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INTENSIFICATION OF THE SOLUBILITY OF BCS CLASS II DRUG
CARVEDILOL USING SPRAY DRYING BY FORMULATING A SOLID
DISPERSION
Tina Raju*
Assistant Professor, DM WIMS College of Pharmacy, Naseera Nagar, Meppadi P. O.,
Wayanad, 673577.
ABSTRACT
Orally administered drugs completely absorb only when they show fair
solubility in gastric medium and such drugs shows good
bioavailability. The solubility and dissolution properties of drugs play
an important role in the process of formulation development. Problem
of solubility is a major challenge for formulation scientist which can be
solved by different technological approaches during the
pharmaceutical product development work. A major problem with
BCS class II drug is their low solubility in biological fluids, which
results into poor bioavailability after oral administration. Carvedilol is
a non-selective beta and alpha blocker which is insoluble in water. It is
used in the treatment of mild to severe congestive heart failure (CHF)
and high blood pressure. As the solubility is very poor the bioavailability is only 25-35%.
The problem of poor solubility can be overcome using any of the physical or chemical
methods of solubility enhancement. The purpose of this research was to improve the
solubility of Carvedilol by spray drying technique using hydrophilic polymers β-Cyclodextrin
and Plasdone-K30. Prepared solid dispersions were evaluated for drug content, saturation
solubility and in-vitro drug release study. The compatibility and surface morphology was
studied by Fourier Transforms Infrared spectroscopy (FTIR), Differential Scanning
Calorimetry (DSC) and Scanning Electron Microscopy (SEM) respectively.
KEYWORDS: Bioavailability, Carvedilol, Hypertension, PVP-K30, Solid dispersion.
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 7.421
Volume 7, Issue 5, 1261-1281 Research Article ISSN 2278 – 4357
*Corresponding Author
Tina Raju
Assistant Professor, DM
WIMS College of
Pharmacy, Naseera Nagar,
Meppadi P. O., Wayanad,
673577.
Article Received on
06 March 2018,
Revised on 26 March 2018,
Accepted on 17 April 2018,
DOI: 10.20959/wjpps20185-11565
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INTRODUCTION
Oral formulation has been the preferred and most common route of drug delivery around
the globe. The popularity of this dosage form is owing to its ease of administration and
good patient compliance. But for many drugs, formulation of solid dosage form can be an
inefficient mode for administration as approximately 40% or more of the NCE being
generated through drug discovery programs have problem in water-solubility. For drugs
with poor aqueous solubility, dissolution is the rate limiting step for its bioavailability.[2,5]
The therapeutic effect of drugs depends on the drug concentration at the site of action.
The absorption of the drug into the systemic circulation is a prerequisite to reach the site of
action for all drugs, except those drugs that are applied at the site of action, or
intravenously injected.[8,9,11]
In general it can be stated that the rate of absorption, therefore,
onset and extent of the clinical effect, is determined by the dissolution of the drug and the
subsequent transport through the biological membrane. Therefore, together with the
permeability, the solubility and dissolution property of a drug are key determinants of its
oral bioavailability.[1,3]
The process of „Solubilization‟ involves the breaking of inter-ionic or intermolecular bonds in
the solute, the separation of the molecules of the solvent to provide space in the solvent for
the solute, interaction between the solvent and the solute molecule or ion.[12,14]
The
formulation of hydrophobic drugs as solid dispersions is a significant area of research
aimed at improving the dissolution and bioavailability of hydrophobic drugs.[5,8]
Solid
dispersions consisting of two components in the solid state are referred to as binary systems.
The two components are a water-soluble carrier and a hydrophobic drug dispersed in the
carrier substance.[5]
Chiou and Riegelman defined the term solid dispersion as „the dispersion of one or more
active ingredients in an inert carrier matrix at solid-state prepared by the melting (fusion),
solvent or melting- solvent method. On the other hand, Corrigan suggested the definition as
„product formed by converting a fluid drug-carrier combination to the solid state‟. Spray
drying can be used to formulate solid dispersion of a hydrophobic drug using the principle of
solvent evaporation in which atomization of a solution of one or more solids via a nozzle,
spinning disk or other device followed by evaporation of the solvent from the droplets takes
place.[25,26]
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MATERIALS AND METHODS
Carvedilol was supplied as a gift sample by Mylan Laboratories, Bangalore. β-Cyclodextrin,
Plasdone K-30 and Methanol were provided by Research Lab Fine Chem. Industries,
Mumbai. The Spray Dryer of model Labultima LU222 Advanced was used for preparing
solid dispersion.
1.0 METHODS
1.0.1 Characterization of drug
1. Organoleptic properties
The sample of Carvedilol was analyzed for its colour, odour and physical appearance.
2. Determination of Melting Point
Melting point of Carvedilol was determined by open capillary method using Thiel‟s tube.
Average of triplicate readings was taken, and compared with literature.
1.0.2 Spectroscopic analysis
1. Determination of λmax
Carvedilol (10mg) was dissolved in 10ml of methanol to obtain the stock solution of
concentration 100μg/ml. From this stock solution, 1 ml was withdrawn and diluted to 10ml to
obtain solution of 10μg/ml. Absorbance was checked using UV-spectrophotometer in the
wavelength range of 200-400nm.
2. Preparation of calibration curve for Carvedilol
Stock solution of 100μg/ml was prepared by dissolving 10mg pure drug into 10ml methanol.
The further dilutions (2-16μg/ml) were prepared using methanol. Absorbance were recorded
at 241nm using UV-Spectrophotometer, standard curve was plotted and values of slope,
intercept and coefficient of correlation were calculated.
3. Determination of saturation solubility of Carvedilol
Solubility of Carvedilol was determined in solution of distilled water, 0.1N HCl (pH 1.2) and
phosphate buffer (pH 6.8). Initially, excess amount of Carvedilol was added to 10ml each of
the above solutions in 10ml volumetric flask. Then these volumetric flasks were shaken using
mechanical shaker for 24hours. The samples were then filtered, diluted suitably and analyzed
spectrophotometrically at 241nm. Triplicate reading were taken.
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1.0.3 Compatibility study between drug and excipients
1. FTIR spectroscopic study of drug and polymers
The infrared absorption spectrum of pure Carvedilol, Plasdone K-30, β-cyclodextrin, and the
physical mixture of carvedilol with the polymers Plasdone K-30, β-cyclodextrin were
recorded on FTIR spectrophotometer for evaluating the chemical compatibility of Carvedilol
with the hydrophilic polymers. The spectra were taken after preparing the pellet using 2-4mg
of sample with potassium bromide as a reference compound and the sample was scanned
under IR radiation from 4000-400cm-1
.
2. Differential Scanning Calorimetry (DSC) study of drug
DSC was performed in order to assess the thermotropic properties and thermal behaviour of
the drug (Carvedilol) and the prepared solid dispersion. Samples were sealed in an aluminium
pan and heated at the rate of 100C/min from 30
0C-300
0C under nitrogen atmosphere with
flow rate of 10ml/min. Thermograms of pure Carvedilol and optimized batch of solid
dispersion were recorded using METTLER DSC 30S, Mettler Toledo India Pvt. Ltd.
instrument equipped with an intracooler.
3. Powder X -Ray diffraction (PXRD) study of drug
Powder X-ray diffraction patterns were recorded for the pure Carvedilol to determine its
crystalline nature using Brucker D2 Phaser X-diffractometer.
1.1 EXPERIMENTAL WORK
1.1.1 Formulation of Solid Dispersion using Spray Drying Technique
1) Composition of solid dispersion of Carvedilol
Solid dispersions of Carvedilol with β-cyclodextrin and Plasdone K-30 were prepared at three
drug:polymer molar ratios, 1:1, 1:2 and 1:3 using spray drying technique. The formulation
table is shown in table no.1.
Table No.1: Formulation Table for preparing solid dispersion.
Batch Code Carvedilol(gm) β-cyclodextrin(gm) Plasdone K-
30(gm)
SD1 1 1 -
SD2 1 2 -
SD3 1 3 -
SD4 1 - 1
SD5 1 - 2
SD6 1 - 3
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2) Formulation of solid dispersion using Spray Drying
Carvedilol solid dispersions were prepared by solvent evaporation method using carriers (β-
cyclodextrin and Plasdone K-30) in proportions viz. 1:1, 1:2 and 1:3 (drug : carrier). The drug
and carrier were dissolved in methanol (100ml). The solvent was evaporated by spray drying
process, which was carried out using laboratory scale spray dryer. The parameters of spray
drying were set as shown in Table no.2. The powder was stored in desiccators until further
evaluation.
Table No.2: Spray Drying Parameters.
Sr. No. Parameters Values
1 Inlet Temperature 350C
2 Outlet Temperature 350 C
3 Cool Temperature 500 C
4 Inlet high 500 C
5 Outlet high 400 C
6 Aspiratory Flow Rate 40 Nm2/hr
7 Feed Pump Flow Rate 2 ml/min
8 D-Block on 1 second
9 D-Block off 60 second
10 Data Log Interval 60 second
1.1.2 Characterization of Solid Dispersion
1) Determination of Percentage yield
The yield of the final solid dispersion of all ratios was calculated by using the final weight of
solid dispersion after drying and the initial weight of drug and polymer used for preparation
of solid dispersion. The following formula is used for calculation of percent practical yield-
2) Determination of drug content of prepared solid dispersions
The percentage drug content in solid dispersion was estimated by dissolving quantities
equivalent to 10mg of solid dispersion in 10ml methanol, centrifuged for 10min and filtered
through 0.45μm membrane filter, appropriately diluted with distilled water and the UV
absorbance were recorded at 241nm by using UV-visible spectrophotometer. The percentage
drug content was calculated using the following formula.
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3) Determination of saturation solubility of prepared solid dispersions
Excess amount of solid dispersions were added to 250ml conical flasks containing 25ml of
distilled water. The sealed flasks were shaken for 24hrs at 37±0.5ºC. Then aliquots were
filtered through Whatmann filter paper. The concentration of Carvedilol was determined by
UV spectrophotometer at 241nm. Saturation solubility study was also performed in 1.2pH
phosphate buffer and 6.8pH buffers.
4) FTIR study of solid dispersion
Infrared spectra of solid dispersion powder was obtained using FTIR spectrometer in the
range of 4000-400cm-1
. This was done to study about the compatibility between drug and
polymers in the solid dispersion.
5) Differential Scanning Calorimetry (DSC) study of solid dispersion
DSC was performed to characterize thermal changes in the melting behavior of Carvedilol
with polymers present in solid dispersion. DSC study also reveals whether the drug is in
crystalline or in amorphous form. The study of prepared solid dispersion were carried out
using thermal analyzer. DSC studies were carried out using thermal analyzer (TA SDT-
2790). The samples were hermetically sealed in an aluminum pan and heated at constant rate
of 100C/min over a temperature range of 30-300
0C. Inert atmosphere was maintained by
purging nitrogen gas at a flow of 10ml/min.
6) Scanning Electron Microscopy (SEM) study of solid dispersion
SEM of optimized solid dispersion batch was carried out using JSM 6360, JEOL India Pvt.
Ltd. to study the morphological characteristics of the solid dispersion.
7) In-vitro dissolution studies of Carvedilol solid dispersion systems
Dissolution study under gastric conditions, intended to select the solid dispersion system with
superior dissolution properties to be incorporated into the formulation of immediate release
tablet, were performed using the USP dissolution apparatus II at 50 rpm. A sample equivalent
to 12.5mg of Carvedilol was placed in the dissolution vessel containing 900ml of 0.1N HCl
maintained at 37±0.50C. At appropriate intervals, samples from the dissolution medium
werewithdrawn, filtered, and concentrations of Carvedilol were determined
spectrophotometrically at 241nm. The dissolution studies were conducted in triplicate and the
cumulative % drug release was plotted against time.
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RESULTS AND DISCUSSION
1.1 AUTHENTICATION OF DRUG
1. Organoleptic Properties
Carvedilol is a white, odourless, bitter fine crystalline powder.
2. Melting point of Carvedilol
The temperature at which solid drug changes into liquid was noted as the melting point of the
Carvedilol. It was found to be 114-1160C. (Std. - 116-118
0C).
1.2 SPECTROSCOPIC ANALYSIS
1.2.1 Determination of λmax of Carvedilol
The standard solution of Carvedilol of concentration 10µg/ml showed maximum
absorbance at the wavelength of 241nm. Hence the λmax of Carvedilol was found to be
241nm.
Fig. 1: λmax of Carvedilol.
1.2.2 Plotting of Calibration curve for Carvedilol
Calibration curve of Carvedilol in 0.1 N HCl (pH 1.2) showed straight line which passes from
origin. The Beer‟s Lambert‟s law was found to be obeyed over the range of 2-16μg/ml.
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Table No.3: Data for calibration curve of Carvedilol in 0.1 N HCl
Concentration
(μg/ml) Absorbance*
0 0.0000±0.012
2 0.0875±0.011
4 0.1874±0.013
6 0.2515±0.011
8 0.3581±0.013
10 0.4312±0.014
12 0.4962±0.012
14 0.5681±0.013
16 0.6620±0.013
*All values are expressed as mean ± SD (n=3)
Fig. 2: Calibration curve of Carvedilol in 0.1N HCl (pH 1.2).
The details of calibration curve are as given below
Equation is, y = mx+c
Where, y =absorbance, m = slope, x = concentration and c = intercept
From the calibration curve equation obtained was.
y= 0.040x+0.012.
Table No.4: Values obtained from standard calibration curve of Carvedilol
Regression
Coefficient (R2)
0.997
Slope(m) 0.040
Intercept(c) 0.012
1.2.3 Saturation solubility of Carvedilol
Solubility of Carvedilol was determined in solution of 0.1N HCl (pH 1.2), distilled water and
phosphate buffer (pH 6.8).
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Table No.5: Saturation solubility of Carvedilol in different solvents
Solvent Saturation Solubility
( mg/ml)*
Distilled Water 0.0044±0.3
0.1N HCl(pH 1.2) 0.7642±0.2
pH 6.8 phosphate buffer 0.5491±0.3
*All values are expressed as mean ± SD (n=3)
1.3 COMPATIBILITY STUDY BETWEEN DRUG AND EXCIPIENTS
1.3.1 FTIR spectra of Carvedilol
Fig.3 shows the typical Fourier transform-infrared (FTIR) spectrum of Carvedilol in the
range of 4000 to 400cm−1
.
Fig. 3: FTIR Spectrum of Carvedilol.
Table no.6: Interpretation of FTIR spectra of Carvedilol.
Sr. No. Peak position Functional Group
1 3408.57cm-1
N-H and O-H stretching
2 2360.44cm-1
C-H stretching
3 1603.52cm-1
N-H bending
4 1347.03cm-1
O-H bending
The IR spectrum of pure carvedilol showed the peak at 3408.57cm–1
which corresponds to N-
H stretching. The hetero-aromatic structure shows the presence of the C-H stretching
vibrations in the region 2360.44cm–1
. The bands corresponding to the in-plane C-H
deformations are observed in the regions 1,000 to 1,300cm−1
. The bands are sharp but of
weak to minimum intensity. A medium experimental peak around 1252 to 1402cm−1
in the
FT-IR was assigned to the C-C stretching vibrations. The bands in the regions 1502 to
1603.52cm−1
observed in both FTIR were assigned to the C = C stretching vibrations.
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1.3.2 FTIR spectra of β-cyclodextrin
Fig. 4: FTIR spectra of β-cyclodextrin.
The IR spectra of β-cyclodextrin shows a broad band at 3381.57cm-1
, which is caused by the
valence vibrations of the O-H bonds in the primary hydroxyl groups (C – 6 - OH) connected
by the intermolecular hydrogen bonds or in the secondary hydroxyl groups connected by the
intramolecular hydrogen bonds (the C – 2 - OH group of one glucopyranose unit and C – 3 -
OH group of the adjacent glucopyranose unit). Also, in the IR spectrum of β-CD the
absorption band with maximum at 2919.7cm-1
is observed. It belongs to the valence
vibrations of the C-H bonds in the CH and CH2 groups. In the region 1400 - 1200cm-1
the
absorption bands of the deformation vibrations of the С-Н bonds in the primary and
secondary hydroxyl groups of β-CD (1384.64cm-1
) and in the interval 1200-1030сm-1
the
absorption bands of the valence vibrations of the С-О bonds in the ether and hydroxyl groups
of β-CD (1157.06 and 1029.8cm-1
) are registered. The absorption bands in the region 950 -
700cm-1
belongs to the deformation vibrations of the С-Н bonds and the pulsation vibrations
in glucopyranose cycle present in β-cyclodextrin structure.
1.3.3 FTIR spectra of Plasdone K-30-
Fig. 5: FTIR spectra of Plasdone K-30.
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A broad band at 2360.44cm−1
in the spectrum of Plasdone K-30 shows the C-H stretching
vibrations, and the vibration band of C=O group appears at 1630.52cm−1
suggesting some H-
bonding carbonyl groups exist in Plasdone K-30. The characteristic C-N stretching vibration
is observed at 1384.64cm-1
.
1.3.4 FTIR spectra of Carvedilol with β-cyclodextrin
Fig. 6: FTIR spectra of Carvedilol with β-cyclodextrin.
Inclusion complex formation may be confirmed by IR spectroscopy because bands resulting
from the included “guest” molecule are generally shifted or their intensities are altered. The
broadening of the peak may be due to the inter-molecular H-bonding between the OH groups
of Carvedilol and β-cyclodextrin during the inclusion complex formation. Also, no significant
change in the characteristic peaks present in the pure drug were observed which shows that β-
cyclodextrin is compatible with Carvedilol.
1.3.5 FTIR spectra of Carvedilol with Plasdone K-30
Fig. 7: FTIR spectra of Carvedilol with Plasdone K-30.
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The results revealed no considerable changes in the IR peaks of Carvedilol, when mixed with
polymer Plasdone K-30. These observations indicated the compatibility of Plasdone K-30
with Carvedilol. IR spectra indicated no well-defined interaction between the drug and
polymer.
1.3.6 DSC study of Carvedilol
DSC enables the quantitative detection of all processes in which energy is required or
produced (i.e., endothermic or exothermic phase transformations). The thermal analysis of a
compound utilizing DSC, usually offers information about several physicochemical
properties such as crystalline nature and thermal stability of the investigated compound.
The DSC curve of Carvedilol showed a sharp endothermic peak (Tpeak = 117.65°C)
corresponding to its melting point which indicates its crystalline nature (Fig.8).
Fig. 8: DSC curve of Carvedilol.
1.3.7 Powder X - Ray diffraction (PXRD) study of Carvedilol
The X-ray diffractogram of Carvedilol was characterized by the presence of sharp peaks
indicative of the crystalline nature of drug (fig. 9).
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Fig. 9: PXRD curve of Carvedilol
1.4 CHARACTERIZATION OF SOLID DISPERSIONS
1.4.1 Percentage Practical Yield
The results of percent practical yield studies are shown in Table no.7. The % Practical yield
of the prepared solid dispersions by spray dryer method was found to be maximum for batch
SD4 (69.73%).
Table No.7: Percentage practical yield of various batches of solid dispersion
Sr. No. Batch code Percentage Yield
1 SD1 62.85%
2 SD2 57.49%
3 SD3 65.28%
4 SD4 69.73%
5 SD5 65.71%
6 SD6 59.14%
1.4.2 Drug content of solid dispersions
The drug content in the spray dried solid dispersion was found to be 66.87 to 87.53%
suggesting that the spray drying process was successful in achieving good encapsulation of
the drug. Percent drug content of Carvedilol in spray dried solid dispersions was found to be
increased with increase in the concentration of hydrophilic carriers. The batch SD6 with
drug:carrier ( Carvedilol: Plasdone K30) ratio of 1:3 showed high drug content. Hence this
batch can be incorporated into tablet formulation. The percent drug content values of
Carvedilol in different solid dispersion batches are shown in Table no.8.
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Table No.8: Drug content of solid dispersion.
Sr. No. Batch code % drug content
1 SD1 66.87%
2 SD2 82.61%
3 SD3 84.42%
4 SD4 72.38%
5 SD5 79.96%
6 SD6 87.53%
1.4.3 Saturation solubility of solid dispersions in various solvents
The solubility of spray dried solid dispersions of Carvedilol in distilled water, 0.1N HCl (pH
1.2) and in phosphate buffer (pH 6.8) was determined so as to select an appropriate batch of
solid dispersion for further formulation of tablets.
The increase in solubility was found to be linear with respect to the increase in the
concentration of carrier. The batch SD6 with drug to Plasdone K-30 ratio of 1:3 showed
greater increase in the solubility as compared to β-cyclodextrin. This is due to the greater
hydrophilicity of Plasdone K30 than β-cyclodextrin. PVP polymers cause a reduction in the
interfacial tension between the drug and the dissolving solution. Moreover, it was suggested
that Plasdone K30 might form soluble complexes with the drug. Also the wettability and
porosity of the particles was also increased. The results of solubility study of solid dispersion
of Carvedilol are tabulated in Table no.9.
Table No.9: Saturation Solubility of various batches of solid dispersion.
Batch
Code Polymer
Drug:Polymer
ratio
Solvents
Distilled
water*
0.1N HCl
(pH 1.2)*
Phosphate
buffer
(pH 6.8)*
SD1 β-
cyclodextrin
1:1 0.3854±0.2 0.8754±0.3 0.6749±0.4
SD2 1:2 0.6749±0.2 0.9916±0.2 0.8443±0.1
SD3 1:3 0.8357±0.4 1.2837±0.4 1.3786±0.1
SD4 Plasdone
K-30
1:1 0.3774±0.3 1.8412±0.3 0.7692±0.2
SD5 1:2 0.8576±0.4 2.6348±0.4 1.0428±0.3
SD6 1:3 1.1729±0.4 4.1587±0.2 1.4287±0.2
*All values are expressed as mean ± SD (n=3)
1.4.4 In-vitro drug release study of solid dispersion
The dissolution profiles of solid dispersion batches are shown in (Table no.10). It was evident
that the pure drug exhibited a slow dissolution even after 60 minutes where the percentage of
drug dissolved after 60minutes only reached about 18.58±0.02%. This is due to the
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hydrophobicity, poor wettability and/or agglomeration of Carvedilol particles resulting into
hindering its dissolution. All solid dispersions showed enhanced dissolution rate compared to
pure Carvedilol that might be due to the effect of hydrophilic carriers on drug wettability and
dispersibility. These results could be attributed to the general phenomenon of particle size
reduction of Carvedilol particle during the spray drying operation. Also, solubilisation,
molecular/colloidal dispersion of drug in the mixture and reduction in the drug crystallinity
(i.e. polymorphic transformation of drug crystals) that were obtained via the formulation of
solid dispersions using spray dryer could have contributed to the increase in solubility.
The batch SD6 with Carvedilol to Plasdone K-30 ratio of 1:3 showed the maximum drug
release as compared to the other batches. The drug release profile of the solid dispersion
batches is shown in fig.10 and 11.
Table No.10: Cumulative % drug release data of Solid dispersion batches.
Sr.
No Time (min)
% Cumulative drug release*
Pure drug SD1 SD2 SD3 SD4 SD5 SD6
1 0 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00
2 10 3.31±0.03 12.45±0.05 19.34±0.06 26.47±0.05 32.67±0.03 39.57±0.03 43.56±0.03
3 20 5.73±0.01 33.48±0.06 39.37±0.03 37.46±0.02 48.29±0.01 47.67±0.03 58.26±0.02
4 30 8.06±0.03 48.87±0.05 46.35±0.02 52.67±0.03 54.42±0.03 59.34±0.01 69.41±0.06
5 40 11.41±0.02 66.48±0.04 59.14±0.03 68.77±0.03 63.97±0.03 69.44±0.02 84.19±0.03
6 50 13.67±0.02 75.95±0.06 76.73±0.03 80.91±0.01 71.26±0.01 76.99±0.01 89.61±0.04
7. 60 18.58±0.02 79.37±0.04 81.16±0.01 88.38±0.03 78.96±0.03 89.76±0.03 93.39±0.06
*All values are expressed as mean ± SD (n=3)
Fig. 10: Cumulative drug release profile of pure drug,SD1,SD2 and SD3.
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Fig. 11: Cumulative drug release profile of pure drug,SD4,SD5 and SD6.
1.4.5 FTIR Spectra of optimized solid dispersion batch (SD6)
Fig. 12: FTIR spectra of batch SD6.
The effect of the polymer Plasdone K-30 on Carvedilol was studied through interaction
studies. The IR spectra of the optimized batch SD6 was scanned in the range of 4000-400cm-
1. If the drug and the polymer would interact, then the functional groups in the FTIR spectra
would show band shifts and broadening compared to the spectra for the pure drug and
polymer. The FTIR spectra obtained from solid dispersions showed peaks which were a
summation of the characteristic peaks obtained with the pure drug and pure carriers and
spectra‟s can be simply regarded as the superposition of those of Carvedilol and carriers. This
showed that there was no chemical interaction of the drug with carriers even in the
amorphous state when the granules were prepared by the solid dispersion method. An
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increase in the polymer content also did not initiate any drug polymer interactions. FTIR
spectra‟s is shown in Fig.12.
From the IR spectra it was found that there was no significant change observed in the
characteristic peaks of the drug which shows that there is no interaction occuring in between
Carvedilol and Plasdone K-30. Also it can be concluded that there was no effect of the spray
drying process on the drug.
1.4.6 DSC study of optimized solid dispersion batch (SD6)
The DSC thermogram of solid dispersion showed a disappearance of the endothermic peak
which was observed in the DSC curve for pure Carvedilol and also there was change in the
peak intensity. The absence of endothermic peak might be due to the formation of solid
dispersion of the drug in the presence of hydrophillic polymer where the crystalline drug
could be transformed into an amorphous state. This amorphousness might be related to the
intermolecular hydrogen bonding and complexation between drug and Plasdone K30,
respectively. The thermogram of spray dried particles of Carvedilol showed change in the
melting point which is shown as a broad peak at 950C. Such change in the melting point
indicates changes in the crystalline state of Carvedilol after spray drying process. Also, the
melting temperature of solid dispersion decreases with decreasing their particle size. The
melting temperature increases as the particle size increases. Thus, as the particle size
decreases surface area-to-volume ratio of the particle increases. The larger surface area
allows a greater interaction with the solvent and ultimately enhances the solubility of the
drug.
Fig. 13: DSC curve of batch SD6.
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1.4.7 Scanning Electron Microscopy (SEM) of solid dispersion batch SD6
SEM images of the prepared Carvedilol solid dispersion is shown in Fig.14. The particles of
the solid dispersion were found to be spherical in shape. The particle size of the spray dried
particles is also decreased. This is essential to enhance the solubility. SEM showed smooth
surface of Carvedilol solid dispersion particles with greater number of pores which indicated
that there is increase in the porosity and hence the dissolution rate of these particles was also
increased. This shows that transformation of the crystalline drug into amorphous state has
occured with enhanced solubilization and dissolution rate of the spray dried particles.
Fig. 14: SEM images of Solid dispersion batch SD6.
CONCLUSION
The main objective of this study was to increase the solubility of Carvedilol using
hydrophillic polymers β-cyclodextrin and Plasdone K-30. Further the incorporation of the
prepared solid dispersion was done in the formulation of press-coated pulsatile drug delivery
system for the treatment of hypertension. The results of saturation solubility, drug content
and in-vitro dissolution study of solid dispersions of Carvedilol indicated that the solubility of
Carvedilol was increased with increasing the concentration of hydrophillic polymers.
The batch SD6 with drug to Plasdone K-30 ratio of 1:3 showed the greater increase in
solubility than the pure drug. The FTIR spectroscopy study showed that there was no
interaction between Carvedilol, β-cyclodextrin and Plasdone K-30. The DSC study of the
pure drug showed melting endotherm at 1180C corresponding to the melting point of the drug
indicating that the drug is crystalline. Whereas the DSC study of solid dispersion indicated
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that the drug is in amorphous state. Thus it can be concluded that spray drying is effective in
increasing the solubility of Carvedilol. Further the results of SEM study showed that the
spray dried solid dispersion particles of batch SD6 are spherical in shape with greater
porosity. This indicates that the solubility was increased which is further confirmed from the
in-vitro dissolution studies.
ACKNOWLEDGEMENT
My heartiest thanks go to my beloved and respected guide Mr. M.A.Bhutkar, Associate
professsor, Department of Pharmaceutics, Rajarambapu College of Pharmacy, Kasegaon, for
his excellent guidance, valuable suggestions, moral support and constant inspiration during
this endaevour. Next with pride and elation I would like to give my humble thanks to my
esteemed teacher respected Dr.C.S.Magdum, Principal, Dr. S.K. Mohite, Vice-Principal and
Head of Department of Pharmaceutical Chemistry, and Dr. M. N. Nitalikar, Associate
professor, Department of Pharmaceutics, Rajarambapu College of Pharmacy, Kasegaon, for
providing the necessary infrastructure and all the facilities required to carry out my research
work.
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