FORMULATION AND EVALUATION OF ORAL DISPERSIBLE TABLETS … · 2019-07-17 · FORMULATION AND...

RESEARCH ARTICLE Jalendhar Nakka et.al / IJIPSR / 1 (2), 2013, 308- 321

Department of Pharmaceutics ISSN (online) 2347-2154

Available online: www.ijipsr.com October Issue 308

FORMULATION AND EVALUATION OF ORAL DISPERSIBLE

TABLETS OF ZOLMITRIPTAN

1Jalendhar Nakka

*,

2M.Srujan Kumar,

3Dr.K.V.Subrahmanyam

1M.Pharmacy Scholar, Samskruti College of Pharmacy, Hyderabad, India.

2Faculty, Samskruti College of Pharmacy, Hyderabad, India.

3Principal, Samskruti College of Pharmacy, Hyderabad, India.

Corresponding Author:

Jalendhar Nakka

Samskruti college of Pharmacy

Department of Pharmaceutics

Email: [email protected]

Contact: +91-949278078

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

Abstract

Objective of this study was to formulate orally disintegrating tablets of Zolmitriptan with sufficient mechanical

integrity, content uniformity, and acceptable palatability to assist patients of any age group for easy

administration by Melt granulation method and direct compression method. Effect of varying concentrations of

different superdisintegrants such as crospovidone, Precirol and Sorbitol on disintegration time was studied.

Tablets were evaluated for weight variation, thickness, hardness, friability, drug content, in vitro disintegrating

time and in vitro drug release. Other parameters such as drug-excipient compatibility were also evaluated. The

disintegration time of the optimized batch was <25 sec.. Release of drug was faster from formulations

containing Precirol and crospovidone (F9) compared to the marketed convetional zolmitriptan tablet. FTIR

studies did not indicate any excipient incompatibility, either during mixing or after compression. F9

formulation is showing better dissolution results at 30th minutes so that it was concluded that direct compression

method was showing more solubility then melt granulation method, when compared to marketed product at 30th

minute percentage of drug release is more.

Key words:, Melt Compression, Precirol, Crospovidone, Disintegration, FTIR.




INTRODUCTION

Tablets dosage forms [1] which rapidly disintegrate in the mouth and can be taken without water

have become extremely popular in recent years. These products offer the convenience of a tablet

with the ease of swallowing a liquid. These dosage forms are of particular advantage in certain

patients group such as children, elderly and psychiatric patients. Certain medical conditions such

as pain, migraine, nausea, panic attack, allergic conditions, cough or cold, and Alzheimer’s may

benefit from these dosage forms. Despite of tremendous innovations in drug delivery, the oral

route remains the preferred route for administration of therapeutic agents because of accurate

dosage, low cost therapy, self medication, non invasive method and ease of administration

leading to high level of patient compliance. However, traditional tablets and capsules

administered with a glass of water may be inconvenient or impractical for some geriatric patients

because of changes in various physiological and neurological conditions associated with aging

including difficulty in swallowing/dysphasia, hand tremors, deterioration in their eyesight,

hearing, memory, risk of choking in addition to change in taste and smell. For these reasons, it is

said that age is a convenient ‘red flag’ [2] that pharmacists can use to alert themselves for

patients who may have special counseling needs [1].

Solid dosage forms also present significant administration challenges in other patient

groups, such as children, mentally challenged, bed ridden and uncooperative patients. Pediatric

patients may suffer from ingestion problems as a result of underdeveloped muscular and nervous

control. Moreover, patients traveling with little or no access to water, limit utility of orally

administered conventional tablets or capsules. Therefore, to cater the needs of such patients,

recent advancements in technology have resulted in development of viable dosage alternatives

popularly known as orally disintegrating tablets (ODTs).

These dosage forms are preferable alternative for oral medication in improving the

quality of life and patient acceptability. ODTs are also known as oro dispersible tablets, mouth

dissolving tablets, rapimelts, melt-in-mouth tablets, fast disintegrating tablets and rapid

dissolving tablets. ODTs are the solid unit dosage forms/entities containing medicinal substances

which disintegrate or dissolve rapidly in oral cavity usually within a few seconds even without

the need of water or chewing. As the tablet disintegrates in mouth, this can enhance the clinical

effect of drug through pregastric absorption from the mouth, pharynx and esophagus. In such




cases, bioavailability of drug is significantly enhanced by avoiding first pass hepatic metabolism

than those observed with conventional tablets

Superdisintegrants [3, 4]

Disintegrants are substances routinely included in tablet formulations and in some hard

shell capsule formulations to promote moisture penetration and dispersion of the matrix of

dosageform in dissolution fluids. An oral solid dosage form should ideally disperse into the

primary particles from which it was prepared. Super disintegrants are generally used at a low

concentration, typically 1-10% by weight relative to total weight of dosage unit. Generally

employed super disintegrants are croscarmellose sodium (Ac-Di-Sol), crospovidone (CP),

sodiumstarchglycolate (SSG) etc. which represent example of crosslinked cellulose, crosslinked

polymer and crosslinked starch respectively.Selection of appropriate formulation excipients and

manufacturing technology is necessary for obtaining the optimized design features of orally

disintegrating dosage forms. Ideally, superdisintegrants should cause the tablet to disrupt, not

only into the granules from which it was compressed but also into powder particles from which

the granules were prepared.

Zolmitriptan binds with high affinity to human recombinant 5-HT1D and 5-HT1B

receptors. Zolmitriptan exhibits modest affinity for 5-HT1A receptors, but has no significant

affinity (as measured by radioligand binding assays) or pharmacological activity at 5-HT2, 5-

HT3, 5-HT4, alpha1-, alpha2-, or beta1- adrenergic; H1, H2, histaminic; muscarinic; dopamine1,

or dopamine2 receptors. The N-desmethyl metabolite also has high affinity for 5-HT1B/1D and

modest affinity for 5-HT1A receptors.

ZOMIG is indicated for the acute treatment of migraine with or without aura in adults

.ZOMIG should only be used where a clear diagnosis of migraine has been established. ZOMIG

is not intended for the prophylactic therapy of migraine or for use in the management of

hemiplegic or basilar migraine Safety and effectiveness of ZOMIG have not been established for

cluster headache, which is present in an older, predominantly male population.The medical and

pharmaceutical communities are seeing increasing opportunities and benefits from the ability to

deliver immediate release dosage forms. To formulate and evaluate zolmitriptan orally

disintegrating Tablets (100mg).




MATERIALS AND METHOD

Zolmitriptan, Sorbitol, PEG6000, Precirol, Aerosil, Mannitol, Crosspovidone,

Pippermint, Magnesium Stearate, Ace sulfate were obtained from Pharma Train Research Lab

Ltd.

1. Preformulation Study [5]:

A. Colour, odor, taste and appearance:

The drug sample was evaluated for its colour and odor. The results are shown in Table.

B. Melting point determination:

Melting point of the drug sample was determined by capillary method by using melting point

apparatus.

C. Determination of solubility

The solubility of the Zolmitriptan was determined by adding excess amount of drug in the

solvent and equilibrium solubility was determined by taking supernatant and analyzing it on

Perkin Elmer Lambda35, double beam spectrophotometer.

D. Fourier Transform Infrared Spectroscopy (FTIR) Interpretation:

The infrared spectra of pure Ritonavir samples were recorded by SHIMADZU 84005

FTIR spectrometer, equipped with an Inferometer detector. Samples were prepared by KBr disc

method (2 mg sample in 100 mg KBr) and examined in the transmission mode. Each spectrum

was measured over a frequency range of 4000–400 cm−1.The software used for the data analysis

was Perkin-Elmer Spectrum 3.02. The peaks obtained in the spectra were then compared with

corresponding functional groups in the structures of Ritonavir.

E. Ultraviolet Visible (UV-visible) spectroscopy:

Construction of Calibration Curve:

Standard Stock solution:

Accurately weighed 100 mg of Zolmitriptan was dissolved in 100 ml of different buffers

(1.2pH 0.1N HCl). The resultant solutions were having concentration of 1000 µg/ml (1.1

mg/ml). 10 ml of this solution was further diluted up to 100.0 ml with buffer and to give a

solution of Concentrations 100 µg/ml. This resultant solution is used as working stock solution

for further study. Further dilutions were prepared from the same solution.




Preparation of calibration curve for Zolmitriptan [6]:

Appropriate aliquots were pipetted out from the standard stock solution in to a series of

10 ml volumetric flasks. The volume was made up to the mark with buffer to get a set of

solutions having the concentration range of 2,3,4,5, and 6 µg/ml for Zolmitriptan. Absorbances

of the above solutions were measured at 225 nm and a calibration curve of absorbance against

concentration was plotted and the drug follows the Beer’s & Lambert’s law in the concentration

range of 2-6 µg/ml. The regression equation and correlation coefficient was determined.

2. Formulation development [7, 8]

Procedures:

The Purpose of key ingredients included in the formulation.

Table1: Composition of Zomitriptan Oral Dispersibe Tablets Melt Granulation

S.NO. Ingredients F1(mg)

(mg)

F2(mg)

(mg)

F3(mg)

(mg)

F4(mg)

(mg)

F5(mg)

(mg) 1 Zolmitriptan 10 10 10 10 10

2 Sorbitol 20 10 7.5 15 15

3 Peg6000 3 1.5 1.125 2.25 2.25

4 Precirol 0 0 0 0 0

5 Aerosil 1 1 1 1 1

6 Mannitol 56.25 67.75 70.625 62 59.25

7 Crosspovidone 7.5 7.5 7.5 7.5 10

8 Pippermint 0.25 0.25 0.25 0.25 0.25

9 Magnesium stearate 0.5 0.5 0.5 0.5 0.5

10 Ace sulfate pt 1.5 1.5 1.5 1.5 1.5

Table2: Composition of Zomitriptan Oral Dispersibe Tablets Direct Compression

SNO Direct

compression

F6(mg) F7(mg) F8(mg) F9(mg) F10(mg)

1 Zolmitriptan 10 10 10 10 10

2 Precirol 5 7.5 10 15 7.5

3 Aerosil 1 1 1 1 1

4 Mannitol 74.25 71.75 69.25 64.25 69.25

5 Crosspovidone 7.5 7.5 7.5 7.5 10

6 Ace sulfate pt 1.5 1.5 1.5 1.5 1.5

7 Pippermint 0.25 0.25 0.25 0.25 0.25

8 Magnesium

stearate

0.5 0.5 0.5 0.5 0.5




Steps in Formulation:

Preparation of Meltgranulation:

1. Melt granulation [8]

Melt granulation technique is a process by which pharmaceutical powders are efficiently

agglomerated by a melt able binder. The advantage of this technique compared to a conventional

granulation is that no water or organic solvents is needed. For accomplishing this process, high

shear mixers are utilized, where the product temperature is raised above the melting point of

binder by a heating jacket or by the heat of friction generated by impellerblades. This approach

to prepare FDT with sufficient mechanical integrity, involves the use of a hydrophilic waxy

binder (Superpolystate©, PEG-6-stearate). Superpolystate© is a waxy material with a melting

point of 33–37°C and a HLB value of 9. So it will not only act as a binder and increase the

physical resistance of tablets but will also help the disintegration of the tablets as it melts in the

mouth and solublises rapidly leaving no residues.

2. Preparation of Direct compression:

1. Drug and polymer pass through 40 # mesh separately and then transfer it to poly bag and

mix it for 3 minutes.

2. Add other excipients to the above mixture. Finally add the Glidant (Magnesium Stearate)

to the above blend mix it for 2min.

3. Compressed the above lubricated blend by using 7mm round punches.

Pre-Compression Parameters:

Pre-compression parameters like bulk density, Tapped density, Angle of repose,

compressibility Index, Hausner’s ratio were evaluated for the Formulation powder.

Post Compression Parameters:

Post compression parameters like physical appearance, shape, weight variation, content

uniformity, hardness, friability, In vitro Drug Release studies and Drug release kinetics for the

optimized formulation were evaluated.




RESULTS AND DISCUSSION

1. Preformulation:

Table 3: Preformulation studies of Pure Drug

Table 4: List of Micromeritic properties of directly compressible powder:

Parameter F1 F2 F3 F4 F5 F6 F7 F8 F9

Angle of repose 27055’ 29

o39’

23.31±

0.1 28

081’ 28

065’ 26

074’ 28

o39’ 21

081’ 24

081’

Bulk

density 0.63 0.55 0.51 0.47 0.60 0.57 0.46 0.42 0.61

Tapped density 0.66 0.63 0.54 0.52 0.64 0.63 0.51 0.53 0.69

%

Compressibility 4.76 14.54 5.88 10.63 6.66 10.52 10.86 26.19 13.11

Hausner’s ratio 1.047 1.14 1.05 1.10 1.06 1.10 1.10 1.15 1.13

2. Calibration of Standard Graph of Zolmitriptan:

Standard graph of Zolmitriptan in 0.1N HCl (1.2 pH buffer):

The construction of standard calibration curve of Zolmitriptan was done by using 0.1N

HCl as the medium. Zolmitriptan was found to have the maximum absorbance at 225 nm. The

S.no API Characterisation Results

1 Physical appearance Zolmitriptan is a pale yellow powder

2 Melting point 139 °c

3 Solubility It is freely soluble in methanol and

sparingly soluble in water 4 Bulk density 0.34 gm/ml

5 Tapped density 0.546 gm/ml

6 Carr’s index/compressibility index 15.05

7 Hausner’s ratio 1.57




standard graph of Zolmitriptan in 0.1N HCl was constructed by making the concentrations of

2µg/ml, 3µg/ml, 4 µg/ml, 5 µg/ml and 6 µg/ml solutions. The absorbance of solutions was

examined under UV- spectrophotometer at an absorption maximum of 225 nm. The standard

graph of Zolmitriptan was constructed by taking the absorbance on Y-axis and concentrations on

X-axis

Table 5: Standard Graph of Zolmitriptan

S. No. CONCENTRATION(µg/ml) ABSORBANCE

1 0 0

2 2 0.221

3 3 0.321

4 4 0.415

5 5 0.535

6 6 0.624

Fig 1: Calibration curve Of Zolmitriptan in 0.1N HCl (1.2 pH buffer)




Fourier Transformation Infrared (FTIR) analysis:

Infra-red spectroscopy analysis was performed by Fourier Transformation Infrared

Spectrophotometer Alpha Brooker FTIR (Tokyo, Japan).The instrument was calibrated by using

polystyrene film.

Table 6: IR Interpretation of drug, other excipients and physical mixture of drug-Sorbitol:

S.NO INTERPRETATION PURE DRUG

(-CM)

DRUG+SORBITOL

(-CM)

1 C-O 1258.27 1082.45

2 C=O 1736.29 1735.96

3 N-H 1290.09 3406.52

4 C-C 3410.19 1259.00

Fig 2: Spectra of Zolmitriptan Fig 3: Spectra of Zolmitriptan and Sorbitol

Fig 4: Spectra of Zolmitriptan & PEG6000 Fig 5: Spectra of Zolmitriptan & Precirol




Fig 6: Spectra of Zolmitriptan & Aerosil Fig 7: Spectra of Zolmitriptan & Mannitol

Fig 8: Spectra of Zolmitriptan & Ace Sulfate Fig 9: Spectra of Zolmitriptan &Peppermint

Fig 10: FTIR Spectra for pure drug and all the Excipients




Evaluation of the Prepared Tablets for Physical Parameters:

All formulations were tested for Physical parameters like Hardness, thickness, Weight

Variation, Friability and found to be within the Pharmacopoeial limits. The results of the tests

were tabulated. The drug content of all the formulations was determined and was found to be

within the permissible limit. This study indicated that all the prepared formulations were good.

Table 7: Results for Evaluation parameters of all formulations:

parameter F1 F2 F3 F4 F5 F6 F7 F8 F9

F10

Weight

variation 97 99 97 98 98 101 100 99 101

101

Thickness

(mm) 15 15.7 23 26.5 29 34 32 41 41 42

Hardness

(kg/cm2)

2.4 2.3 2.5 2.3 2.4 2.5 2.3 2.6 2.5 2.5

Friability

(%W/W) 0.3 0.35 0.4 0.3 0.4 0.5 0.6 0.8 0.9 0.9

Content

uniformity

(%)

98 98.4 98.6 98.8% 99 99.17 99 99.88 99.68 100

In vitro Dissolution studies:

The dissolution conditions used for studying the drug release from tablet of zolmitriptan are:

Apparatus : USP apparatus II (Paddle)

Agitation speed (rpm) : 50rpm

Medium : 0.1N HCl.

Volume : 900 ml

Temperature : 37.0 ± 0.5 0C

Time : 5, 10,15,20,30 and 45 min.

Wavelength : 225 nm




The samples were withdrawn at predetermined time points, and were analyzed

spectrophotometrically at 225 nm.

Table 8: Results of Dissolution profile for F1-F10:

Time

(min) F1 F2 F3 F4 F5 F-6 F-7 F-8 F-9 F10

0 0 0 0 0 0 0 0 0 0 0

5 41 55 40 46 50 51 41 38 55 60

10 50 70 51 62 65 65 61 55 71 74

15 65 85 69 80 82 85 76 75 88 89

20 81 94 87 91 91 92 85 85 95 95

30 95 94 95 94 94 96 94 91 96 95

45 95 95 96 96 96 96 96 92 98 97

Fig 11: Dissolution Profile Comparison of Fig 12: Dissolution Profile Comparison of

Formulations F1-F4 Formulations F1-F4

Fig 13: Dissolution Profile Comparison of F9 & F10




Table 9: Results of Dissolution Profile for Marketed Formulation

Fig 14: Comparision of Marketed Vs Optimised Formulation

KINETIC MODELS:

Dissolution data of above methods was fitted in Zero order.

Table 10: Regression Coefficient of Optimised and Marketed Formulations

Formulation Code

Optimised Formulation Marketed Formulation

Regression Coefficient

(R2)Zero Order

0.582 0.552

Fig 15: Release Kinetics of Optimized Formulations

TIME(min) % OF DRUG RELEASE

5 77

10 89

15 95

20 96

30 97




CONCLUSION

In Vitro Disintegration Time Considering wetting time, ‘R’ value, in vitro DT,

%friability and cumulative % drug released, formulations containing F9 (Precirol and

Crospovidone) was considered to be better than those containing Sorbotol and SSG. F9

was considered as the optimal orally disintegrating tablet formulation among all.

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