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Advancement in Tablet Technology

RAJIV GANDHI PROUDYOGIKI VISHWAVIDYALAYA

Major Project Report submitted for the partial fulfillment of the degree of Bachelor of Pharmacy

BM College of Pharmaceutical Education and Research Indore, (M.P.) Submitted by Anju Katare Supervised by

DECLARATION

I, Ankush Jain, hereby declare that the project report entitled Advancement in Tablet Technology is my original work for the completion of major project to be submitted to RGPV, Bhopal towards the partial fulfillment of degree of Bachelor of Pharmacy and is not submitted anywhere else by me for the award of any other degree.

Signature:

Name of the Student: Anju Katare

CERTIFICATE

This is to certify that the project entitled Advancement in Tablet Technology has been successfully accomplished by Mr. Ankush Jain ,under my guidance towards the partial fulfillment of degree of Bachelor of Pharmacy from RAJIV GANDHI PROUDYOGIKI

VISHWAVIDYALAYA, BHOPAL.

Supervised by Mr. Ankush Jain

Principal Dr. Vimukta Sharma

TABLE OF CONTENTS

S. No. 1.0 2.0 3.0 4.0 5.0

Content Overview Advancement in Tablet Operations Problems & REMEDIES Recent Advancement 5.1 Mouth Dissolving tablet 5.2 Double-layer tablet 5.3 Dow Foam Granulation Technology 5.4 Fast Dissolving Tablet 5.5 Modified release tablet 5.6 Matrix technology

Page No. 1-4 5-17 18-25 26-37

38-52 53-55 56-56 57-67 68-69 70-71 72-73 73

6.0 7.0

Conclusion References

LIST OF TABLES
Table No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Title Page No. 6 20 28 29 30 30 31 31 32 32 33 33 34 35 35 36 37 38 49 67

Types Of Tablets Unit Operation Capping related to Formulation Capping related to Machine Lamination related to Formulation Lamination related to Machine Chipping related to Formulation Chipping related to Machine Cracking related to Formulation Cracking related to Machine Sticking related to Formulation Sticking related to Machine Picking related to Formulation Picking related to Machine Binding related to Formulation Binding related to Machine Mottling Double Impression Commercially available mouth dissolving tablets Fast Dissolving Tablets

LIST OF FIGURES

Figure No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Title Tablet Capping (top) and lamination (right) tablet failure modes Tablet Compressors Standard Compressed Tablet Compression Coated Tablet Inlay Tablets Graphical Comparison Of Blood ConcentrationV/S Time Ringcap (Coated) TableMatrix technology Matrix Tablet. Floating Tablet Sublingual Tablets Buccal Tablets Dental Cones Effervescent Tablets Soluble tablets Unit Operation Sequences Compression

Page No. 1 2 4 8 9 9 10 10 11 12 14 15 15 17 18 20 25

Tablet
A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose. The excipients can include diluents, binders or granulating agents, glidants (flow aids) and lubricants to ensure efficient tabletting; disintegrants to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive. A polymer coating is often applied to make the tablet smoother and easier to swallow, to control the release rate of the active

ingredient, to make it more resistant to the environment (extending its shelf life), or to enhance the tablet's appearance.

Fig no. 1 Tablet The compressed tablet is the most popular dosage form in use today. About two-thirds of all prescriptions are dispensed as solid dosage forms, and half of these are compressed tablets. A tablet can be formulated to deliver an accurate dosage to a specific site; it is usually taken orally, but can be administered sublingually, buccally, rectally or intravaginally. The tablet is just one of the many forms that an oral drug can take such as syrups, elixirs, suspensions, and emulsions. Medicinal tablets were originally made in the shape of a disk of whatever color their components determined, but are now made in many shapes and colors to help distinguish different medicines. Tablets are often stamped with symbols, letters, and numbers, which enable them to be identified. Sizes of tablets to be swallowed range from a few millimeters to about a centimeter. Some tablets are in the shape of capsules, and are called "caplets". Medicinal tablets and capsules are often

Contents
1 Tabletting formulations 2 Advantages and

called pills.

disadvantages 3 Tablet compaction

simulator 4 Tablet presses 5 Pill-splitters

Tabletting formulations

Fig no. 2 Capping (top) and lamination (right) tablet failure modes

In the tablet-pressing process, it is important that all ingredients be fairly dry, powdered or granular, somewhat uniform in particle size, and freely flowing. Mixed particle sized powders can segregate during manufacturing operations due to different densities, which can result in tablets with poor drug or active pharmaceutical ingredient (API) content uniformity but granulation should prevent this. Content uniformity ensures that the same API dose is delivered with each tablet. A binder is added to help hold the tablet together and give it strength. A wide variety of binders may be used, some common ones including lactose, dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose and modified cellulose (for example hydroxypropyl methylcellulose).Some binders, such as starch and cellulose, are also excellent disintegrants.Small amounts of lubricants are usually added, as well. The most common of these is magnesium stearate;

Advantages and disadvantages


Tablets are simple and convenient to use. They provide an accurately measured dosage of the active ingredient in a convenient portable package, and can be designed to protect unstable medications or disguise unpalatable ingredients. Colored coatings, embossed markings and printing can be used to aid tablet recognition. Manufacturing processes and techniques can provide tablets special properties, for example, sustained release or fast dissolving formulations. Some drugs may be deactivated by the liver when they are carried there from the gastrointestinal tract by the hepatic portal vein (the "first pass effect"), making them unsuitable for oral use. Drugs which can be taken sublingually are absorbed through the oral mucosae, so that they bypass the liver and are less susceptible to the first pass effect. The oral bioavailability of some drugs may be low due to poor absorption from the gastrointestinal tract.

Tablet compaction simulator


Tablet formulations are designed and tested using a laboratory machine called a Tablet Compaction Simulator or Powder Compaction Simulator. This is a computer controlled device that can measure the punch positions, punch pressures, friction forces, die wall pressures, and sometimes the tablet internal temperature during the compaction event. Numerous experiments with small quantities of different mixtures can be performed to optimise a formulation. Mathematically corrected punch motions can be programmed to simulate any type and model of production tablet press. Initial quantities of

active pharmaceutical ingredients are very expensive to produce, and using a Compaction Simulator reduces the amount of powder required for product development.

Tablet presses

The tablet pressing operation

Fig no. 3 Tablet Compressors

Pill-splitters
It is sometimes necessary to split tablets into halves or quarters. Tablets are easier to break accurately if scored, but there are devices called pill-splitters which cut unscored and scored tablets. Tablets with special coatings (for example enteric coatings or controlled-release coatings) should not be broken before use, as this will expose the tablet core to the digestive juices, short-circuiting the intended delayed-release effect.

Advancement in Tablets / Types of Tablets


With advancement in technology and increase in awareness towards modification in standard tablet to achieve better acceptability as well as bioavailability, newer and more efficient tablet dosage forms are being developed. The main reasons behind formulation delivery utilize system an that is that of different types of tablets simple to and add inexpensive complexity are to create a to manufacture, regulatory relatively is

provide the dosage form that is convenient from patients perspective and approach unlikely during approval process. To understand each dosage form, tablets here are classified

by their route of administration and by the type of drug delivery system they represent within that route.

Types of Tablets
Table.1. Various Types Of Tablets 1
ORAL TABLETSFOR INGESTION 1.1 Standard compressed tablets 1.2Multiple compressed tablets I. Compression coated tablet II. Layered tablet III. Inlay tablet 1.3 Modified Release tablet 1.4 Delayed action tablet 1.5 Targeted tablet I. Floating tablet II. Colon targeting tablet 1.6 Chewable tablet 1.7 Dispersible tablet

TABLETS USED IN THE ORAL CAVITY

2.1 Lozenges and troches 2.2 Sublingual tablet 2.3 Buccal tablet 2.4 Dental cones 2.5Mouth dissolved tablet

TABLETS

3.1 Vaginal tablet

ADMINISTERED BY OTHER 3.2 Implants ROUTES

TABLETS USED SOLUTION TO PREPARE

4 Effervescent tablet 4.2 Hypodermic tablet 4.3 Soluble tablet

1 Oral tablets for ingestion These tablets are meant to be swallowed intact along with a sufficient quantity of potable water. Exception is chewable tablet. 1.1 Standard compressed tablets These are the standard uncoated tablets made by either direct compression or wet granulation or dry granulation or double compaction.

Figure 4 Standard Compressed Tablet 1.2 Multiple compressed tablets The tablets in this category are prepared for two reasons: to separate physically or chemically incompatible ingredients and to produce repeat action/ prolonged action tablet. I. Layered tablets two to three component system. II. Compression coated tablets tablet within a tablet. III. Inlay tablet coat partially surrounding the core. The layered tablet is preferred over compression coated tablet as the surface contact is less and the production is simple and more rapid. 2) II. Compression coated tablets This type of tablet has two parts, internal core and surrounding coat. The core is small porous tablet and prepared on one turret.

Figure 5 Compression Coated Tablet III. Inlay tablets A type of layered tablet in which instead the core tablet being completely surrounded by coating, top surface is completely exposed. While preparation, only the bottom of the die

cavity is filled with coating material and core is placed upon it. When compression force is applied, some coating material is displaced to form the sides and compress the whole tablet. It has some advantages over compression coated tablets: i)Less coating material is required. ii)Core is visible, so coreless tablets can be easily detected. iii)Reduction in coating forms a thinner tablet and thus freedom from capping of top coating.

Figure 6 Inlay Tablets 1.3 Modified Release tablets The main aim behind formulation of this dosage form is to release the medicament slowly for long time duration after administration of a single tablet.

Figure 7 Graphical Comparison Of Blood ConcentrationV/S Time Coating technologyIt combines semi permeable coatings and osmotic tablet cores to produce zero order release technology. Attention is also focused to trigger drug release at critical time point e.g., to achieve drug release 1 -2 hours before the patient awakens. Alzas prolific research activities have yielded a technology called Ringcap which is based on a tablet, preferentially film coated, partially coated with a series of rings whose respective thickness provides the means of moderating the rate at which the drug is released from final dosage form.

Figure 8 Ringcap (Coated) TableMatrix technology Classically matrix products exhibit first order (or perhaps square-root-of-time) drug release characteristics. In order to achieve zero order release characteristics, its necessary to employ specially designed materials or strategies that seek to manipulate tablet structure or geometry. Combination of conventional HPMC matrix technology with upper and lower layer. This helps to moderate drug release by increase in surface area with concomitant reduction in drug concentration within the device.

Figure 9 Matrix Tablet. 1.4 Delayed action tablets Enteric coated tablet is such an example of delayed action tablet. This formulation is preferred when, i)The API irritates gastric mucosa e.g., aspirin or strong electrolytes ii) Drugs that produce nausea and vomiting. iii) API is sensitive to low pH e.g., erythromycin iv) When its necessary to release the drug undiluted. e.g., intestinal antibacterial, antiseptic agents, intestinal vermifuge, etc.The commonly used coating agents are: Cellulose acetate phthalate, Hydroxy methyl propyl phthalate, polyvinyl acetate phthalate, Eudragit, etc. This dosage form is intended to hydrate and begin to dissolve in duodenum (pH 4 to 6) or in small intestine where pH increases to 7 to 8. The presence of esterase sorbil esaltslike surface active agents plays a role in drug release. 1.5 Targeted tablets When we need to release the API at a specific site in the elementary tract, targeted drug delivery is a preferred option. Depending upon the composition and release mechanism of a tablet, the drug is delivered to a particular region. Under this category, we have two types of tablet: I. Gastro retentive Tablet

This type of dosage form is to be opted when API release is desired in stomach (Antacids, APIs used against H.pylori infection) or site of absorption is either stomach or upper part of small intestine.

Figure.10. Floating Tablet To retain the drug for longer time period in stomach, following approaches can be used: i) Low density tablet (effervescent or non effervescent) ii) Tablets that can expand in gastric environment (swelling or by unfolding) and thus increasing the size so that it cannot cross the pyloric sphincter. iii) Using mucoadhesive polymers that stick to mucosa of stomach and provide slow drug release. Supine position is to be avoided and also high level of fluid is necessary or if the swelling formulation leaves stomach before it swells its ineffective. Drugs like Diazepam, Levodopa, Benserazide, and Ciprofloxacin are successfully marketed in this formulation. II. Colonic tablets When the aim is to deliver the drug into colon without dilution in other regions of gastrointestinal tract or the drug has poor absorption in stomach or small intestine, colonic drug delivery is an answer of choice. The pH in this region varies from 6.4 - 7 and presence of microbial flora plays as important role in drug release especially in this region. Various mechanisms are adopted for drug release in this area are coating with pH sensitive polymer e.g., EudragitS100, Eudragit L100, biodegradable polymer like polymers which are sensitive to colonic bacteria, bioadhesive polymers which selectively sticks to colonic mucosa e.g., polycarbophils or polyethans, redox sensitive polymers that respond to redox potential in colon which expresses the total metabolic and bacterial action.

1.6 Chewable tablets The patients who have difficulty in swallowing tablets whole or for children who have not yet learnt to swallow a tablet, chewable tablet serves as an attractive alternative. The added advantage of this medication is that it can be taken at any time or when water is not available.

1.7 Dispersible tablet These tablets disintegrate either rapidly in water, to form a stabilized suspension, or disperse instantaneously in the mouth to be swallowed without the aid of water. So, its preferred for pediatric patients who cannot swallow a solid dosage form and the API is unstable if formulated in liquid formulation. 2 Tablets used in the oral cavity The tablets under this group are aimed release API in oral cavity or to provide local action in this region. The tablets under this category avoids first-pass metabolism, decomposition in gastric environment, nauseatic sensations and gives rapid onset of action. The tablets formulated for this region are designed to fit in proper region of oral cavity. 2.1 Lozenges and troches The tablet is a flat faced at least about 18mm in diameter and meant to suck and dissolves in the mouth. The compressed tablet is called troches and the tablets produced by fusion or candy molding process are called lozenges. Flavours and sweeteners are added. 2.2 Sublingual tablets They are to be placed under the tongue and produce immediate systemic effect by enabling the drug absorbed directly through mucosal lining of the mouth beneath the tongue.

Figure.11. Sublingual Tablets

2.3 Buccal tablets Completeness of drug absorption is desired but fast drug absorption is not intended. The tablets are designed not to disintegrate. They are flat elliptical or capsule shaped tablets as it can be easily held between gum and cheek. Its placed near the opening of parotid duct to provide the medium to dissolve the tablet.

Figure.12. Buccal Tablets 2.4 Dental cones These tables are designed to be loosely packed in the empty socket remaining following a tooth extraction.

Figure.13. Dental Cones Main purpose behind the use of this tablet is either to prevent multiplication of bacteria in the socket by employing a slow releasing antibacterial compound or to reduce bleeding by an astringent or coagulant containing tablet. Its formulated to dissolve or erode slowly in presence of a small volume of serum or fluid over 20-40 minutes period. 2.5 Mouth Dissolved tablets/ Rapidly Dissolving tablets Known to the FDA as orally disintegrating tablets, they are also called mouth-dissolving, fast-dissolving, rapid-melt, porous, orodispersible, quick dissolving. These kinds of tablets are preferred when fast action or relief is desired. Most commonly used drugs under this formulation are the agents active against Migraine. The tablets are designed to disintegrate as well as dissolve within one minute or some within 10 seconds of oral administration in limited quantity of saliva.

3 Tablets administered by other routes These tablets are administered by other route except for the oral cavity and so the drugs are avoided from passing through gastro intestinal tract. These tablets may be inserted into other body cavities or directly placed below the skin to be absorbed into systemic circulation from the site of application. 3.1 Vaginal tablets This tablet undergoes slow dissolution and drug release in vaginal cavity of women. The shape is kept ovoid or pear shaped to facilitate retention in vagina. The tablet should be made compatible with plastic tube inserters which are designed to place the tablet in the upper region of vaginal tract. These tablets generally release antibacterial, antiseptics or astringents to treat vaginal infections or release steroids for systemic absorption. 3.2 Implants These tablets are inserted into subcutaneous tissue by surgical procedures where they are very slowly absorbed over a period of a month or a year. A special injector with a hollow needle and plunger is used to administer the rod shaped tablet for other shapes, surgery is required. 4 Tablets used to prepare solution The tablets under this category are required to be dissolved first in water or other solvents before administration or application. This solution may be for ingestion or parenteral application or for topical use depending upon type of medicament used. 4.1 Effervescent tablets The oral dosage forms are the most popular way of taking medication despite having some disadvantages like slow absorption and thus onset of action is prolong. This can be overcome by administrating the drug in liquid from but, many APIs have limited level of stability in liquid form. So, effervescent tablets acts as an alternative dosage form. The tablet is added into a glass of water just before administration and the drug solution or dispersion is to be drunk immediately. The tablet is quickly broken apart by internal liberation of CO2 in water due to interaction between tartaric acid and citric acid with alkali metal carbonates or bicarbonates in presence of water.

Figure.14. Effervescent Tablets 4.2 Hypodermic tablets These tablets contain one or more readily water soluble ingredients and are intended to be added in water for injection of sterile water to form a clear solution which is to be injected parenterally. They were widely used by rural physician due to its portability. 4.3 Soluble tablets Tablets are pre-formed solids of uniform shape and dimensions, usually circular, with either flat or convex faces, the distance between faces being less than the diameter. Water soluble tablets are intended for application after dissolution in water and contain an active ingredient should be totally soluble in water at used concentrations.

Fig no. 15

Operations involved in tablet manufacturing


1. Introduction 2 Dispensing (weighing and measuring) 3 Sizing 4 Powder blending 5 Granulation 6 Drying 7 Tablet compression 8 Auxillary equipments

9 Packaging

The manufacture of oral solid dosage forms such as tablets is a complex multi-stage process under which the starting materials change their physical characteristics a number of times before the final dosage form is produced. Traditionally, tablets have been made by granulation, a process that imparts two primary requisites to formulate: compactibility and fluidity. Both wet granulation and dry granulation (slugging and roll compaction) are used. Regardless of weather tablets are made by direct compression or granulation, the first step, milling and mixing, is the same; subsequent step differ. Numerous unit processes are involved in making tablets, including particle size reduction and sizing, blending, granulation, drying, compaction, and (frequently) coating. Various factors associated with these processes can seriously affect content uniformity, bioavailability, or stability.

Figure.16. Various Unit Operation Sequences In Tablet Manufacturing Table.2. Typical Unit Operation Involved In Wet Granulation, Dry Granulation And Direct Compression WET GRANULATION DRY GRANULATION DIRECT COMPRESSION 1. Milling 1. Milling 1. Milling and mixing of drugs

and

mixing

of

drugs

andand

mixing

of

drugs

andand excipients

excipients 2. Preparation of binder solution 3. Wet solution or granulating solvent 4. Screening of wet mass

excipients 2. Compression 2. Compression of

into slugs or roll compaction tablet 3. Milling compacted powder

massing by addition of binderand screening of slugs and

4. Mixing with lubricant and disintegrants

5. Drying of the wet granules 6. Screening of dry granules 7. Blending

5. Compression of tablet

with lubricant and disintegrant to produce running powder 8. Compression of tablet

2 Dispensing (weighing and measuring)

Dispensing is the first step in any pharmaceutical manufacturing process. Dispensing is one of the most critical steps in pharmaceutical manufacturing; as during this step, the weight of each ingredient in the mixture is determined according to dose. Dispensing may be done by purely manual by hand scooping from primary containers and weighing each ingredient by hand

3 Sizing The sizing (size reduction, milling, crushing, grinding, pulverization) is an impotent step (unit operation) involved in the tablet manufacturing. This provides a greater uniformity of dose. A fine particle size is essential in case of lubricant mixing with granules for its proper function.

Advantages associated with size reduction in tablet manufacture are as follows:

i) It increases surface area, which may enhance an active ingredients dissolution rate and hence bioavailability. ii) Improved the tablet-to-tablet content uniformity by virtue of the increased number particles per unit weight. iii) Controlled particle size distribution of dry granulation or mix to promote better flow of mixture in tablet machine. iv) Improved flow properties of raw materials. v) Improved colour and/or active ingredient dispersion in tablet excipients. of

vi) Uniformly sized wet granulation to promote uniform drying.

There are also certain disadvantages associated with this unit operation if not controlled properly. They are as follows: i)A possible change in polymorphic form of the active ingredient, rendering it less or totally inactive, or unstable. ii) A decrease in bulk density of active compound and/or excipients, which may flow problem and segregation in the mix. iii)An increase in surface area from size reduction may promote the adsorption of air, which may inhibit wettability of the drug to the extent that it becomes the limiting factor in dissolution rate. A number of different types of machine may be used for the dry sizing or milling process depending on whether gentle screening or particle milling is needed. The ranges of equipment employed for this process includes Fluid energy mill, Colloidal mill, Ball mill, Hammer mill, Cutting mill, Roller mill, Conical mill, etc. 4 Powder blending The successful mixing of powder is acknowledged to be more difficult unit operation because, unlike the situation with liquid, perfect homogeneity is practically unattainable. In practice, problems also arise because of the inherent cohesiveness and resistance to movement between the individual particles. The process is further complicated in many system, by the presence of substantial segregation influencing the powder mix. They arise because of difference in size, shape, and density of the component particles. The powder/granules blending are involved at stage of pre granulation and/or post granulation stage of tablet manufacturing. Each process of mixing has optimum mixing time and so prolonged mixing may result in an undesired cause

product. So, the optimum mixing time and mixing speed are to be evaluated. Blending step prior to compression is normally achieved in a simple tumble blender. The Blender may be a fixed blender into which the powders are charged, blended and discharged. It is now common to use a bin blender which blends. In special cases of mixing a lubricant, over mixing should be particularly monitered. The various blenders used include V blender, Oblicone blender, Container blender, Tumbling blender, Agitated powder blender, various improved equipments which combines several of processing steps (mixing, granulation and/or drying) are used. They are Mixer granulator or High shear mixing machine. Granulation Following particle size reduction and blending, the formulation may be granulated, which provides homogeneity of drug distribution in blend Drying Drying is a most important step in the formulation and development of pharmaceutical product. It is important to keep the residual moisture low enough to prevent product deterioration and ensure free flowing properties. The commonly used dryer includes Fluidized bed dryer, Vacuum tray dryer, Microwave dryer, Spray dryer, Freeze dryer, Turbo tray dryer, Pan dryer, etc. Tablet compression After the preparation of granules (in case of wet granulation) or sized slugs (in case of dry granulation) or mixing of ingredients (in case of direct compression), they are compressed to get final product. The compression is done either by single punch machine (stamping press) or by multi station machine (rotary press). etc. But now a days to optimize the manufacturing process particularly in wet granulation the

The tablet press is a high-speed mechanical device. It 'squeezes' the ingredients into the required tablet shape with extreme precisionEach tablet is made by pressing the granules inside a die, made up of hardened steel. The die is a disc shape with a hole cut through its centre. The powder is compressed in the centre of the die by two hardened steel punches that fit into the top and bottom of the die.Common stages occurring during compression Stage 1: Top punch is withdrawn from the die by the upper cam Bottom punch is low in the die so powder falls in through the hole and fills the die Stage 2: Bottom punch moves up to adjust the powder weight-it raises and expels some powder Stage 3: Top punch is driven into the die by upper cam Bottom punch is raised by lower can both punch heads pass between heavy rollers to compress the powder Stage 4: Top punch is withdraw by the upper cam Lower punch is pushed up and expels the tablet Tablet is removed from the die surface by surface plate Stage 5: Return to stage 1

Figure.17. Stage Occurring During Compression

Auxiliary Equipments

I.

Granulation Feeding Device:

In many cases, speed of die table is such that the time of die under feed frame is too short to allow adequate or consistent gravity filling of die with granules, resulting in weight variation and content uniformity. These are also seen with poorly flowing granules. To avoid these problems, mechanized feeder can employ to force granules into die cavity.

II.Tablet weight monitoring devices:High rate of tablet output with modern press requires continuous tablet weight monitoring with electronic monitoring devices like Thomas Tablet Sentinel, Pharmakontroll and Killan control System-MC. They monitor force at each compression station by starin gage technology which is then correlated with tablet weight.

III. Tablet Deduster : In almost all cases, tablets coming out of a tablet machine bear excess powder on its surface and are run through the tablet deduster to remove that excess powder.

IV. Fette machine Fette machine is device that chills the compression components to allow the compression of low melting point substance such as waxes and thereby making it possible to compress product with low meting points.

Packaging Pharmaceutical manufacturers have to pack their medicines before they can be sent out fordistribution. The type of packaging will depend on the formulation of them medicine.'Blister packs' are a common form of packaging used for a wide variety of products. They are safe and easy to use and they allow the consumer to see the contents without opening the pack.

Problems in tablet manufacturing


An ideal tablet should be free from any visual defect or functional defect. The advancements and innovations in tablet manufacture have not decreased the problems, often encountered in the production, instead have increased the problems, mainly because of the complexities of tablet presses; and/or the greater demands of quality. An industrial pharmacist usually encounters number of problems during manufacturing. Majority of visual defects are due to inadequate fines or inadequate moisture in the granules ready for compression or due to faulty machine setting. Functional defects are due to faulty formulation. Solving many of the manufacturing problems requires an indepth knowledge of granulation processing and tablet presses, and is acquired only through an exhaustive study and a rich experience. Here, we will discuss the imperfections found in tablets alongwith their causes and related remedies. The imperfections are known as: VISUAL DEFECTS and they are either related to imperfections in any one or more of the following factors: I. Tableting Process II. Excipient

III. Machine The defects related to Tableting Process are as follows: i) CAPPING: It is partial or complete separation of the top or bottom of tablet due air-entrapment in the granular material. ii) LAMINATION: It is separation of tablet into two or more layers due to airentrapment in the granular material. iii) CRACKING: It is due to rapid expansion of tablets when deep concave punches are used. The defects related to Excipient are as follows: iv) CHIPPING: It is due to very dry granules. v) STICKING: It is the adhesion of granulation material to the die wall vi) PICKING: It is the removal of material from the surface of tablet and its adherance to the face of punch. vii) BINDING These problems (v, vi, vii) are due to more amount of binder in the granules or wet granules. The defect related to more than one factor: viii) MOTTLING: It is either due to any one or more of these factors: Due to a coloured drug, which has different colour than the rest of the granular material? (Excipient- related); improper mixing of granular material (Processrelated); dirt in the granular material or on punch faces; oil spots by using oily lubricant. The defect related to Machine ix) DOUBLE IMPRESSION: It is due to free rotation of the punches, which have some engraving on the punch faces. Further, in this section, each problem is described along-with its causes and remedies which may be related to either of formulation (granulation) or of machine (dies, punches and entire tablet press).

Capping Capping is the term used, when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap, during ejection from the tablet press, or during subsequent handling. Reason: Capping is usually due to the airentrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die.

TABLE.3. THE CAUSES AND REMEDIES OF CAPPING RELATED TO FORMULATION (GRANULATION)

Sr. No. 1.

CAUSES

REMEDIES

Large amount of fines in the Remove some or all fines through 100 to granulation 200 mesh screen the granules substance suitably. e.g.: Add

Too dry or very low moisture Moisten 2. proper binding action). 3. Not thoroughly dried

content (leading to loss of hygroscopic

sorbitol,

methyl- cellulose or PEG-4000. Dry the granules properly. Increasing the mount of binder OR

granules.

4.

Insufficient amount of binder Adding dry binder such as pre-gelatinized or improper binder. starch, gum acacia, powdered sorbitol, PVP, hydrophilic silica or powdered sugar.

5. 6.

Insufficient lubricant.

or

improper Increase the amount of lubricant or change the type of lubricant.

Granular mass too cold to Compress at room temperature.

compress firm.

TABLE.4. THE CAUSES AND REMEDIES OF CAPPING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No. 1.

CAUSES

REMEDIES Polish dies properly. Investigate other steels or other materials. Use flat punches.

Poorly finished dies Deep concave punches or bevelededge faces of punches.

2.

3.

Lower punch remains below the Make proper setting of lower punch face of die during ejection. during ejection.

4.

Incorrect adjustment of sweep-off Adjust sweep-off blade correctly to blade. High turret speed. facilitate proper ejection. Reduce speed of turret (Increase

5.

dwell time).

Lamination / Laminating Definition: Lamination is the separation of a tablet into two or more distinct horizontal layers. Reason: Airentrapment during compression and subsequent release on ejection. The condition is exaggerated by higher speed of turret.
TABLE.5. THE CAUSES AND REMEDIES OF LAMINATION RELATED TO FORMULATION (GRANULATION)

Sr. No.

CAUSES

REMEDIES

1.

Oily

or

waxy

materials

in Modify mixing process. Add adsorbent or absorbent.

granules Too much of e.g.:

hydrophobic Use a less amount of lubricant or Magnesium- change the type of lubricant.

2.

lubricant stearate.

TABLE.6. The Causes and Remedies of Lamination related to MACHINE (Dies, Punches and Tablet Press)

Sr. No.

CAUSES

REMEDIES</ b>

Rapid relaxation of the peripheral Use tapered dies, i.e. upper part of the 1. regions of a tablet, on ejection die bore has an outward taper of 3 to from a die. 5. Use 2. Rapid decompression pre-compression step. Reduce

turret speed and reduce the final compression pressure.

Chipping
Definition: Chipping is defined as the breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operations. Reason: Incorrect machine settings, specially mis-set ejection take-off.
TABLE.7. THE CAUSES AND REMEDIES OF CHIPPING RELATED TO FORMULATION (GRANULATION) ARE AS FOLLOWS

Sr. No.

CAUSES

REMEDIES

1.

Sticking on punch faces

Dry the granules properly or increase lubrication. Moisten the granules to plasticize. Add hygroscopic substances.

2.

Too dry granules. Too much binding causes

3.

chipping at bottom.

Optimize binding, or use dry binders.

TABLE.8. THE CAUSES AND REMEDIES OF CHIPPING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No. 1.

CAUSES

REMEDIES to open end, reverse or

Groove of die worn at compression Polish point. Barreled die (center of the die wider than ends) Edge of punch face turned

replace the die. Polish the die to make it cylindrical

2.

3.

inside/inward.

Polish the punch edges

4.

Concavity too deep to compress Reduce concavity of punch faces. Use properly. flat punches.

Cracking
Definition: Small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall are referred to as Cracks. Reason: It is observed as a result of rapid expansion of tablets, especially when deep concave punches are used.

TABLE.9. THE CAUSES AND REMEDIES OF CRACKING RELATED TO FORMULATION (GRANULATION)

Sr. No. CAUSES 1. Large granules. 2. Too dry granules. size

REMEDIES of Reduce granule size. Add fines.

Moisten the granules properly and add proper amount of binder.

3. 4.

Tablets expand. Granulation too cold.

Improve granulation. Add dry binders. Compress at room temperature.

TABLE.10. THE CAUSES AND REMEDIES OF CRACKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No. 1.

CAUSES Tablet expands on ejection due to air entrapment. Deep concavities cause cracking while

REMEDIES

Use tapered die.

2. removing tablets

Use special takeoff.

Sticking / Filming
Definition: Sticking refers to the tablet material adhering to the die wall. Filming is a slow form of sticking and is largely due to excess moisture in the granulation. Reason: Improperly dried or improperly lubricated granules.
TABLE.11. THE CAUSES AND REMEDIES OF STICKING RELATED TO FORMULATION (GRANULATION)

Sr. No. 1.

CAUSES Granules not

REMEDIES dried Dry the granules properly. Make moisture

properly. 2. Too little or improper lubrication. Too much binder Hygroscopic material. Oily or way materials Too soft or

analysis to determine limits. Increase or change lubricant. Reduce the amount of binder or use a different type of binder. granulation and compress under

3.

4. 5. 6.

granular Modify

controlled humidity. Modify mixing process. Add an absorbent.

weak Optimize the amount of binder and granulation technique.

granules.

TABLE.12. THE CAUSES AND REMEDIES OF STICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No. 1. 2. 3.

CAUSES Concavity granulation. Too little pressure. Compressing too fast. too deep for

REMEDIES

Reduce concavity to optimum. Increase pressure. Reduce speed.

Picking
Definition: Picking is the term used when a small amount of material from a tablet is sticking to and being removed off from the tablet-surface by a punch face. The problem is more prevalent on the upper punch faces than on the lower ones. The problem worsens, if tablets are repeatedly manufactured in this station of tooling because of the more and more material getting added to the already stuck material on the punch face. Reason: Picking is of particular concern

when punch tips have engraving or embossing letters, as well as the granular material is improperly dried.
TABLE.13. THE CAUSES AND REMEDIES OF PICKING RELATED TO FORMULATION (GRANULATION)

Sr. No. 1.

CAUSES

REMEDIES Dry properly the granules, determine optimum limit. Increase lubrication; use colloidal silica

Excessive moisture in granules.

2.

Too little or improper lubrication.

as a polishing agent, so that material does not cling to punch faces.

Low 3. may

melting soften

point from

substances, the heat of

Add high melting-point materials. Use high meting point lubricants.

compression and lead to picking. 4.

Low melting point medicament in Refrigerate granules and the entire high concentration. Too warm granules tablet press. when Compress at room temperature. Cool sufficiently before compression. Reduce the amount of binder, change the type or use dry binders.

5.

compressing. Too much amount of binder.

6.

TABLE.14. THE CAUSES AND REMEDIES OF PICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No. 1. 2.

CAUSES Rough or scratched punch faces.

REMEDIES Polish faces to high luster.

Embossing or engraving letters on Design lettering as large as possible. punch faces such as B, A, O, R, P,

Plate the punch faces with chromium Q, G. to produce a smooth and non-adherent face. 3. 4. Bevels or dividing lines too deep. Reduce depths and sharpness. Pressure applied is not enough; too soft tablets. Increase pressure to optimum.

Binding
Definition: Binding in the die, is the term used when the tablets adhere, seize or tear in the die. A film is formed in the die and ejection of tablet is hindered. With excessive binding, the tablet sides are cracked and it may crumble apart. Reason: Binding is usually due to excessive amount of moisture in granules, lack of lubrication and/or use of worn dies.

TABLE.15. THE CAUSES AND REMEDIES OF BINDING RELATED TO FORMULATION (GRANULATION)

Sr. No. 1.

CAUSES Too moist granules and

REMEDIES

extrudes around lower punch. Insufficient lubricant. Too coarse granules. Too hard granules for the or

Dry the granules properly.

2.

improper Increase the amount of lubricant or use a more effective lubricant. Reduce granular size, add more fines, and increase the quantity of lubricant. Modify granulation. Reduce granular size.

3.

4.

lubricant to be effective.

5.

Granular

material

very If coarse granules, reduce its size.

abrasive and cutting into dies. Use wear-resistant dies. Granular material too warm, Reduce temperature. sticks to the die. Increase clearance if it is extruding.

6.

TABLE.16. THE CAUSES AND REMEDIES OF BINDING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No. 1. 2.

CAUSES Poorly finished dies. Rough dies due

REMEDIES Polish the dies properly. to Investigate other steels or other materials or modify granulation.

abrasion, corrosion.

3.

Undersized dies. Too little Rework to proper size. clearance. Increase clearance.

4.

Too much pressure in the Reduce pressure. OR tablet press. Modify granulation.

Mottling
Definition: Mottling is the term used to describe an unequal distribution of colour on a tablet, with light or dark spots standing out in an otherwise uniform surface. Reason: One cause of mottling may be a coloured drug, whose colour differs from the colour of excipients used for granulation of a tablet.
TABLE.17. THE CAUSES AND REMEDIES OF MOTTLING

Sr. CAUSES

REMEDIES

No. A 1. coloured drug used Use appropriate colourants.

along with colourless or white-coloured excipients.

Change the solvent system, A dye migrates to the Change the binder, surface of granulation Reduce drying temperature and while drying. Use a smaller particle size. Improperly 3. mixed dye, Mix properly and reduce size if it is of a larger size to prevent segregation. Incorporate dry colour additive during powder 4. Improper mixing of a blending step, then add fine powdered coloured binder solution. adhesives such as acacia and tragacanth and mix well and finally add granulating liquid.

2.

especially during Direct Compression.

Double impression
Definition: Double Impression involves only those punches, which have a monogram or other engraving on them. Reason: At the moment of compression, the tablet receives the imprint of the punch. Now, on some machines, the lower punch freely drops and travels uncontrolled for a short distance before riding up the ejection cam to push the tablet out of the die, now during this free travel, the punch rotates and at this point, the punch may make a new impression on the bottom of the tablet, resulting in Double Impression. If the upper punch is uncontrolled, it can rotate during the short travel to the final compression stage and create a double impression.

TABLE.18. THE CAUSES AND REMEDIES OF DOUBLE IMPRESSION

Sr. No.

CAUSE

REMEDIES -Use keying in tooling, i.e. inset a key

1.

Free rotation of either upper alongside of the punch, so that it fits the punch or lower punch during punch and prevents punch rotation. ejection of a tablet. -Newer presses have anti-turning devices, which prevent punch rotation.

Mouth Dissolving tablet Technology


Tablet that disintegrate rapidly in the mouth are convenient for patient who have difficulty in swallowing conventional dosages forms. Although various formulation technologies like Zydus Technology, Durasolve Technology, Orasolve Technology, Flash Dose Technology, Wow Tab Technology, Flash Tab Technology, Quicksolv technology, Lyos Technology, Fast Melt Technology and Zip-lets Technology are used. This review highlights numerous techniques to explain the phenomenon of preparing mouth disintegration tablets like Freeze Drying, Moulding, Sublimation, Spray Drying, Direct compression, Wet granulation and Dry granulation.

INTRODUCTION:Recently pharmaceutical preparations used for elderly patients have been investigated to improve the treatment compliances and quality of life of patients. 1 Recent advances in Novel Drug Delivery System (NDDS) aims to enhance safety and efficacy of drug molecule by formulating a convenient dosage form for administration and to achieve better patient compliance. One such approach is Mouth Dissolving Tablet. The concept of Mouth Dissolving Drug Delivery System emerged from the desire to provide patient with conventional mean of taking their

medication. Difficulty in swallowing (Dysphasia) is a common problem of all age groups, especially elderly and pediatrics, because of physiological changes associated with these groups of patients.4 Other categories that experience problems using conventional oral dosage forms includes mentally ill, uncooperative and nauseated patients, those with conditions of motion sickness, sudden episodes of allergic attack or coughing. Some times it may be difficult to swallow conventional products due to unavailability of water. 5 These problems led to the development of novel type of solid oral dosage form called Mouth Dissolving Tablets. This tablet disintegrates instantaneously when placed on tongue, releasing the drug that dissolves or disperses in the saliva. 3 On placing mouth-dissolving tablet in the mouth, saliva serves to rapidly dissolve the dosage form. The saliva containing the dissolved or dispersed medicament is then swallowed and the drug is absorbed in the normal way. Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach & it may produce rapid onset of action. 6 In such a case bioavailability of drug is significantly greater than those observed from conventional tablet dosage form. 2 The dispersible tablets allows dissolution or dispersion in water prior to administration but the Mouth Dissolving Tablet instead of disintegrating or disintegrating in water is expected to dissolve or disintegrate in oral cavity without drinking water. The disintegrated mass then slides down smoothly along the esophagus along with saliva. The growing importance of mouth disintegrating tablet was underlined recently when European Pharmacopoeia adopted the term Orodispersible Tablet as a tablet that to be placed in the mouth where it disperses rapidly before swallowing. 7 - 8 Mouth disintegrating tablets are also known as fast disintegrating tablet, melt in mouth tablet, rapiment, porous tablet, orodispersible tablet, Rapidly Disintegrating tablet, or mouth disintegrating tablet.

9 Fundamentals of Mouth Disintegrating Tablet For rapid dissolution or disintegration of dosage form, water must rapidly penetrate into the tablet matrix to cause quick disintegration & instantaneous dissolution of the tablet. Several techniques are used to achieve these fundamentals, to formulate mouth-disintegrating tablet. Some of the techniques are described below. Patented Technologies 1) Zydus Technology. 2) Durasolve Technology. 3) Orasolve Technology. 4) Flash Dose Technology. 5) Wow Tab Technology. 6) Flash Tab Technology. 7) Quicksolv Technology 8) Lyos Technology 9) Fast Melt Technology 10) Ziplets Technology Dry Granulation In this technique, there is no use of liquids. The process involves the formation of slugs. Then the slugs are screened or milled to produce granules. The granules formed are then compressed to form tablets.12

PATENTED TECHNOLOGIES Zydus Technology Zydus formulation is a unique freeze dried tablet in which drug is physically entrapped or dissolved within the matrix of fast-disintegrating carrier material. The Zydus matrix is composed of many materials designed to

achieve a number of objectives. To impart strength and resilience during handling, polymers such as gelatin, dextran or alginates are incorporated. These form a lossy amorphous structure, which imparts strength. To obtain crystallinity, elegance and hardness, saccharides such as mannitol or sorbitol are incorporated. Water is used in the used to prevent sedimentation of manufacturing process to ensure dispersed drug particles in the production of porous units to achieve rapid disintegration. Various gums are manufacturing process. Collapse protectants such as glycine prevent the shrinkage of Zydus units during freeze-drying process or long-term storage. Zydus products are packed in blister packs to protect the formulation from moisture in the environment. Durasolv Technology Durasolv is the patented technology of CIMA labs. The tablets made by this technology consist of a drug, fillers and a lubricant. Tablets are prepared by using conventional tableting equipment and have good rigidity. These can be packaged into conventional packaging system like blisters. Durasolv is an appropriate technology for products requiring low amounts of active ingredients.

OrasolvTechnology This is also of CIMA lab. In this system active medicament is taste masked. It also contains effervescent disintegrating agent. Tablets are made by direct compression technique at low compression force in order to minimize oral dissolution time. Conventional blenders and tablet machine is used to produce the tablets. The tablets produced are soft and friable and packaged in specially designed pick and place system. Flash Dose Technology This technology is based on the preparation of sugar based matrix known as floss, which is made from a combination of excipients either alone or in combination of drugs. Two platform fuisz technologies called Sheaform and Ceform are currently being utilized in the prepration of a wide range of oral fast disintegrating products. Fuisz has patented Flash dose technology.

Nurofen meltlet, a new form of ibuprofen as melt-in-mouth tablets, prepared using flash dose technology is the first commercial product launched by BiovailCorporation. A flash dose tablet consists of self-binding shearform matrix termed as floss.Shearform matrices are prepared by flash heat processing.

Sheaform Technology The Sheaform technology is based on preparation of floss that is known as Sheaform matrix which is produced by subjecting a feedshock containing a sugar centrifugal force and carrier to a temperature to gradient, which raises flash the heat processing. In this procedure, the sugar is simultaneously subjected to temperature of the mass to create an internal flow condition, which permits part of it to move with respect of the mass. The flowing mass exist through the spinning head that fling the floss. The floss so produced is amorphous in nature so it is further chopped and recrystallised by various techniques to provide uniform flow properties and thus facilitate blending. The recrystallised matrix is then blended with other tablet excipients and an active ingredient. The resulting mixture is compressed into tablet. The active ingredient and other excipients can be blended with floss before carrying out recrystallisation.20,21

Ceform Technology In Ceform technology micro spheres containing active ingredient are prepared. The essence of Ceform micro sphere manufacturing process involves placing dry powder, containing either substantially pure drug material or a special blend of drug material plus other pharmaceutical compounds, and excipients into a precision engineered rapidly spinning machine. The centrifugal force of the rotating head of ceform machine throws the dry drug blend at high speed through small, heated openings; the carefully controlled temperature of the resultant microburst of

liquefied the drug blend to form a sphere without adversely affecting drug stability. The microsphere are then blended and/or compressed into the preselected oral delivery dosage form.

Manufacturing Tablets

Technologies

for

Mouth

Dissolving

Incorporating an existing medicine into a new drug delivery system can significantly improve its performance in terms of efficacy, safety & improved patient compliance. The need for delivering drugs to patients efficiently and with few side effects has prompted pharmaceutical companies to engage in the development of new drug delivery systems. A solid dosage form that dissolve or disintegrates rapidly in oral cavity, resulting in solution or suspension without the need of water is known as fast dispersing dosage form or mouth dissolving tablets. When this type of tablet is placed into the mouth, the saliva will serve to rapidly dissolve the tablet.

Many patients find it difficult to swallow tablets and hard gelatin capsules and do not take their medicines as prescribed. The difficulty experienced in particular by pediatrics and geriatrics patients, but this also applies to the patients who are ill in bed or traveling. Other groups that may experience problems using conventional oral dosage form include the mentally ill, developmentally disable and patients who are uncooperative. A difficulty in swallowing (dysphagia) tablets or capsules is common problem among all age groups, especially in elderly and pediatrics. For this reasons, tablets that can dissolve or disintegrate in oral cavity, have attracted a great deal of attention

1. Indeed, the mouth dissolving tablet is an important and attractive alternative to liquid dosage form. Mouth dissolving tablets are not only indicated for people having difficulty in swallowing but also ideal for unfavorable conditions of administration where water is not available

2. Syrups are best for pediatrics but they are bulky and drugs are not as stable in liquid form as in solid form like tablets. Moth dissolving tablets are also known as fast dissolving, rapid dissolve, rapimelt, fast melts, porous tablets, EFVDAS or Effervescent Drug Absorption system (Elan Corporation), Orosolv (Cima Labs Inc., USA), Zydis (R.P.Scherer, UK) etc.

Advantages of Mouth dissolving tablets 1.Improved patient compliance 2. Rapid onset of action and may offer an improved bioavailability. 3. Patient having difficulty in swallowing tablet can easily administer this type of dosage form 4. Useful fro pediatric, geriatric and psychiatric patients 5. Suitable during traveling where water is may not be available 6. Gives accurate dosing as compared to liquids 7. Good chemical stability. 8. Free of need of measuring, an essential drawback in liquids.

To ensure the tablets fast dissolving attribute, water must quickly egress into the tablet matrix to cause rapid disintegration and instantaneous dissolution of the tablet. Maximizing the porous structure of the tablet matrix and

incorporating an appropriate disintegrating agents or highly water soluble excipients in the tablet formulation are the basic approaches used in current fast dissolving tablet technologies. Basically, the disintegrants major function is to oppose the efficacy of the tablet binder and the physical forces that act under compression to form the tablet. The mechanism by which tablet is broken down into smaller particles and then produces a homogeneous suspension or solution is based on: i) ii) iii) iv) Capillary action High swellabilty of disintegrants Capillary action and high swellability Chemical reaction (Release of Gases)

Different types of technologies have been employed for the formulation of mouth dissolving tablets viz freeze-drying, spray drying and sublimation. These technologies require specialized equipment and process. Tablet Molding In this technology, water-soluble ingredients are used so that tablet disintegrate and dissolve rapidly. The powder blend is moistened with a hydro alcoholic solvent and is molded in to tablet using compression pressure lower than used in conventional tablets compression. The solvent is then removed by air-drying. Molded tablets have a porous structure that enhances dissolution. Two problems commonly encountered are mechanical strength and poor taste masking characteristics. Using binding agents such as sucrose, acacia or poly vinyl pyrrolidone can increase the mechanical strength of the tablet. To overcome poor taste masking characteristic Van Scoik 3 incorporated drug containing discrete particles, which were formed by spray congealing a molten mixture of hydrogenated cottonseed oil, sodium bicarbonate, lecithin, polyethylene glycol and active ingredient into a lactose based tablet triturate form.

Direct Compression Method In this method, tablets are compressed directly from the mixture of the drug and excipients without any preliminary treatment. The mixture to be compressed must have adequate flow properties and cohere under pressure thus making pretreatment as wet granulation unnecessary. Few drugs can be directly compressed into tablets of acceptable quality. A type of disintegrant and its proportion are of prime importance. The other factors to be considered are particle size distribution, contact angle, pore size distribution, tablet hardness and water absorption capacity. All these factors determine the disintegration. The disintegrant addition technology 4,5,6 effective and easy to implement at industrial level. Cousin et al,7 using carboxymethyl cellulose as disintegrating agent and one swelling agent consisting of modified starch or microcrystalline cellulose formulated rapidly disintegrable multi particular tablets. The tablets disintegrate in the mouth in less than 60 seconds. Gas Evolving disintegrants have been used to formulate fast dissolving tablets. The evolution of carbon dioxide as a disintegration mechanism called OROSOLV and DURASOLV have been described in two US Patents assigned to CIMA Labs J. Michaelson 8 describe the use of intimate mixture of alginic acid and a watersoluble metal carbonic acid to prepare tablets. When tablet was placed in water, an acid base reaction takes place forming a metal alginic acid salt and carbonic acid. The salt caused the tablet to swell and the carbonic acid produced carbon dioxide within the swelling tablet whereby rapid disintegration of tablet was effected. is cost

Freeze Drying Technology (Zydus Technology )

Lyophilization can be used to prepare tablets that have very porous open matrix network into which saliva rapidly moves to disintegrate lyophilized mass after it is placed in mouth.

The drug is entrapped in a water soluble matrix which is freeze dried to produce a unit which rapidly disperses when placed in mouth. Apart from the matrix and active constituents, the final formulation may contain other excipients, which improve the process characteristics or enhance the quality of final product. These include colors suspending and agents, The wetting agents, drug preservatives, antioxidants, flavors. preferred

characteristics for freeze drying formulations are water insoluble, low dose, chemically stable, small particle size and tasteless. Corveleyn and Remon investigated the influence of various formulation and process parameters on the characteristics of rapidly disintegrating tablets in lyophilized form using hydrochlorthiazide as a model drug. They have concluded that maltodxtrins are useful in the formulation of fast dissolving tablets made by freeze-drying. Lyophilization is relatively expensive and time consuming manufacturing process. Other drawback includes fragility, which make the use of conventional packing difficult and poor stability during storage under stressful condition.

Spray Drying Spray dryers are widely used in pharmaceuticals and biochemical processes. Due to processing solvent is evaporated rapidly; spray drying can produce highly porous, fine powder. Spray drying can be used to prepare rapidly disintegrating tablets. This technique is based on a particulate support matrix, which is prepared by spray drying an aqueous composition containing support matrix and other components to forma highly porous and fine powder. This is then mixed with active ingredients and compressed into tablets. Allen et al 12 used a spray drying technique to prepare fast dissolving tablets. The tablets made from this technology are claimed to disintegrate within 20 seconds.

Sublimation Technology The basis of this technique is to add inert solid ingredients that volatilize readily, (e.g. camphor, ammonium bicarbonate, naphthalene, urea, urethane etc) to other tablet excipients and the mixture is then compressed into tablets. Volatile material is then removed via sublimation, which generate a porous structure. Koizumi et al 13 applied the sublimation technique to prepare highly porous compressed tablets that were rapidly soluble in saliva. Mannitol and camphor were used as a tablet matrix material and subliming the material respectively. Camphor was iminated by subliming in vacuum at 80 C for 30 minutes to develop pores in the tablets. Makino et al 14 described a method of producing a fast dissolving tablet using water as a pore forming material. A mixture containing active ingredient and carbohydrates (glucose, manitol, xylitol etc) were moistened with water (1- 3 %w/w) and compressed into tablets. The water was then removed yielding highly porous tablet that exhibited excellent ; Sugar Based Excipients Sugar based excipients e.g. sorbitol, manitol, dextrose, xylitol, fructose, maltose etc. have been used as a bulking agents. Because of their high aqueous solubility and sweetness, which impart a pleasant mouth feel and good taste masking properties, can be used to formulate sugar-based mouth dissolving tablet. However, not all sugar-based material have fast dissolution rate and good compressibility. Table 19: Few commercially available mouth dissolving tablets Trade Name Technology Drug Manufacturer

Feldene Melt Zydis Claritin Reditab Tempra Effervescent Zydis

Piroxicam 20 mg Pfizer, New York Loratidine 10 mg Schering Corp., NJ Acetaminophen Bristol Mayers Plough

Quicklets

(Direct Compression)

80 mg

Squibb Co., New York

Zomig Rapimelt

Effervescent (Direct Compression

Zolmitriptan

Astra Zenaca Wayne

Conclusion Recent trends of patient oriented practice demand design of patient oriented dosage form to achieve patient compliance. The number of formulation related factors contributes to the significant amount of non-compliance and hence there is a need to design patient oriented drug delivery system. Mouth dissolving tablets are ideal for many groups of patients including geriatrics, pediatrics, psychiatrics and for those people who have difficulty in swallowing. By using such manufacturing technologies, many drugs can be formulated in the form of mouth dissolving tablets to provide the advantages of liquid medication in the form of solid preparation.

Formulation Technology
Utilising state-of-the-art equipment, we have the following technologies available: Blending and Granulation Wide range of blender / granulator types and sizes, including:

Bin blending systems Dry granulation / roller compaction High shear granulator / driers Top spray fluid bed granulation Fluid bed driers equipped for Wurster coating using both aqueous and organic solvents

Compression

Range of single & multi-station tablet presses capable of producing:


Immediate & modified release Chewable tablets Bi-layer tablets Tab-in-Tab

Encapsulation Manual, semi-automated & fully automated capsule filling of:


Powders Pellets Tablets Combination fills

Coating Wide range of coating scales:

Film coating systems for tablets, pellets and capsules (hard and soft gelatin) Sustained release coatings Enteric coatings Aqueous and organic solvents capability

Sacheting / Pouching Range of equipment for sacheting / pouching:


Granules Powders for reconstitution

Product Development

Blending Dry blending

Dry granulation Wet granulation Compression Encapsulation Coating Sacheting / pouching

Commercial Manufacturing

Blending Dry blending Dry granulation Wet granulation Compression Encapsulation Coating Tablet imprinting

Penicillins

Dry Blending Encapsulation

Cephalosporins

Blending
o o

Dry Blending Wet Granulation

Compression Encapsulation Coating

Primary Packaging

Blisters (thermoform & coldform) Containers (bottles, tubs, jars)

Sachets / Pouches Wallet Cards Labelling

Secondary Labelling and Packaging


Blisters Containers Vials and Ampoules TubesTablet Imprinting Range of equipment with outputs from 50,000 to 300,000 tablets per hour

Advances Technology)

in

double-layer

tablet

manufacturing.

(Tabletting

Pharmaceutical tablet manufacturers have long sought to refine and optimize the processes utilized for producing double-layer tablets. Whether driven by capacity requirements, marketing-based ideas or simple physics, there are always unique factors to be considered when developing a standard procedure for a repeatable manufacturing process. The creation of one solid dosage form, in particular, has long been thought of as a process that could be more accurately described as an art form (or as a pain in the neck, depending on who the speaker is). Certainly it poses technical challenges as

manufacturers seek greater assurances of tighter control while simultaneously looking for higher output rates. Inherent in the successful manufacturing of this dosage form are numerous subtleties, nuances and potential headaches. We're speaking, of course, about the double-layer tablet. Double-layer (or bi-layer) tablets have been around for some time. Quite possibly the earliest uses of this dosage form were driven from a marketing perspective, with emphasis placed on the perception of the consumer who would be utilizing the product. A tablet with two mutually exclusive "layers," represented by two clearly different colors, provided manufacturers with a way to produce a product that looked more interesting than a standard white "pill." While this motivation still has its place in modern pharmaceutical manufacturing the double-layer dosage form has evolved into much more than a product

Tablet

Compression:

Machine

Theory,

Design,

and

Process

Troubleshooting
The most common method of drug delivery is the oral solid dosage form, of which tablets and capsules are predominant. The tablet is more widely accepted and used compared to capsules for a number of reasons, such as cost, tamper resistance, ease of handling and packaging, ease of identification, and manufacturing efficiency. Over the past several years, the issue of tamper resistance has resulted in the conversion of most over-thecounter drugs from capsules to predominantly all tablets. During the 1950s, much research was devoted to Pharmaceutical the physics of products have been manufactured into compressed tablets for many years. compression.1, 2 Since that time, the pharmaceutical industry has attained a much greater understanding of the compression process, which resulted in the development of more robust pharmaceutical formulations.3-53, 4, 5 This has been achieved by the use of instrumented tablet presses and sophisticated data collection systems combined with the development of mathematical models During this time, a significant portion of the development work has been conducted on older equipment, which has been retrofitted to measure compression and ejection-force signals. Recent advances in the design of tablet compression equipment has resulted in

higher-efficiency machines designed to optimize compression efficiency, minimize tablet weight variation, and provide greater flexibility, allowing the production of a greater range of products. However, the modern sophisticated machines still employ the same general concepts of operation: die fill, tablet compression, tablet ejection, and tablet scrape-off. Therefore, studies conducted on older equipment designed to evaluate the compression characteristics of materials, can offer significant insight into material behavior. However, modern machines provide greater accuracy and efficiency as follows:

Improved material feed systems. Improved cam design and material of construction. Multistage compression. Isolated design for quick cleaning and changeover. Improved force-measurement techniques. Introduction of electronics to provide force control. Integration of on-line weight, thickness, and hardness test units feedback control to the force control unit, and

providing weight

High-speed single-tablet sorting to reject out-of-specification tablets.

Therefore, optimal product development can typically be performed on these machines that offer improved compression designs and material feed systems. This article provides the basic information necessary to understand the general process of tablet formation. General machine design characteristics and tablet press nomenclature are presented. Tablet press control systems and process automation are discussed, followed by process and product troubleshooting on tablet compression equipment.

Dow

Foam Squibb

Granulation

Technology

for

Innovative

Tablet

Manufacture Used in Second Drug Candidate at Bristol-Myers

Dow Wolff Cellulosics, a business unit of The Dow Chemical Company and its affiliates, today announced that a second drug candidate developed by Bristol-Myers Squibb Company (NYSE: BMY) will use Dows Foam Granulation Technology (FGT) in the development and manufacturing of tablets intended for clinical and commercial use. This new drug candidate confirms that the benefits and advantages of Dows FGT versus existing granulation technologies are clear, said Hirotsugu Furukawa, global market manager for pharmaceuticals at Dow Wolff Cellulosics. This new technology allows for fast, simple, and cost effective granulation and could help minimize issues associated with conventional processes. Without modifying existing equipment and using a low-cost foam generator, the manufacturing process uses less water than traditional wet granulation processing while rapidly coating particle surfaces and shortening processing time. The inherently large surface areas of foams provide more efficient particle coverage than may be achieved by conventional spray technology. Elimination of spray nozzles removes some of the variables that are commonly encountered in spray granulation. It has been observed by Dow Wolff Cellulosics that particle size distribution is virtually unaffected by foam addition rate; this leads to a dramatic simplification in product scale-up. Drug content uniformity is also improved which is especially important in low-dose formulations. Dow Wolff Cellulosics offers multi-functional excipients METHOCEL and ETHOCEL cellulose ethers WALOCEL sodium carboxymethyl cellulose, and POLYOX poly(ethylene) oxide resins that have been used in pharmaceutical formulations for more than 40 years including applications such as controlled release, tablet coating, hot melt extrusion and granulation.

Fast Dissolving Tablet


Tablet is the most popular among all dosage forms existing today because of its convenience of self administration, compactness and easy manufacturing; however hand tremors, dysphasia in case of geriatric patients, the underdeveloped muscular and nervous systems in young individuals and h case of uncooperative patients, the problem of swallowing is common phenomenon which leads to poor patient compliance1. To overcome these drawbacks, mouth dissolving tablets (MDT) or orally disintegrating tablets; (ODT) has emerged as alternative oral dosage forms. These are novel types; of tablets that disintegrate/dissolve/ disperse in saliva within few seconds'. According to European Pharmacopoeia, the ODT should disperse/disintegrate in less than three minutes. The basic approach used in development of MDT is the use of superdisintegrants like Cross linked carboxymelhylcellulose (Croscarmeliose), Sodium starch glycolate (Primogel, Explotab). Polyvinylpyrrolidone (Polyplasdone) etc. which provide instantaneous disintegration of tablet after putting on tongue, thereby releasing the drug in saliva. The bioavailability of some drugs may be increased due to absorption of drugs in oral cavity and also due to pregastric absorption of saliva containing dispersed drugs that pass down into the stomach. Moreover, the amount of drug that is subject to first pass metabolism is reduced as compared to standard tablets.

Definition A fast-dissolving drug delivery system, in most cases, is a tablet that dissolves or disintrigrants in the oral cavity without the need of water or chewing. Most fast-dissolving delivery system films must include substances to mask the taste of the active ingredient. This masked active ingredient is

then swallowed by the patient's saliva along with the soluble and insoluble excipients. These are also called melt-in-mouth tablets, repimelts, porous tablets, oro-dispersible, quick dissolving or rapid disintegrating tablets.

Requirements Of Fast Dissolving Tablets An ideal FDT should 1. 2. 3. 4. 5. 6. 7. Require no water for oral administration, yet dissolve / disperse/ disintegrate in mouth in a matter of seconds. Have a pleasing mouth feel. Have an acceptable taste masking property. Be harder and less friable Leave minimal or no residue in mouth after administration Exhibit low sensitivity to environmental conditions (temperature and humidity). Allow the manufacture of tablet using conventional processing and packaging equipments. Advantages of FDT Administration to the patients who can not swallow, such as the elderly, stroke victims, bedridden patients, patients affected by renal failure & patients who refuse to swallow such as pediatric, geriatric & psychiatric patients. Rapid drug therapy intervention. Achieve increased bioavailability/rapid absorption through pregastric absorption of drugs from mouth, pharynx & oesophagus as saliva passes down. Convenient for administration and patient compliant for disabled, bedridden patients and for travelers and busy people, who do not always have access to water. Good mouth feel property helps to change the perception of medication as bitter pill particularly in pediatric patients.

The risk of chocking or suffocation during oral administration of conventional formulations due to physical obstruction is avoided, thus providing improved safety.

New

business

opportunity

like

product

differentiation,

product

promotion, patent extension and life cycle management. Salient Features of Fast Dissolving Drug Delivery System Ease of administration to patients who refuse to swallow a tablet, such as paediatric and geriatric patients and, psychiatric patients. Convenience of administration and accurate dosing as compared to liquids. No need of water to swallow the dosage from, which is highly convenient feature for patients who are traveling and do not have immediate access to water. Good mouth feels properly of MDDS helps to change the basic view of medication as "bitter pill", particularly for paediatric patients. Rapid dissolution of drug and absorption which may produce rapid, onset of action. Some drugs are absorbed from the month pharynx and oesophagus as the saliva passes down into the stomach, in such cases bioavailability of drugs is increased. Ability to provide advantages of liquid medication in the form of solid preparation. Pregastric absorption can result in improved bioavailability and as a result of reduced dosage, improved clinical performance through a reduction of unwanted effects.

Following conventional techniques are used for preparation of fast dissolving drug delivery system

Disintegrant Addition

Disintegrant addition technique is one popular techniques for formulating Fast-dissolving tablets because of its easy implementation and costeffectiveness. The basic principle involved in formulating Fast-dissolving tablets by disintegrant addition technique is addition of super disintegrants in optimum concentration so as to achieve rapid disintegration along with the good mouth feel. Microcrystalline cellulose and low substituted hydroxyl propyl cellulose were used as disintegrating agents in the range of 8:2 9.1 to prepare fast dissolving tablet. Agar powder is used as disintegrants for the development of rapidly disintegration tablets by enhancing the porosity of agar by water treatment. Rapidly disintegrating tablets of bitter drugs oxybutynin & pirenzepine were prepared by using the taste masked granules and h mixture of excipients consisting of crystalline cellulose (Avicel PH 02) and low-substituted hydroxypropy cellulose HPC, LH-11), Ishikawa et al. prepared rapidly disintegrating tablets using microcrystalline cellulose (Avicel PH-M series) that was spherical and had a very small particle size 7-32 m). instead of conventional microcrystalline cellulose (PH 102). Tablets prepared using microcrystalline cellulose; PH-M06 and L-HPC in the ratio of 9:1 were very rapidly disintegrating) in saliva. They concluded that Avicel PH-M06 was superior to Avicel PH 102 in terms of the feeling of roughness in the mouth. Fast dissolving table of efavirenz (anti HIV agent) were formulated by using combination of microcrystalline cellulose and sodium starch glycolate as super disintegrant. Gillis et al, prepared a fast-dissolving tablet of galanthamine hydrobromide which comprises of spray dried mixture of lactose monohydrate and microcrystalline cellulose (75:25) as a diluent, a cross linked polymeric disintegrant such as cross povidone and with a direct compression process of preparing such fast-dissolving tablets. Fast-dissolving tablets having analgesic activity was formulated using a combination of superdisintegrants. Rapid oral disintegration tablets were developed by direct compression using co-ground mixture of D-mannitol and crospovidone. CIMA labs patented Orasolv technology by employing the evolution of carbon dioxide or the effervescence as disintegration mechanism in the formulation of fast-dissolving tablets. The OraSolv technology is an oral dosage form, which combines taste-masked drug ingredients with a quick dissolving effervescent excipient

system. Taste masking is achieved through a process of microencapsulation, which coats or entraps the active compound in an immediate release matrix. The effervescent excipient system aids in rapid disintegration of the tablet, permitting swallowing of pharmaceutical ingredients before they come in contact with the taste bud. The OraSolv tablet dissolves quickly without chewing or without water and allows for effective taste masking of a wide variety of active drug ingredients, both prescription and non-prescription. Flashtab technology is a patented technology of Prographarm, which employ combination of taste-masked multiparticulate active drug substances, a disintegrating agent, a swelling agent and other excipients to form a multiparticulate tablet that disintegrates rapidly. Rapidly disintegrating multiparticulate tablet was prepared by using taste-masked microcrystals of drugs, crosslinked disintegrating agent and soluble diluent with binding properties.

Freeze Drying A process in which water is sublimated from the product after freezing. Lyophilization is a pharmaceutical technology which allows drying of heat sensitive drugs and biological at low temperature under conditions that allow removal of water by sublimation. Lyophilization results in preparations, which are highly porous, with a very high specific surface area, which dissolve rapidly and show improved absorption and bioavailability. Moulding In this method, molded tablets are prepared by using water-soluble ingredients so that the tablets dissolve completely and rapidly. The powder blend is moistened with a hydro-alcoholic solvent and is molded into tablets under pressure lower than that used in conventional tablet compression. The solvent is then removed by air-drying. Molded tablets are very less compact than compressed tablets. These possess porous structure that enhances dissolution. Sublimation

The slow dissolution of the compressed tablet containing even highly watersoluble ingredients is due to the low porosity of the tablets. Inert solid ingredients that volatilize readily (e.g. urea, ammonium carbonate, ammonium bicarbonate, hexa methelene tetramine, camphor etc.) were added to the other tablet ingredients and the mixture is compressed into tablets. The volatile materials were then removed via sublimation, which generates porous structures. Additionally, several solvents (e.g. cyclohexane, benzene) can be also used as pore forming agents,

Fig 18 Steps Involved in sublimation Spray-Drying Spray drying can produce highly porous and fine powders that dissolve rapidly. The formulations are incorporated by hydrolyzed and non hydrolyzed gelatins as supporting agents, mannitol as bulking agent, sodium starch glycolate or crosscarmellose sodium as disintegrating and an acidic material (e.g. citric acid) and / or alkali material (e.g. I sodium bicarbonate) to enhance disintegration and dissolution. Tablet compressed from the spray dried powder disintegrated within 20 seconds when immersed in an aqueous medium.

Mass-Extrusion This technology involves softening the active blend using the solvent mixture of water soluble polyethylene glycol, using methanol and expulsion of softened mass through the extruder or syringe to get a cylinder of the product into even segments using heated blade to form tablets. The dried cylinder can also be used to coat granules of bitter tasting drugs and thereby masking their bitter taste.

Direct Compression It is the easiest way to manufacture tablets. Conventional equipment, commonly available excipients and a limited number of processing steps are involved in direct compression. Also high doses can be accommodated and final weight of tablet can easily exceed that of other production methods. Directly compressed tablet's disintegration and solubilization depends on single or combined action of disintegrants, water soluble excipients and effervescent agent. Patented Technologies For Fast Dissolving Tablets

Zydis Technology Zydis, the best known of the fast-dissolving/disintegrating tablet preparations was the first marketed new technology tablet. The tablet dissolves in the mouth within seconds after placement on the tongue. A Zydis tablet is produced by lyophilizing or freeze-drying the drug in a matrix usually consisting of gelatin. The product is very lightweight and fragile, and must be dispensed in a special blister pack. Patients should be advised not to push the tablets through the foil film, but instead peel the film back to release the tablet. The Zydis product is made to dissolve on the tongue in 2 to 3 seconds. The Zydis formulation is also self-preserving because the final water concentration in the freeze-dried product is too low to allow for microbial growth.

Durasolv Technology Durasolv is the patented technology of CIMA labs. The tablets made by this technology consist of a drug, fillers and a lubricant. Tablets are prepared by using conventional tableting equipment and have good rigidity. These can be packed into conventional packaging system like blisters. Durasolv is an appropriate technology for products requiring low amounts of active ingredients. Orasolv Technology Orasolv Technology has been developed by CIMA labs. In this system active medicament is taste masked. It also contains effervescent disintegrating agent. Tablets are made by direct compression technique at low compression force in order to minimize oral dissolution time. Conventional blenders and tablet machine is used to produce the tablets. The tablets produced are soft and friable and packaged in specially designed pick and place system. Flash Dose Technology Flash dose technology has been patented by Fuisz. Nurofen meltlet, a new form of ibuprofen as melt-in-mouth tablets, prepared using flash dose technology is the first commercial product launched by Biovail Corporation. Flash dose tablets consists of self binding shearform matrix termed as "floss". Shearform matrices are prepared by flash heat processing. Wowtab Technology Wowtab Technology is patented by Yamanouchi Pharmaceutical Co. WOW means "Without Water ". In this process, combination of low mouldability saccharides and high mouldability saccharides is used to obtain a rapidly melting strong tablet. The active ingredient is mixed with a low mouldability saccharide and granulated with a high mouldability saccharide and compressed into tablet.

Flashtab Technology

Prographarm laboratories have patented the Flashtab technology. Tablets prepared by this system consist of an active ingredient in the form of micro crystals. Drug micro granules may be prepared by using the conventional techniques like coacervation, micro encapsulation, and extrusion spheronisation. All the processing utilized conventional tabletting technology. Drugs To Be Promising In Corporated In Fast Dissolving Tablets There are no particular limitations as long as it is a substance which is used as a

Pharmaceutical active ingredient. Analgesics and Anti-inflammatory Agents: Aloxiprin, Fenbufen, Auranofin, Fenoprofen Azapropazone, Calcim, Benorylate, Diflunisal, Etodolac,

Flurbiprofen,

Ibuprofen,

Indomethacin,

Ketoprofen, Anthelmintics : Albendazole, Bephenium Hydroxynaphthoate, Cambendazole, Dichlorophen, Iverrnectin, Mebendazole, Oxarnniquine, Oxfendazole, Oxantel Embonate, Praziquantel, Pyrantel Embonate, Thiabendazole. Anti-Arrhythmic Agents: Amiodarone, Disopyramide, Flecainide Acetate, Quinidine Sulphate, Anti-bacterial Agents: Benethamine Penicillin, Cinoxacin, Ciprofloxacin, Clarithromycin, Clofazimine, Cloxacillin, Demeclocycline, Doxycycline, Erythromycin, Ethionamide, Imipenem, Nalidixic Acid, Nitrofurantoin, Rifampicin, Spiramycin, Anti-coagulants: Dicoumarol, Dipyridamole, Nicoumalone, Phenindione. Anti-Depressants: Amoxapine, Ciclazindol, Maprotiline, Mianserin, Nortriptyline, Trazodone, Anti-Epileptics:

Beclamide, Carbamazepine, Clonazepam, Ethotoin, Methoin, Methsuximide, Methylphenobarbitone, Acid. .There are no particular limitations on the amount of these drugs to be mixed as long as it is the usual effective treatment amount. It should be around 50 weight/weight % or below of the entire tablet, and is preferably 20 weight/weight % or below. Optimal disintegration properties often have medium to small size and /or high friability and low hardness. Breakage of tablet edges during handling and tablet rupture during the opening of blister alveolus, all result from insufficient physical resistance. Oxcarbazepine, Paramethadione, Phenacemide, Phenobarbitone, Phenytoin, Phensuximide, Primidone, Sulthiame, Valproic

General Appearance The general appearance of a tablet, its visual identity and over all "elegance" is essential for consumer acceptance. Include in are tablet's size, shape, colour, presence or absence of an odour, taste, surface texture, physical flaws and consistency and legibility of any identifying marking. Size and Shape Tablet thickness Uniformity of weight Tablet hardness Friability Wetting time In vitro dispersion time Packaging

Marketed Fast Dissolving Tablets in India

Name Product

of

the Active Ingredients

Imodium Lingual Imodium Pepcidin Rapitab Quick eleasing antiulcer reparation of pepcid Mosid MT Mouth citrate. Calritin Reditabs Immediate Dissolving formulation of Calritin Nimulid MD Zyrof Meltab Claritin Reditab Feldene Melt Maxalt-MLT Nimesulide Rofecoxib micronized loratadine piroxicam (10 or 20 mg), rizatriptan(5or10mg), flavour Pepcid RPD Zyprexa Zydis Zofran ODT famotidine (20 or 40 mg), olanzapine (5, 10, 15 or 20 mg), ondansetron(4or8mg), flavor Remeron Soltab mirtazepine(15,30,or45mg), orange flavor strawberry peppermint melt tablet of Mosapride

Recent trends of patient oriented practice demand design of patient oriented dosage form to achieve patient compliance. The number of formulation related factors contributes to the significant amount of non-compliance and hence there is a need to design patient oriented drug delivery system. Mouth

dissolving tablets are ideal for many groups of patients including geriatrics, pediatrics, psychiatrics and for those people who have difficulty in swallowing. By using such manufacturing technologies, many drugs can be formulated in the form of mouth dissolving tablets to provide the advantages of liquid medication in the form of solid preparation.

Oral tablets for ingestion Modified release tablet


The main aim behind formulation of this dosage form is to release the medicament slowly for long time duration after administration of a single tablet.More over, these type of formulations are generally used to target the site specific releases.

FIGURE.19. GRAPHICAL COMPARISON OF BLOOD CONCENTRATION V/S TIME A widespread use of this type of tablet is seen in present scenario, as well as many researchers have concentrated their attention in this direction. This is mainly because of improvement in patients compliance as the dosage frequency is reduced, patient can take an undisturbed sleep at night, its also beneficial for psychiatric patients who forget to take their tablets regularly and the dose related side effects and toxicities are reduced. Any adjuvant that can alter water uptake rate, swelling and gelling characteristics of Matrixing agents can alter the release rate of API e.g., electrolytes in HPMC matrix tablet. Its also possible to achieve pulsed drug release. Weakly basic

drugs exhibit good solubility at low pH while less soluble at high pH conditions, which can result in incomplete drug release for sustained release formulations. The drug release can be modified by providing suitable micro environmental pH in the tablet e.g., acidic polymer, succinic acid, etc. Similarly, inclusion of alkaline polymers results in desirable drug release of acidic drugs. On the other hand, formulation of this type of dosage form presents challenge for the formulator: increases the cost of manufacturing, chances of burst drug release and drop in drug release rate in terminal phase and thus incomplete release on API. In case of accidental poisoning, the doctor has to deal with special treatment problems. Due to large size, patient may feel difficulties in swallowing as the matrixing agent to drug ratio is high. Classic approaches are usually based on adaptation of either film coated or multiparticulate technologies or those involving slow release matrices. Coating technology

It combines semi permeable coatings and osmotic tablet cores to produce zero order release technology. Attention is also focused to trigger drug release at critical time point e.g., to achieve drug release 1 -2 hours before the patient awakens. Alzas prolific research activities have yielded a technology called Ringcap which is based on a tablet, preferentially film coated, partially coated with a series of rings whose respective thickness provides the means of moderating the rate at which the drug is released from final dosage form.

FIGURE.20. RINGCAP (COATED) TABLET

Matrix technology
Classically matrix products exhibit first order (or perhaps square-root-of-time) drug release characteristics. In order to achieve zero order release characteristics, its necessary to employ specially designed materials or strategies that seek to manipulate tablet structure or geometry. Combination of conventional HPMC matrix technology with upper and lower layer. This helps to moderate drug release by increase in surface area with concomitant reduction in drug concentration within the device.

FIGURE.21. MATRIX TABLET Release of medicament can follow various mechanisms (2) I) Diffusion is rate limiting Diffusion is driving force where the movement of drug molecules occurs from high concentration in the tablet to lower concentration in gastro intestinal fluids. This movement depends on surface area exposed to gastric fluid, diffusion pathway, drug concentration gradient and diffusion coefficient of the system.

FIGURE.22. DIFFUSION RELEASE PATTERN

In practice, we can follow either of the two methods, 1.The drug is formulated in an insoluble matrix; the gastric fluid penetrates the dosage form and dissolves the medicament and release the drug through diffusion. 2.The drug particles are coated with polymer of defined thickness so as the portion of drug slowly diffuse through the polymer to maintain constant drug level in blood. ii)Dissolution is rate limitingThe drugs with poor water solubility (BCS class 2 and 4) are inherently sustained release forms. While for water soluble drugs, its possible to incorporate a water insoluble carrier to reduce dissolution of the drug particles are coated with this type of materials e.g. Polyethylene Glycol. One may skip the use of disintegrating agent to promote delayed release. iii)Osmotic pressure is rate limiting Osmosis is a phenomenon in which the flow of liquid occurs from lower concentration to higher concentration through a semi permeable membrane which allows transfer of liquid only. The whole drug is coated with a semi permeable membrane with a hole on one end of tablet made by a laser beam. The gastric fluid penetrates through the membrane, solubilizes the drug and increases the internal pressure which pumps the drug solution out of the aperture and releases the drug in gastric environment. The delivery rate is constant provided that the excess of drug present inside the tablet. But, it declines to zero once the concentration drops below saturation.

FIGURE.23. OSMOTIC RELEASE PATTERN

iv) Release is controlled by ion exchange Ion exchangers are water insoluble resinous materials containing salt forming anionic or cationic groups. While manufacturing, the drug solution is mixed with resin and dried to form beads which are tableted. The drug release depends upon high concentration of charged ions in gastro intestinal tract where, the drug molecules are exchanged and diffused out of the resin into the surrounding fluid. This mechanism relies upon the ionic environment of resin and not pH or enzyme on absorption site

Conclusion Fast dissolving tablets constitute an innovative dosage form, which

overcomes the problem of swallowing and provides a quick onset of action. The paediatric and geriatric populations are the primary. Targets, as both the groups found it difficult to swallow conventional tablets. The basic approach followed by all the currently available technologies engaged in the formulation of Fast dissolving tablets is to maximize the porous structure of the tablet matrix and incorporate super disintegrating agents in optimum concentration so as to achieve rapid disintegration and instantaneous dissolution of the tablet along with good taste masking properties and excellent mechanical strength The availability of the various technologies and manifold advantages of Fast dissolving tablets will surely increase its popularity in the near future

Recent trends of patient oriented practice demand design of patient oriented dosage form to achieve patient compliance. The number of formulation related factors contributes to the significant amount of non-compliance and hence there is a need to design patient oriented drug delivery system. Mouth dissolving tablets are ideal for many groups of patients including geriatrics, pediatrics, psychiatrics and for those people who have difficulty in swallowing. By using such manufacturing technologies, many drugs can be

formulated in the form of mouth dissolving tablets to provide the advantages of liquid medication in the form of solid preparation

Tablet

Type of Tablet

Operations involved

Problems in tablet manufacturing

Mouth Dissolving tablet Technology

Manufacturing Technologies

Formulation Technology

Double-layer tablet Tablet

Fast Dissolving Tablet

Modified release tablet

Matrix technology

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