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 Supervised by

Anju Katare

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 Principal

Mr. Ankush Jain Dr. Vimukta Sharma

TABLE OF CONTENTS

S. No.

Content Page No.

1.0 Overview 1-4

2.0 Advancement in Tablet 5-17

3.0 Operations 18-25

4.0 Problems & REMEDIES 26-37

5.0 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

38-52

53-55

56-56

57-67

68-69

70-71

6.0 Conclusion 72-73

7.0 References 73

LIST OF TABLESTable No. Title Page No.

1 Types Of Tablets 6

2 Unit Operation 20

3 Capping related to Formulation 28

4 Capping related to Machine 29

5 Lamination related to Formulation 30

6 Lamination related to Machine 30

7 Chipping related to Formulation 31

8 Chipping related to Machine 31

9 Cracking related to Formulation 32

10 Cracking related to Machine 32

11 Sticking related to Formulation 33

12 Sticking related to Machine 33

13 Picking related to Formulation 34

14 Picking related to Machine 35

15 Binding related to Formulation 35

16 Binding related to Machine 36

17 Mottling 37

18 Double Impression 38

19 Commercially available mouth dissolving tablets 49

20 Fast Dissolving Tablets 67

LIST OF FIGURES

Figure No. Title Page No.

1 Tablet 1

2 Capping (top) and lamination (right) tablet failure modes 2

3 Tablet Compressors 4

4 Standard Compressed Tablet 8

5 Compression Coated Tablet 9

6 Inlay Tablets 9

7 Graphical Comparison Of Blood ConcentrationV/S Time 10

8 Ringcap (Coated) TableMatrix technology 10

9 Matrix Tablet. 11

10 Floating Tablet 12

11 Sublingual Tablets 14

12 Buccal Tablets 15

13 Dental Cones 15

14 Effervescent Tablets 17

15Soluble tablets

18

16Unit Operation Sequences

20

17 Compression 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

called pills.

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

Contents

1 Tabletting formulations

2 Advantages and disadvantages

3 Tablet compaction simulator

4 Tablet presses

5 Pill-splitters

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 of different types of tablets are to create a

delivery system that is relatively simple and inexpensive to manufacture,

provide the dosage form that is convenient from patient’s perspective and

utilize an approach that is unlikely to add complexity during regulatory

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

2 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

3 TABLETS

ADMINISTERED BY OTHER

ROUTES

3.1 Vaginal tablet

3.2 Implants

4 TABLETS

USED TO PREPARE

SOLUTION

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.

Alza’s 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, it’s

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 it’s 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 it’s 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., Eudragit®S100, 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, it’s

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. It’s 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. It’s 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

and mixing of drugs and excipients

1.

Milling

and mixing of drugs and excipients

1. Milling and

mixing of drugs

and excipients

2.

Preparation

of binder solution

2.

Compression

into slugs or roll compaction

2.

Compression of

tablet

3.

Wet

massing by addition of binder solution

or granulating solvent

3.

Milling

and screening of slugs and

compacted powder

4.

Screening

of wet mass

4.

Mixing

with lubricant and disintegrants

5.

Drying

of the wet granules

5.

Compression

of tablet

6.

Screening

of dry granules

7.

Blending

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 ingredient’s dissolution

rate and hence bioavailability.

ii) Improved the tablet-to-tablet content uniformity by virtue of the increased number of

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.

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 cause

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 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, etc. But now a days to

optimize the manufacturing process particularly in wet granulation the 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).

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 in–depth 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 along–with 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 air-entrapment 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 (Process-related); 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 air–entrapment 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.CAUSES REMEDIES

1.Large amount of fines in the

granulation

Remove some or all fines through 100 to 200 mesh

screen

2.

Too dry or very low moisture

content (leading to loss of proper

binding action).

Moisten the granules suitably. Add hygroscopic

substance e.g.: sorbitol, methyl- cellulose or PEG-

4000.

3. Not thoroughly dried granules. Dry the granules properly.

4.Insufficient amount of binder or

improper binder.

Increasing the mount of binder OR

Adding dry binder such as pre-gelatinized starch, gum

acacia, powdered sorbitol, PVP, hydrophilic silica or

powdered sugar.

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

of lubricant.

6.Granular mass too cold to compress

firm.Compress at room temperature.

TABLE.4. THE CAUSES AND REMEDIES OF CAPPING RELATED TO ‘MACHINE’ (DIES, PUNCHES AND

TABLET PRESS)

Sr.

No.CAUSES REMEDIES

1. Poorly finished diesPolish dies properly. Investigate other steels

or other materials.

2.Deep concave punches or beveled-edge

faces of punches.Use flat punches.

3.Lower punch remains below the face of die

during ejection.

Make proper setting of lower punch during

ejection.

4. Incorrect adjustment of sweep-off blade.Adjust sweep-off blade correctly to facilitate

proper ejection.

5. High turret speed. Reduce speed of turret (Increase dwell time).

Lamination / Laminating

Definition: ‘Lamination’ is the separation of a tablet into two or more distinct horizontal layers.

Reason: Air–entrapment 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 granulesModify mixing process. Add adsorbent or

absorbent.

2.Too much of hydrophobic lubricant e.g.:

Magnesium-stearate.

Use a less amount of lubricant or change the

type of lubricant.

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

Press)

Sr.

No.CAUSES REMEDIES</ b>

1.Rapid relaxation of the peripheral regions

of a tablet, on ejection from a die.

Use tapered dies, i.e. upper part of the die bore

has an outward taper of 3° to 5°.

2. Rapid decompressionUse 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.

2. Too dry granules.Moisten the granules to plasticize. Add hygroscopic

substances.

3.Too much binding causes 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. CAUSES REMEDIES

1. Groove of die worn at compression point. Polish to open end, reverse or replace the die.

2.Barreled die (center of the die wider than

ends)Polish the die to make it cylindrical

3. Edge of punch face turned inside/inward. Polish the punch edges

4. Concavity too deep to compress properly.Reduce concavity of punch faces. Use 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 REMEDIES

1. Large size of granules. Reduce granule size. Add fines.

2. Too dry granules. Moisten the granules properly and add proper amount

of binder.

3. Tablets expand. Improve granulation. Add dry binders.

4. Granulation too cold. Compress at room temperature.

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

AND TABLET PRESS)

Sr. No. CAUSES REMEDIES

1. Tablet expands on ejection due to air entrapment. Use tapered die.

2.Deep concavities cause cracking while

removing tabletsUse special take-off.

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. CAUSES REMEDIES

1. Granules not dried properly.Dry the granules properly. Make moisture analysis to

determine limits.

2. Too little or improper Increase or change lubricant.

lubrication.

3. Too much binderReduce the amount of binder or use a different type of

binder.

4.Hygroscopic granular

material.

Modify granulation and compress under controlled

humidity.

5. Oily or way materials Modify mixing process. Add an absorbent.

6. Too soft or weak granules. Optimize the amount of binder and granulation technique.

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

AND TABLET PRESS)

Sr. No. CAUSES REMEDIES

1. Concavity too deep for granulation. Reduce concavity to optimum.

2. Too little pressure. Increase pressure.

3. Compressing too fast. 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.CAUSES REMEDIES

1. Excessive moisture in granules.Dry properly the granules, determine optimum

limit.

2. Too little or improper lubrication.

Increase lubrication; use colloidal silica as a

‘polishing agent’, so that material does not cling

to punch faces.

3.

Low melting point substances, may soften

from the heat of compression and lead to

picking.

Add high melting-point materials. Use high

meting point lubricants.

4.Low melting point medicament in high

concentration.Refrigerate granules and the entire tablet press.

5. Too warm granules when compressing.Compress at room temperature. Cool

sufficiently before compression.

6. Too much amount of binder.Reduce the amount of binder, change the type

or use dry binders.

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

TABLET PRESS)

Sr.

No.CAUSES REMEDIES

1. Rough or scratched punch faces. Polish faces to high luster.

2.Embossing or engraving letters on punch

faces such as B, A, O, R, P, Q, G.

Design lettering as large as possible.

Plate the punch faces with chromium to

produce a smooth and non-adherent face.

3. Bevels or dividing lines too deep. Reduce depths and sharpness.

4. Pressure applied is not enough; too soft Increase pressure to optimum.

tablets.

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.CAUSES REMEDIES

1.Too moist granules and extrudes

around lower punch.Dry the granules properly.

2. Insufficient or improper lubricant.Increase the amount of lubricant or use a more

effective lubricant.

3. Too coarse granules.Reduce granular size, add more fines, and increase

the quantity of lubricant.

4.Too hard granules for the lubricant to

be effective.Modify granulation. Reduce granular size.

5.Granular material very abrasive and

cutting into dies.

If coarse granules, reduce its size.

Use wear-resistant dies.

6.Granular material too warm, sticks to

the die.

Reduce temperature.

Increase clearance if it is extruding.

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

TABLET PRESS)

Sr. No. CAUSES REMEDIES

1. Poorly finished dies. Polish the dies properly.

2.Rough dies due to abrasion,

corrosion.

Investigate other steels or other materials or modify

granulation.

3.Undersized dies. Too little

clearance.

Rework to proper size.

Increase clearance.

4.Too much pressure in the tablet

press.

Reduce pressure. OR

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.

No.CAUSES REMEDIES

1.

A coloured drug used along

with colourless or white-

coloured excipients.

Use appropriate colourants.

2. A dye migrates to the surface

of granulation while drying.

Change the solvent system,

Change the binder,

Reduce drying temperature and

Use a smaller particle size.

3.

Improperly mixed dye,

especially during ‘Direct

Compression’.

Mix properly and reduce size if it is of a larger size to

prevent segregation.

4.Improper mixing of a coloured

binder solution.

Incorporate dry colour additive during powder blending

step, then add fine powdered adhesives such as acacia and

tragacanth and mix well and finally add granulating liquid.

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

1.

Free rotation of either upper punch

or lower punch during ejection of a

tablet.

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

the punch, so that it fits the punch and prevents

punch rotation.

-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

manufacturing process to ensure production of porous units to achieve rapid disintegration.

Various gums are used to prevent sedimentation of dispersed drug particles in the

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 carrier to flash

heat processing. In this procedure, the sugar is simultaneously subjected to centrifugal force and

to a temperature gradient, which raises the 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 pre-selected oral delivery dosage form.

Manufacturing Technologies for Mouth Dissolving Tablets

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 tablet’s 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 disintegrant’s 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) Capillary action

ii) High swellabilty of disintegrants

iii) Capillary action and high swellability

iv) 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 is cost 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 water-soluble 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.

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 suspending agents, wetting agents, preservatives,

antioxidants, colors and flavors. The preferred drug 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 Piroxicam 20 mg Pfizer, New York

Claritin Reditab Zydis Loratidine 10 mg Schering Plough Corp.,

NJ

Tempra

Quicklets

Effervescent

(Direct

Compression)

Acetaminophen

80 mg

Bristol – Mayers 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 Dry Blending

o 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 in double-layer tablet manufacturing. (Tabletting

Technology)

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-the-counter drugs from capsules to

predominantly all tablets. Pharmaceutical products have been manufactured into compressed

tablets for many years. During the 1950s, much research was devoted to the physics of

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 providing weight

feedback control to the force control unit, and

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 Granulation Technology™ for Innovative Tablet

Manufacture Used in Second Drug Candidate at Bristol-Myers Squibb

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 Dow’s 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 Dow’s 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 Cellulosic’s 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. Require no water for oral administration, yet dissolve / disperse/ disintegrate in

mouth in a matter of seconds.

2. Have a pleasing mouth feel.

3. Have an acceptable taste masking property.

4. Be harder and less friable

5. Leave minimal or no residue in mouth after administration

6. Exhibit low sensitivity to environmental conditions (temperature and humidity).

7. 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 cost-effectiveness. 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 μm). 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 water-soluble 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, Auranofin, Azapropazone, Benorylate, Diflunisal, Etodolac, Fenbufen, Fenoprofen

Calcim, 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, Oxcarbazepine, Paramethadione, Phenacemide, Phenobarbitone,

Phenytoin, Phensuximide, Primidone, Sulthiame, Valproic 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.

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 of the Product Active Ingredients

Imodium Lingual Imodium

Pepcidin Rapitab Quick eleasing antiulcer reparation of pepcid

Mosid – MT Mouth melt tablet of Mosapride citrate.

Calritin Reditabs Immediate Dissolving formulation of Calritin

Nimulid – MD Nimesulide

Zyrof Meltab Rofecoxib

Claritin Reditab micronized loratadine

Feldene Melt piroxicam (10 or 20 mg),

Maxalt-MLT rizatriptan(5or10mg), peppermint flavour

Pepcid RPD famotidine (20 or 40 mg),

Zyprexa Zydis olanzapine (5, 10, 15 or 20 mg),

Zofran ODT ondansetron(4or8mg), strawberry flavor

Remeron Soltab mirtazepine(15,30,or45mg), orange flavor

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

patient’s compliance as the dosage frequency is reduced, patient can take an undisturbed sleep

at night, it’s 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. It’s 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. Alza’s 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, it’s 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, it’s 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