INTRODUCTION:

Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API), these compounds are generally added along with the active pharmaceutical ingredients in order to protect, support or enhance stability of the formulation.

Drug products contain both drug substance (commonly referred to as active pharmaceutical ingredient or API) and excipients. The resultant biological, chemical and physical properties of the drug product are directly affected by the excipients chosen, their concentration and interactions.

The objective of a medicinal formulation development project is to deliver drug to the patient in the required amount, at the required rate, consistently within a batch, from batch to batch, and over the product’s shelf life^1,2.

SOURCES OF EXCIPIENTS:

Excipients are of various origins: animal (e.g. lactose, gelatin, and stearic acid), plant (e.g. starches, sugars, cellulose, and alginates), mineral (e.g. calcium phosphate, silica) and synthesis (e.g. PEGs, polysorbates, povidone, etc.) and they often lack a trade name. Their origin and use do not often guarantee the quality required by the pharmaceutical industry, which must therefore submit them to more thorough-going analytical controls. In order to carry out the numerous functions required, new classes of excipients have now become available, derived from old and new materials, alone or in combination, adapted to the manufacture of high performance pharmaceutical dosage forms. Looking at the matter from this angle, excipients can no longer be considered mere inert supports for the active principles, but essential functional components of a modern pharmaceutical formulation. It is also to be borne in mind that the ratio of their weight to that of the active principles is usually very high in a formulation, and such as to cause possible action due to their mass. Like pharmaceutical drugs, they too have their own thermo-dynamic activity which, though generally low, can contribute to reactions leading to degradation or to interactions between the drug and the excipients. Today it is reckoned that over one thousand different materials are used in the pharmaceutical industry to fulfil its various requirements such as diluents, bulking agents, disintegrants, lubricants, colouring agents, sweeteners, etc. They are chemically heterogeneous compounds that go from simple molecules (water) to complex mixtures of natural, semi synthetic or synthetic substances which, from the regulatory point of view, may be subdivided into three categories. In the first category (approved excipients) we find the compounds originating from the food industry (generally recognized as safe: GRAS) or that have been present in pharmaceutical products for a very long time. The intermediate category (essentially new excipients) covers compounds obtained by means of the structural modification of the excipients already approved or those already used in the food or cosmetic industries. The third category covers new compounds, never previously used in the pharmaceutical field and it is growing rapidly due to the present interest in modified-release formulations and the requirements of the modern high-productivity compressing /tabletting machines^1,3.

BINDERS

These are the dry powders or liquid which are added during wet granulation to promote granules or to promote cohesive compact during direct compression. It provides mechanical strength to the tablet. Binders can be in powder form and liquid form. Example of binders are Powder binders: cellulose, methyl cellulose, polyvinyl pyrrolidine, PEG Solution binders: gelatine, PVP, HPMC, PEG, sucrose, starch. Binders can be added in the following ways to the formulation added as powder before wet agglomerisation so that the binder is evenly distributed. As solution form it is used as agglomerisation liquid in the wet granulation. It is called as liquid binder^4-6.

As a dry powder, which is mixed with other ingredients before compaction (slugging or tabletting). It is called as dry binder. Natural binders like acacia and tragacanth are used in solution form in the concentration of 10-25%, alone (or) in combination for wet granulation and they can be added as powder for the direct compression process. Gelatine is used along with acacia (or) alone this form a better binding agent than the above two natural polymers. Polymers like MC, HPMC are used as dry powders in case of direct compaction, they act as good binding agents, in the solution form they act as good adhesives. Ethyl cellulose and HPMC can be used in alcoholic solutions, they act as anhydrous adhesives.

Table:1: Binders used in solid dosage forms

Excipient category	Functions	Working principle	Examples
Binders and Adhesives	Impart cohesive qualities to powdered material.	Improves free flow qualities by formulation of granules to desired hardness and size.	Acacia, Gelatin, Starch paste, Polyvinyl pyrrolidone, Glucose, Carboxymethyl cellulose, Povidone.

TYPES OF BINDERS:

CLASSIFICATION ON THE BASIS OF THEIR SOURCE:

1. Natural polymers: Starch, pre gelatinized starch, gelatin, acacia, tragacanth and gums.

2. Synthetic polymer: PVC, HPMC, methyl cellulose, ethyl cellulose, PEG.

3. Sugar: glucose, sucrose, sorbitol.

CLASSIFICATION ON THE BASIS OF THEIR APPLICATION:

1.Solution binders:

These are dissolved in a solvent (for example water or alcohol can be used in wet granulation processes). Examples include gelatin, cellulose, cellulose derivatives, polyvinyl pyrrolidone, starch, sucrose and polyethylene glycol.

2. Dry binders:

These are added to the powder blend, either after a wet granulation step, or as part of a direct powder compression (DC) formula. Examples include cellulose, methyl cellulose.

1.Natural polymers:

Advantages of Natural binder:

1. Natural polysaccharides are widely used in the pharmaceutical and food industry as excipients and additives due to their low toxicity, biodegradable, availability and low cost.

2. They can also be used to modify the release of drug, thereby, influencing the absorption and subsequent bioavailability of the incorporated drug.

Disadvantage of Polymer binders:

1 Polymer binders can lead to processing difficulties such as rapid over granulation. Over time they occasionally lead to tablet hardening and a decrease in dissolution performance.

2 When polymer binders are chosen, the addition of strong disintegtants such as super disintegrants is typically required but these are considerably expensive and have a negative effect on product stability as well as film coating appearance of the finished products^2,4.

Synthetic binders:

Synthetic binders are special paving materials manufactured by mixing polymers, resins, and oils. These materials may have improved mechanical properties as compared with the traditional modified bitumen. This work is part of a comprehensive study on the design of synthetic binders with selected mechanical properties. In this sense, upgraded mechanical properties of the final synthetic binder can be attained by understanding and correlating the mechanical properties of its individual constituents as a function of composition and temperature. With this aim, this work deals with the thermo mechanical properties of recycled polymer/resin blends, over a wide range of temperature and composition. Recycled polymer/resin blends are thermorheologically complex materials, due to the development of multiphase domains depending on polymer concentration. Thus, these blends show a predominantly gel-like behaviour at high polymer concentrations and a predominantly viscous behaviour, with high thermal susceptibility, for low polymer concentrations. The dynamic viscosities of the blends, as a function of polymer concentration and temperature, can be predicted using a logarithmic mixing rule.

Natural Binding Agent

The role of excipients in determining the quality of a formulation and in many cases the bioavailability of drug from tablets has received considerable attention. Binders are added to tablet formulation to impart plasticity and thus increase the interparticulate bonding strength within the tablet. The development of new excipients for potential use as binding agent in tablet formulations continues to be of interest.

This is because different binding agents can be useful in achieving various tablet mechanical strength and drug release properties for different pharmaceutical purpose. Binders are agents employed to impart cohesiveness to the granules. This ensures the tablet remains intact after compression as well as improving the flow qualities by the formulation of granules of derived hardness and size. The choice of a suitable binder for a tablet formulation requires extensive knowledge of the relative importance of binder properties for enhancing the strength of the tablet and also of the interactions between the various materials constituting a tablet^7,8.

To hold various powders together to form a tablet is a binder, fillers usually do not have good binding capacity, binder is either added in dry mix or mix in granulation or mix in granulating liquid, binder form matrix with fillers and drug embedded in it, on drying solid binder forms glue which holds the particles together, the wet binder is the most important binders are hydrophilic & most times soluble in water⁹.

TYPES OF NATURAL BINDERS:

A. Starch as binder

B. Natural gums as binder

C. Dried fruits as binding agent

Starch as binder:

There are various types of natural polymers like starch, gums, pregelatinised starches are used as binding agent. Starches like rice starch, maize starch, potato starch, wheat starch, corn starch are well known for their binding and disintegrating properties but some other starches like enset starch and banana starch can also be used as binding agent. Starch is also used as fillers. Starch is widely used as thickening, stabilizing, gelling and/or filling agent in many food applications and it considered as the most used excipients in pharmaceutical formulations. It is used mainly in tablets as filler, binder or disintegrant. Starch is the major carbohydrate reserve in plant tubers and seed endosperm where it is found as granules.

It contains mainly two types of polymer molecules several million of highly branched amylopectin molecules (normally 70-80%) accompanied by a higher number of largely linear amylase molecules (normally 20-30%)

Dioscorea rotundata as a binding agent:

Starch is one of the most widely used excipients in the manufacture of solid dosage forms. Starches from different sources have been evaluated and used as excellent binders in either mucilage or the dry powdered form. Although maize starch is the most frequently used excipient in tableting, researchers have tried to develop botanical starches for use tablet excipients.

The effects of pigeon pea and plantain starches on the compressional, mechanical and disintegration properties of Paracetamol tablets have been investigated. The role of ginger starch as binder in acetaminophen tablets was found^10,11.

Starch 1500 as a binding agent:

Starch 1500 performed as an excellent binder producing a granulation that was compressible and produced Lamivudine tablets of improved hardness and friability compared with those prepared with povidone. The formulation of Lamivudine tablets with Starch 1500 exceeded the disintegration and dissolution performance of the povidone formulation that utilized a super disintegrant.

The nature and amount of the binders were found to alter the disintegration and dissolution rates of the tablets by reducing their wet ability as measured by the adhesion tension of water. During pharmaceutical granulation, the objective is to produce granules that have a uniform (and repeatable) distribution of drug particles within the bulk carrier (excipient) solid. This can be difficult to achieve and both drug depletion and enrichment in granules can occur. The use of a natural product tapioca starch as binding agent in the formulation of Diclofenac tablets was identified.

To establish two other commonly used disintegrating agents potato starch and maize starch were selected and formulated for comparison. Different formulations were prepared by using above three disintegrants in the concentration of 20mg per tablet. The tablets were prepared by wet granulation technique^8,10,12-14.

Tapioca starch as a binding agent:

The use of a natural product tapioca starch as binding agent in the formulation of Diclofenac tablets was identified. To establish two other commonly used disintegrating agents potato starch and maize starch were selected and formulated for comparison.

During pharmaceutical granulation, the objective is to produce granules that have a uniform (and repeatable) distribution of drug particles within the bulk carrier (excipient) solid. This can be difficult to achieve and both drug depletion and enrichment in granules can occur^15,16.

Extraction of Different Starches:

Extraction of tapioca Starch:

The starch was extracted from root tubers of cassava (Manihot esculenta) according to the method of Alebiowu using established procedures. Cassava tubers were peeled, washed and cut to small pieces. These small pieces were then soaked in distilled water for specified period of time i.e. for 1 h. At the end of the steeping period, the softened tubers were milled to a pulp, and more distilled water was added to give dilute slurry which was sieved using mesh size 100.

Extraction of rice:

Starch isolation by neutral protease used rice flour (100 g, as is) mixed with deionized water (200 mL) in a 500-mL reaction beaker. The temperature was maintained at 50°C with a circulator, and the slurry pH was adjusted to 7.0 with 1.0 N NaOH.

Different levels of neutral protease (0.01, 0.03, or 0.05% on rice flour basis) were added to the slurry and reacted for 1, 3, or 5 hr with constant stirring using a magnetic stirrer. The flour slurry was then blended with a Waring blender at a high speed for 2 min after the protease digestion. The slurry was passed through a 63-m screen and centrifuged at 1400×g for 10 min. The starch layer was reslurried and washed with deionized water 3 times. The isolated starch was dried at 45°C for 48 h

Extraction of corn starch:

Stage 1:

Consisted of crushing the dry kernels with a hammer,

removing the seed coat, separating the germs, and collecting the starch without drying it under the fan.

Stage 2:

Three corn kernels were placed in screw-top 25-ml test tubes. Sodium meta-bisulfite 0.45% (2 ml) were added to each tube before incubation in a 50°C water bath for48 hr (± 2 hr) to soften the kernel, enhance peeling of the seed coat, and preserve the kernel

during steeping.

Extraction of potato starch:

Enzyme solution was prepared by mixing thoroughly 1g of the enzyme in 10ml of distilled water by a glass rod in a 20ml test tube. The potatoes were washed under tap water so that any dirt adhered to it may be removed. After washing the potatoes were cut into small pieces without peeling with a stainless steel knife to facilitate grinding. Grinding was done in Commercial (Sumeet) grinder having motor rpm of 15000 for 1 min and 15 s after standardizing the time.

The ground potato meal was then transferred to a 500 ml conical flask and appropriate amount of water was added to the meal. The prepared enzyme solution was added to the potato meal using a pipette. For concentration of 0.1g per 100g of potato meal, 1ml of the enzyme solution was added to 100g of potato meal.

The flask was cotton plugged and kept in incubator cum shaker at 45°C with a shaking speed of 125 rpm. The pH of all the samples varied between 6 and 7 and cellulase enzyme is effective between pH 3 and 7. So, the natural pH of the broth was not changed. After incubation the resultant slurry was screened by a nylon tea strainer of mesh size of 100 into a 400 ml beaker. During screening the pomace was washed two times in 150 ml of tap water. Sedimentation was done for 1 h to separate the starch from the other components of the filtrate containing starch. Starch was isolated from flour using a modified protein digestion procedure^1,5,7,17-21.

Extraction of wheat starch: from wheat flour:

Flour (0.3 g) was placed in 50-mL plastic centrifuge tubes with 5.0 mL of water and 2 mL of 0.8% pepsin A (P7012, Sigma, St. Louis, MO) in 0.04N HCl and incubated for 60 min at 37°C.After protease treatment, 1.0 mL of 0.08% Hemicellulase 90 (90,000 U/g activities, a gift from Amano Enzyme U.S.A., Lombard, IL) in 0.1M sodium acetate buffer (pH 4.5) was added to the mixture and incubated for 3 hr at 45°C. A detergent mix (1 mL) (5% SDS, 5% Triton X-100, 5% Tween 40, and 5% Triton X-15) was added after incubation, and the suspension was vortex-mixed for 30 sec.

EXTRACTION METHOD OF DIFFERENT GUMS:

Extraction of gum galbanum:

The powdered dried galbanum (200 g) was macerated in distilled water (100 mL) at 50⁰C and shaked for 30 min, and then the mixture was stirred for 24 h. The mixture was filtered and the filtrate was concentrated to dryness and weighed

Extraction of Gum olibanum:

The gum was isolated from plant and then treated with a mixture of chloroform and water in ratio of 5:95 for 5 days with occasional mixing. Any extraneous materials are then filtered and the gum is then precipitated by adding absolute ethanol. The precipitated gum was filtered, washed with ether and air dried. The dried gum was powdered and passed through 100 mesh for further use.

Extraction of gum Aegle marmelos:

Fresh white gum of Aegle marmelos was collected from authenticated plant fruits. The well dried gum was powdered in mortar, passed through sieve no.80 and solubilised in distilled water. The concentrated solution was precipitated in acetone. The precipitate was separated and dried at 60⁰ C.

Extraction of gum Okra fruit mucilage:

Okra gum was extracted from the pods of Okra fruits. The fruits were cleaned, washed, sliced, crushed and then macerated in distilled water for 10 hours with intermittent stirring.

The mucilage was filtered through a white muslin cloth to extract the gum and acetone was added to precipitate the extracted gum. The gum was then filtered under vacuum to remove acetone and dried in desiccators

Table 1.2: Natural binding agents and uses

Product	Type	Use
Accroides	Resins	Binder in fireworks and flares
Candelilla	Wax	Binder in chewing gum.
Guar	Gums	Binder in baking, meat and tablets.
Gum Arabic	Gums	Binder in baking, cosmetics, incense, photography, watercolour paints, ceramic glazes and fireworks.
Karaya	Gums	Binder in baking and paper manufacturing.
Shellac	Shellac	Binder in mascara, eyeliners, fireworks and pyrotechnics.
Tragacanth	Gums	Binder in icing, tablets, incense and pastel paints
Xanthan	Gums	Binder in baking, laxatives and toothpaste

ADVANTAGE NATURAL BINDER:

1) They can also be used to modify the release of drug and thereby influencing the absorption and bioavailability of the incorporated drugs.

2) Natural binders are widely used in the pharmaceutical and food industry as excipients and additives due to their low toxicity, biodegrable, availability and low cost

DISADVANTAGE OF POLYMER BINDERS:

1) Polymers binder can lead to processing difficulties such as rapid over granulation, tablet hardness increases & dissolution performance decrease.

2) When polymer binders are selected addition of strong disintegrates typically required but these are considerable expensive and have a negative effect on product stability.

CONCLUSION:

There are large numbers of natural polymers have been used in pharmaceutical preparations. Natural substances like starches, mucilages, gums and also dried fruits can be used as binding agent. They have been shown good potential as binding agent as well as they posses some other properties like disintegrating agent, fillers, sustain releasing agent. Natural polymers shown good binding property in wet granulation, granules are stable and less friable in comparison with other binders. They can also be used to modify the release of drug, thereby, influencing the absorption and subsequent bioavailability of the incorporated drug. Furthermore, they act as vehicles which transport the incorporated drug to the site of absorption and are expected to guarantee the stability of the incorporated drug, the precision and accuracy of the dosage, and also improve on the organoleptic properties of the drugs where necessary in order to enhance patient adherence. They should optimize the performances of dosage forms during manufacturing as well as when patients ingest them.

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Received on 27.04.2018 Accepted on 18.06.2018

Asian J. Pharm. Res. 2019; 9(1): 55-60.

DOI: 10.5958/2231-5691.2019.00009.1