Taste is a key factor that impacts whether patients stick to their medication, especially with bitter-tasting oral drugs. This is especially important for children and the elderly, who are more sensitive to unpleasant tastes. Taste buds are nerve-rich structures that respond when substances dissolve in the mouth, sending signals to the brain. Many drugs, including Valsartan, are highly bitter and dissolve in saliva, making them unpalatable.

To improve the taste of such drugs, several masking techniques are used. These include coating the drug with polymers, forming drug-resin complexes, or using inclusion complexes where the drug is trapped within a cavity of a complexing agent. Another method is forming microsponges—tiny porous spheres that can encapsulate the drug and prevent direct contact with taste buds. Similarly, microspheres made via spray drying can enclose the drug in a polymeric shell, improving taste. Valsartan, a medication used to manage high blood pressure, has a very bitter taste. It works by blocking specific receptors (AT1) responsible for blood vessel tightening and hormone release. This action helps lower blood pressure and offers kidney protection, particularly in patients with diabetes or heart conditions. Because hypertension treatment is long-term, masking Valsartan’s bitterness is essential to ensure patients consistently take their medication.

AIM AND OBJECTIVES OF THE STUDY

The aim of the present research work is to study on various techiques used for masking the bitterness of drug and formulation development.

Objectives:

1. To mask bitterness of API by using various techniques such as Ion exchange resin, Coating, Granulation, Solid dispersion etc.
2. To study the effect of drug – polymer ratio on bitterness and release profile of API.
3. To compare the effectiveness of various methods for masking the bitterness of API.
4. To develop suitable Solid dosage form of taste maske API.

To characterize the developed formulation.

DRUG PROFILE

1. VALSARTAN

• Chemical Name : N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-valine.
• Molecular Formula       : C₂₄H₂₉N₅O₃
• Molecular Weight          : 435.52

Properties:

• Melting Point     : 116-117 °C dec.
• Storage Temperature: 2-8°C
• Solubility             : DMSO: ≥20mg/mL
• Physical State     : Powder
• Colour : White
• Boiling point      : 684.9±65.0 °C (rough estimate)
• Density                          : 1.212±0.06 g/cm3 (rough estimate)

Uses:

1. Valsartan is used as a first-line drug for the treatment of uncomplicated hypertension, isolated systolic hypertension, and left ventricular hypertrophy.
2. Used for the treatment of hypertension in patients with diabetes and renal disease.

EXCIPENT PROFILE

1. EHTYL CELLULOSE

• Chemical Name:  Ethyl cellulose
• Molecular Formula:         C23H24N6O
• Molecular Weight:          448.47446
• Melting point:      240-255 °C
• Form powder
• Water Solubility  insoluble

Uses:

1. Film Coating Agent: It serves as an effective film-forming agent.
2. Tablet Binder: Employed as a binder in tablet manufacturing to improve the cohesiveness and mechanical strength of compressed tablets.
3. Microencapsulation:        Utilized           in microencapsulation processes         to enclose        active pharmaceutical ingredients.

2. POLYVINYL ALCOHOL

• • Product Name: Homopolymer
  • Melting point: 222.8°C
  • Form: Powder

Uses: Coating agent, Lubricant, Stabilizing agent.

3. MICROCRYSTALLINE CELLULOSE

• Product Name: Microcrystalline cellulose
• Melting point: 260-270°C

Uses: Microcrystalline cellulose is widely used in pharmaceuticals, primarily as binder/diluents in oral tablets and capsules formulations.

4. MAGNESIUM STEARATE

• Synonyms: Magnesium octadecenoate.
• Melting point: 117-115°C
• Molecular weight: 591.34
• Form: Powder

Uses: Tablet and Capsule Lubricant

5. TALC:

• Chemical Name: Talc
• Form: Powder

Uses:

1. Talc was once widely used in oral solid dosage Formulation as a lubricant and, diluents, although today it is less commonly used.
2. It is widely used as a dissolution retardant in the development of controlled release products.
3. Talc is also used as a lubricant in tablet formulation in a novel powder coating for extended- release pellets and as an adsorbent.

6. CROSSCARMELLOSE SODIUM

• Molecular Formula: C28H30NasO27
• Molecular Weight: 90000-98900 g/ mole
• Form: Powder

Uses: Superdisintegrant

7. SODIUM STARCH GLYCOLATE

• Molecular Weight: 515.6862
• Molecular Formula: C2H4O3-xNax
• Form: Powder

Uses: Superdisintegrant

8. β-CYCLODEXTRIN

• Molecular Formula: C42H70O35
• Molecular Weight: 1134.99 g/mole
• Form: Powder

Uses: Cyclodextrins have also been used in the formulation of solutions, suppositories, and cosmetics. Taste enhancer

9. EUDRAGIT L 100

• Molecular Weight: 125,000 g/ mole
• Molecular formula: C9H14O4
• Form: Powder

Uses: Coating, Miencapsulation.

10. EUDRAGIT RS 100

• Molecular formula: CS6H 108030
• Molecular weight: 407.9g/mole
• Form: White powder with characteristic odour

Uses: Used for developing controlled release formulation.

MATERIAL AND METHOD

1. Preparation of microsponges by Quasi- emulsion solvent diffusion method

Two phases were used, one is organic and the other is the aqueous phase. The organic phase, containing drug and polymer mixture in 40 ml DCM and the aqueous phase containing PVA and in 200 ml distilled water. The aqueous phase was added in a dropwise manner in the organic phase on a mechanical stirrer at 1200 rpm. After two hours of stirring, microsponges were collected by filtration method and dried in an oven at 40 °C for 24 hours.

2. Preparation of Inclusion Complexes by Kneading method

Drug and Polymer with different ratios were mixed and ground in a mortar with a pestle for 1 min. Then, q.s of ethanol was added to the mixture and the obtained paste was further kneaded for 3-6 min. After mixing, the end product was dried in the hot air oven at 50° for 2h. The dried mass was pulverized and kept in desiccator before characterization.

3. Preparation of Spray Dried Microsphere

Spray dried microsphere of Valsartan were prepared by using synthetic polymer like Eudragit L 100. Microspheres of Valsartan and Eudragit L 100 were prepared in different ratio such as 1:1, 1:2, 1:3, 1:4. Different batches of microspheres were prepared by using N, N-Dimethyl formamide and Methanol as a solvent.

4. Analyatical Characterization of Drug Sample

Standard Callibration Curve of Valsartan:

25mg of drug Valsartan was dissolved in pH 6.8 phosphate buffer and volume was made up to 25ml to make stock solution of concentration 1000μg/ml. Then 0.5 ml of stock solution was taken and diluted up to 100 ml with the buffer of pH 6.8 buffer and to get concentration of 5 μg/ml and in similar way dilution were made as 10, 15, 20 and 25 µg/ml respectively and absorbance measured at 250 nm by UV visible spectrophotometer. The absorbance values were plotted against concentration (µg/ml) to obtain the standard calibration curve.

5. FT-IR Spectroscopy

It's important to check any kind of interaction between drug candidate and polymer. The polymers which are to be incorporated into formulation should be compatible with the drug Thi compatibility study or interaction study was done using Fourier Transformed Infrared Spectroscopy. IR Spectra of pure Valsartan and Polymer Viz. Ethylcellulose, Polyvinyl alcohol were taken separately. Then to know if there is any interaction between and polymer, IR spectra of Valsartan and polymers were taken in combination.

6. Morphological Study by using Scanning electron microscopy (SEM):

Morphology of Microsponges Was examined by Scanning electron microscopy.

7. Preparation of Valsartan loaded microsponges:

Table No. 1. Formulation table of Valsartan loaded Microsponge

1. Percentage yield of microsponges

The percentage yield of microsponges were determined by weighing after drying. The measured weight of prepared microsponges was divided by the total amount of all the nonvolatile components used for the preparation of the microsponges, which give the total percentage yield of microspheres.

% Yield=Actual weight of productTotal weight of excipients and drug X 100

2. Particle size analysis:

Particle size of microsponges should be in range of 5-300µm. It is important to analyse particle size of microsponges. Particle size of microponges were determined by the Litisizer DLS 500, utilizes dynamic light scattering (DLS) to determine particle size by measuring the random Brownian motion of particle in a liquid dispersion.

3. Drug Entrapment Efficiency (DEE):

25 mg of drug loaded Microsponges were taken for evaluation. Weighed microspongess were dissolve in 25ml suitable solvent in volumetric flask followed by filtration. Filtered samples were analyzed spectrophotometrically at 250nm using solvent as blank. The entrapment efficiency of various samples was calculated using the following equations:

%DEE=Actual loadingTherotical loading X 100

%Drug Loading=Weight of drug in microspongesWeight of microsponges X 100

4. In vivo-Human Taste Panel:

The study was performed in a group of 5 selected healthy volunteers. Before the test, the mouth was washed with purified water and then microspheres equivalent to 10 mg of Valsartan loading was placed on tongue for 30sec. After this time, the oral cavity was rinsed with purified water again. The same procedure was repeated for all to evaluate the taste, a scale with the following numerical values was used: A- Not Bitter, B-Slightly Bitter, C- Moderately Bitter and D-Very Bitter.

9. Drug Interaction Studies (Compatibility Studies):

On the basis of evaluation parameters such as drug entrapment efficiency, percentage yield and dissolution characteristics the batch that has shown the best results was optimized and advanced studies such as drug polymer interaction Fourier transformed infrared spectroscopy (FT-IR) and scanning electron microscopy studies (SEM), etc

10. Advanced Studies on Optimized Batch of Microsponges

1. Fourier Transform Infrared Spectroscopy (FTIR)

The samples of pure drug and formulation F4 were dispersed in 200 mg of KBr powder and compressed into pellets at a pressure of 6000 kg/cm2 and analyzed. Spectral measurements were obtained by powder diffuse reflectance on a FT-infrared spectrophotometer (Shimadzu, FT-IR 8400S, Japan).

2. Scanning Electron Microscopy (SEM)

Scanning electron microscopy (Joel LV-5600, USA) was applied to obtain photomicrographs which were used to identify and confirm the surface topography of the microsponges.

11. Preparation of Valsartan loaded Inclusion complex

Table. No. 2 Valsartan loaded Inclusion complex batches

12. Evaluation of Valsartan loaded inclusion complex

1. In vivo-Human Taste Panel:

The study was performed in a group of 5 selected healthy volunteers. Before the test, the mouth was washed with purified water and then inclusion complex equivalent to 10 mg of Valsartan loading was placed on tongue for 30sec. After this time, the oral cavity was rinsed with purified water again. The same procedure was repeated for all to evaluate the taste, a scale with the following numerical values was used:1- Not Bitter, 2-Slightly Bitter, 3- Moderately Bitter and 4-Very Bitter.

13. Preparation of Spray Dried Microsphere

Table No. 3: Different Batches Of Spray Dried Microsphere

14. Evaluation of Spray Dried Microsphere

1. Percentage yield of microsphere:

The measured weight of prepared microspheres was divided by the total amount of all the non-volatile components used for the preparation of the microspheres, which give the total percentage yield of microspheres.

% Yield=Actual weight of productTotal weight of polymer and drug X 100

15. Preparation Of Taste Masked Valsartan Fast Dissolving Tablet

The Valsartan FDTs were prepared by direct compression process using MCC and mannitol as diluents. Various types of disintegrant i.e., sodium starch glycolate, Croscarmellose sodium were used. Each ingredient was screened through 40-mesh sieve before mixing. Microsponges containing Valsartan weigh equivalent to 40mg of dose and mixed in polyethylene bag. Magnesium stearate and talc were added as glidant, absorbent, and lubricant mixed for further 2min. The obtained mixture was compressed into tablets of 5 inch in diameter by a direct compression machine. The hardness of the tablets was controlled between 3-4 kg.

Table No. 4: Tablet Formulation of Taste masked Batches of Valsartan Microsponges (Quantity in mg)

1. Preformulation Study:

1.1 Bulk density:

Method

Bulk density Apparent bulk density is determined by pouring a weighed quantity of blend into graduated cylinder and measuring the volume and weight. Bulk density can be calculated by using following formula:

(Db)= M/Vo

Where, M =   mass of powder taken

             Vo = unsettled apparent volume

Determinations were carried out in three replicates. It has been stated that the bulk density values have less than 1.2 g/cm³ indicates good packing and values greater than 1.5 g/cm³ indicates poor packing.

1.2 Tapped density:

Tapped density is the bulk density of powder which has been compacted by tapping or vibration. Tapped density was determined by placing a graduated cylinder containing a known mass of powder on mechanical tapping apparatus, which is operated for a fixed number of taps (100) or until the powder bed volume has reached a minimum. The tapped density is computed by taking the weight of power in cylinder and final volume.           

Tapped density:   Dt = M/Vt

Where, M = mass of powder

 Vt = bulk volume of the powder

1.3 Compressibility Index and Hausner Ratio

Compressibility Index and Hausner Ratio are measures of the propensity of a powder to be compressed. As such they are measures of relative importance of interparticulate interactions. In free flowing powder, such interactions are less significant and bulk and tapped density difference is close. For poorer flowing materials, this difference is greater.

a) Compressibility Index (% Compressibility)

Carr's compressibility index i.e., % compressibility indicates the flow property and packing ability of the tablet. When the % compressibility ranges from 5 to 16, the materials have acceptable flow property and packing ability.

Compressibility Index was calculated using following equation.

Compressibility index = [(Dt-Db)/Dt] x100

Where, Dt = tapped density of powder

        Db = bulk density of powder

Table No. 5: Practicle Consideration Of Compressibility Index

(b) Hausner Ratio:

The Hausner ratio indicates the flowability and packing ability of the tablet. When the Hausner ratio is close to 1, materials have acceptable flow and packing ability.

The Hausner ratio was calculated using the formula

 Hausner ratio = Dt/Do

         Where, Dt= tapped density

            Do= bulk density

Table No.6: Practical Consideration of Hausner Ratio

1.4 Angle of Repose:

Angle of repose is determined by using funnel method. The accurately weighed blend is take in a funnel. The height of the funnel is adjusted in such a way that the tip of the funnel just touches the apex of the heap of blend (2cm). The drug (as solid dispersion)-excipient blend is allow to flow through the funnel freely on to the surface. The diameter of the powder cone is measured and angle of repose is calculated using the following equation.

Angle of repose (0) = tan-1 (h/r)

           Where, h = height of a pile (2 cm)

                        r = radius of pile base.

Acceptable range fot angle of repose is 200 to 400. All the formulation showed and angle of repose within the range. The mean values of three determinations of angle of repose of tablet blend were taken 

Table No.7:  Practical Consideration of Angle of Repose

17. Evaluation of Tablet:

1. Hardness:

The tablet hardness, which is the force required to break a tablet in a diametric compression force. The hardness tester used in the study was Monsanto hardness tester, which applies force to the tablet diametrically with the help of an inbuilt spring. It is expressed in Kg/cm².

2. Friability:

Friability of the tablets was determined using Roche friability (Electrolab, Mumbai). This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25 rpm and dropping the tablets at a height of 6 inches in each revolution. Preweighed sample of tablets was placed in the friabilator and were subjected to 100 revolutions. Tablets were dedusted using a soft muslin cloth and reweighed.

The friability (f) is given by the formula.

F = (1-W0/W) × 100

Where,

WO is weight of the tablets before the test and

W is the weight of the tablet after the test.

3. Weight variation test:

The variation weight testing was carried out as per the method describe in the USP 25NF20,2002

Method: Twenty tablets were selected from each batch and individually weighed the average weight and standard deviation of 10 tablet was calculated the batch passes the test for weight variation test if not more than two of the individual tablet weight deviates from the average weight by more than the percentage shown in officials and none deviated by more than twice the percentage shown. Then the resultants weights were compared to the average does USP weight variation test shown in table no.

Table No. 6: Weight Variation Of Tablet

4. Thickness And Diameter:

As per the USP the thickness and diameter was determined. For each formulation the thickness and diameter was determined by using the Vernier caliper.

5. In vitro disintegration time:

The disintegration time of the tablet was measured in water (37±2°C) according to disintegration test apparatus with disk. The time in minutes taken for the complete disintegration of the tablet with no palpable mass in the apparatus was measured in seconds. Three tablets from batch were tested for the disintegration time calculations.

6. In vitro dissolution profile:

In-vitro drug release study was performed at 37±0.5°C using eight station USP type-II apparatus with paddle rotating at 50 rpm. The drug release study was carried out in pH 6.8 Phosphate buffer by taking about 900ml of the dissolution medium. The drug release study was performed in pH 6.8 phosphate buffer to demonstrate the availability of Valsartan About 3 ml of sample was withdrawn at specified time intervals from the dissolution medium and replaced with equal volume of fresh medium and diluted 6ml of pH 6.8 phosphate buffer. Samples were filtered through whattmann filter paper and analyzed using UV spectrophotometer (Shimadzu UV) at 250nm.

7. Accelerated Stability study:

The tablet formulation was packed in aluminum foil and were exposed to 40°C +2°C/75% 5% RH in humidity control oven as per ICH guidelines118 QIC: "Stability testing of new dosage forms." Sampling was done at predetermined time intervals of 0, 30 and day. These tablets were kept in stability chamber and then were analysed for 30 days. the physical characterization, visual defects, hardness, thickness, friability, dissolution tests disintegration time.

RESULT AND DISCUSSION:

1. Physical Characteristics:

Table No.7:  Physical characteristics of Valsartan

2. Solubility Test

Table No.8: Solubility test

2. Standard calibration curve

Table No.9: Standard Calibration of Valsartan in pH 6.8 Phosphate Buffer

Figure No.1: Standard Calibration curve of Valsartan

3. % Percentage Yield:

Table No.10: % Production Yield

4. Particle size analysis:

Figure No.2 Particle size distribution

Table No.11. Particle size distribution

The particle size of optimized microsponge was found 205.35μm.

5. Drug Entrapment Efficiency:

Table No.12: Drug Entrapment efficiency

The percentage drug entrapment drug loading and drug concentration of formulated batches F1to F5 mention in table No.12 Valsartan loaded microsponge formulations F1 to F5 in which F5 was having highest percentage of drug entrapment 91.53 % here drug entrapment in the microsponge depends upon the preparation condition and drug: polymer.

6. Human Taste Panel Method:

Table No.13: Sensory Evaluation Of Microsponge Formulation F1 To F5

• Taste masking efficiency of microsponge formulated with Ethyl cellulose and Eudragit RS 100 was additionally examined by 4 Healthy volunteers. Formulation F5 were characterized by the Highest taste masking potential and created the most effective barrier. All Volunteer assessed this formulation as not bitter.
• From the various trials of drug and polymer ratio Ethyl cellulose 1:2 ratio shown successfully taste masking of drug and it used for further studies.

7. Drug Interaction Studies

1. FT- IR spectroscopy:

Figure No.3: IR Spectra of Pure Drug Valsartan

Figure No.4:IR Spectra of Valsartan with Ethyl cellulose and PVA

From FTIR graphs, it was seen that all the peaks of functional groups present in Valsartan retained in FTIR of Valsartan groups of with polymer like Ethylcellulose and Polyvinyl alcohol. This retention of peaks interprets that there is no interaction between Valsartan and polymer Ethylcellulose and Polyvinyl alcohol used in this study.

8. Morphological Study by Using Scanning Electron Microscopy (SEM):

Morphology of Microsponges Was examined by Scanning electron microscopy. Scanning electron micrograph of optimized batch of microsponges shows that the surface of microparticles was appearing somewhat rough, cluster and finely porous & particle are present like spherical shape.

Figure No.5,6 SEM of Valsartan Microsponge of Optimized Batch

9. Inclusion Complex: In vivo-Human Taste Panel:

Table No.14: Sensory Evaluation Of Inclusion Complex Formulation F1 To F6

• Taste masking efficiency of Inclusion Complex formulated with β-Cyclodextrin was additionally examined by 4 Healthy volunteers. All Volunteer assessed this formulations as very bitter.
• From the various trials of drug and polymer ratios shown unsuccessfull taste masking of drug from Inclusion complex (Kneading method).
• Inclusion Complexes were not selected for any further study.

10. Valsartan Loaded Spray Dried Microsphere:

1. Percentage yield of microsphere:

Table No.15: Percentage Yield of Valsartan Loaded Microspheres

The Percentage yield was found of all batches and it was noted to be negligible. The production yield achieved negligible however, taste masking of F4 batch was successfully accomplished. There was no possibility for further study of microspheres.

11. Pre-Compression Study of Tablet Blend:

Table No.16: Pre-Compression Study of Tablet Blend