srikanth final presentation

UNDER THE GUIDANCE OF
Smt. BALA Tripura Sundari
Assistant professor
Navuluri Srikanth
170512886003
M.Pharm II yr
Pharmaceutics
FORMULATION AND EVALUATION OF SOLID
DISPERSIONS OF CARVEDILOL

Contents
 Aim and Objective
 Plan of work
 literature survey
 Experimental Methodology
 Results and Discussions
 References
Sri Venkateshwara College of Pharmacy, Madhapur 216/12/2014

Aim and Objective:
 To improve Solubility and dissolution rate of
Carvedilol
 To Prepare and Evaluate Solid Dispersions of
Carvedilol.
 Fill solid dispersions in Capsules and Optimization

INTRODUCTION
 “ Solid dispersion technology is the science of dispersing
one or more active ingredients in an inert matrix in the
solid stage to achieve an increased dissolution rate or
sustained release of drug, altered solid state properties and
improved stability”.

Types of Solid Dispersions
 Simple Eutectic Mixtures
 Solid solutions
 Glass solutions
 Compound or complex formation
 Amorphous precipitation

Methods of preparation of Solid dispersions :
 Various methods used for preparation of solid dispersions
are given bellow-
A) Fusion method
B) Solvent Evaporation method
C) Fusion solvent method (melt evaporation)
D) Melt extrusion methods
E) Lyophilization techniques
F) Melt agglomeration Process
G) The use of surfactant
H) Electro spinning

Applications of solid dispersions
 To obtain a homogenous distribution of small amount of drugs
at solid state.
 To stabilize unstable drugs.
 To dispense liquid or gaseous compounds
 To formulate a faster release priming dose in a sustained
release dosage form.
 To improve the absorption of drugs by improving solubility of
the drug
 The bioavailability of the drug is also increased by using solid
dispersions.

Materials used as carriers for solid dispersions :
 1.Sugars:Dextrose, Sucrose, Galactose, Sorbitol, Maltose, Mannitol.
 2 .Acids :Citric acid, Succinic Acid .
 3 .Polymeric materials : PVP, PEG
 4.Celluloses like HPMC,HEC, HPC, Pectin, Galactomannan, CDs .
 5 .Insoluble/ enteric polymers like HPMC, Phthalate, Eudragits .
 6 .Surfactants : Polyoxyethylene stearate, Renex, Poloxamers, texafor,
Deoxycholic acid, Tweens, Spans.

Solid dispersions can be Formulated in-
 Spraying on sugar beads using a fluidized bed coating
system.
 Direct Capsule filling
 Electrostatic Spinning method
 Self Emulsifying Drug Delivery Systems (Solid
dispersions).

Marketed solid dispersions
S.NO Trade Name Drug Company Polymer
1 Afeditab Nifedifine ELAN CORP. PVP
2 Certican Everolimus NOVARTIS HPMC
3 Fenoglide Fenofibrate LIFE CYCLE PEG
4 Intelence Etaverine TIBOTEC HPMC
5 Isoptin SRE-
240
Verapamil SOLIQS Various
6 Kaletra Ritonavir &
Lopinavir
ABOTT PVP
PVA
7 LCP-Tacro Tacrolimus LIFE CYCLE HPMC
8 Sporanox Itraconazole JANSSEN HPMC

EXPERIMENTAL METHODOLOGY

Plan Of Work
 Selection of drug.
 Determination of λmax of Carvedilol drug and preparation of
standard graph.
 Formulation of Carvedilol Solid dispersions.
 Evaluation of Solid dispersions.
 In vitro drug release studies.
 Selection of the best formulation based on the above studies.
 Drug-Interaction studies for best formulation.
 Stability studies.

Literature survey
 Sarita Jangra Bhyan et al (2013), Formulated and evaluated Mouth
dissolving tablets containing Carvedilol solid dispersions by using Polyvinyl
pyrrolidine (PVP k30) as carrier the formulation showed almost 100% drug
release at the end of 15 minutes.
 Kadam vaishali et al (2013), formulated and evaluated and evaluated
Carvedilol solid dispersions by using various carriers like poloxamer 188,
Polyvinyl pyrrolidine k90 which showed increased dissolution rates. FTIR
showed no shift of peaks and no interaction between drug and excipients.
 Gita Chaurasia et al (2013), formulated and evaluated cyclodextrins based
solid inclusion compounds by using β-cyclodextrins, Hydroxo propyl β
cyclodextrins. The molar ratio containing 1:2 showed to have greater drug
content and aqueous solubility.

 Amit Taps et al (2012), formulated Carvedilol solid dispersions by
using polymers PVP k30 for improving physico chemical properties
of Carvedilol.
 Y. Srinivasa rao et al (2012), formulated and evaluated Carvedilol
solid dispersions by using various polymers such as mannitol,
lactose, urea, PEG 4000 for enhancing dissolution rate. PEG 4000
formulation showed higher dissolution rate.
 G.Sowjanya and T.E.G.K Murthy et al (2011), formulated and
evaluated inclusion complexes of Carvedilol by using β-
cyclodextrins by employing kneading method. The inclusion
complex prepared in 1:2 molar ratio showed 100% release in 4
minutes.

 Gehen balatla et al (2009), formuted and evaluated solid dispersions and
inclusion complexes of Ketocanozole by using pvp k-17 and β-
cyclodextrins respectively and showed improvement in solubility and
dissolution rate of Carvedilol.
 Amit.R.Tapas et al (2008), formulated and evaluated carvedilol solid
dispersions which are in the form of spherical crystals by emulsion solvent
diffusion method by using polymers-pluronics F68 and F127 which showed
better dissolution rates there by bioavailability.
 S.N.Hiremath et al (2007), formulated and evaluated inclusion complexes
of carvedilol by using β-cyclodextrins. In vitro dissolution rate was found to
increase with this formulation.

 Hyma ponnaganti et al (2013), formulated and evaluated Nabumetone
solid dispersion by using polymers like PEG 6000, PEG 4000 as carriers by
using solid evaporation method. Different ratios like 1:2,1:4 were prepared
and characterized by FTIR and XRD.
 Irin deewan et al (2012), formulated and evaluated solid dispersions of
Carvedilol by using various polymers like PEG 6000, poloxamer 407,
HPMC 6 cps and sodium starch glycolate. Solid dispersions prepared by
poloxamer 407 showed higher dissolution rates.
 Annamma devi et al (2012), studied the effect of hydrophilic polymers like
HPMC 6cps,PVA on Carvedilol solid dispersions. The solid dispersions
prepared by HPMC showed maximum dissolution rate.

 Ramesh Jagadeesan et al (2013), listed few novel approaches in the
preparation of solid dispersions for improving solubility. The drying
methods like hot extrusion method, spray drying, surface solid dispersion
technology, solvent evaporation method, lyophilization, electrostatic
spinning method and supercritical fluid technology.
 Kovacic et al (2010), formulated and evaluated solid dispersions of
Carvedilol by using porous silica (sylsia 350) as carrier for improving
dissolution rate and physical stability of carvedilol.
 Anu Sharma and C.P Jain et al (2013), prepared and characterized
carvedilol –β-cyclodextrin inclusion systems and showed in vitro evaluation
of this system which improved solubility and dissolution rate of Carvedilol.

•The drug (Carvedilol) was selected based on its
category (anti hypertensive) and based on its physical
properties
•Carvedilol has less aqueous solubility so it has poor
bioavailability
•It belongs to class 2 (less solubility and
bioavailability) according to BCS classification
•Various methods are there for improving solubility an
bioavailability of carvedilol
Drug selection

Drug profile
1) Name: Carvedilol
2) Molecular weight : 406.50
3) Melting point : 114º C
4) Physico-chemical properties: A white crystalline powder, slightly soluble
in water
Absorption: Carvedilol bioavailability is 25 to 30% due to significant
degree of first-pass metabolism.
 Elimination half life of carvedilol ranges from 4-6 hours.
 Distribution: Carvedilol is widely distributed. It crosses the blood brain
barrier very efficiently due to high lipid solubility.
 Metabolism: Carvedilol is extensively metabolized .
 Excretion: The metabolites are excreted from bile to faeces.

Materials used
 Carvedilol-Drug
 Methanol-Solvent
 Carriers-Polaxomer 407,B-cyclodextrins,D-mannitol,PEG
4000.
 Glassware and Buffers.

Method of preparation of Solid dispersions
Sri Venkateshwara College of Pharmacy,
Madhapur 21
Methanol
Solvent evaporation
Drying
Sieving in 60# mesh
Dessication
Filling of powder
In Capsules
Carvedilol Carrier
16/12/2014

Formulation of solid dispersions
Sri Venkateshwara College of Pharmacy, Madhapur 22
Here in the preparation of solid dispersions Polaxomer 407 is used as a carrier
S.NO INGREDIE
NTS
SDP 2 SDP 3 SDP 5 SDP 8
1 Carvedilol
(mg)
300 300 300 300
2 Methanol
(ml)
1.5 1.5 1.5 1.5
3 Polaxomer
407 (mg)
600 900 1500 2400
16/12/2014

Formulations
S.NO INGREDIE
NTS
SDM 2 SDM 3 SDM 5 SDM 8
1 Carvedilol
(mg)
300 300 300 300
2 Methanol
(ml)
1.5 1.5 1.5 1.5
3 Mannitol
(mg)
600 900 1500 2400
Here in the preparation of solid dispersions Mannitol is used as a carrier
16/12/2014

Formulations
S.NO INGREDIE
NTS
SDPE 2 SDPE 3 SDPE 5 SDPE 8
1 Carvedilol
(mg)
300 300 300 300
2 Methanol
(ml)
1.5 1.5 1.5 1.5
3 PEG 4000
(mg)
600 900 1500 2400
Here in the preparation of solid dispersions PEG 4000 is used as a carrier
16/12/2014

Formulations
S.NO INGREDIE
NTS
SDB 2 SDB 3 SDB 5 SDB 8
1 Carvedilol
(mg)
300 300 300 300
2 Methanol
(ml)
1.5 1.5 1.5 1.5
3 β-
cyclodextri
n (mg)
600 900 1500 2400
Here in the preparation of solid dispersions β-cyclodextrin is used as a carrier
16/12/2014

Formulations
 SDM 2, SDM 3, SDM 5, SDM 8 – solid dispersions using
various ratios of Mannitol.
 Similarly, SDP,SDB and SDPE code for solid dispersions
with Polaxomer 407, B-cyclodextrins and PEG 4000 as
carriers respectively.

EVALUATION
 Powder flow properties
 Solubility studies
 Drug content
 In vitro dissolution
 Surface characteristics
 Drug interaction studies

RESULTS AND DISCUSSIONS

Scan spectrum of Carvedilol
λmax – 240nm
16/12/2014

Standard graph of Carvedilol in 0.1N HCl
Concentration Absorbance
0 0
2 0.218
4 0.475
6 0.678
8 0.928
y = 0.1158x - 0.0034
R² = 0.999
-0.2
0
0.2
0.4
0.6
0.8
1
0 2 4 6 8 10
Absorbance
Concentation (mcgml)
16/12/2014

Standard graph in pH 6.8 Buffer
Concentratio
n
Absorbance
0 0
2 0.228
4 0.422
6 0.580
8 0.736
10 0.893
y = 0.1756x - 0.1382
R² = 0.9935
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 1 2 3 4 5 6 7
Absorbance
Concentration (mcg/ml)
Standard graph
16/12/2014

FTIR spectrum of Pure Carvedilol

Characteristic IR peaks of Carvedilol plain drug
Functional group Observed Frequency
N-H Stretching 3343.34
C-H stretching 2842.60
C=O stretching 1097.31
C-H Stretching 2923.68

Drug content studies
 Solid dispersions were subjected to Drug content studies
by using solvent (methanol) and are analyzed by using Uv
visible spectrophotometer at 240nm. Drug content is
calculated by using the formula
 % Drug content = Mact/Mt x 100

Drug content studies
S.NO FORMULATION % DRUG CONTENT
1 SDP 2 84.27
2 SDP 3 87.42
3 SDP 5 95.25
4 SDP 8 85.12
5 SDM 2 86.18
6 SDM 3 88.36
7 SDM 5 91.17
8 SDM 8 87.26

Drug Content studies
S.NO FORMULATION % DRUG CONTENT
9 SDB 2 88.22
10 SDB 3 91.20
11 SDB 5 93.45
12 SDB 8 89.32
13 SDPE 2 81.23
14 SDPE 3 83.32
15 SDPE 5 90.21
16 SDPE 8 87.29

Solubility Studies
 Solid dispersions were tested for their solubility in water
 In this method initially solid dispersions were added to
distilled water
 Later this solution is filtered and with buffer analyzed for
Carvedilol at 240nm

Formulation solubility
SDP 2 42.80 mcg/ml
SDP 3 53.80 mcg/ml
SDP 5 60.02 mcg/ml
SDP 8 45.70 mcg/ml
SDM 2 39.19 mcg/ml
SDM 3 48.19 mcg/ml
SDM 5 49.71 mcg/ml
SDM 8 43.18 mcg/ml
SDPE 2 40.27 mcg/ml
SDPE 3 45.89 mcg/ml
SDPE 5 50.89 mcg/ml
SDPE 8 43.18 mcg/ml
Pure Drug 17.78 mcg/ml
Solubility studies of Carvedilol
16/12/2014

FTIR Spectrum of Optimized
formulation SDP 5

Percentage yield
 Percentage yield of the prepared solid dispersion powder
was calculated by using the following formula
 % Yield = Actual weight/Theoretical weight x 100
 Yield of the solid dispersion powder was found to be more
than 90 %.

Powdered drug characteristics
 Bulk Density and Taped density
Bulk Density = mass of powder/Bulk volume
Tapped density = mass of powder/Tapped Volume

 Hausner’s Ratio
Hausner’s Ratio = Tapped density/Bulk density
Compressibility index (CI)
CI = Tapped density—Bulk density
------------------------------------- --- x 100
Tapped Density

FLOW PROPERTIES OF POWDER
Code Bulk
density
Tapped0.5
4 density
Carr’s
index
Hausner’s
ratio
Angle of
repose
SDP 2 0.45 0.57 21.05 1.26 30.91
SDP3 0.47 0.54 13.00 1.14 31.23
SDP 5 0.46 0.53 13.70 1.15 29.34
SDP 8 0.46 0.55 16.30 1.19 26.71
SDPE 2 0.50 0.58 13.72 1.16 25.34
SDPE 3 0.43 0.55 21.18 1.27 29.23
SDPE 5 0.49 0.58 15.51 1.18 31.34
SDPE 8 0.41 0.50 18.00 1.21 30.78

FLOW PROPERTIES OF POWDER
Code Bulk
Density
Tapped
density
Carr’s
index
Hausner’s
ratio
Angle of
repose
SDB 2 0.46 0.56 17.80 1.21 32.05
SDB 3 046 0.55 16.30 1.19 26.71
SDB 5 0.46 0.53 13.70 1.15 29.34
SDB 8 0.47 0.54 13.00 1.14 31.23
SDM 2 0.41 0.50 18.00 1.21 30.78
SDM 3 0.49 0.58 15.51 1.18 31.34
SDM 5 0.50 0.58 13.72 1.16 25.34
SDM 8 0.46 0.55 16.30 1.19 26.71

In Vitro Dissolution Studies
 In vitro dissolution studies were performed in USP basket
type I apparatus
 Using 0.1 N Hcl as medium
 Temperature – 37˚ C
 Time intervals -5,10,15,30,45,60 minutes
 Finally analysed by UV visible spectrophotometer at 240
nm.

S.No Time SDP 2 SDP 3 SDP 5 SDP 8 SDPE
2
SDPE
3
SDPE
5
SDPE
8
1 5
4.96 5.68 10.2 9.93 5.28 5.76 10.37 4.04
2 10
6.21 7.14 25.22 13.04 6.49 6.78 23.78 11.48
3 15
15.28 17.13 42.78 19.42 13.04 14.04 33.28 15.62
4 30
38.61 41.76 65.67 41.88 19.33 37.41 59.28 26.04
5 45
51.62 55.4 82.37 50.18 27.33 42.3 75.48 38.98
6 60
53.76 57.65 98.27 59.46 45.2 48.21 90.89 48.23
% Drug release of various formulations
16/12/2014

S.NO Time SDB 2 SDB 3 SDB 5 SDB 8 SDM2 SDM
3
SDM
5
SDM
8
1 5 4.93 5.43 11.23 8.48 4.39 5.97 11.37 9.07
2 10 5.55 6.70 24.37 11.5 5.46 7.62 21.21 13.73
3 15 14.88 15.76 41.72 15.64 11.27 11.24 32.18 16.72
4 30 21.58 39.62 61.89 26.05 19.98 25.78 58.27 26.78
5 45 41.59 43.85 79.9 39.97 28.89 39.48 76.89 32.98
6 60 47.42 52.98 96.27 54.26 42.56 49.27 93.18 51.78
Of this formulations the drug release for SDP 5 was found to be
more so, it is considered as optimized formulation
% Drug release of various formulations
16/12/2014

Comparison of drug release from various SD
Formulations
Time % DR of
SDP5
%DR of SDB
5
% DR of SDM
5
% DR of SDM
5
0 0 0 0 0
5 10.2 11.23 11.37 10.37
10 25.22 24.37 21.21 23.78
15 42.78 41.72 32.18 33.28
30 65.67 61.89 58.27 59.28
45 82.37 79.9 76.89 75.48
60 98.27 96.27 93.18 90.89

Drug release of SDP 5
Time % Drug
release
0
0
5
10.2
10
25.22
15
42.78
30
65.67
45
82.37
60
98.27
0
20
40
60
80
100
120
0 20 40 60 80
cumulative%release
Time (min)
SDP 5
16/12/2014

Comparison of Inclusion complex and Pure
drug
Time
(min)
Cumulat
ive %
drug
release
Cumulat
ive %
drug
release
- SDB 5 Pure
drug
0 0 0
5 11.23 6.14
10 24.37 8.92
15 41.72 16.84
30 61.89 28.12
45 79.9 42.45
60 96.27 45.31
0
20
40
60
80
100
120
0 5 10 15 30 45 60
Cumulative%release
Time (min)
SDB 5
Crude drug
16/12/2014

Drug release of Pure drug and Optimized
Formulation (SDP 5)
Time
(min)
Cumulat
ive %
drug
release
Cumulat
ive %
drug
release
- Crude
drug
SDP 5
0 0 0
5 6.148 10.2
10 8.92 25.22
15 16.848 42.78
30 28.12 65.67
45 42.45 82.37
60 45.31 98.27
Sri Venkateshwara College of Pharmacy, Madhapur
51
0
20
40
60
80
100
120
0 5 10 15 30 45 60
cumulative%release
Time (min)
SDP 5
Pure Drug
16/12/2014

Solid dispersion drug release
0
20
40
60
80
100
120
0 10 20 30 40 50 60 70
Cuulative%reelease
Time (min)
SDP 5
SDB 5
SDM 5
SDPE 5

 In dissolution studies formulation SDP 5 was found to
have better drug release when compared to other
formulations.
 So, it was studied further for FTIR and Surface
Characteristics for optimization.

Surface characteristics
 Surface characteristics of the powdered solid dispersion
can be studied by using Scanning Electron Microscopy
(SEM).
 The optimized solid dispersion (SDP 5) was subjected to
SEM study and powder was found to be Spherical in
shape.

SEM of SDP 5

STABILTY STUDIES
 Solid dispersions are subjected to stability studies for
about 3 months and tested for drug release it gave a very
or little change in drug release so, solid dispersions are
stable at normal and intermediate conditions.

Drug release of SDP 5
TIME % DR
of SDP
5
% DR
of SDP
5 (90
days)
5 10.2 9.8
10 25.22 23.52
15 42.78 40.27
30 65.67 63.45
45 82.37 80.21
60 98.27 98.16
0
20
40
60
80
100
120
0 5 10 15 30 45 60
Cum%drugrelease
Time (min)
Stability studies
SDP 5 (1 month)
SDP 5 ( 3 months)
16/12/2014

Conclusions
 Solid dispersions of carvedilol were successfully prepared
for improving the solubility and dissolution rate of this
poorly water soluble drug and evaluated.
 The results were found to be satisfactory that certain
carriers like Polaxomers when used in the preparation of
solid dispersions improved solubility of poorly water
soluble drugs like Carvedilol,Valsartan

Conclusions
 The stability studies results showed that prepared solid
dispersions drug release and physical appearance.
 The method solvent evaporation is very easy and efficient
for the preparation of solid dispersions.

References
 Irin Dewan et al “Formulation and Evaluation of Solid Dispersions of
Carvedilol, a Poorly Water Soluble Drug by Using Different Polymers”,
IJRPC 2012, 2(3), 585-593.
 J. Vijaya Ratna,” Effect of Hydrophilic Polymers on Solid Dispersions of
Carvedilol For Enhancing Its Dissolution Rate” ,Journal of Global Trends in
Pharmaceutical Sciences Vol.3, Issue 2, pp -708-713, April–June 2012.
 Y. Srinivasa Rao et al,” Formulation and Evaluation of Carvedilol Solid
Dispersions for Dissolution Rate Enhancement, IJAPBC – Vol. 1(4), Oct-
Dec, 2012 489-494.
 T.E.G.K. Murthy, Evaluation of Some Methods For Preparing Carvedilol-
Hydroxy Propyl- Β -Cyclodextrin Inclusion Complexes, Asian Journal of
Biochemical and Pharmaceutical Research Issue 2 (Vol. 1) 2011,676-683.

 Tapan Kumar Giri , Physicochemical Classification and Formulation
Development Of Solid Dispersion Of Poorly Water Soluble Drugs: An
Updated Review , International Journal of Pharmaceutical & Biological
Archives 2010; 1(4): 309-324 .
 Sarita Jangra Bhyan,” Formulation and evaluation of mouth dissolving
tablets containing carvedilol solid dispersion”, Der Pharmacia Lettre, 2013,
5 (6):31-42.
 Dipika Mandal et al,” Effect of Carriers on Solid Dispersions of Simvastatin
(Sim): Physico- Chemical Characterizations and Dissolution Studies, Der
Pharmacia Lettre, 2010, 2(4): 47-56
 Anshu Sharma and C.P. Jain,” Carvedilol-β-cyclodextrin Systems:
Preparation,Characterization and in vitro Evaluation, J. Pharm. Sci. 12(1):
51-58, 2013 (June)

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