TABLE OF CONTENT
1.1 BACKGROUND OF THE STUDY
1.3 Zea mays
1.5 Statement of problem
1.6 Aims and objectives of the study
1.7 Significance of the study
1.8 Scope of the Study
2.0 LITERATURE REVIEW
2.1 Corn fibre
3.0 MATERIALS AND METHODS
3.1 Research Design
3.2 Materials and Methods
3.3 Characterization of SCNR powder
3.4 Physio-technical properties of SCNR
3.5 Flow properties of SCNR
3.6 Moisture Studies of SCNR
3.7 Proximate composition of natural corn seed fibre(SCNR)
3.8 Morphology of SCNR
3.9 Elemental analysis of SCNR
3.10 Thermal properties and drug-excipients compatibility studies of SCNR
3.11 Modification of SCNR
3.12 Percentage yield of SCN1, SCN2 and SCN3
3.13 Characterization of SCN1, SCN2 and SCN3 Powders
3.14 Physio-technical properties of SCN1,SCN2 and SCN3
3.15 Flow properties of SCN1,SCN2 and SCN3
3.16 Moisture Studies of SCN1,SCN2 and SCN3
3.17 Morphology of SCN1, SCN2 and SCN3
3.18 Thermal properties and drug-excipients compatibility studies of SCN1,SCN2 and SCN3
3.19 Identification test for Metronidazole
3.20 Metronidazole dissolution test
3.21 Preparation of SCN1 ,SCN2, SCN3, SA and SG granules
3.22 Characterization of SCN1 ,SCN2, SCN3, SA and SG granules
3.23 Physio-technical properties of SCN1 ,SCN2, SCN3, SA and SG granules
3.24 Flow properties of granules
3.25 Compression of tablet
3.26. Evaluation of metronidazole tablets
3.27 Statistical Analysis
4.0 RESULTS AND DISCUSSIONS
4.1 Result Analysis
4.2 Sample Identification
4.3 Organoleptic properties of powders
4.4 Physico-technical properties of powders
4.5. Proximate composition of corn seed fibre
4.6. Morphology of corn seed fibre
4.7 Some elemental constituents of the natural corn seed fibre powder (SCNR)
4.8 Results of differential scanning calorimetry (DSC)
4.9 Identification of Metronidazole
4.10 Granule properties
4.11 Tablet properties
5.0 SUMMARY, CONCLUSION AND RECOMMENDATION
5.4 Contribution to knowledge
The polymers derived from corn seed fibre were tested as binders in metronidazole tablet using sodium alginate (SA) and gelatin (SG) as standards. Pulverized corn seed fibre was coded SCNR. A 500.0g of SCNR was blended for 10 min in sodium hypochlorite (3.5% w/v) solution, washed, dried (50oC), sized to 125µm and coded SCN1. A 100.0 g of SCN1 was separately blended in 200.0ml of 0.25N and 0.5N NaOH respectively, neutralized and precipitated with ethanol (95%), dried (50oC), sized to 125 µm and labeled SCN2 and SCN3 respectively. Physicochemical properties of SCNR, SCN1, SCN2 and SCN3 were evaluated and employed as binders at 0.5, 1.0, 1.5 and 2.0 % w/w alongside the standards in wet granulations of 200.0 mg metronidazole. The granules were characterized and compressed into tablets. The tablets were evaluated using the B.P, 2012 methods. All the fibre showed poor flowability but swell-able with pH between 6.90±0.10-7.20±0.10 and viscosity in the order: SCNR>SCN1<SCN2<SCN3 (p<0.05). Granules were flowable and compressible, the tablets had coefficient of weight variation between 0.69-1.69%, mechanical strength in the order: SA>SG>SCN3>SCN2>SCN1 (p<0.05). The tablets containing all concentrations of the fibre, 0.5-1.0%w/w of SA and 0.5-1.5%w/w of SG disintegrated within 15.0 min. Tablets prepared with all the fibre attained T50 and T90 faster than those of SA and SG. The release of metronidazole from batches of tablets was in the order: SCN1>SCN2>SCN3>SG>SA. SCN1, SCN2 or SCN3 as binders in the formulation of metronidazole tablets produced good mechanical strength in comparison with the standards.
Keywords: Corn seed fibre, polymer, binder, tablet, metronidazole
LIST OF TABLES
Table 3.1: Formulation of Metronidazole Tablet Weighing 300mg
Table 3.2: Percentage Composition of the Ingredients in Formulation of Metronidazole Tablet Weighing 300.0mg
Table 4.1: Organoleptic Properties of Natural and modified powders derived from corn seed
Table 4.2: Physco-Technical Properties of Natural and Modified Powders derived from corn
Table 4.3: Proximate Composition of Naturals Corn Fibre
Table 4.4: Some Elemental Constituents of the Natural Corn Seed Fibre Powder (SCNR)
Table 4.5: Granule Properties
Table 4.6: Tablet Properties
Table 4.7: Coefficient of Variation of Tablet
Table 4.8: Tablet Tensile Strength
LIST OF FIGURES
Fig. 1.1: Corn Seed
Fig. 1.2: Corn Cob
Fig. 4.1: Scanning Electron Micrograph of SCNR
Fig. 4.2: Scanning Electron Micrograph of SCN1
Fig. 4.3: Scanning Electron Micrograph of SCN2
Fig. 4.4: Scanning Electron Micrograph of SCN3
Fig. 4.5: DSC Thermograph of Metronidazole
Fig. 4.6: DSC Thermograph of SCN1 -
Fig. 4.7: DSC Thermograph of a blend of Metronidazole and SCN1 -
Fig. 4.8: DSC Thermograph of SCN2 -
Fig. 4.9: DSC Thermograph of a blend of Metronidazole and SCN2 -
Fig. 4.10: DSC Thermograph of SCN3 -
Fig. 4.11: DSC Thermograph of a blend of Metronidazole and SCN3 -
Fig. 4.12: Graph Showing the Effect of Concentration of Binders on the Hardness of Tablets
Fig.4.13: Graph Showing the Effect of Concentration of Binders on the Friability of Tablets
Fig.4.14: Graph Showing the Effect of Concentration of Binders on HFR
Fig.4.15: Graph Showing the Effect of Concentration of Binders on Disintegration Time
Fig.4.16: Effect of Concentrations on SCN1 on the Release Rate of Metronidazole
Fig.4.17: Effect of Concentrations on SCN2 on the Release Rate of Metronidazole
Fig.4.18: Effect of Concentrations on SCN3 on the Release Rate of Metronidazole
Fig.4.19: Effect of Concentrations on SA on the Release Rate of Metronidazole
Fig.4.20: Effect of Concentrations on SG on the Release Rate of Metronidazole
ABBREVIATION AND SYMBOLS
Abbildung in dieser Leseprobe nicht enthalten
1.1 BACKGROUND OF THE STUDY
Pharmaceutical excipients are ingredients that are not the active drug substances of the pharmaceutical formulations, which have been properly assessed for safety and are added in a drug delivery system to either assist the processing of the drug delivery system during production, safeguard, support or improve stability, bioavailability or patient acceptability, identification or improve any other qualities of the general safety and efficiency of the drug delivery system during storage or use. Excipients are also called additives or adjuncts. (Ogaji, et al,2012)
Drugs are not always administered alone but usually formulated with the help of these additives into suitable dosage forms. Examples of these excipients includes the binding, lubricating, flavoring, sweetening, bulking agents among others. Excipients make up the largest constituents of any pharmaceutical dosage form and may be natural, semi-synthetic or synthetic in origin (Parott, 1971).
1.2.1 Uses of Excipients
Exipients are normally included with the active drugs in many formulation in order to safeguard, support or improve the stability of the finished products. They also assist to bulk up the pharmaceutical preparations in case of potent or low dose drugs for the accurate formulation of the dosage forms. They are used to enhance patient acceptance, to enhance bioavailability of active drugs especially in cases where the active substances are not absorbed easily in the body. (Shilpa and Pradeep,2012;Ogaji et al,2012 )
1.2.2 Characteristics of an ideal Excipient
Any ingredients to be used as excipients must have some ideal features of excipients. They must be chemically stable, non-reactive, low equipment and process sensitive, non-toxic, eco-friendly, economical, suitable with regards to organoleptic characteristics and having effectiveness in respect with the anticipated use.(Airaksinen, et al,2005).
1.2.3 Selection of Excipients
The of choice excipients usually depends on the required characteristics of the additives such as functionality, material reliability, regulatory, acceptance, cost, availability & sources. Material properties like physico-technical, thermal, rheological, mechanical properties etc. are also considered in the development of drug formulation. The roles of excipients depends on the concentration of the excipients in a particular formulation (Airaksinen, et al, 2005).
1.2.4 The need for new Excipients
With the current use of modern tablet machines high speed, direct compression techniques and increasing desires of researchers to solve some challenges of drug delivery system has posed several problems to tablet manufacturing process. To this regard, excipients with desirable, excellent and improved properties are desired on daily basis to solve these problems. Most natural polymers in their natural forms do not possess good physico-technical properties thereby necessitating the need for polymer modification (Meneesh, et al, 2010; Verbeken, et al, 2003).
Natural polymers employed as pharmaceutical additives have many benefits over synthetic excipients but not also devoid of some demerits. They are usually biodegradable, stable, renewable, non-toxic, environmentally friendly, low cost and available. Their demerits include the fact that they are vulnerable to microbial contaminations, may exhibit batch to batch variation due to ecological & seasonal factors, there is also fear for the presence of genetically modified organism (GMO), variation in rate of hydration due to differences in the collection of natural materials at different times and high sensitivity to moisture and other atmospheric conditions (Meneesh, et al, 2010; Verbeken, et al, 2003;Girish, et al, 2009).
The Nigerian pharmaceutical industries depends largely on imported excipients, in fact nearly 100% of pharmaceutical excipients employed in the local drugs production in Nigeria are imported. Large amount of foreign exchange is involved on the importation of both the active drugs and excipients resulting to the depletion of the nation’s foreign reserve and high cost of drugs in Nigeria (Odeku,2018).
Maize is a multipurpose crop, it delivers food and fuel for human beings and feeds for livestock. Its grain has great nutritional importance and can be used as raw material for the production of many industrial goods and pharmaceutical excipients (CBN, 1992).
Nigeria is the largest producer of maize in Africa with an estimated annual production capacity of 8.0 Million tons.(IITA,2011). Therefore converting the seed fibre obtained from this quantity of maize produce annually into useful pharmaceutical excipients and applying the same in the local drug production will go a long way to reduce our dependence on imported excipients, preserve our foreign exchange, create job opportunities for the teeming unemployed Nigerian youths, create business opportunities for the Nigerian maize farmers and ultimately reduce the cost of drugs in Nigeria.
1.3 Zea mays
1.3.1 Taxonomy of Zea mays (maize)
Maize (zea mays) is an annual crop and a member of the grass family Poaceae. “Zea” ,it is a derivative of an old Greek name for a food grass. The genus Zea comprises of four species of which Zea mays L is of great importance. The other Zea Spp. Known as teosintes, are mainly wild grasses native to Mexico and Central America. This cereal is also known by different synonyms such as zea, corn ,silk corn etc. (Deobley, 1990).
Species : Zea mays
1.3.2 Origin and distribution of maize
Maize (Zea mays L.) also known as corn, is a cereal crop first grown by the indigenous people in Southern Mexico about 10,000 years ago. (The Evolution of Corn, 2014; Benz,2001).
The word maize was a derivative of the English form of the indigenous Taino word for the plant maize. It is also known by different names around the world.In Nigeria, the Igbos call it oka, in Yoruba it known as agbad o and in Hausa it is called masara.
An important study has proven that all maize arose from a single domestication in Southern Mexico about 9,000 years ago( Matsuoka ,et al,2002).The study also established that the oldest survive ng maize types are those of the Mexican uplands and later maize spread from this region over the Americans along two major parts.
In Nigeria, specifically in the northern part of the country, maize serves as a major source of food for man. Maize is the second most significant cereal crop in Nigeria ranking behind sorghum in the number of people it feeds.(Matsuoka, et al, 2002; CBN,199;Darrah, et al,2003;Mangelsdorf,1974).
1.3.3 Types of Corn seeds
A number of corn types can be discerned on the basis of endosperm and kernel compositions (Purseglove,1972).
Flint corn: The Kernels are characterized by their high percentage of hard endosperm around a small soft center. It is grown mostly in Latin America and Europe for food use.
Dent corn: This is the most commonly grown for grain and silage and is the predominant type grown in the USA. Hard endosperm is present on the sides and base of the kernel. The remainder of the kernel is filled with soft starch. When the grain starts drying, the soft starch at the top of the kernel contracts, producing the depression for which it is named.
Floury corn: This is being grown mainly in Andean region. Its endosperm is basically composed of soft starch, making it easy to grind and process into food.
Waxy corn: The kernels comprises of almost entirely amylopectin as their starch (rather than the normal 70.0% amylopectin and 30.0% amylose. Waxy maize is preferred for food in some parts of East Asia and for some industrial use. It produces a starch similar to tapioca.
Pop corn: The kernels are known for their high proportion of hard endosperm which is much higher than in any other maize kernel. Pop maize is grown on a small scale compared to other types but popped kernels are consumed worldwide as a snack food.
Sweet corn: It is grown for green ears (sweet corn). The ears are harvested at approximately 18.0 to 20.0 days post pollination when kernel moisture is approximately 70.0%. The developing grain of sweet maize is higher in sugar content due to one or more recessive mutations blocking conversion of sugar to starch (Darrah, et al, 2003; Paliwal, 2000;Purseglove, 1972;).
1.3.4 Cultivation of maize: climate and soil type
Maize is cold intolerant and in the temperate zones, it must be planted in the spring. Its root system is naturally shallow therefore are easily hindered by less permeable layers of sandy and clay soils. This plant is dependent on soil moisture for growth and survival. Maize is most sensitive to drought at the time of silk appearance, when flowers are ready for pollination. As a warm weather crop, it could be grown in a wide range of climatic conditions. (ICAR, 2006; IITA,1982).
Depending on the stage of the crop growth, its reactions to temperature varies. During germination, the ideal temperature seems to be around 18.0oc, at temperature below 13.0oc, germination is slow. A large population of pathogens causing maize diseases are encouraged by cool weather. The rate of development of the plant is a function of temperature. In the highlands, failing temperature after the onset of rain can limit yield. In Lowland varieties are usually harvested within four months of planting whereas in the highlands the crop may take eight months or more to reach maturity (IITA,1982).
The quantity, distribution and effectiveness of rainfall are very vital factors in successful maize production. The maize crop is particularly sensitive to moisture stress during flowering when a short spell of stress can decrease the crop yield by 30.0 to 50.0%. Requirement of water depends upon several factors but in general 480.0 to 800.0mm of rainfall, if well distributed is adequate and a low pH is unfavorable for maize growth.(IITA,1982; Fernandex, et al,2011).
1.3.5 Pests and Diseases of Maize
There are over 130.0 insect pests that affect maize crop among which are Stem borers, Shootfly, Army worm, Jassids, Thrips, White ants, Pyrilla, Grasshoppers, Grey weevil, Hairy caterpillars, Root worms, Earworms and Leaf miner are more severe, though the severity varies in different agro-ecological regions.. Fall Armyworm (Spodoptera Frugiperda) is another very important pest in tropical and subtropical areas. In India, spotted Stem borer (Chilopartellus) is the most serious pest. Stalk-borer (Chilopartellus) is the major pest throughout the country. (Dhillon, et al, 2001;Darrah, et a l,2003).
Globally, Maize suffers from about 110.0 diseases caused by Fungi, bacteria and viruses and the disease scale varies in different agro-climatic zones. About 13.2% of the economic product of maize is estimated to be lost annually due to diseases (Dhillon, et al, 2001;Darrah, et a l,2003).
1.3.6 Chemical Composition of maize seed
The Proximate composition of maize seeds are; moisture content(9.20 -10.98%),Ash(0.7 to 1.3%),Fat(3.21 to 7.71%),protein(7.71 to 14.60%)crude fibre(0.8 to 2.32%),Carbohydrate 69.66 to 74.55%).(Ikram, et al,2010)
1.3.7 Nutritional and Medcinal benefits of corn
Corn is the second most significant cereal crop in Nigeria coming behind sorghum in the number of people it feed (CBN, 1992). Corn is a multi-purpose cereal crop, providing nutrition for the people and feeds for animals. Its grain has great dietary value and can be used as raw material for manufacturing many industrial goods. (Afzal, et a l ,2009).
Seed are consumed in raw and cooked form that serves as good source of carbohydrates. Corn contains vitamin B-complex such as B1 (thiamine), B2 (Niacin), B3 (Riboflavin), B5 (pantothenic acid) and B6 that makes it recommendable for hair, skin, digestion, heart and brain. It contains vitamin C, A and K together with large amount of beta-carotene and fair amount of selenium that helps to improve thyroid gland and play important role in appropriate functioning of immune system.. Corn silk contains maizeric acid, fixed oils, resin, sugar, mucilage, salt and fibers essential for our diet. Edible oils obtained from seeds are useful in salad and for cooking. Roasted seeds are used as coffee substitute. Phytochemical secondary metabolic such as saponin, allantoin, sterol, stigmasterol, alkaloids hordenine and polyphenols are formed in leaves, seed and corn silk (Breadly,1992; British Herbal Medicinal Association, 1989; Afzal, et a l ,2009).
A very popular product named Ogi or Uji is consumed in Africa, this is prepared by steeping and fermenting then milled and made into slurry. Then it is fermented and made into porridge.(FAO,2003).
The maize whole grain can be dry milled to produce a coarse maize meal or fine flour and it is used in a variety of ways. In Africa, for instances, they used to make cooked paste, fermented or unfermented. The flour is used to make a dough adding water.
This dough is made for preparing unleaved bread and flat thin called chapattis in Asia food. The starch from wet milled Maize can be prepared in to akamu a common break fast in Nigeria. (FAO,2003).
1.3.8 Medicinal importance of corn
For many centuries, corn has been used to treat anorexia, general debilities, emaciation and hemorrhoids. It is a powerful antioxidant that safeguards the body from being harmed by free radicals responsible for cellular damage and/or cancer. It possess analgesic activity as well,it helps in the production of sex related hormones and promotes sexual health, especially for men with erectile dysfunctions. It is believed to improve joint mobility. The major nutrient of corn silk is potassium which is an essential electrolyte and the silk is also used to conquer urinary tract infection and kidney stones (Owoyele, et al, 2010 ;Lans, 2006;Dilip, et al,2003). Corn silk improves blood pressure and aids liver functions as well as production of bile. Roots, leaves and corn silk are prepared as decoction while the decoction of cob as tea is used for stomach complaints. It acts as a good emollient for ulcer, wound and swelling. In some places, decoction of corn silk and parched corn is extremely useful in nausea and vomiting. (Dilip, et al, 2003; Owoyele, et al,2010; Lans,2006).
1.3.9 Industrial and Economic importance of corn
Corn are used in the production of industrial goods and products. Corn syrup is useful in production of jams, jellies, sweets and as well as an additive for cane sugar and maple syrup. The oil present in corn is used for cooking and production of soap. Sticky gums contain dextrin used for sealing envelopes and labels. Corn starch is commonly known for its use in cosmetics and pharmaceutical industries as filler, it can be made into plastics, fabrics, adhesives and many other chemical products. Corn seeds are functional in making alcohol and stem fibre for making of paper. The cobs are also used as biomass fuel and corn steep liquor is generally used in the bio-chemical industry and research as a culture media (Ligget & Koffler, 1948; Dilip, et al, 2003; Torres , et al, 2016).
Metronidazole is 1-(2-hydroxyethyl)-2-methyl-5-nitro imidazole, antibacterial agent used to treat amebiasis, vaginitis, trichomonas Infections, giardiasis, anaerobic bacteria and treponemal Infection.
The chemical formula for metronidazole is: C6H10N3O3. It is soluble at 200C, in 100 parts of water, in 200 parts of alcohol, and in 250 parts of chloroform, slightly soluble in ether. Metronidazole has a molecular weight of 207.614g/mol with melting point of 159oC to 162oC. It is a white or creamy-white crystalline powder with a slight odor and contain not less than 99.0 and not more than the equivalent of 101.0 percent of C6H10N3O3. Loss on drying under prescribed condition is not more than 0.5 percent.
It has a bitter and saline taste, the pH (Saturated aqueous solution) is about 6.5. Metronidazole is stable in air but darkens on exposure to light with vapor pressure of 3.1 x 10–7mmHg at 250C (Osol & Hover, 1975; B.P,2012).
Structure of Metronidazole
Abbildung in dieser Leseprobe nicht enthalten
1.5 Statement of problem
About 75.0% of total drugs consumed in Nigeria are imported especially from Asian countries and only 25.0% are manufactured locally in Nigeria(UNIDO, 2011).The Nigerian pharmaceutical industries largely rely on foreign pharmaceutical excipients for their local drug production. A huge amount of the country’s foreign exchange are spent on the importation of the active pharmaceutical ingredients and excipients (Odeku, 2018). Africa produces about 6.5% of maize in the world annually and Nigeria is the largest maize producer in Africa with an annual production capacity of about 8 million tons (IITA, 2011).
1.6 Aims and objectives of the study
1. The objective of the research work is to modify maize seed fibre.
2. The work is aimed at deriving a hydrophilic polymer from the fibre obtained from maize seed and evaluating it as a binder in Metronidazole tablets .
1.7 Significance of the study
A destarched corn seed fibre is regarded as an agro-waste which could be converted to a very useful pharmaceutical excipient and employed in local drug production .The feasibility of this will go a long way to reduce the cost of drugs production in Nigeria and conserve foreign reserve. Crude corn seed fibre lack some important physico-technical properties of an ideal pharmaceutical excipient like flowablity, compressibility. There is therefore the necessity to modify the fibre in order to improve its quality as pharmaceutical excipient.
1.8 Scope of the Study
The scope of the work involves processing fibre from corn seed, modifying the fibre to obtain a hydrophilic polymer. The polymer will be characterized to elucidate its physico-technical properties. Later, the polymer will be evaluated for its binding properties in the formulation of Metronidazole tablets using standard binders. The tablets obtained will be assessed for tablet properties using official method.
2.0 LITERATURE REVIEW
2.1 Corn fibre
Corn fibre is a possible raw material for making several products and it is commonly available worldwide. It is a byproduct of the corn wet milling industry and very large of it is produced each day in many countries. The major component of corn fibre is the pericarp that consist of 35% Hemicellulose, 18% Cellulose and 20% remaining Starch (protein,fibre oil and Lignin are also present in this material).It is commonly used as livestock feeds.(Maria, et al,2007)
Tablet is a solid unit dosage form intended for oral administration, usually obtained by compression of powders or granules. In certain cases it may be obtained by molding or extrusion techniques and may contain one or more active ingredients formulated with or without excipients(WHO,2011).
They may vary in size, shape and weight depending on the medicaments and mode of administration. Tablet remains the most commonly used pharmaceutical dosage form due to its advantages over other dosage forms, it is estimated that over 70% of medicaments are dispensed in this form (Haritha,2017;Jishan,2015). Tablets are patient friendly due to their ease of ingestion, flexibility, patient compliance, dose precision and do not need sterile conditions hence are less expensive to manufacture.(Nyol & Gupta,2013;Bhattacharjee,2013).
2.2.1 Advantages of tablets
i. Tablet is a unit dose form with dose precision.
ii. Least content variability.
iii. Administration of accurate amounts of minute doses of a drug is possible
iv. Economical of all oral dosage forms as its production doesn’t require additional processing steps.
v. Easy transportation.
vi. Good stability compared to other dosage forms
vii. Sustain release of a drug can be achieved through enteric coating
viii. Medicaments with bitter taste can be masked with coating technique.(Haritha,2017; Jishan,2015)
2.2.2 Disadvantages of tablets.
i. Administrations of tablets are not easy in case of children.
ii. Drugs with slow dissolution is not acceptable for tablet with good bioavailability
iii. Medicaments with low density characters and amorphous in nature are difficult to compress
iv. Hygroscopic nature of drug is not acceptable for tablet compression. (Haritha,2017; Jishan,2015).
2.2.3 Types of tablets
Tablets may be classified as coated or uncoated. Uncoated tablets include chewable tablets, effervescent tablets, soluble tablets, dispersible tablets, lozenge tablets, sublingual tablets, buccal tablets, while coated tablets include enteric coated tablets, sugar coated tablets, film coated tablets and modified release tablets which includes: Delayed-release tablets (gastro-resistance) or enteric-coated tablets and sustained-release tablets; extended/prolonged-release tablets.(WHO,2011,Aulton,2012, Jishan,2015).
(a) Uncoated Tablets
The bulk of uncoated tablets are prepared in such a way that the release of the active ingredients is unchanged. A broken section when examined under a lens, shows either a relatively uniform texture (single-layer tablets) or a stratified texture (multilayer tablets) but without any sign of coating(WHO,2011).
(b) Effervescent tablets
Effervescent tablets are uncoated tablets made by compressing the active ingredients with mixture of sodium bicarbonate and organic acids such as citric and tartaric acid. They are designed to dissolve and release carbon dioxide when in contact with water producing a palatable solution. They can may be prescribed to patients who have difficulties in swallowing the conventional tablets .Effervescent tablets have better absorption and faster onset of action than the conventional tablets.(Lachman, et al,1987; Allen , et al, 2010;Swarbrick & Boylan,2002)
(c) Dispersible Tablets
Dispersible tablets are uncoated tablets expected to be dispersed in water before administration producing a homogeneous dispersion. They are required to disintegrate within 3.0 minutes in water at to 25.0 oC. (Nandhini &Rajalakshmi,2018;WHO,2011).
(d) Chewable Tablets
They are intended to be broken and chewed before being swallowed. These tablets are expected to disintegrate smoothly in the month at a moderate rate either with or without actual chewing. Chewable tablets have a smooth texture upon disintegration, with pleasant taste.(Renu, et al, 2015;WHO,2011)
(e) Lozenges Tablet
Lozenges are solid unit dosage form containing one or more medicaments in a flavored and sweetened base, they are meant to dissolve in the mouth or pharynx for the treatment of local irritations or infections. They contain high amount of binder so as to be able to produce slow dissolution over a long period of time and can deliver drug multi directionally into the oral cavity or to the mucosal surface.(Peters, et al,2005; Mendes, et al, 2006)
(f) Sublingual & Buccal Tablets
Sublingual tablets are required to be placed below the tongue for the slow release of the active drug substance and buccal tablets are placed in either parts of the mouth for systemic absorption. Drugs that are not stable in the gastrointestinal tracts but are absorbed in the oral cavity or drugs whose immediate actions are anticipated are formulated in this form.(WHO,2011)
(g) Coated Tablets
Coated tablets are tablets covered with one or more layers of mixtures of substances such as natural or synthetic resins, polymers, gums, fillers, sugars, plasticizers, polyols, waxes.). Tablets are coated for a number of reasons, which include the control of the release of the active ingredients, masking of objectionable odor and taste, physical and chemical protection, protection of the drug from the gastric environment etc. There are various techniques for tablet coating such as sugar coating, film coating, and enteric coating.(Gupta, et al, 2012;WHO,2011)
(f) Film Coated Tablets
Film-coated tablets are covered with thin layer or film of resins, polymeric substances and/or plasticizers which are capable of forming a film to protect the drug from atmospheric conditions and mask the objectionable taste and odor of the drugs. The choice of polymer mainly depends on the desired site of drug release (stomach/ intestine), or on the desired release rate.(Lechman, et a l,1991;WHO,2011).
(g) Sugar Coated Tablets
This type of tablet is generally made in cases where the drug has some undesirable properties like taste, odor, color etc. Sugar coating of tablets gives the tablets a glossy appearance thereby enhancing the patient acceptability. This type of tablet should be administered in whole form otherwise the patient will experience the unpleasant taste of the active ingredients (Purushottam,et al,2018,WHO,2011).
(h) Enteric coated Tablets
The enteric coated tablets are coated with the material that are resistant to the stomach acid and are not able to release drug in stomach but easily releases drug in the intestine which is an alkaline environment. The drugs have to pass through the stomach and the time of release of drug is delayed and hence it is called delayed action tablet. (Purushottam,et al,2018;WHO,2011).
2.2.4 Tablet excipients
Excipients are physiologically inert substances used in tablet formulation to enhance bulkiness, disintegration, dissolution rate and bioavailability of drug. It is a catch – all term. Tablets excipients are also known as additives and includes diluents or fillers, binders or adhesives, Glidants, Lubricanting, disintegrating, flavoring, coloring and sweetening agents. Excipients must be physiologically and chemically stable, devoid of bacterial or fungal contamination, commercially available, inexpensive and must meet the standards of regulatory bodies (WHO,2011;Ogaji, et al,2011;Karthik,2016;Beneke, et al,2009). While selecting these additives for any preparation, the anticipated excipients must be kept to a lowest number and the amount of each excipient must be the least needed (Karthik, 2016).
They are regarded as essential constituents of drug products and in most of the preparations as they form the bulk of the preparation. Though excipients are regarded as inactive substances, they can react with the drug components, with other additives and also with the packing materials. They may likewise contain different impurities which may lead to the breakdown of the active substances in the formulation, consequently varying the shelf life of the formulation. (Airaksienen, et al, 2005; Zaki,2013; Beneke, et al,2009).
Excipients efficiency can be improved by modification. Modification can be by co- processing and this involves the mixing of two or more existing additives at sub-particle level in order to improve the functionalities of the excipients and to reduce their shortcomings. Co-processed additives can also function as multifunctional or multipurpose additives in formulations. Multipurpose additives are those excipients that serve more than one purpose in a pharmaceutical preparation. Multipurpose additives should be given preference over uni–functional additives in order to reduce the number of excipients included in a dosage form. (Olayemi, et al,2010; Minakshi, et al, 2010).
Binders are also known as adhesives, they are agents employed in pharmaceutical preparations to impart cohesiveness to the powders and granules hence making the tablet to remain intact after compression as well as improving the flow properties of granules. The selection of an appropriate binder for a tablet formulation needs wide knowledge of the comparative significance of binder’s properties for improving the strength of the tablet and also of the interactions between the various materials constituting a tablet (Oyi, et al, 2009; Sunethra, et al,2016).
Binders can be added in dry mix or mix in granulating liquid, binders form matrix with diluents and drug embedded in it, on drying, solid binders form paste which holds the materials together, the wet binder is the most important constituent in the wet granulation method. Most binders are hydrophilic and often soluble in water. Solution binders are dissolved in solvents before using in wet granulation procedure and dry binders are added to the powder blend either after a wet granulation step or as part of direct compression (DC) procedure. Even distribution and the quantity of binders employed in a granulation are very important. Inadequate binders tends to cause poor adhesion, capping and soft tablets. Excessive binder produces slowly disintegrating and hard tablets. The presence of too much binder in a formulation makes granulation & tableting extremely difficult (Patal ,et al, 2012;Duryea,1976; Bhardwarj, et al,2000; Sunethra, et al,2016;Upadastra ,et al,1992; Anthony,1997).
Binding agents experience a high degree of plastic deformation during compression and are forced into inter-particulate spaces, where they increase the area of interaction amongst the particles and form strong links (Itiola & Pilpel, 1991).Binders can be classified on the basis of their origin which can be animal source (e.g. gelatin), vegetable (e.g. starch and cellulose), synthetic (e.g. Polyethylene glycol) or mineral origin. Binders are typically saccharides and their derivatives which includes disaccharides, polysaccharides, sugar alcohols and synthetic polymers (Al-Saidam, et al, 2005; Bhardwarj, et al,2000; Upadastra ,et al,1992).
22.214.171.124 Fillers or diluents
Diluents are agents added to tablet formulation in order to build up the required bulk of the tablets especially for low dose drugs weighing less than 70.0mg.They increase the practical sizes of low dose drugs for easy compression. In certain formulations of potent drugs, the diluents can make up to 90.0% of the total tablet weight. High dose drugs may not require fillers when they are prepared by wet granulation. Diluents permit the use of direct compression manufacturing and improve flowability. The solubility of diluents is also very vital as this will affect how the tablet disintegrates. Commonly used fillers or diluents includes; Lactose, Sucrose, Manitol, starch, cellulose and cellulose derivatives, dicalcium Phosphate Dehydrate. (Ofoefule, et al,2002;Remington,1982).
126.96.36.199 Anti- adherents, lubricants and glidants
Lubricants are ingredients employed in tablets formulation to minimize the friction between die wall and tablets, prevent adhesion of tablet to dies and punches, to reduce inter- pacticulate friction and prevent excessive wear of punches and dies. They aid in easy ejection of tablets from die cavity and can be categorized in to two types. Insoluble lubricants.e.gStearic acid, and Soluble lubricants e.g- Sodium lauryl sulphate,.
Glidants: are ingredients that aid in the free flowing of granules from hopper to die cavity and to minimize friction between particles. Example: Colloidal Silicon dioxide.
Anti-adherents: These are substances added to the formulation in order to prevent adhesion of tablet material to punches and dies. Anti-adherents prevent sticking of tablet to dies and punches. Example Talc.(Karthik,2016)
Disintegrants are substances added to the drug formulation that enable the breakup, fragmentation or disintegration of tablet or capsule content into lesser particles that dissolve more fast. The main purpose of disintegrants is to oppose the effectiveness of the tablet binders and the physical forces that act under compression to structure the tablet. Super-disintegrants are mostly used at a low level in the tablet formulation, usually 1 – 10 %by weight relative to the total weight of the dosage unit and enhances the fragmentation of tablets within 1.0 minute (Bhowmik, et al,2010;Mohanachandra, et al,2011).
(i) Method of addition of disintegrants:
There are two methods of incorporating disintegrating agents into the tablet:
- Internal Addition (Intragranular) .
- External Addition (Extragranular)
- Partly Internal and External In external addition method.
In external addition process, the disintegrant is incorporated in to the sized granulation with mixing prior to compression. In Internal addition technique, the disintegrant is mixed with other powders before wetting the powder blends with the granulating liquid. Consequently the disintegrant is incorporated inside the granules. When these procedures are used, part of disintegrant can be added internally and part externally. This provides immediate breakup of the tablet into previously compressed granules while the disintegrating agent within the granules produces further erosion of the granules to the original powder particles. The two step technique usually produces better and more complete disintegration than the usual method of adding the disintegrant to the granulation surface only.(Basak, et al,2004; Bi et al,1999; Bhowmik, et al,2010;
(ii) Ideal characteristics of disintegrant
- Poor solubility
- Poor gel formation
- Good hydration capacity
- Good molding and flow properties.
(iii) Mechanism of action of disintegrant
The mechanism of disintegration action varies from one disintegrant to the other and the mechanism includes; swelling, porosity and capillary action, deformation, Enzymatic etc. (Basak, et al,2004; Bi al,1995; Bhowmik, et al,2010)
Swelling of disinterants is the most accepted mechanism for tablet disintegration, it is related to dimensional amplification where particles enlarge omni-directionally to push apart the adjoining constituents, thereby initiating the fragmentation of the tablet matrix. Most common disintegrants swell to some extent and the swelling capacity of a disintegrant depends on numerous factors like the chemical structure and degree of crosslinking of particles.Porosity of the compact is also a very essential contributor to the performance of swelling disintegrants, a porous tablet matrix with large void spaces could stifle the swelling action of disintegrants and hinder their effectiveness in tablet crumbling. Equally, low porosity compacts prepared by using very high compression forces could hamper liquid entry and prolong the disintegration time. Therefore, tablets are expected to be prepared at the optimal porosity to provide adequate mechanical integrity without compromising disintegratability. (Alebiowu & itiola, 2003; Quodbach , et al, 2014; El-barghouti, et a l,2008;Kotte & Rudnic,2008;Moreton,2008;Omidian &Park,2008)
Porosity and capillary action
Wicking is defined as a process of liquid entry by capillarity into the microstructured crevices within the compact to dislodge the air. Other tablet components may also confer hydrophilicity to the matrix and can contribute to liquid penetration as well. Hence, wicking cannot be considered as a primary disintegration mechanism. Water imbibition into the compact is a prerequisite to disintegrant activation and the micro-pore structure within the compact will be of great significance. The water penetration rate depends on the balance between capillary and opposite viscous forces.(Van , et al, 1996; Desschoenmaker, et a l,2011; Moreton,2008;Kissa,1996).
Hess had proved that during tablet compression, disintegrated particles get deformed and these deformed particles get back to their normal structure when they come in contact with water. The swelling capacity of starch particles increases when granules are extensively deformed during compression. This increase in size of the deformed particles produces a breakup of the tablet. Starch particles are largely thought to be “elastic” in nature meaning that particles that are deformed under stress will return to their original shape when that stress is removed. But, with the compression forces involved in tableting, these materials are believed to be further deformed permanently and are said to be “energy rich” with this energy being released upon contact with water. In other words, the ability for starch to swell is higher in “energy rich” starch materials than it is for starch particles that have not been deformed under pressure. (Banker , 1990; Alekha , et al,2000)
Heat of wetting
Exothermic (heat generation) or endothermic (heat absorption) interactions are demonstrated by materials on interaction with water. Exothermic characteristics are witnessed when disintegrants interact with the aqueous media. The heat produced can cause localized strain associated with the expansion of air retained in the tablets and this can aid tablet breakup. However, some researchers suggested that the amount of heat generated by wetting is rather small and may not be sufficiently significant to cause effective expansion of the entrapped air in the compact to bring about its break-up.(Lowenthal,1973).
Chemical Reaction (Acid Base Reaction)
The interaction between bicarbonate and carbonate with citric acid or tartaric acid causes the release of carbon dioxide when in contact with water. The tablet fragments due to generation of stress within the tablet. These disintegrants are highly sensitive to small changes in humidity level and temperature, therefore strict control of environment is required. (Banker , 1990; Alekha, et al,2000)
This involves the enzymes presents in the body acting as disintegrants and destroying the binding activities of the binders thereby assisting in tablets disintegration. It is thought that no single mechanism is accountable for the action of most disintegrants. But rather, it is more likely the result of inter-relationships between these major mechanisms. (Banker , 1990; Alekha, et al,2000)
Flavour refers of to a mixed sensation of taste, touch, smell, sight and sound, all of which comprise a mixture of physio-chemical and physiological actions that influence the perception of substances. Flavours agents are therefore chemical agents which successfully mask unpleasant tastes, smell, sight etc of materials without affecting the physical and chemical integrity of the preparations.(Sharma & Sharma,1988).
Colorants or coloring agents are substances that are used to impart a distinctive appearance to the pharmaceutical dosage form in order to improve patient compliance and products differentiation. They are regarded as the cosmetics for the pharmaceutical products because the aesthetic appearance of the products can be improved by using suitable colorant. The elegance and eye appeal of a colored products are valuable especially for children. (Pramod, et al,2015;Krishna , et al,2011)
Sweeteners are additives that used to enhance the taste of pharmaceutical preparations and can be natural or synthetic. Natural sweeteners are sweet-tasting substances with natural source and have ample nutritional value; the major component of natural sweeteners is either mono- or disaccharides. Artificial sweeteners, on the other hand, are compounds that have no or little nutritional worth, artificial sweeteners are synthesized compounds that have high-intensities of sweetness and less of this substance is necessary to achieve the desired sweetness. Artificial sweeteners are mostly incorporated into pharmaceutical preparations to limit caloric intake or to prevent dental cavities. Sugar alcohols are natural compounds with varying degrees of sweetness .(Puneet, et al,2016)
2.2.5 Methods of tablet production
Tablet production technique can be largely categorized as granulation and direct compression. Granulation method could be defined as the size enlargement technique in which fine or coarse particles are transformed into physically stronger and bigger agglomerates having good flow characteristics, improved compression characteristics and uniformity or a process for assembling particles together by building bonds between them. It is the most commonly used procedure for the preparation of materials for tableting .Granulation may be either wet granulation i.e., by using binder solution or dry granulation i.e., by using dry binder. (Remington,2006; Meeus,2011, Ofufule, et al , 2002)
188.8.131.52 Wet Granulation
Is the most extensively used agglomeration method in the pharmaceutical industry. This process involves the mixing of the powder with the granulating fluid, wet sizing and drying.
Some important steps involved in the wet granulation
- . Mixing of the drug(s) and excipients
- Preparation of binder solution
- Mixing of binder solution with powder blend to form wet mass.
- Drying of moist granules
- Mixing of screened granules with disintegrant, glidant, and lubricant.
Advantages of wet granulation
- Permits mechanical handling of powders without loss of quality of blend.
- The flow properties of powder are improved by increasing particle size and sphericity.
- Increases and improves the uniformity of powder density.
- Improves cohesion during and after compaction..
- Reduces the level of dust and cross contamination.
(Venkateswara, et al,2014, Meeus,2011 Debjit, et al,2014, Ofoefule , et al, 2002)
Limitation of wet granulation
- It is an expensive process because of labor, time, equipment, energy and space requirements.
- Loss of material during various stages of processing.
- Stability may be major concern for moisture sensitive or thermo labile drugs.
- Multiple processing steps add complexity and make validation and control difficult.
- Any incompatibility between formulation components is aggravated.
(Venkateswara, et al,2014;Meeus,2011;Debjit , et,al,2014; Ofoefule , et al, 2002)
184.108.40.206 Dry granulation
In dry granulation procedure the compression of the powder does not involves the use of heat and solvent. It is the most appropriate of all methods of granulation. The two basic steps are the formation of compact of material by compression and then to mill the compact to obtain the granules. Two approaches are used for dry granulation. The most widely used process is slugging in which powder is recompressed and resulting tablet or slugs are milled to obtain the granules. The other method is to precompress the powder with pressure rolls using a machine such as Chilsonator.(Venkateswara, et al,2014, Meeus,2011; Debjit , et,al,2014;Ofoefule ,et al, 2002)
- The main advantages of dry granulation or slugging are that it uses less equipment and space.
- It eradicates the need for binder solution, heavy mixing equipment and the costly and time consuming drying step required for wet granulation.
- Can be used for moisture and heat sensitive material
- To enhance disintegration since powder particles are not fused together by a binder (Venkateswara, et al,2014; Meeus,2011; Debjit , et,al,2014;Ofoefule, et al, , 2002).
- It requires a specialized heavy duty tablet press to form slug.
- It does not permit uniform colour distribution as can be achieved with wet granulation where the dye can be incorporated into binder liquid.
- The process tends to create more dust than wet granulation, increasing the potential contamination.
- Venkateswara, et al,2014; Meeus,2011; Debjit , et,al,2014;Ofoefule ,et al, 2002).
220.127.116.11 Direct compression process
This technique involves blending the ingredients or powders together and placed in a tablet press to make a tablet without altering the physical characteristics of any of the ingredient. This is not very common because many tablets have active ingredients and excipients with very poor flow and compressibility properties and may not fit direct n .(Venkateswara, et al,2014; Meeus,2011; Debjit , et,al,2014; Ofoefule ,et al, 2002)
Advantages of Direct Compression:
- Cost Effectiveness
It is more economic than wet granulation method because few unit operations are involved. This requires less equipment, lower power consumption, less space, less time and less labor leading to reduced production cost of tablets.
Direct compression is less appropriate for moisture and heat sensitive active drugs, as it eliminates wetting and drying steps. Fluctuations in dissolution profiles are less likely to occur in tablets made by direct compression than the tablets made from granulations
- Faster Dissolution
The tablets produced by direct compression break up into smaller particles instead of granules which directly come in contact with dissolution fluid and exhibits comparatively faster dissolution
- Less wears & tears of punches
The high compaction force involved in the manufacture of tablets by slugging or roller compaction can be circumvented by adopting direct compression. The likelihoods of wear and tear of punches and dies are less.(Venkateswara, et al,2014; Meeus,2011; Debjit , et,al,2014; Ofoefule, et,al, 2002).
Limitations of direct compression
Direct compression is more prone to segregation due to the difference in density of the active ingredients and excipients. The dry state of the ingredients during mixing may induce static charge and lead to segregation. This may lead to the problems like weight variation and content uniformity.
- Low dilution potential
Most of the directly compressible materials can accommodate only 30-40 % of poorly compressible active ingredients and this may cause the production of large tablets that may create difficulty in swallowing.
- Lubricant sensitivity
Lubricants have a more adverse effect on the filler, which display almost no fracture or shear on compression .The softening effects as well as the hydrophobic effect of alkaline stearates can be controlled by optimizing the length of blending time to as little as 2-5 min.(Venkateswara, et al,2014; Meeus,2011; Ofoefule ,et al, 2002; Debjit , et,al,2014;).
2.2.6 Compaction cycle of powder
Tablet manufacture comprises three steps known as the compaction cycle. They are die filling, tablet formation and tablet ejection. Particles are forced into close proximity with each other in a process called compression and a definite geometry is achieved in a die by the action of the lower and upper punches. This will result in the creation of a compact or tablet. Compaction can therefore be defined as the compression and consolidation of a particulate solid-gas system due to an applied force. Compaction is describes the condition in which powder beds are subjected mechanical force. Compaction represents one of the most essential units of operations in tablet production because both the physical and mechanical properties of the tablets are determined during this process (Leuenberger & Leu, 1992; York , 1992; Alderborn, 2007;Marshall,1987).
Compression of powder means the reduction in volume of a powder bed due an application of force and consolidation on the other hand is an increase in the mechanical strength of the materials arising from particle or particle interaction. Consolidation is a concurrent screening process with compression. The integrity and bioavailability of compact is related to the compression and the consolidation process. (Leuenberger & Leu, 1992; York , 1992; Alderborn, 2007;Marshall,1987).
The compaction process comprises particle arrangement, followed by deformation under pressure and the finer particles formed as a result of fracture of larger particles may undergo further rearrangement.
18.104.22.168 Particle rearrangement and volume reduction
The non-isostatic compression of powder beds to create a compact is a complex process, resulting from the various internal processes that lead to consolidation. The initial compression of powder brings about particles rearrangement under little compaction pressures from a closer packing structure. The finer particles enter the voids between the larger ones and give a closer packing arrangement. In this process, the energy is developed as a result of inter particulate friction and there is a rise in the amount of particle surface area capable of producing inter particulate bonds. As the force increases, further rearrangement is barred and subsequent volume decrease is achieved by plastic and elastic deformation and/or fragmentation of the particles. (Hiestand, et al, 1977).
Plastic substances deform in an irreversible manner, resulting in a permanent change of the particle shape (irreversible process), whereas elastic substances when deformed resume their original shape and it is called reversible deformation. (Sun & Grant ,2001; Shailender,2018).
22.214.171.124 Deformation of Particles
As the upper punch penetrates the die containing the powder bed, originally there are essentially only points of contact between the particles. The application of the external pressure to the bed results in force being transmitted in through these inter particulate points of contact, leading to development of stress and local deformation of the particles. Energy is lost at this stage as a result of inter particulate and the die-wall friction, as well as deformation. Although, under the influence of an applied force, the materials not only deform plastically or elastically, but also fragment to form smaller particles (termed as brittle fracture).The nature of deformation depends not only on the physical properties of the material but also on the rate and magnitude of the applied pressure and the duration of locally induced stress. Elastic deformation is a reversible process and plastic deformation results in a permanent change in the particle shape (Celik, 1994;Shailender,2018).