Formulation Design for Poorly Water-Soluble Drug by Using Solid Dispersion of Telmisartan for Solubility and Dissolution Rate Enhancement
A Deevan Paul*, Jada Vinay, K G RajyalakshmiP V Prasad
Academic Consultant, SV University, India
Submission: June 03, 2019; Published:July 12, 2019
*Corresponding author: A Deevan Paul, Academic Consultant, SVU College of Pharmaceutical Sciences, SV University, Tirupati, India
How to cite this article:A Deevan Paul, Jada Vinay, K G Rajyalakshmi, P V Prasad. Formulation Design for Poorly Water-Soluble Drug by Using Solid Dispersion of Telmisartan for Solubility and Dissolution Rate Enhancement. Glob J Pharmaceu Sci. 2019; 7(3): 555716. DOI: 10.19080/GJPPS.2019.06.555716.
Formulating the drug into solid dispersion (SD) by fusion method and solvent evaporation method using different grades of PEG in comparison to plain telmisartan drug with optimised solid dispersion tablets. The Preformulation studies like FTIR and DSC studies for drug excipient compatibility stated that the drug and carrier selected for the study and are compatible for further studies. SD was prepared by using the drug Telmisartan by two methods, fusion method and solvent evaporation method, eighteen formulations were prepared and characterized in terms of various parameters. The in vitro drug for all the formulations were in the range of 82.38%-95.73% for fusion method and 91.45% to 96.81% for solvent evaporation method and tablets it ranges from 95.70% to 99.40%. The in-vitro release studies have shown that the cumulative drug release values were within the range of 14.23%-94.54% for fusion method, 18.57%- 95.89% for solvent evaporation method and 14.35% - 99.53% for tablets. The fast drug release about 99.53% was found in the F22 formulation by solvent evaporation method in solid dispersion tablets in the ratio of 1:2 and drug content was found to be 99.53% and disintegration time was 1.09 seconds and all parameters were found to be greater than all other formulations.
The enhancements of oral bioavailability of poorly water-soluble drugs often show poor bioavailability because of low and erratic levels of absorption. Drugs that undergo dissolution rate limited, in gastrointestinal absorption and it shows improved dissolution and bio availability by reduction in particle size. However, drugs often lead to aggregation and agglomeration of particles, which results in poor wettability . Solid dispersions of poorly water-soluble drugs with water-soluble carriers have been reduced the incidence of these problems and enhanced dissolution.
The development of solid dispersions as a practically viable method to enhance bioavailability of poorly water-soluble drugs overcame the limitations of previous approaches such as salt formation, solubilisation by co solvents, and particle size reduction. Studies revealed that drugs in solid dispersion need not necessarily exist in the micronized state [2-4]. A fraction of the drug might molecularly disperse in the matrix, thereby forming a solid dispersion. When the solid dispersion is exposed to aqueous media, the carrier dissolves and the drug releases as fine colloidal particles. 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.
The formulation of poorly soluble drug compound for oral delivery now presents one of the greatest challenges to formulation scientist in the pharmaceutical industry [5-6]. They can be used to increase the dissolution rate of a drug with low aqueous solubility, thereby improving its oral bio availability. Poorly water‐soluble drugs present many difficulties in the development of pharmaceutical dosage forms due to their limited water solubility; slow dissolution rate and low bioavailability . Solid dispersions have been widely reported as an effective method for enhancing the dissolution rate and bioavailability of poorly water-soluble drugs . The dissolution rate is directly proportional to solubility of drug. The therapeutic effectiveness of any drug depends upon the bioavailability; i.e. enough drug must reach the site of action to elicit the desired pharmacological response. The bioavailability affected majorly by two factors i.e. solubility and permeability, other factors are chemical stability,poor dissolution rate, purity. Currently only 8% of new drug
candidates have both high solubility and permeability [8-10].
Telmisartan from Vasudha Pharma, Polythylene glycol
from J&K chemicals, Mumbai, Sodium hydroxide from Merck
chemicals, Mumbai, Microcrystalline cellulose form MYL Chem
Mumbai, Magnesium stearate from S.D Fine chem. LTD Mumbai,
Meglumine from Qualigens Mumbai, Crospovidone XL-10 form
Merck Limited and Povidone from MYL Chem Mumbai.
100ml of dissolution medium with various concentration of
carrier is taken in stopper flask an excess of drug was suspended
in medium and equilibrated by intermittent shaking maintained
at 37+0.5c, filter the solution by using what Mann filter paper,
filtrate is suitably diluted. It is analyzed by UV spectroscopy
Melting point of the pure drug was determined by melting
point apparatus. Take a little quantity of sample in the capillary
tube and placed in the apparatus and switch on the button.
Observe through the viewpoint. Temperature was slowly raised
and note that the temperature where the sample melts .
Infrared (IR) spectroscopy studies of Telmisartan, PEG,
Croscarmellose sodium, Meglumine and Microcrystalline
cellulose were recorded in a FTIR spectrophotometer (Thermo-
IR 200) Potassium bromide pellet method was employed, and
background spectrum was collected under identical conditions.
The spectrum for each sample showed the wavelength of
absorbed light which is a characteristic of the chemical bonds in
the sample [15-17]. Each spectrum was derived from 16 single
average scans collected in the region of 4000 - 400cm-1 at a
spectral resolution of 2cm-1.
Thermal analysis of Telmisartan, PEG and physical mixture
were recorded. Netzsch DSC 200PC (Netzsche, Selb, Germany),
the instrument was calibrated with indium (calibration standard,
>99.999%) for melting point and heat of fusion. A heating rate of
10C/min was employed in the range of 25-200C. Analysis was
performed under nitrogen purge (20mL/min). The samples were
weighted into standard aluminum pans and an empty pan was
used as reference. The obtained DSC graphs were interpreted
and compared for any presence of interactions [18-20].
In present work the drug and carrier were used in different
ratios [1:1, 1:2 and 1:3]. The respective amount of polymer (PEG
4000, PEG 6000, PEG8000 and PEG 10000) was placed in a china
dish and allowed to melt by heating up to its melting point. To
the molten mass, an appropriate amount of drug module was
added and stirred constantly until homogenous dispersion was
obtained. The mixture was cooled rapidly by placing the dish in
an ice bath for 5min to solidify. The solid mass was pulverized,
sifted through sieve no. 60 and stored in desiccator for further
studies [21-24]. The formulations were coded as F1, F2, F3, F4,
F5, F6, F7, F8, F9, F10, F11 and F12 for drug- polymer ratios 1:1,
1:2 and 1:3 respectively (Table 1).
Solid dispersions of drug module with a hydrophilic carrier
(PEG 6000, PEG8000) were prepared in different ratios of drug–
carrier. The quantity of carriers for optimization was selected
based on preliminary trial formulations. The solvent evaporation
method was used for the preparation of SD in the present study.
In this method, 1.0g of drug module was accurately weighed
and dissolved in a minimum amount of methanol in which
hydrophilic carrier was suspended .
The solvent was evaporated using a water bath at 450C.The
obtained solid was pulverized, sieved through a sieve no. 60 and
store in airtight containers. The formulations were coded as F13,
F14, F15, F16, F17 and F18 for drug- polymer ratios 1:1, 1:2 and
1:3 respectively  (Table 2 & 3).
Percentage yield was calculated to know about
efficiency of any method and thus its help in selection of
appropriate method of production. The final weights of the
prepared solid dispersions were taken, and percentage yield was
calculated by using the given formula [26,27].
Equivalent weight of prepared solid dispersions containing
100mg drug were taken and transferred into 100ml Standard
flask Then take 1ml from above solution and diluted up to 100ml
simulated salivary fluid pH 6.8 and repeat the same again by
take 1ml from above solution and diluted up to 100ml simulated
salivary fluid pH 6.8. The resulting solutions were filtered
through a 0.45μ membrane filter and diluted accordingly. The
absorbance of the solutions was measured at 296 nm. Percentage
of drug content was calculated by using the given formula .
In vitro dissolution studies of pure telmisartan and solid
dispersions were conducted with the USP type II apparatus
(paddle type). The dissolution studies were performed using
900ml simulated salivary fluid of pH 6.8 as dissolution medium
at 37±0.5C with 50rpm speed. Samples of each preparation
equivalent to 10 mg of drug were added into the dissolution
medium. The sample of 5ml aliquots were withdrawn
periodically (15, 30, 45 and 60min) and filtered through 0.45μ
membrane filter. The withdrawn sample was replaced every
time with same quantity of fresh dissolution medium. The filtered solutions were diluted suitably, and the samples were
analyzed for their drug content by using UV spectrophotometer
at wavelength of 269nm. Percentage of drug dissolved at various
time intervals was calculated by plotting time on X- axis against
percent cumulative drug release on Y-axis [29-31].
The flow property of blend was determined by the angle of
repose values. The maximum angle that can be attained between
the surface of the pile of the powder and the horizontal plain is
defined as “angle of repose” .
Angle of repose was determined by fixed funnel method.
Angle of repose =Tan-1(h /r)
h =Height of pile
r =Radius of pile
7.6. Bulk density
It is defined as the ratio of given mass of powder and its bulk
volume. Bulk density values having less than 1.2g/cm3 indicates
good packing and greater than 1.5g/cm3 indicates poor packing
It indicates the flow property of blend; it is defined as
the ratio of tapped density and bulk density. It was related to
antiparticle friction. Values less than 1.25 indicates good flow
These tests are based on the comparison of the individual
tablets with upper and lower percentage limits of observed
sample average(x-mean). USP provides limits for average weight
of tablets. When tablets contain more than 150mg these limits
It is defined as the force required to breaking a tablet
diametrically. It was determined using the Monsanto hardness
tester. It is measured in kg/cm2. 4kg/cm2 is usually considered as
minimum satisfactory value to tablets. Tablet requires a certain amount of hardness to withstanding of mechanical shocks
during manufacturing, packing and shipping .
Friability was measured by using Roche friabilator. It is
closely related to tablet hardness. It is used in determination of
the ability of the tablet to with stand abrasion in packing, hand
lining and shipping. Tablets that loss less than 10% of its weight
was generally considered as accepted formulation.
It was determined by using disintegration test apparatus
using water as immersion fluid. One tablet was placed in each
tube of all 6 tubes. Then it was subjected to disintegration at 28-
32 cycles/minute. The time taken for complete disintegration
was measured in seconds .
Drug release studies were carried out by using USP dissolution
test apparatus type II. 900ml dissolution medium (pH 6.8
phosphate buffer) is taken in each bucket. Maintain temperature
37+0.5C. Paddle was rotated at 75rpm for 30 minutes. 1ml of
samples was withdrawn at predetermined time intervals of 5,
10, 15, 20, 25 and 30 minutes respectively. Replacing the same
amount of dissolution medium by replacing with equal quantity
of drug free pH 6.8 phosphate buffer. It was diluted and filtered
through membrane filter. Absorbance of sample was analyzed by
UV spectrophotometer at 296nm [41-42].
10μg/ml solution of Telmisartan was prepared in 0.1N HCl,
Phosphate buffer pH 6.8, Phosphate buffer pH 7.4 and Distilled
water. UV-VIS scan was taken between the wavelengths 200-
400nm using UV-VIS spectrophotometer (Shimadzu, UV-1700)
(Table 4 & 5).
Infrared (IR) spectro scopy studies of telmisartan PEG,
Croscarmellose sodium Meglumine and micro crystalline
cellulose were recorded in a FTIR spectro photometer (themo-
IR200) potassium bromide pellet method was employed and
background spectrum was collected under identical conditions
the spectrum for each sample showed the wavelength of
absorbed light which is a characteristic of the chemical bonds
the sample each spectrum was derived from 16 single average
collected in the region of 4000-400cm-1 at a spectral resolution
of 2cm-1 (Figure 1-5).
FT-IR Studies did not show any significant interactions
between the drugs and their respective excipients. From the
compatibility studies PEG, Croscarmellose sodium, Meglumine,
Povidone and microcrystalline cellulose are compatible with
Telmisartan and its optimized formula for solid dispersion and
for tablets states there is no significant interactions between the
excipients (Figure 6 & 7).
The Preformulation studies for compatibility by FTIR
concluded the drug and carrier selected for the study were
compatible and can be used for the further studies. The invitro
drug content for all the formulations were in the range
of 82.38% - 95.73% for fusion method and 91.45% - 96.81%
for solvent evaporation method and for tablets it ranges from
95.70%- 99.40% (Table 6-12) (Figure 8 & 9).
All formulation blends were evaluated to Pre compression
parameters such as angle of repose, bulk density tapped density,
compressibility index, Hausner’s ratio. Angle of repose values of
all formulations blend was found in the range of 23.14 to 25.67 it
indicates free flowing of powder blend. The Carr s index values
were found in between 12.23 to 15.60 indicates them having
good compressibility. Hausner’s ratio was present in the range
of 1.11 to 1.25 that indicates good flow of powder blend. All Pre
compression parameters were present within the limits whereas
for F19 all the parameters were not found to be satisfactory
The post compression parameters were measured for
tablet. Weight variation was in the range of 522.8 to 528.4mg
for 525.00mg. Hardness of all formulation was found to be in
the range of 4.3 to 4.9kg/cm2. Friability values were found to be
0.32 to 0.61. Drug content were found to in the range of 95.70 to
99.50. Thickness of IR layer was found between 5.52 to 5.57mm.
Disintegration time for all formulation was found to be below 2
minutes except F19 (Table 14 & 15) (Figure 10).
The in-vitro release studies have shown that the % drug
release values were within the range of 14.23% - 94.53% for
fusion method, 18.57% - 95.89% for solvent evaporation method
and 14.35% - 99.53% for tablets.
The present study was carried out to develop telmisartan
immediate release tablets by direct compression method
Telmisartan SDs in two methods namely fusion followed by
solvent evaporation method respectively which tends to improve
the solubility of telmisartan. Formulation characteristics were
found to be satisfactory in all formulations shows acceptable
internal specification for weight variation, thickness, hardness,
friability, drug content, disintegration time and in vitro drug
release. The fast drug release about 99.53% was found in the
F22 formulation by solvent evaporation method SDs tablets
in the ration of 1:2, drug content was found to be 99.53% and
disintegration time was 1 minute 09 seconds and all parameters
were found to be greater than all other formulations.
The authors wish to express their heartful gratitude to
Prof. K. Thyagaraju, Principal of SVU College of Pharmaceutical
Sciences, SV University-517502 for providing their unrestricted
support for carrying out this research.