Natural Superdisintegrants: Changed Scenario and Latest Advances

Sudheshnababu Sukhavasi*, V. Sai kishore

Dept. of Pharmaceutics, Bapatla College of Pharmacy, Bapatla-522101, Andhra Pradesh, India.

ABSTRACT:

All pharmaceutical dosage forms contain many additives besides the active ingredients to assist manufacturing and to obtain the desired effect of the pharmaceutical active ingredients. The advances in drug delivery have simultaneously urged the discovery of novel excipients which are safe and fulfil specific functions and directly or indirectly influence the rate and extent of release and /or absorption. Superdisintegrants are added to oral solid dosage formulations to facilitate fast disintegration. The plant derived natural super disintegrants comply with many requirements of pharmaceutical excipients as they are non-toxic, stable, easily available, associated with less regulatory issues as compared to their synthetic counterpart and inexpensive; also these can be easily modified to meet the specific need. They can also be modified in different ways to obtain tailor-made materials for drug delivery systems and thus can compete with the available synthetic excipients. Recent trend towards the use of plant based and natural products demands the replacement of synthetic additives with natural ones. Plant products nowadays are widely used as an alternative to synthetic products due to ease of local accessibility, lower prices as compared to synthetic products, biocompatible, biodegradable nature and environment friendly nature. Extensive swelling, porosity and wicking action of the natural material in the tablet formulation were found to be contributing its superdisintegrant action. This review discusses about the development and extraction of natural superdisintegrants for use in the rapidly disintegrating dosage forms.

KEYWORDS: Superdisintegrants; Natural gum; Extraction, Purification, Pharmaceutical application

INTRODUCTION:

The proper choice of superdisintegrant and its consistency of performance are of critical importance to the formulation of a rapidly disintegrating dosage form. The choice of super disintegrant for a tablet formulation depends largely on the nature of the drug being used. For example, the solubility of the drug component could affect the rate and mechanism of tablet disintegration. Water-soluble materials tend to dissolve rather than disintegrate, while insoluble materials generally tend to disintegrate if an appropriate amount of super disintegrant is included in the formulation ¹. Furthermore, the ionic nature of the drug and superdisintegrants and their potential interactions have been reported to affect the dissolution of tablet formulations². The emphasis on the availability of drug highlights the importance of the relatively rapid disintegration of a tablet as a criterion for ensuring uninhibited drug dissolution behaviour. Disintegrants are an essential component to tablet formulations. The ability to interact strongly with water is essential to disintegrant function. Combinations of swelling and/or wicking and/or deformation are the mechanisms of disintegrant action. In more recent years, increasing attention has been paid to formulating not only fast dissolving and/or disintegrating tablets that are swallowed, but also orally disintegrating tablets that are intended to dissolve and/or disintegrate rapidly in the mouth. Most prior studies have focused on the function related properties of superdisintegrants with special emphasis on correlating these functional properties to disintegrant efficiency and drug release rate.

Mother Nature has gifted India with great variety of flora and fauna. For centuries man has made effective use of materials of natural origin in the medical and pharmaceutical field. Today, the whole world is increasingly interested in natural drugs and excipients. Natural materials have advantages over synthetic materials because they are non toxic, less expensive and freely available. Furthermore, they can be modified to obtain tailor made materials for drug delivery systems allowing them to compete with the synthetic products that are commercially available. Plant products nowadays are widely used as an alternative to synthetic products due to ease of local accessibility, lower prices as compared to synthetic products, biocompatible, biodegradable nature and environment friendly nature. Extensive swelling, porosity and wicking action of the natural material in the tablet formulation were found to be contributing its superdisintegrant action.

Advantages of natural super disintegrants:

Biodegradable: They represent truly renewable source and they have no adverse impact on humans or environmental health.

Biocompatible and non-toxic: Chemically, nearly all of these plant materials are carbohydrates composed of repeating sugar (monosaccharide’s) units. Hence, they are non- toxic.

Low cost: The production cost is also much lower compared with that for synthetic material.

Environmental-friendly processing: Gums and mucilage’s from different sources are easily collected in different seasons in large quantities due to the simple production processes involved.

Local availability: In developing countries, governments promote the production of Gums and mucilages because of the wide applications in a variety of industries.

Better patient tolerance and public acceptance: There is less chance of side and adverse effects with natural materials compared with synthetic one.

Edible sources: Most gums and mucilage’s are obtained from edible sources.

Extraction and Purification of Gums/Mucilage’s:

a. Extraction of locust bean gum:

The seeds are dehusked by treating the kernels with dilute sulfuric acid or with thermal mechanical treatment, elimination of the germ followed by milling and screening of the endosperm (native carob bean gum). The gum may be washed with ethanol or isopropanol to control the microbiological load (washed carob bean gum). It may also be further clarified (purified, extracted) by dispersing in hot water, recovery with isopropanol or ethanol, filtering, drying and milling, which is called as clarified (purified, extracted) carob bean gum³.

b. Extraction of mucilage from fenugreek seeds:

The seeds are powdered using pestle and mortar and 100 g of the powder is extracted with hexane to remove lipophilic compounds using a soxhelet apparatus. To remove pigments and to deactivate enzyme, the defatted powder is boiled in ethanol for 20 min. This treated powder is then soaked in 10 liters water and the pH is adjusted to 3.5 using 0.5 M Hydrochloric acid. The mixture is stirred by a mechanical stirrer for 12 h and then filtered through filtration paper. The filtrate is centrifuged (5000 RPM) and the supernatant is concentrated in vacuum to 50% of its initial volume. The resulting solution is mixed with the same volume of 96% ethanol and stored in a refrigerator for 4 h. The precipitated mucilage is separated by centrifugation (5000 RPM). The collected mucilage is re-suspended in distilled water, agitated for 20 min and re-precipitated one more time to eliminate chloride ions and other impurities. Finally the residue is washed with diethyl ether and acetone and dried overnight at 45°C, resulting in an off-white powder⁴.

c. Preparation of treated agar:

Agar suitable quantity of agar powder (5-10 g) weighed and added in distilled water (100ml). Agitation is done continuously by a stirrer for one day to swell. The swollen contents are dried on a tray for 3 days at room temperature. The dried powders are grinded by mortar and pestle. Then grinded powder is passed through sieve no.100⁵.

d. Extraction of mucilage from hibiscus rosa-sinensis:

The fresh leaves of Hibiscus rosa-sinensis Linn were collected, washed with water to remove dirt and debris, and dried. The powdered leaves were soaked in water for 5 6 h, boiled for 30 min, and kept aside for 1 h for complete release of the mucilage into water . The material was squeezed from an eight fold muslin cloth bag to remove the marc from the solution. Acetone was added to the filtrate to precipitate the mucilage in a quantity of three times the volume of the total filtrate. The mucilage was separated, dried in an oven at a temperature < 50 C, collected, dried powdered, passed through a sieve (number 80) , and stored for further use in desiccators⁵.

e. Extraction of mucilage lepidium sativum:

The seeds of lepidium sativum contain the mucilage around the outer layer. The major problem in isolation of mucilage is that it swells but does not separate from the seeds. Because of this, general methods of separation of mucilage are not applicable to separate the seed mucilage and hence, different procedures were tried for the separation of mucilage⁶.

Method A:

In first method (method A) the seeds (100 g) were boiled with distilled water (1 litres) for 15 minute and the mass was filtered through Buckner funnel without filter paper. The retained residues were boiled with distilled water (0.5 litres) for 15 minute and the combined liquid was passed through eight folds of muslin cloth. The mucilage was precipitated from the filtrate by adding ethanol. The precipitated mucilage was dried in an oven at 45^oC till it was completely dried. The powder was passed through 80 # mesh sieve and weighed to calculate the yield.

Method B:

In the second method (method B) the seeds (100 g) were soaked for 12 hour in distilled water (1litre) and then added to a blender to separate mucilage from seeds. After blending for 15 minute the mass was passed through eight folds of muslin cloth. The mucilage was precipitated from the filtrate by adding 1 litre of acetone. The powder was passed through 80 # mesh sieve and weighed to calculate the yield after drying at 450C for 6 h.

Method C:

In third method (method C) the seeds (100 g) were soaked for 12 hour in distilled water (1litre) and crushed in blender for 15 minute. The dispersion was boiled for 30 minute and the mass was passed was passed through eight folds of muslin cloth. The mucilage was precipitated from the filtrate by adding acetone. The powder was passed through 80 # mesh sieve and weighed to calculate the yield after drying at 45 ^oC for 6 hour.

f. Extraction of gum from seeds of Lallemantia reylenne:

Lallemantia reylenne seeds were powdered and passed through 60-mesh sieve⁷.

g. Mango peel pectin:

Dried mango peel powder was used for extracting pectin using Soxhlet apparatus. Round bottom flask containing acidified water [water acidified (pH 2) using 0.5 N citric acid] was heated continuously at 75°C for 7-8 h after start of first siphon cycle. Powder to solvent ratio was 1:8. After heating period was over, mixture was passed through two fold muslin cloth and cooled to room temperature. Double amount of ethyl alcohol was added to solution with continuous stirring for 15 min. Mixture was kept for 2 h without stirring. Pectin was precipitated and filtered through 4-layered muslin cloth. Precipitate was washed 2-3 times by ethyl alcohol, to further remove any remaining impurity. Finally, precipitate was kept for drying at 35-40°C in hot air oven, sieved (#80) and stored in desicator until use⁸.

h. Banana powder:

Banana powder is formed by using banana pulp, which is mechanically chopped and then processed with hydraulic shear using a colloid mill, turning it into a paste. Sodium metabisulfite is then used to brighten the yellow colour of the paste. The paste is then dried by either spray- or drum-drying, although the latter is more common because none of the paste is lost while drying. The drum-drying also produces about 2% more powder and also dries it more thoroughly. Regardless of the drying process banana powder can generally only stay fresh on the shelf for about a year before passing its expiration date⁹.

i. Plantago ovata:

Mucilage was isolated by soaking seeds of Plantago ovata in water (20-30 times) for at least 48 hrs, boiled for 2 hrs subsequently mucilage was released into the water completely. With the help of the muslin cloth the mucilage was squeezed out and separated from seeds. The mucilage collected and precipitated using 3 times of 95% ethanol. Collected mucilage was dried in the oven at 50-55°. Dried mucilage was scraped and powdered using pestle and mortar. Powder was sieved using mesh no.60 ¹⁰.

j. Preparation of modified gum karaya:

Powdered gum was taken in a porcelain bowl and subjected of heating using sand bath for different time periods at different temperatures. The results of swelling capacity and viscosity studies revealed that the modified forms possessed swelling property similar to GK, but viscosity was decreased as a function of temperature and time period of heating. However, it was observed that GK samples were charred, when heated at 140 ^oC. In the preparation of modified form of GK, no further change in viscosity of GK was observed by heating it at 120 ^oC for more than 2h. Hence, these conditions of heating at 120 ^oC for 2h were selected to prepare modified form of GK. The prepared modified form of GK was finally re-sieved (100 mesh) and stored in airtight container at 25 ^oC ¹¹.

k. Preparation of Modified Tragacanth:

Tragacanth(5g), tween80(0.05g) and hydrogen peroxide(30% w/v) solution(1ml) were taken in 100ml of purified water and boiled for 15min. The mixture was allowed to cool and settle. The clear supernatant fluid was decanted and the sediment was washed repeatedly with water. Finally the sediment was collected by centrifuging at 2500RPM and dried at 80^oC for 4hrs. The dried product was ground to fine powder and passed through mesh no.200 ¹².

Selecting the superdisintegrant:

Although the super disintegrant primarily affects the rate of disintegration, when used at high levels it can also affect mouth feel, tablet hardness, and friability. Thus, several factors must be considered when selecting a superdisintegrant ¹³.

Disintegration: The super disintegrant must quickly wick saliva into the tablet to generate the volume expansion and hydrostatic pressures necessary to provide rapid disintegration in the mouth.

Compactability: When manufacturing rapidly disintegrating dosage form, it is desirable to have tablets with acceptable hardness at a given compression force to produce robust tablets that avoid the need to use specialized packaging while maximizing production speed. Thus, a more compactable superdisintegrant will produce stronger, less-friable tablets.

Mouth feel: To achieve patient compliance, rapidly disintegrating dosage forms must provide a palatable experience to the patient. Large particles can result in a gritty feeling in the mouth. Thus, small particles are preferred.

Flow: As with all direct compression tablet formulations, attaining good flow and content uniformity is important to achieving the required dosage per unit. In typical tablet formulations, superdisintegrants are used at 2–5 wt % of the tablet formulation. With rapidly disintegrating dosage forms, superdisintegrant levels can be significantly higher. At these higher use levels, the flow properties of the superdisintegrant are more important because it makes a greater contribution to the flow characteristics of the total blend.

The selection of the optimal superdisintegrant for a formulation depends on a consideration of the combined effects of all of these factors.

Evaluating physical characteristics of natural super disintegrants:

For excipient analysis, analytical techniques can be classified according to the type of information generated ¹⁴.

Structural: Gums and mucilages are polysaccharides and contain sugars. So, confirmation of the different sugars is carried out by chromatography and structure elucidation can be carried out by NMR and mass spectroscopy.

Purity: To determine the purity of the selected gum and mucilage, tests for alkaloids, glycosides, carbohydrates, flavanoids, steroids, amino acids, terpenes, saponins, oils and fats, and tannins and phenols are carried out.

Impurity profile: Testing for impurities must be carried out using suitable analytical techniques.

Physico-chemical properties: Colour, odour, shape, taste, touch, texture, solubility, pH, swelling index, loss on drying, hygroscopic nature, angle of repose, bulk and true densities, porosity and surface tension. Different ash values are also estimated. The microbial load and presence of specific pathogens are also determined. In vitro cytotoxicity is also determined. Gums and mucilages are highly viscous in nature. So, the rheological properties of excipients are important criteria for deciding their commercial use. The flow behaviour of the samples is determined.

Toxicity: The acute toxicity of gums and mucilages are determined by the followings fixed dose method as per OECD guideline No. 425. A sub-acute toxicity study, determination of the LD50 etc., is carried out in rats and guinepigs of both sexes.

Once analysis is complete, determination of the structure, composition and impurity profile enables a scientific dossier to be prepared describing the excipient. This information is of value for the regulatory dossier of the final pharmaceutical product that would contain the given excipient. Finally, gums and mucialges are added to pharmaceutical formulations. So a compatibility study is important. The compatibility studies of gum/mucilage/ drugs are performed using spectrophotometry/FTIR/DSC.

CONCLUSION:

The natural materials have been extensively used in the field of drug delivery because they are readily available, cost-effective, eco-friendly, capable of multitude of chemical modifications, potentially degradable and compatible due to their natural origin. Overviews of various types of natural Superdisintegrants which are available have been discussed. The ease of availability of these agents and the simplicity in the direct compression process suggest that their use would be a more economic alternative in the preparation of rapidly disintegrating dosage form than the synthetic Superdisintegrants.

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Received on 25.01.2012

Modified on 18.03.2012

Accepted on 06.04.2012

Research Journal of Pharmaceutical Dosage Forms and Technology. 4(2): March-April 2012, 69-73