Senthil Periasamy Sengodan* et al. /International Journal Of Pharmacy&Technology
IJPT | Oct-2012 | Vol. 4 | Issue No.3 | 4749-4758 Page 4749
ISSN: 0975-766X CODEN: IJPTFI
Available Online through Research Article www.ijptonline.com
DESIGN AND EVALUATION OF IMATINIB MESYLATE MICROSPH ERES USING CHITOSAN AND HPMC K100
Nagesh.R.Sandhu1, Senthilkumar. K. Loganathan1, Senthil Periasamy Sengodan*2
1Padmavathi College of Pharmacy, Dharmapuri, Tamilnadu, India 2The Erode College of Pharmacy and Research,
Veppampalayam, Erode, Tamilnadu, India. Email: [email protected]
Received on 08-09-2012 Accepted on 22-09-2012
Abstract
Microencapsulation is one of the novel methods for retarding drug release from dosage forms and minimizing the
adverse effects thereby increasing the patient compliance. Microspheres form homogeneous, monolithic particles which
improve the treatment by providing localization of the drug at the site of action and by prolonging the drug release. The
objective of the present study was to formulate sustained release microspheres of Imatinib mesylate using Chitosan and
HPMC K100 as release retarding agent. The results of FTIR spectral and DSC studies showed that there was no
significant interaction between the drug and polymer. The maximum yield of the microspheres was found to be 86.58%
and the encapsulation efficiency was found to be 96.85%. The prepared microspheres released the drug completely
within 24 hours at lower drug to polymer ratio. At ratio of more than 1:4, the drug release was sustained over a period
of 24 hours. The microspheres were discrete, spherical and uniform in shape. The particle size was of the microspheres
was found to be 102.53µm. The prepared microspheres showed minor changes in particle size only under long term
stability study with no appreciable change in drug content proving good stability of the product conducted both in 0⁰C,
ambient and accelerated temperatures. The present study signifies the utility of microspheres in retarding the drug
release. This may in turn reduces the frequency of dosing, thereby improving the patient compliance.
Keywords: Chitosan, HPMC K100, Imatinib mesylate, Release Kinetics, Solvent Evaporation.
Senthil Periasamy Sengodan* et al. /International Journal Of Pharmacy&Technology
IJPT | Oct-2012 | Vol. 4 | Issue No.3 | 4749-4758 Page 4750
Introduction
Research and development, of drug-delivery systems are increasing at a rapid pace throughout the world. This global
trend will increase in the next decade as cuts in public health expenses require lower costs and higher effectiveness. To
meet this demand, many efficient drugs currently in use will be reformulated within release systems that can be value-
added for best possible molecular activity. Currently, microencapsulation techniques are most widely used in the
development and production of improved drug-delivery systems. These techniques frequently result in products
containing several variably coated particles1.
Imatinib mesylate (α form) is used to treat cancers and act by specifically inhibiting a certain enzymes of a
receptor tyrosine kinase and its characteristics of a particular cancer cell, rather than non specifically inhibiting and
killing all rapidly dividing cells.
1.1 Materials and Method
Imatinib mesylate α-form2, 3 is a gift from Natco Pharma Limited. HPMC K 100 was obtained a gift sample
from micro labs Bangalore, Chitosan was obtained from Ajantha Pharma Mumbai as a gift sample. Dichloromethane,
methanol, is the analytical range from SD fine Chemicals Mumbai.
1.2 Method of preparation
Imatinib mesylate (α form) were prepared by solvent evaporation techniques4, 5. A typical procedure was as
follows: Different amounts of Chitosan, HPMC K100 were dissolved in 8.5 ml of acetone separately by using a
magnetic stirrer. The core material Imatinib mesylate was added to the polymer solution and mixed for 15 minutes. The
resulting dispersion was added in a thin stream to a mixture of 90ml light liquid paraffin and 10ml n-Hexane contained
in a 250 ml beaker, while stirring at 900 rpm using a mechanical stirrer. Stirring was continued for 3 hrs until the
acetone evaporated completely. The microspheres formed were filtered using Whattman no.1 filter paper. The residue
was washed 4-5 times with 50 ml portions of n-Hexane. The product was then dried at room temperature for 24 hrs and
subsequently stored in vaccum desiccators over fused calcium chloride. All the batches were prepared in the same
method[Table1].
Senthil Periasamy Sengodan* et al. /International Journal Of Pharmacy&Technology
IJPT | Oct-2012 | Vol. 4 | Issue No.3 | 4749-4758 Page 4751
Table-1: Formula for Microspheres Preparation.
Formulation code Drug(mg) Chitosan(mg) HPMC K100(mg)
SVF1 400 200 --
SVF2 400 400 --
SVF3 400 600 --
SVF4 400 800 --
SVF5 400 1000 --
SVF6 400 -- 200
SVF7 400 -- 400
SVF8 400 -- 600
SVF9 400 -- 800
SVF10 400 -- 1000
2. Evaluation of Microspheres:
2.1 Particle size determination6, 7, 8
Particle size was determined by using an optical microscope under regular polarized light, and the mean particle
size was calculated by measuring 50-100 particles with a help of a calibrated ocular microscope.
2.2 Tapped density
The sample of specified quantity of granules was carefully introduced into a 20 ml graduated cylinder. The
cylinder was dropped at a two second intervals onto a wood surface 100 times from a height of 1 inch. It was calculated
by using an equation below.
Df = M/Vp
Df = Bulk density
M = Weight of samples in grams
Vp = Final tapped volumes of granules in cm3
Senthil Periasamy Sengodan* et al. /International Journal Of Pharmacy&Technology
IJPT | Oct-2012 | Vol. 4 | Issue No.3 | 4749-4758 Page 4752
2.3 Angle of repose
The angle of repose (θ) i.e., flow property of the microspheres which measures the resistance to particle flow
was calculated as
tan(θ)=2H/D
where,
2H/D is the surface area of the free standing height of the microspheres heap that is formed after making the
microspheres flow from the glass funnel.
2.4 Carr’s index
The percentage compressibility of microspheres was calculated according to equation given below,
% Compressibility= DO-Df/DO × 100
DO = Tapped Density
Df = Bulk Density
2.5 Hausuers ratio
The percentage compressibility of microspheres was calculate according to equation given below,
% Compressibility= DO/ Df
DO = Tapped Density
Df = Bulk Density
2.6 Drug loading %9
50 mg of microspheres were treated with 50 ml of phosphate buffer (pH 7.4), in 100 ml amber colored vial with
stirring at 250 rpm. The temperature was maintained at 37 ± 0.2º C. At the end of two hours it was filtered, and the
filtrate was analyzed photometrically at 230 nm using U.V. Visible spectrophotometer (Shimadzu, Japan). Drug
loading efficiency was calculated as:
Drug encapsulation (%) = (Actual drug concentration / Theoretical drug concentration) × 100
Drug loading (%) = (Weight of drug / Weight of microspheres) × 100
2.7 Percentage yield10
The prepared microspheres with a size range of were collected and weighed from different formulations. The
measured weight was divided by the total amount of all non-volatile components which were used for the preparation
of the microspheres.
Senthil Periasamy Sengodan* et al. /International Journal Of Pharmacy&Technology
IJPT | Oct-2012 | Vol. 4 | Issue No.3 | 4749-4758 Page 4753
% Yield = (Actual weight of product / Total Weight of excipients and drug) × 100
2.8 Differential scanning colorimetry (DSC)11
Thermograms were obtained by using a TGA Q200 V24.4 analyzer at a heating rate 50ºC /min over a
temperature range of 0 to 250°C. The sample was hermetically sealed in an aluminum crucible. Nitrogen gas was
purged at the rate of 100 ml/min for maintaining inert atmospheres.
2.9 In vitro dissolution studies12, 13
The drug release rate from prepared microspheres was carried out using the USP type II (Electro Lab.)
dissolution paddle assembly. A weighed amount of microspheres equivalent to 100 mg drug were dispersed in 900 ml
of 0.1N HCl for the first 2 hrs and the remaining pH 7.4 maintained at 32 ± 0.5°C and stirred at 100 rpm. 5 ml sample
was withdrawn at predetermined intervals and filtered and equal volume of dissolution medium was replaced in the
vessel after each withdrawal to maintain sink condition. The collected samples were suitably diluted with pH 7.4 and
analyzed spectrophotometrically at 230 nm to determine the concentration of drug present in the dissolution medium.
2.10 In vitro drug release kinetic studies14, 15
Kinetic model had described drug dissolution from solid dosage form where the dissolved amount of drug is a
function of test time. The exact mechanism of Imatinib Mesylate release from the microsphere was further studied by
kinetic models. The drug release data was analyzed by zero order, first order, Higuchi, Korsmeyer Peppa’s models. The
criteria for selecting the most appropriate model were chosen on the basis of goodness of fit test.
2.11 Stability study16, 17
The stability protocol was designed based on the ICH guidelines. The microspheres formulations chosen were
stored at 30⁰C ± 2°C and 65 ± 5%RH for a period of 3 months and at 40⁰C ± 2°C and 75 ± 5% RH for a period of 3
months. The stored samples were tested for their drug content and for any physical change. The testing was carried out
at 0, 1, 2, 3 months for accelerated storage condition and for long-term storage condition.
3. Result
3.1 Particle Shape
The shape and surface morphology of imatinib mesylate microspheres were observed by SEM photograph and
Optical Microscopic photograph shows in. Fig 2 and Fig 5. The obtained microcapsules are round to sphere in shape.
Senthil Periasamy Sengodan
IJPT | Oct-2012 | Vol. 4 | Issue No.3 | 4749-
Fig: 2 Scanning electron microscope of optimized formulation
Fig: 5 Optical microscopic Photo of optimized formulation
3.2 Drug polymer interaction studies
Drug-polymer interactions were studied by FT
mesylate, chitosan and HPMC K100 and physical mixture of drug and polymers (1:1). Samples were prepared in KBr
disks (2 mg sample in 200 mg KBr) with a hydrostatic press at a force of 5.2
was 400–4000 cm-1 and the resolution was 4
Senthil Periasamy Sengodan* et al. /International Journal Of Pharmacy&Technology
-4758
Scanning electron microscope of optimized formulation
microscopic Photo of optimized formulation.
polymer interactions were studied by FT-IR spectroscopy. The spectra were recorded for Imatinib
and HPMC K100 and physical mixture of drug and polymers (1:1). Samples were prepared in KBr
disks (2 mg sample in 200 mg KBr) with a hydrostatic press at a force of 5.2 τ cm-2 for 3 minutes.
and the resolution was 4 cm-1.
et al. /International Journal Of Pharmacy&Technology
Page 4754
Scanning electron microscope of optimized formulation.
IR spectroscopy. The spectra were recorded for Imatinib
and HPMC K100 and physical mixture of drug and polymers (1:1). Samples were prepared in KBr
2 for 3 minutes. The scanning range
Senthil Periasamy Sengodan* et al. /International Journal Of Pharmacy&Technology
IJPT | Oct-2012 | Vol. 4 | Issue No.3 | 4749-4758 Page 4755
3.3 Micromeritic properties
The average particle size of the microspheres was determined by using optical microscope. The flow properties
and packing properties were investigated by measuring the angle of repose, tapped density and bulk density [table: 2].
Table-2: Physical Evaluation of Microspheres.
Formulation
code
Particle
Size(µm)
Angle of
Repose(θ)
Bulk Density
(gm/cm)
Tapped Density
(gm/cm)
Carr's
Index
Hausner’s
Ratio
SVF1 93.68+2.56 22.12 ± 0.639 0.800 ± 0.10 0.974+0.041 17.75±3.972 1.22±0.065
SVF2 99.97+1.16 23.42 ± 0.08 0.785 ± 0.02 0.988+0.01 19.88±2.763 1.26±0.055
SVF3 96.48+3.26 22.05 ±0.509 0.828 ± 0.02 1.00+0.030 17.99±0.935 1.22±0.01
SVF4 102.53+0.86 22.310 ± 1.20 0.813 ± 0.02 1.01+0.008 20.20±3.252 1.25±0.051
SVF5 97.87+1.92 24.05 ± 0.39 0.800 ± 0.05 0.991+0.002 19.29±0.473 1.24±0.005
SVF6 99.30+0.45 23.48 ± 1.44 0.804 ± 0.03 0.983+0.006 18.20±3.491 1.22±0.051
SVF7 102.01+0.77 22.88 ± 1.55 0.820 ± 0.08 0.992+0.002 17.34±0.734 1.21±0.01
SVF8 97.96+1.59 25.15 ± 0.46 0.818 ± 0.08 1.026+0.004 20.27±0.470 1.25±0.005
SVF9 97.91+0.38 24.19⁰±0.60 0.822 ± 0.08 1.02+0.007 19.41±1.341 1.24±0.02
SVF10 98.17+1.22 23.41⁰±0.12 0.819 ± 0.01 1.032+0.008 20.60±1.981 1.26±0.03
All the values are mean (n =3) ±SEM
3.4 Drug entrapment
Accurately weighed microspheres equivalent to 100mg of drug was suspended in 25 ml of methanol and
sonicated for 3 minutes. The solution was then filtered, diluted suitably and analyzed for drug content
spectrophotometrically at 230 nm. The percentage drug entrapment was calculated as follows and shown in table: 3.
% Drug Entrapment = Practical drug loading/ Theoretical drug loading X 100
Senthil Periasamy Sengodan
IJPT | Oct-2012 | Vol. 4 | Issue No.3 | 4749-
Table-3: Evaluation of Microspheres.
Formulation code % Yield (%) Drug Content
(in25mg)
SVF1 81.99+0.635 22.33+0.854
SVF2 85.28+0.393 22.05+0.684
SVF3 83.35+1.606 22.47+1.070
SVF4 86.58+1.056 21.65+0.219
SVF5 84.56+1.650 22.62+0.262
SVF6 84.41+1.123 22.72+0.341
SVF7 85.29+1.012 21.94+0.332
SVF8 86.12+0.624 21.49+0.162
SVF9 85.13+1.572 21.68+0.121
SVF10 85.79+0.752 21.71+0.287
All the values are mean (n =3) ±SEM
3.5 Dissolution studies
Dissolution test was performed in USP XXIII dissolution test apparatus by paddle method.The dissolution
media used was 900 ml of 0.1N HCl for first 2hrs and remaining time 900
32 ± 0.5°C and rotated at 100 rpm. Aliquots samples were withdrawn at specified time intervals and replaced with
same volume of fresh media filtered and analyzed spectrophotometrically (Shimadzu
drug release [table: 3] [Fig:1].
Fig: 1
Senthil Periasamy Sengodan* et al. /International Journal Of Pharmacy&Technology
-4758
Drug Content
(in25mg)
Entrapment Efficiency
(%w/w)
Cum.%
Release
22.33+0.854 82.79+0.525 98.70+0.477
22.05+0.684 84.77+0.349 99.48+0.352
22.47+1.070 86.01+1.190 99.10+0.264
21.65+0.219 96.85+0.064 99.26+0.308
22.62+0.262 88.09+1.290 98.76+0.201
22.72+0.341 83.47+1.020 98.16+0.438
21.94+0.332 83.01+0.696 98.72+0.338
21.49+0.162 83.93+0.544 98.55+0.443
21.68+0.121 87.51+0.876 99.22+0.189
21.71+0.287 82.62+0.640 98.89+0.411
Dissolution test was performed in USP XXIII dissolution test apparatus by paddle method.The dissolution
ml of 0.1N HCl for first 2hrs and remaining time 900 ml of phosphate buffer pH 7.4 maintained at
otated at 100 rpm. Aliquots samples were withdrawn at specified time intervals and replaced with
filtered and analyzed spectrophotometrically (Shimadzu Japan
Fig: 1 Cumulative % Drug Release.
et al. /International Journal Of Pharmacy&Technology
Page 4756
R² Value ‘n’ value
98.70+0.477 0.992 0.69
99.48+0.352 0.994 0.689
99.10+0.264 0.991 0.705
99.26+0.308 0.994 0.699
98.76+0.201 0.994 0.658
98.16+0.438 0.992 0.716
98.72+0.338 0.992 0.685
98.55+0.443 0.992 0.648
99.22+0.189 0.991 0.662
98.89+0.411 0.995 0.666
Dissolution test was performed in USP XXIII dissolution test apparatus by paddle method.The dissolution
ml of phosphate buffer pH 7.4 maintained at
otated at 100 rpm. Aliquots samples were withdrawn at specified time intervals and replaced with
Japan) at 230 nm for cumulative
Senthil Periasamy Sengodan
IJPT | Oct-2012 | Vol. 4 | Issue No.3 | 4749-
3.6 Stability Studies Stability study was carried out for the SVF4 formulation by exposing it to different temperature
temperature and 40°C for 3 months. The sample was analyzed for drug content at the regular intervals. It was found
that no remarkable change in the drug content of SVF4 formulation. This indicates that SVF4 was stable at the above
temperature. SEM Analysis was also done for the opti
Fig-:3 scanning electron microscope of optimized
Formulation [Stored at 40oC].
Conclusion
An emulsion solvent evaporation technique has been successfully employed to produce Imatinib Meyslate
loaded Chitosan and HPMC K100 microspheres with maximum drug encapsulation and desirable release profile. The
formulation variable drug-polymer ratio exerted a significant influence on the drug encapsulation. The present study
signifies the utility of microspheres in retarding the drug release. This may in turn reduces the frequency of dosing,
thereby improving the patient compliance.
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Senthil Periasamy Sengodan* et al. /International Journal Of Pharmacy&Technology
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Stability study was carried out for the SVF4 formulation by exposing it to different temperature
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Corresponding Author:
S.P.Senthil*,
Email: [email protected]
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