Ion exchange resin complexes: An approach to mask the taste of bitter drugs

Shailesh Sharma

"Worst the taste of the medication, the cure" was once the prevailing attitude¹.

Today this trend has changed and great importance is given to the organoleptic characteristics of pharmaceutical products i.e. mainly appearance, odor and taste². Masking of the unpleasant taste of a drug ( ex: azithromycin, clarithromycin) patient and product value³.

More than 50% of the pharmaceutical products are administered orally for several reasons, of which better patient compliance and existence of highly developed technology are most important.

Administration of an orally having bitter and obnoxious tastes with acceptable level of palatability is a challenge to the pharmacist in the present world, especially in pediatric and geriatric formulation. Thus taste masking in the present day pharmaceutical industry has become a potential tool to improve patient compliance and commercial success of the product⁴.

Recent years have seen a tremendous progress in the technique of masking the unacceptable taste of an orally administered pharmaceuticals, such as filling in capsules⁵, coating with water in soluble polymers or pH dependent water soluble polymer^6,7, adsorption on ion-exchange resin ^8,9,10,11,12, micro encapsulation with various polymers ^13,14,15 complexing with cyclodextrin¹⁶, chemical modification such as use of insoluble prodrugs ^17,18,19, effervescent systems, salt formation^20,21, and use of excipient like flavors, sweeteners, gelatin, gelatinized starch and surfactants.

Pharmaceutical companies are commercially motivated to invest time, money and resources in developing palatable, pleasant tasting products because good tasting products:

·Enhance patient compliance

·Provide a competitive advantage when a therapeutic category is crowded with similar products e.g. anti-infective category etc.

·Provide brand recognition to combat private-label competition.

Aside from the commercially motivating factors to develop acceptable tasting products, the pharmaceutical industry is also by the regulatory agencies for pediatric drug products. Currently, a drug must comply with the Food and Drug. Administration's (FDA's) campaign to improve labeling for pediatric products. The 23 FDA regulations, known as the Pediatric Rule, may mandate a drug firm to conduct pediatric clinical studies as part of the New Drug Applications. In the pharmaceutical industry, taste-making science broadly covers physiological and physiochemical approaches to prevent active pharmaceutical ingredient (API) or drugs from interacting with taste buds; thereby eliminating or reducing negative sensory response. Physiological approaches consist of inhibiting or modifying an API-mediated bitterness response by incorporating agents into a pharmaceutical formulation. Agents like sodium chloride, phosphatidic acid and peppermint flavor are known to inhibit bitterness by selected API molecules via a mechanism that takes place at the bitterness receptors in the taste buds²².

Taste²³:

The tongue is like a kingdom divided into principalities by sensory talent. The sweet sensations are easily detected at the tip whereas bitterness is most readily detected at the back of the tongue. Sour sensation occurs at the side of the tongue. Western civilization recognizes only four basic taste: Sweet, Sour, Salty and Bitter. The Japanese add a fifth taste called Umami for monosodium glutamate. The high acuity for bitterness may be an evolutionary defense mechanism that keeps us from swallowing poisions¹⁹.

Taste is a sensation, which is realized when a substance such as food, beverages or drug is placed in the oral cavity. This sensation is the result of signal transudation from the receptor organ for taste, commonly known as Taste Buds. These taste buds contain very sensitive nerve endings, which produce and transmit electrical impulses via the seventh, ninth and tenth cranial nerves to those areas of the brain, which are devoted to the perception of the taste buds²⁴.

Fig. 1 Diagram of the tongue showing localized taste buds

Antomy And Physiology Of Taste²⁵:

In mammal’s taste buds are aggregations of 30-100 individual elongated "intraepithelial"cells, which are often embedded in specialization of surrounding epithelium,termed papillae. At the apex of the taste bud, microvillus process protrudes through a small opening, the taste pore, into the oral milieu. At the base of the of the taste bud, afferent taste bud, afferent taste nerve invade the bud and ramify extensively, each fiber typically synapse with multiple receptor cells within the taste bud. Location of taste buds.

The taste buds are found on three types of papillae on the tongue.

1. A large number of taste buds are on the wall of the troughs that surrounds the circumvallated papillae, which forms 'V' line on the posterior surface of the tongue.

2. Moderate numbers of taste buds are on fungi form papillae over the flat a anterior surface of the tongue.

3. Moderate numbers are on the foliate papillae located in the folds along the lateral surface of the tongue.

4. Additional taste buds are located on the palate and few on the tonsillar pillars, the epiglottis and even in the proximal esophagus.

Innervations of tongue: The receptor cell does not have axons. Transmitter relays information onto terminals of sensory fibers. Theses fibers arise form the ganglions cells of the cranial nerves vii (facial - branch called the called the chorda tympani) and IX.

Figure 2 Diagram showing taste buds

Type Of Taste²⁶:

There are five basic tastes i.e. salt, sour, sweet and umami. A person can perceive literally hundreds of different taste. They are all supposed to be combination of the sensations. The sensitivity of tongue to different sensations varies widely. Within individual, a low threshold response to one basic taste is not always accompanied by low threshold for other sensations. Sensitivity for bitterness is always acute.

The average minimum concentration of sucrose (sweet), sodium chloride (salty), citric acid (sour), and quinine (bitter) that can be perceived by humans are approximately 0.5, 0.25, 0.007, and 0.00007% respectively.

1) Salty Taste:

The salty taste is elicited by ionized slat; sodium chloride has a typical salty taste²⁵. Chlorides of potassium, ammonium and calcium have a similar salty taste, but their solution taste differently. Most halide salts (NaCL, KCL, NaBr, Nal) have a dominating salty taste. Potassium bromide and ammonium iodide have a salty, bitter taste, but potassium iodide is intensely bitter, indicating that taste sensitivity of salt shifts to bitterness as the molecular weight increases.

2)Sour taste:

Acids cause sour taste and the intensity of the taste sensation is approximately proportional to the logarithm hydrogen ion concentration²⁴. In dilute solution at the same concentration, is tasteless. This indicates that sour taste is due to hydrogen and not chloride ions, implying that sour sensation in solution can be eliminated by appropriate counter ions. It has been demonstrated that the addition of sodium acetate to acetic acid reduces the hydrogen ion concentration, there by eliminating the sour sensation in acetate solution.

Sour taste is not entirely dependent on hydrogen ions, however the concentration of anions and undissociated species in solution are also important.

3) Sweet taste²⁵

Any single class of common sweet substances, sugars (sucrose, fructose, glucose etc.) and glycerin are polyhydric alcohols - CH₂OH groups, which contribute significantly to sweetness. Saccharine contains a benzene nucleus and is intensely sweet in taste. In contrast, naturally occurring glycosides frequently contains a benzene nucleus but are bitter.

Some amino acids, for example glycine are sweet. Glycine in combination of saccharine is used as sugar substitute. The sodium and calcium salts of cyclohexy sulfuric acid (cyclamates) and dipetide esters aspartame are roughly thirty times more sweeter than sugar and have been used as a sugar substitute²⁶.

4) Bitter Taste:

A bitter taste like a sweet taste is commonly found in a wide in a wide variety of compounds most of which are salts of organic acids.

Two particular classes of substance are especially likely to cause bitterness.

• Long-chain organic substances that contains nitrogen.
• Alkaloids²⁵.

The degree of bitterness of both organic and inorganic compounds is generally related to structural relationship at taste receptor. For example, as the molecular weight of salt increase the taste changes from saline to bitter. Thus, sodium chloride is salty, but cesium chloride and many iodides are bitter.

Bitterness is often associated with the nitro (NO₂) group and the presence of one or more nitro group in a molecule might result in a bitter taste²⁶.

Mechanism of Stimulation of Taste ²⁵.

The membrane of the taste cell, like that of other sensory receptor cells, is negatively charged on the side with respect to outside. Application of taste substance to the taste hairs causes partial loss of this negative potential - i.e. cell is depolarized. The decrease in potential, within the wide range, is approximately proportional logarithm of concentration of stimulating substance. This change in the potential in the taste cell is the receptor potential for taste. The mechanism by which most stimulating substance react with the taste villi is by binding of the taste chemicals to the portion receptor molecule that protrude through the villus membrane. This is turn allows sodium to enter and depolarize the cell. Then the taste chemical is gradually washed away from the taste villus by saliva, which removes the stimulus.

1) Salty taste:

Na⁺ ions enter the receptor cells via Na-channels. These are amilorid-sensative Na⁺ channels. The entry of Na⁺ causes a depolarization, ca⁺ enters through voltage sensitive Ca⁺ channels, transmitter release occurs in increased firing in the primary afferent nerve.

2) Sour taste:

Sour taste is acidic H⁺ ions block K⁺ channels and are responsible for maintaining be cell membrane potential at hyperpolarized level. Block of these cannels causes a depolarization, Ca⁺ entry transmitter releases and increased firing in the primary afferent serve.

3) Sweet Taste:

There are receptors in the apical membrane that bind glucose (sucrose- a combination of glucose and fructose - and other carbohydrates). Binding to the receptor activates adenylyl cyclase, thereby elevating cAMP. This causes a PKA - mediated phosphorylation of K⁺ channels, inhibiting them. Depolarization occurs, Ca²⁺ enters the cell through depolarization - activated Ca²⁺ enters the cell through depolarization-activated Ca²⁺ channels; transmitter is released increasing firing in the primary afferent nerve.

4) Bitter Taste:

Bitter substances cause the second messenger (IP₃) mediated release of Ca²⁺ causes transmitter release and this increases the firing of the primary afferent nerve.

5) Umami taste:

Umami is the taste of certain amino acids (e.g. glutamate, aspartate and related compounds). Recently it has been shown that the metabotropic glutamate receptor (mGluR4) mediates umami taste. Binding to the receptor activates a G-protein and this may elevate intracellular Ca²⁺. Monosodium glutamate, added to many foods to enhance their taste (and the main ingredient of Soy sauce), may stimulate the umami receptors. But, in addition, there are ionotropic glutamate receptors (linked to ion channels), i.e. the NMDA - receptor, on the tongue. When activated by these umami compounds or soy sauce, non-selective cation channels open, thereby depolarizing the cell. Calcium enters, causing transmitter release and increased firing in the primary afferent nerve²³.

Sensory Analysis²⁶

Sensory analysis has been used in developed countries for years to characterize flavors, odors and fragrances. In recent times much progress has been made in development of instrumentation methods for characterizing odors and flavors.

These methods are often more useful in aroma and flavor research than in product development where formulation are usually complex and sensory methods can provide equally reliable data on overall flavor character.

Sensor analysis employs objective or analytical methods and subjective or hedonic methods.

A. Subjective Methods

1. Preference Test

a. Paired Testing

b. Triangle Testing

2. Hedonic scale

B. Objective Methods

1. Difference Test

a. Paired Difference Test

b. Triangle Difference Test

c. Duo-trio Test.

2. Ranking Test

3. Analytical

a. Flavor Profile

b. Time-Intensity Test

c. Single Attribute Test

A. Subjective Methods:

Subjective method assesses the performance of a flavored product using a large number of untrained analysts. Field "Pretest" generally falls in this category. Often several preparations are tested against control. Untrained analysts are used and methods are characterized by spontaneity and results are often biased by emotional and personal attitudes.

1. Preference Tests:

a. Paired testing

Paired testing compares the taste of tow samples, that is, how sweet, bitter, sour or salty they are. Because untrained analysts are employed in such tests, associative effects are not easily quantified. Detection of a difference between samples may be associated with a bias, which would be analogues to the bias attached to things considered different, odd, bad or good. Since analysis of the bias is as important as the magnitude of sample difference, routine testing is not useful in product development. Yet these tests are beneficial in market decision -making because results are based on user preference.

b. Triangle testing:

Like paired tests, triangle test do not provide quantitative data on differences between similar or dissimilar samples. These tests are designed to limit bias and improve confidence in the selection process. They provide quantitative difference between samples. Usually three preparations are tested; two are identical, where as the third is different in one or several respects. Because data generated by triangle testing is largely subjective, criteria for determining accuracy of results and hence validity of prediction from such test are poorly defined and nonexistent. Statistically, the triangle testing is preferred because there is only 33.3% chance of guessing, and only a limited number of test are required compared to a 50% chance of error in paired testing.

2. Hedonic Scale:

The term hedonic applies to a scalar measure used to describe the degree of acceptance of a flavor. Hedonics are designed to recognize a fixed point of neutrality (zero point) for a flavor. This allows rating the flavor on the basis of the degree of its negative or positive sensation on a scale. Negative numbers on the degree of unpleasantness, where as the positive numbers reflect the degree of accepting of flavoring agent.

Hedonics in pharmaceutical flavor work provide subjective estimate of the degree of acceptance of a totally flavored product. They are most useful for trained flavor panelists who can apply a continuum of positive numbers to describe the intensity of a specific element f a flavored product. This has the disadvantage that a continuum of positive number ignores the neutral point and thus compares the relative acceptance to the relative acceptance level for a product based on the performance against a reference.

B. Objective Method:

Objective methods in flavor test generally use a small panel of trained analysts with standardization methods of identifying various tastes. The panel members act like an instrument and use their carefully controlled senses to analyze organoleptic quality of a product in such a way that emotional basis is eliminated.

1. Difference tests:

A. Paired-difference test:

Paired-difference test are useful in screening formulation studies. This test includes a benchmarked product designated as control sample and a treatment sample. Two groups of samples pair are tested. In one group each pair contains a treatment and a control specimen. In the other group, the pair contains only treatment or only control. Sample The primary question is “Are the sample same or different?” samples are randomly coded in order to eliminate bias.

O = control sample. X = treatment sample.

Finding difference between samples then follows this: “Are there difference between the sample?” after completing this test, the panel director analyzes the data concludes that there are no perceptible differences between samples. However comments from panelist suggest that some perceives slight “after taste” difference, where as other do not. With this information the director decides to perform a confirmatory test using a triangle difference test.

B.Triangle Difference Test

The objective of the panel director is to determine which sample is to differs in “lingering bitter after taste”. In each group two samples are alike and contain either control formulation or the reformulated product. Third sample is different but also contains either control formulation or the reformulated product. The samples are presented in straight line and six possible different sample positions.

The experimental protocol is shown below

In this method the director as supportive information to determine consistency of the panelists in identifying different samples uses comments from panelists. Reyes Vega et. al. applied triangle difference tet to detect lot-to-lot variation in organoleptic properties in aluminum and magnesium hydroxide antacid suspension from 22 lots prepared in different dates²⁶.

C. Duo- Trio Test:

In duo- trio test, the panel director designates one sample usually control, as the reference, In addition, several pairs of samples are given to panelists, each consisting of one control and one treatment sample. All samples are labeled in a randomized fashion. The task of the panelists is to identify the pair that is similar in performance to the reference control sample.

2. Ranking Tests

Ranking tests are used when more than two samples are to be evaluated. If six samples are to evaluate of a formulation for sweetness difference, the task panel is to rank the series in order from the least to most sweet. A typical rank test score sheet is shown in Table. 1.1

Table 2 Typical Rank Test Score Sheet

Intensity Score:

0 = Absent, 1 = threshold, 2 = moderate, 3= moderate ranking test are useful to formulation scientist because they provide information about a specific characteristic of flavor or aroma. Ranking test is also used to determine which formulation is most or least bitter²⁷.

3.Analytical Test:

a.Flavor profile:

The flavor profile is widely used descriptive analytical test. It is based on a natural process, often performed instinctively, for evaluating and comparing flavor. A flavor profile measure s objectively, qualitatively the perceptible factors of a product that is aroma flavor by mouth, feeling factor and after use sensations.

b. Time intensity study:

The Arther D. Little flavor Laboratories, 1954, developed this method of flavor analysis. It is useful in time dependent product quality assessment.

Panelist record after taste impression as a function of time and several sessions are allowed until a consensus is arrived at. Data from the test sessions are compiled and graphically summarized with intensity on Y-axis and time on X-axis.

C.Single-Attribute Tests:

Single attribute test are valuable in quality control and routine release testing of products by manufacturer. The technique is similar to the flavor profile method, except that the panel concentrates on one attribute only. For example a product during a mixing step at manufacture relative to time and temperature can be investigated by single attribute.

Taste Masking Of Oral Pharmaceuticals

Sensory development in bitterness reduction and inhibition are an important mainstay of product evaluation in oral pharmaceuticals formulation. Taste is an important parameter governing compliance; however the customer does not care for the taste modality of bitterness in the broadest sense and continue to be displeased with the products of bitter taste. Oral pharmaceuticals with a perceived bitter taste may include chewable and non-chewable tables, capsules, syrups, suspension, concentrates, lozenges, dentifrices and mouthwashes and ingestible ointments. However, proven methods for bitterness reduction and inhibition have resulted in improved palatability.

Bitter oral pharmaceuticals can be processed or formulated to improve taste by masking with ingredients such as flavors, sweeteners, gelatin, gelatinized starch, chitosin, cyclodextrin, liposome’s, lecithin and lecithin like substances, surfactants, salts and ion exchange resins²⁷.

Taste abatement by flavoring: -

Flavoring of Pharmaceuticals applies primarily to liquid dosage forms intended for oral administration. Medications in liquid dosage forms obviously come into immediate and direct contact with taste buds. By the addition of flavoring agents to the liquid medications, the disagreeable taste of drugs may be successfully masked. A combination of flavoring agents usually required for masking disagreeable taste effectively.Menthol, chloroform, and various salts are frequently used as flavor adjuncts. Menthol and chloroform are some times referred as desensitizing agents. They impart a flavor or odor of there own to the product and have mild anesthetic effect. Mouth washes or cough drop formulation with medicinal of bitter taste such as those containing as much as 0.35% eucalyptus oil can be masked by including 0.0025% fenchone, bomeol or subnormal. Such agents can be used to taste masked the bitterness of volatile oils²⁸. 'Anesthetizing agents like sodium phenolate can be added to mask the taste buds sufficiently within 4-5 seconds. That is helpful in inhibiting the perception of the bitter taste of formulation. This approach has been used to produce taste masked medicated floss of Aspirin. Pharmaceutical flavors are available as liquids (essential oils, fluid extracts, tinctures, distillates, etc.) solids (crystalline vanillin, freezed dried cinnamon powders, and dried lemon in fluid extract) and pastes (soft extracts, resins and so called concentrates, which are brittle on outside and soft on the inside). Liquid flavors are widely used because they diffuse readily into substrate. They are available as oily (essential oils) and non-oily liquids.

Natural Flavoring agents for taste masking of bitter drugs:

Natural flavors have been used for a long time to flavor food and to make early medicine palatable. Honey was and remains a sweetener agent, to support the taste masking capabilities of clove, vanilla flavoring such as honey or artificial vanilla are preferred²⁹.

Modern use of natural flavor is limited because they are often unstable and the quality is unpredictable from season to season. The most commonly used are terpeneless citrus oils, which are stable if well protected from light and air.

Commonly used natural flavors are:

1.Anise oil -containing anethole, methyl chavicol, p-methoxy phenyl acetone and acetic aldehyde used at a concentration of 3000 ppm in liquid preparation.

2. Cardamom oil - main constituents are limanon, limol, D-α-terpenol and terpenyl acetate used at concentration of 5 to 50 ppm.

3. Lemon oil - D- α -pinene, camphene, D-limolene, dipentene, L-Iinolol, nerol, and citrol concentration range- 1 to 35 ppm.

4. Pippermint oil- α and β pinene, limonene, cineol, ethylamine carbinol. It has a strong mint odor with a sweet balsam taste masked by a strong cooling effect used at a concentration 8000 ppm.

Artificialflavors:

Unlike natural flavors synthetic flavors are usually stable. The development of synthetic flavors is paralleled to the development of instrumental analysis where actual ingredients in natural flavors are identified and the flavor primarily reconstituted synthetically with reasonable accuracy.

Artificial sweeteners like neohesperidine dehydrochloride, which is a bitterness suppressor and flavor modifier elicits a very intense sweet taste. It is obtained by hydrogenation of bitter flavones neohesperidine.

Vitamins containing oral solutions are rendered bitterness free by adding sugars, amino acids and apple flavors. Oral composition containing vitamin B-complex, sodium 5- ribonucleotide (inosinate), citrous (orange) flavors or fruit flavors also have remarkably improved taste³⁰.

Adrenergic or stimulants usually impart a strong bitter taste. The "chewing not brewing" trend has become quite popular and has lead to increased demand for caffeine chewing gums and lozenges. These gums and lozenges are made palatable by addition of vitamins, essence of garlic, spices, carrot concentration, and four types of sugar for taste masking.

Taste abatement by coating: -

Coating is an extremely useful technique for a number of applications in pharmaceutical field. Although it is used primarily for production of sustained release, Gastro-intestinal dosage forms, it also has major applications in masking the unpleasant ¹³

A great deal of attention has recently been focused on the usefulness of coated fine particles in pharmaceutical technology. By coating drug particle with appropriate polymer system desirable properties can be imparted to the dosage form with resultant elimination of undesirable properties as taste.

Merely applying thicker layer of coating can be in effective in taste masking of certain drugs with objectionable taste. Thick coating can cause problem both in terms of size and cost apart from being problematic in getting desired release profile of drug . Aqueous based coating systems are safe in accordance with regulatory requirements, economical and relatively easy when compared to non-aqueous based coating systems. The elasticity provided by micro encapsulation by polymer inhibits the release of Ibuprofen in mouth when chewed ³¹.

Polymers used for taste masking by coating:

The polymers used for the purpose of taste masking are selected on the basis that they should permit the rapid release of drug in the saliva, but allows it in the gastric cavity or in the duodenal region where the drug is expected to be absorbed. Polymers may be water soluble or dispersible (e.g. hydroxy ethyl methyl cellulose, methyl cellulose) for dissolution in stomach. It may be enteric polymer that does so in small intestine (e.g. cellulose acetate phthalate).

The polymer may be insoluble at pH of the Gl tract such coating can be viewed as diffusion coating²⁶.

Taste abatement by lipophilic vehicles:

Lipids: Oils, surfactants and polyalcohols effectively increase viscosity in the mouth and coat taste buds. A taste masking carrier for acetaminophen composition comprises of aliphatic or fatty acid esters. Stearyl stearate is used as a carrier for acetaminophen by using fluidized bed coating for acetaminophen granules³². Similarly, the experimental drug for seizures, gabapentin, has improved taste when coated with gelatin and with a mixture of partially hydrogenated soybean oil and glycerol monostearate³³. Another approach of coating for taste masking oral medications includes a unique combination of triglyceride and a polymer. The triglyceride mixture melts at the body temperature and copolymer causes the coating to dissolve upon reaching the acidic environment of the stomach. The ingredients necessary for this approach are triglycerides, which when mixed together, melts at the body temperature leaving the polymer, which is insoluble at pH 7.4, but soluble in the stomach. Metronidazole and various other solid drugs with disagreeable or bitter taste have been effectively taste masked by using this approach.

The coating material may be easily applied using a variety of methods, including spray coating and pan coating. In case of suspension, the coating material will maintain its integrity to mask disagreeable taste in a liquid medium with pH greater than 5.5 and stored at the refrigerated temperatures. Clarithromycin was prepared into a wax matrix with glycerol monosterate and amino alkyl methacrylate copolymer E, resulting in a formulation, which was fully taste masked as well as having optimum release characterstics.

Lecithin like substance:

Most recently research has found a specific inhibitor for bitter taste that is universal to several test substances and may be useful for masking the bitter taste of drugs and food. The Kao Corporation in Japan, together with the Faculty of Pharmacy at Hokkaido University, has found that homogenated suspension of posphatidic acid and 6-lactoglobulin from soybean and milk, respectively, completely suppress bitter stimulants such as quinine, L-leucine and isolucine and isoleucine, caffme and papaverine hydrochloride. The suspension was effective in selectively inhibiting the bitter taste and did not affect the sweet, sour of salty taste. Other lipids like triglycerides with G-lactoglobulin and phosphatidylcholin did not have marked effect³⁴.

Taste Abatement by Carbohydrates:

Coating the drugs with polymeric membrane can mask the taste of orally administered bitter drugs. Bitter solids drugs are formulated in an organoleptically acceptable manner by particle coating with a mixture of a water insoluble film forming polymer (cellulose and shellac) and a second film - forming polymer soluble at a pH less than five.

Adsorption onto the polymeric carbohydrate is an effective means for reducing the bitter taste of an active ingredient. Chlorpheniramine maleate can be adsorbed onto avicel PHI01 porous particles as an aqueous solution containing 50 parts Chlorpheniramine maleate onto 3000 parts of polymeric material. The product obtained after adsorption was spray coated with an aqueous solution containing xylitol to get final coated product which was taste masked.The compressible grade formulation of xylitol are available as Xylitab. Triprolidine hydrochloride was taste masked with dispersion coating of water soluble polymer hydroxypropyl cellulose a plasticizing agent, a sweetener and a flavoring agent.

Several drugs can be taste masked with starch or cellulose, containing carboxy methyl groups, example include carboxymethyl cellulose (CMC), sodium CMC, cross- linked sodium CMC, sodium CM starch⁴⁴. Core element of drugs when coated with a water insoluble polymer such as ethyl cellulose offer taste masking and reduced dissolution profiles for a Varity of drugs including paracetamol, doxycycline hydrochloride, theophylline, and aspirin. Pharmaceutical agents with bitter taste are coated with water-soluble polymer of hydroxypropyl cellulose and sugars such as lactose and sucrose to decrease the bitter perception at the time of oral administration .

Sparfloxacin is optimally taste masked by preparing film-coated granules. Higher levels of ethyl cellulose reduce bitterness most effectively. Ibuprofen may also be formulated and coated with a solution of hydroxyethyl cellulose and hydroxypropyl methylcellulose in water to obtain coated granules, which can be compressed into chewable tablets⁴⁷. Aspirin tablets can be taste masked with plasticized thin film of cellulose acetate latex and triacetin along with coated medicaments .A preparation of the antiulcerative drug propentheline bromide coated on low substituted spherical hydroxypropyl cellulose was further coated with ethyl cellulose to mask the unpleasant taste. Croscarmellose sodium has been used to coat bitter tasting active agents to mask their bitter taste and impart the rapid disintegrating properties to tablet. Chewable tablets of acetaminophen were prepared by compressing the coated particles. Particles were coated with a blend of cellulose acetate or cellulose acetate butyrate and polyvinyl pyrrolidone. The coating provides excellent taste masking while still permitting excellent bioavailability. Bianchini et al have successfully taste masked the bitter taste of d-indobufin, a platelet aggregation inhibitor by Eudragit E-100, RL/RS, and ethyl cellulose using fluidized bed drying technique.

Taste abatement by Proteins, Gelatin and Prolamines^35,36:

Tylenol Geltabs (McNeil Consumer Products Co., Fort Washington, PA), which uses Geikote gelatin - coating process, offers ease of swallowing and taste masking. The notable disadvantage of this preparation arises in hot, humid climates, where product stability is affected. Prolamine forms the main protein component of cereal grains and flour and can be extracted from flour with 80% alcohol unlike other proteins. Most important prolamines are zein, gliadin and hordein. Prolamine fraction of grain proteins can be applied as a single coat in weight ratios of 5 to 10%, relative to active substance being coated. This gives a suspension, which effectively masks the extremely bitter taste of orally administered drugs. The taste masking is effective over prolonged period of storage. Besides effectively masking the taste of the bitter drugs, prolamine coatings do not affect immediate bio availability of the active substance. Various antibiotics, vitamins, dietary fibers, analgesics, enzymes and hormones have been effectively taste masked using prolamine coatings. Water insoluble vegetable oil or wax concentration in the range of 2 to 15% is capable of plasticizing the prolamine coatings. Zein or gliadin in combination with plasticizers (thickness 1 to 35u) were highly effective in controlling the release of the active substance from encapsulated particles and masking the unpleasant taste of the coated active substance.

For mint-flavored pharmaceutical gums, incorporating a prolamine/cellulose ingredient can reduce bitterness of the flavor. A high-pH aqueous zein solution, used to coat hydroxypropyl cellulose, is particularly effective in combating the bitterness of spearmint flavor^. Macrolide antibiotics have been coated with a mixture of prolamine and plasticizers such as vegetable oil and wax. The coating prevents dissolution of the drug in mouth and acts as a taste masker. Water insoluble gel formed by sodium alginate in the presence of bivalent metals is also exploited for their taste masking properties. Amiprilose hydrochloride was taste masked by first coating the drug with calcium gluconate and followed by coating it with sodium alginate. Upon oral administration, it forms a gel on the surface of the tablet to mask its bitter taste.

Taste abatement by Rhcological modification³⁷:

Increasing the viscosity with rheological modifiers such as gums or carbohydrates can lower the diffusion of bitter substance from the saliva to the taste buds. The composition comprises of a taste masking liquid excipient base with a relatively higher amount of viscosity inducing agents such as polyethylene glycol and sodium carboxymethyl cellulose. Well-known commercially available pharmaceutical compounds delivered using the present approaches are pseudoephedrine HC1, extromethorphan and ibuprofen.

Taste abatement by ion exchange resins^{38- 39}:

Most of the bitter drugs have amine as a functional group, which is the cause of their obnoxious taste. If the functional groups are blocked by complex formation the bitterness of the drug reduces drastically⁵⁸. Pharmaceutical industry has been doing this type of complex formation by converting the drug to stearates and estolate. But now days the use of ion exchange is done to block the functional group responsible for causing the bitter taste by forming complex between ion exchange resin and the drug. Ion exchange resins are water insoluble, cross-linked polymers containing salt forming groups in repeating position on the polymer chain. Drug can be bound to the ion exchange resin by either repeated exposure of the resin to the drug in a chromatographic column or by prolonged contact of resin with the drug solution. The resins forms insoluble adsorbates or resonates through weak ionic bonding with oppositely charged drugs. The exchange from counter ions from resin is competitive.

Ion Exchange Resins for taste masking of bitter drugs

Ion Exchange Resins have been a useful tool for a production pharmacist to mask taste of drugs since the late 1950’s. Ion-exchange resins (IER), or ionic polymer networks, have received considerable attention from pharmaceutical scientists because of their versatile properties as drug delivery vehicles. In the past few years, IER have been extensively studied in the development of novel drug-delivery systems (DDSs) and other biomedical applications. Some of the DDSs containing IER have been introduced into the market.

They were first developed for applications in waste water purification and were later adopted for downstream processing of fermentation product. The utility of these materials as excipient was first suggested by Saundes and Chaduhary by using them for sustain release of charged drugs⁴⁰.

IER are water insoluble cross linked polymer containing salt forming group in repeating position on the polymer chain²². IER are polymeric particles (or Gels) that contain basic or acidic group, which can form ionic complexes with oppositely charged drugs. The resins are insoluble solids that are not absorbed from GIT; hence, they do not have significant associated side effect⁴¹.

IER have been used as a drug carriers in pharmaceutical; dosage form for taster masking⁴² and controlled release^43-45.

Introduction of synthetic IER have changed the scenario drastically. The present pharmaceutical industry has ion exchangers far more superior and versatile then the original natural and synthetic mineral like products. The basic reason for this is that the modern synthetic ion exchangers can be formulated to required matrix structure, particle size and functionality for any specific purpose⁴⁶.

Figure 3 General classification of ion exchange resins⁴⁷

Taste abatement by ion exchange resins⁴⁸:

Most of the bitter drugs have amine as a functional group, which is the cause of their obnoxious taste. If the functional groups are blocked by complex formation the bitterness of these drugs can be reduces drastically. Pharmaceutical industry has been doing this type of complex formation by converting the drug to stearates and estolate. But now days the ion exchange resins all used to block the functional groupresponsible for causing the bitter taste by forming complex between ion exchange resin and the drug. Drug can be bound to the ion exchange resin by either repeated exposure of the resin to the drug in a chromatographic column or by prolonged contact of resin with the drug solution. The resins forms insoluble adsorbates or resonates through weak ionic bonding with oppositely charged drugs.

Drug release from ion exchange resin depends upon two factors

1. The ionic environment (i.e. pH and electrolyte concentration) with in the gastrointestinal tract.
2. The properties of resin.

Drug molecules attached to the resins are released by appropriate charged ions in the gastrointestinal tract, followed by diffusion of free drug molecules out of the resin as shown below.

Strong acid cation resins (sulfonated styrenedivinyl benzene copolymer products) can be used to mask the taste of basic drugs having bitter taste; as they function through out the entire pH range. Weak acid cation exchange resins function at the pH values above6. Similarly, strong base anion exchange resin function throughout the entire pH range, while the weak base anion exchange resins function well below pH 7.0 ²⁷.

Polystyrene matrix cation exchange resins (Indion CRP-244, Indion CRP-254) have been used to mask the bitter taste of chlorpheniramine maleate, ephedrine HCl, diphenydramine HCI ⁴⁹. Radebaugh and Galen were able to successfully mask the bitter taste of ranatidine and buflomedil by using Amberlite IPR-69⁵⁰.Ion exchange (India Ltd.) has successfully masked the taste of the following drugs like azithromycin by using various grades of Indion ion exchange resins as shown in the table below

Table1. 1.2: Drugs taste masked by various grades of Indion ion exchange resin.

Name of the drug	Ion exchange resin
Ciprofloxacin	Indion-234
Azithromycin	Indion-214
Chloroquine phosphate	Indion-234
Chloprquine sulphate	Indion-234
Dextromethorphan hydrobromide	Indion-234
Norfloxacin	Indion-204

Resinate Preparation and Evaluation^{51 - 53}

Once the selection of a resin is made, the next step involves preparing its complex with drug, before designing a suitable delivery system. The main challenge is to optimize the conditions of resinate preparation, in order to obtain the desired drug loading in the resinates. Generally, the following steps are involved in the preparation of resinates:

• Purification of resin by washing with absolute ethanol, ethanol and water mixture. Final washing with water removes all the impurities.

• Changing the ionic form of IER might occasionally be required to convert a resin from one form to another, if it does not have the desired counter ions. Strongly acidic CER are usually marketed in Na⁺ form and strongly basic AER in Cl^- form. They are generally converted into hydrogen and hydroxide forms, respectively. The conversion can be achieved by soaking the resins with acid or alkali solutions, respectively. After changing the ionic form, the resin is subjected to washing with distilled water until elute becomes neutral in reaction, and finally is dried at 50°C.

• Preparation of resinate is normally done by two techniques:

(a) Batch technique – after suitable pretreatment, a specific quantity of the granular IER is agitated with the drug solution until the equilibrium is established; and

(b) Column technique – resinate is formed by passing a concentrated solution of drug through the IER-packed column until the effluent concentration is the same as the eluent concentration.

The merits of the Ion-Exchange Resin-Drug complex are

(1) Sustained-release preparations can be made by formulating a gel-forming ion-exchange resin.

(2) Reduction of the degradation of drug molecules in the gastrointestinal tract due to complexation.

(3) The bitter taste is masked.

A problem as­sociated with this approach is that drug release can be very rapid in the presence of an excess of ions, and dose dump­ing can occur. This can be prevented by impregnating the ion-exchange resin with an agent to impart plasticity and then coating it with a semi-permeable membrane such as ethyl cellulose so that the release of drug from complex is diffusion controlled⁵⁴.

Factor affecting Resinate Performance^{55 - 58}

Øthe pH and temperature of the drug solution;

Ø the molecular weight and charge intensity of the drug and IER;

Ø geometry;

Ø mixing speed;

Ø ionic strength ofthe drug solution;

Ø degree of cross linking and particle size of IER;

Ø the nature of solvent; and

Ø contact time between the drug species and the IER.

Properties of ion exchange resins⁵⁹

1)Particle size and form

The rate of ion exchange reactions depends on the size of the resin particles. Decreasing the size of resin particle significantly decreases the time required for the reactions to reach equilibrium with surrounding medium. Most of the ion exchange resins are sold in the form of spherical beads. When the beads are immersed in water, they imbibe a limited amount of liquid to form a homogeneous gel like structure.

2) Porosity and Swelling

Porosity is defined as the ratio of the volume of the material to it’s mass. The limiting size of ions, which can penetrate into a resin matrix, depends strongly on the porosity. The porosity of an ion exchanger depends not only on the amount of crosslinking substances used in polymerization but mainly on polymerization procedures. The structural parameter considerably influence the swelling behavior of the resin and consequently have a marked effect on the release characteristic of drug resonates. 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 divinlybenzene crosslinking present in the resin.

3) Crosslinkage

The percentage of cross-linkage effect the purely physical structure of the resin particle. Resins with a low degree of cross-linkage can take up a considerable amount of water and swell into a structure that is soft and gelatinous. However, resins with a divinlybenzene content swell very little, these particles take up only a small amount of water and consequently are somewhat hard and brittle.

4) Available Capacity

The capacity of an ion exchange is a quantitative measures of it’s ability to take up exchangeable counterions and is therefore of major importance. However, in the preparation of drug resonates, the actual capacity obtained under specific experimental conditions depends on the accessibility of the functional groups for the drug of interest.

5) Acid-Base Strength

The acid or base strength of an exchanger is dependent on the various ionogenic groups, incorporated into the resin. Resin containing sulfonic, phosphoric, carboxylic acid exchangers groups have approximate pKa values of <1,2-3 and 4-6, respectively. Anionic exchangers are quaternary, tertiary, or secondary ammonium groups having apparent pKa values of >13,7-9 or 5-9 respectively. The pKa value of the resin will have a significant influences on the rate at which the drug will be released from resinate in the gastric fluids.

6) Selectivity of The Resins For The Couter-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 others than size and charge also contribute to the selection by an one counter in preference to another. The extent of sorption increases with-

a)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 walls forces with the resin matrix.

b)the counter ion at least affected by complex formation with it’s co-ion or non exchange ion.

c) the counterions that induces the greater polarization.

These factors, together with the effect of the size and charge of an ion an exhibiting certain selectivity toward a resin, are at best only general rules, and as a consequence there are many exceptions to them.

7) Stability

The resinous ion exchanges are remarkably inert substances. At ordinary temperature and excluding the more potent oxidizing agents, vinlybenzene cross-linked resins are resistant to decomposition through chemical attack. Nevertheless, these materials are indestructible. Another limitation of these resins is there degradation in the presence of strong gamma ray sources.

Application of Ion Exchange Resins

01. Taste⁶⁰

IER have no taste as they are insoluble in water. This makes them excellent candidate for ­taste-masking foul-tasting drugs. As long as the rate of release of the drug on contact with saliva is sufficiently slow, this technology works extremely well. It is equally applicable to liquid formulations (suspensions) and dissolve-in-the-mouth tablets.

02. Stability⁶¹

The drug resinate is frequently more stable than the original drug. Vitamin B₁₂ has a shelf-life of only a few months but the resinate is stable for more than two years. Another example is nicotine; it discolours quickly on exposure to air and light but the resinate (used in nicotine chewing gums and lozenges is much more stable.

03. Poor Dissolution ⁶¹

Most of the drugs are poorly soluble due to slow dissolution and/or low solubility. The rate of release of a poorly soluble, ionisable drug from a resinate can be much quicker than the rate of dissolution of the pure drug. An excellent example resinate of Indomethacin

04. Deliquescence⁶¹

Deliquescence is the property of a solid- whereby it absorbs so much water that it dissolves in the water it absorbs. While this is not a common problem, it has been a very difficult one to solve and requires the use of specialized equipment or careful scheduling of production in dry seasons. However, the resinate of a deliquescent drug is not deliquescent, permitting its formulation into typical dosage forms with standard equipment. resinates of sodium valproate is the best example of this technique.

05. Polymorphism⁶¹

Ion exchange resins present a unique way of dealing with this problem. A drug resinate is an amorphous solid and cannot crystallize or even form hydrates. In addition, the release of drug from resinate is independent of the crystal form that was used to make it. Consequently, using resinate completely eliminates any problem with polymorphism.

06. Tablet Disintegration⁶¹

Certain amount of ion exchange resins swell significantly on exposure to water. This has led to their use as very effective tablet disintegrant.

07. Sustained release⁶²

Pharmaceutical industry adopted the ion exchange technology to achieve sustained release of drugs. Keating listed the following advantages of adsorbing basic nitrogen containing drugs onto sulfonic acid cation exchange resins and using them in dosage forms

1. Prolonged availability, by releasing the drug from the complex for over 12 hours in the gastro -intestinal tract
2. Reduced toxicity by slowing drug adsorption.
3. Increased stability by protecting the drug from hydrolysis or other degradative changes in the GI tract.
4. Improved palatability.
5. Availability of formulation in liquid and solid sustained release dosage forms.

08. Site-specific DDSs⁶³

Delivering drugs at the desired biological location or site could have several advantages in therapeutics, such as:

Ø localizing the required drug concentration to maintain a minimum effective concentration throughout the treatment;

Ø reducing the systemic toxicity, especially with cytotoxic anticancer drugs; and

Ø bifurcating the hostile environment of the drugs to prevent the drug degradation.

Several studies have reported the use of IER for drug delivery at the desired site of action.

1. Gastric Retentive Systems:

Example of such drug are Frusemide, cycloserine, Allopurinol and Ciprofloxacin. A novel floating extended release system consisting of a bicarbonate charged resin coated with a semi permeable membrane for improving gastric residence time.

1. Site-specific delivery of drugs for cancer treatment;

Several anti-cancer drugs Ex. Doxorubicin are ionic in nature and can be complexed with IER. Attempts have been made to deliver some of these drugs in a controlled-release fashion to the anticancer cells with the help of IER.

1. Sigmoidal Release System:

IER were studied in the development of sigmoidal-release systems; Eudragit RS an AER with limited quaternary ammonium groups, is coated over beads with a sugar core surrounded by organic acid and drug mixture. The ionic environment, induced by the addition of an organic acid to the system was found be responsible for pulsatile release.

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About Authors:

Prof. (Dr.) C.P. Jain, M. Pharm (Ph. D.), Pharmaceutics. HOD, Dept. of Pharmaceutics, B.N.College of Pharmacy, Udaipur, Rajasthan.

Shailesh Sharma

ASBASJS M College of Pharmacy, Bela, Dist Ropar, Punjab
Address for correspondence:
Lecturer,ASBASJS M College of Pharmacy, Bela, Dist Ropar, Punjab
E mail address: shaileshsharma_bela@ yahoo.co.in, Mobile No.: 09888775589

A.S. Deora

Lecturer in Pharmaceutics at B.N. Girls College of Pharmacy, Udaipur, Rajasthan, two year of teaching experience.

P.S. Naruka

Sr. Lecturer in Pharmaceutics at B.N.College of Pharmacy, Udaipur with a five year teaching experience with good academics record.

C.S. Chahuan

Reader in Pharmaceutics at B.N.College of Pharmacy, Udaipur with a six year teaching experience.

Prof. (Dr.) G. D.Gupta

M.Pharm (Ph. D.), Pharmaceutics, Principal, ASBASJSM College of Pharmacy, Bela, Ropar, Punjab, 140111