Patil Manoj D. et al.

/JPBMS 2010, 1 (16)

Available online at www.jpbms.info

Research Article
JPBMS
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL SCIENCES

FORMULATION AND EVALUATION OF SOLID DISPERSION OF TELMISARTAN WITH KOH AS ALKALISER

BY HOT MELT METHOD
Patil Manoj D.1* Keny Ramchandra V1., Saindane Dhananjay S2., Khade Trushali S.3,
Gavitre Bhaskar B.3, Kulkarni Vivek S.3, Bobe Kisan R3 and Gaikwad Dinanath T3.
1.Goa College of Pharmacy, Goa.,India
2.Gangamai College of Pharmacy, Nagoan, Dhule.,India
3.Indira Institute of Pharmacy, Sadavali(Devrukh), Dist-Ratnagiri,India

Abstract
The effect of molecular weight of polyethylene glycols (PEGS) and drug/PEG ratio on the structure and dissolution rates
of the solid dispersions with Telmisartan have been examined. Telmisartan (TEL) was chosen as a model drug due to its
poor and pH dependent water solubility. The alkalizer used to modify the pH of TEL was KOH, in the solid dispersion(SD)
system significantly increased the drug dissolution rate in gastric fluid (pH 1.2) . Structural change in drug crystallinity to
an amorphous form was also a contributing factor based on differential scanning calorimetry (DSC) thermograms and
powder X-ray diffraction (PXRD) patterns. The drug frequency of the C=O band decreased and the O–H broad band in the
Fourier transform infrared (FTIR) spectra disappeared when these alkalizer was added. It was evident that the alkalizer
in PEG 6000 based SDs synergistically enhanced dissolution of TEL not only by modulating pH but also by changing drug
crystallinity to an amorphous form via molecular interactions.

Key words: Telmisartan, Solid dispersion, Alkalizer.

Introduction
In the recent years the progress in treatment of diseases
has been evident with an upsurge in development of new
drugs. An estimated 40% of these drugs are poorly water
soluble. Although most of the drugs have encouraging
experimental data obtained in vitro, in vivo results have
been disappointing. The enhancement of oral
bioavailability of poor water soluble drugs remains one of
the most challenging aspects of drug development A
common method used to improve the dissolution rate of a
poorly water soluble drug is by formation of a solid
dispersion (SD) with hydrophilic polymers such as
polyethylene glycol, hydroxypropylcellulose,
polyvinylpyrrolidone, and other diverse carriers[1-3].
Various approaches have been used to improve the
solubility of drug which in turn leads to increase in in-
vitro drug release. The approaches are preparation of
amorphous form, prodrug, solid dispersion and
complexation with various natural and synthetic
cyclodextrins. Out of which preparation of amorphous
form is the convenient way to enhance aqueous solubility
and dissolution profile of poorly water soluble drugs.
Different techniques used to convert crystalline form of a
drug to the amorphous form are spray drying, jet milling,
hot melt extrusion or drug-polymer co-precipitation.
Materials in the amorphous form are less
thermodynamically stable than any crystalline form,
leading to a tendency for amorphous materials to
transform to a known or potentially unknown crystalline
form. The time scale for any transformation is also
unknown and is evaluated through stability studies.
Amorphous state is characterized by the randomly arrang-
*Corresponding Author:
Patil Manoj D.
Goa College of Pharmacy, Goa, India .
Contact no-09970849937
1 Journal of Pharmaceutical and Biomedical Sciences (JPBMS), Vol. 01, Issue 01
-ed molecules of which the motions are kinetically frozen.
A little provocation by different stressors can accelerate
the mobility of molecules and facilitate the achievement of
most stable and ordered crystalline states
Crystalline and amorphous states of a solid exhibit altered
molecular interactions, which may pose as energy barrier
for phase transformations between them. The importance
of pH control on the dissolution behaviors of water-
insoluble drugs in SD systems became apparent a decade
ago[4-5].
Improving drug bioavailability by changing their water
solubility has been possible by chemical or formulation
approaches Chemical approaches to improving
bioavailability without changing the active target can be
achieved by salt formation or by incorporating polar or
ionizable groups in the main drug structure, resulting in
the formation of a pro-drug. Alternatively, it has also been
reported that the modulation of pH in dosage forms is a
promising way to modify the release rate of several pH-
dependent and ionizable drugs[6,7]. Solid dispersions
appear to be a better approach to improve drug solubility
than these techniques, because they are easier to produce
and more applicable. For instance, salt formation can only
be used for weakly acidic or basic drugs and not for
neutral. Furthermore, it is common that salt formation
does not achieve better bioavailability because of its in
vivo conversion into acidic or basic forms. Moreover, these
types of approaches have the major disadvantage that the
sponsoring company is obliged to perform clinical trials on
these forms, since the product represents a NCE.
Formulation approaches include solubilization and
particle size reduction techniques, and solid dispersions,
among others. Solid dispersions are more acceptable to
patients than solubilization products, since they give rise
to solid oral dosage forms instead of liquid as
 Patil Manoj D. et al. /JPBMS 2010, 1 (16)

solubilization products usually do. Milling or T7 10 - 400

micronizations for particle size reduction are commonly
performed as approaches to improve solubility, on the
basis of the increase in surface area. Solid dispersions are
more efficient than these particle size reduction
techniques, since the latter have a particle size reduction
limit around 2–5 mm which frequently is not enough to
improve considerably the drug solubility or drug release
in the small intestine and, consequently, to improve the
bioavailability . Moreover, solid powders with such a low
particle size have poor mechanical properties, such as low
flow and high adhesion, and are extremely difficult to
handle.
Different antihypertensive agents have been widely used
for the treatment of hypertension. Angiotensin II receptor
antagonist are also used for the antihypertensive drugs.
Most of the Angiotensin II receptor antagonist are
practically insoluble in water and thus were shown to
have dissolution rate limited oral bioavailability.
Telmisartan is a Nonpeptide Angiotensin II receptor (type
AT1) antagonist, which is used in the treatment of
osteoarthritis, rheumatoid arthritis, acute gouty arthritis
and allied inflammatory conditions. TEL is manufactured
and supplied in the free acid form and is characterized by
a very poor solubility, resulting in low bioavailability[8].
Telmisartan shows low aqueous solubility and poor
dissolution of this molecule delays its rate of absorption
and finally the onset of action. Therapy with this drug
offers a good quality of life for hypertensive patients due
to the minimal side effects[9].
Material and Method
Materials
TEL was obtained as a gift sample from Ratiopharm
Private. Ltd. (Goa, India). PEG 6000 was obtained as gift
sample from Colorcon Asia Pvt. Ltd. (Goa, India),
Potassium Hydroxide (KOH), was obtained from Loba
Chem. (Mumbai, India). All other chemicals and reagents
were of analytical grade.
Preparation of Solid dispersion
Solid dispersions of Telmisartan and PEG were obtained
by the hot melt method. Telmisartan: Alkalizer: PEG
mixtures containing 10:1:200, 10:1:400, 10:1:600 ratios
(Table 1) were heated to 100°C with constant stirring. The
Telmisartan was miscible in the PEG melt in all
proportions with alkalizer. The melts were allowed to cool
and solidify at room temperature and then stored at 4°C.
The solid product was ground in a mortar at room
temperature and then sieved (105-250 µm). For
dissolution assays, a sufficient amount of molten material
(equivalent to 100 mg of Telmisartan) was poured into
semi permeable bag (2 cm internal diameter)[10,11]
Table 1 : Formulation of Telmisartan Solid Dispersions
Batch code Ratio
Telmisartan: KOH PEG 6000
T1 10 - 200
T8 10 1 400
T9 10 - 600
T10 10 - 600
T11 10 - 600
T12 10 1 600
Fourier transforms infrared spectroscopy (FTIR)
The spectra of the samples (again including the raw
material of TEL, PEG 6000 and different SD powders) were
recorded (figure 1-3) using a spectrophotometer FTIR-
88101A (Shimadzu). KBr pellets were prepared by gently
mixing 1 mg of the sample with 200 mg KBr. The
wavelength ranged from 400 to 4000 cm−1 with a
resolution of 4 cm−1[12].
Thermal analysis (DSC)
A TA Instruments differential scanning calorimeter DSC-
60 (shimadzu) was used to investigate the thermal
behaviors (Figure 4-6) of the raw material of TEL, PEG
6000 and the different SD powders. The amount of sample
used ranged from 2-8mg for the SD powder and PEG 6000,
and was 0.4 mg for pure TEL. The samples were weighed
in a standard open aluminum pan, while an empty pan of
the same type was used as a reference. The heat running
for each sample was set from 30 to 300 °C at 10 °C/min,
using nitrogen as a purge gas at heat flow of 40ml/min.[13-
14].
Powder X-ray diffraction (PXRD)
PXRD patterns were obtained (figure 7) with using XRD-
COMPACT 3K using Powder X-ray diffractometer, CuKα
radiation, a voltage of 40 KV and a current of 20 mA. The
samples were scanned at the scanning rate of 0.02° /min
over the 5-60° 2θ range[15].
Scanning Electron Microscopy (SEM) analysis
The scanning electron microscope is used to study the
surface morphology of the samples. Photomicrographs of
the sample were taken (figure 8) using the Jeol Model JMS-
6300 scanning electron microscope (Jeol Technics
Company, Japan). The samples for SEM were mounted on
sample stubs with double sided adhesive tape, vacuum
coated with gold and photomicrographed at suitable
magnification. The SEM uses a beam of electron to scan the
surface of the sample to build a three dimensional image
of the specimen[16].
In-vitro dissolution
Dissolution studies were conducted using a USP II paddle
method (50 rpm, 37 °C, and 900 mL dissolution medium)
with a dissolution apparatus (Labinda, India). The SD
powder equivalent to 80 mg TEL was exposed for 1 hr to
gastric fluid (pH 1.2). Samples were withdrawn (Table 2)
from the dissolution medium at predetermined intervals
(10, 20, 30, 40, 50, 60, 70, 80 and 90 min) and then drug
concentration was determined by UV (Figure 9).
Figure 9: Dissolution profiles of T1 to T12 SD batches
120
T1

T2 10 - 200 100 T2
T3
Drug release (%)

80
T4
T3 10 - 200 60
T5
T6

T4 10 1 200 40 T7
T8
20 T9
T5 10 - 400 T10
0 T11
0 20 40 60 80 100
T6 10 - 400 time(min)
T12

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An equivalent amount of fresh medium was added to Figure 3 : IR spectra of Telmisartan with KOH
maintain a constant dissolution volume[17].
Stability Conditions
The batches were subjected to room temperature for a
period of three months. The microcrystals were then
analyzed for the drug release profile (Table 3) by carrying
out in-vitro dissolution studies[18].
Result and Discussion
Fourier Transform Infrared Spectroscopy (FTIR)
Structural changes and the lack of a crystal structure can
lead to changes in bonding between functional groups that
can be detected by FTIR spectroscopy. Fig 1-3 shows the
FTIR spectra of Telmisartan, PEG 6000 and their SDs with
or without alkalizer. The spectrum of pure Telmisartan
showed a distinct absorption band for the carbonyl group
C=O at 1700 cm−1 and the O–H band at 3100 cm−1. Based
on the variation of these two FTIR bands, we could classify
alkalizer of the SDs into two groups. The spectra of the
KOH, showed a change in the C=O bond and the O–H bond, It has been described that a lowering of the frequency of
such that the frequency of C=O was shifted from 1695 the carbonyl stretching band from carboxylic acid is
cm−1 to 1580 cm−1 and the broad O–H band could hardly typically indicative of strong hydrogen bonding
be recognized. interactions. Moreover, the disappearance of the O–H peak
Figure 1 : IR spectra of pure Telmisartan of carboxylic acid attributable to hydrogen bonding
confirmed that this moiety could be protonated by
alkalizer mainly via a Lewis acid-base interaction .
Therefore, it was evident from FTIR spectra that there was
a molecular interaction between Telmisartan and the
alkalizer, resulting in enhanced dissolution of Telmisartan
in SDs[12].
Powder X-Ray Diffraction Studies (PXRD)
The PXRD patterns of Telmisartan, PEG 6000 and their SDs
with or without alkalizer are given in Fig. 7.
Figure 7: X-RD of Pure drug ,PEG 6000 and solid dispersion
batches

Figure 2 : IR spectra of pure Telmisartan with PEG 6000

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 Patil Manoj D. et al. /JPBMS 2010, 1 (16)

Figure 5 : DSC thermogram of KOH

The PXRD pattern of PEG 6000 had two characteristic

peaks of high intensity at 19.0° and 22.0°. The diffraction
pattern of pure Telmisartan was highly crystalline in
nature as indicated by numerous peaks. Three peaks at
7.0°, 14.0°, 20.0°, 23.0° and 25.0° were noticeable and the
main peak at 7.0° was particularly distinctive. It is known
that the lack of a distinctive peak of a drug in SD systems
demonstrates that a high concentration of the drug is
dissolved in the solid state. Moreover, a large reduction in Figure 6: DSC thermogram of PEG6000
characteristic peaks indicates an amorphous state. Based
on the diffractograms of SDs,we could classify the
diffraction patterns into two groups according to the
presence or absence of a Telmisartan crystalline peak at
7.0° KOH were in the group for which there was no
distinct Telmisartan crystalline peak at 7.0°.
The PXRD patterns of binary SD (Telmisartan and
PEG6000) also showed the distinctive peak at 19.0° and
22.0°, indicating that Telmisartan was still in the
crystalline form. The results of the PXRD patterns were
quite different from that of DSC thermograms In fact; PEG
6000 can play a role as the SD carrier and change the
crystalline structure of Telmisartan into a partially
crystalline structure. The incorporation of a suitable
alkalizer in PEG based SDs can definitely promote the
change of a crystalline drug to a totally amorphous form
leading to an enhanced dissolution rate[19].

Differential Scanning Calorimetry (DSC)

The DSC thermograms of TEL, PEG 6000 and their SDs are
shown in Fig. 4-6.
Figure 4 : DSC thermogrames of Pure Telmisartan
The DSC curve of pure TEL and PEG 6000 exhibited single
endothermic peaks at 269.06 °C (TEL) and 60.39 °C (PEG
6000), respectively, which corresponded to their intrinsic
melting points. The characteristic peaks of PEG 6000were
invariably identified in the DSC curves of SDs, suggesting
that PEG was present in the same physical state after
making the SD powder by the Hot Melt Method. No
characteristic melting peak of TEL was identified in the
DSC curves obtained from these PEG 6000 based SD
formulations[20].
Scanning Electron Microscopy (SEM)
Scanning electron microscopy is very helpful in studying
the change in the surface topography and shape of the
particles of pure drug and solid dispersions. The batches
of engineered crystals covering extreme polymer
concentrations from the entire range of experimental
batches were taken for SEM studies. Photomicrographs of
the pure drug (a) and SD (b) are shown in Fig 8.
Photomicrographs of the pure drug and the formulated
batches reveled the change in particle shape and surface
topography.
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Figure 8 : SEM Photomicrograph of Pure Drug (a) and SD (b)

SEM thus indicates that the polymer has formed a In -Vitro Dissolution
uniform coating over the individual drug particles thus The percentage drug release of all solid dispersion batches
resulting in the formation of spherical particles with are shown in Table 2.
improved crystal properties as revealed from later
studies.

Table 2: Cumulative % drug released of T1 to T12 SD batches

Time
( Min) T1 T2 T3 T4
0 0 0 0 0
.
10 42.9 ±2.12 34.72±2.66 17.18±2.46 51.1±1.33
20 62.65±1.26 48.16±1.33 24.31±2.68 60±2.18
30 76.53±1.78 61.02±1.56 36±2.58 72.56±2.15
40 91.19±2.77 70.13±1.89 50.44±2.90 83.3±2.43
50 106.18±2.56 80.64±2.66 59.92±1.43 94.92±2.38
60 - 87.08±2.89 72.74±2.44 -
70 - 96.52±2.56 83.99±2.87 -
80 - - 93.76±2.37 -
90 - - 99.59±2.53 -

Time
( Min) T5 T6 T7 T8
0 0 0 0 0
10 31.2±3.1 34.72±2.19 24.12±1.6 40.05±1.38
20 46.14±2.55 47.36±1.73 41.28±1.39 54.4±1.58
30 57.44±2.17 54.56±1.38 46.16±2.47 64.63±2.41
40 68.14±2.38 65.78±2.63 62.18±2.53 78.43±2.64
50 71.43±2.12 74.61±2.31 69.68±2.90 87.25±2.83
60 77.73±2.76 86.12±2.18 81.76±2.44 103.61±2.54
70 88.29±2.43 87.47±2.17 85.19±1.43 -
80 94.93±2.82 94.71±2.94 100.14±2.47 -
90 101.28±1.66 103.2±2.46 - -
Time
( Min) T9 T10 T11 T12
0 0 0 0 0
10 30.63±2.57 35.55±1.68 36.57±1.49 39.26±2.99
20 38.8±2.51 47.27±1.83 55.56±1.33 50.28±2.32
30 52.28±2.95 58.15±1.44 71.7±2.53 69.06±1.84
40 59.73±1.52 70.8±2.16 82.07±2.41 75.11±1.94
50 74.13±1.90 78.33±2.95 87.83±2.68 86.45±1.52
60 81.2±1.72 84.55±1.48 104.94±2.59 97.97±1.86
70 97.75±1.83 99.61±1.58 - -
80 101.36±1.59 - - -
90 - - - -

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The incorporation of pH modifiers was attempted due to
the fact that the chemical structure of TEL is pH-
dependent so one can assume that pH modifiers can
modulate TEL solubility leading to an increase in the
dissolution rate. The effect of alkalizer on TEL release
rate in gastric fluid (pH 1.2) shown in Fig 9. Since the
drug is highly soluble in low pH conditions, the
dissolution rate of the drug after 90 min reached almost
Table 3: Stability Conditions
Time in minutes Cumulative % drug released
T1 T2
10
40.9 33.68
20
61.24 46.10
30
72.52 60.49
40
90.12 68.14
50
102.24 79.69
60 - -
86.08
70 - -
95.27
80 - -
90 - -
Conclusion
A significant enhancement in the aqueous solubility and
dissolution profile of the drug is seen. Among the various
batches containing alkaliser being used in the study
namely, KOH., PEG6000 exhibited significant enhancement
in solubility and dissolution profile of the drug. A
significant enhancement in solubility and dissolution rate
was seen when polymers were used in the ratio of 1:400
(KOH:PEG6000) (T8).SEM studies revealed the spherical
nature of the solid dispersion . Spherical nature indicates
improvement in micromeritic properties thus anticipating
improved tabeletting properties. Infra red study revealed
the compatibility of the drug with the polymer. XRD
diffractogram of the solid dispersions revealed a decrease
in the crystallinity of the drug reflecting amorphization of
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