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: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/017 ISSN 0974 – 9446

FORMULATION AND DESIGN OF FAST DISSOLVING TABLETS OF FELODIPINE USING NOVEL


CO-PROCESSED SUPERDISINTEGRANTS

Dr. Raghavendra Rao N. G 1*, Upendra Kulkarni 2


1
PG. Department of Pharmaceutics,
Luqman College of Pharmacy,
Gulbarga- 585 103, Karnataka, India.
2
.Department of Pharmaceutics.
Dr. Raghvendra Rao RME’s College of Pharmacy,
Gulbarga-585102, Karnataka, India.
Email:ngraghu@rediffmail.com
ABSTRACT

In the present study, novel co-processed superdisintegrants were developed by solvent evaporation
method using crospovidone and sodium starch glycolate in different ratios (1:1, 1:2 and 1:3) for use in
the fast dissolving tablet formulations. The developed excipients were evaluated for angle of repose,
Carr’s index and Hausner’s ratio in comparison with physical mixture of superdisintegrants. The angle
of repose of the developed excipients was found to be < 300, Compressibility (%) index in the range of
15.22 to 16.88 % and Hausner’s ratio in the range of 1.15-1.27. Felodipine is used in the present study
and widely accepted for its excellent antihypertensive and antianginal properties since it is calcium
antagonist compound (calcium channel blocker). Fast dissolving tablets of Felodipine were prepared
using the above co-processed superdisintegrants and evaluated for pre-compression and post-
compression parameters. Effect of co-processed superdisintegrants (such as crospovidone, and
sodium starch glycolate) on wetting time, disintegrating time, drug content, in-vitro release, and stability
parameters have been studied. The prepared tablets were characterized by FTIR Studies. Based on in-
vitro dispersion time (approximately 17 sec), promising formulation CP1 was tested for in-vitro drug
release pattern in phosphate buffer pH 6.5 containing 0.1% SLS. Among the designed formulations, the
formulation (CP1) containing 4% w/w of co-processed superdisintegrant (1:1 mixture of crospovidone
and sodium starch glycolate) emerged as the overall best formulation (t 50% 1.97 min) based on drug
release characteristics in phosphate buffer pH 6.5 containing 0.1% SLS. Short-term stability studies on
promising formulation indicated that there were no significant changes in drug content and in- vitro
dispersion time (p<0.05). From this study, it can be concluded that dissolution rate of felodipine could
be enhanced by tablets containing co-processed superdisintegrant.

Key Words: co-processed superdisintegrants, felodipine, fast dissolving tablets, sodium starch
glycolate, and crospovidone.

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INTRODUCTION excipients, new grade of existing materials and


new combination of existing materials [6]. New
Felodipine which is used in the present combinations of existing excipients are an
study is a dihydropyridine derivative, that is interesting option for improving excipients
chemically described as ethyl methyl-4-(2, 3- functionality because all formulations contain
dichlorophenyl)-1, 4-dihydro-2, 6-dimethyl-3, 5- multiple excipients. One such approach for
pyridinedicarboxylate, widely accepted for its improving the functionality of excipients is co-
excellent antihypertensive and antianginal processing of two or more excipients. Co-
properties since it is calcium antagonist processing is based on the novel concept of two
compound (calcium channel blocker). or more excipients interacting at the sub particle
Felodipine is practically insoluble in water and level, the objective of which is to provide a
its dissolution rate is limited by its synergy of functionality improvement as well as
physicochemical properties [1]. For poorly masking the undesirable properties of individual
[7]
soluble orally administered drugs the rate of . Co-processing excipients lead to the
absorption is often controlled by the rate of formulation of excipients granules with superior
dissolution. The rate of dissolution can be properties, compared with physical mixtures of
increased by increasing the surface area of components or individual components, like
available drug by various methods improved flow properties, improved
(micronization, complexation, solid dispersion compressibility, better dilution potential, fill
etc). Another prerequisite for the fast dissolution weight uniformity, and reduced lubricant
[8]
may be the disintegration time of tablets. sensitivity . Several co-processed
Because, faster disintegration of tablets delivers superdisintegrants are commercially available:
a fine suspension of drug particles and thus, Ludipress (lactose monohydrate,
greater dissolution of the drug [2]. Solid oral polyvinylpyrrolidone and crospovidone), Starlac
dosage forms, especially tablets, remain one of (lactose and maize starch), Starcap 1500 (corn
the most popular because of advantages like starch and pregelatinized starch), Ran Explo-C
patient convenience, ease of storage and (microcrystalline cellulose, silica and
dispensing, dose accuracy and easy crospovidone), Ran Explo-S (microcrystalline
manufacturability. cellulose, silica and sodium starch glycolate),
Major challenge for tablets manufacturing PanExcea MH300G (microcrystalline cellulose,
comes from the flow properties of the materials hydroxy propyl methyl cellulose and
[9]
to be compressed. Most of the formulations (> crospovidone) . The widely used
70%) contain excipients at higher concentration superdisintegrants are crospovidone,
than active drug [3]. In recent years drug croscarmellose sodium and sodium starch
formulation scientists have recognized that glycolate. In the present investigation, the
single-component excipients do not always preparation and evaluation of fast dissolving
provide the requisite performance to allow tablets by using co-processed
certain active pharmaceutical ingredients to be superdisintegrants containing crospovidone and
formulated or manufactured adequately[4]. sodium starch glycolate was studied. The
Hence, there is a need to have excipients with reasons for selection of crospovidone are high
multiple characteristics built into them such as capillary activity, pronounced hydration capacity
better flow, low/no moisture sensitivity, superior and little tendency to form gels [10]. Sodium
compressibility and rapid disintegration ability[5]. starch glycolate was chosen because of its high
Excipients with improved functionality can be swelling capacity [11]. The concept of formulating
obtained by developing new chemical fast dissolving tablets (FDT) of Felodipine

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(excellent antihypertensive and anti-anginal were weighed and mixed in geometrical order
properties) using co-processed and compressed into tablets of 150mg by direct
superdisintegrants helps to increase the water compression method using 7 mm bi concave
uptake with shortest wetting time and thereby punches on a ‘Rimek mini press 1’ a 10 station
decrease the disintegration time of the tablets rotary compression machine.
by simple and cost effective direct compression
technique. The compositions of which are given Evaluation of Felodipine tablets: The
in (Table 1). prepared tablets were evaluated for hardness,
thickness and diameter, friability, disintegration
time, wetting time, drug content, in-vitro
MATERIAL AND METHODS:
dissolution studies, and stability studies. Pfizer
Felodipine as procured as a gift sample hardness tester was used for the determination
from Cipla Ltd, Bangalore, India. of the hardness of tablets. Tablet was placed in
Superdisintegrants (Maruti Chem. Ahmadabad), contact between the plungers, and the handle
Aspartame, Directly compressible mannitol (Pe was pressed, the force of the fracture was
arlitol SD 200), microcrystalline cellulose (MCC, recorded. The thickness and diameter of 4
PH-102), and sodium stearyl fumerate (Aan tablets (2 tablets from each batch) were
Pharma Pvt Ltd., Rakanpur-Gujarat). Sodium recorded during the process of compression
lauryl sulphate (SLS), Talc, and Magnesium using calipers (Mitotoyo; Japan). The friability
stearate purchased from S.D. fine chem., of tablets was determined using Roche
Mumbai. friabilator (Cambel Electronics, Mumbai, India).
Preparation of Co-processed Two tablets were accurately weighed and
Superdisintegrants [12]: placed in the friabilator and operated for 100
The co-processed superdisintegrants were revolutions. The tablets were de-dusted and
prepared by solvent evaporation method. A reweighed. Percentage friability was calculated
blend of crospovidone and sodium starch using the following formula.
glycolate (in the ratio of 1:1, 1:2 and 1:3) was F = (1- W 0 / W) × 100
added to 10 ml of ethanol. The contents of the Where, W 0 is the weight of the tablets
beaker (250 ml capacity) were mixed thoroughly before the test and W is the weight of the tablet
and stirring was continued till most of ethanol after the test. Six tablets were tested from each
evaporated. The wet coherent mass was formulation. In the disintegration time [14] study
granulated through # 44-mesh sieve. The wet tablet was put into 100 ml distilled water at 37 ±
granules were dried in a hot air oven at 60º C 20. Time required for complete dispersion of a
for 20 minutes. The dried granules were sifted tablet was measured with the help of digital
through # 44- mesh sieve and stored in airtight tablet disintegration test apparatus and in
container till further use. wetting time [15] study a piece of tissue paper
folded twice was placed in a small Petri dish
Preparation of fast dissolving tablets by (internal diameter = 6.5cm) containing 5 ml of
direct compression method [13]: distilled water. A tablet was placed on the
Fast dissolving tablets of Felodipine were paper, and the time for complete wetting of the
prepared by direct compression. All the tablet was measured in seconds. For the
ingredients (except granular directly determination of drug content tablets were
compressible excipients) were passed through weighed individually, pulverized, and diluted to
# 60-mesh separately. Then the ingredients 250ml with sufficient amount of phosphate
buffer pH 6.5 containing 0.1% SLS. After that an

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aliquot of the filtrate was diluted and analyzed and Hausner’s ratio in the range of 1.13-1.16
spectrophotometrically (UV-1700 Shimadzu (Table 2). Fast dissolving tablets of Felodipine
Corporation, Japan) at 362 nm. were prepared using above co-processed
The in-vitro dissolution study was carried superdisintegrants and physical mixtures of
out in the USP dissolution test apparatus superdisintegrants. Directly compressible
(Electrolab TDT - 08 L Dissolution tester USP) mannitol (Pearlitol SD 200) was used as a
type 2 (paddle). 900 ml of the dissolution diluent to enhance mouth feel. A total of six
medium (phosphate buffer pH 6.5 containing formulations and control formulation CP0
0.1% SLS) was taken in vessel and the (without superdisintegrant) were designed.
temperature was maintained at 37 ± 0.50C. The The data obtained from post-
speed of the paddle was set at 50 rpm. 5 ml of compression parameters such as hardness,
the dissolution medium was withdrawn and the friability, thickness, drug content, wetting time,
same amount of fresh medium was replenished and in-vitro disintegration time. The results are
to the dissolution medium. The sample shown in (Table 3). In all the formulations,
withdrawn was filtered and diluted with hardness test indicated good mechanical
phosphate buffer pH 6.5 containing 0.1% SLS strength results were ranges from 3.08 to 3.55
prior to analysis in the UV spectrophotometer kg/cm2, friability is less than 1%, indicated that
(UV-1700 Shimadzu Corporation, Japan) at 362 tablets had a good mechanical resistance.
nm. The stability study of the tablets was carried Thickness of the tablets range from 2.12 to 2.27
out according to ICH guidelines at 40 ± 20C/75 ± mm. Drug content was found to be in the range
5% RH for three months by storing the samples of 98.00 to 99.85 %, which is within acceptable
in stability chamber (Lab-Care, Mumbai). limits. The wetting time is an important criteria
for understanding the capacity of disintegrants
Characterization of felodipine tablets: to swell in presence of little amount of water
FTIR Studies: IR spectra for drug, excipients were found to be in the range of 28 to 110 sec.
and formulations CP1 and PM1 were recorded Among all the designed formulations,
in a Fourier transform infrared (FTIR) formulation CP1 was found to be promising and
spectrophotometer (FTIR 1615, Perkin Elmer, was displayed an in-vitro dispersion time of 17
USA) with KBr pellets. sec, which facilitates its faster dispersion in the
mouth.
Among all the formulations CP1
RESULTS AND DISCUSSION: containing 4% w/w of co-processed
Co-processed superdisintegrants were superdisintegrant (1:1 mixture of crospovidone
prepared by solvent evaporation using and sodium starch glycolate) was found to be
crospovidone and sodium starch glycolate in promising and has shown an in-vitro dispersion
different ratios (1:1, 1:2, and 1:3). The co- time of 17 sec, wetting time of 28 sec when
processed superdisintegrants were evaluated compared to the formulation PM1 containing 4%
for their flow and compression properties in w/w of physical mixture of superdisintegrants
comparison with physical mixture of (1:1 mixture of crospovidone and sodium starch
superdisintegrants. The angle of repose of co- glycolate) which shows in-vitro dispersion time
processed superdisintegrants was found to be of 34 sec, wetting time of 42 sec and control
<300 which indicate excellent flow in formulation (CPO) which shows 97 sec, 110 sec
comparison to Physical mixture of values respectively for the above parameters
superdisintegrants (<300) due to granule (Table 3).
formation, Carr’s index in the range of 10- 15%

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The dissolution of felodipine from the REFERENCES:


tablets is shown in Fig 1. In-vitro dissolution
studies on the promising formulation CP1, PM1 1. Evangelos Karavas, Emmanuel
is formulation containing physical mixture of Georgarakis, Dimitrios Bikiaris. Application
superdisintegrants in 1:1 ratio, and CP0 control of PVP/HPMC miscible blends with
formulations were carried out in pH 6.5 enhanced mucoadhesive properties for
phosphate buffer containing 0.1 % SLS, and the adjusting drug release in predictable
various dissolution parameter values viz., pulsatile chronotherapeutics. J Pharm Sci,
percent drug dissolved in 5 min, 10 min, 15 min 64 (2006) 115-126.
and 20 min (D5, D10, D15, and D20), t 50%, and t 90 2. Alfred Martin. Physical Pharmacy. 4th edn.
% are shown in Table 4. This data reveals that Philadelphia: Lippincott Williams and
among all the formulation CP1 shows nearly Wilkins; 1993.
faster drug release. The formulations CP1 50 % 3. York P. Crystal engineering and particle
of drug released in 1.97 min, and 90 % of drug design for the powder compaction process.
released in 9.75 min, CP0 control formulations Drug Dev Ind Pharm, 18(6, 7): 677-721
50 % of drug released in 14.24 min, and 90 % (1992).
of drug released in more than 30 min. 4. Lawrence H Block, Richard C, Moreton,
The stability study for all the formulations Shireesh P, Apte, Richard H, Wendt, Eric J,
were carried according to ICH guidelines by Munson, Joseph R, Creekmore, Indira V,
storing the tablets in a stability chamber Persaud, Catherine Sheehan, and Hong
(Labcare, Mumbai) at 40o ± 20 C/ 75 ± 5% RH Wang. Co-processed excipients.
for three months. There was no significant Pharmacopoeial forum, 35(4): 1026-1028,
change in in-vitro dispersion time, wetting time (2009).
and drug content of the formulation CP1 and 5. Avachat A, Ahire VJ. Characterization and
PM1. (Table 5). evaluation of spray dried co-processed
In Fig 2 shows the IR spectrum of the excipients and their application in solid
pure drug and formulations CP1, and PM1. The dosage forms. Indian J Pharm Sci, 69(1):85-
IR spectra of pure felodipine and formulation 90 (2007).
reveled that there is no appreciable changes in 6. Moreton RC. Tablet excipients to the year
the position of absorption band. This reveled 2001: A look into the crystal ball. Drug
that there was no chemical interaction between Develop Ind Pharm, 22: 11-23 (1996).
drug and the polymer. 7. Reimerdes D. The near future of tablet
CONCLUSION: excipients. Manuf chem, 64:14-5 (1993).
Felodipine is a dihydropyridine calcium 8. Nachaegari SK, Bansal AK. Co-processed
channel blocker. It’s widely used in the excipients for solid dosage forms. Pharm
management of hypertension and angina Technol, 28(1): 52-64 (2004).
pectoris. Felodipine tablets containing co- 9. Gohel MC, Jogani PD. A review of co-
processed superdisintegrants exhibit quick processed directly compressible excipients.
disintegration and improved drug dissolution. It J Pharm Sci, 8: 76-93 (2005).
can be concluded from the present work that 10. He, Kibbe AH. Crospovidone. In: Rowe RC,
co-processed superdisintegrants of Sheskey PJ, Weller PJ (eds.) Handbook of
crospovidone and sodium starch glycolate are pharmaceutical excipients, 4th Edn.
superior to physical mixtures of crospovidone Washington, DC: American Pharmaceutical
and sodium starch glycolate used in Felodipine Association, London, Pharmaceutical Press,
fast dissolving tablets. 2003, pp.184-5.

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11. Miller RW. Sodium starch glycolate. In: 13. Kuchekar BS, Badhan AC, Mahajan HS.
Rowe RC, Sheskey PJ, Weller PJ (eds.) Mouth dissolving tablets of salbutamol
Handbook of pharmaceutical excipients, 4th sulphate: A novel drug delivery system.
edn. Washington, DC: American Indian Drugs, 41:592-8 (2004).
Pharmaceutical Association, London, 14. United States Pharmacopoeia. Rockville.
Pharmaceutical Press, 2003,pp.581-4. MD: 27 th revision. USP Convention, Inc.;
12. Gohel MC et al. Preparation and 2004. p. 2302.
Assessment of Novel Co-processed 15. Sunada H, Bi YX, Yonezawa Y, Danjo K.
Superdisintegrant Consisting of Preparation evaluation and optimization of
Crospovidone and Sodium Starch Glycolate: rapidly disintegrating tablets. Powder
A Technical Note. AAPS Pharm Sci Tech, Technol 2002; 122:188-98.
8(1); Article 9: p.E1-E7 (2007).

TABLES AND FIGURES:

Table 1: Formulations of Felodipine FDT Prepared by Direct Compression Method

Formulation code CP0 PM1 PM2 PM3 CP1 CP2 CP3


Felodipine 5 5 5 5 5 5 5
Superdisintegrants (CP+SSG) -- 6 6 6 6 6 6
Aspartame 3 3 3 3 3 3 3
Sodium stearyl fumarate 1.5 1.5 1.5 1.5 1.5 1.5 1.5
Talc 3 3 3 3 3 3 3
Pine apple Flavour 1.5 1.5 1.5 1.5 1.5 1.5 1.5
Microcrystalline cellulose (Avicel PH-
30 30 30 30 30 30 30
102)
Mannitol (Pearlitol SD 200) 106 100 100 100 100 100 100
Total weight in mg/tab 150 150 150 150 150 150 150

PM - Physical Mixture of crospovidone and sodium starch glycolate in different ratios (1:1, 1:2, 1:3), CP
- Co-processed Superdisintegrants of crospovidone and sodium starch glycolate in different ratios (1:1,
1:2, 1:3), CP0 - Control formulation (without superdisintegrants), CP – Crospovidone, SSG – sodium
starch glycolate.

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Table 2: Pre-compression parameters of co-processed superdisintegrants and physical mixture


of superdisintegrants

Angle of Repose Compressibility


Formulation Hausner’s Ratio
(θ) (%) (±SD),
code (±SD), n=3
(±SD), n=3 n=3
PM1 28.68 (2.22) 16.66 (0.22) 1.27 (0.06)
PM2 26.97 (3.52) 16.24 (0.060) 1.27 (0.05)
PM3 24.71 (0.28) 15.34 (0.34) 1.24 (0.02)
CP1 24.11 (1.12) 16.88 (0.60) 1.15 (0.04)
CP2 23.14 (0.95) 15.22 (0.67) 1.17 (0.03)
CP3 22.62 (0.25) 15.74 (0.30) 1.19 (0.02)

Note: Values in parenthesis are standard deviation (±SD)

Table 3: Evaluation of Felodipine FDT Formulations:

FC Hardness Friability Thickness Drug Wetting Disintegration


test (%) (mm) content time (sec) time (sec)
(kg/cm2) (±SD), (±SD), n=4 (%) (±SD), n=6 (±SD), n=6
(±SD), n=6 n=10 (±SD), n=6
CP0 3.15 (0.28) 2.25 (0.02) 99.35
0.46 (0.04) 110 (4.42) 97 (1.00)
(1.50)
PM1 3.55 (0.10) 0.59 (0.04) 2.26 (0.05) 98.00
42 (1.32) 34 (2.00)
M2 (1.30)
PM2 3.46 (0.15) 0.67 (0.02) 2.27 (0.04) 98.07
62 (2.12) 49 (2.10)
(0.90)
PM3 3.52 (0.20) 0.53 (0.04) 2.23 (0.06) 99.00
71 (2.24) 58 (1.50)
(2.20)
CP1 3.32 (0.31) 0.57 (0.02) 2.12 (0.055) 98.55 17 (2.00)
28 (2.00)
(1.50)
CP2 3.08 (0.20) 0.51 (0.02) 2.15 (0.050) 99.85
39 (1.50) 33 (1.00)
(0.80)
CP3 3.15 (0.25) 0.49 (0.05) 2.14 (0.100) 99.58
56(2.14) 44 (1.50)
(2.30)

Note: Values in parenthesis are standard deviation (±SD)


FC- Formulation code

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120

100

80
% Drug release

60

40

20

0
0 5 10 15 20 25 30 35
Time (min.)

CP O (Control) PM 1 PM 2 PM 3 CP 1 CP 2 CP 3

Fig 1: Dissolution studies of the formulations.

Table 4: In- vitro Dissolution parameters in phosphate buffer pH 6.5 containing 0.1% SLS

Formulation Parameters
Code D5 D 10 D 15 D 20 T 50% T 90%
CP 0 36.23 58.36 75.34 88.88 14.24 >30 min
min
PM1 59.11 80.33 94.88 -- 4.23 min 13.53
min
CP1 57.20 86.52 -- -- 1.97 min 9.75 min

CP0 is control formulation, CP1 is promising fast dissolving tablet formulation, PM1 is formulation
containing physical mixture of superdisintegrants in 1:1 ratio, D5 is percent drug released in 5 min, D10
is percent drug release in 10 min, D15 is percent drug release in 15 min, D20 percent drug release 20
min, t 50% is time for 50 % drug dissolution, t 90% is time for 90% drug dissolution.

.
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Table 5: Tablet parameters after stability studies.

Wetting Dispersion
Drug content
Formulation Period time(sec) time (sec)
(%)
(± SD), n=6 (± SD), n=6
1 Month 98.60 (1.45) 28 (1.00) 17 (1.00)
CP1 2 Month 98.55 (1.50) 29 (2.00) 16 (2.00)
3 Month 98.50 (1.40) 29 (1.00) 17 (1.00)
1 Month 98.10 (1.35) 42 (1.32) 34 (2.00)
PM1 2 Month 98.05 (1.45) 43 (1.22) 34 (1.00)
3 Month 98.10 (1.30) 42 (1.11) 34 (2.00)

Fig 2: FTIR spectrum of pure drug Felodipine (A), spectrum of formulation CP1 (B), spectrum of
formulation PM1 (C).

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