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Der Pharmacia Lettre, 2013, 5 (4):145-152

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ISSN 0975-5071
USA CODEN: DPLEB4

Formulation and evaluation of zolmitriptan fast dissolving buccal films

S. Vidyadhara*, T. Balakrishna, R. L. C. Sasidhar, Ch. Showri Babu and D. Lakshmi Harika

Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, Guntur, Andhra Pradesh, India

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ABSTRACT

The present study deals with the formulation of fast dissolving buccal films of Zolmitriptan which is used for the
treatment of Migraine. The concept of fast dissolving drug delivery emerged from the desire to provide patient with
more conventional means of taking their medication. In the present research work polyvinyl alcohol and polyvinyl
pyrrolidine were used as film forming agents. Solvent evaporation method was used for the preparation of films. The
prepared films were evaluated for film thickness, folding endurance, dispersion test, drug content and dissolution.
The In vitro dissolution studies were carried out using simulated salivary fluid (pH 6.8 phosphate buffer).
Formulation FP7 released 99% of the drug from the film within 5 minutes which is an essential character for faster
absorption and also exhibited all desirable characteristics of the film..

Keywords: Buccal films, Zolmitriptan, Polyvinyl alcohol, polyvinyl pyrrolidone, Solvent evaporation method.
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INTRODUCTION

The oral cavity has been investigated as a site for drug delivery for a long period of time. Drug delivery through the
oral cavity offers many advantages. Amongst all the routes of administration the oral route is most preferred route in
the designing of dosage form than drug delivery design by other routes (1-2). The oral mucosa is conveniently and
easily accessible and therefore allows uncomplicated application of Dosage forms. Furthermore, the oral mucosa is
robust against local stress or damage and shows fast cellular recovery. Active Substances can be administered
locally to treat oral diseases like periodontal disease, bacterial and fungal infections. A systemic action can be
achieved via drug permeation through the mucosal epithelium (3-4). Fast dissolving films recently have acquired
great importance in the pharmaceutical industry due to their unique properties and specific advantages like no need
of water for disintegration, accurate dosing, rapid onset of action, ease of transportability, ease of handling, pleasant
taste and improved patient compliance (5-6). Fast dissolving film is a type of drug delivery system, which when
placed in the oral cavity it rapidly disintegrates and dissolves to release the medication for oromucosal and
intragastric absorption, without chewing and intake of water (7- 8). This technology evolved over the past few years
from the confection and oral care markets in the form of breath strips and became a novel and widely accepted form
by consumers. These films have potential to deliver the drug systemically through intragastric, sublingual or buccal
route of administration and also has been used for local action (9-10).

Zolmitriptan is a seratonin (5-HT 1) agonist used for the treatment of migraine. The half life of Zolmitriptan is 2.5 to
3 hrs and it undergoes hepatic metabolism. The absolute oral bioavailability is about 40 to 50% (11-13). The present
work was aimed to improve the bioavailability and efficacy of Zolmitriptan by preparing rapidly dissolving buccal
films.

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MATERIALS AND METHODS

Zolmitriptan was obtained as gift sample from M/S Life Line Formulations Vijayawada. Polyvinyl alcohol(PVA)
and Polyvinyl pyrrolidine (PVP) were commercially obtained from M/S Yarrow Chem Products, Mumbai. Poly
Ethylene Glycol (PEG) was obtained commercially from Sisco research laboratories pvt, Ltd, Mumbai. Saccharin
sodium was obtained commercially from High-Pure fine Chemicals, Chennai. All ingredients used in the
formulation were of pharmacopoeial grade.

Preparation of Zolmitriptan Buccal Film

Zolmitriptan buccal films were prepared by solvent evaporation method. Aqueous solutions of plasticizers Polyvinyl
alcohol (PVA) and Polyvinyl pyrrolidine (PVP) were prepared individually in 100ml beakers to get clear solutions.
Then the solution of PVP was added to PVA aqueous solution and mixed well to get homogenous solution which is
labeled as solution A. Specified quantities of zolmitriptan and saccharin sodium were weighed and dissolved in
suitable amount of PEG 200 to get a drug, plasticizer solution which is labeled as solution B. The solution B was
added to the homogenous aqueous solution A and mixed throughly. The obtained solution was casted on the non
adhesive base plate and dried under IR lamp for 24 hours. After complete drying the films were cut into required
sizes. Various trials were carried out to optimize the formula for the preparation of zolmitriptan buccal films.
Composition of various zolmitriptan buccal films was given in Table 1.

Evaluation of Fast Dissolving Films

Film thickness
Thickness of the film was measured by using screw gauge with a least count of 0.01 mm at different places on the
film. The thickness of the film was measured at three different places and the average was measured. Results were
given in table 2.

Folding endurance
Folding endurance of the film was determined by repeatedly folding a small strip of the film at the same place till
number of times the film could be folded at the same place without breaking was recorded as the folding endurance.
The film was folded at an angle of 1800 at the same place till it broke or folded up to 100 times without breaking.
The experiment was performed in triplicate and the mean was calculated. Results were given in table 2.

Drug content uniformity

The films were tested for drug content uniformity by UV-visible Spectrophotometric method. The absorbance values
was measured at a wavelength of 222 nm. The percentage drug content was determined for various films and the
results were given in table 2.

Dispersion test
A strip equivalent to 5mg of Zolmitriptan was placed in 200ml of 6.8pH phosphate buffer and was stirred for 3
minutes. The resulting solution was passed through sieve number 22. The film is said to be passed the dispersion test
only when no residue is left on the sieve. Results were given in the table 2.

Dissolution study by using Franz diffusion cell

Franz Diffusion Cell contains a volume capacity of nearly 15 ml was used for dissolution studies. The strip of film
equivalent to 5mg of Zolmitriptan was placed in between the donar and receptor compartment of Franz diffusion cell
and 15 ml of 6.8 pH buffer (pH of saliva) was added to receptor compartment. cell is placed on magnetic stirrer and
bead in the cell is maintained at a speed of 50 RPM and medium maintained at a temperature of nearly 320C±0.50C
and withdraw 1ml of samples were withdrawn at various time intervals and and the samples were suitably diluted
with 6.8 pH phosphate buffer and measured the absorbance at 222nm against 6.8 pH Buffer as Blank. The
dissolution profiles for various films were given in table 3 and shown in figure 1 and 2. The in vitro dissolution
parameters were given in Table 4.

Drug Excipient Interaction Studies

Drug excipient interaction studies were carried out by using BRUKER FT I.R. to confirm possible interactions
between the drug and polymer. The film was finely ground with KBr to prepare the pellets under a hydraulic
pressure of 600 psi and a spectrum was scanned in the wavelength range of 400 and 4000 cm-1. The physical state of
the drug in the formulation was characterized by using differential scanning calorimeter (DSC 60, Shimadzu). The

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analysis was performed by heating 10 mg of sample on aluminum crimp pans at a rate of 100c/min in a nitrogen
atmosphere (50ml, min-1).

RESULTS AND DISCUSSION

The present study deals with the formulation of fast dissolving buccal films of zolmitriptan which is used for the
treatment of migraine. The present study was intended to select the best possible polymer and excipient
combinations to formulate fast dissolving films of zolmitriptan. zolmitriptan fast dissolving films were prepared by
solvent evaporation method. PVA and PVP were used at different compositions as film forming agents. PEG 200
was used as plasticizer to enhance the flexibility of the film. Saccharin Sodium was used as sweetening agent. All
the films were prepared under identical conditions to minimize processing variables. Further these films were
evaluated for various physical properties such as thickness, folding endurance, drug content uniformity and
dispersion test to ensure the stability of films. The composition of various zolmitriptan buccal films was given in
table 1.

The prepared films were further evaluated for thickness, folding endurance, dispersion test, drug content and invitro
dissolution studies. The film thickness was found in the range of 0.31+0.003 to 0.34+0.003 mm. The optimized ZP7
film was found to have thickness of 0.342mm. The folding endurance values of the prepared films ranged from 30 to
100 percent. The optimized ZP7 film was found to have folding endurance of 100% which is highly desirable. The
drug content was found to be in the range of 4.7+1.2mg to 5.12+0.6mg. The optimized film ZP7 was found to have
4.99 mg. The films were further subjected to dispersion test as per the Indian pharmacopoeial specification. All the
film formulations were found to disperse in 6.8 pH phosphate buffer within 3 minutes. No residue was left on the 22
mesh when the dispersion was passed through it. The film thickness, drug content, folding endurance and dispersion
test values obtained for various films were given in table 2.

Zolmitriptan fast dissolving buccal films were further subjected to In vitro dissolution studies by using Frantz
diffusion cell with 15ml of 6.8 pH phophate buffer as a medium which is maintained at 320C. The dissolution
medium in the cell was maintained to rotate at 50rpm by using magnetic stirrer. Dissolution samples were
withdrawn at various time intervals and were subsequently diluted with the same buffer and Absorbance values were
noted at 222nm by using ELICO Double beam spectrophotometer. The dissolution profiles were given in Table 3
and were shown in figures 1 and 2. Formulations ZP1, ZP2, ZP3, ZP6, ZP7, ZP8 and ZP9 were found to release
more than 90% of the drug within 5 minutes. The formulations ZP4 and ZP5 were failed to release 90 % of the drug
in 5 minutes. The formulations ZP7 and ZP8 were found to be suitable for fast dissolving and also these two films
possessed all the physical characteristics required for the film. The formulations ZP7 and ZP8 containing 30%of
PVP and 50 % of PVA found to exhibit good film forming properties with 100 % folding endurance value. These
two formulations with 20 – 25 % of PEG found to exert rapid dispersion in the dissolution media and readily
dissolved in the same medium which indicated quick and fast dissolving characteristics of the film. The order of
drug release from various zolmitriptan films was given as ZP 7> ZP8 > ZP1 > ZP6 > ZP2 > ZP3 > ZP9 > ZP4
>ZP5.

The first order plots for various films were found to be linear with Co-relation coefficient values obtained were in
the range of 0.9331 to 0.9965. This indicated that the drug release from the films was found to be concentration
dependent.

The Hixon Crowell Cube Root plot for all the buccal film formulations were found to be linear with R2 values
obtained in the range of 0.928 to 0.983. This indicated that the dissolution of the drug from the film was greatly
dependent on unit weight of the film that undergoes dissolution per unit time. The in vitro dissolution parameters
were given in Table 4.

The films were characterized by FTIR and DSC studies. The FTIR spectra of the commercial sample of zolmitriptan
displayed bands at 3350 cm-1 due to N-H Stretch and 1735 cm-1 due to C=O Stretching. The FTIR spectra of
zolmitriptan buccal film ZP7 exhibited characteristic bands at 3350 cm-1 due to N-H Stretch and 1735 cm-1 due to
C=O Stretching. The IR spectra of the film indicated that there are no interactions between drug and excipients used.
Thus the spectra of optimized ZP7 film formulation exhibited all the principle peaks present in the Zolmitriptan pure
drug. Hence there is no interaction between drug and polymers used in formulation. The FTIR spectra of the pure
Zolmitriptan and formulation ZP7 film were shown in figures 3 and 4.

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Further DSC thermographic studies were carried out on Zolmitriptan pure drug and formulation ZP7 film. The
endothermic peak for pure Zolmitriptan drug was obtained at 139.50C whereas for the ZP7 film the broad
endothermic peak was observed at 630C-1600c. The DSC thermogram for zolmitriptan and ZP7 formulation were
shown in figure 5 and 6. The broad endothermic peak for ZP7 formulation was due to the formation of zolmitriptan
complex with the film forming agents used such as PVA and PVP at higher concentrations in the film. Hence no
interaction between drug and polymers were observed with DSC studies.

Table 1. Composition of various Zolmitriptan buccal films

FORMULATIONS
INGREDIENTS
S. No ZP1 ZP2 ZP3 ZP4 ZP5 ZP6 ZP7 ZP8 ZP9
mg/10 films
1 Zolmitriptan 50 50 50 50 50 50 50 50 50
2 Polyvinyl pyrrolidine 300 300 300 300 300 300 300 300 300
3 Polyvinyl alchol 300 350 400 450 500 500 500 500 500
4 Poly ethylene glycol-200 300 250 200 150 100 150 200 250 300
5 Sodium saccharin 20 20 20 20 20 20 20 20 20
6 Water 10 10 10 10 10 10 10 10 10
Total weight of film (mg) 979.8 979.8 979.8 979.8 979.8 1029.8 1079.8 1129.8 1179.8

Table 2: Physical Parameters Evaluated for Zolmitriptan Buccal Films.

Weight
S. No Formulation Thickness (mm) Drug content (mg) Folding endurance (%) Dispersion test (sec)
of the film (mg)
1 ZP1 0.341 97.60 4.75 30 40
2 ZP2 0.324 97.89 4.85 32 60
3 ZP3 0.312 98.00 5.10 35 60
4 ZP4 0.333 98.28 5.15 58 67
5 ZP5 0.344 97.98 4.98 88 70
6 ZP6 0.323 102.8 4.80 92 51
7 ZP7 0.342 107.9 4.99 100 45
8 ZP8 0.344 112.9 4.95 100 47
9 ZP9 0.335 118.0 5.09 89 63

Table 3: Drug Release Profiles of Zolmitriptan Buccal Films

Time Cumulative % drug released

S. No
(mins) ZP1 ZP2 ZP3 ZP4 ZP5 ZP6 ZP7 ZP8 ZP9
1 0 0 0 0 0 0 0 0 0 0
2 0.5 64 39 30 32 36 46 56 58 30
3 1 80 60 57 48 44 78 88 86 51
4 1.5 84 68 63 56 52 80.2 90 89 62
5 2 90 72.8 68 63 64 82.3 95 92 68
6 2.5 92 77.8 73 68 70 84.5 98 94.8 73
7 3 85 80 78 72 76 86 99 97 78
8 3.5 96 84.6 85 78 78 89 99 98.2 82
9 4 97.2 88 87 82 82 92 99 98.6 86
10 4.5 98 90.6 90 86 84.5 94.6 99 98.9 88
11 5 99 95 92 89 86 97 99 99 91
12 T50 % 0.4 0.75 0.8 1.25 1.4 0.6 0.45 0.45 ----
13 T90% 2.1 4.5 4.5 5.0 --- 3.65 1.4 1.4 ----

Table 4. Evaluation of In vitro dissolution parameters of Zolmitriptan Buccal Films

First order constant k1 Hixon-crowell

S. No Formulations R2 R2
(min-1 ) Constant (mg/min)
1 ZP1 0.2882 0.9331 0.267 0.940
2 ZP2 0.2913 0.9462 0.235 0.943
3 ZP3 0.2653 0.9411 0.248 0.954
4 ZP4 0.2012 0.9555 0.169 0.960
5 ZP5 0.1557 0.9871 0.194 0.965
6 ZP6 0.1274 0.9956 0.183 0.956
7 ZP7 0.0593 0.9932 0.142 0.983
8 ZP8 0.0473 0.9965 0.155 0.945
9 ZP9 0.0346 0.9917 0.165 0.928

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100

80
% Drug released

60 ZP1
ZP2
ZP3
40 ZP4

20

0
0 1 2 3 4 5
Time(min)

Figure 1: Drug Release profiles of Zolmitriptan buccal films ZP1 to ZP4

100

80
% Drug released

60

ZP5
40
ZP6
ZP7
20 ZP8
ZP9
0
0 1 2 3 4 5
Time(min)

Figure 2: Drug Release profiles of Zolmitriptan buccal films ZP5 to ZP9

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Figure3: FT IR Spectra of Zolmitriptan pure drug

Figure 4: FT IR Spectra of ZP7 Zolmitriptan Buccal film.

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Figure 5: DSC of pure Zolmitriptan pure drug

Figure 6: DSC of ZP7 Zolmitriptan buccal film

CONCLUSION

Fast dissolving films prepared in the study exhibited good film characteristic features as indicated by thickness
measured, folding endurance, etc. The prepared films were found to be uniform, flexible and 99% of drug was
released from ZP7 film within 5 minutes which was desirable for fast absorption. Hence fast dissolving films of
Zolmitriptan were found to be suitable for eliciting better therapeutic effect in the treatment of migraine.

Acknowledgements
The authors express their gratitude to Life Line Formulations, Vijayawada for providing the gift samples. The
authors are thankful to the management of Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, Guntur for
providing the facilities to carry out the research work.

REFERENCES

[1] SP Vyas; RK Khar. Controlled oral administration. Controlled drug delivery concepts and advances, 1st ed,
Vallab Prakasham Publications, Delhi, 2002.
[2] H Goel; P Rai; V Rana; AK Tiwary. Recent patents on drug delivery and formulation. 2008, 2, 258 – 274.
[3] S Nehal; G Garima. Advances in Biological research. 2011, 5, 291-303.
[4] A Narasimha Rao; K Sindhu. International Journal of Pharmacy and Biological Sciences. 2011, 3, 145-159.
[5] A Arun; C Amrish. International Journal of Chem Tech Research. 2010, 2, 576-583.
[6] B Gavaskar; S Vijaya Kumar; G Sharan; Y Madhusudan. International Journal of Pharmacy and
Pharmaceutical Sciences. 2011, 2(3), 29 -33.

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[7] VK Subash; G Basani; G Sharan; YMadhusudan Rao. International journal of Pharmacy and Pharmaceutical
sciences. 2010, 2, 29-33.
[8] RP Dixit; SP Puthli. Journal of Control Release. 2009, 139, 94 – 107.
[9] SD Barnhart; MS Sloboda. Drug Delivery Technology. 2007, 7 (8): 34 – 37.
[10] G Vijaykumar; P Ajaykumar; P Satishkumar; S Karunasri; K Raghavender; P Priya. World Journal of Medical
Pharmaceutical and Biological Sciences. 2011, 1(1): 06-12.
[11] D Prasanna; S Manoranjan. International Research Journal of Pharmacy. 2012, 5, 373 – 376.
[12] E Seaber. British Journal of Clinical Pharmacology. 1997, 43: 579–87.
[13] KD Tripathi. Essentials of Medical Pharmacology, 6th edition, New Delhi; Jaypee brothers Medical
publishers.2005, 531.

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