International Standard Serial Number (ISSN): 2319-8141 .... RPA1300119.pdf · carrageenans, Microcrystalline cellulose with CMC, Propylene glycol alginate, Siliconedioxide, colloidal

International Standard Serial Number (ISSN): 2319-8141 International Journal of Universal Pharmacy and Bio Sciences 2(3): May-June 2013

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES

Pharmaceutical Sciences Review Article……!!!

Received: 11-05-2013; Accepted: 18-05-2013

A REVIEW ON TASTE MASKING PEDIATRIC DRY SYRUP

Parmar Pratik*, Dr.M.R.Patel, Dr.K.R.Patel, Dr.N.M.Patel

Department of pharmaceutics, Shri B.M.Shah College of Pharmaceutical Education and

Research, Modasa.

KEYWORDS:

Taste masked dry

suspension, Dry

suspension, Dry syrup,

Reconstitutable oral

suspension.

For Correspondence:

Kumpawat K. S*

Address:

Department of

pharmaceutics, Shri

B.M.Shah College of

Pharmaceutical

Education and Research,

Modasa.

Tel. +91 9099507979

ABSTRACT

The oral route of administration is the most important method of

administering drugs for systemic effects. The most popular dosage

forms beings tablets and capsules, but one important drawback of the

dosage forms however is the difficulty to swallow especially when a

dosage form is developed for children. So the major drawback is that

there is a problem in swallowing a tablets or capsules when it is

given to children. So it is necessity to develop another dosage form

for children. One best option of such tablets and capsules is dry syrup

form of that respective drug. Dry syrup is a granules or simply

powder mixture form of drug with appropriate excepients. So the

direction of use of this dosage form is to take the dry syrup in water

and shake well so it will fastly disintegrate in to water and make a

suspension. Now this suspension is taken as same as water drinks. So

no need to swallow dosage form. Dry syrup form of drug is also

useful in case of bioavailability as it have high bioavailability rather

than tablets and capsules as it disintegrates in water outside of oral

cavity and directly the suspension is gone through the GIT. So the

suspension easily absorb in the GIT.

552 Full Text Available On www.ijupbs.com

International Standard Serial Number (ISSN): 2319-8141

1. INTRODUCTION:

A number of patients, especially pediatric and geriatric patients, have difficulty in swallowing

solid dosage forms hence liquid dosage forms are needed. So drugs which are slightly soluble in

water hence formulation of a suspension will be most suitable but product may not be

physically and chemically stable. In the present work, attention is paid to develop a

Reconstitutable suspension dosage form.

Dry Syrups: Dry Syrups Suspensions are commercial dry mixtures that require the addition of

water at the time of dispensing.

A number of official and commercial preparations are available as dry powder mixtures or

granules that are intended to be suspended in water or some other vehicle prior to oral

administration.

Most of the drugs prepared as a dry suspension for oral suspension are antibiotics. The dry mix

of oral suspension is prepared commercially to contain the drug, colorants, flavours,

sweeteners, stabilizing agents, suspending agents and preserving agents that may be need to

enhance the stability of the formulation.

The granules in the sachets must be taken as a suspension in a glass containing prescribed

amount of ingestible liquid, mostly water.

Although studies have demonstrated that the dry oral suspension after constitution in a liquid is

stable for 24 hours after preparation, it is recommended that the suspension should be consumed

immediately after preparation.

Advantages of dry syrup

Accurate single dosing: Single dose sachets

Sachets: 4 layered aluminium foils making the formulation extremely stable and

convenient to carry.

Enhanced convenience of single dosage regimen.

Coloured, flavoured, sweet to taste formulation administration among pediatric patients.

2.1 Major Application - Pediatric therapy: Taste masking

Oral Route of administration is the route of choice for administration of medicines in children.

The only hurdle for dosage form designing for pediatric patients is the patient’s acceptance of

the dosage form. Pediatric Patients tend to become un-co-operative during the administration of

oral medication; the most common reason being the taste of the oral formulation administered

among the children.

Most of the drugs administered as granules for oral suspension under pediatric therapy are

Antibiotics, which when administered orally as any other dosage form have a bitter taste


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making it unpleasant for Children to consume the medication.

The solution for this is Taste masking and the major application of taste masking can be

observed in Granules for oral suspension.

2.2 Dry Oral Suspensions Advantages Over Liquid Oral Suspensions:

Advantages of Dry Granules for oral suspension:

Accurate single dosing: Single dose sachets

Drug dose is comparatively independent of any physical factors i.e. temperature,

sedimentation rate and liquid flow properties

Sachets: 4 layered aluminium foils making the formulation extremely stable and

convenient to carry.

Enhanced convenience of single dosage regimen.

Coloured, flavoured, sweet to taste formulation administration among pediatric patients.

Palatable and widely accepted in Pediatric patients all over the world.

Stability: Stable on storage and when constituted with an ingestible liquid for

administration, the corresponding liquid suspension is stable for the duration in which

the therapy is required.

Disadvantages of liquid oral suspensions include:

Bulk formulation- inaccurate single dosing

Drug Dose dependent on various physical factors of the dosage form including:

o Temperature of storage

o Sedimentation rate of the formulation

o Liquid flow properties-viscosity, pourability, redispersion, flocculation

o Content uniformity

Stability of the liquid suspension largely depends on the temperature of storage

o Caking upon storage

2.4 Required Characteristics of Suspensions for Reconstitution :

Required Characteristics of Suspensions for Reconstitution Powder blend must be a uniform

mixture of the appropriate concentration of each ingredient.

During reconstitution, the powder blend must disperse quickly and completely in the aqueous

vehicle.

Reconstituted suspension must be easily re-dispersed and poured by the patient to provide

accurate and uniform dose.

Final product must have an acceptable appearance, odor and taste.




2.5 Commonly used Ingredients: Suspending agent, Anticaking Agent, Wetting agent,

Flocculating agent, Sweetener , Solid diluents, Preservative, Antifoaming agent, Flavor,

Granule binder, Buffer, Color , Antioxidant, Lubricant.

No. of ingredients should be kept minimum.

All ingredients should disperse rapidly on reconstitution.

Nearly all drugs formulated as reconstitutable oral suspensions are antibiotics.

Sodium dicloxacillin is water soluble, it is formulated as an insoluble form in

suspension to help mask the odor and taste.

Suspending agents: Suspending agents suitable for use in Suspensions for Reconstitution,

Acacia, Tragacanth, Xanthan gum, Povidone, Carboxy methyl cellulose sodium, Lota

carrageenans, Microcrystalline cellulose with CMC, Propylene glycol alginate, Siliconedioxide,

colloidal. Suspending agents should be easily dispersed by vigorous hand shaking during

reconstitution. Combination of microcrystalline cellulose and sodium CMC is a common

suspending agent.

Natural gums: Anionic and include exudates of tree and extracts from seaweed e.g.

Carrageenan and alginates. Alginates produce highly viscous solutions and the iota

carrageenans produce thixotropic dispersions. Acacia.and tragacanth have been used as

suspending agents for many years.

Disadvantages: Variation in color, viscosity, gel strength and hydration rate.

Xanthan gum: Common suspending agent in suspensions for reconstitution. Produced by

microbial fermentation, good batch-to-batch uniformity and few microbial problems. Required

concentrations for rapid dispersion during reconstitution must be determined for each

suspending agent.

Sweeteners: Sweeteners can mask the unfavorable taste and enhance patient acceptance in the

pediatric population that uses this product. Any increased viscosity as a result of the sweetener

aids suspension of the drug particles. Sucrose can perform both above functions of sweetener

and suspending agent, and serve as a diluent in the dry mixture. Others include Mannitol,

Dextrose, Aspartame, Saccharin Sod.

Wetting Agents: Drugs in suspension are hydrophobic, repel water and are not easily wetted.

Surfactants are commonly used to aid in the dispersion of hydrophobic drugs. Excess wetting

agent can produce foaming and impart an unpleasant taste. Polysorbate 80 is a common wetting

agent. Nonionic and is chemically compatible with both cationic and anionic excipients and

drugs. Used in concenrations < 0.1 %. Another common wetting agent is sodium lauryl sulfate.

Anionic and may be incompatible with cationic drugs.




Other ingredients

Buffers, Preservatives, Flavors & Colors

Buffers are used to maintain the optimum pH for all ingredients.

- Sodium citrate buffer.

Preservatives are required in most suspensions because the suspending agents and sweetener are

often good growth media for microorganisms.

- Sucrose in sufficent concentrations (60% w/w)

- Sodium benzoate

Natural and Artificial flavors – Raspberry, Pineapple

FD&C Red No 40 and Yellow No 6.

2.6 Preparation of Dry Mixture

Powder Blends

Granulated Products

Combination Products

Powder Blends

Mixing the ingredients of the dry mixture in powder form. Ingredients present in small

quantities may require a two stage mixing operation. Mixer should rapidly and reliably produce

a homogeneous mixture.

Advantages

Least capital equipment and energy

Least likely to have chemical and stability problems because no heat or solvents are

used.

Low moisture content can be achieved in dry mixture.

Disadvantages

Prone to homogeneity problems – Particle size and Powder flow

Loss of the active ingredient during mixing

Potent drug used in very low concentrations.

Granulated Products

Wet granulation is the usual process and granulating fluid is water or an

aqueous/nonaqueous binder solution.

Drug can be dry blended with other ingredients or it can be dissolved or suspended in

the granulating fluid.

Solid ingredients are blended and massed with granulating fluid in a planetary mixer.

Wet mass is formed into granules : Vibratory sieve, Oscillating granulator or mill.




Granules dried in a tray oven or Fluid bed drier.

Dried granules screened in a vibratory seive or oscillating granulator to break up or

remove aggregates or granules.

Advantages

Improved appearance

Improved flow characteristics

Less segregation problems

Less generation of dust during filling operations

Disadvantages

More capital equipment and energy

Difficult to remove the last traces of granulating fluid, reduce the stability

Uniform granulation is necessary, excess of very small particles, or fines, will result in

rapid segregation.

Combination Product

Less energy and equipment for granulation may be required if majority of the diluent can be

added after granulation. Heat sensitive ingredients, such as flavors can be added after drying of

granules. First to granulate some of the ingredients and blend the remaining ingredients with the

dried granules before filling into container.

Disadvantages

Risk of nonuniformity

Particle sizes of various fractions should be carefully controlled

TYPE

ADVANTAGES DISADVANTAGES

Powder blend

Economy

Low incidence of instability

Mixing and segregation

problems

Losses of drug

Granulated product

Appearance

Flow characteristics

Less segregation

Less dust

Cost

Effect of heat and granulating

fluid on drug and excepient

Combination product

Reduced cost

Use of heat sensitive

ingredients

Ensuring nonsegregating mix of

Granular and non granular

ingredients




2.7 Processing the Dry Mixture

Recommended Guidelines for processing the Dry mixture

Use efficient mixing.

Determine an adequate duration of mixing time.

Avoid accumulation of heat and moisture during mixing.

Limit temperature/humidity variations {70 c at <40% RH}

Finished batch should be protected from moisture.

Sample for batch uniformity.

2.8 Stability of Dry Mixtures

CHEMICAL STABILITY

Chemical stability should be determined in both the dry mixture and reconstituted suspension.

Both should be examined not only at controlled room temperature but also at temperatures of

potential exposure such as during shipment or storage of the product.

Stability evaluations of reconstituted oral suspensions should be conducted in a container of the

same material and size in which the product is marketed.

Effectiveness of the preservative is determined by challenge tests.

Drug products are often exposed to elevated temperatures for the determination of a shelf-life

(i.e., accelerated stability studies).

PHYSICAL STABILITY

Physical stability should evaluate both the dry mixture and reconstituted suspension.

Common evaluations on reconstituted suspensions include Sedimentation volume and ease of

re-dispersion.

Exposure to a cycle of temperature changes (Freeze and Thaw).

2.9 Guidelines for Stability Testing

A screen based on temperature is a common test. Samples of the reconstituted suspension are

stored in containers at room temperature, 37°, and 45°C.

Evaluated monthly for up to 4 months and should include:

Chemical analysis for drug and preservative

Preservative challenge test at the initiation and conclusion of the study

Appearance compared to that of sample stored at 2° to 5°C

Viscosity

Homogeneity

pH

Sedimentation volume

Ease of re-dispersion.




Freeze-thaw test

Conducted by placing the sample in a freezer for 18 hours followed by thawing at room

temperature for 4 to 6 hours. Evaluate the appearance and conduct any other appropriate tests at

this time. Repeat the Freeze-Thaw cycle for up to 10 times.

Full-Scale Stability

Final formulation should be placed in the container for marketing and should be stored at 2° to

5°, RT, 37°, and 45°C.

2.10 Introduction To Taste Masking Technologies [3-4]

Introduction

The sense of taste: Taste is the ability to respond to dissolved molecules and ions‐“gatekeeper

to the body”. Human detects taste with taste receptor cells that are clustered in to onion‐shaped

organs called taste buds. Each taste bud has a pore that opens out to surface of the tongue

enabling molecules and ions taken into the mouth to reach the receptor cells inside.

Human have around 10,000 taste buds which appear in fetus at about three months. A single

taste bud contain 50‐100 taste cells. Each taste cells receptors on its apical surface. These are

trans membrane proteins which bind to the molecules and ions that give rise to the four primary

taste sensations namely ‐ salty, sour, sweet and bitter. Recently, a fifth basic taste umami has

been discovered. The umami is the taste of certain amino acids (eg., monosodium glutamate).

There is often correlation between the chemical structure of a compound and its taste. Low

molecular weight salts tend to taste salty where as high molecular weight salts tend toward

bitterness. Nitrogen containing compounds, such as alkaloids, tend to be quite bitter. Organic

compounds containing hydroxyl groups tend to become increasingly sweet as number of OH

group increase. Receptor mechanism involves initial de-polarisation at apical receptor site,

which causes local action potential in receptor cell. This in turn causes synaptic activation of

the primary sensory neuron.




Four basic tastes are confirmed to specific regions of tongue. But some workers deny the

presence of specific regions of the tongue for a particular taste and consider it as a

misconception.

Threshold for taste is a minimum concentration of a substance that evokes perception of a taste.

The following table 1 gives the threshold concentration of four primary taste sensations.

It can be seen that tongue is 10,000 times more sensitive to the bitterness of quinine than to

sweetness of sugar. Saccharine, on this scale would rate about 0.001%.

Pharmaceutical companies can save themselves much grief by addressing the taste factor early

in the product development. In so doing, they can get their medications to market more quickly,

ensure patient compliance, gain market leadership and reap generous economic rewards. They

can also stay in compliance with FDA’s final rule, which went into effect December 2000.

So major taste masking efforts are required before bitter drugs are acceptable for market trials.

Major taste masking technologies are based on the reduction of solubility of the drug in the

saliva so the drug concentration in saliva will remain below taste threshold value. The desire for

improved palatability of formulations has prompted the development of various new

technologies for taste abatement. Many of these technologies have been successfully

commercialized. But, the ideal solution of taste masking would be the discovery of universal

inhibitor of bitter taste of all drug.

2.11 CURRENT TRENDS IN TASTE MASKING TECHNOLOGIES

Different taste masking technologies have been used to address the problem of patient

compliance. Quantitative analysis was performed to compare the multitude of existing taste

masking technologies based on the patents filed. It also discusses the possible reasons for the

current trend. The worldwide database of European patent office (http://ep.espacenet.com) was

used to search the taste masking patents and the patent applications published in the period of

year 1997 to 2007. Patents and patent applications filed in different countries such as Republic

of Korea, Japan, USA, Canada, China, France, Russia, Mexico, South Africa, United Kingdom,

Australia and Ukraine were included in the analysis. As indicated in Fig. (1) from the collected

76 patents and 108 patent applications, about 49.34% of taste masking patents and patent

applications are contributed from Asia. North America accounts for about 41.45% of which

62.67% were filed in USA and about 9.30% from Europe.

Taste masking technologies are increasingly focused on aggressively bitter tasting drugs like

the macrolide antibiotics, non-steroidal anti-inflammatory drugs and penicillins. Taste masking

of water soluble bitter drugs, especially those with a high dose, is difficult to achieve by using

sweeteners alone.




As a consequence, more efficient techniques such as coating, microencapsulation and

granulation have been used in combination with the sweeteners. Coating, which accounts for

27% of patents and patent applications, was the most commonly used technique in the decade.

An almost equivalent percentage of patents were filed on the flavors and sweeteners for taste

masking. Microencapsulation, granulation technologies, suppressants and potentiators also hold

a prominent share of patents in this field. Less commonly used taste masking technologies such

as use of viscosity modifiers, solid dispersions, complexing agents, ion exchange resins, pH

modifiers hold 5% share of the total taste masking patents and patent applications.

Taste masking techniques

To achieve the goal of taste abatement of bitter or unpleasant taste of drug, Various techniques

reported in the literature are as follows:

By Addition of flavouring and sweetening agents.

By Microencapsulation

By Ion‐exchange resins.

By Inclusion complexation

By Granulation

By Adsorption

By Prodrug approach

By Bitterness inhibitor

By Multiple emulsion technique

By Gel formation

By solid dispersion

By mass extrusion

By wax embedding of drug

By liposomes

By lipophilic vehicle like lipids and lacithins

By taste suppressants and potentiators

By modifying ph

By freeze drying process

By viscocity modification

By salt preparation

By gelation

2.12 Taste masking by ion exchange resins [5-7]

Ion exchange resin are synthetic inert organic polymers consisting of a hydrocarbon network to

which ionisable groups are attached and they have the ability to exchange their labile ions for

ions present in the solution with which they are in contact. The most frequently employed

polymeric network used is a copolymer of styrene and divinylbenzene (DVB). Apart from this

other polymers such as those of acrylic and methacrylic acid crosslinked with divinyl benzene

and containing appropriate functional groups, have been used as ion exchange drug carriers.




History:

Ion exchange (IE), particularly Base Exchange, has been the subject of several scientific

investigations since the middle of the 20th century. In the beginning, it was primarily

significant process in the field of agricultural and organic analytical chemistry, which later

attracted research by healthcare professionals into this subject. Until 1934, natural and synthetic

siliceous materials, known as zeolites, were available for use as IE adsorbents for the

purification of water. In 1934, Adams and Holmes synthesized phenol formaldehyde resin and

showed that this resin can be used as a substitute for zeolites. In 1939, the Resins Products and

Chemical Company began investigations into the synthesis and production of ionexchange

resins (IER) under the original Adams and Holmes patent. In fact, it paved the way for the

application of IER to several industrial processes and biomedical applications. It was not until

1950 however, that IER were studied for pharmaceutical and biomedical applications. At this

time, Saunders and Srivatsava studied the uptake and release of alkaloids from IER and

suggested that these resins might act as a suitable chemical carrier for the development of

sustained-release formulations. IER have since been extensively explored in the field of drug

delivery, leading to some important patents.

Chemistry :-

An ion exchange resin is a polymer (normally styrene) with electrically charged sites at which

one ion may replace another.

Natural soils contain solids with charged sites that exchange ions, and certain minerals called

zeolites are quite good exchangers.

Ion exchange also takes place in living materials because cell walls, cell membranes and other

structures have charges.

In natural waters and in wastewaters, there are often undesirable ions and some of them may be

worth recovering.

For example, cadmium ion is dangerous to health but is usually not present at concentrations

that would justify recovery. On the other hand, silver ion in photographic wastes is not a serious

hazard, but its value is quite high. In either case, it makes sense to substitute a suitable ion such

as sodium for the ion in the wastewater.

Synthetic ion exchange resins are usually cast as porous beads with considerable external and

pore surface where ions can attach. The resins are prepared as spherical beads 0.5 to 1.0 mm in

diameter. These appear solid even under the microscope, but on a molecular scale the structure

is quite open. Whenever there is a great surface area, adsorption plays a role. If a substance is

adsorbed to an ion exchange resin, no ion is liberated.




Testing for ions in the effluent will distinguish between removal by adsorption and removal by

ion exchange. Of course, both mechanisms may be significant in certain cases, and mass

balances comparing moles removed with moles of ions liberated will quantify the amounts

of adsorption and ion exchange. While there are numerous functional groups that have charge,

only a few are commonly used for man-made ion exchange resins.

These are:

• -COOH, which is weakly ionized to -COO¯

• -SO3H, which is strongly ionized to -SO3¯

• -NH2, which weakly attracts protons to form NH3+

• -secondary and tertiary amines that also attract protons weakly

• -NR3+, which has a strong, permanent charge (R stands for some organic group)

These groups are sufficient to allow selection of a resin with either weak or strong positive or

negative charge.

Types of resins

Ion exchange resins contain positively or negatively charged functional group and are thus

classified as either anionic or cationic exchangers. Within each category, they are classified as

strong or weak, depending on their affinity for capable counter ions.

Cation exchangers (Anionic resin):- Cation-exchange resin is prepared by the

copolymerization of styrene and divinyl benzene and have sulphonic acid groups ( -SO3H)

introduced into most of benzene rings. The functional group

of these resins undergoes reaction (exchange) with the cations in the surrounding medium.

Mechanism: Resin- - ex+ + C+ Resin

- - C+ +ex

+

Where, Resin- indicates polymer with SO3 - sites available for bonding with exchangeable

cation (ex+) and C + indicates cation in the surrounding solution getting exchanged.

Anion exchangers (Cationic resin):-These are the poly electrolytes undergoing reaction

with the anions of the surrounding solutions. They are prepared by first chlormeythylating

the benzene rings of styrene-divinylbenzene copolymer to attach CH2Cl groups and then

causing these to react with tertiary amine such as triethylamine.

Mechanism: Resin+ - ex - + A- Resin

+ - A- + ex-

Where, Resin+ indicates polymer with N+ sites available for bonding with exchangeable

anion (ex-) and A-indicates cation in the surrounding solution getting exchanged.

2.13 Exchange capacity

The exchange capacity of an ion exchange resin refers to the number of ionic sites per unit

weight or volume (meq./gram or meq./mL).




Sulfonic acid resin derived from polystyrene matrix have lower exchange capacities, about 4

meq/gm, than carboxylic acid resin derived from acrylic acid polymer, about 10 meq/gm,

because of bulkier ionic substituents of sulfonic acid resin and polystyrene matrix.

Weak acid cation exchange resins have a pKa value of about 6, so that at pH 4 or above their

exchange capacity tends to increase. Ionisation of weak acid cation exchange resin occurs to an

appreciable extent only in alkaline solution, i.e., in their salt form. This is reported that their

exchange capacity is very low below pH 7 and moderately constant values at pH above about 9.

The rate of ion exchange is influenced by the permeability of the solvent and solute through the

pores of the resin, whose number and size are influenced by the amount of cross-linking. The

diffusion path length is obviously also related to the size of the resin particles.

2.14 METHOD OF IER-DRUG COMPLEX FORMATION-

Ion exchange resins may be supplied in case of cation exchangers as sodium, potassium or

ammonium salts and of anion exchangers usually as the chloride. It is frequently necessary to

convert a resin completely from one ionic form to another.

Charged drugs are normally loaded on to ion exchange resins by two methods,

column method

batch method.

Column method- In this method a highly concentrated drug solution is passed through a

column of resin particles. Since the reaction is an equilibrium phenomenon, maximum potency

and efficiency is best obtained by the column method.

Batch method- In this method the drug solution is agitated with a quantity of resin particles

until equilibrium is established. The reaction involved during complexation of drug with resin

maybe indicated as follows

Re-COO-H+ + Basic drug+ → Re-COO- Drug

++ H

+

Re-N (CH3) +3Cl- + Acidic drug

- → Re-N (CH3)

+3Drug

- +Cl

-

Upon ingestion, drugs are most likely eluted from cation exchange resins by H+, Na+ or K+

ions and from anion exchange resins by Cl-, as these ions are most plentiful available in

gastrointestinal secretions.

Typical reactions involved in the gastrointestinal fluids may be envisaged as follows:

In the stomach:

Re-COO- Drug

+ + HCl → Re-COOH + Drug Hydrochloride

Re-N (CH3)+

3 Drug - + HCl → Re-N(CH3)3 Cl + Acidic drug

In the intestine:

Re-COO- Drug

+ + NaCl → Re-COONa + Drug Hydrochloride

Re-N (CH3)+

3 Drug - + NaCl → Re-N(CH3)3 Cl + Sodium salt of drug.




2.15 CONFIRMATION OF COMPEXATION-

FTIR studies-

Drug, Resin, and physical mixture of both and DRC are subjected to Fourier transform infrared

spectroscopy(FTIR) studies. Samples are prepared using KBr disc method and spectra are

recorded over the range 400 to 4,000 cm−1. Spectra are analyzed for drug–resin interactions

and functional groups involved in the complexation process.

Powder X-ray diffraction studies-

X-ray diffractograms of Drug, Ion-exchange resin, and DRC are recorded using Philips PW

3710 diffractometer and analyzed for interactions between drug and resin and confirmation of

complexation.

Thermal analysis: Differential scanning calorimetry (DSC) is carried out using Mettler

Toledo 823e instrument equipped with intra-cooler. Indium zinc standards are used to calibrate

the temperature and enthalpy scale. The samples are hermetically sealed in aluminum pans and

heated over the temperature range 30°C to 300°C with heating rate of 10°C/min. Inert

atmosphere is provided by purging nitrogen gas flowing at 40 mL/min.

2.16 PROPERTIES OF ION-EXCHANGE RESINS-

1) PARTICLE SIZE & FORM: The rate of ion exchange reaction depends on the size of

the resin particles. Decreasing the size of the resin particles significantly decreases the time

required for the reaction to reach the equilibrium with the surrounding medium; hence larger

particle size affords a slower release pattern.

2) POROSITY & SWELLING: Porosity is defined as the ratio of volume of the material to

its mass. The limiting size of the ions, which can penetrate into a resin matrix, depends strongly

on the porosity. The porosity depends upon the amount of cross-linking substance used in

polymerization method. The amount of swelling is directly proportional to the number of

hydrophilic functional groups attached to the polymer matrix and is inversely proportional to

the degree of DVB cross linking present in the resin.

3) CROSS LINKING: The percentage of cross-linking affects the physical structure of the

resin particles. Resins with low degree of cross-linking can take up large quantity of water and

swell into a structure that is soft and gelatinous. However resins with high DVB content swell

very little and are hard and brittle. Cross-linkage has dramatic effect on loading efficiency. It

affects porosity and swelling properties of resin. Low cross-linking agents remarkably upon

hydration. Higher grade have finer pore structure thus reducing loading efficacy with increase

in cross- linking. Low cross linkage increase loading efficacy but also increases release rates.




4) MOISTURE CONTENT: A physical property of the ion exchange resins that changes

with changes in cross-linkage are the moisture content of the resin. For example, sulfonic acid

groups (-SO3H) attract water, and this water is tenaciously held inside each resin particle. The

quaternary ammonium groups of the anion resins also behave in a similar manner.

5) EXCHANGE CAPACITY: The exchange capacity refers to the number of ionic sites

per unit weight or volume (mEq. Per gram or meq per ml). The weight basis values (mEq. per

gm) are much higher than the volume based exchange capacity since the wet resin is highly

hydrated. The exchange may limit the amount of drug that may be adsorbed on a resin, hence

affect potency of the complex. Carboxylic acid resins derived from acrylic acid polymers have

higher exchange capacities (10meq. /gm) than sulfonic acid (about 4meq. / gm) or amine resins

because of bulkier ionic substituent and the polystyrene matrix. Therefore, higher drug

percentages may often be achieved with carboxylic acid resins.

6) ACID BASE STRENGTH-

It depends on various inorganic groups incorporated into resins. Resins containing sulphonic,

phosphoric or carboxylic acid exchange groups have approximate pKa values of <1, 2, 3 and 4-

6 respectively. Anionic exchangers are quaternary, tertiary or secondary ammonium groups

having pKa values of >13, 7-9 or 5-9 respectively. The pKa values of resin will have significant

influence on the rate at which the drug will be released in the gastric fluid.

7) STABILITY-

The ion exchange resins are inert substances at ordinary temperature and excluding the more

potent oxidizing agent are resistant to decomposition through chemical attack. These materials

are indestructible. They get degraded and degenerated in presence of gamma rays.

8) PURITY AND TOXICITY-

Since drug resin combination contains 60% or more of the resin, it is necessary to establish its

toxicity. Commercial product cannot be used as such. Careful purification of resins is required.

Resins are not absorbed by body tissue and are safe for human consumption. Test for

toxicological tolerance showed that it does not have any pronounce physiological action at

recommended dosage and is definitely non-toxic.

9) SELECTIVITY OF THE RESINS FOR THE COUNTER-ION

Resin selectivity is attributed to many factors. Since ion exchange involves electrostatic forces,

selectivity at first glance should depend mainly on the relative change and the ionic radius of

the (hydrated) ion competing for an exchange site. Factors other than size and charge also

contribute to the selection of one counter ion in preference to another.




The extent of adsorption increases with:

1. The counter ion that in addition to forming a normal ionic bond with the functional group of

an exchanger also interacts through the influence of van der Waal forces with the resin matrix.

2. The counter ion at least affected by complex formation with its co-ion or non-exchange ion.

3. The counter ions that induce the greater polarization. These factors, together with the effect

of the size and charge of an ion on exhibiting certain selectivity toward a resin, are at best only

general rules, and as a consequence there are many exceptions to them.

2.17 Desired properties of pharmaceutical grade IERs-

a) Fine, free flowing powders

b) Particle size of 25 - 150 microns

c) Contain functional group that capable of exchanging ions and/or ionic groups

d) Insoluble in all solvents, all pH’s

e) Not absorbed by body

f) Do not have a defined molecular weight

2.18 Advantages of Ion Exchange Resin as a Taste Masking Agent-

1. These method requires few and simple equipment.

2. The numbers of excipients required are less and are easily available.

3. The Bioavailability of drug is not altered.

4. The resins are easy to process and has high margin of safety.

5. The manufacturing can be carried out at room temperature and no other special experimental

conditions are required

6. It has low cost of manufacturing.

2.19 Applications of Ion Exchange Resins

Taste Masking: The taste perception of bitter drugs is experienced in the mouth at taste buds.

Taste masking has therefore become a potential tool to improve patient compliance. Since most

drugs possess ionic sites in their molecule, the resin's charge provides a means to loosely bind

such drugs and this complex prevents the drug release in the saliva, thus resulting in taste

masking. Generally, less cross-linked IER are helpful in taste masking. For taste masking

purpose weak cation exchange or weak anion exchange resins are used, depending on the nature

of drug. The nature of the drug resin complex formed is such that the average pH of 6.7 and

cation concentration of about 40meq/L in the saliva are not able to break the drug resin complex

but it is weak enough to break down by hydrochloric acid present in the stomach. Thus the drug

resin complex is absolutely tasteless with no after taste, and at the same time, its bioavailability

is not affected.




Examples of drugs in which this technique has been successfully demonstrated include

ranitidine, paroxetine and dextromethorphan. Same principle of taste masking has been

implemented in the rapidly disintegrating dosage form prepared using Zydis technology.

Studies have also showed the taste masking in case of quinolone category antibacterial

ciprofloxacin hydrochloride using Indian 234.

REFERENCE:-

1. Kuchekar bs, pattan sr, godge rk, et al. (2009), formulation and evaluation of

norfloxacin dispersible tablets using natural substances as disintegrants. J chem

pharm res., 1: 336-341.

2. File:///h:/cefixime/cefixime%20details/goutham.atla-426327-dry-syrups-education-

ppt-powerpoint.html

3. Shalini sharma and shaila lewis (2010), Taste masking technologies: A Review,

International journal of pharmacy and pharmaceutical sciences vol 2, issue 2, 2010

4. Zelalem ayenew trends in pharmaceutical taste masking technologies: a patent

review recent patents on drug delivery & formulation 2009, 3, 26-39

5. Fredrickson, j.k., reo, j.p.: wo2004066911 (2004).

6. Shalini sharma and shaila lewis (2010), Taste masking technologies: A Review,

International journal of pharmacy and pharmaceutical sciences vol 2, issue 2, 2010.



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