FORMULATION AND EVALUATION OF IMMEDIATE RELEASE
TABLETS OF PRASUGREL HYDROCHLORIDE
Mehul B. Vyas *, Mitesh S. Patel, Dr. Samir K. Shah
Sardar Patel College of Pharmacy,
Department of Pharmaceutics,
Vidyanagar Vadatal Road,
Bakrol, Anand.
No of Tables: 19
No of Figures: 07
For correspondence,
Mehul B. Vyas,
Assistant Professor,
Sardar Patel College of Pharmacy,
Department of Pharmaceutics,
Vidyanagar Vadatal Road,
Bakrol, Anand.
Mobile No: 8866747170
Email ID: mehulvyas_85@yahoo.co.in
ABSTRACT:
Prasugrel hydrochloride is a anti platelet agent with treatment of acute coronary syndrome.
The purpose of the investigation was to increase the solubility and dissolution rate of
prasugrel hydrochloride by using Tween 80 and different super disintigrant such as
Croscarmellose sodium, sodium starch glycolate, cross povidone and different grades of
microcrystalline cellulose. Immediate release tablets of prasugrel hydrochloride were
prepared by direct compression method using super disintigrant such as Croscarmellose
sodium and different grades of microcrystalline cellulose in different ratios. Sodium starch
glycolate was added to aid disintegration. Tablets were subjected to physicochemical
characterization such as thickness, hardness, friability, weight uniformity, drug content,
disintegration time, in vitro drug release, and stability study. The in vitro drug release in
optimized formulation F6 was found to be 97.04 % in 60 min. Accelerated stability study
was carried out for the optimized formulation which indicated insignificant difference
between before and after storage of formulation.
KEYWORDS: Prasugrel Hydrochloride, Tween 80, Sodium starch glycolate, Croscarmellos
ssodium, crosspovidone, Direct Compression, Immediate release tablet.
INTRODUCTION: [1-40]
Oral route of drug administration is perhaps the most appealing route for the delivery of
drugs. The various dosage forms administered orally, the tablet is one of the most preferred
dosage forms because of its ease of manufacturing, convenience in administration, accurate
dosing, stability compared with oral liquids, and because it is more tamperproof than
capsules. The bioavailability of drug is dependent on in-vivo disintegration, dissolution and
various physiological factors. In recent years, scientists have focused their attention on the
formulation of quickly disintegrating tablets. The task of developing rapidly disintegrating
tablets is accomplished by using a suitable diluents and super disintegrant
[18-21]
.The
gastrointestinal tract provides sufficient fluid to facilitate disintegration of the dosage form
and dissolution of the drug. The large surface area of gastric mucosa favors the drug
absorption. Therefore the oral route has continued to be the most appealing route for drug
delivery despite the advancements made in the new drug delivery systems. Banker and
Anderson stated that at least 90% of all drugs used to produce systemic effect are
administered orally. Rapidly disintegrating tablets have received much attention in recent
years, as they are preferred by paediatric and geriatric patients. Moreover, the drug
dissolution is facilitated by the tablets quick disintegration. [22]
MECHANISM OF TABLET DISINTEGRATION:
The tablet breaks to primary particles by one or more of the mechanisms listed below:1.
By capillary action.
2.
By swelling.
3.
Because of heat of wetting.
4.
Due to disintegrating particle/particle repulsive forces.
5.
Due to deformation.
6.
Due to release of gases.
7.
By enzymatic effects.
Advantages of tablets: [24-25]
 They are unit dosage form, and they offer the capabilities of all oral dosage forms for
the dose precision and the least content variability during dosing
 Accuracy and uniformity of drug content
 Optimal drug dissolution and hence, availability from the dosage form for absorption
consistent with intended use (i.e., immediate or extended release).
 Usually taken orally, but can be administered sublingually, rectally or intravaginally.
 Their cost is lowest of all oral dosage forms
 They are the most compact of all oral dosage forms
 They are in general the easier and cheaper to package and ship as compare to other
oral dosage forms
 Product identification is simple and cheap, requiring no additional processing steps
when employing an embossed or monogrammed punch face
 They are ease to administer, does not require a specialist
 They are better suited to large-scale production than other unit oral forms
 They have the better properties of chemical, mechanical and microbiological stability
Prasugrel, a thienopyridine derivative, is a platelet activation and aggregation inhibitor
structurally and pharmacologically related to clopidogrel and ticlopidine. Similar to
clopidogrel, prasugrel is a prodrug that requires enzymatic transformation in the liver to its
active metabolite, R-138727. R-138727 irreversibly binds to P2Y12 type ADP receptors on
platelets thus preventing activation of the GPIIb/IIIa receptor complex. As a result, inhibition
of ADP-mediated platelet activation and aggregation occurs. Prasugrel was developed by
Daiichi Sankyo Co. and is currently marketed in the United States and Canada in cooperation
with Eli Lilly and Company for acute coronary syndromes planned for percutaneous coronary
intervention (PCI). FDA approved in 2009. Prasugrel is an thienopyridine and a prodrug
which inhibits ADP receptors by irreversibly acting on the P2Y12 receptor on platelets. The
active metabolite of prasugrel prevents binding of adenosine diphosphate (ADP) to its platelet
receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex.
Prasugrel is proposed to have a similar mechanism of action to clopidogrel. Prasugrel
produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light
transmission aggregometry. Following a 60-mg loading dose of the drug, about 90% of
patients had at least 50% inhibition of platelet aggregation by one hour. Maximum platelet
inhibition was about 80%. Mean steady-state inhibition of platelet aggregation was about
70% following three to five days of dosing at 10 mg daily after a 60-mg loading dose. Platelet
aggregation gradually returns to baseline values over five to 9 days after discontinuation of
prasugrel, this time course being a reflection of new platelet production rather than
pharmacokinetics of prasugrel. Discontinuing clopidogrel 75 mg and initiating prasugrel
10 mg with the next dose resulted in increased inhibition of platelet aggregation, but not
greater than that typically produced by a 10-mg maintenance dose of prasugrel alone.
Increasing platelet inhibition could increase bleeding risk. The relationship between
inhibition of platelet aggregation and clinical activity has not been established.39 Prasugrel is
a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive
metabolites. The active metabolite has an elimination half-life of about 7 hr (range 2–15 hr).
Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show
similar pharmacokinetics.40 Also by considering following reasons the work was done and
attempt has been made to prepare the dosage form.
 Prasugrel hydrochloride is a member of the thienopyridine class of ADP receptor
inhibitors. These agents reduce the aggregation (clumping) of platelets.
 Prasugrel inhibits adenosine diphosphate induced platelet aggregation more rapidly,
more consistently, and to a greater extent.[72]
 However it has very low solubility (practically insoluble), which leads to its poor
dissolution in the gastrointestinal tract, resulting in variable bioavailability.[73]
 Many methods have been reported for the enhancement of solubility and dissolution
rate.
 Tween 80 is a common excipient and solubilizing agent used in the enhancement of
solubility and dissolution rate.
 Polysorbate 80 (also known as polyoxyethylene-sorbitan-20 mono-oleate, or Tween
80) is used in the pharmaceutical and cosmetic industry in lotions, medical
preparations (e.g., vitamin oils, vaccines, and intravenous preparations) and as an
excipient in tablets.[74]
 May toxicity avoided.
 Immediate release dosage forms rapidly disintegrate results in rapid drug release and
enhance the onset of action.
MATERILAS & METHOD: Prasugrel Hydrochloride was obtained as gift sample from
Themis pharmaceutical, Ahmedabad, Gujarat-380015. Tween80, Aerosil, Micro crystalline
cellulose, Talc, Magnesium stearate, Crosscarmilose sodium, Sodium stachglycolate,
Crosspovidone were provided by Orbit Pharmaceuticals, Ahmedabad, Gujarat.
PREFORMULATION STUDY OF OPTIMIZED COMPLEX: [40-83]
Preformulation study includes methodologies to characterize physicochemical properties of
the API, the compatibility and stability issues, as well as the kinetics of various processes.
Preformulation studies provide formulation scientists with valuable information essential to
selection of the most appropriate excipients and formulation approach, with the least
possibility
of
incompatibility,
instability,
and
manufacturing
complications.
The
preformulation study in present research was limited to physicochemical studies relevant to
the projected formulation goals. In a low dose tablet formulation like paliperidone, where
drug compound constitutes a very small percentage of the inclusion complexation (maximum
amount 20 mg) and properties such as density, surface characteristics, compatibility and
compressibility of the active ingredient were not expected to influence the final powder
properties. Several preformulation studies on inclusion complexation of paliperidone relevant
to formulation of an immediate release tablet were selected and performed to find the flow
properties and compressibility.
BULK DENSITY:
Apparent bulk density (pb) was determined by pouring the blend into a graduated cylinder.
The bulk volume (Vb) and weight of the powder (M) was determined. The bulk density (pb)
was calculated using following equation.
Pb =M/Vb
PROCEDURE: Weighed quantity of Prasugrel HCL were transferred into a 50ml measuring
cylinder without tapping during transfer the volume occupied by granules was measured.
TAPPED DENSITY (DT):
The measuring cylinder containing a known mass of blend (M) was tapped for a fixed time
(100 tapping). The minimum volume (Vt) occupied in the cylinder and weight of the blend
was measured. The tapped density (pt) was calculated using following equation.
Pt =M/Vt
COMPRESSIBILITY INDEX (CI):
Compressibility is indirectly related to the relative flow rate, cohesiveness and particle size
distribution of the powder. Powders with compressibility values lesser than about 15% has
been found to exhibit good flow properties. Tapped (pt) and Apparent (pb) bulk density
measurements can be used to estimate the compressibility of a material.
CI =pt -pb/pt x 100
Percent compressibility
Type of flow
5-15
Excellent
12-16
Good
18-21
Fair to passable
23-25
Poor
33-38
Very poor
>40
Extremely poor
TABLE 1: CARR’S INDEX
HAUSNER'S RATIO:
It is the ratio of bulk volume to tapped volume or tapped density to bulk density.
H =pt/ pb
Lower Hausner's ratio (<1.25) indicates better flow properties than higher ones (>1.25).
Hausner’s Ratio
Flow of Powder
1-1.2
Free flow
1.2-1.6
Cohesive flow
TABLE 2: HAUSNER’S RATIO
ANGLE OF REPOSE:
Angle of repose is the tan inverse of angle between height of pile of powder and the radius of
the base of conical pile. Angle of repose was determined using flowing through funnel
method. The blend was poured through a funnel that can be raised vertically until a
maximum cone height (h) was obtained. Radius of the heap (r) was measured and angle of
repose (0) was calculated using the following equqtion.
Values for angle of repose less than or equal to 30 degrees suggest a free flowing material
and angles greater than or equal to 40 degrees suggest a poorly flowing material.
0 = tan-1 (h/r)
Angle of repose
Powder flow
<25
Excellent
25-30
Good
30-40
Passable
>40
Very poor
TABLE 3: ANGLE OF REPOSE
PREPARATION OF IMMEDIATE RELEASE TABLET:
Immediate release tablets of prasugrel hydrochloride were prepared by direct compression.
First mix the drug and solubilizing agent tween 80 after add the microcrystalline cellulose
and disintegrating agent. All mixture were passed through # 40-mesh. Then the aerosil passed
through # 80-mesh after mix the above mixture. Then the talc and magnesium stearate
separately passed through # 60-mesh then all the ingredients mix for 2 min. then the
ingredients were weighed and compressed into tablets of 180mg using 6 mm round flat
punches on 10-station rotary tablet machine. A batch of 30 tablet of each formulation was
prepared for all the designed formulations.
Ingrediants
A1
A2
A3
A4
Prasugrel HCL
5mg
5mg
5mg
5mg
Tween 80
2mg
2mg
2mg
-
Aerosol
2mg
2mg
2mg
-
Microcrystalline cellulose-102
85mg
85mg
85mg
73mg
Crosspovidone
-
-
4mg
8mg
Sodium starch glycolate
-
4mg
-
4mg
Crosscarmelose sodium
4mg
-
-
8mg
Megnesium stearate
1mg
1mg
1mg
1mg
Talc
1mg
1mg
1mg
1mg
TABLE 4: FORMULA FOR PRELIMINARY BATCH
EVALUATION PARAMETER [80-81]:
1. WEIGHT VARIATION TEST
Every individual tablet in a batch should be in uniform weight and weight variation within
permissible limits. To study weight variation, 20 tablets of formulation were weighed and the
test was performed according to the official method given in IP.
2. DIAMETER AND THICKNESS
The diameter and thickness of six tablets were determined by using vernier caliber and the
average values were calculated.
3. HARDNESS AND FRIABILITY
The hardness of 10 tablets was determined by diametral compression using a dial type
hardness tester and friability of 20 tablets was determined by Roche Friabiliator.
4. IN VITRO DISINTEGRATION TIME
Disintegration time was determined using USP-XIV tablet disintegration test apparatus using
900 ml of distilled water without disk at 37 ± 0.5°C temperature.
FACTORIAL DESIGN FORPRASUGREL HCL OF IMMEDIATE RELEASE
TABLETS
X1
X2
Crosscarmellose
Sodium
sodium
glycolate
X3
starch Crosspovidone
TABLE 5: CODING OF VARIABLE23 FULL FACTORIAL DESIGN
Coded value
X1 (mg)
X2 (mg)
X3 (mg)
-1
4
4
4
1
8
8
8
TABLE 6: CODING VALUE OF FULL FACTORIAL BATCH
Batches
X1
X2
X3
F1
-1
-1
-1
F2
1
-1
-1
F3
-1
1
-1
F4
1
1
-1
F5
-1
-1
1
F6
1
-1
1
F7
-1
1
1
F8
1
1
1
TABLE 7: FORMULATION LAYOUT OF FACTORIAL FORMULATION
COMPOSITION OF 23 FACTORIAL DESIGN FOR PRASUGREL HCL OF
IMMEDIATE RELEASE TABLET
A 23 full factorial design was used for optimization of the tablet for which the formula is
shown in the table and procedure for the tablet preparation is the simple dry granulation
method.
Ingredients(mg)
F1
F2
F3
F4
F5
F6
F7
F8
Prasugrel HCL
5
5
5
5
5
5
5
5
Tween 80
2
2
2
2
2
2
2
2
Microcrystalline
77
73
73
69
73
69
69
65
4
8
4
8
4
8
4
8
4
4
4
4
8
8
8
8
starch 4
4
8
8
4
4
8
8
Aerosil
2
2
2
2
2
2
2
2
Talc
1
1
1
1
1
1
1
1
Mag.stearate
1
1
1
1
1
1
1
1
100
100
100
100
100
cellulose
Croscarmellose
sodium
Crosspovidone
Sodium
glycolate
Total weight for 100
100 100
1 tablet
TABLE 8: FORMULA FOR FACTORIAL BATCH (mg)
IN-VITRO DISSOLUTION STUDY
Medium
pH 1.0 HCl
Apparatus
Apparatus II (paddle)
Speed
50 rpm
Temperature
37±0.5°C
Run time
5, 10, 20, 30 and 60 min
Dissolution medium
Distilled water
TABLE 9: IN-VITRO DISSOLUTION STUDY
PROCEDURE:
6 tablets were placed in each of 6 dissolution flasks containing 900 ml of pH 1.0 HCl,
previously maintained at 37±0.5°C. The apparatus was run for 60 minutes. A suitable volume
of sample was withdrawn at regular intervals of time and filtered through 0.45 μm membrane
filter. The absorbance of the sample preparations were measured at 249 nm, using pH 1.0
HCl as blank.82
STABILITY STUDY: [83]
Stability of a drug has been defined as the ability of a particular formulation in a specific
container, to remain within its physical, chemical, therapeutic and toxicological
specifications.
The purpose of stability study is to provide evidence on the quality of a drug substance or
drug product which varies with time under the influence of a variety of environmental factors
such as temperature, humidity and light. Recommended storage conditions, re-test periods
and shelf-lives are to be established. The international Conference of Harmonization (ICH)
Guidelines titled, “stability testing of new drug substance and products” describes the
stability test requirements for drug registration application in the European Union, Japan and
the United States of America. ICH specifies the length of study and storage conditions
Long-term testing- 25°C ± 2°C/ 60% RH ± 5% for 12 months.
Accelerated testing- 40°C ± 2°C/ 75% RH ± 5% for 6 months.
Accelerated stability studies were carried out at 40°C / 75% RH for the best formulation for 1
month.
RESULT & DISCUSSION:
Various evaluation pre compression parameters of preliminary batch like bulk density, tapped
density, Hausner’s ratio, Carr’s index and angle of repose were presented here.
1. EVALUATION PARAMETER OF PRE COMPRESSION
Bulk density (gm/ml) of Batch A1 to A4 is 0.47±0.030, 0.46±0.015, 0.43±0.023, 0.50±0.025
respectively. Tapped density (gm/ml) for Batch A1 to A4 is 0.55±0.22, 0.54±0.22, 0.52±0.011,
0.62±0.030 respectively. Hausner’s ratio for all the batches was 1.17±0.04, 1.32±0.03, 1.15±0.02,
1.39±0.05 respectively. Carr’s index (%) was 15.35±0.4, 14.22±0.25, 12.51±0.24, 16.28±0.35
respectively. Angle of repose (Ɵ) was 26.5±1.22, 29.2±1.44, 23.5±0.30, 27.4±1.26 respectively.
2. EVALUATION PARAMETER OF POST COMPRESSION
Various evaluation post compression parameters for Batch A1 to A4 like weight variation,
thickness, hardness friability and disintegration time were measured. Weigh variation test by
taking the average weight and the formula. Hardness test was performed by Hardness Tester
(Monsanto). Friability test was performed by Roche Friabilator (25 rpm for 4 mins). Invitro
disintegration time was measured by disintegration apparatus in the suitable media. All the
four batches passed the weight variation test. Thickness (mm) of Batch A1 to A4 was
2.19±0.12, 2.61±0.11, 2.21±0.23, 2.22±0.16 respectively. Hardness (gm/cm2) of all the batches was
3.27±0.16, 3.25 ± 0.11, 3.45 ±0.18, 3.16 ±0.14 respectively. Friability (%) was 0.65±0.14, 0.68±0.15,
0.69±0.25, 0.66±0.23 respectively. Disintegrating time (sec) was 18.25±0.09, 17.30±0.04,
19.55±0.07, 10.45±0.06 respectively.
3. EVALUATION OF PRE COMPRESSION PARAMETER OF FACTORIAL
BATCH
Various evaluation pre compression parameters of factorial batch like bulk density, tapped
density, Hausner’s ratio, Carr’s index and angle of repose were given in the following table.
Batch
Bulk density
(gm/ml)
Tapped
density
(gm/ml)
Compressibility
Hausner’s
Angle of
index (%)
ratio
repose (0)
F1
0.48±0.1
0.54±0.15
11.11±0.14
1.12±0.01
30.42±0.25
F2
0.45±0.5
0.52±0.23
13.46±0.20
1.15±0.54
31.43±0.3
F3
0.51±0.03
0.53±0.25
12.04±0.17
1.20±0.04
28.41±0.16
F4
0.43±0.15
0.54±0.25
12.79±0.17
1.26±0.03
29.02±0.25
F5
0.41±0.02
0.47±0.11
12.76±0.16
1.14±0.2
28.43±0.05
F6
0.44±0.8
0.50±0.3
12.00±0.6
1.13±0.41
28.10±0.3
F7
0.41±0.2
0.48±0.5
14.58±0.25
1.17±0.5
28.76 ±0.6
F8
0.42±0.3
0.50±0.25
14.00±0.24
1.19±0.6
29.10±0.01
TABLE 10: EVALUATION OF PRE COMPRESSION PARAMETER OF
FACTORIAL BATCH
4. EVALUATION OF POST COMPRESSION PARAMETER OF FACTORIAL
BATCH
Various evaluation post compression parameters for factorial Batch F1 to F8 like weight
variation, thickness, hardness friability and disintegration time were measured. Weigh
variation test by taking the average weight and the formula. Hardness test was performed by
Hardness Tester (Monsanto). Friability test was performed by Roche Friabilator (25 rpm for 4
mins). Invitro disintegration time was measured by disintegration apparatus in the suitable
media. The results of all the tests were tabulated in the following table.
Batch
Weight
Hardness
variation (mg)
(kg/cm2)
Friability (%)
In-vitro
disintegration time
F1
92.14±3.79
3.27±0.16
0.935
14.55±0.12
F2
91.25±4.21
3.26±0.12
0.942
13.15±0.36
F3
90.25±3.84
3.24±0.12
0.645
16.40±0.42
F4
98.63±3.91
3.51±0.19
0.667
12.4±0.15
F5
95.23±5.21
3.45±0.16
0.575
11.46±0.19
F6
96.36±3.96
3.42±0.12
0.647
6.15±0.13
F7
96.12±5.38
3.55±0.18
0.723
10.18±0.24
F8
98.51±5.61
3.52±0.19
0.895
9.38±0.19
TABLE 11: EVALUATION OF POST COMPRESSION PARAMETER OF
FACTORIAL BATCH
5. IN-VITRO DISSOLUTION STUDY OF TABLETS
PROCEDURE:
6 tablets were placed in each of 6 dissolution flasks containing 900 ml of pH 1.0 HCl,
previously maintained at 37±0.5°C. The apparatus was run for 60 minutes. A suitable volume
of sample was withdrawn at regular intervals of time and filtered through 0.45 μm membrane
filter. The absorbance of the sample preparations were measured at 249 nm, using pH 1.0
HCl as blank.
Time
F1
F2
F3
F4
0
0
0
0
0
5
12.57692
14.30769
15.57692
16.03846
10
28.80064
27.07949
25.35577
30.78141
20
37.775
40.41923
41.79423
41.13205
30
60.67051
64.72372
63.23141
58.61218
60
92.3129
96.7276
93.1654
95.1359
(mins)
TABLE 12: IN- VITRO DISSOLUTION STUDY OF TABLETS FOR F1 TO F4
Cumulative % drug release
120
100
80
F1
60
F2
40
F3
F4
20
0
0
10
20
30
40
50
60
70
Time (min)
FIGURE 1: CUMULATIVE % DRUG RELEASE OF F1 TO F4 BATCH
Time
F5
F6
F7
F8
0
0
0
0
0
5
13.15385
15.23077
16.84615
18.11538
10
26.15
31.93077
28.13205
29.52372
20
41.10641
36.40769
43.425
39.27885
30
58.61218
62.85513
65.43269
59.87115
60
94.1667
97.04038
94.3199
95.7314
(min)
TABLE 13: IN- VITRO DISSOLUTION STUDY OF TABLETS FOR F5 TO F8
BATCH
120
100
80
F5
F6
60
F7
40
F8
20
0
0
10
20
30
40
50
60
70
FIGURE 2: CUMULATIVE % DRUG RELEASE OF F5 TO F8 BATCH
The results of In-vitro release of drug from formulations F-1 to F-8 were shown in Table- 12
& 13 and Fig-1 and 2. But the formulation F-6 exhibited similar release profile to that of
marketed product at each time point. Hence, F-6 was considered as the best formulation.
6. STATASTICAL ANALYSIS OF THE 23FULL FACTORIAL DESIGN
The statistical analysis of the factorial design batches was performed by multiple linear
regression analysis carried out in Microsoft Excel 2007.
Disintegration time (Y) = βo+β1X1+β2X2+β3X3+β12X1X2+β13X1X3+β123X1X2X3
Batch code
X1
X2
X3
DT
DISSO
F1
-1
-1
-1
14.55
92.3129
F2
1
-1
-1
13.15
96.7276
F3
-1
1
-1
16.40
93.1654
F4
1
1
-1
12.4
95.1359
F5
-1
-1
1
11.46
94.1667
F6
1
-1
1
6.15
97.04038
F7
-1
1
1
10.18
97.04038
F8
1
1
1
9.38
95.7314
TABLE 14: FULL FACTORIAL DESIGN LAYOUT
Regression statistics
R Square
0.9042
Adjusted R Square
0.8324
Standard Error
0.9527
Observations
8
TABLE 15: REGRESSION STATISTICS FOR DT
Df
SS
MS
F
P value
Regression
1
5.3186
5.3186
11.9011
0.013636
Residual
6
2.6814
0.4469
Total
7
8
TABLE 16: ANOVA DATA FOR DT
Design-Expert® Software
Factor Coding: Actual
DT
16
DT
8.00
13
6
X1 = A: ccs
X2 = B: ssg
7.00
B : ssg
Actual Factor
C: Cross povidone = 6.00
12
6.00
11
10
5.00
4.00
4.00
5.00
6.00
A: ccs
FIGURE 3: COUNTER PLOT FOR DT
7.00
8.00
Design-Expert® Software
Factor Coding: Actual
DT
16
6
X1 = A: ccs
X2 = B: ssg
15
14
Actual Factor
C: Cross povidone = 6.00
13
DT
12
11
10
9
8
8.00
8.00
7.00
7.00
6.00
B: ssg
6.00
5.00
5.00
4.00
A: ccs
4.00
FIGURE 4: RESPONSE SURFACE PLOT FOR DT
Regression statistics
R Square
0.8637
Adjusted R Square
0.7616
Standard Error
1.09674
Observations
8
TABLE 17: REGRESSION STATISTICS FOR DISSOLUTION
Df
SS
MS
F
P value
Regression
1
0.782879
0.782879
0.650851
0.450595
Residual
6
7.217121
1.202854
Total
7
8
TABLE 18: ANOVA DATA FOR DISSOLUTION
Design-Expert® Software
Factor Coding: Actual
Dissolution
97.04
Dissolution
8.00
92.31
X1 = A: ccs
X2 = B: ssg
7.00
B : ssg
Actual Factor
C: Cross povidone = 6.00
94
6.00
95
96
5.00
4.00
4.00
5.00
6.00
7.00
8.00
A: ccs
FIGURE 5: COUNTER PLOT FOR DISSOLUTION
Design-Expert® Software
Factor Coding: Actual
Dissolution
97.04
92.31
X1 = A: ccs
X2 = B: ssg
Actual Factor
C: Cross povidone = 6.00
D is s o lu tio n
97
96
95
94
93
92
8.00
8.00
7.00
7.00
6.00
B: ssg
6.00
5.00
5.00
4.00
4.00
A: ccs
FIGURE 6: RESPONSE SURFACE PLOT FOR DISSOLUTION
STABILITY STUDY:
The optimized formulation (F6) sealed in aluminium foil and kept in humidity chamber
maintained 40 ± 2 °C / 75 ± 5 % RH for 1 month.
The optimized formulation (F6) stored at 40 ± 2 °C / 75 ± 5 % RH was found stable.
At the end of studies, samples were analyzed for the in vitro drug release, disintegration time,
% friability, hardness.
IN-VITRO DISSOLUTION PROFILE OF OPTIMIZED BATCH STORED AT 40 ±
2°C / 75 ± 5%
Time
Cumulative % drug release (Mean ± S.D)
(mins)
0 day
After 30 days at 40 ± 2 °C / 75 ±
5% RH
0
0
0
5
13.1205
15.2308
10
28.6523
31.9308
20
35.2360
36.4077
30
60.5324
62.8551
60
96.7825
97.0404
TABLE 19: IN-VITRO DISSOLUTION PROFILE OF OPTIMIZED BATCH
STORED AT 40 ± 2°C / 75 ± 5%
Cumulative % drug release
120
100
80
60
initial
40
after stability
20
0
0
20
40
60
80
Time (min)
FIGURE 7: DISSOLUTION PROFILE OF OPTIMIZED FORMULATION BEFORE
AND AFTER STABILITY STUDY
EVALUATION PARAMETER:
Batch
Initial
After storage
at 40o C and 75%
RH for 1 month
Wt. variation(mg)
96.36±3.96
96.36±4.15
Hardness(kg/cm2)
Friability (%)
Disintegration time(sec)
3.42±0.12
3.42±0.08
0.647
0.678
6.15±0.13
6.14±0.25
TABLE 22: COMPARISON OF EVALUATION PARAMETERS OF OPTIMIZED
BATCH F6 AFTER STABILITY STUDIES
From Table 22, it can be concluded that the optimized formulation remained stable under
accelerated conditions of stability study because no or slight change was observed in the
evaluation parameters like in vitro drug release, disintegration time, Hardness, % Friability.
Similarity factor for drug release profile of sample after storage at 40 ± 2 °C/ 75 ± 5 % RH
was also done.
CONCLUSION:
Immediate release Prasugrel hydrochloride tablet was successfully prepared using different
combinations of binder, disintegrants and lubricant. For all the prepared formulations
evaluation parameters like thickness, hardness, friability, weight variation and drug content
were found to be satisfactory. The prepared tablet formulation was found to be stable for 1
month under accelerated stability condition. Formulation of immediate release tablet by using
super disintegrants such as Sodium starch glycolate, Crospovidone, Croscarmellose sodium
of different concentration.The complex prepared with tween 80 for solubilizing agent by
direct compression method was found to be best complex than other complex on the basis of
in-vitro drug release and drug content. Accelerated stability studies were carried out at 40°C /
75% RH for the best formulation for 1 month. The formulation F6 containing 8% of
Croscarmelose sodium, 8% of Crosspovidone and 4% of Sodium Starch Glycolate showed
minimum disintegration time of 6 seconds. Different parameters like hardness, friability,
weight variation, drug content uniformity, in-vitro drug release etc. were evaluated for these
formulations. The optimized formulation F6 showed good release profile with maximum drug
being released at all time intervals. The release of drug from the F6 formulation was quick
when compared to other formulations. Based on these results formulations F6 was found to
be the most promising formulation. Stability studies were conducted for the optimized
formulations as per ICH guidelines for a period of 1 month which revealed the stability of the
formulations.
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