Fast orodispersible tablets of Naratriptan Hydrochloride

ORIGINAL ARTICLE
Formulation development and optimization of fast orodispersible tablets of
naratriptan hydrochloride by using factorial design
N.A. Oza1*, A.R. Sahu1, S.N. Tripathi2, P.U. Patel3, L.D. Patel4, A. Ramkishan5
1
Assistant Professor, 2PG Student, 4Director and Professor, C.U. Shah College of Pharmacy and Research, Wadhwancity, Surendranagar.
3
Professor and Head, S.K. Patel College of Pharmaceutical Education and Research, Kherva, Gujarat.
5
Depyuty Drug Controller, Central Drug Standard Control Organization, New Delhi.

ABSTRACT
BACKGROUND: The present research was to develop oral fast disintegrating tablets of naratriptan hydrochloride.
MATERIALS AND METHODS: Tablets containing naratriptan hydrochloride, sodium starch glycolate (SSG),
croscarmellose sodium (CCS) and kyron-T314 were prepared by direct compression technique. Among three super
disintegrating agents, croscarmellose sodium was found to have better fast disintegrating properties and higher
dissolution efficiency. A 32 full factorial design was employed to investigate the influence of two formulation
variables: amount of croscarmellose sodium and kyron-T314. The tablets were evaluated for friability and
disintegration time. RESULTS: The results of multiple linear regression analysis revealed that for obtaining a
rapidly disintegrating dosage form, tablets should be prepared using an optimum ratio of croscarmellose sodium and
kyron-T314. Contour plots were also presented to graphically represent the effect of the independent variables on
the disintegration time and percent friability. CONCLUSION: A checkpoint batch was prepared to prove that
validity of the evolved mathematical model. There was no difference observed in release profile and drug content
after accelerated stability study for 1 month.
Keywords: Contour plot, Croscarmellose sodium, Factorial design, Naratriptan Hydrochloride tablets,
Orodispersible tablets

INTRODUCTION
Oral route of drug administration is the most Naratriptan hydrochloride is approved for acute oral
appealing route for the drug delivery. Among the migraine therapy. The drug is a selective agonist of
various dosage forms tablet is one of the most 5-hydroxytryptamine1 (5-HT1) receptors, so it used
preferred dosage form because of its ease of in treatment of migraine attack and as well as in
manufacturing, convenience in administration,
accurate dosing, stability compared with other forms nausea, vomiting and headache. Naratriptan
etc. The bioavailability of a drug is dependent on hydrochloride half life is 5 to 6 hrs. Hence, it is most
disintegration, dissolution, and various physiological suitable for manufacture of ODT because of its
factors. In the recent yrs, scientists have focused longer half life. In the Phase III trials of naratriptan
their attention on the formulation of quickly hydrochloride compared with placebo, the relief at
disintegrating tablets and orodispersible tablets four hours was obtained in 60% and 68% of patients
(ODTs). Food and Drug Administration of United using the 2.5 mg dose, with recurrence of headache
States defined ODT as: “A solid dosage form in 24 hours in 27% and 28% of patients3,4,5. The aim
containing medicinal substance or active ingredient of present study was to develop fast disintegrating
which disintegrates rapidly usually within a second
when placed upon the tongue”. The disintegration tablet of naratriptan with possible advantages like,
time for ODTs generally ranges from several quick onset of action due to rapid dissolution and
seconds to about a minute1,2. Orally disintegrating enhanced rapid absorption. Sodium starch glycolate
tablets are formulated by employing many processes, (SSG), croscarmellose sodium (CCS) and kyron-
which differ in their methodology and the ODTs T314 were screened in the present study, and the
may vary in various properties such as, mechanical best one was used for further studies. Another
strength of tablets, taste and mouth feel, swallow approach used in developing ODT was to maximize
ability, drug dissolution in saliva, bioavailability and the pore structure of the tablets. The direct
stability. The task of developing rapidly compression technique was adopted for formulating
disintegrating tablets is accomplished by using a
suitable diluent and superdisintegrant. the ODT of naratriptan hydrochloride. A 32 full
factorial design was applied in optimization of the
*Corresponding Author
oral disintegrating tablets of naratriptan
Mr. Nishant A. Oza (Assistant Professor)
hydrochloride. The concentration of
Department of Pharmaceutics,
superdisintegrants CCS or kyron-T314 was taken as
C.U. Shah College of Pharmacy and Research,
an independent variable. The dependent variables
Wadhwancity, Surendranagar (Gujarat-India)
were friability and disintegration time to find out the
Email: ozanishant@gmail.com

48 Int J Res Med. 2013; 2(4);48-53 e ISSN:2320-2742 p ISSN: 2320-2734

 Fast orodispersible tablets of Naratriptan Hydrochloride

effect of independent variables on dependent test was performed using a dissolution test apparatus
variables6,7. (USP TDT 06 PL, Electrolab, Mumbai) with a
MATERIALS AND METHODS paddle rotation at 50 rpm. After placing a tablet
Materials: Naratriptan hydrochloride, sodium starch containing 2.5 mg of naratriptan in 6.8 pH buffer
glycolate (SSG), croscarmellose sodium (CCS), solution, the 5 ml solution was withdrawn and
polacrellin potassium (kyron-T314), talc, citric acid, filtered through a watmen filter of 0.2 mm pore size
mannitol, avicell pH 102, manitol megnesium at different intervals of 1, 2, 3, 4, 6, 8, 10, 20, 30 min
stearet, sodium steryfumret were obtained as and diluted suitably using 6.8 pH buffer solution and
generous gift from West Coast Pharmaceuticals Ltd., analyzed at 224 nm for cumulative drug release
Ahmedabad, Gujarat. (India). List of Equipments: using (UV-2450, Shimadzu Corp., Japan) spectro
Digital weighing balance (Contact Equipments Pvt. photometer13. Accelerated Stability Study: Stability
Ltd), UV Spectrophotometer {UV (USP)–1700, M/s study of batch F5 was carried out at 400C in a
Shimadzu}, Dissolution test apparatus (Electrolab- humidity chamber having 75% RH. Samples were
TDT-08L), FTIR apparatus (M/s Shimadzu), pH withdrawn at regular intervals during the study of 60
meter (Lab India), Tray Dryer (EIE-103, EIE days. Formulation is evaluated for change in in-vitro
Instrument Pvt. Ltd., Ahmedabad, India), Rotary drug release, hardness and disintegration time14,15,16.
Tablet Compression Machine LAB-Press 8 station; RESULTS
(Hardik Engineering Works, Ahmedabad, India.) Table 1: Formulation of batches T1 –T11 for
Hardness Tester (Monsanto Hardness Tester), Bulk Optimizing Super disintegrating agent
Density measuring apparatus (EIE-Instrument), Ingredie Batch
Stability Chamber (Thermo Lab), Roche Friabilator nts (mg) T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11
(EIE- Instrument). Preparation of Orodispersible Naratrip
Tablets: Each ingredient was passed through #60 tan
2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5
mesh sieve separately. The drug and the diluents hydrchl
oride
were mixed in small portion and blended to get SSG 3 4.5 6 7.5 - - - - - - -
uniform mixture. The remaining ingredients were CCS - - - - 3 4.5 6 - - - -
weighed and mixed in geometrical order. The tablets Kyron
- - - - - - - 3 4.5 6 7.5
314
were prepared by direct compression technique8,9. Avicel
Optimization of Super Disintegrating Agent: Oral 90 90 90 90 90 90 90 90 90 90 90
PH102
fast disintegrating tablets were prepared by direct Manitol 45.5 44 43 41 45.5 44 42.5 45.5 44 42.5 42
compression. Croscamellose sodium, sodium starch SSF 2.25 2.25 2.25 2.25 2.25 2.25 2.25 2.25 2.25 2.25 2.25
Talc 3 3 3 3 3 3 3 3 3 3 3
glycolate and kyron-T314 were used in varying D.M
concentration as shown in Table-1. Batch (T1 to T4) 3 3 3 3 3 3 3 3 3 3 3
orange
contained 2, 3, 4 and 5% of sodium starch glycolate, Citric
1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5
acid
respectively. Batch (T5 to T7) contained 2, 3 and 4% Final
croscamellose sodium, respectively and batch (T8 to 150 150 150 150 150 150 150 150 150 150 150
weight
T11) contained 2,3,4, and 5% kyron-T314, Table 2: FTIR Drug-excipient compatibility data
respectively10,11. Drug Excipient Compatibility Individua Mixture
Drug / Function
Study: Drug- excipient interaction plays a vital role l Peak Peak Inference
Excipiets al group
( cm-1) (cm-1)
in the release of drug from formulation. Fourier 2⁰ Amine
Naratryptan
transform infrared spectroscopy (FTIR) has been 3450 3447 No Change
Hydrochloride R2-NH
used to study the physical and chemical interactions Sodium starch Carboxyl
1242 1247 No Change
glycolate Group
between drug and the excipients used. Fourier
Ether 1157 1153 No Change
transform infrared (FTIR) spectra of naratriptan Croscarmrllose
Methylene 1457 1458 No Change
sodium
hydrochloride, croscarmellose sodium, sodium Ether 1114 1108 No Change
starch glycolate, kyron-T 314, mannitol, and Methylene 1473 1472 No Change
Mannitol Hydroxyl
physical mixture of naratriptan hydrochloride were 1⁰-OH
1044 1041 No Change
recorded using KBr mixing method on FTIR Kyron-T314
Carbonyl
1557 1558 No Change
instrument 12. Spectrograph shown as in Figure 1 and Group
MCC Ether 1143 1140 No Change
2. Drug expcipient compatibility data were presented 2
Full Factorial Design: A 3 randomized full
in Table-2. Evaluation of Orodispersible
factorial design was adopted to optimize the
Tablets: The tablets were evaluated for various
variables. In the design, 2 factors were evaluated,
parameters like weight variation, thickness,
each at 3 levels, and experimental trials were
hardness, friability, wetting time, water absorption
performed at all 9 possible combinations. The
ratio, disintegration time ware measured as described
amount of superdiintegrating agent (croscarmellose
by Gohel M et al13, Swamy P A et al14 and Malke S
sodium, X1) and (kyron-T314, X2) were chosen as
et al15. In vitro Dissolution Test: In vitro dissolution
49 Int J Res Med. 2013; 2(4);48-53 e ISSN:2320-2742 p ISSN: 2320-2734
 Fast orodispersible tablets of Naratriptan Hydrochloride

independent variables in a statistical model Figure 1: FTIR spectrum of Naratriptan

incorporating interactive and polygonal terms were Hydrochloride
used to evaluate the responses. The disintegration
time (DT) and percent friability (%F) were
selected as depende nt variables. Batches of
factorial design were shown in Table-4.
Table 3: Result and Evaluation of Batch T1- T11
Water
Weight Fria Weting Thic
Form Hard Drug Absorp
varia bilit Tim kn D.T
ulatio nes content tion
tion y e ess (sec)
n Kg/cm2 % ratio
(mg) % (sec) (mm)
%
T1 148.7 3.5 0.81 95.17 59.02 83.70 2.98 62.9
Figure 2: FTIR Spectrum of Physical mixture
T2 148.7 3.1 0.64 97.58 56.08 87.70 2.97 59.9
T3 148.7 2.98 0.73 98.41 53.03 93.40 2.99 55.2
T4 148.8 2.97 0.63 98.27 51.05 94.50 3.1 58.3
T5 148.1 3.6 0.93 99.17 40.4 79.60 2.97 43.2
T6 148.9 3.2 0.62 101.5 37.8 83.60 2.96 41.1
T7 148.4 2.98 0.8 102.4 35.7 91.20 2.94 39.5
T8 148.7 3.5 0.73 94.17 55.5 79.80 2.93 59.3
T9 148.5 3.12 0.67 98.48 43.5 85.80 2.94 47.2
T10 148.9 2.98 0.74 101.4 40.25 89.30 2.97 45.3
T11 148.8 2.97 0.79 102.5 38.08 92.40 2.96 43.3
n=6 Figure 3: Cumulative % drug release of Batches
Table 4: Full Factorial Design Batches of Oral T3, T7 and T11
disintegrating Tablets
Variable Levels in
CPR vs TIME
Cumulative

Batch Coded Form D.T %F

% drug

Code
release

X1 X2 200
0
B1 -1 -1 41±1.02 0.98 0 10 20 %CPR T3
B2 -1 0 37±1.12 0.76
B3 -1 1 31±0.97 0.43 Time %CPR T7
B4 0 -1 29±0.87 1.02
B5 0 0 25±0.98 0.82
B6 0 1 21±0.78 0.51
B7 1 -1 30±0.89 0.98 Figure 4: Response surface plot for
B8 1 0 23±0.23 0.93 Disintegrating Time
B9 1 1 16±0.02 0.62
Check Point 0.33 -0.5 20.1 0.7
Actual Values
Coded
Values X1 (Croscarmelose
X2 (Kyron-T314)
sodium)
-1 2 3
0 3 4
1 4 5
Table 5: Result of Evaluation parameters of
tablets of factorial batches B1 to B9
Fact
Avg. Drug Wetting
orial Hardness Thickness
Wt. content time
Batc (kg/cm2) (mm)
(mg) (%)
Figure 5: Response surface plot for % Friability
hes
B1 3.7±0.13 2.97 ±0.7 148.5 98.2±0.34 39±1.13
B2 3.2±0.21 2.9±0.13 148.5 100.2±0.56 31±1.19
B3 3.0±0.09 3.0±0.12 149.4 97.1±0.12 27±0.92
B4 2.88±0.32 2.9±0.06 151.1 102.1±0.29 20±1.2
B5 3.1±0.24 2.9±0.02 149.8 101.3±0.17 9±1.23
B6 2.7±0.17 2.9±0.14 151.5 99.3±0.21 19±0.98
B7 3.2±0.27 2.9±0.06 148.4 97.4±0.07 23±1.34
B8 3.24±0.34 3.0±0.04 149.2 96.6±0.3 18±1.21
B9 2.87±0.14 3.0±0.07 150.3 98.2±0.9 16±0.98

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 Fast orodispersible tablets of Naratriptan Hydrochloride

DISCUSSION generate the statistical relationship between the

For the preparation of ODTs of naratriptan independent variables and responses. For graphical
hydrochloride, formulations were designed by representation of the influence of factors, the contour
selecting appropriate ingredients in appropriate plots were generated for all dependent variables
concentrations and the concentrations of using Sigma Plot 12. The disintegrating time and %
superdisintegrants were optimized thereafter. The friability for the nine batches (B1 to B9) showed a
batches T1-T11 were prepared to achieve an wide variation (i.e., 16 to 41 sec and 0.43% to
optimized concentration of superdisintegrant and the 1.02%, respectively time) in Table-3. The data
most efficacious one among the three clearly indicate that the disintegrating time and %
superdisintegrants incorporated to prepare ODTs as friability values are strongly dependent on the
shown by the Table-1. Among the formulations selected independent variables. The fitted equations
containing SSG (T1-T4), T3 exhibited the lowest (full model) relating the responses disintegrating
wetting time, disintegration time and highest % time and % friability to the transformed factors are
cumulative drug release as shown in Table-3. This shown in Table-6. The polynomial equations and
might be due to the reason that SSG swells in 3D. response surface plot for % friability (Figure 3 and
Up to 5% of SSG decreased disintegrating time and 4) can be used to draw conclusions after considering
wetting time. Therefore, as the concentration of SSG the magnitude of co-efficient17.
increases from 2% to 4%, wetting time, Table 7: Summary of results of Regression
disintegration time not extends beyond 1 minute and Analysis
also the increased in drug release is seen. Among the Coefficients D.T %F
b0 25.22 0.83
formulations containing CCS (T5-T7), T7 exhibited b1 -6.66 0.06
lowest dispersion time, disintegration time and b2 -5.33 -0.23
highest % cumulative drug release as revealed by b12 -1.02 0.01
b11 4.66 0.041
Table-3. The formulations containing kyron-T314 b22 -0.33 0.085
(T8-T11), T11 depicted lowest wetting time R2 0.9941 0.9933
disintegration time and highest % cumulative drug In Table-7 the negative sign which gives synergistic
release as shown in Table-3. Thus the optimized effect and positive sign give antagonistic effect for
concentrations of superdisintegrants were found to disintegration time b1 and b2 posses negative sign
be 4% SSG, 4% CCS and 4% kyron-T314. So, we which gives positive effect on disintegration time
can conclude that among these three but b1 have greater value than b2 it means
superdisintegrants, CCS came out to be the most crosscarmellose sodium is more responsible for
efficacious superdisintegrant to prepare ODT of faster disintegration than kyron314 because
naratriptan hydrochloride as indicated by Figures 4, porous structure was responsible for faster water
which exhibits the disentrigating time of optimized uptake; hence it facilitates wicking action of
concentration of each superdisintegrant. Figures 1 kyron314 and for percent friability b1 posses
exhibit dissolution profiles of formulations T3, T7, positive sign and b2 posses negative sign i.e.
T11 respectively. For optimization of concentration croscarmellose sodium increase the friability
of CCS and kyron-T314 to be used, A 32 factorial because create porous structure in tablet but b2
design was employed in the investigation. The posses negative i.e. addition of kyron314 will helps
amount of superdisntegrating agent (croscarmellose to decrease in friability. For disintegrating time, as
sodium, X1) and (kyron 314, X2) were chosen as shown in figure 2 the surface plot reveled that a
independent variables in a 32 full factorial design. A corresponding increase in the disintegrating time
statistical model incorporating interactive and was observed with increase in concentration of
polygonal terms was used to evaluate the responses. croscarmellose sodium and kyron-T314. This may
Y=b0+ b1X1+ b2X2+ b12X1X2+ b11X1X1+ be due to powerful disintegrating properties. For
b22X2X2. Where Y is the dependent variable, b0 is percentage friability as shown in figure 3 the surface
the arithmetic mean response of the 9 runs, and b is plot reveled that a corresponding increased in the
the estimated coefficient for the factor Xi. The main percentage friability was observed with increase in
effects (X1 and X2) represented the average result of concentration of croscarmellose sodium because of
changing 1 factor at a time from its low to high porous structure but the % Friability decreased when
values. The interaction terms (X1, X2) showed how the concentration on kyron-T314 was increase.
the response changes when two factors are Check point batch (optimized batch) was prepared
simultaneously changed. The polynomial terms (X12 shown in table-4 at X1= 0.33 level and X2= -0.5. The
and X22) were included to investigate nonlinearity. percentage friability of check point batch found to be
Multiple linear regression analysis was performed 0.7% and the disintegration time found to be 21 sec.
using Sigma State 3.5 Demo version software to Table-7 indicates that the results are expected. Thus,

51 Int J Res Med. 2013; 2(4);48-53 e ISSN:2320-2742 p ISSN: 2320-2734

 Fast orodispersible tablets of Naratriptan Hydrochloride

we can conclude that t he statistical model is REFERENCES

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