Novel Approach of Layered Tablet Technology

Novel Approach of Layered Tablet
Technology
A Dissertation Submitted to the Department of Pharmacy, University of
Asia Pacific for Partial Fulfillment of the Requirements for the Degree of
Master of Science in Pharmaceutical Technology
Submitted By
Name: Nusrat Jahan
Registration Number: 13207029
Department of Pharmacy
University of Asia Pacific

DEDICATED
To
My Beloved Parents
&
All the Teachers Who Teaches All Over the World

ACKNOWLEDGEMENT
In the name of Allah and entire praise for only Almighty Allah who has given me the
opportunity to study in this subject.
I would like to express my gratitude to my honorable supervisor Md. Asaduzzaman for his
kind supervision, patience and valuable support in making a difficult task to a pleasant one.
I wish to express my thanks and regards to SM Ashraful Islam, Associate Professor and
Coordinator for MS Pharm Tech program and Dr. Mohiuddin Ahmed Bhuiyan, Professor and
Head of the Department, Department of Pharmacy, University of Asia Pacific, for their
support and cooperation.
Sincere thanks to my family and friends for their encouragement, advice and support to
complete my project.

SUMMARY OF STUDY
Layered tablets have got more attraction compared to other dosage forms because of simple,
inexpensive, highest stability, most suitable nature of tablets. Layered tablets are having
greater advantages in current research and development. More number of polymers are
available for the preparation of matrix core and these are also acting as release retarding
agents. Several methods are used to alter the release rate of drugs by oral route of
administration. Layered matrix tablets are one of the methods which are used for effective
controlled drug delivery.
Bi-layer tablet is suitable for sequential release of two drugs in combination, separate two
incompatible substances and also for sustained release tablet in which one layer is immediate-
release as initial dose and second layer is maintenance dose.
Multi-layered systems which contains bi-layered, triple-layered, quadruple-layered, etc. are
becoming increasingly recognized as controlled-release drug delivery systems. Multi-layered
tablets possess various benefits, namely the ability to prevent incompatibility between drugs
and excipients. Compaction of different granules in the form of various layer in single tablets
are called as multi-layer tablets. It generally consists of parallel, clear, colored, visual distinct
layers. Usually it contains two to three or more APIs or APIs along with functional or non-
functional placebo layers, sometimes to avoid interaction between different incompatible
layers.
In this project types of layered tablets, approaches for layered tablets, challenges in bi-layer
manufacturing, preparation of bi-layer tablets, trouble shooting of processing problem in bi-
layer tablet compression, various techniques for bi-layer tablets, various tablet presses,
floating drug delivery system, polymeric bio-adhesive system, swelling system, evaluation,
characterization of bi-layer tablets, tablet surface characterization by various imaging
techniques, design of multi-layered tablets, multi-layered tablets for controlled drug delivery,
multi-layered tablet technology, factors affecting the rate of drug release from multi-layered
tablet, type of polymers influencing the behavior and release characteristics of multi-layered
tablets, recent developments in the field of bi-layer tablets, marketed products were analyzed
in detailed manner.

TABLE OF CONTENTS
SL. NO. CHAPTER 1: INTRODUCTION PAGE NO
1.1. General Introduction 1
1.2. Layer Tablets 1
1.3. Types of Layer Tablets 2
1.4. Approaches for Layered Tablets 2
SL. NO. CHAPTER 2: LAYERED TABLET TECHNOLOGY PAGE NO
2.1. Bi-Layer Tablet 4
2.2. Need of Bi-Layer Tablet 4
2.3. Advantages of Bi-Layer Tablet Dosage Form 4
2.4. Disadvantages of Bi-Layer Tablet Dosage Form 5
2.5. Major Applications 5
2.6. Ideal Characteristics of Bi-Layer Tablets 5
2.7. Challenges in Bi-Layer Manufacturing 6
2.7.1. Delamination 6
2.7.2. Cross-Contamination 6
2.7.3. Production yields 7
2.7.4. Cost 7
2.8. Preparation of Bi-Layer Tablets 7
2.8.1. Compaction 7
2.8.2. Compression 8
2.8.2.1. Bi-Layer Compression Basics 8
2.8.2.2. Compression Force for Bi-Layer Tablets 9
2.8.2.3. Compression Cycle for Bi-Layer Tablet 10
2.8.3. Consolidation 10
2.9. Quality and GMP Requirements 13
2.10. Various Techniques for Bi-Layer Tablets 13
2.10.1. OROS Push Pulls Technology 13
2.10.2. L-OROS Technology 14
2.10.3. EN SO TROL Technology 14

2.10.4. DUROS Technology 15
2.10.5. DUREDAS Technology 15
2.10.6. GEMINEX Technology 16
2.10.7. PRODAS Technology 17
2.10.8. Erodible Molded Multi-Layer Tablet 17
SL. NO. CHAPTER 3: VARIOUS TABLET PRESSES FOR LAYERED
TABLETS
PAGE NO
3.1. Types of Bi-Layer Tablet Press 18
3.1.1. Single Sides Press 18
3.1.1.1. Single Sided 16-23 Stations (JS) Standard and GMP Heavy Duty
Machine
18
3.1.1.2. Limitations of Single Sided Press 19
3.1.1.3. Dwell Time 19
3.1.1.4. Compression Force 19
3.1.2. Double Sided Tablet Press 19
3.1.2.1. ADEPT Double Sided Tablet Press 20
3.1.2.2. Advantages 21
3.1.2.3. Limitations 21
3.1.3. Bi-Layer Tablet Press with Displacement Monitoring 21
3.1.3.1. The Courtoy R292F: Bi-Layer Tablet Press with Displacement
Monitoring
22
3.1.3.2. Additional Important Features: The Courtoy R292F 23
3.1.3.3. Advantages 23
SL. NO. CHAPTER 4: FORMULATION AND EVALUATION OF BI-
LAYERED TABLETS
PAGE NO
4.1. Challenges in the Formulation of Bi-Layered Tablets 25
4.2. Various Approaches Used in the Bi-Layer Tablet 25
4.2.1. Floating Drug Delivery System 25
4.2.1.1. Approaches to Design Floating Drug Delivery 25
4.2.1.1.a. Intra Gastric Bi-Layered Floating Tablets 25

4.2.1.1.b. Multiple Unit Type Floating Pills 26
4.2.1.2. Disadvantages 26
4.2.2. Polymeric Bio Adhesive System 26
4.2.2.1. Disadvantages 26
4.2.3. Swelling System 27
4.3. Evaluation of Bi-Layer Tablets 27
4.3.1. General Appearance 27
4.3.2. Size and Shape 27
4.3.3. Tablet Thickness 27
4.3.3. Uniformity of Weight 27
4.3.4. Weight Variation 28
4.3.5. Tablet Hardness 28
4.3.6. Stability Study 29
4.3.7. Friability 29
4.3.8. Dissolution Studies 30
4.3.9. Drug Content 30
4.3.10. Buoyancy Determination 30
4.3.11. Swelling Study 30
4.3.12. In-Vitro Drug Release Study 31
4.4. Characterization of Bi-Layer Tablets 31
4.4.1. Particle Size Distribution 31
4.4.2. Photo Microscope Study 31
4.4.3. Angle of Repose 31
4.4.4. Moisture Absorption Capacity 31
4.4.5. Compressibility 32
4.4.6. Density 32
4.5. Tablet Surface Characterization by Various Imaging Techniques 32
4.5.1. Terahertz Pulsed Imaging (TPI) 33
4.5.2. SEM (Scanning Electron Microscopy) 33
4.5.3. Atomic Force Microscopy (AFM) 33
4.5.4. Laser Profilometry 34
4.6. Recent Developments in the Field of Bi-Layer Tablets 34

SL. NO. CHAPTER 5: APPROACHES FOR MULTI-LAYERED
TABLETS
PAGE NO
5.1. Multi-Layer Tablet 37
5.2. Advantages of Multi-Layer Tablet Dosage Form 38
5.3. Disadvantages of Multi-Layer Tablet Dosage Form 38
5.4. Types of Multi-Layer Tablets 39
5.5. Multi-Layer Tablet Dosage Forms are Designed for Variety of
Reasons
39
5.6. Design of Multi-Layered Tablets 39
5.6.1. Zero Order Sustained Release 39
5.6.2. Quick / Slow Delivery System 40
5.6.3. Time Programmed Delivery System 40
5.6.4. Bimodal Release Profile 40
5.7. Multi-Layered Tablets for Controlled Drug Delivery 40
5.8. Multi-Layered Tablet Technology 42
5.8.1. Sodas Multi-Layer Tablet Technology 42
5.8.2. Geomatrix Multi-Layer Tablet Technology 43
5.9. Factors Affecting the Rate of Drug Release from Multi-Layered
Tablet
44
5.9.1. Polymers Employed in Multi-Layered Tablets 44
5.9.2. Structure of the Device 45
SL. NO. CHAPTER 6: CONCLUSION PAGE NO
6.1. Conclusion 48
REFERENCES 49

LIST OF TABLES
Table 2.1 Trouble Shooting of Processing Problem in Bi-Layer Tablet
Compression
11
TABLETS
PAGE NO
Table 3.1 Bi-Layer Tablet Press Available in the Market 24
LAYERED TABLETS
PAGE NO
Table 4.1 Weight Variation Parameters 28
Table 4.2 Stability Condition as Per ICH Guideline Study 29
Table 4.3 Advantages and Limitations of Techniques for Layer Separation
Risk Assessment
34
Table 4.4 Various Advancements in the Field of Bi-layer Tablets 35
Table 4.5 Commercially Marketed Bi-layer Tablets 36
TABLETS
PAGE NO
Table 5.1 Advantages of Multi-Layered Tablets over Conventional Tablets 41
Table 5.2 Summary of the Type of Polymers Influencing the Behavior and
Release Characteristics of Multi-Layered Tablets
43
Table 5.3 Summary of Various Technologies That Utilize Geometric
Factors in Drug Delivery
47

LIST OF FIGURES
SL. NO. CHAPTER 1: INTRODUCTION PAGE NO
Figure 1.1 Single-Layer Tablet 1
Figure 1.2 Bi-Layer Tablet 1
Figure 1.3 Multi-Layer tablet 1
Figure 1.4 Bi & Tri-Layer Tablets 2
Figure 1.5 Core Coated Tablets 3
Figure 1.6 Inlay Tablets 3
Figure 2.1 Delamination 6
Figure 2.2 Cross-Contamination 6
Figure 2.3 Preparation of Bi-Layer Tablet 7
Figure 2.4 A Schematic Diagram Showing the Different Stages Occurring
During Bi-Layer Tablet Uniaxial Compaction
8
Figure 2.5 Schematic Diagram Showing the Manufacture of Single and Bi-
Layered Tablets Utilizing Uniaxial Compaction
8
Figure 2.6 Bi-Layer Compression Process 10
Figure 2.7 Compression Cycle of Bi-Layer Tablet 10
Figure 2.8 Preparation of Bi-Layer Tablet Compaction 10
Figure 2.9 Bi-Layer and Tri-Layer OROS Push Pull Technology 14
Figure 2.10 L-OROS Technology 14
Figure 2.11 EN SO TROL Technology 14
Figure 2.12 DUROS Technology 15
Figure 2.13 DUREDAS Technology Consists of Control-Release and
Immediate-Release Layer
15
Figure 2.14 DUREDAS Technology Consist of Two Control-Release Layers 15

TABLETS
PAGE NO
Figure 3.1 Single Sided Tablet Press 18
Figure 3.2 Single Sided Bi-Layer Press 19
Figure 3.3 Double Sided Tablet Press 20
Figure 3.4 ADEPT Double Sided Tablet Press 20
Figure 3.5 Bi-Layer Tablet Press with Displacement Monitoring 22
Figure 3.6 Courtoy R292F Bi-Layer Press 23
LAYERED TABLETS
PAGE NO
Figure 4.1 Multiple Units of Oral FDDS 26
TABLETS
PAGE NO
Figure 5.1 It Shows Types of Multi-Layered Systems 37
Figure 5.2 It Shows Types of Layering Patterns 38
Figure 5.3 Various Polymeric Formulations of Multi-Layered Tablets and
Possible Drug Release Behavior
42
Figure 5.4 A schematic Representation of Sodas Multi-Layer Tablet
Technology
43
Figure 5.5 A Typical Geomatrix Multi-Layered Tablet 44
Figure 5.6 Smartrix Technology 46

CHAPTER 1: INTRODUCTION
1.1. General Introduction
Pharmaceutical products that are designed for oral delivery are currently available mostly in
the immediate-release type. These are designed for immediate release of drug and rapid
absorption. For added advantages of therapy and enhanced efficacy sustained and controlled-
release formulations are being used more and more. These forms also offer the advantage of
patient compliance. Several advantages over the conventional are seen but still some
problems arises in preparation of this kind of dosage form such as physical incompatibility,
chemical incompatibility etc. Therefore the bi-layer and multi-layer tablets are known as a
novel drug delivery system. Multi-layered tablets possess various benefits, namely the ability
to prevent incompatibility between drugs and excipients and by providing multiple release
kinetics profiles in single delivery system of either the same or different drugs, by means of
different release control mechanisms (Nikhil et al., 2013).
1.2. Layer Tablets
Layer tablets are composed of two or three layers of granulation compressed together. As the
edges of each layer are exposed, they have the appearance of a sandwich. This dosage form
has the advantage of separating two incompatible substances with an inert barrier between
them. It makes possible sustained-release preparations with the immediate-release quantity in
one layer and the slow release portion in the second. A third layer with an intermediate
release might be added (Pramodaganta et al., 2013).
Figure 1.1: Single- Figure 1.2: Bi-Layer Figure 1.3: Multi-
Layer Tablet Tablet Layer Tablet

1.3. Types of Layer Tablets
1. Single-layer tablet.
2. Bi-layer tablet.
3. Multi-layer tablet.
1.4. Approaches for Layered Tablets
1. Multi-layered tablets: two to three component systems.
When two or more active pharmaceutical ingredients are needed to be administered
simultaneously and they are incompatible, the best option for the formulation pharmacist
would be to formulate multi-layered tablet. It consists of several different granulations that
are compressed to form a single tablet composed of two or more layers and usually each layer
is of different color to produce a distinctive looking tablet. Dust extraction is essential during
compression to avoid contamination. Therefore, each layer under goes light compression as
each component is laid down. This avoids granules intermixing if the machine vibrates.
Figure 1.4: Bi & Tri-Layer Tablets
2. Compression coated tablets: tablet within a tablet.
This type of tablet has two parts, internal core and surrounding coat.The core is small porous
tablet and prepared on one turret. For preparing final tablet, a bigger die cavity in another
turret is used in which first the coat material is filled to half and then core tablet is
mechanically transferred, again the remaining space is filled with coat material and finally
compression force is applied. This tablet readily lend itself into a repeat action tablet as the
outer layer provides the initial dose while the inner core release the drug later on. But, when
the core quickly releases the drug, entirely different blood level is achieved with the risk of
over dose toxicity. To avoid immediate-release of both the layers, the core tablet is coated

with enteric polymer so that it will not release the drug in stomach while, the first dose is
added in outer sugar coating. Even so, coating operation requires interpretation while
manufacturing and dawdling the manufacturing process. Sometimes, inner core may be of
liquid formulation to provide immediate-releaseof core after the coat gets dissolved.
Figure 1.5: Core Coated Tablets
3. Inlay tablet: coat partially surrounding the core.
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.
To reduce capital investment quite often existing but modified tablet presses are used to
develop and produce such tablets. The development and production of quality bi-layer tablets
needs to be carried out on purpose built tablet presses to overcome common bi-layer
problems. Using a modified tablet press may therefore not be your best approach to
producing a quality bi-layer tablet under GMP conditions. Especially when in addition high
production output is required (Pradeep et al., 2013).
Figure 1.6: Inlay Tablets

CHAPTER 2: LAYERED TABLET TECHNOLOGY
2.1. Bi-Layer Tablet
Bi-layer tablet is a new era for successful development of controlled-release formulation
along with various features to provide successful drug delivery. It is suitable for sequential
release of two drugs in combination and also for sustained-release of tablet in which one
layer is for immediate-release as loading dose and second layer is maintenance dose. So use
of bi-layer tablets is a very different aspect for anti-hypertensive, diabetic, anti-inflammatory
and analgesic drugs where combination therapy is often used (Gopinath et al., 2013).
2.2. Need of Bi-Layer Tablet
1. For the administration of fixed dose combinations of different APIs, prolong the drug
product life cycle, buccal / mucoadhesive delivery systems; fabricate novel drug delivery
systems such as chewing device and floating tablets for gastro-retentive drug delivery.
2. Controlling the delivery rate of either single or two different active pharmaceutical
ingredients.
3. To modify the total surface area available for API layer either by sandwiching with one or
two in active layers in order to achieve swell-able / erodible barriers for modified release.
4. To separate incompatible Active pharmaceutical ingredient (APIs) from each other, to
control the release of API from one layer by utilizing the functional property of the other
layer such as, osmotic property (Ashok and Kumar, 2012).
2.3. Advantages of Bi-Layer Tablet Dosage Form
1. Bi-layer execution with optional single layer conversion kit.
2. Low cost compared to all other oral dosage form.
3. Greatest chemical and microbial stability over all oral dosage form.
4. Objectionable odour and bitter taste can be masked by coating technique.
5. Flexible concept.
6. Offer greatest precision and the least content uniformity.
7. Easy to swallow with least hang up problems.
8. Fit for large scale production.
9. Bi-layer tablet is suitable for preventing direct contact of two drugs and thus to maximize
the efficacy of combination of two drugs.

10. Bi-layer tablets can be designed in such a manner as to modify release as either of the
layers can be kept as extended and the other as immediate-release.
11. Expansion of a conventional technology.
12. They are unit dosage form.
13. Easiest and cheapest to package and strip.
14. Prospective use of single entity feed granules.
15. Separation of incompatible components.
16. Patient compliance is improved leading to improve drug regimen efficiency.
2.4. Disadvantages of Bi-Layer Tablet Dosage Form
1. Bi-layer rotary presses are expensive.
2. Insufficient hardness, layer separation, reduced yield.
3. Imprecise individual layer weight control.
4. Cross-contamination between the layers.
5. Difficult to swallow in case of children and unconscious patients.
6. Some drugs resist compression into dense compacts, due to amorphous nature, low density
nature.
7. Drugs with poor wetting, slow dissolution properties, optimal absorption high in GIT may
difficult to manufacture as a tablet that will still provide ample drug bio availability
(Gundaraniya et al., 2013).
2.5. Major Applications
1. Bi-layer tablets are mainly used in the combination therapy.
2. Bi-layered tablets are used to deliver the loading dose and sustained dose of the same or
different drugs.
3. Bi-layered tablets are used for floating tablets in which one layer is floating layer another
one is immediate-release layer of the drugs.
4. Bi-layered tablets are used to deliver the two different drugs having different release
profile (Patel and Shah, 2013).
2.6. Ideal Characteristics of Bi-Layer Tablets
1. A bi-layer tablet should have elegant product identity while free of defects like chips,
cracks, discoloration and contamination.

2. It should have sufficient strength to withstand mechanical shock during its production,
packaging, shipping and dispensing.
3. It should have the chemical and physical stability to maintain its physical attributes over
time. The bi-layer tablet must be able to release the medicinal agents in a predictable and
reproducible manner.
4. It must have a chemical stability shelf-life, so as not to follow alteration of the medicinal
agents (Gopinath et al., 2013).
2.7. Challenges in Bi-Layer Manufacturing
Conceptually, bi-layer tablets can be seen as two single-layer tablets compressed into one. In
practice, there are some manufacturing challenges.
2.7.1. Delamination
Tablet falls apart when the two halves of the tablet do not bond completely. The two
granulations should adhere when compressed.
Figure 2.1: Delamination
2.7.2. Cross-Contamination
When the granulation of the first layer intermingles with the granulation of the second layer
or vice versa, cross-contamination occurs. It may conquer the very purpose of the bi-layer
tablet. Proper dust collection goes a long way toward preventing cross-contamination.
Figure 2.2: Cross-Contamination

2.7.3. Production yields
To prevent cross-contamination, dust collection is required which leads to losses. Thus, bi-
layer tablets have lower yields than single-layer tablets (Aggarwal et al., 2013).
2.7.4. Cost
Bi-layer tableting is more expensive than single-layer tableting for several reasons. First, the
tablet press costs more. Second, the press generally runs more slowly in bi-layer mode. Third,
development of two compatible granulations is must, which means more time spent on
formulation development, analysis and validation. These factors, if not well controlled /
optimized, in one way or another will impact the bi-layer compression and the quality
attributes of the bi-layer tablets (sufficient mechanical strength to maintain its integrity and
individual layer weight control). Therefore, it is critical to obtain an insight into the root
causes to enable design of a robust product and process (Verma et al., 2014).
2.8. Preparation of Bi-Layer Tablets
Bi-layer tablets are prepared with one layer of drug for immediate-release with the second
layer designed to release drug later, either as a second dose or in an extended-release form.
The bi-layer tablets with two incompatible drugs can also be prepared by compressing
separate layers of each drug so as to minimize area of contact between two layers. An
additional intermediate layer of inert material may also be included.
Figure 2.3: Preparation of Bi-Layer Tablet
2.8.1. Compaction
To produce adequate tablet formulation, certain requirements such as sufficient mechanical
strength and desired drug release profile must be met. At times, this may be difficult task for
formulator to achieve these conditions especially in bi-layer tablet formulation where double
compression technique is involved, because of poor flow and compatibility characteristic of

the drug which will result in capping and / or lamination. The compaction of a material
involves both the compressibility and consolidation.
2.8.2. Compression
It is defined as reduction in bulk volume by eliminating voids and bringing particles into
closer contacts.
2.8.2.1. Bi-Layer Compression Basics
A) Initial layer die filling and compaction.
B) Initial layer compaction showing the predominant stress transmission profile.
Figure 2.4: A Schematic Diagram Showing the Different Stages Occurring During Bi-Layer
Tablet Uniaxial Compaction
C) Density profile of initial layer before die filling of the final layer.
D) Final layer die filling and compaction.
E) Final layer compaction showing the predominant stress transmission profile.
F) Density profile of bi-layer tablet before ejection.
G) Ejection of a bi-layer tablet.
Figure 2.5: Schematic Diagram Showing the Manufacture of Single and Bi-Layered Tablets
Utilizing Uniaxial Compaction

Dashed arrows show the postulated radial expansion due to energy dissipation. Black areas
correspond to regions of localized high density. Arrows show the direction of the applied
stress.
A. Die filling.
B. Compression.
C. Decompression.
D. Lower punch removal and re-application of load to the upper punch.
E. Tablet fully ejected.
2.8.2.2. Compression Force for Bi-Layer Tablets
Since the material in the die cavity is compressed twice to produce a bi-layer tablet,
compressed first with layer one followed by both the layers, the compression force affects the
interfacial interaction and adhesion between the two layers. A certain amount of surface
roughness of the initial layer is required for particle inter-locking and adhesion with the
second layer. As the surface roughness of the first layer is reduced, the contact area for the
second layer is significantly reduced at the interface and makes the adhesion weaker.
Immediately after final compaction, the compressed second layer may release the stored
elastic energy unevenly and may produce crack on the first layer which could act as a stress
concentrator and eventually making the tablet interface weaker. This may result in capping or
delamination of the tablet along the interface either during manufacturing or immediately
after the level of compression force used in the first layer compaction determines the degree
of surface roughness of the first layer. The higher the first layer compression force, the lesser
the surface roughness resulting in reduced adhesion with the second layer. Therefore, for a
given final compression force the strength of interfacial adhesion decreases with the
increasing first layer compression force. It implies that the extent of plastic / elastic
deformation of the first layer has profound effect on the strength of the interface. Thus,
understanding the interaction and adhesion behavior between different layers composed of
various ingredients with differing physico-chemical properties during compaction is critical
to understand the failure mechanisms of bi-layer tablets. Understanding of material attributes
of the excipients and API that under goes compression and compaction is decisive in
predicting the interaction (Pradeep et al., 2013).

Figure 2.6: Bi-Layer Compression Process
2.8.2.3. Compression Cycle for Bi-Layer Tablet
Bi-layer tablets are made by compressing two different granulations feed into a die
succession, one on top of another, in layers. Each layer comes from a separate feed frame
with individual weight control. Rotary tablet press can be set up for two or three layers. More
are possible but the design becomes very special. Mechanism of compression of bi-layer
tablet is shown in figure 2.7 (Devtalu et al., 2013).
Figure 2.7: Compression Cycle of Bi-Layer Tablet
2.8.3. Consolidation
It is the property of the material in which there is increased mechanical strength due to inter-
particulate interaction (bonding). The compression force on layer one was found to be major
factor influencing tablet delamination (Verma et al., 2014).
Figure 2.8: Preparation of Bi-Layer Tablet Compaction

Table 2.1: Trouble Shooting of Processing Problem in Bi-Layer Tablet Compression (Patel
and Shah, 2013).
Trouble Possible Cause Remedies
Tablet weight
variation
Poor flow characteristics of
material
a. Wrong setting of hopper
b. Material bridging in
hopper
c. Too much recirculation
Dies not filling a. Press running too fast
b. Wrong feeder paddle
speed or shape
Material loss or gains after
proper die fill
a. Recirculation band leaking
b. Excessive vacuum or
nozzle improperly located
Product yield Die table scraper action
insufficient
a. Scraper blade worn or
binding
b. Outboard edge permitting
material to escape
Incorrect action onrecirculation
band
a. Gap between bottom edge
and die table
b. Binding in mounting
screw
c. Too little hold down
spring pressure
Incorrect feeder fit to die table a. Feeder bases incorrectly
set (too high or not level)
Loss at compression point a. Compressing too high in
the die
b. Excessive or misdirected
suction on exhaust nozzle

Low hardness Factors related to machine a. Tablet press having pre-
compression and main
compression facilities
b. Press speed is reduced to
increase total compression
time
Lubricant level a. Over mixing can reduce
tablet hardness
Capping and
lamination
Non-optimized formulation a. Incorporate plastically
deforming matrix
High compression force a. Reduced compression
force
b. Reduced press speed
Ratio of pre-compression to
main compression is insufficient
a. Pre-compression force
high can be harmful
b. Use large compression
roller diameter
Curled or damaged punches a. Tools should be rewashed
or replaced
Picking and sticking Excessive heat generation during
compression
a. Use of cooling system for
the compression section
b. Lower mechanism section
may be helpful
Fouling the punch faces a. Startup should always be
close to optimum conditions
Separation of two
individual layers
Insufficient bonding between the
two layers during the final
compression of bi-layer tablet
a. First layer should be
compressed at a low
compression force so that
this layer can still interact
with second layer during
final compression of the
tablet

Mottling Improper setting of both feed
frame
a. Both feed frame should set
properly
Due to weak suction a. Suction capacity should be
such that, all waste material
is sucked
2.9. Quality and GMP Requirements
To produce a quality bi-layer tablet, in a validated and GMP way, it is important that the
selected press is capable of:
1. Preventing capping and separation of the two individual layers that constitute the bi-layer
tablet.
2. Preventing cross-contamination between the two layers.
3. Producing a clear visual separation between the two layers.
4. Providing sufficient tablet hardness and high yield (Kumar et al., 2013).
5. Accurate and individual weight control of the two layers these requirements seem obvious
but are not as easily accomplished as this article aims to demonstrate.
6. Very short first layer dwell time due to the small compression roller, possibly resulting in
poor de-aeration, capping and hardness problems. This may be corrected by reducing the
turret rotation speed (to extend the dwell time) but with the consequence of lower tablet
output.
7. Very difficult first layer tablet sampling and sample transport to a test unit for inline
quality control and weight re-calibration to eliminate these limitations, a double-sided tablet
press is preferred over a single sided press. A double-sided press offers an individual fill
station, pre-compression and main compression for each layer. In fact, the bi-layer tablet will
go through for compression stages before being ejected from the press.
These requirements seem obvious but are not so easily accomplished (Namrata et al., 2013).
2.10. Various Techniques for Bi-Layer Tablets
2.10.1. OROS Push Pulls Technology
This system consist of mainly two or three layer among which the one or more layer are
essential of the drug and other layer are consist of push layer. The drug layer mainly consists
of drug along with two or more different agents. So this drug layer comprises of drug which

is in poorly soluble form. There is further addition of suspending agent and osmotic agent. A
semi-permeable membrane surrounds the tablet core.
Figure 2.9: Bi-Layer and Tri-Layer OROS Push Pull Technology
2.10.2. L-OROS Technology
This system used for the solubility issue Alza developed the L-OROS system where a lipid
soft gel product containing drug in a dissolved state is initially manufactured and then coated
with a barrier membrane, than osmotic push layer and then a semi-permeable membrane,
drilled with an exit orifice.
Figure 2.10: L-OROS Technology
2.10.3. EN SO TROL Technology
Solubility enhancement of an order of magnitude or to create optimized dosage form Shire
laboratory use an integrated approach to drug delivery focusing on identification and
incorporation of the identified enhancer into controlled-release technologies.
Figure 2.11: EN SO TROL Technology

2.10.4. DUROS Technology
The system consists from an outer cylindrical titanium alloy reservoir. This reservoir has high
impact strength and protects the drug molecules from enzymes. The DUROS technology is
the miniature drug dispensing system that opposes like a miniature syringe and release
minute quantity of concentrated form in continues and consistent from over months or year
(Patel and Shah, 2013).
Figure 2.12: DUROS Technology
2.10.5. DUREDAS Technology
DUREDAS technology is a bi-layer tablet which can provide immediate or sustained-release
of two drugs or different release rates of the same drug in one dosage form. The tableting
process can provide an immediate-release granulate and a modified-release hydrophilic
matrix complex as separate layers within the one tablet. The modified-release properties of
the dosage form are provided by a combination of hydrophilic polymers.
Figure 2.13: DUREDAS Technology Consists of Control-Release and
Immediate-Release Layer
Figure 2.14: DUREDAS Technology Consist of Two Control-Release Layers

Benefits offered by DUREDAS Technology
1) Bi-layer tableting technology.
2) Tailored release rate of two drug components.
3) Capability of two different CR formulations combined.
4) Capability for immediate-release and modified-release components in one tablet.
5) Unit dose tablet presentation.
The DUREDAS system can easily be manipulated to allow incorporation of two controlled-
release formulations in the bi-layer. Two different release rates can be achieved from each
side. In this way greater prolongation of sustained-release can be achieved. Typically an
immediate-release granulate is first compressed followed by the addition of a controlled-
release element which is compressed onto the initial tablet. This gives the characteristic bi-
layer effect to the final dosage form. A further extension of the DUREDAS technology is the
production of controlled-release combination dosage forms where by two different drugs are
incorporated into the different layers and drug release of each is controlled to maximize the
therapeutic effect of the combination. Again both immediate-release and controlled-release
combinations of the two drugs are possible. A number of combination products utilizing this
technology approach have been evaluated. The DUREDAS technology was initially
employed in the development of a number of OTC controlled-release analgesics. In this case
a rapid release of analgesic is necessary for a fast onset of therapeutic effect. Hence one layer
of the tablets is formulated as immediate-releases granulate. By contrast, the second layer of
the tablet, through use of hydrophilic polymers, releases drug in a controlled manner. The
controlled-release is due to a combination of diffusion and erosion through the hydrophilic
polymer matrix (Namrata et al., 2013).
2.10.6. GEMINEX Technology
GEMINEX is a dual drug delivery technology that can deliver one or more drugs at different
times. The GEMINEX technology controls the release rate of the two drugs to maximize their
individual therapeutic effect and minimize side effects. The benefit of GEMINEX to the
pharmaceutical industry, and ultimately to patients, is that two different actives or the same
active can be delivered at differing rates in a single tablet. Pen west is actively applying its
GEMINEX technology to the following therapeutic areas: cardiovascular disorders, diabetes,
cancer and disorders of the central nervous system.

2.10.7. PRODAS Technology
PRODAS or Programmable Oral Drug Absorption System (Elan Corporation) is a multi-
particulate drug delivery technology that is based on the encapsulation of controlled-release
mini-tablets in the size range of 1.5 to 4 mm in diameter. This technology represents a
combination of multi-particulate and hydrophilic matrix tablet technologies and thus provides
the benefit of both these drug delivery systems in one dosage forms. Mini-tablets with
different release rates can be combined and incorporated into a single dosage form to provide
the desired release rates. These combinations may include immediate-release, delayed-
release, and / or controlled-release mini-tablets. In addition to controlled absorption over a
specified period, PRODAS technology also enables targeted delivery of drug to specified
sites of absorption throughout the GI tract, combination products also are possible by using
mini-tablets formulated with different active ingredients.
2.10.8. Erodible Molded Multi-Layer Tablet
Egalet erodible molded tablets are erosion based platforms. It has the advantages of
delivering zero-order or delayed-release with minimal impact from the gastro-intestinal
conditions. Egalet erodible molded multi-layered tablets are prepared by injection molding.
Egalet technology contains a coat and a matrix. Drug release is controlled through the gradual
erosion of the matrix part. The mode and rate of release are designed and engineered by
altering the matrix, the coat, and the geometry to achieve either a zero-order release or a
delayed-release. For a zero-order release, a drug is dispersed through the matrix. The coat is
bio-degradable but has poor water permeability to prevent its penetration. The matrix tends to
erode when in contact with available water. The erosion of the matrix is caused by GI fluids
and promoted by gut movements in the GI tract. The drug release is mediated almost wholly
by erosion because the dosage form is designed to slow down the water diffusion into the
matrix. It is definitely more desirable for drugs with chemical and physical stability issues
after contacting with water. Egalet delivery technology is developed based on standard plastic
injection molding to ensure accuracy, reproducibility, and low production cost (Ashok and
Kumar, 2012).

CHAPTER 3:VARIOUS TABLET PRESSES FOR LAYERED TABLETS
3.1. Types of Bi-Layer Tablet Press
1. Single sided tablet press.
2. Double sided tablet press.
3. Bi-layer tablet press with displacement monitoring.
3.1.1. Single Sides Press
The simplest design is a single sided press with both chambers of the double feeder separated
from each other. Each chamber is gravity or forced feed with different powers, thus
producing the two individual layers of the tablets. When the die passes under the feeder, it is
at first loaded with the first layer powder followed by the second layer powder. Then the
entire tablet is compressed in one or two steps (Verma et al., 2014).
Figure 3.1: Single Sided Tablet Press
3.1.1.1. Single Sided 16-23 Stations (JS) Standard and GMP Heavy Duty Machine
1. Suitable for veternity, herbal, chemicals, minerals, confectionary, metal.
2. Pharmaceuticals and neutraceuticals.
3. R & D / Pilot scale model.
4. Machines with pre-compression.
5. PLC & computer interfaced controls.
6. 23- station machine is with B-tooling (Devtalu et al., 2013).

Figure 3.2: Single Sided Bi-Layer Press
3.1.1.2. Limitations of Single Sided Press
1. No weight monitoring / control of the individual layers.
2. No distinct visual separation between the two layers.
3. Very short first layer dwell time due to the small compression roller, possibly resulting in
poor de-aeration, capping, and hardness problems.
3.1.1.3. Dwell Time
Dwell time is defined as the time during which compression force is above 90% of its peak
value. Longer dwell times are a major factor in producing a quality tablet, especially when
compressing a difficult formulation.
3.1.1.4. Compression Force
Many bi-layer formulations requires a first layer compression force of less than 100 daN in
order toretain the ability to bond with the second layer. Above 100daN, this ability may be
lost and bonding between both layers may not be sufficient, resulting in low hardness of the
bi-layer tablet and separation of the two layers.
3.1.2. Double Sided Tablet Press
Most double sided tablet presses with automated production control use compression force to
monitor and control tablet weight. The effective peak compression force exerted on each
individual tablet or layer is measured by the control system at the main compression of the

layer. This measured peak compression force is the signal used by the control system to reject
out of tolerance tablets and correct the die fill depth when required (Verma et al., 2014).
Figure 3.3: Double Sided Tablet Press
3.1.2.1. ADEPT Double Sided Tablet Press
Offers significant technical advantages that permit higher output and increased efficiency in
production. Special emphasis has been given on durability while designing so that the
machine can be used in a 24 / 7 production environment. The higher load bearing capacity of
ADEPT tablet press makes it suitable for bigger tablets. The machine also offers flexibility to
produce both single-layer and bi-layer tablets on the same platform (Devtalu et al., 2013).
Figure 3.4: ADEPT Double Sided Tablet Press

3.1.2.2. Advantages
1. Displacement weight monitoring for accurate and independent weight control of the
individual layer.
2. Low compression force exerted on the first layer to avoid capping and separation of the
individual layer.
3. Increased dwell time at pre-compression of both first and second layer to provide sufficient
hardness at maximum turret speed.
4. Maximum prevention of cross-contamination between two layers.
5. A clear visual separation between the two layers.
6. Maximized yield.
3.1.2.3. Limitations
Separation of the two individual layers is due to insufficient bonding between the two layers
during final compression of bi-layer tablet. Correct bonding is only obtained when the first
layer is compressed at a low compression force so that this layer can still interact with the
second layer during final compression. Bonding is too restricted if first layer is compressed at
a high compression force. The low compression force required when compressing the first
layer unfortunately reduces the accuracy of the weight monitoring / control of the first layer
in the case of tablet presses with “compression force measurement”. Most of the double sided
tablet presses with automated production control use compression force to monitor and
control tablet weight. Compression force control system is always based on measurement of
compression force at main compression but not at pre-compression.
3.1.3. Bi-Layer Tablet Press with Displacement Monitoring
The displacement tablet weight control principle is fundamentally different from the principle
based upon compression force. When measuring displacement the control system sensitivity
does not depend on the operation point, but depends on the applied pre-compression force. In
fact the lower the pre-compression force, the more the monitoring control system and this
ideal for good inter-layer bonding of the bi-layer tablet. The upper pre-compression roller is
attached to an air-piston which can move up and down in air cylinder. The air pressure in the
cylinder is set as a product parameter at initial product setup and is kept at a constant value by
the machine‟s control system. This pressure multiplied by the piston surface is the constant
force at which the piston and consequently the roller are pushed downwards against affixed
stop. The lower pre-compression roller is mounted on a yoke and its vertical position can be

adjusted through the control system by means of a servo-motor. The position of the lower
pre-compression determines the pre-compression height. At every pre-compression the upper
punch hits the upper roller and is initially pushed downwards into the die. As the lower punch
is pushed upwards by the lower roller the power is being compressed, while the exerted
compression force increases. At a certain point the reaction force exerted by the power on the
upper punch equals the force exerted by the air pressure on the piston. The punch has to
continue its way under the roller because the turret is spinning (Gundaraniya et al., 2013).
Figure 3.5: Bi-Layer Tablet Press with Displacement Monitoring
3.1.3.1. The Courtoy R292F: Bi-Layer Tablet Press with Displacement Monitoring
This double sided tablet press has been specifically designed and developed for the
production of quality bi-layer tablets and provides:
1. Displacement weight monitoring / control for accurate and independent weight control of
the individual layers.
2. Low compression force exerted on the first layer to avoid capping and separation of the
two individual layers.
3. Increased dwell time at pre-compression of both first and second layer to provide sufficient
hardness at maximum turret speed.
4. Maximum prevention of cross-contamination between the two layers.
5. A clear visual separation between the two layers.
6. Maximized yield is measured by the control system at main compression of that layer
(Devtalu et al., 2013).

Figure 3.6: Courtoy R292F Bi-Layer Press
3.1.3.2. Additional Important Features: The Courtoy R292F
The R292F can be used for both single-layer double output production and bi-layer single
output tableting. The press is equipped with „air compensation‟ on both pre-compression
stations for „displacement‟ based tablet weight control as described above. However, the
R292F has several extra features specifically designed for the production of bi-layer tablets:
1. The R292F has a pneumatically driven ejection cam, allowing the sampling of first layer
tablets for inline process control and automatic weight re-calibration. The required time to
sample is extremely short to minimize powder loss. The time delay between sampling and re-
calibration is also very shortto minimize the length of the control loop.
2. Powder is always re-circulated around the die table using a standard feeder with
recuperation of re-circulated powder, while the other feeder is a closed type feeder. This
closed type feeder is provided with a suitable wear plate to maximize its life expectancy.
3. The R292F is equipped with several blow and suction nozzles, located at carefully
determined points around the die table. The combined action of blowing and extracting air
allows for very specific powder removal, which is vital to the elimination of cross-
contamination. At the same time, powder loss is reduced to a minimum (Shinde, 2014).
3.1.3.3. Advantages
Weight monitoring / control for accurate an independent weight control of the individual
layers. Low compression force exerted on the first layer to avoid capping and separation of

the two individual layers. Independence from the machine stiffness increased dwell time at
pre-compression of both first and second layer to provide sufficient hardness at maximum
turret speed. Maximum prevention of cross-contamination between the two layers clears
visual separation between the two layers and maximized yield (Devtalu et al., 2013).
Table 3.1: Bi-Layer Tablet Press Available in the Market (Devtalu et al., 2013).
Bi-Layer Tablet Press Make
Expert 1 bi-layer tablet press for R & D Kambert
ModulTM
P with bi-layer ECM GEA Courtesy
XM 12 small scale bi-layer tablet press Korsch
OYSTAR Manesty Xpress® 700 Tablet
Press
Thomasnet
ADEPT double sided tablet press Adept
Piccola bi-layer tablet press Smtmc
Double sided bi-layer tablet press Jaguar
Bi-layer tablet press Aayush TechnoPvt. Ltd.
Double tablet press Kambert Engineering Ltd.
Double rotary double layer tablet press Karnavati Engineering Ltd.

CHAPTER 4: FORMULATION AND EVALUATION OF BI-LAYERED
TABLETS
4.1. Challenges in the Formulation of Bi-Layered Tablets
1. One of the major challenges is lack of sufficient bonding and adhesion at the interface
between the adjacent compacted layers which often results in interfacial crack driven by
residual stresses.
2. The compacted layers should not be too soft or too hard, they will not bond securely with
each other which can lead to compromised mechanical integrity.
3. The other challenges include establishing the order of layer sequence, layer weight ratio,
and elastic mismatch of the adjacent layers, first layer tamping force and cross-contamination
(Bhavani et al., 2012).
4.2. Various Approaches Used in the Bi-Layer Tablet
4.2.1. Floating Drug Delivery System
These are designed to have a low density and thus float on gastric contents
afteradministration until the system either disintegrates or the device absorbs fluid to the
point where its density is such that it loses buoyancy and can pass more easily from the
stomach with a wave of motility responsible for gastric emptying. The bi-layer tablet is
designed in such a way gives the immediate dosing of the drug which gives faster onset of
action while other layer is designed as a floating layer which floats in the stomach (Shah et
al., 2013).
4.2.1.1. Approaches to Design Floating Drug Delivery
The following approaches have been used for the design of floating dosage forms of single
and multiple unit systems.
4.2.1.1.a. Intra Gastric Bi-Layered Floating Tablets
These are also compressed tablet and contain two layers.
1. Immediate-release.
2. Sustained-release.

4.2.1.1.b. Multiple Unit Type Floating Pills
These systems consist of sustained-release pills as „seeds‟ surrounded by double layers. The
inner layer consists of effervescent agents while the outer layer is of swell-able membrane
layer. When the system is immersed in dissolution medium at body temperature, it sinks at
once and then forms swollen pills like balloons, which float as they have lower density
(Gopinath et al., 2013).
Figure 4.1: Multiple Units of Oral FDDS
4.2.1.2. Disadvantages
1. It may not have the controlled loss of density alternatively required for it to eventually exit
from the stomach.
2. These are not applicable to higher dose levels of highly water soluble drugs where large
amounts of polymer is needed to retard the drug release.
3.The performance of floating formulation may be posture dependent (Shah et al., 2013).
4.2.2. Polymeric Bio Adhesive System
These are designed to imbibe fluid following administration such that the outer layer
becomes a viscous, tacky material that adheres to the gastric mucosa / mucus layer. This
should encourage gastric retention until the adhesive forces are weakened. These are prepared
as one layer with immediate dosing and other layer with bio adhesive property.
4.2.2.1. Disadvantages
The success is seen in animal models with such system has not been translated to human
subjects due to differences in mucous amounts, consistency between animals and humans.
The system adheres to mucous not mucosa. The mucous layer in humans would appear to
slough off readily, carrying any dosage form with it. Therefore, bio adhesive dosage form
would not appear to offer a solution for extended delivery of drug over a period of more than
a few hours (Gopinath et al., 2013).

4.2.3. Swelling System
These are designed to be sufficiently small on administration so as not to make ingestion of
the dosage form difficult. On ingestion they rapidly swell or disintegrate or unfold to a size
that precludes passage through the pylorus until after drug release has progressed to a
required degree. Gradual erosion of the system or its breakdown into smaller particles enables
it to leave stomach (Barthwal et al., 2013).
4.3. Evaluation of Bi-Layer Tablets
4.3.1. General Appearance
The general appearance of a tablet, its visual identity and overall “elegance” is essential for
consumer acceptance. Includes in are tablet‟s size, shape, color, presence or absence of an
odour, taste, surface texture, physical flaws and consistency and legibility of any identifying
marking.
4.3.2. Size and Shape
The size and shape of the tablet can be dimensionally described, monitored and controlled.
4.3.3. Tablet Thickness
Tablet thickness is an important characteristic in reproducing appearance and also in counting
by using filling equipment. Some filling equipment utilizes the uniform thickness of the
tablets as a counting mechanism. The thickness of individual tablets is measured with a
micrometer, which gives us information about the variation between tablets. Tablet thickness
should be within a ±5% variation of a standard value. Any variation in thickness within
aparticular lot of tablets or between manufacturer‟s lots should not be clear to the unaided eye
for consumer acceptance of the product. In addition, thickness should be controlled to smooth
the progress of packaging.
4.3.3. Uniformity of Weight
Uniformity of weight is an essential parameter of tablets. Here, randomly select 30 tablets. 10
of these assayed individually. The tablet pass the test if 9 of the 10 tablets must contain not
less than 85% and not more than 115% of the labeled drug content and the 10th
tablet may not
contain less than 75% and more than 125% of the labeled content. If these conditions are not
met, remaining 20 tablets assayed individually and none may fall outside of the 85% to 115%
range (Shinde et al., 2014).

4.3.4. Weight Variation
Weight variation test would be a satisfactory method for determining drug content uniformity
of drug distribution. In practice this test is performed by following process:
 Weigh 20 tablet selected at random, each one individually X1, X2, X3 …..X20.
 Determine the average weight, X=(X1+X2+X3+…..+X20) / 20
 Not more than two of the individual weights deviate from the average weight by more
than the percentage given in the pharmacopeia and none deviates by more than twice
that percentage.
 IP/BP & USP limits for tablet weight variation are given below (Devtalu et al., 2013).
Table 4.1: Weight Variation Parameters (Devtalu et al., 2013).
Average weight of tablet
(IP / BP)
Limit Average weight of tablet
(USP)
80 mg or less ±10% 130mg or less
>80 mg and <250 mg ±7.5% >130 mg and <324 mg
250 mg or more ±5% 324 mg or more
4.3.5. Tablet Hardness
The resistance of tablets to capping, abrasion or breakage under conditions of storage,
transportation and handling before usage depends on its hardness. Hardness is nothing but
crushing strength. If the tablet is too hard, it may not disintegrate in the required period of
time to meet the dissolution specifications. If it is too soft, it may not be able to withstand the
handling during subsequent processing such as coating or packaging and shipping operations.
The force required to break the tablet is measured in kilograms and a crushing strength of 4
kg is usually considered to be the minimum for satisfactory tablets. Oral tablets normally
have a hardness of 4 to 10 kg; however, hypodermic and chewable tablets are usually much
softer (3 kg) and some sustained-release tablets are much harder (10 -20 kg). Tablet hardness
has been associated with other tablet properties such as density and porosity. Hardness
generally increases with normal storage of tablets and depends on the shape, chemical
properties, binding agent and pressure applied during compression. Hardness is expressed in
Newton or Kpa. Hardness could be determined by following process:
From each batch 3 tablets would be taken at random and subjected to test. The mean of these
3 tablets would be calculated (Deshpande et al., 2011).

4.3.6. Stability Study
The bi-layer tablets would be packed in suitable packaging and stored under the following
conditions for a period as prescribed by ICH guidelines for accelerated studies. The tablets
would be withdrawn after a period of 15 days and analyzed for physical characterization
(visual defects, hardness, friability and dissolution etc.) and drug content. The data obtained
is fitted into first order equations to determine the kinetics of degradation. Accelerated
stability data are plotting according Arrhenius equation to determine the shelf life at 25°C
(Shinde et al., 2014).
Table 4.2: Stability Condition as Per ICH Guideline Study (Shinde et al., 2014).
Study Storage Condition Minimum Time Period Covered
by Data at Submission
Long term 25°C ± 2°C/60% RH ± 5%
RH or 30°C ± 2°C/65% RH
± 5% RH
12 months
Intermediate 30°C ± 2°C/65% RH ± 5%
RH
6 months
Accelerated 40°C ± 2°C/75% RH ± 5%
RH
6 months
4.3.7. Friability
Friction and shock are the forces that most often cause tablets to chip, cap or break. The
friability test is closely related to tablet hardness and is designed to evaluate the ability of the
tablet to withstand abrasion in packaging, handlingand shipping. It is usually measured by the
use of the Roche friabilator. Friability could be determined by following process:
A number of tablets would be weighed and placed in the apparatus where they are exposed to
rolling and repeated shocks as they fall 6 inches in each turn within the apparatus. After 4
minutes of this treatment or 100 revolutions, the tablets would be weighed and the weight
compared with the initial weight. The loss due to abrasion is a measure of the tablet friability.
The value is expressed as a percentage. A maximum weight loss of not more than 1% of the
weight of the tablets being tested during the friability test is considered generally acceptable
and any broken or smashed tablets are not picked up. Normally, when capping occurs,
friability values are not calculated. A thick tablet may have fewer tendencies to cap where as

thin tablets of large diameter often show extensive capping, thus indicating that tablets with
greater thickness have reduced internal stress the loss in the weight of tablet is the measure of
friability and is expressed in percentage as:
% Friability = 1 - (Loss in weight / Initial weight) x 100 (Kumar et al., 2013).
4.3.8. Dissolution Studies
The release of drug from the tablet into solution per unit time under standardize condition is
called dissolution test. Bi-layer tablets would be subjected to in-vitro drug release studies in
simulated gastric and intestinal fluids to assess their ability in providing the desired
controlled drug delivery. Dissolution medium can be chosen according to site of dissolution.
At different time intervals, 5ml of the samples would be withdrawn and replaced with 5ml of
drug-free dissolution medium. The samples withdrawn would be analyzed by UV
spectrophotometer using multi component mode of analysis (Divya et al., 2011).
4.3.9. Drug Content
The assay of the drug content would be carried by weighing 10 tablets and calculated the
average weight. Then the tablets would be triturated to get a fine powder.
4.3.10. Buoyancy Determination
The time taken for dosage form to emerge on surface of medium is called floating lag time,
duration of time by which the dosage form constantly emerges on surface of medium is called
total floating time (TFT). One tablet from each formulation batch would be placed in
dissolution apparatus containing 900 ml dissolution medium using desired RPM. The
temperature of medium would be maintained at 37±2°C. The time would be taken for tablet
to emerge on surface of medium and the duration of time by which the tablet constantly
remains on surface of medium would be noted.
4.3.11. Swelling Study
The individual tablets would be weighed accurately and kept in 50 ml of water. Tablets
would be taken out carefully after 60 min, blotted with filter paper to remove the water
present on the surface and weighed accurately. Percentage swelling would be calculated by
using formula:
Swelling study = Wet weight - Dry weight / Dry weight x 100

4.3.12. In-Vitro Drug Release Study
Dissolution of the tablet of each batch would be carried out using dissolution apparatus. 900
ml of dissolution media would be filled in a dissolution vessel and the temperature of the
medium would be set at 37±2°C. One tablet would be placed in each dissolution vessel and
the rotational speed is set at desired RPM. The 10 ml of sample would be withdrawn at
predetermined time interval and same volume of fresh medium would be replaced. The
samples would be analyzed for drug content against dissolution media as a blank at desired
nm using double beam UV visible spectrophotometer (Gundaraniya et al., 2013).
4.4.Characterization of Bi-Layer Tablets
4.4.1. Particle Size Distribution
The particle size distribution would be measured using sieving method.
4.4.2. Photo Microscope Study
Photo microscope image of TGG and GG would be taken (X 450 magnifications) by photo
microscope.
4.4.3. Angle of Repose
The angle of repose of granules would be determined by the funnel method. The granules
would be allowed to flow through the funnel freely onto the surface. The diameter of the
powder cone would be measured and angle of repose would be calculated using the following
equation:
Tan Ø = h / r
Where,
h = Height
r = Radius of the powder cone.
4.4.4. Moisture Absorption Capacity
All disintegrates have capacity to absorb moisture from atmosphere which affects moisture
sensitive drugs. Moisture absorption capacity would be performed by taking 1 g of
disintegrate uniformly distributed in petri-dish and kept in stability chamber at 37±1°C and
100% relative humidity for 2 days and investigated for the amount of moisture uptake by
difference between weights.

4.4.5. Compressibility
The compressibility index of the disintegrate would be determined by Carr‟s compressibility
index.
C = 100 x (1 - ÞB / ÞT)
4.4.6. Density
The loose bulk density (LBD) and tapped bulk density (TBD) would be determined and
calculated using the following formulas:
LBD = Weight of the powder / Volume of the packing
TBD = Weight of the powder / Tapped volume of the packing (Kale et al., 2011).
4.5. Tablet Surface Characterization by Various Imaging Techniques
Experimental methodologies to determine surface parameters of materials include optical
microscopy, scanning electrical microscopy (SEM), laser profilometry and atomic force
microscopy (AFM). It has been shown that although providing useful information about
surface quality optical microscopy and SEM are unable to produce quantitative comparable
data. AFM and laser profilemetry are able to provide a quantitative analysis of the surface but
operate on different scales. Laser profilometry is able to provide data covering an area of
millimeters whereas AFM provides much more detailed information over areas typically in
the micron range making laser profilometry a better choice for relatively large scale
geometric analysis. Tomography is a non-destructive method which uses radiographic images
taken from multiple angles, by sample rotation, to obtain a full three-dimensional image of
the sample. The X-ray tomography imaging process is based on the attenuation of X-rays
through matter. The way an X-ray will be attenuated will depend on the density and atomic
number of the material being sampled. The use of X-ray tomography to determine density
distributions in compacts has recently become appropriate due to the evolutionary progress in
the focus size of X-rays increasing the resolution of these instruments from 1 mm in the early
1990s up to approximately 5 to10 microns. It should be noted however that for large objects
the resolution is determined by the number of pixels in the CCD camera and not the focus of
the X-ray tubes. The main disadvantage of X-ray systems is the undesirable presence of
artifacts seen in the re-constructed image: the most troubling of these resulting from beam
hardening. A direct result of having polychromatic X-ray tubes is that the X-rays emitted will
contain a spectrum of different energies. As the X-rays traverse through the sample the lower

energy rays will be preferentially absorbed. As the higher energy X-rays pass through the
sample the beam becomes „harder‟. As harder beams are less likely to attenuate the total
attenuation, given by the logarithm of the ratio of the incoming and the attenuated X-ray
beam is not strictly proportional to the sample thickness (Shinde et al., 2014).
4.5.1. Terahertz Pulsed Imaging (TPI)
The terahertz region of the electromagnetic spectrum spans the frequency range between the
mid-infrared (IR) and the millimeter / microwave. The center portion of the terahertz region
(0.1-4 THz, 3.3-133 cm-1
) has a unique combination of properties in that many amorphous
pharmaceutical excipients are transparent or semi-transparent to terahertz radiation whilst
many crystalline materials have characteristic spectral features in terahertz region.
Absorption features within the mid-IR region are dominated by intermolecular vibrations of
sample molecules thus mid-IR spectral features are “molecule finger-prints”. In contrast,
absorption features in terahertz region are dominated by intermolecular vibrations,
corresponding to motions associated with coherent, delocalized movements of large numbers
of atoms and molecules. Recent pharmaceutical applications of terahertz pulsed spectroscopy
and imaging. The following application areas are highlighted.
1. Discrimination and quantification of polymorphs / hydrates.
2. Analysis of solid form transformation dynamics.
3. Quantitative characterization of tablet coatings: off-line and on-line.
4. Tablet coating and dissolution.
5. Spectroscopic imaging and chemical mapping.
4.5.2. SEM (Scanning Electron Microscopy)
It gives an accurate image of the surface but they do not produce quantitative information
about surface roughness. It visually detect defect in tablet but data insufficient in process
control testing.
4.5.3. Atomic Force Microscopy (AFM)
AFM also has very good resolution in organic crystal samples compared to SEM and the
optical microscope. The disadvantages of AFM are the small measurement area, slow speed
and the need for flat samples.

4.5.4. Laser Profilometry
It uses in pharmaceutical compact and pellets as means of evaluating differences in roughness
Table 4.3: Advantages and Limitations of Techniques for Layer Separation Risk Assessment
Techniques Advantages Limitations
Tensile strength A traditional technique,
easy to test
Poor correlation to layer
separation risk
Friability testing A convenient method for
rough estimation
Detection of only actual
layer separation rather than
its risk
SEM High spatial resolution,
visual identification of
defect within sample
Qualitative analysis (cannot
predict the magnitude of the
layer separation risk)
TPI Quantitative analysis (can
predict the magnitude the
risk), non-destructive 3D
imaging, faster data
acquisition and processing
time
Lower spatial resolution
XRCT High spatial resolution,
non-destructive 3D
imaging, visual
identification of defect
within sample
Qualitative analysis (can
predict the magnitude of the
risk), longer data acquisition
and processing time
4.6. Recent Developments in the Field of Bi-Layer Tablets
The introduction of bi-layer tablets into the pharmaceutical industry has enabled the
development of pre-determined release profiles of active ingredients and incorporation of
incompatible active ingredients into the single unit dosage form. Large number of work has
been done in this field. Some of the recent findings are explained in the table 4.4 (Gopinath et
al., 2013).

Table 4.4: Various Advancements in the Field of Bi-layer Tablets (Gopinath et al., 2013).
Drugs Dosage Form Rationale
Diclofenac, Cyclobenza-
prine
Bi-layer tablets Synergistic effect in pain
Atenolol, Lovastatin Bi-layer floating tablets Synergistic effect in hypertension
and biphasic
release profile
Atorvastatin, Calcium Bi-layer buccal tablets To overcome bioavailability
problem, reducing
side effects and frequency of
administration
Ascorbic acid, Cyano-
cobalamine
Double layer suppositories To avoid interaction b/w
incompatible vitamins
Rifampicin, Isoniazid Capsule & tablet in
capsule
To avoid interaction b/w
incompatible drugs
Metformin HCL,
Glimipiride
Bi-layer tablets Synergistic effect in diabetes
Metformin HCL,
Atorvastatin Calcium
Bi-layer tablets To develop poly therapy for the
treatment of NIDDS &
hyperlipidemia
CefiximeTrihydrate,
Dicloxacilline Sodium
Bi-layer tablets Synergistic effect in bacterial
infections
Piracetam, Vinpocetin Bi-layer tablets Synergistic effect in Alzheimer
disease
Metformin HCL,
Pioglitazone
mellitus
Diclofenac Sodium,
Paracetamol
Bi-layer tablets Synergistic effect in pain
Indomethacin Bi-layer floating tablets Biphasic drug release
Metformin HCL,
Pioglitazone
mellitus
Artesunate, Amlodipine Tablet-in-tablet To minimize contact b/w drugs
Tramadol, Acetaminophen Bi-layer tablets Synergistic effect of drugs in pain

Montelukast, Levocetrizine Bi-layer tablets To improve the stability of drugs
in combination
Salbutamol, Theophylline Bi-layer tablets Synergistic effect of drugs in
asthma
Glipizide, Metformin HCL Bi-layer tablets To avoid interaction b/w
incompatible drugs
Amlodipine, Atenolol Bi-layer tablets To improve the stability of drugs
in combination
Misorostol, Diclofenac Bi-layer tablets To minimize contact b/w drugs
Telmisartan, Simvastatin Bi-layer tablets To minimize contact b/w
Simvastatin & telmisartan
Statin, Aspirin Bi-layer tablets To minimize interaction b/w two
drugs and side effects due to
aspirin
Table 4.5: Commercially Marketed Bi-layer Tablets (Nilwar et al., 2013).
Product Name Chemical Name Developer
ALPRAX PLUS Sertraline, Alprazolam Torrent Pharmaceuticals Ltd.
Glycomet®-GP2Forte Metformin hydrochloride,
Glimepiride
USV Limited
Newcold Plus Levocetrizine
hydrochloride,
Phenylpropanolamine,
Paracetamol
Piramol Healthcare Ltd.
DIUCONTIN-K®20/250 Furosemide, Potassium
chloride
T.C. Health Care Pvt. Ltd.
TRIOMUNE 30 Nevirapine, Lamivudine,
Stavudine
Cipla Ltd.
PIOKIND®-M15 Pioglitazone, metformine
hydrochloride
Psychotropics India Ltd.

CHAPTER 5: APPROACHES FOR MULTI-LAYERED TABLETS
5.1. Multi-Layer Tablet
Multi-layered systems which contains bi-layered, triple-layered, quadruple-layered, etc. are
becoming increasingly recognized as controlled-release drug delivery systems. Multi-layered
tablets possess various benefits, namely the ability to prevent incompatibility between drugs
and excipients, such as:
1. Multi-layered systems consist of a hydrophilic matrix layer containing either or only one
active ingredient and one or more impermeable or semi-permeable layers with other drugs
incorporation.
2. The presence of the barrier layers modifies hydration, swelling rate, lag time for diffusion,
dissolution etc.
3. By varying the number of layers and geometry of devices provide different drug release.
4. These multi-layered formulations may swell gel or erode to modulate drug release.
5. The controlling effect of a polymer material on drug release depends on its physico-
chemical properties and the embedding procedure during the preparation of the system,
which may be due to the polymers, its molecular weight, nature of monomer, type of
substitution, degree of substitution and viscosity.
These systems are generally having two approaches:
a. Swell-able barrier technique.
b. Erodible barrier technique.
Figure 5.1: It Shows Types of Multi-Layered Systems
6. Layered tablets are used for zero order release, combination therapy as well for multiple
rate delivery of the drug from formulation.

7. The layering patterns are of various types as shown in following figure, single face coated,
double face coated, side coated, face and side coated tablets.
Figure 5.2: It Shows Types of Layering Patterns
5.2. Advantages of Multi-Layer Tablet Dosage Form
1. Unit dosage form, offer greatest dose precision and least content variability.
2. Easiest and cheapest for packaging.
3. Cost is lower compare to other oral dosage form.
4. Product identification is easy.
5. Lighter, compact and flexible concept.
6. Suitable for large scale production.
7. Greatest chemical and microbial stability over all oral dosage form.
8. Easy to swallowing.
9. Objectionable odour and bitter taste can be masked by coating techniques.
10. Greatest chemical and microbial stability compare to all oral dosage form.
5.3. Disadvantages of Multi-Layer Tablet Dosage Form
1. Manufacturing steps are increased.
2. Difficult to swallow in case of children and unconscious patients.
3. Time consuming.
4. Some drugs resist compression into dense compacts, owing to amorphous nature and low
density character.
5. Problems during in-process quality control.
6. Difficult to formulate by direct compression technique when the dose of drug is high (Shah
et al., 2013).

5.4. Types of Multi-Layer Tablets
1. Bi-layer tablet.
2. Triple-layer tablet.
3. Tablet-in-tablet.
4. Surrounding coated core tablet (Nikhil et al., 2013).
5.5. Multi-Layer Tablet Dosage Forms are Designed for Variety of Reasons
1. To modify the total surface area for active pharmaceutical ingredient to achieve modified
release.
2. To separate incompatible active drug from each other, to control the release of each drug
layer.
3. To overcome multiple disease condition by incorporating more than one active drug in
separate layer in appropriate dose.
4. To administer fixed dose combinations of different active drugs, for novel drug delivery
system, prolong the drug product life cycle and other drug delivery system such as
mucoadhesive delivery system and floating delivery system (Shah et al., 2013).
5.6. Design of Multi-Layered Tablets
The design of multi-layered tablets layer through varying the geometry of the devices or
modulating layers which allows different tablet design for the production with specific
release properties to achieve different dissolution patterns like pulsatile, bimodal, delayed and
multi modal delivery. Different designs have been discussed below:
1. Zero order sustained release.
2. Quick / slow delivery system.
3. Time programmed delivery system.
4. Bimodal release profile.
5.6.1. Zero Order Sustained Release
Zero order sustained release system comprises hydrophilic or hydrophobic polymer as matrix
or barrier layer in their formulation to control the release of drug via coating of polymer to
both side of the matrix but leaving other sides for exposure to the dissolution medium to
sustain the release of the drug.

5.6.2. Quick / Slow Delivery System
Quick / slow delivery system which is characterized by initial rapid release followed by
extended / prolonged release of the drug to achieve immediately a therapeutic effect and to
sustain a constant release of drug to maintain plasma level concentration. This concept
applied on where doses regimen not satisfies simple release of the drug.
5.6.3. Time Programmed Delivery System
Time programmed delivery system provide immediate-release of the drug followed by time
controlled-release, when the delivery of drug is required in a time controlled fashion in the
gut, rather than release of drug in continuous manner according to circadian rhythm. This
system consists of core which is coated with different polymeric barriers. The release of drug
from the core tablet after swelling/eroding of hydrophobic or hydrophilic barrier of coating
that show pulsatile release of the drug.
5.6.4. Bimodal Release Profile
Bimodal release profile shows an initial rapid release followed by slow release and again a
second phase of rapid drug release i.e. sigmoidal release profile. This system compensates the
slow absorption in the stomach and small intestine and for programmed pulse releases that
perform more effectively at the site of action to undertake periodic changes (Yadav et al.,
2013).
5.7. Multi-Layered Tablets for Controlled Drug Delivery
Multi-layered systems (bi-layered, triple-layered, quadruple-layered, etc.) are becoming
increasingly recognized as controlled-release drug delivery systems. These systems have
been shown to be advantageous over typical tablet systems that multi-layered tablets have
demonstrated promise, possessing various benefits, namely the ability to prevent interactions
between drugs and excipients and by providing an array of release profiles in one delivery
system of either the same or different drugs, treatment for conditions that require a regimen
of more than one drug, immediate drug release using a disintegrating monolithic matrix in
order to achieve an initial peak in plasma drug level, delayed drug release using an eroding
monolithic matrix which may deliver another active drug to a different part of the
gastrointestinal tract, providing controlled drug release instituting a swell-able monolithic
matrix and better control and regulation of release profiles by retarding initial burst release

and achieving zero-order kinetics. It would be beneficial if research focused on further
modification of these systems for improved and comprehensive drug release capabilities that
enable a larger scope of application in drug delivery.
Table 5.1: Advantages of Multi-Layered Tablets over Conventional Tablets (Moodley et al.,
2013).
Multi-Layered Matrix Tablets Conventional Tablets
May be used to incorporate more than one
drug and separate them if any chemical
incompatibilities exist
Drug is released in only one kinetic model
Drug release behavior is not restricted to one
type, this system may offer varied drug
release kinetics of the same or different drugs
such as extended and immediate-release
If more than one drug is incorporated,
there is no way of avoiding chemical
incompatibilities
Controlled-release multi-layered tablets typically involve a drug core layer that is surrounded
by barrier layers that may be made up of hydrophilic swell-able polymers such as HPMC and
Poly Ethylene Oxide (PEO) or hydrophobic polymers such as Ethyl Cellulose (EC). The
barrier layers minimize and therefore delay the interaction of the gastrointestinal environment
with the active core, by decreasing the surface area available for drug release or by
controlling the rate at which the solvent penetrates the layers. This allows the initial burst
release to be minimized and therefore the drug release can be controlled at a near constant
level while the barrier layers undergo erosion or swelling. The swelling barrier layers
undergo erosion as time goes on, thus increasing the surface area which ultimately allows
more drug to be released. Following the same principle, it is possible to obtain a constant
release profile as well as other types of dissolution patterns such as pulsatile or delayed
delivery as well as extended drug delivery depending on the characteristics of the polymers
employed. In either case the system should ideally erode completely (i.e. leaving no residue
in the gastrointestinal tract after the entire amount of drug is released). The different types of
multi-layered tablet designs with varying drug release behaviors are shown in figure 5.3.

There are multi-layered tablets that can provide zero-order sustained-release where the tablet
consists of either a hydrophilic or hydrophobic core layer with barrier layers that are press
coated to the surfaces of the core layer. This leaves the sides of the core layer exposed. It has
been shown that generally constant drug release can be achieved when both barrier layers are
hydrophilic and the core layer is hydrophobic. However, other factors also need to be
controlled in order to achieve zero-order drug release.
Figure 5.3: Various Polymeric Formulations of Multi-Layered Tablets and Possible Drug
Release Behavior
5.8. Multi-Layered Tablet Technology
5.8.1. Sodas Multi-Layer Tablet Technology
Sodas multi-layer tablet technology is a multi-layer drug delivery system which focuses on
the production of controlled-release beads. The Sodas technology is characterized by its
inherent flexibility that enables the production of customized dosage forms that respond
directly to individual needs such as pain and blood pressure. The technology essentially leads
a pulsatile drug release where the drug is released in pulses that are separated by defined time
intervals. It is observed that there are great variations of multi-layered tablet technology

proving flexibility which affords possibilities for positive research development with the
intuitive selection of polymers and the appropriate employment of geometric principles,
multi-layered tablets may emerge as the future bench mark for the treatment of chronic
diseases. However, the difficulties that may occur with the scale up of more intricate layered
drug delivery systems may be considered to be unfavorable to the pharmaceutical industry.
The necessity of specialized equipment may add to the difficulties in commercialization of
these systems.
Figure 5.4: A schematic Representation of Sodas Multi-Layer Tablet Technology
Table 5.2: Summary of the Type of Polymers Influencing the Behavior and Release
Characteristics of Multi-Layered Tablets (Moodley et al., 2013).
Type of Polymer
Used as Drug Carrier
Type of Polymer
Used
in Barrier Layers
Type / Dimensions
of Tablet
Drug Release
Achieved
Hydrophilic Hydrophilic Bi-layered tablet Extended drug
release
Hydrophilic Hydrophobic Bi-layered tablet Drug release
retarded
to lesser extent
Hydrophobic Hydrophilic
(Methocel K4M)
Triple-layered tablet Zero-order drug
release kinetics
Hydrophobic (CW) Hydrophobic
(Carnauba wax)
Triple-layered tablet Non-linear drug
release
5.8.2. Geomatrix Multi-Layer Tablet Technology
The Geomatrix multi-layer tablet technology was developed by Conte and co-workers for
constant drug release. The technology includes triple-layered and bi-layered tablets. The

triple-layered tablet consists of an active core which is a hydrophilic matrix layer and two
polymeric barrier layers on either side that are hydrophobic or semi-permeable. The bi-
layered tablet consists of the drug layer and one barrier layer. The barrier layer modifies the
swelling rate of the active core and reduces the surface area available for diffusion of drug.
Zero-order drug release can be achieved with the Geomatrix system; however release is
limited to one drug.
Figure 5.5: A Typical Geomatrix Multi-Layered Tablet
5.9. Factors Affecting the Rate of Drug Release from Multi-Layered Tablet
5.9.1. Polymers Employed in Multi-Layered Tablets
Generally, a multi-layered system should initially swell, then gel and ultimately slowly erode.
A study done by Efentakis and co-workers investigated the effect of polymeric substances on
drug release. Hydrophilic and swell-able polymers such as HPMC (Methocel K100M),
microcrystalline cellulose (MC) and PEO and the hydrophobic polymer cellulose acetate
propionate (CAP) were employed in this study in which venlafaxine HCL was used as the
model drug. The study focused on a core tablet that contained venlafaxine HCL and Methocel
K100M as the drug carrier. Bi-layered and triple-layered tablets were prepared using the core
tablet. The bi-layered tablet consisted of a core tablet where one surface was covered with
either Cellulose Acetate Phthalate (CAP) or Methocel E50LV, while both surfaces of the core
tablet were covered with both of the polymers to form the triple-layered tablets. Hydrophilic
polymers were employed as drug core matrices due to their swelling ability. The release
profiles obtained demonstrated that drug release was slower from the multi-layered tablets
than from the core tablet alone. When the core tablet came into contact with the dissolution
medium, it swelled and expanded. This caused an increase in the diffusion path length for the
drug and the drug release rate was therefore reduced. Upon employing HPMC as a barrier
layer, the layer swelled concurrently with the core tablet, merging the core surfaces thereby
enveloping part of the core, which resulted in the limiting of drug transport through the

barriers. CAP did not swell due to its impermeability and therefore drug dissolution and the
drug release rate was retarded. The use of HPMC or CAP in the barrier layers showed similar
results in terms of retarding drug release except that Methocel showed slow erosion as
opposed to CAP. Generally, HPMC devices presented with slower drug release when
compared to CAP devices, the reason being that they form a more efficient and solid barrier.
Overall, the study showed that the characteristics of the polymers employed had a significant
influence on the release profiles of the tablets although the choice of polymers employed in
the study was conservative. Further research that focuses on the use of novel specialized
polymers that are competent in providing zero-order drug release is necessary. A study
performed by Chidambaram and co-workers assessed the behavior of layered diffusional
matrices for zero-order sustained drug release. Layered tablets were formulated with a
hydrophobic core layer which contained the drug; this layer typically consisted of 24% w/w
pseudoephedrine HCL, 40% w/w carnauba wax and lactose filler. The barrier layers were
composed of either hydrophilic (Methocel K4M or K100M or Avicel PH 101) or
hydrophobic polymers. Three different types of matrices were formulated. In the first type,
the two barrier layers were hydrophilic, in the second type, one of the barriers was
hydrophobic while the other was hydrophilic and in the third type, the two barrier layers were
both hydrophobic. Results showed that more desirable linear release profiles were obtained
with the first and second type of matrices as depicted, while the barrier layers in the third
system needed to be manipulated in order to achieve zero-order release kinetics. The
proposed mechanism for the zero-order drug release from the first type of matrix was that as
the hydrophilic barriers swelled and eroded, the rate of diffusion of drug from the
hydrophobic middle layer decreased. According to the study, the release rate from the lateral
surface was influenced by polymer viscosity and concentration. These factors ultimately
influence diffusion path length as well as the diffusion co-efficient. The use of polymers that
possess mechanical or chemical characteristics to intrinsically alter the geometry, via
modification of the diffusion path length, of matrices for controlled release may be an
interesting perspective to study for future drug delivery research.
5.9.2. Structure of the Device
A study undertaken by Efentakis and co-workers illustrated that the structure of a system
plays an important role in its drug release behavior. They found that covering a larger area of
the core tablet by a barrier layer results in the retardation of drug release to a greater extent,
as it forms a more efficient barrier there by decreasing the drug release rate. Another study by

Efentakis and Peponaki reiterated the significance of structure and geometry of triple-layered
tablets with isosorbide mono-nitrate as a model drug. The weight and thickness of the barrier
layers also had a pivotal role in drug release behavior. Chidambaram and co-workers
established that drug release from the surfaces of the core was dependent on the thickness of
the hydrophilic barrier layers. An investigation by Streubel and co-workers looked at bimodal
drug release from multi layered matrix tablets. It was discovered that by increasing the
weight of the barrier layers from 50 mg to 150 mg it resulted in a more effective retardation
of drug release, thus it was concluded that by manipulating the weight and thickness of the
outer layers a desirable drug release profile of individual drugs may be achieved, thus
complementing their pharmacokinetic behavior. The concept of barrier layers have proven to
be beneficial in multi-layered tablet designs; however converting the barrier layers into
additional controlled-release drug matrices may hold further potential for future application.
Zerbe and co-workers have shown that there are also complex multi-layered tablet systems
with layers of various shapes that are able to provide zero-order drug release. The Smartrix
tablet technology in figure 5.6 that was developed by LTS employs modified geometrical
shapes that compensate for the varying surface area caused by erosion or swelling. The triple
layered tablet is composed of a drug core that has a specific shape. The core is enclosed
between two rapidly erodible outer layers. The middle layer has a biconcave shape that the
two outer layers bonded tightly after compression. The thickness of the outer layers and the
shape of the drug core control the release of drug usually in a linear fashion. The Smartrix
system is also able to achieve bimodal drug release, as an added advantage of being flexible.
This technology has proven to be useful as it does not require specialized polymers to
perform the desired function. The study that emanated in the development of the Smartrix
system has further emphasized the functionality of shape and geometry in altering drug
release behavior. However, this technology requires specialized dry tablet press machines
that may pose as a disadvantage (Moodley et al., 2013).
Figure 5.6: Smartrix Technology

Table 5.3: Summary of Various Technologies That Utilize Geometric Factors in Drug
Delivery (Moodley et al., 2013).
Technology Design Factors Affecting
Drug Release
Type of Drug
Release That May Be
Achieved
Geomatrix Triple / bi-layered
tablet
Type of polymer
used, thickness of
layers
Zero-order kinetics
Smartrix Triple-layered tablet
with core layer
having a specific
shape different to
that of the outer
layers
Shape of core layer According to shape
of core, zero-order
kinetics
Sodas Multi-layer tablet Type of polymer
used, thickness of
layers, shape of core
layer
Pulsatile drug release
Geolock Triple-layered tablet Polymer layers,
single or combination
of drugs in the inner
core
Immediate or
modified-release
Doughnut-shaped
tablets
Single / triple-layered
tablets with a central
hole / holes
Size and number of
holes, type of
polymer used
Zero-order kinetics
Procise Uniformly dispersed
drug core containing
a hole
Geometry of core According to
geometry
of core, zero-order
kinetics
VersaTab Bi-layered tablet Core drug, polymer
layers
Immediate-release
and controlled-
release

CHAPTER 6: CONCLUSION
6.1. Conclusion
Layered tablets offer an excellent opportunity for manufacturers to separate themselves from
their competitors, improve their products efficacy, and protect against impersonator products.
Quality of layered tablets can be improved and GMP requirements greatly achieved by using
recent sophisticated technologies.
Layered tablets are able to provide abundant advantages like to get immediate-release as well
as controlled-release in single dosage form, to avoid incompatibility between two or more
active pharmaceutical ingredient, cost reduction and stability enhancement.
The feature of multi-layered tablets provides unique product performance objectives which
are otherwise not achievable by conventional tablets, but also brings a new set of challenges
for formulation design, manufacturing process, controls and product life performance
requirements. In addition to manufacturing science challenges, they also add challenges in
establishing relevant regulatory controls to meet the product performance requirements over
the life of the drug product. To meet these requirements a higher level of understanding in the
ingredients and manufacturing variables is critical to manage the risks associated with
product acceptability over the life cycle to avoid batch failures and batch recall.
The development and production of quality bi-layer tablets require a comprehensive
understanding of the product and process in order to address challenges in manufacturing
such as accuracy in weight control of each individual layer, delamination / layer-separation
during manufacturing and storage, insufficient tablet breaking force and cross-contamination
between the layers (especially for incompatible APIs).
The objective of the dosage form is to ensure that the drugs available to the patient are not
only safe and effective, but are also properly manufactured and packaged to meet the
established quality and target product profile over its shelf-life. A well-developed product
will effectively address these issues by including appropriate control strategies and
establishing the functional relationships of the material attributes and process parameters
critical to the layer tablet quality.
So, layered tablets may be considered as improved beneficial technology to overcome the
shortcoming of other tablets.

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