Formulation And Evaluation of Oral Dispersible Tablets of Amlodipine Besylate with Natural and Synthetic Super Distengrants

Tablet is the most widely used dosage form because of its convenience in terms of self-administration, compactness and ease in manufacturing. However, geriatric and pediatric patients experience difficulty in swallowing conventional tablets, which leads to poor patient compliance. To overcome these problems, scientists were developed innovative drug delivery systems known as “Oral Disintegrating Tablets” (ODT)

Definition: The Centre for Drug Evaluation and Research (CDER), USFDA defines ODT as “a solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds when placed upon the tongue”. European Pharmacopoeia described orally disintegrating tablets as “uncoated tablets intended to be placed in the mouth where they disperse rapidly before being swallowed and as tablets which should disintegrate within 3 min”.9 Oral disintegrating tablets were kept on tongue where they get dispersed in saliva, resulting in a solution or suspension without the need of water or chewing

Desired Characteristics for Oral Dispersible           

TABLETS Should not require water to swallow but it should disperse or disintegrate in the mouth within a short period (<2 min). Be compatible with taste masking. Be portable without fragility concern. Have a pleasing mouth feel. Leave minimal or no residue in the mouth after oral administration. Exhibit low sensitivity to environmental conditions such as humidity and temperature. Allow the manufacture of tablets using conventional processing and packaging equipment at low cost.

Formulation Problems

Hygroscopicity

Most of the products of mouth dissolving drug delivery technologies are moisture sensitive, hygroscopic and often physically unstable under ambient temperature and humidity condition. Many mouth dissolving drug delivery systems require specialized packing to protect the product from moisture.

Friability

In order to maximize tablet porosity and minimize oral disintegration time, mouth dissolving dosage forms are either very porous, soft-moulded matrices or tablets compressed at very low compression forces, this causes mouth dispersible/mouth dissolving dosage forms to be soft, friable or brittle, often requiring specialized peelable blister packaging.

Importance of bioequivalence 

Mouth dissolving tablet formulations are ideal for extension for existing conventional drugs that are already in market. Creating a mouth dissolving tablet version of an existing immediate release product means that the two formulations must be bioequivalent (create the same therapeutic effect in the same time frame). This can be challenging, especially if the method of taste masking retards the dissolution rate of the active ingredient after disintegration of the mouth dissolving tablets.

Techniques Used for Taste Masking

Mouth dissolving tablets come in contact with taste buds for a longer time as it dissolves in the oral cavity. Taste masking is an essential requirement for mouth dissolving tablets for commercial success. Taste masking of the active ingredients can be achieved by various techniques.

Polymeric coating strategies (microencapsulation)

This is the simplest and most feasible option to achieve taste masking. The coating acts as a physical barrier to the drug particles, thereby minimizing interaction between the drug and taste buds. In case of giving coating to the drug particles, it will result in an increase the particle size. The extent to which the particle size increase will affect the mouth feel and tablet size will depend on the dose of the drug and the amount of coating material required to achieve taste masking 

Complexation with cyclodextrin

In inclusion complex formation, the drug molecule fits into the cavity of a complexing agent, i.e. the host molecule, forms a stable complex. The complexing agent is capable of masking the bitter taste of drug by either decreasing its oral solubility on ingestion or decreasing the amount of drug particles exposed to taste buds, thereby reducing the perception of bitter taste.

Use of ion exchange resins

Ion exchange resins are solid and suitably insolubilized high molecular weight polyelectrolytes that can exchange their mobile ions of equal charge with the surrounding medium reversibly. Bitter cationic drugs can get adsorbed on to the weak cation exchange resins of carboxylic acid functionality to form the complex, which is non bitter. The complex of cationic drugs and weak cation exchange resin does not break at pH 6-7, of saliva with cation concentration of 40 meq/lit. But at high cation concentration of stomach pH of 1-3, free drug is immediately released.

Use of effervescent systems

The effervescent agents are used for the taste masking of drugs. Generally, these formulations contain a carbon dioxide generator for taste masking, optionally a taste bud desensitizing composition, sweetener, and flavouring agent.

Salt formation or functional group modification

Adding alkaline metal bicarbonate such as sodium bicarbonate masks the unpleasant taste of water-soluble drugs.

Incorporation of sweeteners and Flavors

Flavors, sweeteners, gelatin, acidic amino acids, lecithin or lecithin-like substances and surfactants are used for taste masking of bitter drugs

Mechanism Of Tablet Disintegration

Disintegrants, an important excipient of the tablet formulation, are always added to tablet to induce breakup of tablet when it comes in contact with aqueous fluid and this process of desegregation of constituent particles before the drug dissolution occurs, is known as disintegration process and excipients which induce this process are known as disintegrants. When a mouth dissolving tablet is placed in the mouth, upon contact with saliva the tablet disintegrates or dissolves instantaneously.

The tablet breaks to primary particles by one or more of the mechanisms:

• Capillary action (Wicking) swelling
• Due to deformation Due to release of gases

MATERIALS AND METHODS:

Amlodipine Besylate

Introduction:

Amlodipine besylate which belongs to the class of calcium channel blockers. Its primarily used to treat high blood pressure and coronary artery disease.

Empirical formula: Amlodipine [C20H25CIN205] Besylate [C6H603S]

Chemical name: 2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester benzenesulfonate.

Pharmacological Profile:

Pharmacodynamics: Amlodipine besylate is a calcium channel blocker of the dihydropyridine class it primarily acts on vascular smooth muscles to produce vasodilation, reducing blood pressure and cardiac workload.

Mechanism of action:  Amlodipine besylate is a calcium ion influx inhibitor (calcium entry blocker or calcium ion antagonist). Amlodipine is a member of the dihydropyridine class of calcium antagonists. The therapeutic effect of this group of drugs is believed to be related to their specific cellular action of selectively inhibiting transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The contractile processes of these tissues are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound and its kinetic interaction with the calcium channel receptor is characterized by the gradual association and dissociation with the receptor binding site. Experimental data suggest that amlodipine binds to both dihydropyridine and no dihydropyridine binding sites.

Hypertension - The mechanism by which amlodipine reduces arterial blood pressure involves direct peripheral arterial vasodilation and reduction in peripheral vascular resistance. 

Angina - The precise mechanism by which amlodipine relieves angina has not been fully delineated. Amlodipine is a dilator of peripheral arteries and arterioles which reduces the total peripheral resistance and, therefore, reduces the workload of the heart (afterload). The unloading of the heart is thought to decrease ischemia and relieve effort angina by reducing myocardial energy oxygen consumption and oxygen requirements. Pharmacokinetics and Metabolism:   After oral administration of therapeutic doses of amlodipine besylate tablets, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine besylate tablets is not altered by the presence of food. Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing

Analtytical Profile:

Identification tests:

Infrared Spectroscopy (IR): The IR spectrum of Amlodipine Besylate tablets should match the reference spectrum. High-Performance Liquid Chromatography (HPLC): The retention time of Amlodipine Besylate in the sample solution should match that of the reference solution.

Quantitative Tests

Assay: Determine the content of Amlodipine Besylate in the tablets using HPLC.

Limit: 90.0% to 110.0% of the labeled amount.

Impurities: Determine the content of impurities in the tablets using HPLC.

Limit: Not more than 0.5% of any individual impurity.

Performance Tests: Dissolution Determine the dissolution rate of Amlodipine Besylate tablets using the USP Apparatus 2. Limit: Not less than 80% of the labelled amount should dissolve within 30 minutes.

Disintegration: Determine the disintegration time of Amlodipine Besylate tablets using the USP Apparatus.

Limit: Not more than 15 minutes.

EXCIPIENTS PROFILE:

1)Fenugreek:

Non-proprietary names: fenugreek, Trigonella foenum-graceum

Synonyms: Bird's Foot, Greek Hay, Methi 

Chemical Name: Trigonella foenum-graecum

Structural Formula: Not applicable, as Fenugreek is a complex mixture of compounds

Functional Category: Herbal supplement, Nutritional supplement, Galactagogue

Applications in Pharmaceutical Formulation or Technology: Fenugreek is used: As a galactagogue to increase milk production in lactating women. As a nutritional supplement to lower cholesterol and blood sugar levels. As an herbal supplement to relieve digestive issues and menstrual cramps.

Therapeutic Uses: Fenugreek is used to:

Increase milk production in lactating women, Lower cholesterol and blood sugar levels Relieve digestive issues and menstrual cramps.

2)Cross povidone:

Non-Proprietary Names: Cross povidone, Polyvinylpolypyrrolidone (PVPP)

Synonyms: Cross povidone, PVPP, Polyvidone, PVP-P

Chemical Name: Polyvinylpolypyrrolidone

Structural Formula: Complex, cross-linked polymer structure

Functional Category: Disintegrant, Super disintegrant

Applications in Pharmaceutical Formulation or Technology: Crospovidone is used as: Disintegrant: Aids in tablet disintegration and drug release. Super disintegrant: Enhances tablet disintegration and dissolution rates.

Description:  Cross povidone is a white, odourless, and tasteless powder.

Solubility: Practically insoluble in water, dilute acids, and organic solvents.

Safety: Crospovidone is generally recognized as safe (GRAS) by regulatory agencies worldwide.

Therapeutic Uses: None, used as an excipient only.

3)Sodium Saccharin:

Non-Proprietary Names: Sodium Saccharin, Saccharin Sodium:  Saccharin Sodium Salt, Sodium o-Benzosulfimide

Chemical Name: Sodium 2,3-dihydro-3-oxobenzo[d]isothiazol-2-ide

Functional Category: Artificial sweetener, Flavouring agent

Applications in Pharmaceutical Formulation or Technology:

Sodium saccharin is used as a sweetening agent in various pharmaceutical formulations, such as: Tablets and capsules Syrups and elixirs Solutions and suspensions Lozenges and troche sit is also used to mask bitter tastes and as a flavouring agent.

Description: Sodium saccharin is a white, crystalline powder with a sweet taste, approximately 300 times sweeter than sucrose.

Solubility: Sodium saccharin is soluble in water (1 g in 1.5 mL) and slightly soluble in ethanol.

Safety: Sodium saccharin is generally recognized as safe (GRAS) by regulatory agencies worldwide. However, high doses may cause: Bladder cancer (animal studies)Allergic reactions (rare) Gastrointestinal upset (rare) Ingestion of large amounts may also lead to saccharin accumulation in the body

4)Magnesium Stearate:

Synonyms: Magnesium Octadecenoate, Magnesium Salt of Stearic Acid

Chemical Name: Magnesium Octadecenoate

Empirical Formula and Molecular Weight: C36H70MgO4, 591.24 g/mol

Structural Formula: (CH3(CH2)16COO)2Mg

Functional Category: Lubricant, Anti-adherent, Emulsifier

Applications in Pharmaceutical Formulation or Technology: Magnesium stearate is widely used in pharmaceutical formulations as:

Lubricant: Reduces friction between particles, facilitating tablet ejection and preventing sticking. Anti-adherent: Prevents sticking of tablets to dies and punches. Emulsifier: Stabilizes emulsions and suspensions. Tablet coating: Improves tablet coating uniformity.

Description: Magnesium stearate is a white, powder or flakes with a characteristic fatty acid Odor.

Solubility: Practically insoluble in water, soluble in hot ethanol and ether.

Safety: Magnesium stearate is generally recognized as safe (GRAS) by regulatory agencies worldwide. However: Ingestion of large amounts may cause gastrointestinal upset. May cause skin and eye irritation. Inhalation of dust may cause respiratory problems.

5)Talc:

Non-Proprietary Names: Talc, Hydrous Magnesium Silicate

Synonyms: Magnesium Silicate Hydrate, Talcum Powder  

Chemical Name: Hydrous Magnesium Silicate

Structural Formula: Mg3Si4O10(OH)2 (layered structure)

Functional Category: Anti-caking agent, Lubricant, Glidant

Applications in Pharmaceutical Formulation or Technology: Talc is used in pharmaceutical formulations as:

Anti-caking agent: Prevents powder agglomeration and improves flow.

Lubricant: Reduces friction between particles and equipment surfaces.

Glidant: Enhances powder flow and prevents sticking.

Description: Talc is a white, odourless, and tasteless powder.

Solubility: Practically insoluble in water, dilute acids, and organic solvents.

Safety: Talc is generally recognized as safe (GRAS) by regulatory agencies worldwide.

However: Inhaling talc powder may cause respiratory problems.

6)Mannitol:

Non-Proprietary Names: Mannitol

Synonyms: D-Mannitol, Mannite, Osmitrol

Chemical Name: D-Mannitol

Structural Formula: HOCH2(CHOH)4CH2OH

Functional Category: Osmotic diuretic, Antihypertensive

Applications in Pharmaceutical Formulation or Technology: Mannitol is used as:

Osmotic diuretic: Increases urine output and reduces intracranial pressure.

Antihypertensive: Reduces blood pressure in acute hypertension.

3 Description. Excipient: Used as a filler, binder, or coating agent in tablets and capsules.  

Mannitol is a white, crystalline powder with a sweet taste.

Solubility: Soluble in water, slightly soluble in ethanol.

Safety: Mannitol is generally recognized as safe (GRAS) by regulatory agencies worldwide.

However:

1.High doses may cause gastrointestinal upset, diarrhoea, and dehydration.

2.May worsen heart failure, renal impairment, or pulmonary edema.

3.Contraindicated in patients with severe renal impairment or anuria.

Therapeutic uses: Mannitol is used to

Reduce intracranial pressure in traumatic brain injuries. Treat cerebral edema. Manage acute glaucoma. Reduce blood pressure in acute hypertension.

Dosage and Administration: Mannitol is administered Intravenously: 0.5-1.5 g/kg over 3060 minutes. Orally: 0.5-2 g/kg/day in divided doses.

7)Microcrystalline Cellulose:

Non-Proprietary Names: Microcrystalline Cellulose (MCC)

Synonyms: Cellulose Microcrystalline, Microcrystalline Cellulose NF

Chemical Name: Cellulose

Structural Formula: Complex, branched polysaccharide structure

Functional Category: Excipient, Binder, Diluent, Disintegrant

Applications in Pharmaceutical Formulation or Technology: Microcrystalline cellulose is used as:

Binder: Enhances tablet cohesion and hardness.

Diluent: Increases tablet size and facilitates swallowing.

Disintegrant: Aids in tablet disintegration and drug release.

Filler: Adds bulk to tablets and capsules.

Description: Microcrystalline cellulose is a white, odourless, and tasteless powder.

Solubility: Practically insoluble in water, dilute acids, and organic solvents.

Safety: Microcrystalline cellulose is generally recognized as safe (GRAS) by regulatory agencies worldwide.

Therapeutic Uses: None, used as an excipient only.

Dosage and Administration: Varies depending on the specific pharmaceutical formulation.

Experimental Methodology

List Of Equipment’s and Materials  

Equipment used for preparation and analysis

Analytical Methodology: Standard curve of Amlodipine besylate in compendial media of pH 6.8 in water was performed to quantify the samples. All the solutions were prepared in fresh before use.   

Preparation of 6.8 pH Phosphate buffer       

0.2 M Potassium di hydrogen phosphate: Dissolve 27.218g of potassium di hydrogen phosphate in water and make up the volume up to 1000ml    

Preparation of 0.2 M sodium hydroxide: Dissolve 8g of sodium hydroxide in water and make up the volume to 1000ml with water.     Preparation of 6.8pH phosphate buffer:  Transfer 50ml of 0.2M potassium di hydrogen phosphate in a 200ml volumetric flask and 22.4ml of 0.2m sodium hydroxide and then add distilled water.    Preparation of standard solution of Amlodipine besylate in 6.8 pH Phosphate buffer

Preparation of stock I Solution  

100 mg of Amlodipine besylate was weighed accurately, transferred into 100 ml volumetric flask. The volume was made to 100 ml with 6.8 pH Phosphate buffer to give 1000 mcg/ml solution.   

Preparation of Stock II Solution  

10 ml of stock I solution was pipetted out into a 100 ml volumetric flask and the volume was made up to 100 ml with 6.8 pH Phosphate buffer to get 100 mcg/ml solution.  

Preparation of stock III solution  

10 ml of stock II solution was pipetted out into a 100 ml volumetric flask and the volume was made up to 100 ml with 6.8 pH Phosphate buffer to get 10 mcg/ml solution.  

Preparation of standard curve for amlodipine besylate in pH 6.8 Phosphate buffer  

2 mcg, 4 mcg, 6 mcg, 8 mcg, 10 mcg were prepared by taking 2 ml, 4 ml, 6 ml, 8 ml, 10 ml from third stock solution and volume made up to 10 ml and 20 mcg was prepared by taking 2 ml from second stock solution and volume made up to 10 ml. The absorbances of respective solutions were determined using UV-Visible spectrophotometer at 239nm against pH 6.8 phosphate buffer as the blank. The experiment was repeated six times in the same medium and a calibration curve was determined from the mean value.   

Preparation of Fenugreek Powder    

It was a natural super disintegrant and it is scientifically known as “Trigonella fenugraceum commonly known as “fenugreek” is an herbaceous plant of Leguminosae. It is one of the oldest cultivated plants and has found wide applications as a food additive and as a traditional medicine in every region. Fenugreek seeds contain a high percentage of mucilage which can be used as disintegrant for use in orally disintegrating tablets. Mucilage is off-white cream yellow colored amorphous powder that quickly dissolves in warm water to form viscous colloidal solution.     Formulation The seeds are dried for removing moisture after that they are grinded in a mixer and the powder was sieved with sieve no.#40. The powder sealed in a box and used as a super disintegrant in the formulations.   

Preparation of Co-processed Super disintegrants    

The co-processed Super disintegrants were prepared by solvent evaporation method. A blend of Crospovidone and fenugreek seed powder was added to 10 ml of ethanol. The contents of the beaker were mixed thoroughly and stirred continuously till most of ethanol evaporated. The wet coherent mass was granulated through # 44 mesh sieve. The wet granules were dried in a hot air oven at 60° C for 20 minutes. The dried granules were sifted through # 60 mesh sieve and stored in airtight container till further use.   

Preformulation Studies  

Preformulation testing is an investigation of physical and chemical properties of a drug substance alone and when combined with excipients. It is the first step in the rational development of dosage forms.  Objective The overall objective of pre formulation testing is to generate information useful to the formulation in developing stable and bio available dosage forms.    Scope. The use of pre formulation parameters maximizes the chances in formulating an acceptable, safe, efficacious and stable product.  

Drug- Excipients Compatibility Study by FTIR     

The spectrum analysis of pure drug and physical mixture of drug and different excipients which are used for preparation of tablets was studied by FTIR. FTIR spectra were recorded by preparing potassium bromide (KBr) disks using a Shimadzu Corporation (Koyto, Japan) facility (model - 8400S). Potassium bromide (KBr) disks were prepared by mixing few mg of sample with potassium bromide by compacting in a hydrostatic press under vacuum at 6-8 tons pressure. The resultant disc was mounted in a suitable holder in IR spectrophotometer and the IR spectrum was recorded from 4000 cm^-1 to 500 cm^-1 in a scan time of 12 minutes. The resultant spectrum was compared for any spectral changes. They were observed for the presence of characteristic peaks for the respective functional group in the compound. 

Precompression Parameters of the Powder Blend

Preparation of mixed blend of drug and excipients  

All the ingredients were passed through mesh no 60. Required quantity of each ingredient was taken for each specified formulation (Table 3.6) and all the ingredients were subjected to grinding to a required degree of fineness. The powder blend was subjected to pre compression parameters.  

Angle of repose  

This is the maximum angle possible between the surface pile of powder and horizontal plane. The frictional forces in the lose powder can be measured by angle of repose. The tangent of angle of repose is equal to the co-efficient friction (µ) between the particles. Hence the rougher & more irregular the surface of particles the greater will be angle of repose.  

Procedure: 100 gm of the blend was accurately weighed and carefully poured through the funnel whose tip was secured at a height of 2.5 cm above the graph paper which is placed on a horizontal surface. The blend was poured until the apex of the conical pile just touches the tip of the funnel. The interrelationship between the angle of repose and flow properties of powder are shown in the Table 3.5. Angle of repose is calculated by the following formula.  

????=Tan^-1(h/r) Where, ???? = angle of repose, r=radius of the pile, h=height of the pile,

Bulk density: Bulk density   is defined as a mass of a powder divided by the bulk volume.   

Procedure:  Apparent bulk density (*b) was determined by pouring the blend into a graduated cylinder. The bulk volume (V*) and weight of the powder (M) was determined.

The bulk density was calculated using the formula.   *b=M/V*  

Tapped density:  The measuring cylinder containing a known mass of blend was tapped for a fixed time (around 250). The minimum volume (V_t) occupied in the cylinder and the weight (M) of the blend was measured. The tapped density (*t) was calculated using the formula           *t=M/V_t  

Compressibility index:  The simplest way for measurement of free flow of powder is compressibility, a indication of the ease with which a material can be induced to flow is given by compressibility index (C.I) which is calculated using the formula,       

C.I (%) = Tapped density –Bulk density×100  

                                    Tapped density  

Correlation between compressibility index and flow properties of powder

Hausner Ratio:  

Hausner ratio is an indirect index of ease of powder flow. It was calculated by the using the formula,  

Hausner ratio = *t/*d  

Where *t=tapped density. *d =bulk density

 All ingredients were triturated individually in a mortar and passed through #60 sieve. Then required quantity of all ingredients was weighed for a batch size of 100 tablets and mixed uniformly in a mortar magnesium stearate. Finally, magnesium stearate was added as lubricant. This uniformly mixed blend was compressed in to tablets containing 10mg drug using 4mm flat face surface punches on a Rimek-1 rotary tablet machine by direct compression method.  Total weight of tablet was kept 50mg.  

Flow chart of the direct compression method

Formulations of amlodipine besylate containing different   super disintegrants

ACP= Crospovidone, AFG= Fenugreek powder, ACPF = Cross povidone and Fenugreek powder.

Evaluation Of Orodispersible Tablets  

The prepared tablets can be evaluated for various parameters like

• • Weight variation
  • Thickness
  • Hardness
  • Friability
  • Wetting time
  • Water absorption ratio
  • Content uniformity
  • Invitro disintegration time
  • Swelling index
  • In vitro drug release

Weight Variation: Twenty tablets were randomly selected and average weight was determined.  

Then individual tablets were weighed and percent deviation from the average was calculated.

Percentage deviation allowed for the tablets

Thickness: Control of physical dimensions of the tablets such as size and thickness is essential for consumer acceptance and tablet-tablet uniformity. The diameter size and punch size of tablets depends on the die and punches selected for making the tablets. The thickness of tablet is measured by screw gauge. The thickness of the tablet related to the tablet hardness and can be used an initial control parameter. Tablet thickness should be controlled within a ± 5% variation of a standard value. In addition, thickness must be controlled to facilitate packaging. The thickness in millimetres (mm) was measured individually for 10 pre weighed tablets by using screw gauge. The average thickness and standard deviation were reported 2.

Hardness: The strength of tablet is expressed as tensile strength (Kg/cm). The tablet crushing load, which is the force required to break a tablet into pieces by compression. It was measured using a tablet hardness tester (Monsanto hardness tester). Three tablets from each formulation batch were tested randomly and the average reading noted.   

Friability: Friability of the tablets was determined using Roche Fibrillator (Electrolab, India). This device consists of a plastic chamber that is set to revolve around 25 rpm for 4 minutes dropping the tablets at a distance of 6 inches with each revolution. Pre weighed sample of 20 tablets was placed in the friabilator and were subjected to 100 revolutions. Tablets were dusted using a soft muslin cloth and reweighed. The friability (F %) is given by the formula  

F % = (1-W₀ /W) ×100    Where, W₀ is weight of the tablets before the test and W is the weight of the tablets after test  

Wetting time: Five circular tissue papers of 10-cm diameter were placed in a petri dish with   a 10-cm diameter. 10 ml of water at 37⁰C+0.5⁰C containing eosin, a water-soluble dye, was added to the petri dish. A tablet was carefully placed on the surface of tissue paper. The time required for water to reach the upper surface of the tablets was noted as the wetting time. Six tablets from each formulation batch were tested randomly and the average reading noted.³   Water absorption ratio: A piece of tissue paper folded twice was placed in a small Petri dish containing 6 ml of water. A tablet was put on the paper and the time required for complete wetting was measured. The wetted tablet was then weighed.³  

Water absorption ratio R, was determined using following equation  

R = W_a – W _b /W_b ×100                        

Where W_a = weight of tablet after absorption  

W_b = weight of tablet before absorption   

Content uniformity: 20 tablets were randomly selected and average weight was calculated. Tablets were powdered in a glass mortar. Powder equivalent to 10mg was weighed and dissolved in 100 ml of 6.8pH Phosphate buffer filtered and drug content analysed spectrophotometrically at 239 nm.  

Invitro disintegration time:  

Disintegration time was measured using a modified disintegration method. For this purpose, a petri dish was filled with 10 ml of water at 37⁰ C±0.5⁰C. The tablet was carefully put in the centre of the Petri dish and the time for the tablet to completely disintegrate into fine particles was noted.³  

Swelling index:    

Swelling index is the volume in millilitres that is occupied by 1 gm of drug or any adhering mucilage after it has swollen in an aqueous liquid for 4 h. The methods of studying swelling index for fenugreek powder, Crospovidone, and processed powder tablets were carried out.  

Swelling index was calculated from mean readings of three determinations. ⁵⁴  

In-vitro release:            

In-vitro drug release of on amlodipine besylate orodispersible tablets was determined using USP Dissolution Apparatus II (Paddle type) (Electrolab TDT-08L). The dissolution test was performed using 500 ml 6.8pH Phosphate buffer at 37⁰C ± 0.5⁰C. The speed of rotation of paddle was set at 50 rpm. 5 ml samples were withdrawn at time points of 5, 10, 15, 20, 25, and 30min and same volume was replaced with fresh media. Absorbance of solution was checked by UV spectrophotometer (ELICO- 164 double beam spectrophotometer, Hyderabad, India) at a wavelength of 239 nm and drug release was determined from standard curve.  

Dissolution study of amlodipine besylate Oro dispersible tablets:

RESULTS AND DISCUSSION

The present investigation was undertaken to formulate and evaluate the orodispersible tablets of amlodipine besylate by direct compression using synthetic super disintegrants namely, crospovidone, and natural super disintegrant i.e.  fenugreek seed powder. Super disintegrants are generally used by formulation scientists for developing ODTS or for improvement of solubility for active pharmaceutical ingredients. The primary requirement for both dosage forms is quicker disintegration. 

Preparation of standard graph  

Standard solutions in the range of 2 to 20 mcg/ml were prepared and absorption values were recorded at 239 nm against the blank. From this data, the standard curve of amlodipine besylate was obtained by plotting absorbance on Y-axis against concentration on X-axis

Standard graph of Amlodipine besylate in 6.8pH phosphate buffer

Standard graph of amlodipine besylate in 6.8ph phosphate buffer

Selection Of Superdisintegrants 

The basic approach used in the development of oral dispersible tablets is the use of super disintegrants. Super disintegrants selected in the present study are crospovidone, and natural super disintegrant i.e. fenugreek powder. The main objective in the present study was to prepare orodisperble tablets which will disintegrate rapidly. 

Selection Of Superdisintegrants 

The basic approach used in the development of oral dispersible tablets is the use of superdisintegrants. Superdisintegrants selected in the present study are crospovidone, and natural superdisintegrant i.e. fenugreek powder. The main objective in the present study was to prepare orodisperble tablets which will disintegrate rapidly. 

Preformulation Studies  

Drug-excipients compatibility study by FTIR 

 FTIR study was done to verify if there was any interaction between the pure drug and various excipients were employed. The various FTIR graphs both of pure drug and various excipients were mixed and the blend was formulated into IR pellet and scanned. The different plots are given below.

FTIR spectra of Amlodipine besylate 

FTIR spectra of amlodipine besylate and fenugreek powder   

FTIR spectra of amlodipine besylate and crosspovidone

FTIR spectra of amlodipine besylate and crosspovidone and fenugreek powder

Interpretation of Amlodipine besylate IR graph

Precompression parameters of the powder blend of all formulations of   crospovidone and fenugreek powder.

Values are expressed as Mean ±SD, *n = 3, ACP= Formulations of cross povidone, AFG: Formulations of fenugreek powder.

Precompression parameters of all formulations blend were conducted for angle of repose, bulk density, tapped density, compressibility index, Hausner’s ratio. The two most important attributes for the direct compression formula are good flow and good compressibility. Interparticle interactions that influence the bulking properties of a powder with powder flow. A comparison of the bulk density and tapped density can give a measure of the relative importance of this interaction in a given powder, such a comparison is often used as an index of the ability of the powder to flow. The angle of repose gives important information about the flow characteristics of the powder mixture. The powder flow depends on three general areas: the physical properties of the particle (e.g., shape, size, compressibility), the bulk powder properties (e.g., size distribution, compaction), and the processing environment (e.g., storage, humidity). The angle of repose <30° indicates free flowing material and >40° with poor flow properties. Values for angle of repose were found in the range of 23.52±0.98 to 25.56±1.03° showing that the blend of powder was free flowing and can be used for direct compression. The value for Carr’s index was in between 11.24±1.491 to 14.53±0.926 indicating that all batches of powder blends were having good compressibility. Hausner’s ratio was to be within the limits 1.17 (<1.25). All the formulations showed good blend properties for direct compression and hence tablets were prepared by direct compression technology. 

Evaluation of Tablets:

In the present study amlodipine besylate oro dispersible tablets were prepared by using synthetic super disintegrants namely, crospovidone, and natural super disintegrant i.e. fenugreek powder. All the formulations were evaluated for various parameters like hardness, friability, drug content, wetting time, water absorption ratio, disintegration time and in vitro drug release studies.  The hardness of the tablets was found to be 2.9 + 0.54 to 3.1 + 0.69 kg/cm² and friability was found to be below 1% indicating good mechanical resistance. The thickness of the tablets was found to be 2.59± 0.04 to 2.79± 0.05. All the tablets passed weight variation test, as percentage weight variation was within the pharmacopoeia limits i.e. ±10%. The drug content was found to be 99.24±0.58 to 101.13±0.73%, indicating uniform distribution of drug in the tablets.  

Determination of swelling index Table no 4.5: Swelling index of super disintegrants

Values are expressed as mean ± S.D, n=3

Disintegration time of different superdisintegrants with different concentrations

The most important parameter that needs to be optimized in the development of orodispersible tablets is the disintegration time of tablets. In the present study disintegration time of all batches were found in the range of 29 ± 1.52 to 101± 1.28 sec fulfilling the official requirements (?3 min) for dispersible tablets. Fig. 4.6 depicts the disintegration behaviour of the tablets in water. It was observed that the disintegration time of the tablets decreased with increasing concentration of co processed cross povidone fenugreek powder, and fenugreek powder. However, the disintegration time of tablets decreased with increasing concentration of Co processed powder up to 3%, but further increasing level of that powder had no significant effect on disintegration time of tablets. Batch ACPF3 was selected as optimized batch containing co processed CP-fenugreek powder as super disintegrant in 3 % concentration. It showed less disintegration time of 32 seconds. It was observed that less disintegration time was observed with ACPF3 that may be due to swelling at faster rate upon contact with water and elimination of lump formation after disintegration when compared with mucilage of fenugreek powder, and crospovidone. So ACPF3 was taken as optimized formulation based on disintegration time.    

Wetting time of different superdisintegrants with different concentrations

depicts the relation between the concentration of super disintegrants and wetting time. Wetting time was used as a parameter to correlate with disintegration time in oral cavity. This is an important criterion for understanding the capacity of disintegrants to swell in the presence of little amount of water. Since the dissolution process of a tablet depends upon the wetting followed by disintegration of the tablet, it could be assumed that wetting was the only cause of disintegration. This indicates that that aqueous medium penetrates into the tablet and replaces the air adsorbed on the particles, which weakens the intermolecular bonds and breaks the tablet into fine particles. The wetting time of the formulated tablets were found in the range of 28±1.91 to 75±1.21sec.    Water absorption ratio was increased and disintegration time and wetting time was decreased with an increase in concentration of super disintegrants. The water absorption ratio of the formulated tablets was found in the range of 110±1.23 to 139±1.43 

Cumulative percentage drug release of all formulations of cross povidone and fenugreek powder

Dissolution profile Amlodipine besylate tablets of ACP1, AFG1, ACPF1

Dissolution profile Amlodipine besylate tablets of ACP2, AFG2, ACPF2

Dissolution profile Amlodipine besylate tablets of ACP3, AFG3, ACPFG3