‘Stealth’ Lipid-based Formulations- Poly(Ethylene Glycol)-Mediated
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J Pharm Chem Biol Sci, December 2018 - February 2019; 6(4):355-364
Journal of Pharmaceutical, Chemical and Biological Sciences
ISSN: 2348-7658 CODEN : JPCBBG
December 2018 - February 2019; 6(4):355-364
Online available at https:/ /www.jpcbs.info
Appraising Best Poly Ethylene Glycol Carrier for Thiocolchicoside Solid
Dispersions
Hemanth A1, Hindustan Abdul Ahad2*, Devanna N2
1Research Scholar, Research and Development, Jawaharlal Nehru Technological University,
Ananthapuramu 515001, AP, India. 2Jawaharlal Nehru Technological University-Oil Technological and Pharmaceutical Research Institute,
Ananthapuramu 515001, AP, India
*CORRESPONDING AUTHOR
Hindustan Abdul Ahad, Jawaharlal Nehru Technological
University-Oil Technological and Pharmaceutical Research
Institute, Ananthapuramu 515001, AP, India
Email: [email protected]
ARTICLE INFORMATION
Received October 17, 2018
Revised December 16, 2018
Accepted December 22, 2018
Published February 17, 2019
INTRODUCTION
In Industry the pharmacist makes so many
trials with the aim to increase the solubility of
drugs which are poorly soluble, in an
inexpensive way. Among the different
techniques of increasing solubility, solid
dispersion technique was attaining the fame [1].
Thiocolchicoside is a colchicoside derivative
(Gloriosa superba) and Colchicum autumnale.
Thiocolchicoside is used as muscle relaxant for
the treatment of painful muscle contractions,
acute and arthritic problems and pains. It is
prescribed in combination with many NSAIDs
[2-5].
Electromagnetic irradiation in microwave oven
is ranged from 0.3 to 300 GHz of infrared and
radio frequencies which resembles to
wavelengths of 1 mm to 1 m. This technique can
be used to get rapid and constant heating even
in materials presenting low heat conductivity
(E.g., polymers), because the transfer of energy
does not trust on heat diffusion [6, 7].
The present exploration was to increase the
solubility of Thiocolchicoside by making solid
Research Article
The work is licensed under
ABSTRACT
The present attempt is to discover the best Poly Ethylene Glycol as solid dispersion carrier by taking
Thiocolchicoside as a model drug. Different Poly Ethylene Glycol bases viz., PEG- 3350, PEG- 4000,
PEG- 6000, PEG- 8000 and PEG- 20000 were evaluated in the study. Thiocolchicoside: PEG in the
ratios ranged from 1:1, 1:2, 1:4 and 1:6 were prepared as solid dispersions by microwave irradiation
method and compressed by 8 station tablet compression machine. The fabricated solid dispersion
tablets were evaluated for physicochemical characteristics and drug release rates. The release of
Thiocolchicoside from the designed solid dispersions were further analyzed by kinetic models. All the
solid dispersion formulations were shown satisfactory physicochemical characteristics and
Thiocolchicoside release. Among the Poly Ethylene Glycol carriers, PEG-6000 was found to be the best
carrier for increasing the solubility and release rate form the solid dispersions of Thiocolchicoside.
KEYWORDS: Thiocolchicoside; Poly Ethylene Glycol; solid dispersions; evaluation
Hemanth et al 356
J Pharm Chem Biol Sci, December 2018 - February 2019; 6(4): 355-364
dispersions using Poly Ethylene Glycol carriers,
viz., PEG- 3350, PEG- 4000, PEG- 6000, PEG-
8000 and PEG- 20000 [8-12] and finding out the
best polymer among them. The solid dispersions
were fabricated by microwave melting method.
MATERIALS AND METHODS
Materials
Thiocolchicoside was procured from Yarrow
chemicals. (PEG- 3350, PEG- 4000, PEG- 6000,
PEG- 8000 and PEG- 20000) were obtained from
Amrutha organics, Hyderabad. Microcrystalline
Cellulose, Talc and Magnesium stearate were
acquired from Colorcon, India. Double distilled
water was used when ever desirable.
METHODS
Stability studies
Thiocolchicoside pure drug and excipients (1:1)
compatibility study at stressed storage
conditions i.e., at a temperature of 40°C and RH
of 75% in stability chamber [13] (Classic
Scientific India, Mumbai) was performed.
Hygroscopic studies
The hygroscopic study of Thiocolchicoside pure
drug was done under 33, 53 and 75% RH for 30
days and the weight gain was studied. These
studies were performed in triplicates [14].
Solubility studies
Thiocolchicoside pure drug was tested for
solubility in 0.1N HCl, water, pH 4.5 Acetate
buffer, pH 6.8 and pH 7.4 Phosphate buffers
[15].
Designing of Solid dispersions
The various formulae of Thiocolchicoside solid
dispersions with PEG were shown in table 1.
Table 1: Drug (Thiocolchicoside): Carrier (PEG) ratios in various formulations
Drug: Carrier Ratio Formulation code
TCS: PEG-3350 1:1 TPEG3-1
1:2 TPEG3-2
1:4 TPEG3-3
1:6 TPEG3-4
TCS: PEG-4000 1:1 TPEG4-1
1:2 TPEG4-2
1:4 TPEG4-3
1:6 TPEG4-4
TCS: PEG-6000 1:1 TPEG6-1
1:2 TPEG6-2
1:4 TPEG6-3
1:6 TPEG6-4
TCS: PEG-8000 1:1 TPEG8-1
1:2 TPEG8-2
1:4 TPEG8-3
1:6 TPEG8-4
TCS: PEG-20000 1:1 TPEG20-1
1:2 TPEG20-2
1:4 TPEG20-3
1:6 TPEG20-4
Flow properties
The designed solid dispersions were evaluated
for Micromeritic properties [16-18].
Preparation of solid dispersion tablets
The solid dispersions equivalent to 4 mg of
Thiocolchicoside were fabricated by direct
compression [19] in to tablet dosage form, after
mixing with required amounts of different
ingredients as shown in table 2 by using 8
station tablet compression machine (Karnavati
Engineering, Ahmedabad, India).
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Table 2: Formulation of tablet containing solid dispersions
Ingredients Quantity per tablet
Solid dispersions equivalent
to 4 mg of Thiocolchicoside
125
Lactose 50
Starch 15
Micro Crystalline Cellulose 50
Magnesium stearate 5
Talc 5
Weight of the tablets 250
Evaluation Thiocolchicoside Solid
Dispersions
The following parameters were tested for
Thiocolchicoside solid dispersions [20-24].
Morphological characteristics
In this study, tablets were verified for size and
shape.
Thickness
Tablets were assessed for their thickness using
vernier Calipers (Qumos Enterprises, Mumbai,
India). These trails were made in triplicates.
Hardness
The force required to break the tablets were
noted using Monsanto tablet hardness tester
(Vinsyst Technologies, Mumbai). These tests
were performed in triplicates.
Uniformity in weight
20 tablets from each batch were weighed
individually using an electronic digital balance
(Citizen, CY-104, Mumbai, India) and calculated
the average weight and compared with the
individual tablet weights. From this, percentage
weight difference was calculated and then
checked for IP specifications (Limit ± 7.5% of
average weight).
Friability
It is the occurrence in which tablet surfaces are
injured when subjected to physical tremor or
erosion. This test was performed using Roche
Friabilator. 10 tablets were weighed before the
test (W initial) and moved into a friabilator. The
equipment was run at a speed of 25 rpm for the
period of 4 minutes and the final weight of
tablets (W final) was determined. The loss on
friability was then measured by the following
equation.
Yield
The % recovery of formulated solid dispersion
was resolute after complete removal of moisture.
Thus % recovery calculation involves the weight
of dried Solid dispersion to sum of the weight of
drug and pharmaceuticals required for the
formulation.
Uniformity of drug content
5 tablets from each batch were taken and
weighed and crushed in a mortar and pestle. A
weight equal to 4 mg of Thiocolchicoside was
dissolved in 100 ml of Phosphate Buffer solution
(PBS) (pH 7.4). From this 0.2 ml sample was
taken later diluted to 10 ml PBS. The
absorbance was determined [25] at 259 nm with
double beam UV-Visible spectrophotometer (Lab
India, Mumbai). The content uniformity was
calculated from Thiocolchicoside standard
calibration graph.
Thiocolchicoside calibration curve
The process of determining Thiocolchicoside by
UV spectrophotometer at 259 nm was
standardized and the drug was found to obey
Beer-Lambert’s law in 2-10 µg/ml concentration
[26].
Dissolution rate/in-vitro drug release
The dissolution specifications were as below [27]
Apparatus used: USP XXIII dissolution
test apparatus
Dissolution medium: PBS (pH 7.4)
Volume of dissolution medium: 900 ml
Temperature: 37±0.5°C
Speed of basket paddle: 50 rpm
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Sampling intervals: 5 min
Sample withdraws: 10 ml
Absorbance measured at: 259 nm
Kinetic modeling of drug release
The mechanism of the drug release was
analyzed and rate kinetics of the dosage form
was obtained as [28, 29]:
Cumulative percentage drug released
Vs. Time (Zero order plots)
Log cumulative percentage drug
remaining Vs Time (First order plots)
Cube root of drug remaining Vs time
(Hixon Crowell’s plots)
Accelerated Stability studies of
Thiocolchicoside solid dispersions
The prepared Thiocolchicoside solid dispersions
tablets were further subjected to stability
studies for a period of 3 months under stressed
storage conditions [30].
RESULTS
Physical observations were made by storing
Thiocolchicoside with various PEG carriers used,
at stressed storage conditions were tabulated in
table 3.
Table 3: Thiocolchicoside Excipients (1:1) compatibility study physical Observations
Binary
mixture
Initial Storage condition
Room temperature 40°C/75%RH
10
days
20
days
30
days
10
days
20
days
30
days
Thiocolchicoside Pale yellow powder NCC NCC NCC NCC NCC NCC
T+PEG-3350 White waxy
powder
NCC NCC NCC NCC NCC NCC
T+ PEG-4000 White waxy
powder
NCC NCC NCC NCC NCC NCC
T+ PEG-6000 White waxy
powder
NCC NCC NCC NCC NCC NCC
T+ PEG-8000 White waxy
powder
NCC NCC NCC NCC NCC NCC
T+ PEG-20000 White waxy
powder
NCC NCC NCC NCC NCC NCC
T+ Lactose Pale yellow powder NCC NCC NCC NCC NCC NCC
T+ Starch Pale yellow powder NCC NCC NCC NCC NCC NCC
T+ MCC Pale yellow powder NCC NCC NCC NCC NCC NCC
T+ MS Pale yellow powder NCC NCC NCC NCC NCC NCC
T+ Talc Pale yellow powder NCC NCC NCC NCC NCC NCC
PEG- Poly Ethylene Glycol; MCC- Micro Crystalline Cellulose; MS- Magnesium Stearate
The hygroscopic study of Thiocolchicoside at room temperature (25±2oC) & humidity conditions was
shown in table 4.
Table 4: Hygroscopicity Data of Thiocolchicoside
Time Interval % Weight Change
33% RH 53% RH 75% RH
Day 0 0.00 0.00 0.00
Day 2 0.00 0.01±0.001 0.01
Day 4 0.00 0.01±0.001 0.01±0.001
All values mentioned as mean ±SD; number of trials (n=3)
The solubility of Thiocolchicoside pure drug in
0.1N HCl, water, pH 4.5 Acetate buffer, pH 6.8
Phosphate buffer and pH 7.4 Phosphate buffer
were shown in fig. 1.
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Fig. 1: Solubility of Thiocolchicoside at various media
The flow properties of fabricated Thiocolchicoside solid dispersions were shown in table 5.
Table 5: Flow character specifications
Formulation Flow properties
Angle of repose (0) LBD TBD CI HR
TPEG3-1 34.53±0.02 0.654±0.03 0.704±0.05 7.102±0.02 1.076±0.01
TPEG3-2 29.19±0.03 0.758±0.01 0.789±0.08 3.929±0.03 1.041±0.08
TPEG3-3 29.30±0.04 0.528±0.05 0.584±0.04 9.589±0.05 1.106±0.04
TPEG3-4 29.05±0.06 0.625±0.03 0.689±0.02 9.288±0.03 1.102±0.03
TPEG4-1 26.54±0.09 0.452±0.07 0.498±0.01 9.236±0.01 1.101±0.01
TPEG4-2 31.21±0.06 0.235±0.04 0.255±0.03 7.843±0.05 1.085±0.01
TPEG4-3 31.56±0.08 0.255±0.03 0.269±0.03 5.204±0.03 1.054±0.01
TPEG4-4 29.49±0.06 0.366±0.06 0.389±0.02 5.912±0.08 1.062±0.07
TPEG6-1 26.31±0.08 0.268±0.08 0.274±0.02 2.189±0.07 1.022±0.05
TPEG6-2 30.50±0.06 0.365±0.01 0.387±0.01 5.684±0.04 1.060±0.01
TPEG6-3 29.15±0.02 0.854±0.02 0.878±0.03 2.733±0.04 1.028±0.03
TPEG6-4 27.30±0.04 0.524±0.04 0.564±0.05 7.092±0.03 1.076±0.01
TPEG8-1 29.06±0.06 0.254±0.08 0.268±0.03 5.223±0.05 1.055±0.01
TPEG8-2 28.30±0.01 0.625±0.06 0.635±0.09 1.574±0.03 1.016±0.04
TPEG8-3 30.24±0.06 0.369±0.05 0.389±0.07 5.141±0.03 1.054±0.05
TPEG8-4 30.56±0.08 0.582±0.03 0.595±0.05 2.184±0.08 1.022±0.01
TPEG20-1 31.50±0.06 0.565±0.04 0.578±0.03 2.249±0.09 1.023±0.06
TPEG20-2 26.19±0.04 0.485±0.01 0.496±0.03 2.217±0.03 1.022±0.01
TPEG20-3 31.32±0.02 0.258±0.03 0.269±0.01 4.089±0.07 1.042±0.01
TPEG20-4 26.05±0.08 0.569±0.03 0.584±0.03 2.568±0.04 1.026±0.02
All values mentioned as mean ±SD; number of trials (n=3)
The fabricated Thiocolchicoside tablets were
observed to have uniform in size, shape, off
white in colour, odourless with smooth surface.
The thickness of prepared formulations,
uniformity of weight, hardness, friability,
percent yield and drug content uniformity were
shown in table 6.
Table 6: Physical Characteristics of Prepared solid dispersions
Formulation Physical parameter
Uniformity of
weight (mg)
Hardness
(cm2)
Thickness
(mm)
Friability (%) Yield (%) Assay
(%)
TPEG3-1 253.1±0.01 4.5±0.04 4.51±0.01 0.59±0.05 96.3±0.06 96.3±1.27
TPEG3-2 254.3±0.01 5.2±0.05 4.53±0.04 0.60±0.05 98.5±0.06 96.9±3.25
TPEG3-3 255.2±0.01 6.3±0.01 4.50±0.01 0.53±0.05 97.9±0.06 99.4±1.21
TPEG3-4 255.2±0.02 5.3±0.01 4.51±0.02 0.45±0.02 99.8±0.06 97.2±0.11
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TPEG4-1 255.1±0.02 4.5±0.05 4.53±0.04 0.51±0.03 90.5±0.06 96.8±0.86
TPEG4-2 250.9±0.01 5.2±0.03 4.50±0.02 0.72±0.03 91.5±0.06 99.2±0.15
TPEG4-3 252.3±0.01 6.3±0.05 4.51±0.07 0.11±0.01 98.3±0.06 97.2±0.35
TPEG4-4 253.8±0.02 5.3±0.05 4.53±0.05 0.25±0.02 97.8±0.06 96.3±0.01
TPEG6-1 250.5±0.02 4.5±0.05 4.50±0.03 0.56±0.04 94.5±0.06 99.1±1.29
TPEG6-2 250.1±0.01 5.2±0.01 4.51±0.04 0.09±0.01 96.5±0.06 100.6±4.25
TPEG6-3 254.2±0.02 6.3±0.05 4.53±0.01 0.50±0.05 98.7±0.06 97.3±0.96
TPEG6-4 252.2±0.01 5.3±0.04 4.50±0.03 0.25±0.02 98.2±0.06 96.4±3.25
TPEG8-1 251.3±0.01 4.5±0.04 4.51±0.01 0.53±0.07 90.3±0.06 99.2±1.25
TPEG8-2 252.3±0.02 5.2±0.02 4.53±0.04 0.68±0.04 91.8±0.06 100.6±0.82
TPEG8-3 251.2±0.01 6.3±0.04 4.50±0.02 0.50±0.03 95.6±0.06 97.1±0.66
TPEG8-4 250.2±0.01 5.0±0.03 4.51±0.02 0.25±0.01 94.4±0.06 96.4±0.72
TPEG20-1 250.2±0.02 4.5±0.07 4.53±0.05 0.59±0.04 95.6±0.06 99.2±0.89
TPEG20-2 251.2±0.02 5.2±0.04 4.50±0.04 0.66±0.01 98.8±0.06 100.9±2.31
TPEG20-3 250.1±0.01 6.6±0.05 4.51±0.02 0.50±0.04 96.5±0.06 97.2±1.55
TPEG20-4 252.1±0.01 5.4±0.03 4.53±0.07 0.21±0.02 98.7±0.06 96.1±0.44
All values mentioned as mean ±SD; number of trials (n=3)
The solubility of prepared tablets was found
good in distilled water and 0.1N HCl. These
values were shown in figure 2 to 6.
Fig. 2: Solubility of Thiocolchicoside and
solid dispersions with
PEG-3350 in various media
Fig. 3: Solubility of Thiocolchicoside and
solid dispersions with
PEG-4000 in various media
Fig. 4: Solubility of Thiocolchicoside and
solid dispersions with
PEG-6000 in various media
Fig. 5: Solubility of Thiocolchicoside and
solid dispersions with
-8000 in various media
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Fig. 6: Solubility of Thiocolchicoside and
solid dispersions with
PEG-20000 in various media
The estimation of Thiocolchicoside was
determined by plotting calibration curve of
Thiocolchicoside (fig. 7).
Fig. 7: Calibration curve for the estimation
of Thiocolchicoside
The dissolution of prepared tablets was found
good in formulations containing
Thiocolchicoside: PEG ratios 1:6. These were
shown in figs. 8 to 12.
Fig. 8: In vitro drug dissolution plots of
Thiocolchicoside and
PEG-3350 solid dispersions
Fig. 9: In vitro drug dissolution plots of
Thiocolchicoside and
PEG-4000 solid dispersions
Fig. 10: In vitro drug dissolution plots of
Thiocolchicoside and
PEG-6000 solid dispersions
Fig. 11: In vitro drug dissolution plots of
Thiocolchicoside and
PEG-8000 solid dispersions
Fig. 12: In vitro drug dissolution plots of
Thiocolchicoside and
PEG-20000 solid dispersions
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The drug release mechanism from prepared
tablets formulations was determined by kinetic
treatment of in vitro drug dissolution data. The
correlation (r2) values were shown in table 7.
First order and Hixon Crowell’s plots were
shown in fig. 13 and 14.
Fig. 13: First order plots for TPEG tablets
Fig. 14: Hixson Crowell’s plots for TPEG-4 tablets
Table 7: Correlation coefficients (R2) for different release kinetics of Thiocolchicoside solid
dispersions
Formulation Correlation (R2)
Zero order First order Hixson
Crowell’s
TPEG3-4 0.9738 0.9936 0.9979
TPEG4-4 0.5025 0.9885 0.9868
TPEG6-4 0.8823 0.9494 0.9206
TPEG8-4 0.9785 0.9868 0.9860
TPEG20-4 0.9738 0.9666 0.9804
DISCUSSION
The compatibility study between
Thiocolchicoside and the polymer carriers used
revealed that Thiocolchicoside was found to be
compatible with the excipients used.
The hygroscopic study of Thiocolchicoside at
room temperature (25±2oC) & humidity
conditions proves that Thiocolchicoside was non-
hygroscopic (% weight gain < 0.2%).
Thiocolchicoside shown good solubility of
0.2958±0.0065 µg/ml in 0.1N HCl and
0.2019±0.0024µg/ml in water. The solubility of
Thiocolchicoside was found to be 0.2698±0.0095,
0.1054±0.0024 and 0.1924±0.0058 µg/ml in pH
4.5 Acetate buffer, pH 6.8 Phosphate buffer and
pH 7.4 Phosphate buffer respectively. The
solubility data indicates that drug has very poor
solubility.
The fabricated Thiocolchicoside solid dispersions
showed good flow properties (26.05±0.08 to
34.53±0.02o). The compressibility Index was
between 1.574±0.03 to 9.589±0.05, indicating
good compression properties while tableting. The
fabricated Thiocolchicoside tablets were
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observed to have uniform in size, shape, off
white in colour, odourless with smooth surface.
The prepared tablets were found to have
uniform thickness (4.5 mm) and weight. The loss
on friability was less than 1% and the hardness
was more than 4 Kg/cm2 indicating that the
prepared tablets having good mechanical
strength. The uncoated tablets disintegrated
within 15 min, the yield was found to good
(>90%) and the drug content was also found to
be uniform.
The formulations TPEG3-1, TPEG3-2, TPEG3-3
and TPEG3-4 showed good solubility in distilled
water (up to 1.25±0.01µg/ml) and in 0.1 N HCl
(up to 1.13±0.02 µg/ml). TPEG4-1, TPEG4-2,
TPEG4-3 and TPEG4-4 showed good solubility
in 0.1 N HCl (up to 0.63±0.01 µg/ml) and in
distilled water (up to 0.52±0.01 µg/ml). TPEG6-
1, TPEG6-2, TPEG6-3 and TPEG6-4 showed
good solubility in 0.1 N HCl (up to 0.61±0.01
µg/ml) and in distilled water (up to 0.57±0.01
µg/ml). TPEG8-1, TPEG8-2, TPEG8-3 and
TPEG8-4 showed good solubility in distilled
water (up to 0.58±0.01 µg/ml), in 0.1 N HCl (up
to 0.56±0.03µg/ml). The formulations TPEG20-
1, TPEG20-2, TPEG20-3 and TPEG20-4) showed
good solubility in 0.1 N HCl (up to 0.74±0.02
µg/ml) and in distilled water (up to 0.68±0.01
µg/ml).
Thiocolchicoside followed Beer’s Lamberts law at
the concentration of (2 to 10 µg/ml). The
regression (R2 value was found to be 0.9998 with
the slope of 0.0743x+0.0149.
The dissolution of prepared tablets was found
good in formulations containing
Thiocolchicoside: PEG ratios 1:6 with all carriers
viz., PEG- 3350, PEG- 4000, PEG- 6000, PEG-
8000 and PEG- 20000. The regression (R2 value
was found to be 0.9936, 0.9885, 0.9494, 0.9868
and 0.9666 for first order plots and 0.9979,
0.9868, 0.9206, 0.9860 and 0.9804 for Hixson
Crowell’s models for formulations TPEG3-4,
TPEG4-4, TPEG6-4, TPEG8-4 and TPEG20-4.
Accelerated stability studies for the optimized
formulation (TPEG6-4) revealed that these
formulations were retained their physical
parameters even after stressed storage
conditions.
CONCLUSION
In the investigation of finding best PEG carrier
for preparing solid dispersions by taking
Thiocolchicoside as a model drug. The
formulation TPEG6-4 in the ratios 1: 6 was
found to have good solubility and drug
dissolution characteristics. And among the PEG-
3350, PEG-4000, PEG-6000, PEG-8000 and
PEG-20000, Poly Ethylene Glycol 6000 was
found to be best PEG among the tested one as
solid dispersion.
CONFLICT OF INTEREST
The authors declare no conflict of interest in this
research article.
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Cite this article as:
Hemanth A, Hindustan Abdul Ahad, Devanna N. Appraising Best Poly Ethylene Glycol Carrier for
Thiocolchicoside Solid Dispersions. J Pharm Chem Biol Sci 2018; 6(4):355-364