Technical JRS PHARMA LP
Information
Multilayer tablets
Introduction
Multi-layer tablet manufacture is more complex than compacting single-
layer tablets from a blend containing multiple active pharmaceutical
ingredients (APIs). Multi-layer tablets offer benefits for overcoming
API-API interactions and stability issues, tailoring dissolution profiles,
and bringing brand recognition to finished dosage forms. Multi-layered
tablets bring together differently formulated powder mixtures, which
typically contain a different API, into a single tablet with two or more
layers. In many cases, the layers differ in color as well for providing
additional brand recognition.
Typical reasons for multi-layer tablets include:
Incompatible API separation
Different disintegration times for each layer
Combination of different dissolution profiles
Creating an easy-to-recognize brand
For multi-layer tablets manufacture, specialized tableting equipment
is necessary. In addition, excipient selection is critical since the
layers require certain properties, which only can be achieved
using few excipients.
Pic. 1 : Example of bi-layer tablets
A significant challenge when formulating multi-layer tablets is the
tablet layer interfaces, which require good adhesion. Poor adhesion
may compromise dosage form integrity, causing multi-layer tablets to
lose desired functionality. Issues, such as friability, lamination, and/or
dissolution problems may result requiring reformulation. An appro-
priate formulation of the individual layers and overall tablet is the key
to a good multilayer tablet.
THE EXCIPIENT
FAMILY
A Member of the JRS Group
Page 1
Excipients for multi-layer tablets
The formulation
The quality/integrity of multi-layer tablets depends of the formulation.
Each layer within the tablet should be formulated individually keeping
in mind the importance of the layer interfaces. Ingredient particle
sizes and size distributions should be optimized to provide content
uniformity within each layer, yet provide sufficient binding performan-
ce at layer interfaces forming robust tablets during compaction.
The first layer, typically the bottom layer, is the key of the formulati-
on. The surface of the first layer should be moderately porous to
provide adhesion at the interface with the second layer and so on
with each additional layer. In turn, each layer must contribute
sufficient compactibility for a robust and physically stable monolithic
dosage form. For both, porous surface and compactibility,
PROSOLV SMCC provides excellent flexibility in multi-layer tablet
formulation development and manufacture.
Microcrystalline cellulose (MCC) possesses an approximate 1
2 2
m /g specific surface area. PROSOLV SMCC possesses a 5 m /g
2
to 6 m /g surface area, which means a five-fold surface area
increase
Pic. 2 : Example of a tri-layer tablet
Content page
Introduction ..............................................................................1
Excipients for multi-layer tablets.................................................1
Practical advice for multilayer tablets formulations ......................2
JRS PHARMA excipients for multilayer tablets .............................3
Tablet press...............................................................................3
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 Technical JRS PHARMA LP THE EXCIPIENT

Information FAMILY
A Member of the JRS Group

Page 2

compared MCC. The greater surface area provides a larger

contact area between the layers of a multilayer tablet and leads
to greater physical tablet stability. The surface structure of the
compressed tablet depends not only on the appearance of the binder,
but also on the compaction force. Below are scanning electron
micrographs (SEMs) of tablets produced using PROSOLV SMCC 90
compressed at different forces.

Even with compaction forces below 10 kN, PROSOLV SMCC tablets

offer excellent hardness and surface structure for adhesion between
layers.

Recommendations advice for multilayer

tablets formulations
Pic. 3: Surface of PROSOLV SMCC 90 Placebo Tablets Compacted at 2 kN Force
Binder particle size should be fairly coarse to provide porous surfaces,
but not so large that compaction is compromised. PROSOLV SMCC
90 and PROSOLV SMCC HD 90's particle is approximately 110 m
and is ideal for multi-layer tablets. Ideally, each layer should be at its
individual equilibrium moisture content at the time of manufacture. If
not at equilibrium moisture content, water (other residual solvents)
may migrate across layer interfaces until a moisture balance results.
Water transport across layer interfaces may not always adversely
affect tablet integrity. In some cases, water transport across layer
interfaces may initiate swelling causing weakening and leading to
other issues. Additionally, solvent transport across layer interfaces
could promote API instability.

The lubricant level should be as low as possible without

compromising tablet ejection upon completion of dosage form
Pic. 4: Surface of PROSOLV SMCC 90 Placebo Tablets Compacted at 10 kN Force
manufacture. PRUV , sodium stearyl fumarate, in place of
magnesium stearate is preferred during multi-layer tablet
manufacture. PRUV is more hydrophilic and allows better binding
at layer interfaces and results in overall harder tablets. since
magnesium stearate can compromise tablet bond formation, not
only within each layer, but at the layer interfaces, softer, laminating
tablets may occur.

Avoid excipients, which undergo polymorphic (crystal habit) changes

with time or when exposed to various environmental conditions.
Lactose, for example, exhibits polymorphism given certain conditions.
Changes in crystal habit can often weaken tablet interfaces causing
layers to separate.

Pic. 5: Surface of PROSOLV SMCC 90 Placebo Tablets Compacted at 20 kN Force

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 Technical JRS PHARMA LP THE EXCIPIENT

Information FAMILY
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Page 3

JRS PHARMA excipients

for multilayer tablets
As previously stated, interface surfaces should be moderately
porous to provide adhesion between layers.

Silicified microcrystalline cellulose, PROSOLV SMCC 50,

PROSOLV SMCC 90, and/or PROSOLV SMCC HD 90, offer
physical and functional characteristics ideally suited for
multi-layer tablet formulation development and manufacture.

Sodium stearyl fumarate, PRUV, leads to a improved adhesion

at layer interfaces compared to magnesium stearate. PRUVs
batch-to-batch consistency also offers an advantage over
magnesium stearate.

Tablet press
Typically, multi-layer tablets are compacted using specialized rotary
tablet presses. Bi-layer presses require two compression phases, two
feed areas, and one ejection position. During one turn of the press,
two individual compression cycles are performed producing one bi-
layer tablet.

In most modern bi-layer tablet presses, bi-layer tablet production

requires six steps:

1. Filling the die with powder for the first layer

2. Pre-compressing the first layer with low forces

in preparation of adding the second layer

3. Adjusting the die volume for the second layer

4. Filling the die with powder for the second layer

(onto the first layer)

5. Compressing the tablet in its entirety

6. Tablet ejection

Since multiple feed areas are required during multi-layer tablet

manufacture. Individual layer weight uniformity, as well as overall
tablet weight uniformity, is critical. This is one of the many challenges,
particularly during high-speed manufacture. This is only achieved
through robust formulation development, proper equipment set-up, Pic. 4 : Tablet press example for
the production of multi-layer tablets
and rigorous sampling protocols for individual layers and finished (Fette Compacting: Model 3090i).
tablets.

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 Technical JRS PHARMA offers:
Information Excipients
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