Int. J. Pharm. Sci. Rev. Res., 29(1), November – December 2014; Article No.

31, Pages: 161-165 ISSN 0976 – 044X

Research Article

Solubility and Dissolution Enhancement of Carvedilol by Solid Dispersion Technique

Using Gelucire 50/13
1 2
Shinkar Dattatraya Manohar*, Dhake Avinash Shridhar , Setty Chitral Mallikarjuna
*Department of Pharmaceutics, KCT’S R. G. Sapkal College of Pharmacy, Anjaneri, Nashik, Maharashtra, India.
1
Department of Pharmaceutics, S. M .B. T. College of Pharmacy, Dhamangaon, Nashik, Maharashtra, India.
2
Department of Pharmaceutics, The Oxford College of Pharmacy, Bangalore, Karnataka India.
*Corresponding author’s E-mail: [email protected]

Accepted on: 31-08-2014; Finalized on: 31-10-2014.

ABSTRACT
Solid dispersions in water-soluble carriers have attracted considerable interest as a means of improving the dissolution rate and
hence possibly bioavailability, of a range of hydrophobic drugs. Inclusion behavior of gelucire 50/13 was studied towards carvedilol,
an antihypertensive agent in order to develop mucoadhesive oral dosage form with enhanced dissolution rate and bioavailability,
following gelucire carvedilol solid dispersion. The present work was investigated to examine the release of carvedilol from various
molecular weight fractions of gelucire solid dispersions. Solid dispersions of carvedilol were prepared in different molar ratios of
drug: carrier by using solvent evaporation and melting methods. The physical mixture and solid dispersion (s) were characterized for
drug-carrier interaction, drug content, solubility and dissolution rate. The release rate of carvedilol from the resulting complexes was
determined from dissolution studies by use of USP dissolution apparatus 2 (paddle method). The physical state and drug: gelucire
interaction of solid dispersions and physical mixtures were characterized by X-ray diffraction (XRD), Infra Red Spectroscopy (IR) and
Differential Scanning Calorimetry (DSC). The dissolution rate of carvedilol was increased significantly in all of the solid dispersion
systems compared to that of the pure drug and physical mixtures. The solid dispersion prepared in the molar ratio of 1:2 by the
solvent evaporation method was found to have the fastest dissolution profile.
Keywords: Carvedilol, Gelucire 50/13, Solvent Evaporation method, Melting method, Dissolution enhancement.

INTRODUCTION different molar proportions viz. 1:1 and 1:2 (drug:carrier)

by using various techniques, physical mixing, melting

C
arvedilol is an antihypertensive agent used in the
method and solvent evaporation method thereby to
treatment of hypertension, congestive cardiac
improve its oral bioavailability.
failure, angina pectoris, cardiac arrhythmias and
myocardial infarction. It is a nonselective beta MATERIALS AND METHODS
adrenoreceptor blocker with selective alpha adrenergic
Materials
blocking. 1 However drug bioavailability is very limited
(25-30%), since it is practically insoluble in water and its Carvedilol was provided by Cipla Ltd., Kurkumbh, India
dissolution is the rate limiting step for its absorption and gelucire 50/13 from Glenmark Pharmaceutical Ltd.,
through gastrointestinal tract.2, 3 Solid dispersion Sinnar, India as a gift sample. All other chemicals and
technique has been extensively used to increase the reagents were used of analytical grade.
4,5
solubility of a poorly water-soluble drug. Solid
Phase solubility studies8
dispersion, which was introduced in the early 1970s, is
essentially a multi-component system, having drug Solubility measurements were performed according to
dispersed in hydrophilic carrier(s) by different methods. method reported by Higuchi and Connors. An excess
In solid dispersion systems, a drug may exist as an amount of the drug was added to 10 ml volumetric flask
amorphous form in polymeric carriers, and this may result containing 10%, 20%, 30%, 40%, 50% aqueous solution of
in improved solubilities and dissolution rates as compared gelucire 50/13. The samples were shaken for 48 hours at
with crystalline material. Drugs molecularly dispersed in room temperature 25±1°C on an orbital shaker incubator.
polymeric carriers may achieve the highest levels of After 48 hours of shaking to achieve equilibrium, 5 ml of
particle size reduction and surface area enhancement, aliquots were withdrawn after 1 hour and filtered
which result in improved dissolution rates. Furthermore, immediately using membrane filter (0.45 µ). The filtered
no energy is required to break up the crystal lattice of a samples were diluted suitably and assayed for carvedilol
drug during dissolution process and drug solubility and by measuring absorbance at 284 nm using UV/Visible
wettability may be increased by surrounding hydrophilic spectrophotometer (Jasco-V630). Solubility studies of
carriers.6-7 physical mixtures and solid dispersion were also
performed in same manner. The apparent 1:1 stability
The present study aims to enhance the aqueous solubility
constant, Kc1:1, were calculated from the linear portion of
and dissolution rate of carvedilol through formation of
phase solubility diagrams using the equation:
solid dispersions of carvedilol and gelucire 50/13 in

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Kc(1:1)= Slope/S0 (1-Slope) Powder X- Ray Diffraction (PXRD)

Where, S0 is the drug solubility in the absence of gelucire PXRD patterns were recorded using Philips PW 1729 X-
50/13 (intercept). ray generator, USA fitted with a copper target, a voltage
of 40 kV, and a current of 30 mA. The scanning rate was
Preparation of Physical Mixtures and Solid Dispersions
1°/min over a 2θ range of 1-40°. Powder X- ray diffraction
of` Carvedilol
patterns were traced for carvedilol, physical mixture and
The solid dispersions of carvedilol and gelucire 50/13 solid dispersions. The samples were slightly ground and
were prepared 1:1M and 1:2M by three methods, packed into the aluminum sample container. 21, 22
physical mixture, melting and solvent evaporation
In vitro Dissolution Studies 17, 18, 23, 24
method.
The release rate of carvedilol from solid dispersions was
Physical mixture
studied using USP XXIV dissolution testing apparatus 2
Carvedilol and gelucire 50/13 in molar ratio of 1:1 and 1:2 (paddle method; Electrolab, Mumbai, India). The
(PM1, PM2) were prepared by simple trituration for 1 hr dissolution test was performed using 900 ml of pH 6.8
in glass mortar with pestle and passed through a sieve no phosphate buffer, at 37±0.5 °C and 50 rpm for 2 hours.
100 and stored in a desiccator. 9, 10, 11 Complex equivalent to 12.5 mg of carvedilol was used in
each test. Samples (5 ml each) of dissolution medium
Melting method
were withdrawn at predetermined time interval and
Carvedilol and gelucire 50/13 in molar ratio of 1:1 and 1:2 analyzed for drug release by measuring absorbance at
(M1, M2) were taken. Gelucire was heated at 50ºC in an 284 nm after suitable dilution with pH 6.8 phosphate
oil bath, until it melted completely. The drug was added buffer. The volume withdrawn at each interval was
to the molten polymer and mixed thoroughly in mortar replaced with fresh quantity of dissolution medium.
with pestle. The dispersion was cooled to ambient
RESULTS AND DISCUSSION
conditions, milled, and passed through a 40-mesh sieve
and stored in a desiccator.12 Phase solubility studies
Solvent evaporation method Phase solubility diagram for complex formation between
carvedilol and gelucire 50/13 in water is AL type according
Carvedilol and gelucire 50/13 were dissolved in minimum
to Higuchi and Connors, (Figure 1) which illustrate
quantity of methanol. Different molar ratios of 1:1 and
solubility enhancement capability of gelucire 50/13. The
1:2 (S1, S2) of carvedilol and gelucire 50/13 were taken.
aqueous solubility of carvedilol increased linearly
This solution was continuously stirred using magnetic
(r=0.977) as a function of gelucire concentration with KC
stirrer and solvent was evaporated. Then it was stored
of 246.01 M-1.
over night in a desiccator. Solid dispersion thus obtained
was grounded by using a mortar and pestle and sieved 0.1
through a 40 mesh screen.13, 14
Solubility of carvedilol

0.08
Characterization of Physical Mixtures and Solid
(mg/ml)

0.06
Dispersions of Carvedilol
0.04
Fourier Transform Infrared Spectroscopy (FTIR)
0.02
Fourier transform infrared spectra were obtained using
Shimadzu FTIR- 8400S spectrometer, Japan. Samples of 0
carvedilol, gelucire 50/13, physical mixtures and solid 0 20 40 60
dispersions were ground and mixed thoroughly with Concentration of gelucire 50/13 (%w/v)
potassium bromide at a 1:5 sample/KBr ratio. The KBr
discs were prepared by compressing the powders at a Figure 1: Phase solubility curve of carvedilol with gelucire
pressure of 5 T for 5 min in a hydraulic press. The 50/13.
-1
scanning range was 40 to 4000 cm and the resolution FTIR Studies
-1 15, 16, 17
was 4 cm .
FTIR spectra of carvedilol (Figure 2) showed characteristic
Differential Scanning Calorimetry (DSC) peaks at 3346.27 cm–1 (O-H and N-H stretching vibration
Differential Scanning Calorimetry (DSC) analysis of the peaks merged together), 2925.81 cm–1 (C-H stretching
samples was carried out on a Perkin-Elmer DSC. Samples vibrations), 1598.88 cm–1 (N-H bending vibrations) and
–1
(6.5-10 mg) were heated under nitrogen atmosphere on 1253.64 cm (O-H bending and C-O stretching
an aluminum pan at a heating rate of 100C/min over the vibrations). The FT-IR spectra of physical mixtures PM1,
temperature range of 50 to 3000C. DSC analysis was PM2 retain all the characteristic peaks of pure drug. No
carried out under nitrogen gas flow of 20 lb/in2. 18,19,20 significant shifts in the peaks corresponding to the drug
were observed on storage. The binary systems M1, M2,
S1 and S2 revealed disappearance of the characteristic

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Int. J. Pharm. Sci. Rev. Res., 29(1), November – December 2014; Article No. 31, Pages: 161-165 ISSN 0976 – 044X

peaks suggesting possible entrapment of carvedilol broadened endothermic peak at 70°C. Complete
moiety into the gelucire 50/13 cavity. As such, the FTIR disappearance of endothermic peak due to carvedilol
spectra of carvedilol and gelucire 50/13 compositions did with these systems indicated the formation of an
not show significant shifts suggestive of an interaction. amorphous solid dispersion of drug in case of complexes
Instead, the spectra show few to no changes in the prepared by solvent evaporation method at 1:1M (S1)
absorption bands characteristic of carvedilol. The study and 1:2M (S2).
indicates that carvedilol has strong physical interaction
Powder X- Ray Diffraction (PXRD)
with gelucire 50/13 in solid state. FTIR spectroscopy
revealed the possibility of inter-molecular hydrogen Powder X-ray diffraction analysis can be used to judge any
bonding in solid dispersions. changes in crystallinity of the drug which precipitated in
an amorphous form, when formulated into a solid
dispersion. PXRD could be used to study any changes in
crystallinity of the drug which could be one of the
mechanisms responsible for improved dissolution.
Numerous diffraction peaks of carvedilol were observed
at 2θ of 12.8°, 15.62°, 17.46°, 18.56°, 20.1°, 24.3° and
26.2° indicating the presence of crystalline nature of
carvedilol. Gelucire 50/13 is crystalline in nature and gives
two characteristic peaks: one at 19° and the other
broader one between 22° and 27°. XRD-scanning of
physical mixture (PM1, PM2) showed decreasing number
of peaks with lower intensity indicating partial
Figure 2: FTIR spectrums of pure carvedilol, gelucire amorphous nature of the drug in its binary mixtures
50/13 and formulations (PM1, PM2, M1, M2, S1 and S2) (Figure 4). In case of solid dispersion prepared by melting
Differential Scanning Calorimetry (DSC) (M1, M2) method, there was a decrease in the intensity
of carvedilol but the major peaks remained at the same
Differential scanning calorimetry enables the quantitative positions. The PXRD of solid dispersion prepared by
detection of all processes in which energy is required or solvent evaporation (S1, S2) method exhibited the
produced (i.e., endothermic and exothermic phase absence of characteristic peaks of carvedilol, suggesting
transformations). The thermal behavior was studied using that carvedilol is completely soluble in the liquid phase
differential scanning calorimetry in order to confirm the with gelucire 50/13 and confirming that carvedilol, is in
formation of solid dispersions. The thermograms for pure amorphous form with SDs.
carvedilol and gelucire 50/13, physical mixture and solid
dispersions are presented in Figure 3.

Figure 4: X ray diffractograms of pure carvedilol, gelucire

Figure 3: DSC thermograms of pure carvedilol, gelucire 50/13 and formulations (PM1, PM2, M1, M2, S1, S2)
50/13 and formulations (PM1, PM2, M1, M2, S1, S2)
In vitro Dissolution Studies
The carvedilol showed a melting endotherm at 115 °C
whereas gelucire 50/13 showed a melting endotherm at The in vitro dissolution profiles of the pure drug, various
450C. Thermograms of carvedilol and gelucire 50/13 solid dispersions prepared by using gelucire 50/13, and
physical mixture (PM1, PM2) and melting (M1) method their respective physical mixtures in pH 6.8 phosphate
showed endothermic peak at 900C. This is may be due to buffer for 2 hours shown in Figure 5. At the end of 2
shift of characteristics peak of carvedilol, which was hours, 53.16 %, 61.23 %, 64.46 %, 72.59 %, 84.63 % 92.65
observed at 115 °C, indicates weak interaction of drug % and 99.85 % carvedilol was released from pure drug
and gelucire 50/13. Thermal curve of carvedilol gelucire sample, PM1, PM2, M1, M2, S1 and S2 respectively. All of
50/13, prepared by melting (M2) method has shown the physical mixture and solid dispersion samples showed
improved dissolution of carvedilol over pure drug. All of
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Int. J. Pharm. Sci. Rev. Res., 29(1), November – December 2014; Article No. 31, Pages: 161-165 ISSN 0976 – 044X

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Source of Support: Nil, Conflict of Interest: None.

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