formulation and evaluation of taste masked …

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Bhalekar et al. World Journal of Pharmacy and Pharmaceutical Sciences

FORMULATION AND EVALUATION OF TASTE MASKED

SUSPENSION OF OSELTAMIVIR PHOSPHATE

Mangesh R. Bhalekar*, Ashwini R. Madgulkar, Rahul R. Padalkar, Ashwini H. Sathe

Department of Pharmaceutics, AISSMS College of Pharmacy, Kennedy Road, Near R.T.O,

Pune -411001, India.

ABSTRACT

The present work was aimed to mask the bitter taste of oseltamivir

phosphate using ion exchange. Oseltamivir phosphate is an antiviral

drug used in the treatment and prophylaxis of both influenza A and

influenza. The drug resin complex was prepared by batch method and

Indion 234 was selected for ion exchange complex formation. The

drug loading process was carried out using various cationic resins and

it was optimized using different drug: resin ratio and pH. Resinates

were characterized by infrared spectroscopy and thermal analysis.

Indion gave the best loading efficiency at drug resin ratio of 1:1; pH

had no effect on drug loading. Taste evaluation was carried out by

panel method found resinate as tasteless and agreeable. The drug

release from resinates in 0.1N HCL was found to be 96% within 45

min. Taste masked suspension of resinate was formulated and

evaluated for taste, drug content, viscosity, sedimentation volume, drug release. The efficient

taste masking was obtained from drug–resin complex which was formulated as oral

suspension in order to increase better patient compliance.

KEY WORDS: Oseltamivir phosphate, Indion 234, Taste masking.

1. INTRODUCTION

A wide variety of active pharmaceutical agents shows the undesirable characteristic of bitter

taste after oral administration, there for palatability was most important factor designing

dosage form to children and infants. Various techniques have been identified for masking

bitter taste which includes use of ion exchange resin, inclusion complex formation with β-

cyclodextrin, polymer coating, spray drying method, etc. The use of sweeteners and flavoring

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 5.210

Volume 4, Issue 10, 382-393. Review Article ISSN 2278 – 4357

Article Received on

05 Aug 2015,

Revised on 30 Aug 2015,

Accepted on 20 Sep 2015

*Correspondence for

Author

Dr. Mangesh R.

Bhalekar

Department of

Pharmaceutics, AISSMS

College of Pharmacy,

Kennedy Road, Near

R.T.O, Pune -411001,

India.


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agents shows inadequate in masking the taste of highly bitter drugs which was conventional

taste masking techniques. Oseltamivir phosphate is an antiviral drug, it was a neuraminidase

inhibitor used in the treatment and prophylaxis of the both influenza A and influenza B.

Oseltamivir is a prodrug (usually administered as phosphate), it was hydrolysed hepatically to

the active metabolite, the free carboxylate of Oseltamivir acts as a transition –state analogue

inhibitor of influenza neuraminidase. Ion exchange resins are water insoluble, cross-linked

polymer-carrying, ionisable functional groups. In which depending upon nature of drug, weak

cation exchange resin or weak anion exchange resin was selected for taste masking .In this

research work to form tasteless resinate of oseltamivir phosphate with Indion 234 and this

resinate incorporated in suspension by using suitable suspending agents like Xanthum gum.[1-

5]

2. MATERIALS AND METHODS

2.1 Material

Oseltamivir Phosphate (Strides Arcolab limited), Indion234 (Ion Exchange Ltd., Mumbai,

India), were obtained as a gift sample. All other Chemicals used were of Analytical Reagent

grade and procured from the local suppliers.

2.2. Methodology

2.2.1 Method of analysis

The drug was estimated spectrophotometrically at 215nm using UV–VIS spectrophotometer.

In this research work taste masking products of oseltamivir Phosphate was prepared by using

resin.

2.2.2 Suspension of taste masked drug: resin complex

Drug: resin complex was prepared using suitable ion exchange resin. Taste masking was done

by using Indion 234 resin. These prepared resinate was incorporate into suspending medium

to formulate taste masking suspension.

2.2.3 Preparation of taste masked resinate

Drug resin complexes were prepared by batch method.The drug –resin were accurately

weighed, 1g of drug added into 100 ml deionised water. After in this drug solution required

amount of resin was added to form various drug –resin ratios like 1: 0.5, 1: 1, 1:1.5 and

stirred for 3 hour. The amount of drug adsorbed was determined by the difference between

amount of drug present in stock solution and amount remaining in filtrate at the end of


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equilibrium. The drug resin ratio with highest drug loading was further checked for effect of

pH to find optimum conditions for drug loading.

2.2.4 Evaluation of Resinate

2.2.4.1 Drug content

The resinate equivalent to 75 mg was dissolved in 100 ml of 0.1N HCL and stirred for 2 h,

till the entire drug leached out, and then the solution was filtered through a Whatman filter

paper. Further diluted to volume with 0.1 N HCl and the drug content were determined

spectrophotometrically at 215 nm using 0.1 N HCl as blank.

2.2.4.2 Taste evaluation

It was done in 2 parts

A) Threshold bitterness concentration of oseltamivir Phosphate

Various concentrations (10-50 mcg /ml) of drug were prepared in phosphate buffer pH 6.8.

Human volunteers were used to rinse the oral cavity with buffer solution and then, l0 ml of

most dilute solution was asked to taste by swirling it in the oral cavity mainly near the base of

the tongue for 30 seconds. If the bitter sensation was no longer felt in the oral cavity after 30

seconds, the solution was spat out and waited for 1 minute to ascertain whether this is due to

delayed sensitivity. Then mouth was rinsed with safe drinking water. The next highest

concentration was not tasted until at least 10 minutes had passed. The threshold bitter

concentration is the lowest concentration at which a material continues to provoke a bitter

sensation after 30 seconds. After the first series of tests, mouth was rinsed thoroughly with

safe drinking water until no bitter sensation remained. Interval of at least 10 minutes was

observed between two tests.

B) In vitro taste evaluation

A quantity of DRC equivalent to dose of oseltamivir Phosphate was added to each of the 3

volumetric flasks containing 10 ml of phosphate buffer of pH 6.8. The mixtures were

vortexed for 20, 40 and 60 seconds and filtered. Content of oseltamivir Phosphate in each

filtrate was determined. For satisfactory taste masking, the amount of drug dissolved at the

end of 60 seconds should not be more than the threshold bitterness concentration of the drug.

2.2.4.3 Micromeritic properties

Compressibility, angle of repose, and bulk density were determined using the methods which

are mentioned in USP


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2.2.4.4 FTIR diffraction

Infrared (IR) spectroscopy was conducted using a FTIR Spectrophotometer and the spectrum

was recorded over the region 400-4000 cm–1 for the oseltamivir phosphate, Indion 234 and

drug resin complex

2.2.4.5 Differential scanning calorimetry study (DSC)

A Mettler Toledo Differential Scanning Calorimeter (DSC) 821 (Mettler Toledo, Greifensee,

Switzerland) equipped with an intracooler and a refrigerated cooling system was used to

analyze the thermal behavior of oseltamivir Phosphate , Indion 234 and D RC loaded beads,

in hermetically sealed flat aluminium crucibles, with temperature range from 30 to 300ºC.

Indium standard was used to calibrate the DSC temperature. Nitrogen was purged at 40

ml/min and 100 ml/min through cooling unit.

2.2.4.6 In vitro release of oseltamivir Phosphate from resinate

Weighed quantity of resinate equivalent to 75 was subjected to 75mg dissolution studies

using USP Type II dissolution test apparatus at 100 rpm with temperature of 37 ± 0.5°C and

900 ml 0.1 N HCl used as the dissolution medium. An aliquot equal to 5 mL was withdrawn

at specific time interval, and it was filtered through Whatman filter paper. Absorption of the

filtered solution was checked by UV spectroscopy at 215 nm and quantity of drug released

was determined periodically.[6-9]

2.3 Formulation of oral suspension of taste masked resinate of oseltamivir phosphate

A series of formulations were prepared with various concentration of suspending agent and

then evaluated for sedimentation volume, viscosity and redispersibility. From this one media

selected for formulation (Table 1)

Table 1- Formulation of Suspension

Ingredients F1 F2 F3

DRC 75mg 75mg 75mg

Xanthum Gum 0.2% 0.4% 0.6%

Propyl Paraben 10mg 10mg 10mg

Methyl Paraben 5mg 5mg 5mg

Sucrose 14g 14g 14g

Pineapple Flavour Quantity sufficient Quantity sufficient Quantity sufficient

Purified Water Up to 30 ml Up to 30 ml Up to 30 ml


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A) Preparation of syrup base

A weighed quantity of sugar (14 gm) was dissolved in 25 ml of boiled water and filtered.

Weighed quantities of Propyl Paraben, Methyl Paraben and varying amount of xanthan gum

(o.2%, 0.4%.0.6%) were added in sugar solution under stirring.

B) Mixing of DR complex with Syrup

The drug resin complex obtained was added in to sugar solution under stirring. Weighed

quantity of flavoring agent was added in above solution & stirred for 15 min. The volume of

suspension was made up to required quantity by using purified water.

2.4. Evaluation of taste masked suspension

Viscosity: The viscosity of suspensions was determined at ambient condition using

Brookfield viscometer. In adapter 15ml of suspension was taken and the adapter is set over

the viscometer by a stand such a way that spindle is completely immersed in the suspension.

Spindle no. S 21 was used to measure the viscosity of suspension.

Sedimentation characteristic

The formulated suspensions were evaluated for physical stability by determining the

Sedimentation ratio. 25 ml each of suspension was taken in 25 ml stopped graduated

measuring cylinder. The suspension was dispersed thoroughly by moving upside down for

three times. Later, the suspension was allowed to settle for three minutes and the volume of

sediment was noted. This is the original volume of sediment (Ho). The cylinder was kept

undisturbed for 14 days. The volume of sediment read on the 14th day was considered as

final volume of sediment (Hs).

Separation ratio = Hs/Ho

Where Hs= Height of upper clear layer in mm and Ho= Original height of sample column in

mm.

Resuspendability

Resuspendability of suspension was expressed in terms of number of shakes required to

redispersed the settled layer resulting after one month storage period at room temperature.

The redispersibility of the suspensions was checked by tilting the stoppered cylinder upside

down until there was no sediment at the bottom of the cylinder. Number of tilts required for

suspension was shown in table.


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pH

pH of the suspension was determined by the use of pH meter.

Drug content of suspension

5 ml of suspension was diluted suitably using 0.1 N HCL and drug content was estimated

spectrophotometrically.

In vitro Taste Evaluation

Suspension equal to normal dose of drug was added to each of the 3 volumetric flasks

containing 10 ml of phosphate buffer of pH 6.8. The mixtures were vortexes for 20, 40 and

60 seconds and filtered. Content of Oseltamivir phosphate in each filtrate was determined.

For satisfactory taste masking, the amount of drug dissolved at the end of 60 seconds should

not be more than the threshold bitterness concentration of the drug.

In-vitro drug release profile

The dissolution studies were carried out in USP Dissolution Test Apparatus Type II. 900ml

of 0.1 N HCl was used as dissolution medium maintained at 37◦C ± 0.5

◦C. Paddles were

rotated at 75 rpm. 5ml samples were collected at interval of 5 min for 30min. The collected

samples were analyzed for drug release by spectrophotometric analysis.[10-11]

3. RESULT AND DISCUSSION

3.1 Preparation of taste masked resinate

Oseltamivir phosphate was loaded on Indion 234 by the batch process. Complexation is

essentially a process of diffusion of ions between the resin and surrounding drug solution. As

reaction is equilibrium phenomenon, maximum efficacy is best achieved in the batch process.

For the preparation of resinate, batch method was used because of its most convenience.

Table() shows that’s maximum amount of oseltamivir phosphate binds to Indion 234 while

Indion 204 and Indion 264 reported 82.12% and 81.12% drug loading, respectively. This can

be attributed to the difference of cross-linking, exchange capacity, and form of resin. The

loading capacity of Indion 234 is a function of exchange of K+ ions in the resin with ions in

solution.

3.2 Effect of oseltamivir phosphate: Indion-234 ratio on loading

Indion-234 gives best loading efficiency i.e. 96% at 3 h; hence it was selected for the further

studies. Different drug resin (oseltamivir phosphate: Indion-234) ratios such as 1:0.5, 1:1,


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1:1.5 were studied result show that (table.). Oseltamivir phosphate: Indion 234 (1: 1) ratio

gives best loading was 96%.

Table 2 – % Drug Loading

Resin Drug: Resin % Drug loading

Indion 294 1: 1 81.11

Indion 464 1: 1 82.12

Indion 234 1: 1 96

3.3 Drug content

When DRC was prepared using optimized parameters for drug loading, the percent drug

loading was found to be 96% and the drug content was 44.00 % wt/wt. An increase in amount

of resin does not give correspondingly high increment in % drug content.

3.4 Taste evaluation

A) Threshold bitterness of oseltamivir Phosphate

Most of the volunteers reported the threshold bitterness at 40 µg/ ml. Threshold for taste is a

minimum concentration of a substance that evokes perception of taste.

Table 3 -Threshold bitterness of oseltamivir phosphate

Volunteer no Rating on the scale of bitterness

10ug/ml 20ug/ml 30ug/ml 40ug/ml 50ug/ml

1 0 0 0 1 1

2 0 0 0 1 2

3 0 0 0 2 2

4 0 0 0 1 3

5 0 0 0 1 1

6 0 0 0 1 2

7 0 0 0 2 2

8 0 0 0 1 2

9 0 0 0 1 2

10 0 0 O 1 1

0 =No bitterness, 1=Threshold bitterness, 2=bitter, 3=Moderate bitter, 4=Strong bitter

B) In vitro taste evaluation

Resinate with drug: resin concentration 1:1 show satisfactory result with 23.13μg/ml in vitro

drug release within 60 sec lower than threshold bitterness concentration of oseltamivir

Phosphate (Table 4)


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Table 4- In vitro taste evaluation of resinate

(n =4)

3.5 Micromeritic properties of resinate

Micromeritic properties of Drug resin complex were evaluated such as bulk density, angle of

repose and compressibility (Table 5). It was found that the flow and compressibility of

resinate were satisfactory.

Table 5- Micromeritic properties of resinate

3.6 FTIR study

The IR spectrum of Oseltamivir phosphate showed amine stretch at 3552 cm-1 , C-H stretch

at 2873 cm-1 , C-C stretch at 875 cm-1 , C=O stretch at 1720 cm-1 and peak corresponding to

ether, ester groups at 1261,1133 cm-1 ; also for alkene groups at 1658 cm-1. Indion 234

shows Characteristics peak at 3400-240 cm-1 corresponding to OH stretching of carboxylic

acid. The absence of peak at 3552 cm-1in spectra of DRC confirms Complexation of

secondary amine group in the drug to with resin. (Figure 1)

3.7 Differential scanning calorimetry study (DSC)

The thermogram of Oseltamivir Phosphate shows a sharp endothermic peak at 199°C which

is melting point of pure drug. The endothermic peak of Oseltamivir phosphate was absent in

the thermogram of DRC therefore it was confirmed that drug was completely dispersed in

matrix structure of Indion234 resin shown in figure 2.

Sr. No. Time(Sec) Concentration of drug(μg/ml)

1 0 3.28± 1.25

2 20 6.09± 1.45

3 40 14.24± 1.34

4 60 23.13 ± 0.91

Sr. No. Property Observation

1 Bulk density 0.2857 g/ml

2 Tap density 0.333 g/ml

3 Angle of repose 26

4 Carr’s index 6.34 %


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Figure 1: Infra-red spectra of A) oseltamivir phosphate B) Indion 234 C) Drug resin

complex

Figure 2: Differential scanning thermograms A) oseltamivir phosphate B) Indion 234 C)

DRC

3.8 In vitro drug release

In vitro release profile of DRC 234 shows drug release of 96 % within 35 min (Figure 3).

Indion 234 is a weak cationic resin and has high affinity for H+ ions. So, in acidic

environment, it readily loses the adsorbed drug species hence drug release is observed at a

faster rate.


391


Fig.3: In vitro drug release profile from taste masked suspension of resinate

3.9 Evaluation of suspension

Physiological characteristics of suspension

Sedimentation studies showed that the sedimentation ratio of all formulations was in the

range 0.98 to 1, which indicates that the formulations were acceptable.

Table 6 – Evaluation of Suspension

Evaluation parameter Resinate

F1 F2 F3

Viscosity (cps) 1.98 7.89 15.7

pH 5.3 5.2 5.0

Sedimentation ratio 1 1 0.98

Resuspendability

(no. of tilts) 2 2 2

The formulation F1 was optimized and used further study on their viscosity. The viscosity of

the formulation F1 was such that it would be easily pourable from the container. The Results

of the evaluation of oseltamivir phosphate suspension formulations are shown in above

Table7.

3.10 Accelerated stability Study

The accelerated stability study did not show any significant drug loss or changes in the

viscosity, pH, sedimentation ratio and resuspendability of the taste masked suspension of

resinate and microsphere at the end of 3 months. The taste masked suspensions were

therefore considered to be stable under ambient storage conditions for 3 months.

Table 7 – Accelerated stability study

Evaluation parameter Resinate

Initial One month Two month Three month

Colour Yellow Yellow Yellow No change

Viscosity (cps) 1.98 1.89 1.91 1.95


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pH 5.0 4.9 4.9 4.8

Sedimentation ratio 1 1 1 1

Resuspendability (no. of tilts) 2 2 2 2

3.11 In vitro taste evaluation of Suspension

Under in vitro taste masking evaluation study, the drug release in pH 6.8 phosphate buffer

was studied. It was observed that the drug release from taste masked suspension at 0, 20, 40

and 60s was less than threshold concentration in 6.8 phosphate buffer. This indicated that

satisfactory taste masking was done.

Table 8 – In vitro taste evaluation of Suspension

(n =4)

3.12 In-vitro drug release profile

The Study was carried out in 0.1 N HCL using USP Type -II apparatus at 75 rpm. The

formulation showed 95% drug release within 35 min. The drug- resin complex was stable in

salivary pH for a period of administration. It also shows that the resin does not retard the

release of drug from suspension

Fig.4: In vitro drug release profile from taste masked suspension of resinate

4. CONCLUSION

The efficient taste masking was obtained from drug–resin a complex that was formulated as

oral suspension for better patient compliance. Use of weak cation exchange resin offers

superior method for preparing taste-masked substrates of oseltamivir phosphate. Results

Sr. No. Time (sec) Concentration of drug(μg/ml)

1 0 4.15± 1.85

2 20 8.09± 1.44

3 40 16.24± 1.14

4 60 24.11 ± 0.91


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obtained in this work shows that drug-resin complexes effectively masked bitter taste of

oseltamivir phosphate while liquid formulation provides easier way to administer and getting

the child to swallow.

5. ACKNOWLEGDEMENT

Authors are thankful to A.I.S.S.M.S. College of pharmacy, Pune, for providing the required

facilities for the research work.

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