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Formulation Development and Evaluation of Ticagrelor Tablet for Regulatory

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Article in Journal of Applied Pharmaceutical Science · October 2013

DOI: 10.7324/JAPS.2013.31020

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Journal of Applied Pharmaceutical Science Vol. 3 (10), pp. 114-118, October, 2013
Available online at http://www.japsonline.com
DOI: 10.7324/JAPS.2013.31020
ISSN 2231-3354

Formulation Development and Evaluation of Ticagrelor Tablet for

Regulatory Market
Md. Shafayat Hossain1 *, Md. Anisuzzaman2, Md. Anwar Hossain1 and Vikash Kumar Shah1
1
Pharmacy Discipline, Khulna University, Bangladesh.
2
Lecturer, Pharmacy Discipline, Khulna University, Bangladesh.

ARTICLE INFO ABSTRACT

Article history: The aim of the study was to develop a formulation of Ticagrelor 90 mg tablets that is equivalent to the reference
Received on: 09/07/2013 product using similar excipients to match the in-vitro dissolution profile. A compressed coated tablet was
Revised on: 16/09/2013 formulated consisting of Ticagrelor and excipients conforming to the USP/BP monograph and below maximum
Accepted on: 03/10/2013 amount allowed per unit dose. The physical characteristics of powder blends were evaluated for bulk density,
Available online: 31/10/2013 tapped density, compressibility index, hausner ratio, angle of repose and moisture content. The compressed core
and coated tablets were evaluated for thickness, hardness, weight variation, friability, disintegration, dissolution,
Key words: drug content and stability. The powder blends for all formulations showed satisfactory bulk density, tapped
Ticagrelor, platelet density, compressibility index, hausner ratio, angle of repose and moisture content. All the core and coated
aggregation inhibitor, wet tablets showed acceptable pharmaco-technical properties in terms of thickness, hardness, weight variation,
granulation, in-vitro friability, disintegration. Dissolution performances were varied depending on the composition of matrix tablet.
dissolution. Finally a formulation batch B05 consisting of Ticagrelor (34.61%), mannitol (61.15%), sodium starch glycolate
(2.69%), hypromellose (HPMC-2910, 5cps) (0.77%), purified talc (0.38%), magnesium stearate (0.38%) and
opadry grey (21k57558) (2%) showed maximum similarity with the reference product. Using this formulation a
pharmaceutical will be able to met regulatory compliance.

INTRODUCTION The amount of fluid that will be given in wet powder, because it
causes too hard, fragile, they are too soft during the wet ability and
According to the USP 29 Monogram, ''Tablets are solid
the well controlled. Compared with solvent-based systems, the
dosage forms containing medical substances with or without
aqueous solution has the advantage that the handling is safe, but to
suitable diluents. They may be classed, according to the method of
break loose upon hydrolysis may not be appropriate.
manufacture, as compressed tablets or molded tablets. The vast
Ticagrelor is a platelet aggregation inhibitor which was
majority of all tablets manufactured are made by compression, and
approved for use in the European Union by the European
compressed tablets are the most widely used dosage form in this
Commission on December 3, 2010. It was accepted by the US Food
country. Compressed tablets are prepared by the application of
and Drug Administration on July 20, 2011 (FDA, 2011). Ticagrelor
high pressures, utilizing steel punches and dies, to powders or
is indicated for the prevention of thrombotic events (for example
granules. Tablets can be prepared in a wide variety of sizes,
stroke or heart attack) in patients with acute coronary syndrome or
shapes, and surface marking, depending upon the design
myocardial infarction with ST elevation.
of the punches and dies.'' Direct Compression is by far
Combined Ticagrelor with acetylsalicylic acid which
the easiest method of the processing of tablets, because it only
unless the latter is contraindicated. (Haberfeld, 2010) Treatment
involves the main steps of powder blending, lubrication and
with Ticagrelor for acute coronary syndrome which is superior as
compaction. The process by means of wet granulation binder
compared with Clopidogrel because significantly reduces the rate of
liquid is added to the slightly agglomerate of the powder mixture.
.
death (Husted et al., 2009). The proper dosage regimen's design is
* Corresponding Author an important factor in accomplishing this objective. (Lachman et
Md. Shafayat Hossain, Pharmacy Discipline Khulna University, al., 1976). In addition to the active ingredient (the drug), tablets
Khulna-9208, Bangladesh. Phone: +8801717283523;
contain a number of inert components known as additives, added to
E-mail: [email protected]

© 2013 Md. Shafayat Hossain et al. This is an open access article distributed under the terms of the Creative Commons Attribution License -NonCommercial-
ShareAlike Unported License (http://creativecommons.org/licenses/by-nc-sa/3.0/).
 Hossain et al. / Journal of Applied Pharmaceutical Science 3 (10); 2013: 114-118 115

impart acceptable manufacturing characteristics and properties to Wet granulation method

the formulation. The tablet formulation problem can be stated as Weigh active ingredient & other excipients accurately,
follows: given the drug with its physical and chemical properties then pass ticagrelor, maize starch, hypromellose (HPMC-2910,
with the most wanted drug dose in the tablet, find the 16 5cps), mannitol, microcrystalline cellulose (Avicel PH 101),
Excipients and their quantities for getting satisfactory properties microcrystalline cellulose (Avicel PH 102) and sodium starch
when mixed & they can be compressed into a tablet. To formulate glycolate through sieve (mesh no.16) where applicable and mix
typically 25% active ingredient is required. Filler is used increase properly in rapid mixer granulator. Add maize starch &
bulk in order to produce a tablet of practical weight for hypromellose (HPMC-2910), 5cps solution and mix properly. The
compression (typically 65%), binder is used to impart cohesive lumps thus produced are passed through s.s screen (12mm) using
properties to the powders by the formulation of granules, milling machine. The small lumps are dried in FBD at 65C. These
Lubricants added to reduce interparticulate friction to prevent dried small lumps are passed through s.s screen (3mm) and
adhesion of powder to the surfaces of punches and dies and to checking loss on drying (%LOD). These granules are blended with
facilitate tablet ejection from the die, Disintegrant is incorporate sodium starch glycolate (type A) & purified talc for 20 minutes
to facilitate rapid breakup and disintegration after administration, into the blender and blend properly. After that it was lubricated
Surfactant is used to aid wetting and dissolution of the drug with magnesium stearate and evaluated as direct compression
(Rowe, 1993). method.
Since it is imperative that, the prepared tablet must
conform the quality parameters, like, weight and content Coating
uniformity, hardness, friability, disintegration time and dissolution For all formulations (B01-B05), same coating materials
and it is known that all these are influenced by both the with same amount is applied where using auto coating machine
formulation components and method of research, it is clear that a (China) and default coating parameter.
high degree of technical knowledge and expertise is needed for
best formulation requires. Evaluation of Powder Blend and granules
Before compression of tablets, powdered mixture and
MATERIALS AND METHOD granules were applied to determine some parameters such as loose
bulk density, tapped bulk density, angle of repose, compressibility
For the present study Ticagrelor was obtained from
index and hausner ratio. To get original data, reading were taken
Shanghai Panso pharma technology co. ltd., China, Ludipress
in triplicates and expressed as mean±SD.
was procured from BASF, Germany; Hypromellose (HPMC-2910,
5cps) was from the Dow chemicals, USA; Purified talc was from
Bulk Density
Asian minerals, Thailand. Maize starch & Mannitol were
Loose Bulk Density (LBD) and Tapped Bulk Density
procured from Roquette, France and Pregelatinized starch
(TBD) were determined by using Digital Automatic Tap Density
(Starch 1500) & Opadry grey (21k57558) were from Colorcon,
Tester (Vegoo, VTAP/ MATCO-II, India). 2 g of powder from
India, Microcrystalline cellulose (Avicel PH101),
each formula (previously lightly shaken to break any agglomerates
Microcrystalline cellulose (Avicel PH102) & Croscarmellose
formed) were taken into a 10 ml measuring container. After
sodium were procured from Mingtai chemical co. ltd., Taiwan,
observed initial volume, the equipment was on and the cylinder
others were from local commercial source. Preparation of
was allowed to fall under its own weight onto a hard surface. The
Ticagrelor tablets were prepared by direct compression method as
reading of tapping was continued until no further change in
well as wet granulation method according to formula given in the
volume. Using the following equation (Shah et al., 1997) LBD and
Table 1.
TBD was calculated:
Weight of the powder
Direct Compression method LBD = volume of the packing
Weigh active ingredient & other excipients accurately, Weight of the powder
TBD = Tapping volume of the packing
then pass Ticagrelor, ludipress, microcrystalline cellulose (Avicel
PH 102), mannitol, dibasic calcium phosphate, pregelatinized
starch (Starch 1500), lactose, sodium lauryl sulphate Compressibility Index
and purified talc through sieve (mesh no.16) where The compressibility index of the powder blend was
applicable and place in blender and mix properly. After determined by Carr’s compressibility index (Aulto, 2002).
checking Loss on drying (%LOD), lubricated with Carr’s index (%) = {(TBD – LBD) X 100}/TBD
magnesium stearate prior to compression, all prepared granules
were evaluated for several tests such as loose bulk density, Hausner’s Ratio
tapped bulk density, compressibility index, hausner ratio Hausner ratio which is interconnected with the flow
and angle of repose. The tablets were compressed in CIP 8 ability of a powder blend or granules.
station compression machine (China) using 9 mm, round punch. Hausner’s factor = Tapped bulk density/Loose bulk density
116 Hossain et al. / Journal of Applied Pharmaceutical Science 3 (10); 2013: 114-118

Angle of Repose and the solution was shaken thoroughly. The undissolved
To calculate the angle of repose of the granules Funnel substance was detached by filtration through whatman filter
method was used (J Cooper and G gun. 1986). The accurately paper. Finally the serial dilutions were done. The
weighed granules were taken in a funnel. The correctly absorbance of the diluted solutions was measured at 222 nm.
weighed powder mix was taken in the funnel then the height of the The concentration of the drug was determined from the
funnel was adjusted in such a way the tip of the funnel just standard curve of the Ticagrelor in phosphate buffer of pH
touched the top of the powder mix (Train, 1958). The powder mix 3.0.
was permitted to flow through the funnel freely onto the surface.
The powder cone's diameter was measured and angle of In-vitro dissolution testing
repose was calculated using the following equation (Carter, In-vitro dissolution of Ticagrelor was done by using
1986): Shing kwang machinery, type DT-6 dissolution test apparatus
Angle of Repose θ = tan-1 h/r (Japan). The dissolution test was performed using 900 ml of
Where, h = Height of the powder cone. phosphate buffer (pH 3.0) as the dissolution media at 50 rpm and
r = Radius of the powder con. 37°C ±5°C. 5 ml of aliquots were periodically withdrawn and the
sample volume was replaced with an equal volume
Evaluation of Tablet of fresh dissolution medium. The prepared samples were
The formulated tablets were assessed for average evaluated spectrophotometrically at 222 nm for drug dissolved at
weight, diameter, thickness, hardness, friability, disintegration that time.
time and dissolution test. (Gohel et al., 2005; Patel & Baria
2000) Stability Studies
Stability studies were done of one selected batch
Weight variation test according to ICH guidelines to assess the drug content and
To evaluate weight variation, twenty tablets from each formulation stability (Cartensen, 1995). One selected fabricated
formulation was weighed and the test was performed. tablet batch was alu-alu blister packaged and kept at 40±20C and
75±5% RH. Samples were withdrawn at one month, two
Thickness month and three month for evaluation of appearance, hardness,
For determining thickness digital slide caliper is used. 5 drug content and percentage dissolution during the stability
tablets from each batch (B01-B05) were used and average values studies.
were calculated.
RESULTS AND DISCUSSION
Hardness test
Manual tablet hardness tester but digital (Shin Kwang Properties of Powder blend and Granules
Machinery, type- TH- 20B, Japan) was used to determine the The Powder blend and granules of different prepared
hardness. From each formulation, 6 tablets were crushed and formulations (B01 to B05) were evaluated for LBD, TBD,
recorded. compressibility index angle of repose and LOD (Table. 2).
The results of LBD ranged from 0.526±0.02 to 0.635±0.02
Disintegration time g/ml and TBD ranged from 0.682±0.01 to 0.792±0.02 g/ml.
Except chewable tablet, disintegration is a very important The bulk densities of granules for B04 and B05 were quite lower
parameter which is intended by mouth. Six tablets were taken from than those of other granules because they were manufactured
each batch and performed disintegration time according to the through wet granulation method where granulation fluid, purified
official monogram. water is incorporated.
The compressibility index (%) found ranged from
Friability test 14.52±0.03 to 23.21±0.02. According to the USP 29 guidelines,
20 tablets of each formulation were weighed with an compressibility index 11% to 15% result in good flow
analytical weighing balance (model: CPA 2245, Sartorious, properties, 16-20% results in good and 21-25% results in
JAPAN) and determined to check by using a friability tester (Shin passable flow properties. So the granules of B01 & B05
kwang machinery co., ltd., Taiwan) at 25 rev/min for 4 min. The showed fair flow properties while the batch B02 & B03
tablets were finally weighed and compared with their preliminary revealed fair flow properties and the rest one was passable. The
weight for obtaining percentage friability. angle of repose ranged from 27.64±0.08 to 30.75±0.04. According
to the Pharmaceutical guidelines, the angle of repose (<30o)
Content uniformity indicate excellent flow properties of granules for all prepared
At random 20 tablets were weighed and powdered. The formulation. For hausner ratio, formulation B01 & B05 were
powder equivalent to 90 mg was weighed correctly and dissolved possessed good powder flow property and others were passable.
in 100 ml of phosphate buffer (dihydrogen phosphate) of pH 3.0 (Table 02)
 Hossain et al. / Journal of Applied Pharmaceutical Science 3 (10); 2013: 114-118 117

Table. 1: Composition of all prepared formulation of Ticagrelor tablet

Sl Ingredients (mg/Tablet) B01 B02 B03 B04 B05
For tablet core
1 Ticagrelor 90 mg 90 mg 90 mg 90 mg 90 mg
2 Ludipress ---- 90 mg --- ---- ----
3 Maize starch ---- --- --- 38 mg ---
4 Microcrystalline cellulose (Avicel PH 101) ---- --- --- 51 mg ---
5 Microcrystalline cellulose (Avicel PH 102) ---- 52.5mg --- 70 mg ---
6 Mannitol 151mg ------ 98 mg --- 159 mg
7 Pregelatinized starch (Starch 1500) ---- ---- 70 mg --- ---
8 Dibasic calcium phosphate 10mg ---- --- --- ----
9 Lactose monohydrate --- 20 mg --- --- ---
10 Croscarmellose sodium --- 5 mg --- --- ---
11 Sodium starch glycolate 7 mg --- --- 8 mg 7 mg
12 Hypromellose (HPMC-2910, 5cps) ------ ---- --- --- 2 mg
13 Purified talc 1 mg --- --- 1.5 mg 1 mg
14 Magnesium stearate 1 mg 2.5 mg 2 mg 1.5 mg 1 mg
15 *Purified water ---- ---- ----- 50 mg 80 mg
Compression weight 260 mg 260 mg 260 mg 260 260 mg
For coating materials
16 Opadry grey (21k57558) 5.200 mg
17 * Methanol 34.500 mg
18 *Dichloromethane(methylene chloride) 34.500 mg
(*)Marked items will not appear in the final product

Table. 2 Result of bulk density, Compressibility Index, Hausner ratio and Angle of Repose of different formulation.
Loose bulk density Tapped bulk density Angle of
Formulation Carr’s index (%) Hausner ratio LOD (%)
(LBD) (gm/ml) (TBD) (gm/ml) repose
B01 0.603±0.01 0.710±0.05 15.07±0.04 1.18±0.02 30.33±0.05 2.75
B02 0.635±0.02 0.792±0.02 19.82±0.05 1.25±0.01 30.75±0.04 2.84
B03 0.596±0.02 0.714±0.04 16.53±0.02 1.198±0.01 30.02±0.06 2.69
B04 0.526±0.03 0.685±0.03 23.21±0.02 1.30±0.02 28.30±0.03 2.92
B05 0.583±0.02 0.682±0.01 14.52±0.03 1.17±0.01 27.64±0.08 3.08

Table. 3: Physiochemical properties of Tablet of different formulations (B01-B05).

Thickness Hardness Friability Disintegra-tion time Drug content (%)
Average weight Diameter
Batch (mm) ± SD (kg/cm2)±SD (%) (Sec.) ±SD ± SD
(mg)±SD (N=20) (mm)
(N=20) (N=6) (n= 20) (n= 3) (n = 5)
B01 260.45±0.76 4.12±0.02 4.91±0.44 0.11 92.2±3.4 100.0±1.12
B02 261.68±0.62 4.05±0.05 5.02±0.39 0.23 99±2.7 99.75±0.98
B03 260.95±0.80 9 4.28±0.04 5.90±0.57 0.10 95.02±1.9 100.41±0.87
B04 259.23±0.71 4.34±0.04 6.80±0.25 0.24 96.17±3.3 100.02±1.20
B05 259.39±0.66 4.31±0.03 6.98±0.34 0.27 90.9±2.9 99.97±1.01

Table. 4: Stability study of best formulation from B05.

Characteristics Initial 1st month 2nd month 3rd month
Hardness (kg/cm2) 4.90±0.34 4.51±0.29 4.53±0.35 4.41±0.30
Assay (%) 99.97±1.01 99.52±1.29 98.57±1.54 98.35±1.40
Disintegration time (sec) 95.9±2.9 93.87±1.25 93.51±1.01 92.47±1.15
Dissolution (%) 96.6±1.57 96.17±1.87 95.45±2.09 94.07±1.94
Appearance off white no change no change No change

For Tablets batch B02 showed the highest disintegration time (99±2.7 sec).
The results of physical parameters (average weight, After coating the weight gain achieved was about 1.67% w/w with
diameter, thickness, hardness, friability and disintegration time) 45 seconds as the disintegration time increased of coated tablets.
and drug content of the prepared tablets are given in Table. The drug content of each formulation was found near about to
3. The thickness of the tablets were found between 4.05±0.05 100% of labeled content. From observing all physical properties,
mm to 4.34±0.04 mm. Different density and porosity indicate it is said that physical properties and drug content of the
different hardness of a tablet. The hardness range of tablets was compressed tablets were acceptable. (Table. 3)
found from 4.91±0.44 kg/cm2 to 6.98±0.25kg/cm2. Friability The content of active ingredients in the formulation was
ranged from 0.10% to 0.27% which was observed from my found in between 99.75±0.98% to 100.41±0.87% w/w.
experiments. According to the British Pharmacopoeia (BP-2011), In vitro release studies of the formulations B01, B02 and
the weight variations of all formulated tablets were complied. . In B03 prepared through direct compression method by using
all batches (B01-B05), core and coated tablets were disintegrated ludipress, microcrystalline cellulose (Avicel PH 102), lactose
within 2 minutes (Table 03). Formulation batch B05 showed the monohydrate, croscarmellose sodium & sodium starch glycolate
lowest disintegration time (90.9±2.9 sec) where as formulation (where applicable) with different amount. The drug released from
118 Hossain et al. / Journal of Applied Pharmaceutical Science 3 (10); 2013: 114-118

the formulation B01 to B03 was found to be 93.8± 0.27, 93.19 ± The tablet was evaluated for flow property and after compression
0.46, and 94.09 ± 0.4% for Ticagrelor respectively. (Figure 1) parameters. The dissolution result of formulation B05 showed
In-vitro release studies of B04 and B05 formulated equivalent or more % release of drug as compared to the
through wet granulation method & the drug released were found innovator products. The stability result of formulation B05
94.8 ± 0.17 & 96.6 ± 0.25 for Ticagrelor respectively. (Figure 1) revealed that the alu-blister was the suitable packing for Ticagrelor
The best release rate found from B05 formulation when tablet. Further pharmacokinetic and pharmacodynamic study is
compared to other formulations this is due to the incorporation of badly needed in-vivo for recommendation of B05 in suitable
hypromellose (HPMC-2910, 5cps) as a granulation agent. animal models.
When the %cumulative drug release of B05 formulation
compared with the innovators (Brilinta) sample at different time ACKNOWLEDGEMENT
intervals, similar result was found (Figure 2). The tablets were
The authors are grateful to the Management and
found to release more than 90% after 25 min. Maximum release
Staff of General Pharmaceuticals Ltd., Gazipur, Bangladesh for
was found to be 96.6 % by B05 formulation. On the other hand,
providing the all facilities like gift sample and standard of
the Brilinta tablet was found to release of 97% of drug. So, the
Ticagrelor.
formulation B05 was similar with the innovator. (Figure 2)

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The selected batch B05 was evaluated after three months
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RH and the result are mentioned in table 04. It was establish that
the Ticagrelor tablets are stable in the Alu-alu pack of stability
period.

CONCLUSION
How to cite this article:
The present research was carried out to develop a tablet
dosage form of Ticagrelor evaluated from direct compression and Md. Shafayat Hossain, Md. Anisuzzaman, Md. Anwar Hossain
and Vikash Kumar Shah. Formulation Development and
wet granulation method. We found most suitable method is wet
Evaluation of Ticagrelor Tablet for Regulatory Market. J App
granulation where less excipient were used like mannitol, Pharm Sci, 2013; 3 (10): 114-118.
hypromellose (HPMC-2910, 5cps) & sodium starch glycolate etc.

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