Chirag Thesis Word
Chirag Thesis Word
Chirag Thesis Word
Chennai-600032
In partial fulfillment of the requirements for the award of degree of
MASTER OF PHARMACY
IN
PHARMACEUTICS
Submitted by
DEPARTMENT OF PHARMACEUTICS
ELAYAMPALAYAM
TIRUCHENGODE-637205
TAMILNADU.
MARCH-2013
CERTIFICATES
SWAMY VIVEKANANDA COLLEGE OF PHAMACY
Elayampalaym, Tiruchengode, 637205
Namakkal (DT), Tamilnadu.
Phone: 04288-234417 (8 lines)
Fax: 04288-234417
Principal
CERTIFICATE
CERTIFICATE
CERTIFICATE
This work is original and has not been submitted earlier for the award of any
other degree or diploma of this or any other university.
The Joyness, Satisfaction and euphoria that comes along with successful
completion of any work would be incomplete unless we mention names of the people
who made it possible, whose constant guidance and encouragement served as a beam
of light crowned out effects.
First and foremost I express bow down before Lord Almighty for his splendid
blessings and care in completing my project work and throughout my life till this very
second.
I take this opportunity to tell my special thanks to Ms. R.LATHA, for their
help and support in all my laboratory tests.
Also, I would like to thank the Tamil Nadu Dr. M.G.R. Medical University
for providing a nice environment for learning.
I fell delighted to express my whole hearted gratitude to all those who gave
their helping hands in completing my course and my project successfully.
V.Sella kumar
Reg.No:26115406
CONTENTS
CONTENTS
1. INTRODUCTION 1
2. REVIEW OF LITERATURE 3
3. AIM AND OBJECTIVE OF THE STUDY 16
4. PLAN OF WORK 17
5. DRUG PROFILE 18
6. MATERIALS AND METHODS 26
7. METHODOLOGY 27
10. CONCLUSION 62
11. REFFERENCES 63
INTRODUCTION
1. INTRODUCTION
The enhancement of oral bioavailability of poor water soluble drugs remains one
of the most challenging aspects of drug development. The development of solid
dispersions as a practically viable method to enhance bioavailability of poorly water-
soluble drugs overcame the limitations of previous approaches such as salt formation,
The poor solubility and low dissolution rate of poorly water soluble drugs in
form, poor bioavailability, increased food effect, and high inter-patient variability.³
Solid dispersion of drug helps to reduce the particle size of drug due to
enhance the dissolution rate; however, the apparent solubility remains unaltered. At
the molecular level, polymorphs offer a limited solubility advantage because of a
small difference in free energy. In contrast, amorphous systems with excess
thermodynamic properties and lower energetic barrier can offer significant
solubility benefits.8
2
REVIEWOF
LITERATURE
2. REVIEW OF LITERATURE
circulation.11
Where, dC/dt - is the rate of dissolution, A -is the surface area available for
dissolution, D - is the diffusion coefficient of the compound, Cs- is the solubility of
the compound in the dissolution medium, C -is the concentration of drug in the
medium at time t and h - is the thickness of the diffusion boundary layer adjacent to
the surface of the dissolving compound.13
3
To increase the dissolution rate from equation the following approaches are
available.
4
Nanosuspension:
Nanosuspensions are sub-micron colloidal dispersion of pure particles of
drug, which are stabilised by surfactants. Nanosuspension technology solved the
problem of drugs which are poorly aqueous soluble and less bioavailability.
Nanoemulsion:
Nanoemulsions are a nonequilibrium, heterogeneous system consisting of
two immiscible liquids in which one liquid is dispersed as droplets in another liquid.
Sonocrystallization:
Sonocrystallization is a novel particle engineering technique to enhance
solubility and dissolution of hydrophobic drugs and to study its effect on crystal
properties of drug.
Supercritical fluid method:
A supercritical fluid (SCF) can be defined as a dense noncondensablefluid is
another novel nanosizing and solubilisation technology whose application has
increased in recent years.
Spray freezing into liquid and lyophilization:
This technique involves atomizing an aqueous,organic, aqueous-organic
cosolvent solution, aqueous organic emulsion or suspension containing a drugand
pharmaceutical excipients directly into a compressed gas (i.e. carbon dioxide,
helium, propane,ethane), or the cryogenic liquids (i.e. nitrogen, argon or
hydrofluroethers).
Evaporative precipitation into aqueous solution:
This process utilizes rapid phase separation to nucleate and grow
nanoparticles and microparticles of lipophilic drugs.
Use of surfactant:
Surface active agents (surfactants) are substances which at low
concentrations, adsorb onto the surfaces or interfaces of a system and alter the
surface or interfacial free energy andthe surface or interfacial tension.
Use of co-solvent:
Cosolvent addition is a highly effective technique for enhancement of
solubility of poorly soluble drugs. It is well-known that the addition of an organic
cosolvent to water candramatically changes the solubility of drugs.
5
Hydrotropy method:
Hydrotropy is a solubilization phenomenon whereby addition of large
amount of a second solute results in an increase in the aqueous solubility of another
solute. The term “Hydrotropy” has been used to designate the increase in aqueous
solubility of various poorly watersoluble compounds due to the presence of a large
amount of additives.
Use of salt forms:
A major improvement in solubility and dissolution rate can be achieved by
forming a salt. Salts of acidic and basic drugs have, in general, higher solubilities
than their corresponding acid or base forms.
Solvent deposition:
In this technique drug is dissolved in a solvent like methylene chloride to
produce a clear solution. The carrier is then dispersed in the solution by stirring and
the solvent is removed by evaporation under temperature and pressure.
Solubilizing agents:
Solubilizing materials like super disintegrants such as
crospovidone,crosscarmellose sodium and sodium starch glycolate used as
solubilizing agents in many formulations which increase the solubilty and
dissolution rate of poorly water soluble drugs. The superdisintegrants acts as
hydrophilic carrier for poorly water soluble drug.
Modification of the crystal habit:
Polymorphism is the ability of an element or compound tocrystallize in more
than one crystalline form. Different polymorphs of drugs are chemically
identical,but they exhibit different physicochemical properties including solubility,
melting point, density, texture, stability etc.
Co-crystallisation:
The new approach available for the enhancement of drug solubility is
through the application of the co-crystals, also referred as molecular complexes.
6
Complexation:
7
1. Particle size reduction:
Solid dispersion represents the last state of the size reduction. It includes the
principle of drug release by creating a mixture of poorly water soluble drug and
highly soluble carriers, and after dissolution of carrier, the drug get molecularly
dispersed in dissolution medium.
2. Wettability:
Carriers having surface activity like cholic acid and bile salts, when used, can
significantly increase the wettability properties of drug. Recently, in third
generation solid dispersion surfactants have been included that is the emerging
technique.
3. Higher porosity:
Solid dispersions containing linear polymers produce larger and more
porous particles than those containing reticular polymers and therefore, result in a
higher dissolution rate.
4. Amorphous state of drug particles:
Drug particles in amorphous state have higher solubility.
5. Approaches for avoiding drug recrystallisation
Recrystallisation is the major disadvantage of solid dispersions, as we are
using amorphous drug particles and they are thermodynamically instable and have
the tendency to change to a more stable state. Several polymers are being used for
improving the physical stability of the amorphous drugs by increasing the Tg of the
miscible mixture.
8
DETECTION OF CRYSTALLINITY IN SOLID DISPERSIONS:
3. Water Vapoursorption
4. Isothermal Microcalorimetry
5. Dissolution Calorimetry
11
Tabel.1 Classification of Carriers Enhancing Dissolution of Drugs18
Galactomannan
4 Surfactants Polyoxyethylene stearate, Poloxamer,
Hydroxyalkyl xanthines
12
Fig.1 Methods of Preparation of Solid Dispersion
Fusion Method
The melting or fusion method, first proposed by Sekiguchi and Obi involves
the preparation of physical mixture of a drug and a water-soluble carrier and
heating it directly until it melted. The melted mixture is then solidified rapidly in an
ice bath under vigorous stirring. The final solid mass is crushed, pulverized and
sieved. However many substances, either drugs or carriers, may decompose or
evaporates during the fusion process which employs high temperature. Some of the
means to overcome these problems could be heating the physical mixture in a
sealed container or melting it under vacuum or in presence of inert gas like nitrogen
to prevent oxidative degradation of drug or carrier.20
13
Advantages
The main advantage of direct melting method is its simplicity and economy.
In addition melting under vacuum or blanket of an inert gas such as nitrogen
may be employed to prevent oxidation of drug or carrier.20
Disadvantages
Firstly, a major disadvantage is that the method can only be applied when
drug and matrix are compatible and when they mix well at the heating
temperature
A problem can arise during cooling when the drug-matrix miscibility
changes. In this case phase separation can occur. It was observed that when
the mixture was slowly cooled, crystalline drug occurred, whereas fast
cooling yielded amorphous solid dispersions.
Degradation of the drug and or matrix can occur during heating to
temperatures necessary to fuse matrix and drug. For example, to melt a
sugar matrix of galactose a temperature of 169°C was required and in order
to get the glassy PVP in the rubbery state a temperature of about 170°C is
required. Poly ethylene glycols melt at around 70°C and are therefore often
used for the preparation of solid dispersions with the fusion method.22
14
Work done so far to improve the solubility of atorvastatin calcium
15
AIM AND OBJECTIVE
3. AIM AND OBJECTIVE
AIM:
To Prepare and evaluate the novel drug – drug solid dispersion of
Atorvastatin calcium – Losartan potassium and to improve the solubility of
atorvastatin calcium by fusion method.
OBJECTIVE
To estimate the following parameters.
FTIR analysis of pure drugs, physical mixtures and solid dispersions.
Calibration curve of atorvastatin calcium.
Calibration curve of losartan potassium.
Preparation of physical mixtures (1:2, 1:4, 1:8 ratios).
Preparation of solid dispersions (1:2, 1:4, 1:8 ratios).
Phase solubility study of Atorvastatin calcium - Losartan potassium.
In-vitro dissolution of pure drugs, physical mixtures and solid dispersions.
Release kinetic study.
16
PLAN OF WORK
4. PLAN OF WORK
PREFORMULATION STUDY
ESTIMATION OF DRUGS
PREPARATIONS EVALUATIONS
METHOD I
PHYSICAL MIXTURE FTIR analysis
Calibration curve of
Atorvastatin (Atorvastatin calcium) and
Losartan potassium [1:2, 1:4, 1:8])
Phase solubility
METHOD II study
17
PROFILES
5. PROFILES
DRUG PROFILE
Atorvastatin calcium32
Chemical structure :
Isopropyl-3-phenyl-4-(phenylcarbamoly) pyrrole-1-
heptan
18
Pharmacology
Mechanism of Action
Pharmacokinetics
Absorption:
19
Distribution:
Metabolism
Excretion
Duration
Contraindications
20
10 to 80 mg/day.
Pharmacodynamics
Adverse Reactions
Respiratory : Bronchitis
edema.
Drug Interaction
21
LOSARTAN POTASSIUM33
Category : Antihypertensive
Mechanism of Action
Angiotensin II [formed from angiotensin I in a reaction catalyzed by
angiotensin converting enzyme (ACE, kininase II)], is a potent vasoconstrictor, the
primary vasoactive hormone of the renin-angiotensin system and an important
component in the pathophysiology of hypertension. It also stimulates aldosterone
secretion by the adrenal cortex. Losartan and its principal active metabolite block
the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively
blocking the binding of angiotensin II to the AT1receptor found in many tissues,
(e.g., vascular smooth muscle, adrenal gland). There is also an AT2receptor found in
many tissues but it is not known to be associated with cardiovascular homeostasis.
Both losartan and its principal active
22
metabolite do not exhibit any partial agonist activity at the AT1 receptor and have
much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2
receptor. In vitro binding studies indicate that losartan is a reversible, competitive
inhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by
weight than losartan and appears to be a reversible, non-competitive inhibitor of the
AT1 receptor. Neither losartan nor its active metabolite inhibits ACE (kininase II, the
enzyme that converts angiotensin I to angiotensin II and degrades bradykinin); nor
do they bind to or block other hormone receptors or ion channels known to be
important in cardiovascular regulation.
Pharmacokinetics
23
INDICATIONS
Hypertension
Adult’s Initial dose
Maintenance dose
PO 25 to 100 mg/day.
Maintenance dose
Drug Interactions:
Losartan may increase levels of blood potassium (hyperkalemia), which can lead to
serious heart problems (arrhythmias). Therefore, concomitant use of other drugs or
substances that increase blood-such as potassium-sparing diuretics (for
example, spironolactone [Aldactone], triamterene, and amiloride), potassium
supplements, or salt substitutes containing potassium may lead to dangerous
increases in serum potassium.Combining losartan or other ARBs with non steroidal
anti-inflammatory drugs (NSAIDs) in patients who are elderly, fluid-depleted
(including those on diuretic
24
therapy), or with poor kidney function may result in reduced kidney function,
including kidney failure. These effects usually are reversible. The antihypertensive
effect of losartan may be reduced by aspirin and other NSAIDs such
as ibuprofen (Advil, Children's Advil/Motrin, Medipren, Motrin, Nuprin, PediaCare
Fever, etc.), indomethacin (Indocin, Indocin-SR), and naproxen (Anaprox, Naprelan,
Naprosyn, Aleve).
Contraindications
25
MATERIALS
6. MATERIALS AND METHODS
INSTRUMENTS USED:
Mixed Standard
27
PREPARATION OF PHYSICAL MIXTURE AND SOLID DISPERSION:
28
Evaluation of formulations
The prepared formulations of solid dispersion and physical mixture were evaluated
for the following
a. Physico-chemical characterization.
b. In vitro dissolution studies
Compatibility study
For drug content uniformity test, The powder equivalent to 10 mg of AVT was
dissolved in about 10 ml of methanol an transferred into 100 ml of volumetric flask
and volume was made up using phosphate buffer (pH 6.8) and the solution was
filtered using (Whatmann No. 1 filter paper). The AVT content in the filtrate was
determined by measuring the absorbance at 248 nm using UV spectrophotometer
after appropriate dilution with phosphate buffer (pH 6.8). The drug content was
determined using the standard calibration curve.
For drug content uniformity test, The powder equivalent to 10 mg of LSP was
dissolved in about 10 ml of methanol an transferred into 100 ml of volumetric flask
and volume was made up using phosphate buffer (pH 6.8) and the solution was
filtered using (Whatmann No. 1 filter paper). The AVT content in the filtrate was
determined by measuring the absorbance at 248 nm using UV spectrophotometer
after appropriate dilution with
29
phosphate buffer (pH 6.8). The drug content was determined using the standard
calibration curve.
Drug solubility studies were performed in triplicate by adding excess amount of ATV
to distilled water and buffer solutions having different pH (6.8). Solutions containing
flasks were kept on a Rotary Shaking Incubator for 24 hrs. After 24 hrs, solutions
were analysed using UV spectrophotometer.
In vitro dissolution studies of the pure drug (AVT), the selected ratios of solid
dispersions and physical mixtures (equivalent to 10mg ATV filled in hard gelatin
capsules using stainless steel sinkers) were performed using USP type II (Paddle)
apparatus with paddle rotating at 75 rpm in 900ml of phosphate buffer pH 6.8 at 37
± 0.5ºC. At fixed time intervals, 5ml samples were withdrawn, filtered and replaced
with phosphate buffer pH 6.8. Concentration of AVT in each sample was determined
by UV spectrophotometer.
The results of in vitro release profile obtained for all the formulations were
plotted in modes of data treatment as follows:-
1. Zero-order kinetics
At = A0 - K 0 t
30
Where,
When the data is plotted as cumulative percent drug release versus time, if the
plot is linear then the data obeys zero-order release kinetics, with a slope equal to
K0.
Where,
When the data is plotted as log cumulative percent drug remaining versus
time yields a straight line, indicating that the release follow first order kinetics. The
constant K can be obtained by multiplying 2.303 with slope values.
31
RESULTS
8. RESULTS
y = 0.062x - 0.002
calibration curve of Atorvastatin calcium R² = 0.998
0.4
0.3
Absorbance
0.2
0.1
0
-0.1 0 1 2 3 4 5 6
concentration(µg/ml)
Fig.2
32
0 0 0
1 1 0.0656
2 2 0.1290
3 3 0.1825
4 4 0.2482
5 5 0.3166
0.2
0.15
0.1
0.05
0
0 1 2 3 4 5 6
Concentration (µg/ml)
Fig.3
33
Compatibility study (Fourier transform infrared spectroscopic studies)
34
Fig.4 FTIR SPECTRA OF PURE ATORVASTATIN CALCIUM
35
Fig.5 FTIR SPECTRA OF PURE LOSARTAN POTASSIUM
36
Fig.6 FTIR SPECTRA OF AVT AND LSP (F2PM) (1:4)
37
Fig.7 FTIR SPECTRA OF HCT AND LSP (F3PM) (1:8)
38
Fig.8 FTIR SPECTRA OF HCT AND LSP (F2SD) (1:4)
39
Fig.9 FTIR SPECTRA OF HCT AND LSP (F3SD) (1:8)
40
ESTIMATION OF DRUG CONTENT
Absorbance of Absorbance of
S.No Concentration 0f drug Atorvastatin calcium Losartan potassium
(µg/mL) At 248nm at 236nm
1 10 0.02 0.03
2 20 0.73 0.82
3 30 1.44 1.72
4 40 2.19 2.58
5 50 2.78 3.25
6 60 3.57 4.01
2
1.5
1 ATV
0.5 LSP
0
0102030405060
concentration(µg/ml) Fig.10
41
PHASE SOLUBILITY STUDY
Phase solubility study was carried out in order to ascertain the effect of LSP
on the solubility characteristics of AVT. The results are presented in Table -8 and
Figure -11. Solubility of AVT was increased as the concentration of LSP increased.
The solubility of AVT was minimal in PH 6.8 and increased approximately eight fold
at 0.01% w/v of LSP in 6.8buffer. These data indicates that LSP in PH 6.8 acted as a
new vehicle and solubility of AVT was greatly enhanced, possibly due to the solvent
effect of LSP.
Table. 8
2 0.0025 0.3610
3 0.0050 0.5270
4 0.010 0.010
0.15
0.1
(µg/ml)
0.05
0
0 0.5 1 1.5 2 2.5 3 3.5
concentration (µg/ml)
Fig.11
42
In-vitro dissolution studies
43
Table. 9 In-Vitro Dissolution Profile of Pure Atorvastatin calcium
0 0 0 0 0
30
20
10
0
0 20 40 60 80 100
Time Fig.12
44
Table. 10 In-Vitro Dissolution Profile of Pure Lossartan potassium
0 0 0 0 0
100
50
0
0 20 40 60 80 100
Time
Fig.13
45
Table. 11 In-vitro Dissolution Profile for F1PM
46
%Drug release of AVT from F1PM
250
%Drug release
200
150
100
50
0
0 20 40 60 80 100
Time Fig.14
200
150
100
50
0
0 20 40 60 80 100
Time
Fig.15
2
1.5
1
0.5
0
-0.5 0
20 40 60 80 100
Time
Fig.16
47
Table. 12 In-vitro Dissolution Profile for F2PM
48
% Drug Release of AVT from F2 PM
300
% Drug Release
200
100
0
0 20 40 60 80 100
Time
Fig.17
y = 1.024x + 16.37
Zero order plot of AVT from F2 R² = 0.884
PM
300
%Drug Release
200
100
0
0 20 40 60 80 100
Time
Fig.18
y = -0.019x + 1.663
First order plot of AVT from F2PM R² = 0.959
3
%Drug Remaning
2
1
0
-1 0
20 40 60 80 100
Time
Fig.19
49
Table. 13 In-vitro Dissolution Profile for F3PM
50
% Drug release of AVT from F3PM
300
% Drug Release
200
100
0
0 20 40 60 80 100
Time Fig.20
300
% Drug Release
200
100
0
0 20 40 60 80 100
Time
Fig.21
2.5
%Drug Remaning
2
1.5
1
0.5
0
-0.5 0 20 40 60 80 100
Time
51
F
i
g
.
2
2
51
Table. 14 In-vitro dissolution profile for F1SD
52
% Drug release of AVT from F1SD
300
% Drug Release
200
100
0
0 20 40 60 80 100
Time Fig.23
y = 1.026x + 19.38
Zero order plot of AVT From F2SD R² = 0.881
300
% Drug Release
200
100
0
0 20 40 60 80 100
Time Fig.24
3
% Drug Reamining
2
1
0
0 20 40 60 80 100
Time
Fig.25
53
Table. 15 In-vitro dissolution profile for F2SD
54
% Drug Release of AVT from F2SD
300
% Drug Release
200
100
0
0 20 40 60 80 100
Time Fig.26
200
100
0
0 20 40 60 80 100
Time
Fig.27
2
1
0
-1 0 20 40 60 80 100
Time
Fig.28
55
Table. 16 In-vitro dissolution profile for F3SD
56
% Drug release of AVT from F3SD
250
% Drug Release
200
150
100
50
0
0 20 40 60 80 100
Time Fig.29
200
100
0
0 20 40 60 80 100
Time
Fig.30
2
1
-1 0 20 40 60 80 100
Time
Fig.31
57
Table. 17 Release kinetic study
Zero order 0.989 0.992 0.894 0.884 0.868 0.881 0.816 0.806
“R2”value
First order 0.994 0.997 0.946 0.959 0.970 0.922 0.883 0.868
“R2”value
Best fit First First First First First First First First
model order order order order order order order order
58
Table. 18 Comparative % Dissolution of physical mixtures
60 F1PM AVT
40 F1PM LSP F2PM AVT F2PM LSP F3PM AVT
20 F3PM LSP
0
020406080100
Time Fig.32
59
Table. 19 Comparative % dissolution profile of solid dispersions
0 0 0 0 0 0 0
80 F1SD AVT
60 F1SD LSP F2SD AVT
40 F2SD LSP
20
0
60
DISCUSSION
9. DISCUSSION
The results of the present study demonstrate that a novel drug-drug solid
dispersion approach can improve dissolution and pharmacokinetic characteristics of
the poorly soluble drug that was presented with the soluble drug. This novel
approach will obviate the need for inclusion of physiological water soluble inert
carriers in solid dispersion and so cost effective. Besides, this approach stabilizes the
formulation from the effect of moisture that is normally encountered in solid
dispersions prepared with physiological inert carriers.
The amorphous form of AVT was more soluble than its crystalline form and
so an improved dissolution of AVT was observed from solid dispersion. Additionally
LSP which is freely soluble has increased the solubility of AVT due to its solvent
effect as shown in phase solubility study.
The pure drug AVT at 90 min dissolved 59% of release and pure drug LSP AT
90 min dissolved 98% of release. The PM AVT shows at 90 min dissolved 97% of
release the PM LST shows at 90min dissolved 98% of release. The SD AVT shows at
90min dissolved 98% of release the SD LSP shows at 90min dissolved 99% of
release.
61
CONCLUSION
10. CONCLUSION
The present study shows improved dissolution of AVT from a modified novel
drug - drug solid dispersion along with LSP.
Dissolution of AVT was better from AVT - LSP solid dispersion as compared to
physical mixture and pure drug.
This novel solid dispersion is stable as no physiological inert carriers that are
affected by moisture are used.
Cost effective and economical as this approach is free of the economical
burden of physiological inert carriers.
62
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