FORMULATION AND EVALUATION OFDIMENHYDRINATE MOUTH DISSOLVING TABLETS

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www.wjpr.net Vol 4, Issue 09, 2015.

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FORMULATION AND EVALUATION OFDIMENHYDRINATE

MOUTH DISSOLVING TABLETS

Senthil Kumar Krishnan*, Rakesh Rauniyar, Mohmmed GulzarAhmed

Department of Pharmaceutics, SAC College of Pharmacy, B.G Nagara-571448 India.

ABSTRACT

Dimenhydrinate is a salt of Diphenhydramine and

8-chlorotheophylline. Diphenhydramine is an Antihistaminic drug that is

antagonistic at the H1receptor in order to prevent and treat nausea and

motion sickness. 8-chlorotheophylline is added to counteract

drowsiness triggered by diphenhydramine. Dimenhydrinate mouth

dissolving tablets were prepared by direct compression technique by

using mannitol as a diluent, crospovidoneand sodium starch glycolate

as a superdisintegrants, Aspartame as a sweetening agent which is

suitable for diabetic patients. Drug compatibility with excipients was

checked by FTIR studies. After examining the flow properties of the

powder blends, the results are found to bewithin prescribed limits and indicated good flow

property, it was subjected to tablet compression. All the formulations were subjected to post

compression parameters such ashardness and friability (≤1%), indicated that tablets had a

good mechanical strength and resistance.Percentage cumulative drug release was found to be

in the range of 87.08 to 94.35 %. The wetting time was found to be in the range of 15.9±0.62

to 32.4±0.47 seconds. Among all the designed formulations, formulation MDF2 was found to

be promising and displayed an in-vitro disintegration time, in-vitro dispersion time of

10.57±0.93 and 25.87±1.29 seconds respectively, which facilitates its faster disintegration

and dispersion in the mouth.Depend upon percentage cumulative drug release, in-vitro

disintegration time, in-vitro dispersion time, wetting time results, oneformulationMDF2 were

selected for stability studies and subjected at 400C/75%RH for 2 months. Formulations

MDF2 found tobe stable after performing physical and chemical parameters at suitable

intervals.

KEYWORD: Mouth dissolving tablets, Dimenhydrinate, Crospovidone, Sodium Starch Glycolate, Direct compression.

Volume 4, Issue 9, 1123-1134. Research Article ISSN 2277– 7105

Article Received on 30 June 2015,

Revised on 24 July 2015, Accepted on 18 Aug 2015

*Correspondence for

Author

Senthil Kumar Krishnan

Department of

Pharmaceutics, SAC

College of Pharmacy, B.G

Nagara-571448 India.

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1124 INTRODUCTION

The most popular solid dosage forms are being tablets and capsules. Drinking water plays an

important role in the swallowing of oral dosage forms. Difficulty in swallowing tablet is a

common problem of all age groups, especially elderly and Paediatrics, because of physiologic

changes associated with these groups of patients. Many patients feel difficulty in swallowing

conventional tablets when water is not available, in the case of the motion sickness

(kinetosis) and sudden episodes of coughing during the common cold, allergic condition and

bronchitis. To overcome these drawbacks, MDT has emerged as alternative oral dosage

forms. These are novel type of tablets disintegrate in saliva within few seconds of time. The

bioavailability of some drugs in oral cavity may be increased due to absorption of drugs.[1,2]

United States Food and Drug Administration (USFDA) mention fast dissolving tablet (FDT)

as a solid dosage form containing medicinal substance or active ingredient which disintegrate

rapidly usually within a matter of seconds when placed upon the Tongue. Fast dissolving

tablets are also known as mouth dissolving tablets, melt-in mouth tablets, Orodispersible

tablets, rapid melts, porous tablets, quick dissolving tablet. Fast dissolving tablets dissolve or

disintegrate in the oral cavity without the need of water.[3]

Mouth dissolving tablets are easy to administer, pregastric absorption, convenient for

administration to traveling patients, quick dissolution and rapid absorption, convenience of

administration and accurate dosing compared to liquids.[4] and demerits are insufficient

mechanical strength. Hence; careful handling is required,[5] requires special packaging for

proper storage and safety of product and it possesses mouth feeling.[6]

MDT’s are prepared by various techniques, mainly direct compression, lyophilization and

moulding. The simplicity and cost effectiveness of the direct compression process have

positioned this technique as an attractive alternate to traditional granulation technologies.[7]

Usually superdisintegrants are added to a drug formulation to facilitate the break-up or

disintegration of tablet into smaller particles that can dissolve more rapidly than in absence of

disintegrants.[8]

Dimenhydrinate is a salt of Diphenhydramine and Chlorotheophyllinate which shows the

Antiemetic and Antivertigo action. Dimenhydrinate produces Antiemetic action by its central

action on Chemoreceptor Trigger Zone (CTZ). It decreases the sensitivity of Labyrinth

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1125 Dimenhydrinate is a potent H1 receptor antihistaminic agent. It has anticholinergic and central

sedative action also. it is used in migraine due to its sedative as well as antiemetic actions.[9]

MATERIALS AND METHODS MATERIALS

Dimenhydrinate (Gift from S.S Pharma, Mumbai, India), Crospovidone, Sodium Starch

Glycolate, Mannitol, Microcrystalline cellulose, Magnesium stearate, Talc, Aspartame and

Menthol From S.D Fine Chemicals, Mumbai, India.

METHODS Solubility studies

The solubility of Dimenhydrinate was checked in different solvents such as water, alcohol,

chloroform, buffer, ether, benzene.

Compatibility study FTIR

Weighed amount of drug (3 mg) was mixed with 100mg of potassium bromide (dried at

40-50oC). The mixture was taken and compressed under 10 ton pressures in a hydraulic press to

form a transparent pellet. The pellet was scanned by IR spectrophotometer. Similar procedure

is followed for all relevant excipients used.[10]

Pre-formulation parameter studies Angle of repose

Angle of repose is an indication of the frictional forces excited between granule particles. It is

the maximum angle possible between the surface of the pile of granules and the horizontal

plane11:

Tan θ = h/r

Where, θ = the angle of repose,h = height of the heap of the powder, r = radius of the heap of

the powder.

Determination of Bulk Density and Tapped Density

20 g of the mixed blend was introduced into a 100 ml measuring cylinder, and the Initial

volume was observed. The cylinder was allowed to fall under its own weight onto a hard

surface from the height of 2.5 cm at 2 sec intervals. The tapping was continued until no

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1126 The bulk density, and tapped density were calculated using the following formulae.

Where, W = weight of the granules, VO = initial volume of the granules, VF = final volume

of the granules.

Hausner’s ratio

Flow properties of granules were determined by hausner’s ratio calculated by following

formula.[12]

Compressibility index (Carr’s Index)

Compressibility index is an important measure that can be obtained from the bulk and tapped

densities. In theory, the less compressible a material the more flowable it is. A material

having values of less than 20% has good flow property.[13]

CI = (Tapped Density – Bulk Density) × 100

Tapped Density

Preparation of mouth dissolving tablets by direct compression technique

Dimenhydrinate mouth dissolving tablets were prepared by direct compression method by

using superdisintegrants such as Crospovidone, Sodium Starch Glycolate. Mannitol,

Microcrystalline Cellulose used as a diluent, Aspartame used as a sweetening agent, Mint

used as a flavour, Magnesium Stearate, Talc used as a lubricant and glidant, and starch is

used as a binder, diluent, and disintegrant.All the ingredients (except granular directly

compressible excipients) were passed through # 60-mesh separately. Then, the ingredients

were weighed and mixed in geometrical order after sufficient mixing of drug as well as other

components and compressed into tablets of 150 mg using 4mm round flat punches on 12

station rotary tablet machine. The formulations are shown in table no.1. Bulk density = W / VO

Tapped density = W / VF

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1127 Evaluation of MDT’s tablets (post-compression parameters)

Weight variation

Randomly, twenty tablets were selected after compression and the mean weight was

determined. None of the tablets deviate from the average weight by more

than±10.5%(USPXX).[14]

Tablet Hardness

Hardness of the tablets was measured by using hardness testers such as Monsanto hardness

tester, Pfizer hardness tester. The pressure required to break the tablets is measured as a

function of hardness (kg/cm2). The values obtained must meet the standard value.[15]

Friability

20 tablets were weighed and the initial weight of these tablets was recorded and placed in

Roche friabilator and rotated at the speed of 25 rpm for 100 revolutions. Then tablets were

removed from the friabilator dusted off the fines and again weighed and the weight was

recorded.[11]

Percentage friability was calculated by using the formula:

%Friability = Initial weight of tablets-final weight of tablets X100

Initial weight of tablets

Tablet thickness

Thickness of the tablet is important for uniformity of tablet size. Thickness was measured

using Vernier Calipers. It was determined by checking the thickness of ten tablets of each

formulation.[11]

Drug content

Twenty tablets were weighed and powdered. An amount of powder equivalent to 150 mg of

Dimenhydrinate was dissolved in 100ml of pH 7.4 phosphate buffer, filtered, diluted suitably

and analysed for drug content at 278 nm using UV-Visible spectrophotometer.[14]

In-vitro dispersion time

In-vitro dispersion time was measured by dropping a tablet in a Petridish containing 10 ml of

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1128 Disintegration time

The test was carried out on 6 tablets using the apparatus specified in I.P.-1996 saliva fluid

(Ph6.8) at 37ºC ± 2ºC was used as a disintegration media and the time in second taken for

complete disintegration of the tablet with no palatable mass remaining in the apparatus was

measured in seconds.[6]

Wetting time

A piece of tissue paper (12cmx10.75cm) folded twice was placed in a petri dish (internal

diameter=9cm) containing 9 ml of buffer solution simulating saliva pH 6.8. A tablet was

placed on the paper and the time taken for complete wetting was noted. Three tabletsfrom

each formulation were randomly selected and the average wetting time was noted.[16]

In-vitro dissolution studies

Dissolution testing of Dimenhydrinate dissolving tablets was carried out with paddle type in

USP dissolution apparatus at rpm 50 and temperature 37±0.5°C in 6.8 phosphate buffers. At

each specified intervals of time 5 ml sample was withdrawn and replaced by fresh media. The

samples were analytically tested to determine the concentration by UV spectroscopy method

at wavelength of 278nm.[17]

RESULTS AND DISCUSSION Solubility studies

Dimenhydrinate is soluble in ethanol, methanol and phosphate buffer 6.8 solution. But it was

found to be partially insoluble in water, different basic phosphate buffers of pH 6.8.

[image:6.595.71.530.589.758.2]

TABLES AND FIGURES

Table no.1: Formulation development of Dimenhydrinate MDT’s by direct compression technique

Code MDF1 MDF2 MDF3 MDF4

Dimenhydrinate 50 50 50 50

Mannitol 83 80 73 73

Crospovidone 2.5 3 5 -

Sodium starch glycolate 2.5 6 - 5

Starch 5 4 15 15

Aspartame 2 2 2 2

Magnesium stearate 3 3 3 3

Talc 2 2 2 2

Flavour(Menthol) QS QS QS QS

Total 150 150 150 150

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[image:7.595.66.530.90.181.2]

1129 Table no.2 Pre-Compression Parameter results

Code MDF1 MDF2 MDF3 MDF4

Bulk density (g/cm3) 0.537±0.004 0.521±0.006 0.523±0.002 0.503±0.002

Tapped density (g/cm3) 0.568±0.005 0.602±0.003 0.603±0.0031 0.598±0.008

Carr’s index(%) 10.718±0.190 14.840±0.334 14.013±0.422 15.678±0.397

Hausner’s ratio 1.275±0.206 1.300±0.226 1.154±0.025 1.176±0.029

Angle of repose(°) 26.77±0.221 27.38±0.340 24.84±0.151 24.887±3.205

Table no. 3 Post - Compression parameter results.

CODE MDF1 MDF2 MDF3 MDF4

Weight variation

(mg) 150.48±2.70 149.21±2.69

150.6±1.40

150.44±2.10

Hardness

(kg/cm2) 3.27±0.06 3.0±0.10 2.83±0.11 3.37±0.15

Friability

(%) 0.66±0.01 0.54±0.025 0.67±0.015 0.89±0.02

Thickness

(mm) 3.27±0.05 3.3±0.10 3.23±0.1 3.43±0.06

Wetting time

(sec) 21.17±0.65 15.9±0.62 27.87±0.35 32.4±0.47

Drug content

(%) 99.83±0.06 98.23±0.06 98.67±0.15 100.33±0.15

Disintegration time

(sec) 14.9±0.26 10.57±0.93 23.87±0.97 27.87±0.23

In-vitro dispersion

time(sec) 26.07±1.62 25.87±1.29 33.4±2.1 35.27±1.00

%CDR 93.06 94.35 87.08 88.25

Table no.4 Stability studies Time (Days)

MDF2 MDF2

HARDNESS

(Kg/cm2) %CDR

15 3.0 93.95

30 2.9 93.33

45 2.82 92.44

[image:7.595.66.541.210.471.2]

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[image:8.595.79.508.74.311.2] [image:8.595.71.529.189.585.2]

1130 Fig 1: FT-IR spectrum of pure drug (Dimenhydrinate).

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[image:9.595.79.546.61.797.2]

1131 Figure 3: FT-IR spectrum of drug + Sodium Starch Glycolate.

Figure 4: FT-IR spectrum of drug + Mannitol.

[image:9.595.86.549.66.277.2]

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1132 Figure6: Comparative drug release profilebetween MDF2 and MDF4MDT’s formulations.

DISCUSSIONS

FTIR studies revealed that there was no physico-chemical interaction between

Dimenhydrinate and other excipients results were displayed from figure no. 1 to 4. For each

designed formulation, blends of drug and excipients were prepared and evaluate for

Micromeritic properties shown in table 2.Bulk density was found to be in the range

of0.503±0.002to0.537±0.004 g/cm3, tapped density was found between 0.568±0.005 to

0.603±0.0031, Carr’s index was found between 10.82 to 15.92%,Hausner’s ratio found below

1.189 and angle of repose is found in the range of 24.84±0.151 to 27.38±0.340. This indicates

the good flow properties of powders. Four formulation of mouth dissolving tablets were

prepared by direct compression technique using superdisintegrants such as Crospovidone,

sodium starch glycolate in different ratios, Starch as a binder and Aspartame as a sweeting

agent. All the formulation was evaluated for various physical parameters shown in table 3.The

weight variation of all formulation was within the ranges of 149.21±2.69 to 150.60±1.40, the

hardness of all MDT’s was in the ranges of 2.83±0.11 to 3.37±0.15, the friability of all formulation were below 1% indicates within the standard limit, Thickness of all MDT’s

formulation below 3.43, drug content was found to be in the ranges of 98.23 to 100.3, in-vitro

dispersion time was found between 25.87±1.29 to 35.27±1.00, The lowest in-vitro Dispersion

time for formulation F2 was 25.87 seconds and highest Dispersion time was found to be

formulation F4 was 35.27 seconds, The average in-vitro disintegration time for all the

formulations were in the range of was 10.57±0.93 to 27.87±0.23 seconds. The lowest in-vitro

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1133 was found to be formulation MDF4 was 27.87 seconds. So the amount of water uptake and

swelling will be more for this formulation F6 and this increased disintegration. The average

wetting time for all the formulations was in the range of 15.9±0.62 to 32.4±0.47 seconds. The

maximum wetting time of 32.4 seconds and minimum wetting time of 15.9 seconds were

shown by MDF4 and MDF2 respectively. The average percentage of drug release for MDT’S

formulation was found in the range of 87.08 to 94.35 % which is shown in table 3 and

comparative drug release profile of MDT’s formulation showed in fig 5 and 6. Out of all four

formulations, MDF2 is found to be best formulation. There was no change in color and shape.

There were no significant changes in hardness and %CDR. Two months of stability studies

revealed that there was no any significant degradation of the drug. The results found to be

satisfactory showed in table no.4.

CONCLUSION

Mouth dissolving tablets of Dimenhydrinate were prepared by using superdisintegrants such

as Crospovidone and Sodium Starch Glycolate by direct compression technique. A total of

four formulations were prepared which was confirmed by various characterization and

evaluation studies.All the formulations get disintegrated within a time period of 27.87

seconds when tested for in-vitro disintegration time, The MDF2 formulation containing

Crospovidone and Sodium Starch Glycolate in 1:2 ratios was found to have the higher

percentage of drug release compared with other formulations and The MDF3 formulation

containing Crospovidone and 10% Starchwas found to have the lesser percentage of drug

release compared with other formulations.

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