: minimize fluctuation Cephalexin ,BCS class drug has short half life (80min) and low bioavailability hence it is suitable for gastroretentive system. Method (W/O/W emulsion solvent evaporation method):simple ,economic & short processing time Optimization: good % yield and good % drug release
5

Introduction
Drug

Cephalexin:

Antibiotic, BCS class drug ,short half life,Low bioavailability

Gastro retentive Floating drug

delivery system
Floating Microspheres

spherical Size range-10m to 1000 m

What is UTI???
The urinary tract is the body's filtering system for removal

of liquid wastes. Because have a shorter urinary tract, women are especially susceptible to bacteria that may invade the urinary tract and multiply -- resulting in infection known as a urinary tract infection, or UTI. Fortunately, these infections are easily treated with antibiotics.

Approches to GRDDS
Incorporati on of passage delaying food agents Floating Systems Bio/Mucoadhesive Systems

High density systems

Approches to Gastric retention

Ion exchange resins

Osmotic regulated systems

Deshpandey.A A,Shah,Pharm res.1997 Atyabi,F.,Sharma H L,J control.Rel 1996

Swelling and Expanding Systems

8

Types of Gastroretentive drug Delivery system Effervescent system Volatile liquid containing system Non Effervescent system Colloidal barrier system Microporous compartment system Alginate bead system

Gas Generating system

Hollow Microspheres
gaba Poonam,Floating microspheres a: Review,Volume 6 ,2008
9

Advantages of floating Microspheres

Improves patient compliance Bioavailability enhances Gastric retention time is increased Drug releases in controlled manner for prolonged period. Superior to single unit floating dosage forms Avoidance of gastric irritation Better therapeutic effect of short half-life drugs can be achieved.

2010

Nayak Amit Kumar, Gastroretentive drug delivery systems: a review, January-March

10

Need for gastric Retention

When Drugs are absorbed

from specific site like from stomoch or upper GIT. When such drugs are incorporated in SR system. Only few drugs dissolve at absorption region and all other drug is going waste.

11

Limitation of Floating Drug Delivery system

12

Criteria for selection of Drug

Method of preparation of floating microspheres

Step 1

Preparation of aqueous phase

Step 2 organic solvent (DCM:Acetone+ Polymer)W/O emulsion Step 3 primary emulsion poured to aq phase containing PVA(0.5%) Step 4 The resultant emulsion ( w/o/w type) was continually stirred ( 550 to 950 rpm) Step 5 fitration ,collection,washing and vaccum drying

Dr.Jose GR, Omidian H, Shah K. Pharm Tech 2003 14

List of Review of related litereture

DRUG Verapamil hydrochloride WORK DONE preparation and evaluation of floating microspheres of verapamil hydrochloride for improving the drug bioavailability by prolongation of gastric residence time. Microspheres can be successfully designed for sustained delivery of Glipizide and to improve dosage form characteristics for easy formulation. Microspheres developed for prolongation of gastric residence time. AUTHOR
Tanwar Yuveraj Singh

YEAR

2007

Glipizide

Phutane P 2010

Ketoprofen

Garg Rajeev et

2010

15

Drug Piroxicame Famotidine

Work done Microspheres with improvedmicromeritics property Microsphreresto achieve an extended retention in the upper gastrointestinal tract, which may result in enhanced absorption and thereby improved bioavailability Microspheres for prolongation of gastric residence time by the solvent evaporation method using polymers hydroxypropyl -methyl cellulose and ethyl cellulose.

Auther RD Kale et al Jain Abhishek Kumar

year

2007

2009

Cimetidine

Srivastava Anand kumar

2005

Ketorolac trometamol

Developed microspheres which can be prepared to improve the absorptionand bioavailability of ketorolac trometamol by retaining the system in to the stomach for prolonged period of time.

Barhate Shashikant

2009

16

DRUG Cefpodoxime proxatile

WORK DONE Developed microsphere in order to achieve an extended retention in the upper GIT, which may result in enhanced absorption and thereby improved bioavailability.

AUTHER M.K.Deepa

YEAR

2009

metformin

Developed Microspheres may be used in clinic for prolonged drug release in stomach for at least 8 hrs, thereby improving the bioavailability and patient compliance.

Patel Asha et al
2006

diltiazem hydrochloride

microspheres developed ,The data obtained in this study thus suggest that a micro particulate floating dosage form of diltiazem hydrochloride can be successfully designed to give controlled delivery and improved oral bioavailability. Microspheres developed for for prolonged gastric residence time and increased drug bioavailability.

Gattani Yogesh S 2008

silymarin

Rajeev Garg

2010

Introduction to Cephalexin
Name of Drug Cephalexin
Anti-Bacterial Agents C16H17N3O4S

Drug Category Chemical Formula Chemical IUPAC Name

(6R,7R)-7-[[(2R)-2-amino-2-phenylacetyl]amino]-3-methyl-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

Chemical structure:

BCS class

Class

18

Cephalexin Dose for Bacterial Infections Administration

Half Life : Protein Binding

65mg

Orally
1 hour

14%

Mechanism of Action :

Cephalexin, like the penicillins, is a beta-lactam antibiotic. By binding to specific penicillinbinding proteins (PBPs) located inside the bacterial cell wall, it inhibits the third and last stage of bacterial cell wall synthesis.

19

Absorption :

Well absorbed from the gastrointestinal tract. 80% excreted unchanged in urine within 6 hours of administration

Metabolism:

Excreation: Toxicity:
Clinical use

Renal diarrhea, nausea, upper abdominal pain, and vomiting.

to treat urinary tract infections, respiratory tract infections, and skin and soft tissue infections. It is also sometimes used to treat acne. diarrhea, dizziness, headache, indigestion, joint pain, stomach pain and tiredness.
20

Side-effects

POLYMER PROFILE

Ethyl Cellulose: Functional Category Coating agent; flavoring agent; tablet

binder; tablet filler; viscosity increasing agent. Description Ethyl cellulose is a tasteless, free-flowing, white to light tan-colored powder. Density (bulk): 0.4 g/cm3 Glass transition temperature: 129133C Solubility Ethyl cellulose is freely soluble in chloroform, ethanol ( 95%), ethyl acetate, methanol, and toluene,acetone. Specific gravity: 1.121.15 g/cm3.
21

EXPERIMENTAL WORK
1.Materials and Equipments 2.Priliminary study 2.1Spectrophotometric analysis of cephalexin 2.2DrugExcipients COMPABILITY Study 2.3IN Process Optimization 3.Application of Full factorial design layout 4.Characterization of Micromeritics property 5.Other evaluation parameters 6.Formulation and evaluation of check point batch S10 7.Fiting to kinetic model 8.Stability Study
22

1.MATERIALS

MATERIALS

sources
Innova captab Ltd(chandigadh) Qualikems Finechem pvt.ltd,Nandesari,vadodara Aatur Instra chem,Vadodara Suvidhinath laboratories,vadodara Qualikems Finechem pvt.ltd,Nandesari,vadodara Finar chemicals Ltd
23

Cephalexin Ethyl cellulose(EC) (18-24cps) Acetone Dichloromethane Polyvinyl alcohol (25-32cp) Hydrochloric acid IP

EQUIPMENTS

Equipments
Digital electronic balance Propeller stirrer Optical microscope Tap density Tester UV spectrophotometer

Sources
Scaletec mechatronics pvt.Ltd Remimotor Ltd USICO, india Electrolab , USP ETD: 1020 Shimadzu , UV-1700, Pharmaspec

Dissolution Test apparatus

Electrolab,TDT-08L

24

2.Preliminary study

2.1Spectrophotometric analysis of cephalexin 2.2DrugExcipients COMPABILITY Study 2.3IN Process Optimization

2.1 SPECTROPHOTOMETRIC ANALYSIS OF CEPHALEXIN

Determination of absorption maxima (max) of

Cephalexin max for cephalexin is 257 nm.

26

Determination of U.V absorption maxima

Calibration curve
No of sample 1 2 3 4 5 6 7 8 Concentration(g/ ml)
10 20 30 40 50 60 70

Conc (g/ml) vs Abs

Abs
1

0.109 0.25 0.357 0.465 0.567 0.668 0.791

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 0 50

0.901 0.791 0.668 0.567 0.465 0.357 0.25 0.109 100

y = 0.011x + 0.01 R = 0.998 Concentration (g/ml)

Linear (Concentratio n(g/ml))

80

0.901

Concentration(g/ml)
27

2.2 DRUG-EXCIPIENTS COMPATIBILITY

FT-IR spectra of drug

Functional group
O-H -Lactom Amide -COOH -COOH

Standard Cephalexin

3148.13

1758.31

1689.43

1595.00

1399.94

28

DRUG-EXCIPIENTS COMPATIBILITY
FT-IR Spectra of Drug+polymer(E.C+PVA)
Functional group
O-H Lactom Amide -COOH -COOH

CFL+EC+PVA

3168.49

1758.36

1689.36

1595.90

1399.01

There is no chemical interaction between Cephalexin and other excipients.

29

2.3 OPTIMIZATION OF PROCESS VARIABLES

A. Volume of aqueous phase for primary emulsion

B. Volume of organic phase C. Acetone : Dichloromethane

D. Stirring rate
E. Polymer:Drug

30

A. VOLUME OF AQUEOUS PHASE FOR PRIMARY EMULSION

Volume of the organic phase Acetone: DCM ratio Stirring rate Concentration of PVA 10 ml 1:1 550 rpm 0.5% w/v

Optimization of volume of aqueous phase for primary emulsion

Batch No.

Volume of the aqueous

Phase

characteristic

A1

5 ml

Thick emulsion(Not easily pourable)

A2

10 ml

Proper amount to form

emulsion
A3 15 ml Break down of emulsion
31

B.VOLUME OF ORGANIC PHASE

Volume of the aqueous phase 10 ml

Acetone:DCM ratio
Stirring rate

1:1
550 rpm

Concentration of PVA

0.5 % w/v

Optimization of volume of the organic phase

Batch No. Volume of the organic
Phase B1 10 ml Aggregated lump

Product characteristic

B2 B3

20 ml 30 ml

Spherical microspheres Coarse, not complete

spherical
32

C.ACETONE:DICHLOROMETHANE

Volume of the aqueous phase Volume of the organic phase

10 ml 20 ml

Stirring rate
Concentration of PVA

550 rpm
0. 5 % W/V

Optimization of Acetone:Dichloromethane ratio

Batch No. C1 C2 C3 C4 C5 ACT:DCM ratio 3:1 2:1 1:1 1:2 1:3 Product characteristic Spherical microspheres Spherical microspheres Irregular microspheres Spherical microspheres Spherical microspheres Aggregation ++ + ++ +++ +++
33

D.STIRRING RATE
Volume of the aqueous phase Volume of the organic phase Acetone: DCM ratio Concentration of PVA 10 ml 20 ml 2:1 0.5 % W/V Optimization of stirring rate
Batch No.
D1 D2

Stirring rate
350 rpm 550 rpm

Product characteristic
Very large size particles Larger size,Nearly spherical

Aggregation
+++ ++

D3 D4

750 rpm 950 rpm

Small size, spherical Small size microparticles

++ +

D5

1150rpm

very small,breakdown of microparticles

++
34

E.P0lymer :Drug
Batch No. Polymer: drug ratio
P1 P2 P3 P4 P5 P6 P7 P8 6:1 5:1 4:1 3:1 2:1 1:1 1:1.5 1:2

Product characteristic
Spherical Spherical Spherical spherical Spherical Spherical Spherical Irregular

Aggregation

% yield

+ + + + + ++ ++ +++

78.93% 70.28% 63.95% 59.41% 55.81% 53.89% 49.45% -----

+++:high aggregation

35

OPTIMIZED BATCH
Parameter Selected batch Specification

Volume of aqueous phase

A2

10 ml of aqueous phase

Volume of organic phase

B3

20 ml of organic phase

Acetone : DCM ratio

C2

2:1 ratio of ACT:DCM

Stirring rate

D3

550rpm

750rpm
950 rpm
36

3. APPLICATION OF FULL FACTORIAL DESIGN

32 FACTORIAL DESIGN
Independent variables
X1:Polymer concentration X2: Stirring speed

Dependable variables
Y1:particle size(m) Y2:% Drug encapsulation efficiency Y3:t80%(min)

37

FACTORIAL DESIGN

level

INDEPENDENT VARIABLES

X1(polymer concentration)(%) Low 8.33

X2(stirring speed)(rpm) 550

Medium

10.43

750

high

12.50

950

38

32 DESIGN LAYOUT
Batch code X1 (%) 8.33 S1 10.43 S2 550 X2(rpm) 550

12.50 S3
8.33 S4 10.43 S5 12.50 S6 8.33 S7 10.43 S8

550
750 750 750 950 950

12.50 S9

950
39

Evaluation of microspheres

Micromeritics property
Scanning Electron Microscopy % buyovancy Evaluation of dependent variables

Particle size ii. % drug Encapsulation efficiency iii. t80%

i.

4.MICROMERITICS PROPERTY

TAPPED DENSITY

BULK DENSITY
COMPRESSIBILITY INDEX ANGLE OF REPOSE

41

Characterization of microspheres
FORMULATION CODE S1 S2 S3 S4 S5 S6 S7 S8 S9 BULK DENSITY(gm /cm)
0.3500.013
0.3750.009 0.4000.110 0.4120.050 0.4370.060 0.4620.007 0.4870.060 0.5250.090 0.5620.030

TAPPED COMPRESSIBIL DENSITY(gm ITY INDEX /cm)

0.3940.006
0.4340.009 0.4500.003 0.4710.005 0.5070.010 0.5210.007 0.5570.015 0.5830.009 0.6330.016

ANGLE OF REPOSE
19.290.22
21.000.34 22.190.29 18.670.18 22.580.65 24.950.22 19.290.65 25.170.54 27.110.27

11.160.231
13.590.942 11.110.620 12.610.742 13.800.426 11.320.378 12.590.672 10.170.722 11.210.465

Mean S.D., n=3 Micromeritics property shows good flowability and packagability
42

Scanning electron Microscopy

Spherical and uniform in shape,porous in nature and rough surface,shows good floating characteristics and flowability to the dosage form.

43

% Buoyancy study
Formulation code
S1 S2 S3 S4 S5 S6 S7 S8 S9

% buoyancy(%)

Buoyancy (% ) = ( Qf * 100 ) / ( Qf + Qs )
971.71 881.81 843.07 912.65 851.85 812.85 835.43 814.41 802.91 Mean S.D., n=3

Good %buoyancy shows good floating ability for prolong period of time.
44

6.EVALUATION OF DEPENDABLE VARIABLES

Formulation code

Particle size (m)

%encapsulation efficiency(%)
67.953.75 74.284.00 81.934.39 64.743.51

t80% (min)

S1 S2 S3 S4 S5 S6 S7 S8

4751.32 4811.53 4910.95 3750.99

6577.02 6603.05 6956.00 5736.43

3851.17
3901.11 2391.56 2500.99 275+1.56

72.332.63
77.454.32 59.523.21 70.472.75 74.162.42

5865.03
6002.31 5212.30 5272.00 5663.50

S9

Mean S.D., n=3

45

EFFECT OF X1 AND X2 ON PARTICLE SIZE

Batch code
S1 S2 S3 S4

Particle size(m)
4751.32 4811.53 4910.95 3750.99 3851.17 3901.11 2391.56 2500.99 275+1.56

S5
S6 S7

S8
S9

Mean S.D., n=3

46

Graphical representation of Effect of FactorX1 & X2 On particle size

Contour plot
Design-Expert Software Factor Coding: Actual particle size Design Points 491 239
870.00 950.00

Response Surface plot

particle size
300
Design-Expert Software Factor Coding: Actual particle size Design points above predicted value Design points below predicted value 491 239 X1 = A: polymer concentration X2 = B: stirring speed

X1 = A: polymer concentration X2 = B: stirring speed

X2Stirring speed

350

790.00

X2Stirring speed

400

710.00

particle size

500 450 400 350 300 250 200

12.50 11.81 11.11 10.41 870.00 790.00 710.00

630.00

450

950.00

A: polymer concentration 9.72

9.02 630.00 550.00 8.33

550.00 8.33 9.02 9.72 10.41 11.11 11.81 12.50

X1: A: polymer concentration X2: B: stirring speed

B: stirring speed

Conclusion: As Polymer concentration increases particle size increases,and with incresing stirring speed it will decreases.

By Design expert version 8.0.5.2

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SUMMURY OUT PUT OF REGRESSION ANALYASIS Table Out put of regression analysis for Effect of X1 and X2 on PARTICLE SIZE

Regression statistics

R Square Adjusted R Square Standard error Coefficient Intercept X1 X2

0.9922 0.9896 3.99

Coefficients
coefficient Value 373.44 11.17 -113.83 P-value < 0.0001 0.0360 < 0.0001

Equation: Y1==+381.89+11.17X1-113.83X2+5.00 X1X2+2.17X12-14.83X22

P value <0.05 indicats model is significant and +sign of coefficient of X1if polymer concentration increases,particle size increases - Sign of coefficient of X2 shows if stirring speed decreases,particle size increases

EFFECT OF X1 AND X2 ON ENCAPSULATION EFFICIENCY(Y2)

Batch code S1 S2 S3 S4 S5 S6 S7 S8 S9
Y2 (%encapsulationefficiency) 67.953.75 74.284.00 81.934.39 64.743.51 72.332.63 77.454.32 59.523.21 70.472.75 74.162.42

49

EFFECT OF X1 AND X2 ON %Encapsulation efficiency (Y2)

Contour plot
Design-Expert Software Factor Coding: Actual %encapsulation efficiency Design Points 81.93 59.52
870.00 950.00

Response surface plot

%encapsulation efficiency
Design-Expert Software Factor Coding: Actual %encapsulation efficiency Design points above predicted value Design points below predicted value 81.93 59.52

X2Stirring speed

85
65

%encapsulation efficiency

X1 = A: polymer concentration X2 = B: stirring speed

X1 = A: polymer concentration X2 = B: stirring speed

80 75 70 65 60 55

790.00

70

75

710.00

630.00

80
550.00 8.33 9.02 9.72 10.41 11.11 11.81 12.50

950.00 870.00 790.00 710.00 9.72 9.02 A: 8.33 10.41

12.50 11.81 11.11

X1: A: polymer concentration X2: B: stirring speed

B: stirring speed 630.00

550.00

polymer concentration

Conclusion :As Polymer concentration increases % encapsulation efficiency increases,and with incresing stirring speed %encapsulation efficiency decreases.

By Design expert version 8.0.5.2

50

SUMMURY OUT PUT OF REGRESSION ANALYSIS

Table Out put of regression analysis for Effect of X1 and X2 on % ENCAPSULATION EFFICIENCY. Regression statistics

R Square Adjusted R Square

0.9694 0.9592

Standard error
Coefficient

0.45
Coefficients coefficient Value P-value

Intercept
X1 X2

71.43
6.89 -3.34

< 0.0090
< 0.0001 0.0010

Equation: Y1=72.44+6.89 X1-3.34X2+0.17X1X2-1.40X12-0.12 X22

P value <0.05 indicats model is significant and +sign of coefficient of X1if polymer concentration increases,% encapsulation efficiency increases - Sign of coefficient of X2 shows if stirring speed decreases,%encapsulation efficiency increases

EFFECT OF X1 AND X2 ON t80%(Y3)

Batch code S1 S2 S3 S4 S5 S6 S7 S8 S9

t80% (min) 6577.02 6603.05 6956.00 5736.43 5865.03 6002.31 5212.30

5272.00
5663.50

52

EFFECT OF X1 AND X2 ON t80%(Y3)

Contour plot
Design-Expert Software Factor Coding: Actual t80% Design Points 725.62 586.22
870.00

Response surface plot

t80%
600
Design-Expert Software Factor Coding: Actual t80% Design points above predicted value Design points below predicted value 725.62 586.22

950.00

X1 = A: polymer concentration X2 = B: stirring speed

620

X1 = A: polymer concentration X2 = B: stirring speed

740 720 700

X2 Stirring speed

790.00

680

640

660

t80%

640 620 600 580 12.50

710.00

660

680
630.00

950.00

11.81 870.00 790.00 11.11 10.41 710.00 9.72

700 720
550.00 8.33 9.02 9.72 10.41 11.11 11.81 12.50

B: stirring speed

630.00 550.00 8.33

9.02

A: polymer concentratio

X1: A: polymer concentration X2: B: stirring speed

Conclusion :As Polymer conc increases ,t80% increases & t80% decreases with increasing stirring speed.

By Design expert version 8.0.5.2

53

SUMMURY OUT PUT OF REGRESSION ANALYSIS

Table Out put of regression analysis for Effect of X1 and X2 on t80% Regression statistics

R Square Adjusted R Square Standard error Coefficient Intercept X1 X2

0.9633 0.9511 4.48 Coefficients coefficient Value 598.33 18.33 -66.33 P-value < 0.0031 0.0005 < 0.007

Equation: Y1==+644.42+13.69X1-57.98X2-3.23X1X2+2.76X12+5.93X22
P value <0.05 indicats model is significant and +sign of coefficient of X1if polymer concentration increases,t80% increases - Sign of coefficient of X2 shows if stirring speed decreases,t80% increases

Overlay plot for Optimization

Design-Expert Software Factor Coding: Actual Overlay Plot particle size %encapsulation efficiency t80% Design Points
950.00

Overlay Plot
t80%: 605.140 %encapsula 74.5152 particle size: 299.191

particle size 271.014 t80%: X1 X2 605.153 12.44 950.00

870.00

X1 = A: polymer concentration X2 = B: stirring speed

X2Stirring speed

790.00

particle size: 400.000

710.00

630.00

550.00 8.33 9.02 9.72 10.41 11.11 11.81 12.50

X1: A: polymer concentration X2: B: stirring speed

The overlay plot of the responses generates an optimized area, as per the

desired criteria. The polymer concentration value was targeted 12.44 and Stirring speed was set to 950.15

By Design expert versio 8.0.5.2

55

6.Formulation and evaluation of check point batch

FORMULATION INGREDIENT Volume of aqueous phase Volume of organic phase Aceton:DCM FORMULATION BATCH F10 10 ml of aqueous phase 20 ml of organic phase 2:1 ratio of ACT:DCM 605.15 rpm 200mg 12.44% 0.5%

Stirring speed
Cephalexin Polymer concentration PVA

TEST PARAMETERS

BATCH S10 PREDICTED ACTUAL

% Error

Particle size
% Encapsulation Efficiency t80%

271m
74.51% 605.15min

275m
73.21% 599.27min

0.014%
0.017% 0.0097%
56

In vitro drug release (% cumulative drug release)

TIME(hr) 0min 0.5min 1hr 2hr 3hr 4hr 5hr 6hr 7hr 8hr 9hr 10hr 11hr 12hr
0
1.97

S1
0

S2
0
0.987

S3
0
0.074

S4
0
3.94

S5
0
2.96

S6
0
1.97

S7
0
6.9

S8
0
4.93

S9

2.96

8.92 16.02
23.27 30.67 38.22 46.91 53.79 60.81 67.95 72.26 78.61 84.1

6.92 12.99
18.21 26.49 32.96 38.58 46.28 53.15 61.93 68.27 74.57 84.1

4.93 9.86
13.2 16.13 23.38 29.79 36.33 42.02 58.75 64.86 71.08 79.38

6.99 11.09
20.2 29.51 37.04 45.71 54.54 61.57 69.73 77.04 83.5 89.5

7.93 11.09
18.98 24.32 34.7 42.34 51.11 59.07 68.42 77.04 82.15 86.74

4.93 10.01
18.89 22.26 32.6 41.18 48.94 57.85 64.95 73.16 79.55 84.1

10.94 18.08
27.34 36.8 44.48 53.3 60.31 67.71 76.7 81.18 89.8 98.17

8.92 14.07
24.26 33.65 42.25 52.01 58.02 64.13 74.3 81.74 88.28 96.91

7.93 13.42
23.18 31.57 39.14 47.85 54.76 63.77 71.96 79.32 86.8 57 93.22

%cumulative drug release of Batch S1 to S9

120 100 80

%cumulative drug release vs time(hr)

S3 S4

%cumulative drug release

60 40 20 0 0 20 40 60 80 100 120

S5
S6 S7 S8 S9 S1 S2

Time(hr)

58

%cumulative drug release of Batch S10

TIME(hr) 0min 0.5min 1hr 2hr 3hr 4hr 5hr 6hr 7hr 8hr 9hr 10hr 11hr 12hr Batch S10
0
4.934 9.974 14.136 25.290 32.733 39.339 48.048 56.928 64.994 74.196 84.556 92.149 98.885 59

7.Fitting to kinetic model

Results of Model Fitting of optimized Batch

Intercept

Slope

R2

Zero order plot

8.24

0.322

0.998

First order plot

0.0125

0.753

0.773

Higuchi

30.48

19.21

0.920

Korsmeyer peppas

1.17

0.749

0.828

n > 0.749 > 1.0 indicates Drug release mechanism was non-fickian transport

60

8.Stability Study
Stability Study Days Particle Size(m) %drug Encapsulation efficiency(%) Before Storage 0 Days 2750.23 After storage 73.211.23 599.273.65

t80%(min)

7days
15days 30days

2750.84
2730.43 2710.32

72.130.21
71.091.23 70.322.21

597.335.43
595.453.25 592.255.21

*Storage at 40 and 75%RH for 1month,meanSD;n=3

Conclusion: Stability studies indicated that there was no significant difference observed between the release pattern of microspheres at 40C and 75% RH for one months
61

conclusion
The results of a 32 full factorial design revealed that

the polymer ratio (X1) and stirring speed (X2) significantly affected the dependent variables The microspheres of the check point batch (F10) exhibited 73.21% drug encapsulation efficiency, mean particle size of 275 m and 599.27 min t80% which were nearer to predicted values obtained from overlay contour plot of all the responses. These result shows a good relationship between the experimental & predicted values,which confirms the practicability of the model.
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