adv a cement in tablet technology
TRANSCRIPT
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