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Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 68 No. 4 pp. 571ñ583, 2011 ISSN 0001-6837Polish Pharmaceutical Society
Fast disintegrating dosage forms are the drugdelivery systems that disintegrate in the oral cavityin just a minute without the intake of water (1ñ3).Thus, these tablets are easily swallowed and havehigh patient compliance. Nowadays, the mainemphasize is on the development of newer disinte-grating systems, which would not only disintegratethe tablet rapidly, but also, have high mechanicalstrength. The water insoluble diluents such asAvicel (PH 102) and dicalcium phosphate werehighly preferable excipients for FDTs. However,these agents are now often not preferred becausethey cause an unacceptable feeling of grittiness inthe mouth. Therefore, water soluble diluents such asspray dried lactose, glycine and biodegradable poly-mers (like chitin, chitosan-alginate complex) wereselected as model excipients considering theiradvantages in terms of sweet taste, easy availability,cost effectiveness and non grittiness in the mouth.
Ondansetron is a serotonin (5-hydroxytrypta-mine) subtype3 (5HT3) receptor antagonist used in
the management of nausea and emesis (4ñ6). It isadministered orally and intravenously in a dose of 8mg. Rapid action of ondansetron is not achievableby administering it in conventional tablet form. Inaddition, swallowing conventional tablets requiresconsiderable quantity of water, which is often diffi-cult for patients suffering from vomiting. Hence,FDTs of ondansetron seem to offer distinct advan-tage over its conventional tablet form in terms ofease of administration and enhanced pre-gastricabsorption, thereby ensuring immediate effect.
Direct compression method is inexpensive,most convenient and produces tablets of sufficientmechanical integrity without the use of complicatedunit operations (7). However, the disintegration ofFDTs is often compromised while improving themechanical strength of tablets prepared by directcompression method. Superdisintegrants likecroscarmellose sodium, crospovidone and sodiumstarch glycolate can disintegrate the tablets faster.However, they are of limited use when tablets are
FABRICATION AND OPTIMIZATION OF FAST DISINTEGRATING TABLETSEMPLOYING INTERPOLYMERIC CHITOSAN-ALGINATE COMPLEX
AND CHITIN AS NOVEL SUPERDISINTEGRANTS
HONEY GOEL1*, ASHOK K. TIWARY2 and VIKAS RANA2*
1Pharmaceutics Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh (U.T.), India
2Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
Abstract: The objective of the present work was to optimize the formulation of fast disintegrating tablets(FDTs) of ondansetron HCl containing novel superdisintegrants, possessing sufficient mechanical strength anddisintegration time comparable to those containing crospovidone or croscarmellose sodium. The FDTs wereformulated using a novel superdisintegrant (chitosan-alginate (1:1) interpolymer complex and chitin) to achievea sweet tasting disintegrating system. The results revealed that chitin (5ñ20%) increased the porosity anddecreased the DT of tablets. At higher concentrations chitin maintained tablet porosity even at 5.5 kg crushingstrength. Ondansetron HCl was found to antagonize the wicking action of glycine. Further, evaluation of themechanism of disintegration revealed that glycine transported the aqueous medium to different parts of thetablets while the chitosan-alginate complex swelled up due to transfer of moisture from glycine. This phenom-enon resulted in breakage of the tablet within seconds. For preparing optimized FDTs, the reduced model equa-tions generated from BoxñBehnken design (BBD) were solved after substituting the known disintegration timeof FDTs containing superdisintegrants in the reduced model equations. The results suggested that excipient sys-tem under investigation not only improved the disintegration time but also made it possible to prepare FDTswith higher crushing strength as compared to tablets containing known superdisintegrants.
Keywords: fast disintegrating tablets, glycine, chitosan-alginate complex, chitin, ondansetron HCl,BoxñBehnken design
571
* Corresponding author: e-mail: [email protected]
572 HONEY GOEL et al.
prepared with crushing strength of more than 4 kg(8). Also, microcrystalline cellulose (Avicel- PH101& PH102) or dicalcium phosphate added in FDTsfor enhancing their disintegration, often causeunpleasant feeling of grittiness in mouth. Attemptsaimed at using amino acids in combination withcarmellose for preparing FDTs with sufficientmechanical strength by direct compression have notbeen found suitable for water soluble drugs likeondansetron HCl (9, 10). Hence, there is a need todevelop an alternative sweet tasting disintegratingsystem for preparing FDTs for water soluble drugs.
Chitin (β-(1→4)-N-acetyl-D-glucosamine) is anatural polysaccharide obtained from crab andshrimp shells. It possesses amino group covalentlylinked to acetyl group as compared to free aminogroup in chitosan (11, 12). Bruscato et al. (13)reported that when chitin was included in the con-ventional tablets, the tablets disintegrated with in5ñ10 min irrespective of solubility of the drug. Thedisintegration time in the oral cavity (DT) as well aswetting time (WT) could be analyzed by surface freeenergy (8). For faster wetting, a molecule shouldhave high polar component of surface free energy.However, for faster disintegration, the dispersioncomponent should have larger value. Therefore, itseems essential to select additives possessing wick-ing, swelling and disintegrating properties for suc-cessful performance of FDTs containing water solu-ble drugs.
In the light of the above, the present investiga-tion was aimed at evaluating the role of variouscombinations containing chitosan-alginate complex,chitin and glycine for use as sweet tasting disinte-grating system in FDTs of ondansetron HCl. Anattempt was made to understand the mechanismsresponsible for rapid disintegration of these tabletsthrough evaluation of water sorption time (WST),swelling index (SI), water absorption ratio (WAR),wetting time (WT) and tablet porosity.
MATERIALS AND METHODS
Crospovidone and croscarmellose sodium(Panacea Biotech Ltd., Lalru, India), andondansetron HCl (99.9% Ind-Swift Labs,Chandigarh, India) were received as gift samples.Chitosan (Indian Sea Foods, Cochin, India), chitin(High Media Pvt. Ltd., Mumbai, India), glycine(Qualigens Fine Chemicals, Mumbai, India), n-hexane (Loba Chemie, Mumbai, India) and spraydried lactose (CDH, Mumbai, India) were used assupplied. All other reagents were of analyticalgrade.
Tab
le 1
. Pla
cket
Bur
man
scr
eeni
ng d
esig
n (o
f 8
expe
rim
ents
) fo
r id
entif
ying
act
ive
form
ulat
ion
and
proc
ess
vari
able
s in
flue
ncin
g D
T, W
T a
nd W
AR
.
BA
TC
HX
1X
2X
3X
4X
5X
6 X
7Y
1(s)
Y
2(s)
Y
3(%
)N
O.
(%w
/w)
(%w
/w)
(%w
/w)
(Kg)
(%w
/w)
1+1
(60
%)
+1 (
15%
)+1
(30
%)
ñ1 (
3.0)
+1(8
%)
ñ1ñ1
12 ±
29
± 1
2.99
± 0
.02
2ñ1
(40
%)
+1 (
15%
)+1
(30
%)
+1 (
5.0)
ñ1(4
%)
+1ñ1
29 ±
227
± 2
1.32
± 0
.03
3ñ1
(40
%)
ñ1 (
5%)
+1 (
30%
)+1
(5.
0)+1
(8%
)ñ1
+133
± 1
36 ±
11.
34 ±
0.0
4
4+1
(60
%)
ñ1 (
5%)
ñ1 (
10%
)+1
(5.
0)+1
(8%
)+1
ñ128
± 3
24 ±
21.
68 ±
0.0
1
5ñ1
(40
%)
+1 (
15%
)ñ1
(10
%)
ñ1 (
3.0)
+1(8
%)
+1+1
22 ±
228
± 2
2.68
± 0
.02
6+1
(60
%)
ñ1 (
5%)
+1 (
30%
)ñ1
(3.
0)ñ1
(4%
)+1
+126
± 1
21 ±
32.
24 ±
0.0
2
7+1
(60
%)
+1 (
15%
)ñ1
(10
%)
+1 (
5.0)
ñ1(4
%)
ñ1+1
23 ±
214
± 2
1.98
± 0
.01
8ñ1
(40
%)
ñ1 (
5%)
ñ1 (
10%
)ñ1
(3.
0)ñ1
(4%
)ñ1
ñ128
± 2
33 ±
11.
89 ±
0.0
4
X1
= C
once
ntra
tion
of g
lyci
ne; X
2=
Con
cent
ratio
n of
CT
N-A
LG
com
plex
; X3
= C
once
ntra
tion
of c
hitin
; X4
= T
able
t cru
shin
g st
reng
th; X
5=
Con
cent
ratio
n of
ond
anse
tron
HC
l; X
6, X
7 ar
e du
mm
y va
riab
les
Fabrication and optimization of fast disintegrating tablets employing... 573
Preparation of chitosan-alginate complex (CTN-
ALG)
The CTN-ALG was prepared by coacerva-tionñphase separation method. Chitosan solutionwas prepared by dissolving chitosan (3.0% w/v) in20 mL of 2% v/v acetic acid. Separately, a solutionof sodium alginate (4.0% w/v) in 20 mL of distilledwater was prepared. Chitosan solution was added toalginate solution dropwise with constant stirring(1000 rpm). Isopropyl alcohol (150 mL) was thenadded to completely separate chitosan-alginateinterpolymer complex. The washed CTN-ALG wasdried in oven (50OC, 48 h) followed by microwavedrying (85 W, 10 s) and then sieved (#22) to obtainuniform size powder.
Preparation of ondansetron FDTs by direct com-
pression
Plackett Burman screening design was used forscreening the effect of selected process and formu-lation variables (Table 1) on disintegration time(DT), wetting time (WT) and water absorption ratio(WAR). Additional FDTs were prepared accordingto BoxñBenkehn design (BBD) using active vari-ables [(i.e., concentration of glycine (X1), concentra-tion of chitosan-alginate complex (X2) and tabletcrushing strength (X4)] that were found to signifi-cantly influence the DT, WT and WAR during ini-tial screening studies. The disintegration time ofFDTs that were prepared using spray dried lactose,ondansetron HCl and croscarmellose sodium orcrospovidone was compared with that of tablets pre-pared with CTN-ALG, glycine and chitin mixture.Multiple linear regression was performed betweenactive variables obtained from BBD and dependentvariables and analyzed using StatisticaÆñ 7.0(StatSoft Inc., Tulsa, USA). All the FDTs were pre-pared by the following method.
Glycine (40ñ60 %w/w), chitin (10ñ30% w/w)and CTN-ALG complex (5ñ15% w/w) were mixedin dry state. To this mixture, spray dried lactose(22ñ55% w/w) and ondansetron HCl (8% w/w) wereadded and blended by tumbling. The resulting blendwas compressed into tablets with a multipunch sixstation rotary tableting machine (A. K. Industries,Nakodar, Punjab, India). The average weight anddiameter of round shaped FDT was 100 ± 5 mg and6 ± 0.5 mm, respectively.
Formulation of ondansetron HCl FDTs using
superdisintegrants
Crospovidone (2.5ñ10% w/w) or croscarmel-lose sodium (2.5ñ10% w/w), ondansetron HCl (8%w/w) and spray dried lactose (81ñ88.5% w/w) were
added and blended by tumbling. The resulting blendwas compressed into tablets. The average weightand diameter of round shaped FDT was 100 ± 5 mgand 6 ± 0.5 mm, respectively.
Evaluation of powder blends
Pure excipients alone or their combinations indry state were subjected to estimation of water sorp-tion time, effective pore radius and swelling index.
Water sorption time (WST) and swelling index
(SI)
The sample (250 mg) was filled intomicropipette tips (transparent, 2 mL) for estimatingWST and SI. The tip outlet was first blocked with atiny swab of Nylon fiber to avoid leakage of thepowder. After placing the solid sample into the tip,it was tapped 10 times by dropping on a hard surfacefrom 10 cm height to repeatedly obtain approxi-mately the same packing. The plastic tip wasweighed (Wa) then dipped into a 2ñ3 mm layer ofphosphate buffer pH 6.8. The time taken by the liq-uid to reach to the top of the powder bed was esti-mated as WST. The filled tip was again weighed(Wb) at the end of the experiments were repeated sixtimes. The SI was estimated as:
SI = Wa ñ Wb/Wa × 100 (1)The experiments were repeated six times and aver-age values were taken for calculation.
Effective pore radius (Reff-p.)
Reff-p. of the powder blend was estimatedaccording to the method reported by Chibowski etal. [14]. In brief, the micropipette tip (2 mL, trans-parent) was filled with the powder and weighed(WA). Then n-hexane [surface tension (γ) 18.4mN/m, contact angle (θ) = 0O] was poured dropwiseon the bedtop till the solvent filtered out at the bot-tom of the tip. The tip was weighed again (WB). Theexperiments were repeated six times.
Reff-p = Wb ñ Wa/2πγ (2)
Evaluation of FDTs
Tablet crushing strength
Pfizer hardness tester was used to measure thetablet crushing strength. The data reported are themean of six individual determinations.
Wetting time (WT)
Five circular pieces of tissue paper (10 cmdiameter) were placed in a Petri dish and 10 mL of0.05% w/v eosin dye solution in water was added. Atablet was carefully placed on the surface of the tis-
574 HONEY GOEL et al.
sue paper. The time required for the dye solution toappear on the upper surface of tablet was noted asWT (15).
Water absorption ratio (WAR)
The procedure used for determining WT wasrepeated using distilled water instead of dye solu-tion.
WAR = (Wb ñ Wa) / Wb ñ Wa (3)where, Wa and Wb are the weights of the tabletbefore and after water absorption, respectively.
Tablet porosity
The tablet porosity was calculated using theequation:
ε (%) = [(1- M)/Vρ] 100 (4)where ρ is true density, M and V are the tabletweight and tablet volume, respectively. The diame-ter and thickness of tablet for calculating M and Vwere measured using micrometer. The true densityof the powder was determined using a pyknometer.The experiments were repeated six times.
Weight variation
The weight variation test was performed onrandomly collected 20 tablets from a batch of 100tablets according to the method specified in USP30-NF25.
Friability
Friability of the tablets was evaluated usingRoche friabilator according to the method specifiedin USP30-NF25.
Content uniformity
Thirty tablets were randomly selected fromeach batch and 10 tablets were analyzed individual-ly. The amount of ondansetron HCl was analyzed at310 nm in 0.1 M HCl (Beckman DU-640BUV/VIS).
In vivo disintegration time (DT)
The in vivo DT was assessed in six healthymale volunteers for each batch of tablets (16). Thevolunteers were informed of the protocol and pur-pose of the study. All the volunteers were asked torinse their oral cavity with distilled water prior tothe test. Each volunteer was asked to place onetablet on the tongue and a stopwatch was startedimmediately. The volunteers were given strictinstructions not to chew or swallow the tablets,although licking was allowed. The end point of dis-integration in the oral cavity was measured as thetime when the tablet placed on the tongue disinte-grated without leaving any lumps. All the volun-teers were instructed to rinse their mouth after com-pletion of test.
Table 2. Box-Benkehn Design (33 BBD) using active formulation and process variables influencing DT (Y1), WT (Y2) and WAR (Y3).
Exp X1 X2 X4 Y1 Y2 Y3
no. (%w/w) (%w/w) (kg) (sec) (sec) (%)
1B 0 ñ1 ñ1 23 ± 2 27 ± 3 2.06 ± 0.02
2B 0 ñ1 1 31 ± 3 30 ± 3 1.51 ± 0.02
3B 0 1 ñ1 16 ± 2 17 ± 2 2.84 ± 0.01
4B 0 1 1 23 ± 1 22 ± 1 1.65 ± 0.05
5B ñ1 0 ñ1 24 ± 2 32 ± 3 2.12 ± 0.04
6B ñ1 0 1 36 ± 2 31 ± 2 1.99 ± 0.02
7B 1 0 1 15 ± 1 12 ± 2 2.62 ± 0.02
8B 1 0 1 25 ± 2 18 ± 2 1.83 ± 0.01
9B ñ1 ñ1 0 31 ± 3 35 ± 2 1.54 ± 0.04
10B ñ1 1 0 26 ± 2 22 ± 2 2.0 ± 0.02
11B 1 ñ1 0 23 ± 2 23 ± 2 1.98 ± 0.03
12B 1 1 0 17 ± 2 12 ± 1 2.48 ± 0.08
13B 0 0 0 24 ± 2 22 ± 2 1.92 ± 0.02
14B 0 0 0 24 ± 3 22 ± 3 1.92 ± 0.02
15B 0 0 0 24 ± 2 22 ± 2 1.92 ± 0.03
X1 = Concentration of glycine, X2 = Concentration of CTN-ALG complex, X4 = Tablet crushing strength. aValues represent the mean ±SD of five experiments
Fabrication and optimization of fast disintegrating tablets employing... 575
In vitro release studies
Ondansetron HCl released from FDTs wasevaluated by using USP dissolution apparatus II ñpaddle (Tab-Machines, Mumbai, India) using 500mL of 0.1 M HCl as dissolution medium at 37 ±0.5OC and stirring speed of 50 rpm (USP 30-NF 25).Aliquots (5 mL) withdrawn at different time inter-vals were immediately filtered through Whatmanfilter paper (11 µm pore size) diluted suitably andanalyzed for ondansetron HCl spectrophotometri-cally (Beckman DU 640B UV/VIS spectrophotome-ter) at 310 nm. The absorbance values were trans-formed to concentration by reference to a standardcalibration curve obtained experimentally (r2 =0.9996).
Similarity and dissimilarity factors
A model independent approach was used toestimate dissimilarity factor (f1) and similarity factor(f2) to compare dissolution profile of FDTs contain-ing chitosan-glycine mixture with FDTs containingsuperdisintegrant. The following equations wereused for calculating f1 and f2.
f1 = {[Σn
t=1(Rt ñ Tt)]/[Σ
n
t=1Rt ]} × 100 (4)
The similarity factor (f2) is given by following equa-tion:
f2 = 50 × log{[1 + 1/nΣn
t=1(Rt ñ Tt)2]ñ0.5 × 100 (5)
where, n is number of pull points, Rt is the referencebatch profile at time ëtí and Tt is the test batch pro-file at the same time point. For in vitro dissolutioncurves to be considered similar, the value of f1
should be in the range of 0ñ15 while the value of f2
should lie within 50ñ100 (17).
RESULTS AND DISCUSSION
The statistical optimization designs are com-monly used for optimizing formulations, analyticalmethods, pharmaceutical process etc. (18).Therefore, formulation and process variables wereoptimized by employing an experimental design fol-lowed by mathematical tools in an attempt to pre-pare FDTs possessing lower DT than those preparedusing superdisintegrants.
Screening of active process and formulation vari-
ables
PlackettñBurman screening design was used toformulate FDTs for screening the process and for-mulation variables that produced a significant (p <0.05) effect on DT, WT or WAR as shown in Table1. The results revealed that all these dependent vari-
Table 3. Quadratic model and the coefficients for DT, WT and WAR.
Coefficients of quadratic model
Y Terms b0 b1 b2 b4 b1b2 b1b4 b2b4 b12 b2
2 b42 R2
→ %
CF 24.0 ñ4.50 ñ3.25 4.75 ñ0.25 ñ0.25 ñ0.25 1.12 ñ0.87 0.12
SE 0.84 0.51 0.51 0.51 0.72 0.72 0.72 0.75 0.75 0.75
DT SE◊* 1.78 1.09 1.09 1.09 1.54 1.54 1.54 1.60 1.60 1.60 97ttable = C
aSig S S S S NS NS NS NS NS NS
CF 22.0 ñ6.88 ñ5.25 1.62 0.5 1.75 0.5 0.12 0.88 1.12
SE 1.18 0.72 0.72 0.72 1.02 1.02 1.02 1.06 1.06 1.06
WT SE◊* 2.50 1.53 1.53 1.53 2.17 2.17 2.17 2.26 2.26 2.26 97 ttable = C
aSig S S S S NS NS NS NS NS NS
CF 1.92 0.16 0.24 ñ0.33 0.01 ñ0.17 ñ0.16 0.10 ñ0.02 0.12
SE 0.092 0.06 0.06 0.06 0.08 0.08 0.08 0.08 0.08 0.08
WAR SE◊* 0.195 0.12 0.12 0.12 0.17 0.17 0.17 0.18 0.18 0.18 94ttable = C
aSig S S S S NS NS NS NS NS NS
The*ttable value for 15 degree of freedom and 5% level confidence is 2.13, asig ñ significance, S ñ significant difference (if CF > C); NS ñno significant difference (if CF < C). CF = coefficients, SE = standard error, R2 = regression roefficients, Y = Responses.
576 HONEY GOEL et al.
ables were significantly influenced (p < 0.05) byconcentration of glycine (X1), concentration ofCTN-ALG (X2) and tablet crushing strength (X4).Further, the DT and WT of FDTs containing 60%
w/w of glycine and 15% w/w of CTN-ALG werelower than those of FDTs containing 40% w/w ofglycine and 5% w/w of CTN-ALG complex at alltablet crushing strengths examined.
Figure 1. Coefficients associated with the effect of various formulations and process variables on DT, WT and WAR of ondansetron HClFDTs
Table 4. Reduced model equations for relating influence of concentrations of glycine (X1), concentration of CTN-ALG complex (X2) andtablet crushing strength (X4) on DT (Y1), WT (Y2) and WAR (Y3).
Responses Treatment
X1 v/s X2 X1 v/s X4 X2 v/s X4
DT (Y1) Y1 = 24.0 ñ 4.5X1 ñ 3.25X2 Y1 = 24.0 ñ 4.5X1 + 4.7X4 Y1 = 24.0 ñ 3.25X2 + 4.75X4
WT(Y2) Y2 = 22.0 ñ 6.88X1 ñ 5.25X2 Y2 = 22.0 ñ 6.88X1 + 1.63X4 Y2 = 22.0 ñ 5.25X2 + 1.63X4
WAR (Y3) Y3 = 1.9 + 0.158 X1 + 0.24X2 Y3 = 1.9 + 0.158X1 ñ 0.33X4 Y3 = 1.9 + 0.24X2 ñ 0.33X4
Table 5. Disintegration time (DT) of ondansetron HCl FDTs containing crospovidone (CP) or croscarmellose sodium (CS).
Formulation SprayTablet
(in mg) driedCroscarmellose Crospovidone Ondansetron Colloidal Total crushing
DTno. lactose
sodium (CS) (CP) HCl silica weight strength(kg)
CP1 88.5 ñ 2.5 8 1 100 3.5 46 ± 3
CP2 86 ñ 5.0 8 1 100 3.5 36 ± 3
CP3 83.5 ñ 7.5 8 1 100 3.5 31 ± 2
CP4 81.0 ñ 10.0 8 1 100 3.5 26 ± 1
CS1 88.5 2.5 ñ 8 1 100 3.5 50 ± 3
CS2 86.0 5.0 ñ 8 1 100 3.5 42 ± 3
CS3 83.5 7.5 ñ 8 1 100 3.5 33 ± 2
CS4 81.0 10.0 ñ 8 1 100 3.5 28 ± 1
Fabrication and optimization of fast disintegrating tablets employing... 577
Mechanism of disintegration
The results of multiple linear regressionrevealed that the effect of various formulation andprocess variables (X1ÖX7) on DT (Y1), WT (Y2) andWAR (Y3) could be represented by the equations: Y1 = 25.12 ñ 2.875X1 ñ 3.625X2 ñ 0.125X3 +3.125X4 ñ 1.375X5 +1.125X6 + 0.875X7... (6) Y2 = 24.0 ñ 7.0X1 ñ 4.5X2 ñ 0.75X3 + 1.25X4 +0.25X5 + X6 + 0.75X7... (7) Y3 = 2.01 + 0.2075X1 + 0.228X2 ñ 0.0425X3 ñ0.435X4 + 0.1575X5 ñ 0.035X6 + 0.045X7... (8)
In the above equations, a negative sign signi-fies an antagonistic effect, whereas a positive signsignifies a synergistic effect. Therefore, the equationgenerated after multiple linear regression revealedthat increasing the concentration of glycine had anantagonistic effect and decreased the DT and WT.However, the WAR decreased with a decrease inconcentration of glycine (Fig. 1). DT and WTdecreased with an increase in concentration of CTN-ALG, whereas, the WAR increased with an increasein concentration of CTN-ALG. On the other hand,the process variable, tablet crushing strength (X4)had an opposite influence. An increase in tabletcrushing strength increased the DT as well as WTand decreased the WAR.
WST, Reff-p and SI of individual excipients ortheir combination were evaluated for investigatingtheir role in the disintegration of FDTs (Fig. 2).WST indicates the rate at which water gets trans-ported through the powder bed, Reff-p is an indicatorof porosity of powder and SI indicates swelling
nature of powder. Buffer pH 6.8 was found to wetthe CTN-ALG complex in 117 s, suggesting poorwicking property of CTN-ALG complex. However,it had a SI of 17.69% which indicated its goodswelling property. Glycine was found to exhibitexcellent wetting as it was wetted by buffer pH 6.8in 32 s and the tablets were porous in nature. But, theglycine powder exhibited SI of 5.93% indicatingless water holding capacity. When CTN-ALG com-plex was mixed with glycine, the WST drasticallydecreased to 11 ± 1 s. This reduction was 10.7 foldas compared to CTN-ALG alone. Also, glycineincreased the Reff-p of CTN-ALG to 1.6 fold. Further,increasing the concentration of glycine in the GLY,CTN-ALG mixture increased the Reff-p and decreasedthe WST (Fig. 2A). On the other hand, decreasingthe concentration of CTN-ALG complex in theGLY, CTN-ALG mixture decreased the SI.Therefore, these results are a pointer towards theproperty of glycine to reduce the WST of CTN-ALGand hence, its pivotal role in transporting aqueousmedium to different parts of the tablet due to wick-ing action and porosity enhancing property. Further,these two properties of glycine were observed to beoperative in tablets compressed to high crushingstrengths. Therefore, an increase in concentration ofCTN-ALG increased the swelling action which ledto reduced DT and WT and increased WAR. Hence,it seems logical to expect that glycine created aque-ous channels, which contributed to water transportto CTN-ALG eventually resulting in swelling of thetablets. Therefore, it could be postulated that CTN-
Table 6. Optimized compositions of FDTs and comparison with superdisintegrants.
Tablets containing croscarmellose sodium or crospovidone (A)
Batch No. CS3 CS4 CP3 CP4DT* (s) (Y) 33 ± 2 28 ± 1 31 ± 2 26 ± 1
Tablets containing CTN-ALG complex, glycin and chitin (B)
Batch No. Q1 Q2 Q3 Q4
Solved X1 40.0 45.5 42.2 47.7
values (% w/w)
and X2 3.07 6.92 4.62 8.46
optimized (% w/w)
tablet X4 4.9 4.4 4.7 4.3
composition (kg)
DT* (s) (Y1) 29 ± 3 23 ± 2 28 ± 3 21 ± 3
t-test between DT of A and DT of B
Statistical difference NS NS NS NS
*Data represent the mean ± SD (n = 6). NS = no statistical defference
578 HONEY GOEL et al.
ALG complex could be successfully used fordecreasing the DT.
Effect of ondansetron HCl on DT
Ondansetron HCl when present up to 15% w/vwas not found to be an active factor. However, atconcentrations greater than 15% w/w the DT ofFDTs was recorded to be more than 50 s. The WSTof ondansetron HCl powder in buffer pH 6.8 was 78s at its Reff-p of 1.062 ± 0.04 mm (Fig. 2B). The addi-tion of increasing concentration of ondansetron HCl
to a mixture containing CTN-ALG: GLY (30:70)and chitin (10 % w/v) mixture increased the WST aswell as Reff-p. However, it did not affect the SI. Thisindicated that ondansetron HCl antagonized thewicking action of glycine. This could be attributedto the high aqueous solubility of ondansetron HCl(19). The water penetrated initially during disinte-gration process shall rapidly produce a solution inthe core of FDT. As a consequence, the penetrationof additional water is expected to get obstructed dueto clogging of space by dissolved ondansetron HCl.
Figure 2. Effect of mixture containing A) CTN-ALG and glycine; B) Chitin and CTN-ALG or C) ondansetron on water sorption time(WST), Effective pore radius (Reff.p×10) and swelling index (SI)
Fabrication and optimization of fast disintegrating tablets employing... 579
This possibly led to delayed disintegration oftablets. Therefore, all the FDTs were prepared usingadult dose of ondansetron HCl (8 mg) whichamounted to 8% w/w of total tablet weight.
Effect of chitin on DT
Chitin (a copolymer of N acetyl-glucosamineand N-glucosamine) is reported to act as disinte-grant and exhibits less DT as compared to starch(13). However, the results (Fig. 1) revealed thatconcentration of chitin (X3) did not produce anysignificant effect on DT, WT and WAR. The effectof increasing concentration of chitin on DT andtablet porosity in tablets compressed at differentcrushing strengths was investigated (Fig. 3). Theresults revealed that chitin decreased the DT withan increase in tablet porosity, when the concentra-
tion of chitin in the FDTs was 20% w/w (Fig. 3A).However, no significant effect on DT and tabletporosity was observed when concentration ofchitin was increased to more than 20% w/w, irre-spective of the tablet crushing strength of tablets.Further, the addition of chitin in the FDTs made itpossible to prepare tablets with higher crushingstrength of 5.5 kg (Fig. 3B). These findings sug-gested that addition of chitin in FDT formulationscontributed more towards enhancement of tabletcrushing strength as compared to DT. Further,increasing the concentration of chitin from10ñ30% w/v in presence of a mixture of CTN-ALG: GLY (30:70) did not affect WST or SI (Fig.2C). However, both Reff-p as well as WST increasedin the powder mixture containing different concen-tration of chitin as compared to CTN-ALG : GLY
Figure 3. A) The effect of concentration of chitin on disintegration time (DT) and tablet porosity (TP) of tablets compressed at differenttablet crushing strengths. B) Effect of tablet crushing strength on disintegration time (DT) and tablet porosity (TP) of tablets containingdifferent concentration of chitin
580 HONEY GOEL et al.
(30:70) mixture alone. This indicated that chitinacted as a porosity enhancer.
BoxñBehnken design
The relationship between one or more responsevariables and a set of quantitative parameters can beeasily examined by using response surface methods,such as central composite designs or BoxñBehnkendesigns (20, 21).
BoxñBehnken design (BBD) was used to esti-mate extended effect of active process and formula-tion variables (X1, X2 and X4) on dependent vari-ables (Y1, Y2 or Y3) in an extended spherical domain(Table 2).
A statistical model incorporating interactiveand polynomial terms used for evaluating theresponses obtained from BBD is given below:Y = b0 + b1X1 + b2X2 + b3X3 + b12X1X2 + b13X1X3 +b23X2X3 + b11X1
2 + b22X22 + b33X3
2 (9)where, Y represents the selected response, b0 is thearithmetic mean of individual response and bi is theestimated coefficient for the factor Xi. Further, thevalues of the coefficients relate to the respectiveeffect on DT (Y1), WT (Y2) and WAR (Y3).
Table 3 summarizes the coefficients associatedwith active variables. The main effects (X1, X2 or X4)represent the average result of changing one factor ata time from its low to high value. The interactionterms (X1X2, X1X4, and X2X4) show the variation inresponse when two or three factors were simultane-ously changed. The second order quadratic terms (X1
2,X2
2 and X42) were included to investigate non linearity.
The regression statistics of quadratic modelrevealed that DT in oral cavity or WT and WARwere 97% and 94% correlated with factors (X1, X2
and X4), respectively. However, the interactionterms and second order quadratic terms revealed nosignificant influence (p < 0.05) on DT, WT or WAR.Therefore, a reduced model was generated by omit-ting interactions and quadratic terms. The reducedequations were generated by utilizing coefficients ofactive variables and responses (DT, WT and WAR)as shown in Table 4.
The variation of two active factors and theirinfluence on DT (Y1), WT (Y2) or WAR (Y3) can beeasily visualized by constructing response surfaceplots. It was observed that increasing the concentra-tion of both glycine (X1) and CTN-ALG (X2) pro-duced a decrease in DT (Y1) but increased the WAR(Y3) and WT (Y2) (Fig. 4A, D and G). However, anincrease in the concentration of CTN-ALG com-plex (X2) alone (keeping concentration of glycine(X2) constant) resulted in the reduction of DT (Y1)and WT (Y2) but increased the WAR (Y3). On the
Tab
le 7
. Com
pari
son
of o
ptim
ized
FD
Ts
(Q1-
Q4)
with
FD
Ts
cont
aini
ng c
rosc
arm
ello
se s
o-di
um (
CS)
or
cros
povi
done
(C
P).
Form
ula-
Tab
let
t
ion
no.
CS3
Q1
*Sig
CS 4
Q2
Sig
CP 3
Q3
Sig
CP 4
Q4
Sig
prop
etie
s
Wei
ght v
aria
tion
(%)
± SD
2.89
± 0
.06
1.92
± 0
.04
NS
2.54
± 0
.08
2.39
± 0.
05N
S2.
59 ±
0.0
62.
28 ±
0.0
4N
S1.
89 ±
.03
2.24
± 0
.07
NS
Dru
g co
nten
t(%
) ±
SD (
%)
97.8
± 0
.03
98.7
± 0
.07
NS
97.6
± 0
.04
98.6
± 0.
03N
S98
.4±
0.06
98.3
± 0
.04
NS
98.8
± 0
.04
98.3
± 0.
03N
S
% F
riab
ility
± SD
(%
)1.
16 ±
0.0
20.
54±
0.04
S0.
79 ±
0.0
30.
63±
0.02
S0.
94 ±
0.0
30.
58 ±
0.0
1S
0.83
± 0
.04
0.69
± 0
.03
S
Ave
rage
wei
ght
(mg)
of
2097
.6 ±
1.2
899
.1 ±
0.4
9N
S97
.4 ±
1.3
898
.5±
1.68
NS
97.6
± 1
.27
96.4
± 1
.35
NS
97.2
± 1
.43
98.1
± 1
.46
NS
tabl
ets
* Si
g -
sign
ific
ance
, NS
- no
sig
nifi
cant
dif
fere
nce,
S -
sig
nifi
cant
dif
fere
nce,
dat
a gi
ven
are
the
mea
n ±
SD (
n =
6).
Fabrication and optimization of fast disintegrating tablets employing... 581
other hand, addition of low concentration of glycine(keeping concentration of CTN-ALG constant)resulted in significant enhancement of WT (Y2) andDT (Y1) and a decrease in the WAR (Y3). This sug-gested that a minimum concentration of glycine incombination with CTN-ALG complex is essentialfor achieving a minimum DT. Further, an increasein the crushing strength and concentration ofglycine decreased the WT (Y2) (Fig. 4B, E, H).Also, a decrease in crushing strength and CTN-ALG complex increased the DT (Y1) as well asWAR (Y3) but decreased the WT (Y2) (Fig. 4C, F,I). This indicated that a change in hardness of FDTschanged the WAR (Y3). However, an increase in theWT with increasing crushing strength nullified theeffect on WAR (Y3). Therefore, a linear effect onDT with increasing tablet crushing strength wasobserved in FDTs containing glycine and CTN-ALG mixture.
Figure 4. Response Surface Plots showing effect of concentration of glycine (X1), concentration of CTN-ALG complex (X2) and tabletcrushing strength (X4) on DT (Y1), WT (Y2) and WAR (Y3)
Figure 5. Effect of tablet crushing strength on DT, WT or WAR ofQ1, CS3 and CP3 batches
582 HONEY GOEL et al.
Optimization of FDTs
Croscarmellose sodium swells to a large extentwhen it comes in contact with water. It has fibrousnature that allows intraparticulate as well as extra-particulate wicking of water even at low concentra-tion level (22). Crospovidone has excellent wickingnature though it swells only to a small extent (23).The FDTs containing croscarmellose sodium orcrospovidone generally disintegrated within 30 s attablet crushing strength of 3.5 kg. However, at tabletcrushing strength of more than 4 kg, the DT oftablets is reported to be more than 60 s (8). Hence,the maximum value of tablet crushing strength ofFDTs prepared using croscarmellose sodium orcrospovidone was fixed at 3.5 kg. Therefore, forcomparative studies, FDTs of ondansetron HCl wereprepared by direct compression method utilizingvarious concentrations of croscarmellose sodium orcrospovidone as summarized in Table 5. The DT ofFDTs containing croscarmellose sodium (CS1ñCS4)or crospovidone (CP1ñCP4) was observed todecrease with an increase in their respective concen-trations. Hence, the batches CS3, CS4, CP3 and CP4
were selected for further study as they showed min-imum DT.
DT in oral cavity (Y1) was selected as adependent variable and different formulations wereprepared for optimizing the concentration of glycineand CTN-ALG. The reduced model equation gener-ated from correlation of Y1 and three active vari-ables of BBD as in Table 6 were solved for calcu-lating optimum values of X1 (concentration ofglycine), X2 (concentration of CTN-ALG) and X4
(tablet crushing strength). For this purpose, additionor subtraction method for solving quadratic equa-tions was used for obtaining the optimized values ofX1, X2 and X4 in terms of Y1 and constant terms inthe equation. The disintegration time of FDTsobtained from various formulations (CS3, CS4, CP3
and CP4, Table 5) was then substituted in place of Y1
to get respective calculated optimized values of X1,X2 and X4. These calculated optimized values wereused for preparing FDTs containing glycine, CTN-ALG and ondansetron HCl that would exhibit DTcomparable to the DT of FDTs prepared usingcrospovidone or croscarmellose sodium as given inTable 6. The optimized variables X1, X2 and X4 gen-erated for preparing ondansetron HCl FDTs indicat-ed that tablets containing CTN-ALG complex couldbe prepared at higher tablet crushing strengths ascompared to FDTs containing croscarmellose sodi-um or crospovidone. Also, it is evident from Table 6that ondansetron HCl FDTs prepared by using theoptimized values of active variables (Q1ñQ4, Table
6) exhibited lower DT in oral cavity as compared toFDTs containing croscarmellose sodium orcrospovidone (CS3, CS4, CP3 and CP4, Table 6).
Evaluation of optimized FDTs: A comparison
with superdisintegrants
A comparison of optimized FDTs (Q) withFDTs containing croscarmellose sodium (CS) orcrospovidone (CP) revealed that the percentage fri-ability of optimized FDTs was significantly (p <0.05) lower than that of FDTs containingcroscarmellose sodium or crospovidone as shown inTable 7. No statistical difference (p < 0.05) wasobtained with respect to weight variation, drug con-tent and average weight of tablets. The angle ofrepose of the granules of optimized batch (Q1) wasfound to be 23.4 ± 1.54O. This indicated excellentflowability of ondansetron HCl granules preparedusing CTN-ALG complex and glycine.Interestingly, the DT of the optimized FDTs thatwere compressed to higher crushing strength wassimilar to the DT of FDTs containing croscarmel-lose sodium or crospovidone compressed at crush-ing strength of less than 3.5 kg. Therefore, the bestbatch Q1 of optimized FDTs was selected for furtherevaluation as it was compressed at highest tabletcrushing strength of 4.9 kg. Figure 5 shows theeffect of crushing strength on DT and WT of FDTsprepared using croscarmellose sodium (CS3),crospovidone (CP3) and optimized FDTs (Q1). Acomparison of the tablets prepared with glycine-CTN-ALG with those prepared using superdisinte-grants revealed a nonlinear relationship between DTin oral cavity and tablet crushing strength and alsobetween WT and tablet crushing strength (Fig. 5).However, a linear relationship was observedbetween DT in oral cavity and tablet crushingstrength of Q1 tablets. Also, a linear relationship wasseen between WT and tablet crushing strength of Q1
tablets. Further, DT in oral cavity and WT followedthe order: CS3 > CP3 > Q1 at more than 3.5 kg crush-ing strength. This indicated that FDTs of Q1 batchwere most rapidly wetted and disintegrated in theoral cavity even when prepared at tablet crushingstrength of more than 3.5 kg. On the other hand,tablets of CS3 and CP3 batches did not exhibit thisproperty.
The release of ondansetron HCl from tablets ofCS3, CP3 and Q1 batches was evaluated in 0.1 MHCl. The dissolution profile of all the three FDTbatches revealed that 86.1% of ondansetron HClwas released within 5 min. Further, a comparison ofdissolution data of FDTs of CS3, CP3 and Q1 batcheswas conducted using f1 and f2 statistics. Values of
Fabrication and optimization of fast disintegrating tablets employing... 583
0.78 and 1.82 were obtained for CS3 vs. Q1 and CP3
vs. Q1, respectively, for f1. Also, values of 85.5 forCS3 vs. Q1 and 90.6 for CP3 vs. Q1 were obtained forf2. This indicated that the release profiles of FDTstablets of CS3, CP3 and Q1 batches in 0.1 M HClwere comparable.
CONCLUSION
The present investigation revealed that a combi-nation of chemometric and mathematical tools couldbe advantageously used for optimizing FDT formula-tions of ondansetron. Further, the results indicatedthat screening of factors with respect to response wasnecessary for studying extended domains and interac-tion behavior of different active factors. Chitin wasfound to function as an excellent tablet hardness pro-moter at a concentration higher than 10% w/w. Acombination of chitin (10% w/w), glycine (40% w/w)and CTN-ALG (3% w/w) was found to have super-disintegrant activity. This combination was found tobe the optimum for formulating FDTs even at crush-ing strength of 5.0 kg and containing water solubledrugs like ondansetron HCl. The evaluation of opti-mized FDTs containing glycine, CTN-ALG andchitin revealed that optimized FDTs were comparableto those containing croscarmellose sodium orcrospovidone with respect to DT and friability.
Acknowledgments
We gratefully acknowledge Panacea BiotechLtd. (Lalru, India), and Ind-Swift Labs.,(Chandigarh, India) for providing gift samples ofcroscarmellose sodium, crospovidone andondansetron HCl, respectively. (Central Instrumen-tation Facility) SAIF, Panjab University, Chandi-garh, India is acknowledged for providing facility ofSEM for this investigation.
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Received: 08. 07. 2010
